What is passive smoking?
A smoker inhales only 15% of smoke from a cigarette and other 85% goes directly into the air. So the passive smoking means the inhalation tobacco smoke in the air around a person. It is known as secondhand smoking / involuntary smoking or ETS exposure (exposure to environmental tobacco smoke) as well. There are two types of passive smoking.
 ‘Side-stream smoke’
It means the exposure to the smoke released from a burning tip of a cigarette.
 ‘Main-stream smoke’
It means the inhalation the smoke that is exhaled by a smoker.
Not only smokers, but also non-smokers are prone to lot of health problems due to this passive smoking. It causes many diseases, disabilities and also death as same as the active smoking. So it is said that there is nothing passive in passive smoking. This is one of the main factors that lead to smoking bans in work places and indoor public places.

Environmental tobacco smoke
In a crowded room, tobacco smoke can produce six times the pollution of a busy motorway. 1It contains many harmful chemicals. Nicotine and CO are two main agents in the tobacco smoke that harm human bodies. The body breaks down nicotine to cotinine. This cotinine can be measured in blood, urine, saliva and hair. It is considered as the best available marker of environmental tobacco smoke since it has a favorable biological half-life and sensitivity for techniques quantifying it.
It also contains carcinogenic benzopyrene, ammonia, arsenic, formaldehyde, vinyl chloride, hydrogen cyanide and potentially toxic gases.

Studies conducted regarding the passive smoking
During 1980’s several reports have been published by following councils and committees regarding the health impact of passive smoking.
• The US National Research Council
• The 1986 Report of the US Surgeon General
• The National Health and Medical Research Council of Australia
• The UK Independent Scientific Committee on Smoking and Health
• The US Environmental Protection Agency
Also more recently, further major reviews on passive smoking have been published.
• Studies by the UK Government-appointed Scientific Committee on Tobacco and Health (SCOTH).
• A World Health Organization (WHO) consultation report on Environmental Tobacco Smoke and Child Health.
• A report by the California Environmental Protection Agency (EPA).
• A review by the International Agency for Research on Cancer (IARC).

Health effects of passive smoking Short-term effects
 Since the tobacco smoke is an irritant, allergy sufferers can experience allergy symptoms as mentioned below.
 1Stuffy or runny noses
 1Watery or burning eyes
 1Sneezing
 Coughing
 Wheezing
 A feeling of suffocation
These symptoms can be appeared within a few minutes of exposure.
 Worsening the asthma.
 A healthy person may experience the cough, headache, nausea, drowsiness and other ill effects when they are in a smoke-filled room.
 Some people do not like the odor. It makes the hair, skin, teeth, fingernails, clothes, furniture and rugs stink.
Many of these short-term effects terminate after the exposure ends. However repeated exposure will lead to more severe long-term effects.

Long-term effects
 2Heart disease
 2Lung cancer
 Chronic obstructive pulmonary disease (COPD)
 Bronchitis, asthma, emphysema
 Breast cancer
 Infections of ear, nose and throat
 3Premature births
 3Risk of SIDS (Sudden Infant Death Syndrome)
 Increased risk of developing tuberculosis if exposed to a carrier
 Allergies
 Crohn’s disease
 Learning difficulties and behavior problems in children
 Eye diseases
 Cervical and nasal cancer
 Increased risk of death

Passive smoking and heart disease

There is an increased risk of coronary artery disease linked with passive smoking. Exposure to high amounts of environmental tobacco smoke causes several effects on a person’s heart and blood vessels.
Nicotine in the smoke temporarily increases the blood pressure, heart rate, amount of blood pumped by the heart and blood flow in the coronary arteries. It also causes the arteries in the arms and legs to constrict and narrow.
Nicotine is not the only bad element in the smoke. Carbon monoxide in the smoke joins with haemoglobin in blood and reduces the oxygen availability to the heart and other tissues. So it is associated with the oxidative stress and decreased antioxidant defence.
Researchers at the University of Nottingham in Britain have found that the people who have exposed to secondhand smoke had high levels of two indicators of heart disease, homocysteine and fibrinogen than who were not exposed. This fibrinogen causes the blood to clot.
So the cigarette smoke causes the platelets in blood to become sticky and cluster, reduces clotting time and makes blood thicker. Also it damages the layer of cells that line the coronary arteries and other blood vessels. Tobacco smoke contributes to inflammation of the arteries and hardens them.
Non-smokers who have high blood pressure or high blood cholesterol have a greater risk of developing heart disease when they’re exposed to passive smoke.
Evidence of a link between passive smoking and heart disease were found in the mid 1980’s. The first qualitative reviews were included in the Report of the US Surgeon General, 1986 and the report of the US National Research Council, 1986.
Studies show that the risk of death from heart disease is about 30% higher among people exposed to tobacco smoke at home. This figure could be much higher for people working in the smoke-filled environment. According to the Environmental Protection Agency, environmental tobacco smoke causes about 10 times as many cardiovascular deaths as cancer deaths.
In the early 1990’s Glantz and Parmley has estimated that heart disease caused by passive smoking was the third leading preventable cause of death in the United States, ranking behind active smoking and alcohol abuse. In the United States, around 35,000 – 40,000 non-smokers die from heart disease each year as a result of ETS exposure.
Research in New Zealand by Bonita et al revealed that passive smoking increases the risk of stroke. The study found passive smoking exposure increased the risk of stroke in non-smokers by 82%. It is significant in men than in women.

Passive smoking and respiratory diseases
Passive smoking has significant effects on respiratory system of non-smoking adults.
 Increased coughing
 Phlegm production
 Chest discomfort
 Reduced lung function
 Chronic obstructive pulmonary disease
 Asthma
 Chronic bronchitis
 Emphysema
 Lung cancer
 Asthma
Cigarette smoke is a common trigger for asthma attacks. There are 3.5 million asthma patients in the UK and 80% of them have been exposed to ETS. Adults exposed to ETS at home or in the workplace have a 40-60% increase in the risk of asthma compared to adults who are not exposed in these places. According to new research people whose partner’s smoke are nearly five times more likely to develop asthma in adulthood than those who are not exposed to passive smoking.
 Chronic bronchitis
Bronchitis is long-term inflammation of the bronchi. It is characterized by coughing over a long period of time.
 Emphysema
This is a chronic lung condition that affects the alveoli in lungs. It is characterized by shortness of breath, coughing, fatigue, sleep and heart problems, weight loss and depression. Here, elastic recoil of lungs will be lost due to destruction of respiratory tissue. So the area available for gas exchange is reduced.
Pathogenesis of emphysema is thought to be parenchymal destruction by secreted extracellular proteases and inactivation or absence of normal defensive protease inhibitors.
When a person is exposed to tobacco smoke neutrophils and macrophages begin to release elastase. This elastase destroys alveolar wall. So it causes emphysema.

In addition to these major conditions, the normal ciliated columnar mucous secreting respiratory epithelium in bronchi is replaced by a squamous epithelium under the influence of chronic irritation by cigarette smoke. This condition is known as squamous metaplasia.

Passive smoking and cancer
2Environmental Protection Agency has classified ETS as a known human carcinogen in 1992. Also International Agency for Research on Cancer concluded in 2002 that “involuntary smoking” is carcinogenic to humans.
According to the researchers tobacco smoke is composed of over 4000 chemicals and 69 of them are known or suspected carcinogens. In some experiments, animals have been exposed to these chemical agents in the smoke and they have been developed neoplasia. Polycyclic hydrocarbons, a potent chemical agent found in tars in the smoke mainly causes lung cancer.
 Lung cancer
In lung cancer, an abnormal, continual multiplying of cells that can result in lumps, masses or tumors can begin in the lining of the bronchi or other areas of respiratory system.
Many studies from the USA (1986, 1992, 1997, 2001, 2003), the UK (1998) and Australia, Pooled international cohorts (2004) have shown that there is a significant increase in relative risk of lung cancer among those exposed to passive smoke. According to the meta-analyses, there is a statistically significant risk of lung cancer among non-smokers living with smokers. This risk is 20% for women and 30% for men. Also studies of ETS exposure at work have shown a 16-19% increased risk of lung cancer. Another thing is that passive smoking is responsible for 5% of all lung cancer deaths.
The incidence of lung cancer is slightly higher in urban than rural areas. This may reflect the difference in atmospheric pollution (including the tobacco smoke).
According to a report published by the Environmental Protection Agency in US said that 3800 non-smoking Americans die each year from lung cancer cased by secondhand smoke.
 Breast cancer risk
Most studies have reported that there is an increased risk of breast cancer among women who were passively exposed to tobacco smoke. Two of these studies have shown that there is a “dose-relationship” between the increased risk and high level of exposure to ETS. Other studies have shown conflicting associations with breast cancer risk.
But some studies reported decrease in risk and some reported no association with risk. All of these studies were recently reviewed by the IARC.
Several studies have found that there is a similar increase in breast cancer risk for both active and passive smoke exposures. Some researchers criticized these results. They say that this is impossible as smokers are exposed to smoke both actively and passively. So, further investigations will be required to solve this problem.
In addition to lung and breast cancers, California EPA report mentioned a link between passive smoking and the following.
o Cervical cancer
o Nasal sinus cancer
Passive smoking does not appear to be associated with pancreatic cancer.

The impact of passive smoking on children
According to the WHO, about half of the children in the world (700 million) are exposed to tobacco smoke by the 1.2 billion adults who smoke. They have concluded in their one document that passive smoking causes following diseases in children.
 Bronchitis
 Coughing and wheezing
 Pneumonia
 Asthma attacks
 Meningococcal infections
 Childhood cancers and leukaemia
 Middle ear infection (glue ear)
 Cot death
 Cardiovascular and neurobiological impairment
Approximately half of the all children in the UK are exposed to tobacco smoke at home. Especially young children are more prone to health effects of passive smoking. It has been estimated by the Royal College of Physician in its 1992 report “Smoking and the young” that 17,000 children under the age of five are admitted to the hospital every year in the UK due to illnesses resulting from the passive smoking.
The major source of tobacco smoke for the young children is smoking by parents and other household members. Maternal smoking is more serious than the paternal smoking. Because smoke can affect on embryo during pregnancy. Also there is a close connection between mother and infant during the early life.
Results from more than 40 studies have shown that there is a 1.7-fold higher risk of respiratory illnesses in children of smoking mothers than the children of non-smoking mothers. Also paternal smoking alone causes a 1.3-fold increase in risk.
 Respiratory diseases
Bronchial tubes of young children’s are smaller than adults. So they breathe faster and take in more harmful chemicals than adults in a given time. So they are more vulnerable to lower respiratory tract infections such as bronchitis and pneumonia. Also their lung function is decreased and severity of asthma is increased when they are exposed to tobacco smoke. One study has shown that there is about 72% increased risk of respiratory diseases among children whose both parents are smokers.
Asthma is the most common chronic disease of childhood. The California EPA report shows that tobacco smoke induces new asthma cases and induces the severity of established asthma in children. In the UK, 1600-5400 new cases of asthma occur every year in children as a result of parental smoking.
 Sudden Infant Death Syndrome (SIDS)
Maternal smoking is a major cause of SIDS. It is also known as the cot death. It is characterized by unexpected sudden death, usually during sleep of an apparently healthy infant.
4The cause for this condition is the low birth weight. It is common in infants whose mothers are under 20 years old, unmarried, have had inadequate prenatal care, did not breast feed the infant or have more than one infant.
It is noted in a WHO document that ETS exposure among non-smoking pregnant women can cause a low birth weight and if the infant is exposed to ETS there is a risk of SIDS.
 Dental care
5Researchers believe that passive smoking can rot children’s teeth. This gives some explanations to why children from poor families get more bad teeth than those from rich families. They have found passive smoking is responsible for up to 27% of tooth decay in children.
According to the latest researchers in the US, children whose parents smoke are more likely to develop tooth cavities. Dr. Andrew Aligne and his collegians have carried out a research using about 4000 children. They found that the higher the children’s exposure to the secondary smoke, the greater the number of tooth cavities. This condition arises as young children spend much more time with their parents and so the time that they exposed to the tobacco smoke is high.
 Olfactory function
Exposure to the tobacco smoke may cause impairment of olfactory function in children. A Canadian study has found that passive smoking reduces children’s ability to detect a wide variety of odours when compared with children from non-smoking houses.
 Effect on endothelial function
A research has been carried out in children between 8 and 11 years old to find out endothelial dependent flow mediated vasodilatory responses of brachial artery by measuring serum cotinine concentration. By that, it is revealed that exposure to ETS causes impairment of endothelial function in 11 years old children.
 Tuberculosis risk
6A study conducted in South Africa shows that there is an association between passive smoking and increased risk of Mycobacterium tuberculosis infection in children living in a home with a tuberculosis patient. Tobacco smoke affects the immune system of the child and increases the ability to get infected. Also exposure to tobacco smoke causes the changes of cell function and it lowers the clearance of inhaled substances and causes abnormal permeability of cells and blood vessels.
 Behavior problems in children and pre-teens
7,8A new Cincinnati Children’s Hospital Medical Center study shows behavior problems can be seen in children and pre-teens when they are exposed to tobacco smoke even at extremely low levels.
Dr. Kimberly Yolton, a researcher at the Children’s Environmental Health Center at Cincinnati Children’s and the study’s main author has found that children who are exposed to tobacco smoke show depression and anxiety.
Dr. Yolton examined 225 children and pre-teens exposed to at least five cigarettes a day. Approximately they have been exposed to 14 cigarettes a day, on average. Dr. Yolton used this study to find out the link between asthma as well as behavior problems in children and passive smoking.
As the cotinine is considered as the best indicator of ETS, Dr. Yolton measured levels of cotinine in the children’s blood. Then he found a relationship between cotinine levels and following.
o Increases in acting out.
o Increases in holding things in.
o Anxiety and depression.
o Increases in behavior problems as rated by parents.
o Behavior and school problems as rated by teachers.
o Decreases in the ability to adapt to behavior problems.
Dr. Yolton has mentioned that the greater the exposure to tobacco smoke, the greater the problems these children had. Also he said that behavior problems in children are now increasing. But the reasons for this condition are not clear. It is now mentioned that the environmental tobacco smoke is a risk factor for child behavior problems.
According to Dr. Yolton, about 25% of children in the US are exposed to environmental tobacco smoke in their own homes and more than 50% of children have blood with detectable levels of cotinine.
Also he found, in his ground-breaking study in 2002 that exposure to ETS even at extremely low levels is associated with decreases in certain cognitive skills including reading, math and logic and reasoning in children and adolescents.

Passive smoking and risk of degenerative eye disease
Passive smoking doubles the risk of the progressively degenerative eye disease, an age related macular degeneration.
9The macula lies at the center of retina at the back of the eye. It is important for fine central vision that is essential for tasks such as reading and driving. The risk of macular degeneration increases once someone is over the age of 60. It is the main cause of partial sightedness and blindness in many European countries and the USA.
The researchers used 435 people with end stage macular degeneration and 280 partners who lived with them.
There are two types of macular degeneration; geographic atrophy and choroidal neurovascularisation.
Smoking triples the risk of both types of macular degeneration, the research showed. It has also shown that there is a doubled risk of macular degeneration among non-smokers who had lived with smokers five years or more.

Passive smoking and reproductive system
Passive smoking may harm the fertility of both male and female. Some researchers have found that it prevents women from being pregnant.10 Researchers of Bristol University have carried out a study by using 8500 couples and they found a non-smoking woman exposed to passive smoke in the workplace was 14% less likely to be able to conceive within a year. If her partner smokes more than 20 cigarettes a day, the odds of delayed conception were 34%.
The research published in the Journal Fertility and Sterility is one of the first to suggest even passive smoking can affect on female fertility. Now, it is clear that smoking women have low chances of conceiving. But nobody knows why passive smoke affects female fertility. There may be some influence by slight thickening of the blood.
Also the study has shown that the passive smoking affects men’s fertility similar to the age, obesity and level of education.
In addition, passive smoking causes miscarriages. It also affects the growth of the fetus during pregnancy. It accounts for 14% of 1premature births and 10% of infant deaths.

Passive smoking and risk of diabetes
Researchers from Birmingham Veterans Affairs Medical Center in Alabama found that passive smoking is a new risk factor for glucose intolerance. This is the first time the relationship between the tobacco smoke and the diabetes has been established. Study shows a 17% increased risk of diabetes in people exposed to tobacco smoke.

Passive smoking and deaths
1Deaths from passive smoking are less than those from active smoking. Many people die from lung cancer and heart disease due to exposure to ETS. Professor Konrad Jamrozik in London has estimated that domestic exposure to secondhand smoke in the UK causes around 2700 deaths in people aged 20-64 and 8000 deaths among people of 65 years of age per year.
Overall increased risk of deaths in adults is estimated as 53,000 non-smokers per year. It is the third leading cause of preventable death in the US.

Summary
Smoking should be eradicated from the society to reduce the effects of passive smoking and it should be prohibited in public and workplaces. Parents should be much more responsible of their children to avoid them being exposed to environmental tobacco smoke.

References
1. http://www.national jewish.org/disease-infor/wellness/smoking/secondhand aspx.
2. Robbins and Cotran; Pathologic basis of disease; chapter 9; Environmental and Nutritional Pathology; Kumar-Abbas-Fusto; 7th edition; page 421.
3. Children and passive smoking; Journal of family practice; Anne Charlton; March; 1994.
4. US surgeon’s general report; chapter 5; page 180-194; 10/07/2007.
5. Journal of the American Medical Association; 2003; 289; 1258-64.
6. S.den Boon, S. Verver, B.J. Marais, D.A. Enarson, C.J. Lombard, E.D. Bateman, E. Irusen, A. Jithoo, R.P. Gie, M.W. Borgdorff, N. beyers; Association between passive smoking and infection with Mycobacterium Tuberculosis in children; Pediatrics; April 1, 2007; 119(4); 734-739.
7. Passive smoking associated with behavior problems in children and pre-teens; Medical Studies/Trials; 3-May-2006.
8. Child psychiatry and human development; 09/07/2007.
9. Susan Aldridge, PhD, medical journalist; British Journal of Ophthalmology; January 2006; Volume 90; pages 73-80.
10. Passive smoking may harm fertility; Friday, 29 September 2000.

MD/2006/3394

CHAPTER 1
INTRODUCTION

1.1 Structure and gene of the human growth hormone (GH) molecule
The genes for human growth hormone are localized in the q22-24 region of chromosome 17 (GH1) and are closely related to human chorionic somatomammotropin (hCS, also known as placental lactogen) genes. GH, human chorionic somatomammotropin (hCS), and prolactin (PRL) are a group of homologous hormones with growth-promoting and lactogenic activity.
The major isoform of the human growth hormone is a protein of 191 amino acids and a molecular weight of about 22,000 daltons. The structure includes four helices necessary for functional interaction with the GH receptor. GH is structurally and apparently evolutionarily homologous to prolactin and chorionic somatomammotropin. Despite marked structural similarities between growth hormone from different species, only human and primate growth hormones have significant effects in humans 1
1.2 Secretion of GH
Several molecular forms of GH circulate in our body. Much of the growth hormone in the circulation is bound to a protein (growth hormone binding protein, GHBP) which is derived from the growth hormone receptor.GH is secreted into the blood by the somatotrope cells of the anterior pituitary gland, in larger amounts than any other pituitary hormone. Secretion levels are highest during puberty. The transcription factor PIT-1 stimulates both the development of these cells and their production of GH. Failure of development of these cells, as well as destruction of the anterior pituitary gland, results in GH deficiency. The hypothalamic hormones are referred to as releasing hormones and inhibiting hormones, reflecting their influence on anterior pituitary hormones2.

1.3 Regulation
Peptides released by neurosecretory nuclei of the hypothalamus into the portal venous blood surrounding the pituitary are the major controllers of GH secretion by the somatotropes. However, although the balance of these stimulating and inhibiting peptides determines GH release, this balance is affected by many physiological stimulators and inhibitors of GH secretion.
1.3.1 Regulators of Release
• Age-Dependence:
Growth hormone levels are highest during puberty. Accordingly, this is when we are growing the most rapidly. After about 30 years of age our growth hormone levels begin to decline at a rate of about 14% per decade.
• Sleep-Dependence:
After an hour, or so, of initiating sleep we enter into a mode of deep sleep known as Slow Wave Sleep, or SWS. SWS occur only during the initial hours of sleep and appear to be inhibited as the night progresses. Growth hormone is principally released from the anterior pituitary during moments of SWS. Therefore, anything that interferes with our SWS will likewise interfere with the release of growth hormone. Alcohol, in particular, interrupts SWS and consequently will also inhibit the release of growth hormone from the anterior pituitary.
• Exercise-Dependence:
Growth hormone is also released following exercise. This aspect of growth hormone release is extremely important for muscle recovery following exercise.

1.4. Other Releasers:
Growth hormone is also released in response to these other physiological stimuli:
• Fasting
• Low blood sugar
• Stress
• Injury or Trauma
• Fever
• Dopaminergic Agonists (Neurotransmitters)
1.5 Central nervous system release
The Hypothalamus is a part of the brain that serves to integrate and respond to information it receives from the rest of the body. In particular, the hypothalamus exerts control over the secretions of the Anterior Pituitary, a small gland located at the base of our brains. The pituitary is also important for this mechanism. Therefore, the hypothalamus, via its direct control over the anterior pituitary, indirectly governs the body’s growth and metabolic processes.
Rather than a steady stream, however, growth hormone is released from the anterior pituitary in spurts due to the competing actions of stimulatory and inhibitory factors originating from the hypothalamus.
1.6. Hypothalamic Factors
Stimulatory: Growth Hormone Releasing Hormone, or GHRH, produced by the hypothalamus mainly stimulates the anterior pituitary to secrete growth hormone.

Inhibitory: Growth hormone inhibitory hormone (GHIH) or Somatostatin antagonizes the release of growth hormone from the anterior pituitary. Like GHRH, somatostatin is produced in the hypothalamus from where it acts on the anterior pituitary.
1.7. Regulatory Feedback
Growth hormone is not wasted. Once secreted into the blood stream growth hormone inhibits its further release from the anterior pituitary (and hypothalamus). The net result is that growth hormone release is favored when its levels are low and is inhibited when it is present in adequate amounts. This is a negative feedback and this prevents the overproduction of growth hormone.
1.8 Effects of Growth Hormone
1.8.1 Direct Effects
Growth Hormone Receptors: Growth hormone directly activates cells expressing growth hormone receptors on their surface. These receptors bind growth hormone after being released from the Anterior Pituitary into the blood stream. The binding of growth hormone to the receptor activates the cell.
Fat Reserves: Fat cells (adipocytes) express high levels of growth hormone receptor. The binding of growth hormone to these receptors causes the adipocyte to release lipids into the blood stream and simultaneously prevents them from taking up lipids from the exterior. In other words, growth hormone mobilizes fats for energy usage. The ultimate result is that our fat reserves get reduced when growth hormone levels are high in circulation.
Growth hormone also slows the use of glucose for energy metabolism
1.9.2. Indirect Effects: (Insulin-like Growth Factor-1)
The majority of growth hormone’s actions, however, are indirect. Most of them are mediated by Insulin-like Growth Factor 1, or IGF-1. IGF-1 is produced by the liver when stimulated by growth hormone; liver cells (hepatocytes) also express high levels of growth hormone receptor. Therefore, increases in growth hormone are commonly mirrored by increased IGF-1. When the growth hormone receptor isn’t functioning properly, however, IGF-1 levels are low relative to growth hormone.
• Muscle Growth: IGF-1 causes muscle cells (myocytes) to increase protein synthesis, reduce protein breakdown, and take up amino acids and to proliferate. In other words, our muscles grow when stimulated by IGF-1.3An athlete or bodybuilder who abuses growth hormone in an attempt to gain muscle size and strength is likely to use other drugs to speed up their physical transformation. The dangers of mixing these drugs aren’t fully known. Some of the drugs used may include:
• Steroids – synthetic versions of the male sex hormone testosterone that build muscle tissue and aid rapid recovery.
• Amphetamines – to aid in fat loss.
• Beta-blockers – to counteract trembling, a common side effect of steroids.
• Diuretics – to counteract fluid retention.
• Bone Growth: Bone cells (chondrocytes) also respond to IGF-1 by proliferating; our bones grow. Connective tissue and cartilage also increase in response to IGF-1.
• Kidneys: Our kidneys and internal organs increase in size in response to IGF-1.

1.10 Regulatory Feedback:
Growth hormone eventually shuts off its own release through a process of regulatory feedback. IGF-1 also feedbacks upon the hypothalamus and anterior pituitary to inhibit further growth hormone release. More precisely, IGF-1 promotes the release of somatostatin from the hypothalamus, as well as directly inhibits growth hormone release from the anterior pituitary.
CHAPTER 2
GROWTH HORMONE TREATMENT
2.1 Who needs to take human growth hormone?
Synthetic human growth hormone is available only by prescription and is administered through an intramuscular injection. It’s currently approved to treat adults with true growth hormone deficiency — not the expected decline in growth hormone due to aging. Growth hormone deficiency can be caused by pituitary tumors and radiation or surgery to the pituitary gland, among other causes3.Human growth hormone is also approved for:
• Children with short stature
• Children with kidney failure
• Children with Prader-Willi syndrome
• Children with Turner’s syndrome
• Muscle wasting associated with AIDS and HIV
Studies of adults with growth hormone deficiencies show that injections of human growth hormone can:
• Increase bone density
• Increase muscle mass
• Decrease body fat
• Bolster the heart’s ability to contract
• Improve mood and motivation
• Increase exercise capacity
Because of those results, people believe that synthetic human growth hormone can help healthy older adults who have naturally low levels of growth hormone regain some of their youth and vitality.
2.2 Assessment of growth hormone secretion
Growth hormone deficiency is a miserable at the world now and it is necessary to identify growth hormone retarded persons among human population. Normally plasma GH level is vary variable, but usually 4it is less than 2mU/l (it may be up to 50 with stress).In order to assess pituitary function and growth hormone secretion following tests4 can be used.
• Post- exercise
• 1 hour after going to sleep Physiological
• frequent sampling during sleep
• Insulin – induced hypoglycaemia
• Clonidine Pharmacological
• Arginine
• Glucagon
2.3 Growth Hormone Disorders
There are numerous conditions associated with alterations of growth hormone production or receptor recognition.

2.4 Growth Hormone Deficiency
2.4.1. Childhood–Dwarfism:
Dwarfism results if the liver and other target tissues are not sufficiently stimulated by growth hormone. This condition arises because either too little growth hormone is produced during childhood, or because the growth hormone receptors expressed by cells are non-functional. Under conditions where the growth hormone receptor isn’t functioning properly, IGF-1 levels are low in comparison to growth hormone.
Mental retardation is also commonly observed in cases of growth hormone deficiency (GHD). Other symptoms of GHD resemble the normal aging process.
2.4.2. Adulthood–Growth Hormone Deficiency (GHD):
Adult onset GHD is characterized by reduced lean body mass, bone density and strength, while visceral fat and mortality, principally due to cardiovascular disease, increases. A characteristic elevation in plasma cholesterol (high LDL/low HDL) is most likely responsible for the increased incidence of cardiovascular disease in GHD patients. Insulin resistance is also frequently encountered. This condition frequently results from the medical intervention of a Pituitary tumor with resultant loss of the growth hormone producing cells, or Somatotropes.
2.4.3. Adulthood–Normal Aging:
This increase in body fat is in large part due to an age dependent decrease in growth hormone. The reduction in growth hormone with age is associated with increased body fat, and reduced muscle mass and bone density. This is a clinical condition referred to as Somatopause. Other aspects of the normal aging process that is correlated with a reduction of growth hormone are cardiovascular disease, wrinkling, gray hair, decreased energy, and reduced sexual function. Many of these same symptoms are present in younger adults with GHD.
2.4.5. Hyper Growth Hormone or Overabundance
Too much growth hormone can have different effects depending on the age at which it occurs. Alarmingly, reduced life expectancy is frequently encountered in natural disorders where growth hormone levels are abnormally elevated.
• Childhood-Giagantism: An overabundance of growth hormone during childhood or adolescence gives rise to giagantism. It is a very rare condition that usually results from a tumor of the cells that produce growth hormone.
• Adulthood–Acromegaly: Acromegaly results from an excess of growth hormone (or IGF-1) during adulthood. IGF-1 is responsible for longitudinal growth (increase in height) during childhood and adolescence. However, an excess of IGF-1 during adult life (after our bones have stopped elongating) causes bones to widen and increase in girth. This disfigures our features, particularly in the face (large square jaw), hands and feet. Glucose intolerance is also commonly observed in acromegliacs. In fact, about one quarter of all acromegliacs develop diabetes mellitus due to peripheral resistance to insulin
2.5 Replacement Therapy
This is a field that is still in its infancy. Previously, human growth hormone was isolated directly from the anterior pituitary of cadavers. This approach yielded extremely small amounts of painfully expensive growth hormone. With the recent advent of genetic engineering, recombinant growth hormone can now be produced more economically in bacteria. Although this has reduced the cost considerably, it is still expensive.
2.6 Uses in Growth Hormone Deficiency (GHD)
Children: GHD in children is most noticeably characterized by stunted growth. Recombinant growth hormone is often used in children with GHD to augment growth.
Adults: Increases in bone density and lean body mass are often observed in patients with adult-onset GHD when treated with recombinant growth hormone. Plasma cholesterol has also been observed to stabilize (lower Low density Lipo protein/higher High DL).

CHAPTER 3
GROWTH HORMONE: USES AND ABUSES
The therapeutic use of human growth hormone was first shown 45 years ago5. In these years the number of approved and proposed uses of human growth hormone has grown and the number of patients being treated with it has increased from a handful to tens of thousands worldwide. The officially approved uses of human growth hormone vary from country to country, but it is commonly used for children with growth hormone deficiency or insufficiency, poor growth due to renal failure, Turner syndrome (girls with a missing or defective X chromosome), Prader-Willi syndrome (usually due to uniparental disomy in chromosome 15), and children born small for gestational age with poor growth 2 years of age. In adults the approved uses include AIDS related wasting and growth hormone deficiency (usually due to a pituitary tumour). The evidence supporting these uses of human growth hormone comes from double blind controlled studies, clinical observations, and systematic meta-analyses. In addition to the generally accepted therapeutic uses of human growth hormone, many proposed uses have not been established. Human growth hormone is undisputedly a potent hormone with a wide variety of biological effects. The anabolic actions of human growth hormone have made it attractive as a potential agent for catabolic problems in a wide range of clinical conditions, including severely catabolic patients in an intensive care environment, burns, cystic fibrosis, inflammatory bowel disease, fertility problems, osteoporosis, and Down’s syndrome, and also for people wishing to reverse the effects of ageing and promote athletic prowess. These last two potential uses have received the most attention as abuse of growth hormone.
The definitions of the word abuse include “improper or excessive use.” The classic forms of “abuse” of human growth hormone are athletes or bodybuilders who use it as a way to gain an unfair advantage over their competitors. No good evidence exists that human growth hormone actually works in this setting. The lay bodybuilding literature is full of testimonials, but as human growth hormone is as least as potent as an anabolic agent no doubt is left that growth hormone should be banned in sport. The use of human growth hormone in sport is promoted by the fact that as yet no practical method exists to detect that is in use in competition at the Olympic level. The use of human growth hormone to increase the height of children who are already of normal height should also be considered abuse. Another common form of use of human growth hormone outside the established indication is in its alleged action of reversing or slowing the effects of ageing. The quest for a “fountain of youth” is an age old dream; advertisements in print media and on the internet promote the use of human growth hormone or agents touted as increasing human growth hormone levels. Many of these agents are not growth hormone and do not lead to a sustained increase in concentrations of growth hormone. Although anabolic effects and changes in body composition have clearly been associated with the use of human growth hormone, in elderly people little or no evidence exists of an important positive functional effect on the processes of ageing.
In addition to the lack of evidence for effectiveness of human growth hormone in these proposed uses, it causes side effects such as diabetes, carpal tunnel syndrome, fluid retention, joint and muscle pain, and high blood pressure. Many of these side effects were seen in studies that used much higher doses of human growth hormone than are now used in elderly people, so there is hope that studies using lower doses alone or in combination with modest doses of anabolic steroids may show a positive ratio of benefits to side effects. Well controlled clinical studies are needed to explore the potential uses of human growth hormone in elderly people and of its other potential uses as an anabolic agent. Innate to the use of growth hormone for athletic enhancement6 or age reversal is the idea that if some growth hormone is good, more must be better.7The belief that taking higher doses or more frequent injections of growth hormone can speed up or enhance its supposed beneficial effects can be a risky one. By increasing the amount of growth hormone taken, one may significantly increase the chance of serious side effects. While it may be some years before it is possible to accurately assess the dangers of growth hormone abuse, one need only consider the condition of acromegaly, where levels of growth hormone are elevated for many years, to see the detrimental effects on the body of prolonged excess growth hormone. Serious abnormalities of the heart, skeletal system, and nervous system are seen in these patients along with an increase in heart disease and tumors
3.1 Pharmaceutical and Biotechnological Uses of Growth Hormone
In years past, growth hormone purified from human cadaver pituitaries was used to treat children with severe growth retardation. More recently, the virtually unlimited supply of growth hormone produced using recombinant DNA technology has lead to several other applications to human and animal populations. Human growth hormone is commonly used to treat children of pathologically short stature. There is concern that this practice will be extended to treatment of essentially normal children – so called “enhancement therapy” or growth hormone on demand. Similarly, growth hormone has been used by some to enhance athletic performance. Although growth hormone therapy is generally safe, it is not as safe as any therapy and does entail unpredictable health risks. Parents that request growth hormone therapy for children of essentially-normal stature are clearly misguided. A number of proposed therapeutic uses exploit the anabolic effects of growth hormone in, for example, severely catabolic patients – the evidence for these is limited. Most obvious of these is use by athletes to gain unfair advantage over competitors, although there is no evidence that this works.8The role of growth hormone in normal aging remains poorly understood, but some of the cosmetic symptoms of aging appear to be amenable to growth hormone therapy. This is an active area of research, and additional information and recommendations about risks and benefits will undoubtedly surface in the near future.
Growth hormone is currently approved and marketed for enhancing milk production in dairy cattle. There is no doubt that administration of bovine somatotropin to lactating cow results in increased milk yield, and, depending on the way the cow are managed, can be an economically-viable therapy. However, this treatment engenders abundant controversy, even among dairy farmers. One thing that appears clear is that drinking milk from cattle treated with bovine growth hormone does not pose a risk to human health. Another application of growth hormone in animal agriculture is treatment of growing pigs with porcine growth hormone. Such treatment has been demonstrated to significantly stimulate muscle growth and reduce deposition of fat.
3.2 Research Findings
1. Jovanna Dahlgren and colleagues at Gothenburg University in Sweden analyzed data from 415 short pre-pubertal children who had undergone GH treatment to develop a model that predicts an individual’s response. The team gathered data including the children’s length and weight at birth, height before and during treatment and their parents’ height. The model was then validated by applying it to a group of 112 different children. The model’s accuracy was substantially improved by including data on blood levels of growth hormone and other growth-related hormones, such as insulin-like growth factors and leptin. The models presented serve as a practical clinical tool for selecting children for successful growth hormone treatment, and provide the highest prediction accuracy available. Growth hormone treatments are expensive, involve daily injections, and are associated with the risk of overdose. To assess whether growth hormone treatment would be appropriate for a particular child, an accurate prediction of how much growth would result from the treatment is crucial.9 This new research will help clinicians determine the children most likely to benefit from treatment, and the most appropriate dose.
2. Towards the Development of a Test for Growth Hormone Abuse – A Study of Extreme Physiological Ranges of Growth Hormone Dependent Markers in 813 Elite Athletes in the Post-Competition Setting.
10Study has demonstrated that there are predictable age dependent levels of GH-dependent markers in elite athletes that are consistent even at the extremes of physical exertion and that these are independent of sporting category. Normative data applicable to white athletes is provided. This provides important groundwork for the development of a test for GH abuse, although these values may be specific for the reagents and assays used.
3. Growth hormone abuse- 11 Doping with growth hormone (GH) has become an increasing problem in sports during the last 10 years. GH has a reputation of being fairly effective among GH users, although the effectiveness is not undisputed, and the few controlled studies that have been performed with supraphysiological GH doses to athletes have shown no significant positive effects of GH in the aspect of a doping agent. There is no method yet to discover GH doping, but current intensive research in this matter will hopefully produce a method in the years to come. This article describes the GH physiology, the clinical use of GH, the athlete’s view, administration regimens and side effects.

REFERENCES
1. http//www. wikipedia.org/ wiki/growth_hormone html
2. www.vivo.colostate.edu/hbooks/pathphys/endocrine/hypopit/anatomy.html
3. http://www.mayoclinic.org/ Human_growth_hormone htm
4. Davidson s., Edward C.R.W., Bouchier I.A.D, 1996. Davidson’s Principle and practice of medicine 17th edition, Great Britain. Pg 675,1152
5. http://www.pubmed.com/ Growth hormone: uses and abuses html (Raymond L Hintz,)
6. Martin M. Zdanowicz, 1997. Human Growth Hormone: Ethical and Economic Considerations of Use and Misuse, Boston (review article)
7. http// dsonline\dsarticles.nsf\pages\health_conditions\ Hormonal system\general htm
8. http://www.ukmicentral.nhs.uk/headline/database/story.asp?NewsID=3165
9. http://www.sciencedaily.com/releases/2007/12/071212201410.htm
10. http://jcem.endojournals.org/cgi/content/abstract/jc.2004-0386v1
11. http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&uid=10932811&cmd=showdetailview&indexed (Ehrnborg C, Bengtsson BA, Rosén T.)

MD/2006/3469

Atherosclerosis.

Atherosclerosis, disease of large and medium-size arteries, common in socially advanced countries. Atherosclerosis is the most common underlying cause of heart attacks and strokes.

The disease probably starts in childhood and develops slowly over main cause of heart attacks and strokes. Many years, giving no indication of its presence. It is rare for its effects to become apparent before the age of 40 or 50; thereafter, it becomes progressively more common with advancing age. When it does show itself, it usually does so as a heart attack, most commonly in middle-aged men. Strokes—brain damage from loss of an adequate blood supply—occur later and affect the sexes about equally, mainly because women are believed to have a remarkable degree of protection from the disease so long as they are secreting the female hormone oestrogen. After the menopause, this protection is lost and the condition tends to progress rapidly.

Nature of Atherosclerosis.

The disease affects the innermost of the three layers of the artery. This layer is lined with a dense, single-celled surface that in a healthy person prevents any abnormal substances in the blood from entering the thickness of the wall. It also prevents clotting of the blood. It has repeatedly been shown experimentally that diets high in saturated fats lead to the development of fatty streaks in this inner layer. If such diets are continued, the streaks thicken and become invaded by new muscle cells and cells from the immune system. Eventually new blood vessels invade these areas, which develop a core of cholesterol, other fats, and degenerate muscle cells and other debris, and are known as atheromatous plaques.

Effects of atherosclerosis.

The main effect of arterial plaques is that by growing out towards the centre of the vessel, they impede the flow of blood to an organ. Also, because plaques no longer have the properties of healthy vessel lining, blood will readily clot on their surface. Finally these conditions will lead to heart attacks, strokes etc.

Risk Factors.

There are two outstanding and avoidable risk factors. They are the unsuitable diet and cigarette smoking. The evidence is not purely epidemiological. Much scientific research has now elucidated the various pathological stages by which a diet high in saturated fats or the toxic substances in tobacco smoke can lead to damage to the artery lining and the progression of atherosclerosis. Regular exercise is valuable largely because it helps to improve circulation, control appetite, and control weight.
Blood cholesterol tests are of little value in the diagnosis of atherosclerosis (because such tests do not reveal the state of the arteries) except in cases in which there is a family history of early atherosclerosis-induced disease.
Recent studies shows that Atherosclerosis is most often associated with hypercholesterolemia & hyperlipidaemia.

Recent findings Show that atherosclerosis has a distinct relationship with hereditary.

Genes contribute to both the cause and the pathogenesis of virtually all abnormalities of human physiology and behaviour, including, of course, atherosclerosis. A variety of genetic factors, in addition to well studied errors of lipid metabolism, clearly predispose to atherosclerosis. Few genes apart other than those involved in lipid metabolism have such an overwhelming impact that they may be identified on the basis of family history. However, genes that predispose to hypertension and diabetes mellitus; control arterial diameter, reactivity and branching angles; affect platelet adhesiveness, thrombosis and fibrinolysis; and regulate endothelial and smooth muscle function can all be considered candidate genes for study in families predisposed to atherosclerosis.

Genetics of non-Mendelian forms of atherosclerosis

The Human Genome Project has ushered in new opportunities for studying the genetic non-Mendelian disorders through construction of SNP (Single nucleotide polymorphisms) maps and genome-wide SNPs association studies While there is a considerable debate regarding the best approach for genome -wide SNP association studies, candidate gene approach has emerged as the practical approach that could be pursued at multiple levels. Because SNPs do not exist in isolation, comprehensive analysis of the selected candidate genes is necessary. Moreover, because a positive association does not establish causality and often indicates linkage disequilibrium with the actual mutation, the results are considered provisional pending confirmation through in vitro and in vivo experimentations .

Rare and Common Genetic Differences Contributing to Susceptibility to Atherosclerosis.

Single-gene (mendelian) disorders with large effects are the most dramatic examples of the genetic contributions to atherosclerosis.1,2 However, most forms of the disease are the product of many genes with small effects that are modified by the environment and the effects of other genes, rather than of a single highly penetrant gene. Studies of identical twins are particularly informative because these twins share all of their genes, and such studies consistently indicate that genetic effects powerfully influence athrosclerosis as well as most of its risk factors.2,3,4

Familial Combined hyperlipidemia (FCH):

FCH is a relatively common disease that affects approximately 1 – 2:100 in the population. It is not yet clear whether FCH is an autosomal recessive or a polygenic disease, and the causal genes and mutations are still unknown. The primary defect is impaired transfer of cholesteryl ester from HDL to LDL and VLDL cholesterol, which results in elevation of LDL and VLDL cholesterol and premature atherosclerosis.

The classic genetic trait in heart disease & atherosclerosis are familial hypercholesterolemia (FH). Carl Miller, a physician at Oslo County Hospital, Norway, first described the disorder _70 years ago.1,2 He noted that the triad of elevated cholesterol, tendon xanthomas, and early heart disease segregated together in families, providing strong evidence for an association between blood lipids and atherosclerosis.

Joseph Goldstein and Michael Brown further examined the disease in the early 1970s, and over the last 3 decades, their landmark studies have fostered many insights in the control of cholesterol levels and the aetiology and treatment of atherosclerosis.2,3
Along the way, they discovered receptor-mediated endocytosis and mechanisms for transcriptional regulation by lipids. Their studies revealed that FH is the result of mutations that destroy the ability of the LDL receptor to mediate the binding, internalization, or degradation of LDL.
Individuals carrying 2 mutant copies have extremely high levels of cholesterol (600 mg/dL), whereas heterozygotes with 1 mutant copy have levels of 400 mg/dL. The penetrance of atherosclerosis in FH varies widely, dependent on modifier genes and the same lifestyle environmental risk factors that determine risk in noncarriers, including diet, smoking, and activity level.4

The frequency of heterozygotes in most populations is surprisingly high for a lethal disease, 1 in 500.5 Because a significant fraction of heterozygous individuals are unaware that they carry a lethal dominant gene that is shared by half of their first-degree relatives, it would seem that DNA screening of the disease would be worthwhile, particularly because effective treatments for the heterozygous disease are available.6 Unfortunately, FH is heterogeneous in most populations, the exception being founder populations such as French Canadians and Afrikaners, involving hundreds of different mutations of the LDL receptor gene. Nevertheless, rapid mutation screening methods for FH have been developed.7

Single nucleotide polymorphisms(SNP) in atherosclerosis.

It has become clear that the genome, carried by each of us and inherited from our parents, most often differs between individuals in terms of single base changes. In the 20th century only a few thousand of these so called single nucleotide polymorphisms (SNPs; Fig. 1) identified. But after a short period, In the 21st century number increased 1000- fold. The main use of the human SNP map will be to identify the contributions of individual genes to diseases that have a complex, multi gene basis, such as atherosclerosis. Knowledge of genetic variation already affects patient care to some degree. For example, gene variants lead to tissue and organ incompatibility, affecting the success of transplants. Studies on SNPs and atherosclerosis will become more efficient when a few more problems are solved. First, although 82% of SNP variants are found at a frequency above 10% in the global human population, the ‘micro distribution’ of SNPs in individual populations is not known.11

Second, not all SNPs are equal, and it will be essential to know as much as possible about their effects from computational analysis before studying their involvement in disease. For example, each SNP can be classified by whether it codes or not. Coding SNPs can be classified by whether they alter the sequence of protein encoded by the altered gene; changes that alter protein sequences can be classified by their effects on protein sequences. Non-coding SNPs can be classified according to whether they are found in gene-regulating segments of the genome; atherosclerosis may arise from quantitative rather than qualitative differences in gene products.11 Third, the technology for the assay of thousands of SNPs, in thousands of patients and control individuals, is not yet fully developed.11

Figure 1 The most common sources of variation
between humans are single nucleotide polymorphisms
(SNPs) – single base differences between genome
sequences. Fragments of two sequences with eight SNPs
are shown (indicated by lighter text).

Relationship with apolipoprotein B deficiency.

Familial defective apolipoprotein B (apoB), another relatively common hypercholesterolemia (1 in 800), is the result of the mutations of apoB, the major protein of LDL, which prevent its binding to the LDL receptor. In contrast to FH, this disorder is homogeneous, with most cases resulting from a single nucleotide substitution at codon 3500.

Although the cholesterol levels of these patients are somewhat lower than are those with FH, they are still highly elevated. Like FH, the disorder exhibits dominant inheritance; therefore, half of the first-degree relatives of an individual with familial defective apoB will be affected. Most other single-gene traits associated with CHD are rare and of lesser clinical significance.2As was the case with FH, studies of rare disorders have led to many novel insights into the pathways involved in atherogenesis..

Similarly, Lifton’s studies7of rare mendelian forms of hypertension have identified key processes in the control of blood pressure.During the past 20 years, the study of human genetics has been revolutionized by positional cloning, a combination of genetic and physical mapping that allows genetic differences to be identified solely on the basis of their locations in the genome.8,9To day different mendelian disease genes have been identified by positional cloning. Unfortunately, the complex etiology of common diseases, involving many different genetic factors as well as important environmental influences, has made it difficult to apply positional cloning. So there is a great success achieved in identifying single-gene disorders for atherosclerosis, but understanding of the common, complex forms remains limited.

ApoE plays a major role in lipid metabolism and has a close link with atherosclerosis.
Most of success in understanding the genetic basis of common forms of atherosclerosis has come from studies of “candidate genes,” genes identified by biochemists and subsequently examined for genetic differences and associations in populations. A good example of a candidate gene is apolipoprotein E (apoE). ApoE has been studied intensively as a central player in plasma lipid metabolism, in which it mediates the uptake of chylomicron and VLDL remnants by the LDL receptor and its cousin, LDL receptor-related protein (LRP).

Common genetic differences (polymor- phisms) of apoE were identified by Utermann and colleagues10 in the 1970s, and subsequent studies by many laboratories revealed clear associations with plasma cholesterol levels and type III hyperlipidemia (and later, Alzheimer disease).Hyperlipidemia is associated with several alleles,namely E1,E2,E3..etc.Almost all individuals with this uncommon (1 in several thousand) hyperlipidemia are homozygous for the E2 allele, but most individuals who are homozygous for the E2 allele do not have the disorder.10 Thus, other genetic or environmental interactions are required to produce hyperlipidemia in addition to homozygosity for the E2 allele.

Our knowledge of genetic differences contributing to CHD & atherosclerosis risk is greatest in lipid metabolism. In addition toapoE, convincing evidence suggests that common variations of hepatic lipase influence levels of HDL,11 that variations of the apoAI-CIII-AIV-AV locus contribute to plasma triglyceride levels,12 and that variations of the apo(a) gene determine _90% of the population variance of Lp(a) levels.13 Both hepatic lipase and the apoAI-CIII-AIV-AV cluster appear to influence LDL particle size, a predictor of CHD & atherosclerosis risk.14 However, these genetic differences together explain only a small fraction of the total variance of plasma lipid phenotypes

More than 2 dozen studies have revealed significant associations between polymorphisms of paraoxonase-1 (PON1) and measures of atherosclerosis.15,16 PON1 is a serum esterase bound to HDL, first recognized for its ability to hydrolyze a metabolite of the insecticide parathion. PON1 was identified as a candidate gene for atherosclerosis because of its ability to inhibit the oxidation of LDL and transgenic studies in mice have confirmed that PON1 is antiatherogenic in vivo.17 The studies with PON1 are especially significant in providing support for the oxidation hypothesis of atherosclerosis18 Many other candidate genes have been examined in population-association studies. Common variations in some of these genes have been convincingly associated with CHD or atherosclerosis and its risk factors.

Most associations, however, require confirmation, and many are likely to prove to be false positives.19 A clustering of atherosclerotic risk factors termed the “metabolic syndrome”. MetSyn is characterized by visceral adiposity, insulin resistance, low HDL cholesterol, hypertriglyceridemia, a systemic proinflammatory state, and small dense LDL, and it is a strong predictor of atherosclerosis,CHD and type 2 diabetes mellitus.20

The assessment and treatment of MetSyn have yet to be effectively integrated into clinical practice.20 MetSyn, like atherosclerosis, clearly is complex, with a host of genetic and environmental contributions. Genetic differences in the nuclear receptor peroxisome proliferator-activatorreceptor-(PPAR_) appear to play a key role in MetSyn and type 2 diabetes mellitus.21 Interestingly, PPAR agonists are effective in correcting a number of features of MetSyn. Recent studies also have implicated common variations of the lipoprotein lipase (LPL) gene in MetSyn.22LPL is an enzyme in capillary surfaces that hydrolyzes the triglyceride in plasma chylomicrons and VLDL, releasing free fatty acids for uptake by peripheral tissues. Human studies that suggest a role for PPAR and LPL in MetSyn are strongly supported by studies with transgenic mice.22

Therapies

Probably the most significant impact of genetic studies on medicine pertains to the development of therapies. The outstanding example is the impetus that genetic studies of familial hypercholesterolemia (FH) provided in the development of hepatic hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins)23.Several therapeutic approaches based on genetic studies are under development.

The identification of a naturally occurring variant of apolipoprotein AI, known as apoAI Milano, in a village in northern Italy in 198024 led to investigations of the therapeutic potential of HDL and this protein variant as antiatherogenic therapy.

Carriers of the apoAI Milano gene are characterized by extremely low levels of HDL cholesterol (10 to 30 mg/dL) and a decreased risk of atherosclerosis relative to the low level of HDL. The apoAI Milano protein differs from native apoAI in that a cysteine is substituted for arginine at position 173. This cysteine confers different properties to this protein as compared with normal apoAI, including the ability to form disulfide-bonded dimers with other apoAI Milano molecules and other HDL proteins such as apoAII.

Recombinant apoAI Milano has been formulated in a complex with phospholipids to mimic the properties of nascent HDL (ETC-216, Pfizer)25. Studies in mice and rabbits with experimental atherosclerosis have demonstrated that recombinant apoAI Milano/phospholipids complexes rapidly reduce the lipid and macrophage content of atherosclerotic plaques after a single infusion.26

The effect of short-term intravenous recombinant apoAI Milano/ phospholipid complexes on atheroma burden in patients with acute coronary syndromes was studied in a recent clinical trial27.

The intravenous administration of ApoAI Milano for doses at weekly intervals produced statistically significant regression in coronary atheroma volume in the target segment as compared with baseline measurements by intravascular ultrasound. No change was seen with saline placebo control.26

It remains to be determined whether apoAI Milano has unique properties that result in greater antiatherogenic potential than normal apoAI and whether the exciting results of this first study in humans can be confirmed in large-scale randomized clinical outcome trials.

HDL is involved in reverse cholesterol transport, the process by which cholesterol is transported from peripheral tissues to the liver, where it can be excreted in bile. Studies since the mid-1990s have provided strong evidence that HDL also may protect against atherosclerosis by virtue of its antiinflammatory properties. These studies, based in part on genetic variations that influence the antioxidant properties of HDL, indicate that HDL can selectively remove and destroy proinflammatory oxidized lipids from the vessel wall, thereby inhibiting the vicious cycle of LDL trapping, LDL oxidation, and inflammation.

Navab et al28 have demonstrated that short, synthetic amphipathic helices, similar to those in apoAI, exert powerful protective effects against atherosclerosis when administered orally to mice or monkeys..

Genetic studies implicated 5-lipoxygenase (5-LO) in atherosclerosis susceptibility in mice and then humans,29 and recent studies suggest that polymorphisms of other enzymes in leukotriene metabolism also are associated with atherosclerosis 30.5-LO polymorphisms were implicated originally in asthma, and a variety of leukotriene synthesis inhibitors are widely used to treat asthma.31

Risk Stratification, Prevention, and Treatment

National guidelines from the American Heart Association and the National Heart, Lung, and Blood Institute’s National Cholesterol Education Program recommend an approach to initial global risk assessment of the asymptomatic patient to obtain an estimate of absolute cardiovascular risk.32,33 On the basis of standard risk factors and related risk correlates, the concept was set forth that asymptomatic patients can be placed into 1 of 3 risk categories: low, intermediate, and high. The techniques used in office assessments include history, physical examination, laboratory testing, and ECG.The focus of the examination is on the detection of risk factors that either can be directly modified or will modify the overall intensity of risk-reduction therapies.

The major causal risk factors identified for routine assessment include age, smoking, elevated blood pressure, elevated serum LDL cholesterol, low HDL cholesterol, and diabetes. The approach to therapy is guided by the principle that the intensity of risk-factor management should be adjusted by the severity of risk.

Low-risk patients should be encouraged to adhere to healthy lifestyle habits. High-risk patients are advised to directly begin a regimen of aggressive risk reduction through a combination of nondrug and drug regimens. Patients at intermediate risk become candidates for further risk stratification through the measurement of the inflammatory marker high-sensitivity C-reactive protein or non-invasive procedures that test for the presence of myocardial ischemia or coronary atherosclerotic burden, or both techniques.

Although several of the conventional causal risk factors used in global risk assessment clearly have a genetic basis, specific genetic testing has not been recommended for routine clinical practice. Because conventional risk factors account for only 50% of the variability in risk, the identification of genetic differences influencing the pathways of measurable atherosclerotic risk factors or novel pathways may allow for the determination of risk that is additive to the measurement of conventional risk factors. Moreover, some genetic differences, such as those in the genes for apoE, lipoprotein lipase (LPL), and interleukin-6, show evidence of specific environmental interactions (e.g., with smoking), in which the overall risk is more than additive.34,35

Thus, the predictive models used in the Framingham risk score may be greatly enhanced by theaddition of pivotal single-nucleotide polymorphisms and haplotypes that have been shown to affect CHD. It can be envisioned that genotypic information could transform the value of the risk score and be integrated in routine clinical practice to guide preventive therapy. It also seems likely that genetic differences would be useful in predicting specific complications of atherosclerosis.

Figure 2
Expressiveness of the genes that related to atherosclerosis is influenced by the environmental factors and other modifier genes. By all these means one can clearly say that atherosclerosis is a polygenic disease which has a strong genetic relationship.

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34.Stephens JW, Humphries SE. The molecular genetics of cardiovascular disease: clinical implications. J Intern Med. 2003;253:120–127.
35.Wang Q, Rao S, Shen GQ, et al. Premature myocardial infarction nove susceptibility locus on chromosome 1P34-36 identified by genomewide linkage analysis. Am J Hum Genet. 2004;74:262–271.

MD/2006/3475.

Platelets
Platelets or thrombocytes are the cell fragments circulating in the blood that are involved in the cellular mechanisms of primary hemostasis leading to the formation of blood clots.1 Dysfunction or low levels of platelets predisposes to bleeding, while high levels, although usually asymptomatic, may increase the risk of thrombosis.
Platelets are anuclear and disc shaped; they measure 1.5–3.0 μm in diameter. Human body has a very limited reserve of platelets, so they can be rapidly depleted. Platelets contain RNA, mitochondria, a canalicular system, and several different types of granules; lysosomes containing acid hydrolases, dense bodies containing ADP, ATP serotonin and calcium and alpha granules containing fibrinogen, factor V, vitronectin, thrombospondin and von Willebrand factor. The contents are released upon activation of the platelets.
Platelets are produced in the bone marrow & the progenitor cell for platelets is the megakaryocyte. Megakaryocyte is about twelve times larger than an erythrocyte, possesses a lobed nucleus and sheds platelets into the circulation.1 Thrombopoietin is a hormone, mainly produced by the liver, that stimulates platelet production. It is bound to circulating platelets; if platelet levels are adequate, serum levels remain low. If the platelet count is decreased, more thrombopoeitin circulates freely and increases platelet production.
The circulating life of a platelet is 8–10 days.1 After this it is sequestered in the spleen. Decreased function (or absence) of the spleen may increase platelet counts, while hypersplenism (overactivity of the spleen, e.g. in Gaucher’s disease, leukemia, and cirrhosis) may lead to increased elimination and hence low platelet counts.
Platelets are activated when brought into contact with collagen (which is exposed when the endothelial blood vessel lining is damaged), thrombin, ADP, receptors expressed on white blood cells or the endothelial cells of the blood vessels, a negatively charged surface (e.g., glass), or several other activating factors. Once activated, they release a number of different coagulation factors and platelet activating factors. Platelet activation further results in the scramblase-mediated transport of negatively charged phospholipids to the platelet surface. These phospholipids provide a catalytic surface (with the charge provided by phosphatidylserine and phosphatidylethanolamine) for the tenase and prothrombinase complexes. The platelets adhere to each other via adhesion receptors or integrins, and to the endothelial cells in the wall of the blood vessel forming a haemostatic plug in conjunction with fibrin. The high concentration of myosin and actin filaments in platelets are stimulated to contract during aggregation, further reinforcing the plug. The most abundant platelet adhesion receptor is glycoprotein (GP) IIb/IIIa; this is a calcium-dependent receptor for fibrinogen, fibronectin, vitronectin, thrombospondin and von Willebrand factor (vWF). Other receptors include GPIb-V-IX complex (vWF) and GPVI (collagen)

A scanning electron microscope (SEM) image of normal circulating human blood.
Red blood cells, several white blood cells including lymphocytes, a monocyte, a neutrophil, and many small disc-shaped platelets can be seen.
Platelet Activators.
• Collagen2
Collagen is exposed when endothelial blood vessel lining is damaged, and binds to its receptors GPVI and α2b-β1 on the platelet surface.
• Von Willebrand factor 2
Circulates in the blood and binds to its receptor GPIb-IX-V on the platelet surface.
• Thrombin
Primarily through cleavage of the extracellular domain of PAR1 and PAR4;
• Thromboxane A2 (TxA2)
Binds to its receptor, TP.
• ADP 2
By the action on its two cell surface receptors, P2Y1 and P2Y12.
• Adrenaline
Activates its receptor (α 2) on the platelet surface. Adrenaline will also activate an inhibitory β 2 receptor on platelets, but this effect is normally masked by its predominant effect on α 2.
• Serotonin
Activates its receptor (5HT-2c) on the platelet surface.
• Human neutrophil elastase (HNE)
Cleaves the αIIbβ3 integrin on the platelet surface;
• P-selectin
Binds to PSGL-1 on endothelial cells and white blood cells and which is normally exposed on the surface of platelets following initial activation by other activators.

Platelet Inhibitors.
• Prostacyclin
Opposes the actions of most platelet agonists by increasing intracellular cAMP levels
• Adenosine
By the action on its cell surface receptor (A2 receptor) by increasing intracellular cAMP levels.
• Nitric oxide
Released by the endothelium and platelets themselves in some instances.
• Clotting factors II, IX, X, XI, XII
• Nucleotidases such as CD39 ecto-ADP’ase break down ADP
• Some drugs
o Aspirin irreversibly inhibits cyclooxygenase-1, preventing positive feedback3
o Clopidogrel inhibits ADP receptors
o Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis
o Abciximab blocks fibrinogen receptors
o β-lactam antibiotics alteration of agonist receptors
o Quinidine calcium channel blocker

Diseases & conditions associated with abnormal platelet counts.
A normal platelet count in a healthy person is between 150,000 and 400,000 per mm³ of blood (150–400 x 109/L).4 95% of healthy people have platelet counts in this range. Some will have statistically abnormal platelet counts while having no abnormality, although the likelihood increases if the platelet count is either very low or very high.
Both thrombocytopenia (thrombopenia) and thrombocytosis may present with coagulation problems. Generally, low platelet counts increase bleeding risks, although there are exceptions, (e.g. immune heparin-induced thrombocytopenia) and thrombocytosis (high platelet counts). Thrombocytosis may lead to thrombosis when the elevated count is due to myeloproliferative disorder.
Low platelet counts are generally not corrected by transfusion unless the patient is bleeding or the count has fallen below 5 x 109/L; it is contraindicated in thrombotic thrombocopenic purpura (TTP) as it fuels the coagulopathy. In patients having surgery, a level below 50 x 109/L is associated with abnormal surgical bleeding, and regional anaesthetic procedures such as epidurals are avoided for levels below 80-100.
Normal platelet counts are not a guarantee of adequate function. In some states the platelets, while being adequate in number, are dysfunctional. For instance, aspirin irreversibly disrupts platelet function by inhibiting cyclooxygenase-1 (COX1), and hence normal hemostasis; normal platelet function may not return until the aspirin has ceased and all the affected platelets have been replaced by new ones, which can take over a week. Similarly uremia; a consequence of renal failure leads to platelet dysfunction that may be ameliorated by the administration of desmopressin.

Diseases & conditions associated with reduced platelet activity.
 Disorders leading to a reduced platelet count:
• Thrombocytopenia
o Idiopathic thrombocytopenic purpura (immune thrombocytopenic purpura (ITP))5
o Thrombotic thrombocytopenic purpura6
o Drug-induced thrombocytopenia7,2, e.g. heparin-induced thrombocytopenia (HIT)
• Gaucher’s disease
• Aplastic anemia
 Alloimmune disorders:
• Fetomaternal alloimmune thrombocytopenia
• Some transfusion reactions.
 Disorders leading to platelet dysfunction or reduced count:
• HELLP syndrome
• Hemolytic-uremic syndrome
• Chemotherapy
• Dengue
 Disorders of platelet adhesion or aggregation:
• Bernard-Soulier syndrome
• Glanzmann’s thrombasthenia
• Scott’s syndrome
• von Willebrand disease
• Hermansky-Pudlak Syndrome
 Disorders of platelet metabolism:
• Decreased cyclooxygenase activity, induced or congenital
• Storage pool defects, acquired or congenital
 Disorders that compromise platelet function:
• Haemophilia
 Disorders featuring an elevated count:
• Thrombocytosis, including benign essential thrombocytosis (elevated counts, either reactive or as an expression of myeloproliferative disease); may feature dysfunctional platelets

Thrombocytopenia.
The presence of a lower blood platelet count than the normal is called thrombocytopenia. This can be due to various causes; due to decreased production, increased destruction, or may be induced by medication.
 Decreased production in:
• vitamin B12 or folic acid deficiency
• leukemia or myelodysplastic syndrome
• Decreased production of thrombopoietin by the liver in liver failure.
• Sepsis, systemic viral or bacterial infection
• Dengue fever can cause thrombocytopenia by direct infection of bone marrow megakaryocytes as well as immunological shortened platelet survival
• Hereditary syndromes
o Thrombocytopenia absent radius syndrome
o Fanconi anemia
o Bernard-Soulier syndrome, associated with large platelets
o May-Hegglin anomaly, the combination of thrombocytopenia, pale-blue leuckocyte inclusions, and giant platelets
o Grey platelet syndrome
o Alport syndrome
 Increased destruction in:
• idiopathic thrombocytopenic purpura (ITP)
• thrombotic thrombocytopenic purpura (TTP)
• hemolytic-uremic syndrome (HUS)
• disseminated intravascular coagulation (DIC)
• paroxysmal nocturnal hemoglobinuria (PNH)
• antiphospholipid syndrome
• systemic lupus erythematosus (SLE)
• post transfusion purpura
• neonatal alloimmune thrombocytopenia (NAITP)
• Splenic sequestration of platelets due to hypersplenism
• Dengue fever has been shown to cause shortened platelet survival and immunological platelet destruction
 Induction by medication in:
• Direct myelosuppression due to:
o Valproic acid
o Methotrexate
o Carboplatin
o Interferon
o Other chemotherapy drugs
• Immunological platelet destruction due to:
o quinidine
o Heparin
Often, low platelet levels do not lead to clinical problems; rather, they are picked up on a routine full blood count. Occasionally, there may be bruising, particularly purpura in the forearms, nosebleeds and/or bleeding gums.
It is vital that a full medical history is elicited, to ensure the low platelet count is not due to a secondary process. It is also important to ensure that the other blood cell types red blood cells, and white blood cells, are not also suppressed.
For the diagnosis of the disease, following laboratory tests are carried out;
 full blood count
 liver enzymes
 renal function
 vitamin B12 level
 folic acid level
 erythrocyte sedimentation rate
 peripheral blood smear.
If the cause for the low platelet count remains unclear, bone marrow biopsy is often undertaken, to differentiate whether the low platelet count is due to decreased production or peripheral destruction.
The main concept in treating thrombocytopenia is to eliminate the underlying problem; discontinuing suspected drugs that cause thrombocytopenia, or treating underlying sepsis.

Gaucher’s Disease.
Gaucher’s disease is the most common of the lipid storage diseases. It is named after the French doctor who originally described it in 1882. It is caused by a deficiency of the enzyme glucocerebrosidase, leading to an accumulation of its substrate, the fatty substance glucocerebroside.
The disease is caused by a defect in the housekeeping gene lysosomal gluco-cerebrosidase (β-glucosidase) on the first chromosome (1q21).2,8 The enzyme catalyses the breakdown of glucocerebroside, a cell membrane constituent of red and white blood cells. The macrophages that clear these cells are unable to eliminate the waste product, which accumulates in fibrils, and turn into Gaucher cells.
Different mutations in the β-glucosidase determine the remaining activity of the enzyme, and, to a large extent, the phenotype.
In the brain, glucocerebroside accumulates due to the turnover of complex lipids during brain development and the formation of the myelin sheath of nerves.
Fatty material can collect in the spleen, liver, kidneys, lungs, brain and bone marrow. Symptoms include enlarged spleen and liver, liver malfunction, skeletal disorders and bone lesions that may cause pain, severe neurologic complications, swelling of lymph nodes and occasionally adjacent joints, distended abdomen, a brownish tint to the skin, anemia, low blood platelets and yellow fatty deposits on the sclera. Persons affected most seriously may also be more susceptible to infection. The disease affects males and females equally. It is the most common lysosomal storage disease.
Gaucher disease has three common clinical subtypes;
Type I ( nonneuropathic type) is the most common form of the disease (more than 99% of cases). It occurs most often among persons of Ashkenazi Jewish heritage. Symptoms may begin early in life or in adulthood and include enlarged liver and grossly enlarged spleen, which can rupture and cause additional complications. Skeletal weakness and bone disease may be extensive. Spleen enlargement and bone marrow replacement cause anemia and leukopenia. The brain is not affected, but there may be lung and, rarely, kidney impairment. Patients in this group usually bruise easily and experience fatigue due to low blood platelets. Depending on disease onset and severity, type 1 patients may live well into adulthood. Many patients have a mild form of the disease or may not show any symptoms.
Type II ( acute infantile neuropathic Gaucher disease) typically begins within 6 months of birth. Symptoms include an enlarged liver and spleen, extensive and progressive brain damage, eye movement disorders, spasticity, seizures, limb rigidity, and a poor ability to suck and swallow. Affected children usually die by age 2.
Type III (the chronic neuronopathic form) can begin at any time in childhood or even in adulthood. It is characterized by slowly progressive but milder neurologic symptoms compared to the acute or type 2 version. Major symptoms include an enlarged spleen and/or liver, seizures, poor coordination, skeletal irregularities, eye movement disorders, blood disorders including anemia and respiratory problems. Patients often live into their early teen years and adulthood.
All three types of Gaucher’s disease are inherited in an autosomal recessive fashion. Both parents must be carriers in order for a child to be affected. If both parents are carriers, there is a one in four, or 25%, chance with each pregnancy for an affected child. Genetic counseling and genetic testing is recommended for families who may be carriers of mutations.
Biochemical abnormalities such as the high alkaline phosphatase, angiotensin-converting enzyme (ACE) and immunoglobulin levels.
The diagnosis is made with genetic testing of the β-glucosidase gene. As there are numerous different mutations, sequencing of the gene is sometimes necessary to confirm the diagnosis. Prenatal diagnosis is available, and is useful when there is a known genetic risk factor.9
For type 1 and most type 3 patients, enzyme replacement treatment with mannose-terminated recombinant glucocerebrosidase, 60 Units/kg, given intravenously every two weeks can dramatically decrease liver and spleen size, reduce skeletal abnormalities, and reverse other manifestations.9 This treatment is becoming the standard in treating Gaucher’s. Successful bone marrow transplantation cures the non-neurological manifestations of the disease, because it introduces a monocyte population with active β-glucosidase. However, this procedure carries significant risk and is rarely performed in Gaucher patients. Surgery to remove the spleen (splenectomy) may be required on rare occasions if the patient is anemic or when the enlarged organ affects the patient’s comfort.9 Blood transfusion may benefit some anemic patients. Other patients may require joint replacement surgery to improve mobility and quality of life. Other treatment options include antibiotics for infections, antiepileptics for seizures and liver transplants. Substrate reduction therapy may prove to be effective in stopping Type 2, as it can cross through the blood barrier into the brain. There is currently no effective treatment for the severe brain damage that may occur in patients with types 2 and 3 Gaucher disease.

Aplastic anaemia.
In this condition bone marrow does not produce sufficient new cells to replenish blood cells.Here, the bone marrow suffers from an aplasia & is unable to function properly. Anemia is the condition of having fewer red blood cells than normal, or fewer than needed to function properly. Typically, anemia refers to low red blood cell counts, but aplastic anemia patients have lower counts of all three blood cell types; red blood cells, white blood cells, and platelets.
One known cause for aplastic anaemia is an autoimmune disorder, where the white blood cells attack the bone marrow.
Aplastic anemia is also associated with exposure to substances such as benzene, radiation, and rarely due to the use of certain drugs, including chloramphenicol, carbamazepine, phenytoin, quinine, and phenylbutazone. Also it is present in up to 2% of patients with acute viral hepatitis
Signs & symptoms of the disease are;
• Anemia with malaise, pallor and associated symptoms
• Thrombocytopenia leading to increased risk of hemorrhage and bruising
• Leukopenia (low white blood cell count), leading to increased risk of infection
The diagnosis can only be made on bone marrow examination. Before this procedure is undertaken, a patient will generally have had other blood tests to find diagnostic clues, including a full blood count, renal function and electrolytes, liver enzymes, thyroid function tests, vitamin B12 and folic acid levels.
Treating aplastic anemia involves suppression of the immune system, an effect achieved by daily medicine intake, or, in more severe cases, a bone marrow transplant, a potential cure but a risky procedure. The transplanted bone marrow replaces the failing bone marrow cells with new ones from a matching donor. The pluripotent stem cells in the bone marrow reconstitute all three blood cell lines, giving the patient a new immune system, red blood cells, and platelets. However, besides the risk of graft failure, there is also a risk that the newly created white blood cells may attack the rest of the body.
Medical therapy of aplastic anemia often includes a short course of anti-thymocyte globulin (ATG or anti-lymphocyte globulin) and several months of treatment with cyclosporin to modulate the immune system. Mild chemotherapy with agents such as cyclophosphamide and vincristine may also be effective. Antibodies therapy, such as ATG, targets T-cells, which are believed to attack the bone marrow. Steroids are generally ineffective.

Foetomaternal alloimmune thrombocytopenia.
In fetomaternal alloimmune thrombocytopenia (Neonatal Alloimmune Thrombocytopenia or NAIT) maternal IgG antibodies (specific for platelet antigens) pass through the placenta and attack platelets in the fetal circulation. This results in the fetus having low numbers of platelets and a tendency for the fetus or neonate to bruise and bleed. Medical treatment is problematic.

HELLP Syndrome.
Hemolytic anemia, Elevated Liver enzymes and Low Platelet count are the main findings of HELLP syndrome, which are also been abbreviated in its name. It is a life-threatening obstetric complication which occurs during the latter stages of pregnancy, or sometimes after childbirth. Its incidence is reported as 0.2-0.6% of all pregnancies. Mortality is 7-35% and perinatal mortality of the child may be up to 40%.10 HELLP usually begins during the third trimester, and usually in Caucasian women over the age of 25. Rarely, cases have been reported as early as 23 weeks gestation. It was identified as a distinct clinical entity by Dr Louis Weinstein in 1982.
The exact cause of HELLP is unknown, but general activation of the coagulation cascade is considered the main underlying problem. Fibrin forms crosslinked networks in the small blood vessels. This leads to a microangiopathic hemolytic anemia: the mesh causes destruction of red blood cells. Additionally, platelets are consumed. As the liver appears to be the main site of this process, downstream liver cells suffer ischemia, leading to periportal necrosis. Other organs can be similarly affected. HELLP syndrome leads to a variant form of disseminated intravascular coagulation (DIC), leading to paradoxical bleeding, which can make emergency surgery a serious challenge.
Often, a patient who develops HELLP syndrome has already been followed up for gestational hypertension, or is suspected to develop high blood pressure and proteinuria. Up to 8% of all cases present after delivery.
There is gradual but marked onset of headaches (30%), blurred vision, malaise (90%), nausea/vomiting (30%), “band pain” around the upper abdomen (65%) and tingling in the extremities. Oedema may occur. Arterial hypertension is a diagnostic requirement, but may be mild. Rupture of the liver capsule and a resultant hematoma may occur. If the patient gets a seizure or coma, the condition has progressed into full-blown eclampsia.11
Patients who present symptoms of HELLP can be misdiagnosed in the early stages, increasing the risk of liver failure and morbidity. Rarely post caesarean patient may present in shock condition mimicking either pulmonary embolism or reactionary haemorrhage.

HELLP syndrome has been classified into three classes;
Class I
The platelet count has been found to be moderately predictive of severity: under 50 m illion/L. This is the most severe condition.
class II
Platelet count is between 50 and 100. This condition is moderately severe.
class III
Platelet count is higher than100. The severity is mild.
To diagnose the disease, a group of blood tests is performed; a full blood count, liver enzymes, renal function and electrolytes and coagulation studies. Often, fibrin degradation products (FDPs) are determined, which can be elevated. Lactate dehydrogenase is a marker of hemolysis and is elevated more than 600 U/liter. Proteinuria is present, but can be mild.11
The only effective treatment is delivery of the baby. The DIC is treated with fresh frozen plasma to replenish the coagulation proteins, and the anemia may require blood transfusion. In mild cases, corticosteroids and antihypertensives such as labetalol, hydralazine & nifedipine may be sufficient. Intravenous fluids are generally required.

Dengue Fever.
Dengue fever and dengue hemorrhagic fever (DHF) are acute febrile diseases, found in the tropics.They are caused by one of four closely related virus serotypes of the genus Flavivirus, family Flaviviridae, each serotype is sufficiently different that there is no cross-protection and epidemics caused by multiple serotypes can occur. Dengue is transmitted to humans by the Aedes aegypti & rarely by the Aedes albopictus mosquitoes.12 This mosquitoes tends to bite just after dawn and just before sunset .
The signs & symptoms of the disease includes a sudden onset of fever, severe headache, muscle and joint pains and rashes. The dengue rash is characteristically bright red patch and usually appears first on the lower limbs and the chest. There may also be gastritis with some combination of associated abdominal pain, nausea, vomiting or diarrhea.
Patients with dengue can only pass on the infection through mosquitoes or blood products while they are still febrile.
The classic dengue fever lasts about six to seven days. Clinically, the platelet count will drop until the patient’s temperature is normal. Cases of DHF also show higher fever, haemorrhagic phenomena, thrombocytopenia and haemoconcentration. A small proportion of cases lead to dengue shock syndrome (DSS) which has a high mortality rate. Weak rapid pulse & narrow pulse pressure less than 20 mm Hg are the features of DSS.
The mainstay of treatment is supportive therapy. The patient is encouraged to keep up oral intake, especially of oral fluids. If the patient is unable to maintain oral intake, supplementation with intravenous fluids may be necessary to prevent dehydration and significant hemoconcentration. A platelet transfusion is rarely indicated if the platelet level drops significantly or if there is significant bleeding. But the transfusion is recommendable on platelet count falling below 20,000 without hemorrhage / bleeding or approx 50,000 with hemorrhage/bleeding.12
It is very important to avoid Aspirin and non-steroidal anti-inflammatory medications. Because in this case, they may actually aggravate the bleeding tendency associated with some of these infections.

Von Willebrand disease.
Von Willebrand disease (vWD) is the most common hereditary coagulation abnormality described in humans, although it can also be acquired as a result of other medical conditions.13 It arises from a qualitative or quantitative deficiency of von Willebrand factor (vWF), a multimeric protein that is required for platelet adhesion. There are three types of hereditary vWD, but other factors such as ABO blood group may also play a part in the cause of the condition.13
The various types of vWD present with varying degrees of bleeding tendency. Severe internal or joint bleeding is rare, bruising, nosebleeds, heavy menstrual periods in women and blood loss during childbirth (rare) may occur. Death may also occur.
When suspected, blood plasma of a patient needs to be investigated for quantitative and qualitative deficiencies of vWF.14 Other tests performed in any patient with bleeding problems are a full blood count (especially platelet counts), APTT (activated partial thromboplastin time), prothrombin time, thrombin time and fibrinogen level.14 Testing for factor IX may also be performed if hemophilia B is suspected. Other coagulation factor assays may be performed depending on the results of a coagulation screen.14
Patients with vWD normally require no regular treatment. Prophylactic treatment is sometimes given for patients with vWD who are scheduled for surgery. They can be treated with human derived medium purity factor VIII concentrates complexed to vWF.15Mild cases of vWD can be trialled on desmopressin which works by raising the patient’s own plasma levels of vWF by inducing release of vWF stored in the Weibel-Palade bodies in the endothelial cells.

References.
1 Paula L. Bockenstedt & Alvin H. Scamaier, Platelet Function Disorders, Alvin H. Scamaier, Haematology For Medical Students.
2 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=40336
3 http://www.pnas.org/cgi/content/abstract/251543298v1
4 William F. Ganong, Review of Medical Physiology, 22nd ed, Lange Medical Publications: 1989.p.531
5 Bussel J, Kuter D, George J, McMillan R, Aledort L, Conklin G, Lichtin A, Lyons R, Nieva J, Wasser J, Wiznitzer I, Kelly R, Chen C, Nichol J (2006). “AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP”. N Engl J Med 355 (16): 1672- 81.
6 Tsai H (2003). “Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura”. J Am Soc Nephrol 14 (4): 1072-81.
7 Howard C, Adams L, Admire J, Chu M, Alred G (1997). “Vancomycin-induced thrombocytopenia: a challenge and rechallenge”. Ann Pharmacother 31 (3): 315-8.
8 Aharon-Peretz J, Rosenbaum H, Gershoni-Baruch R. Mutations in the Glucocerebrosidase Gene and Parkinson’s Disease in Ashkenazi Jews. N Engl J Med 2004;351:1972-1977.
9 Barranger JA, Rice EO. Gaucher disease: diagnosis, monitoring and management. Gaucher Clin Persp 1997;5:1-6.
10 Weinstein L. Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy. Am J Obstet Gynecol 1982;142:159-67.
11 Padden MO. “HELLP Syndrome: Recognition and Perinatal Management.” Am Fam Physician. 1999 Sep 1;60(3):829-36, 839.
12 Gubler D (1998). “Dengue and dengue hemorrhagic fever”. Clin Microbiol Rev 11 (3): 480-96.
13 Sadler, J. E. “Biochemistry and Genetics of von Willebrand factor.” Annu Rev Biochem 1998; 67:395-424.
14 Laffan m. Brown S. etal. The diagnosis of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors Organisation. Haemophilia; 2004, 10, 199-217
15 Mannucci PM. Treatment of von Willebrands disease. N Engl J Med 2004;351:683- 94.

MD/2006/3453

Botulinum Toxin

Botulinum toxin is a potent toxin. It is derived from botulinum clostridium botulinum.It is a poisonous biological substance and it acts as a neurotoxin. It binds to the nerve endings at the point, the nerve joins a muscle. It blocks the realizing of the principle neurotransmitter. It is called acetylcholine. Acetylcholine at the neuromuscular junction prevent the muscle from antracting.Tise course to weakness and paralysis of the muscle. This blackase of releasing acetylcholine is irreversible. Sprouting of nerve terminals and the formation of new synaptic ontracts, the function can be recorrecd.It takes 2 to 3 months.

There are many types of Botulinum toxin. They are named as type A, B, C, D, E, F and G different strand for bacteria produce them and defined by the international strands for clostridium botulinum.The seven types of designated A to G distinct neurotoxins have a similar molecular weight and structure consisting of a heavy chain and light chain, joined by disulfide bond. All the types act in a similar manner. The toxin is heat labile. If it is heated at 800 C for about 10 minutes or more it can be destroyed. (1).

Very small amounts of botulinum toxin can be caused botulism. There are two ways of it By ingesting the toxin itself (food borne botulism) as in produce and release the toxin in the body (infectious botulism).The infection may occur in the intensive (intestinal botulism) as in newborn, or deep within a wound (wound botulism) only the Types A, B, E and F are known to cause botulism in human all the types.
As first line therapy Botulinum toxin is used for some muscular disorders. It is efficacious in treating hypersecretory and some point syndromes. It has a god safety profile. A number of conditions have been evaluated in treating. There is no obvious effective or benhicial treat mint yet. The use of Botulinum toxin will be increased with the grater acceptance. For the physicians the understanding of pharmacology and potential adverse effects are essential. When prevents having or who are benefited from Botulinum from Botulinum therapy.(2)

Clostridium Botulinum

A group of bacteria commonly found in soil is named as clostridium Botulinum. It is strictly anaerobic gram negative rod shaped bacillus. It is motile with meretricious flagella and has spores. They are oval and sub terminal until they are exposed to conditions that can be supported to their growth, spores’ abow them to survive in dormant state. The exposed conditions can be found in vegetables, fruits, leaves, silage, and manure, the mud in the lakes and the mud in the sea. The optimum growth temperature is about 350c but at 1- 50 c temperature some strains have been shown to grow and produce toxin.

The nature of clostridium Botulinum is its ability to produce a potent neuron toxin in food. The resistance of its spores to inactivation combine to male a formidable pathogen of humans and a range of animals and birds. When boiling in water for several hours the spores of some stains with stand. When they are heated up to 1200 c for 5 minutes they are destroyed. Spore of type E strains are much less heat resistance. In the causation of botulism insufficient heating in the presence of preserving food is an important factor and great care must be taken in canning factories to ensure that adequate heating is achieved in all part of the can. in the food processing the resistance of the spores to radiation is a special relevance.(3)

(1)The structure of Botulinum Toxin and Mechanism of Toxic Action;

All outline toxins are synthesized as single-chain polypeptides with a molecular weight of
Approximately 150KDa.The complete amino acid sequences for the various serotypes are known and region of sequence homology among the serotypes suggest that all employ similar mechanism of biological action..In the single- chain form, toxins have relatively little potency as neurotoxins. Neurotoxic activation requires a tow-step modification in the tertiary structure of the protein.In the first step ,the parent chain is cleaved between amino acids 448 and 449.The result is one light chain(amino acids 1-448,approx 100KDa) and one heavy chain ( amino acid 449-1295, approx.100KDa) connected via disulfide bond. The light chain is associated with one atom of zinc..In this form, the toxin enters the axon terminal. The second activating step, disulfide reduction, occurs only after internalization by the target cell.

Botulinum neurotoxins are potent blockers of synaptic transmission in peripheral cholinergic nervous system synapses; thereby causing paralysis .Resent studies on the biochemical dissection of the components involved in the fusion of secretary vesicles with the plasma membrane have set outline toxins at center of this process. Outline toxins are Zn+2-metalloproteases that selectively cleave proteins implicated in fusion process and accordingly, block neurotransmitter release Into the synaptic cleft .Outline toxin A, E and C proteolyses the plasma membrane associated proteins SNAP-25 and outline toxin C cleave still syntax in .Outline toxins B, D, F, and G proteolyses synaptobrevin, a vesicle-associated membrane protein, also known as VAMP. The protease activity of the toxins is confined ton there light chains .Botulinum toxins have an inherent propensity to insert into membranes, especially at acidic PH. This property is compatible with ion channel activity observed. When outline toxins B, C, D, and E are reconstituted in lipid bilayers A novel combination of theoretical approaches was exploited to predict which amino acid residues of various botulinum neurotoxin serotypes participate in forming ion channels Image reconstruction analysis of electron micrographs of outline toxin inserted in membrane suggests the occurrence of a tetramer as the structural entity underling the outline toxin channel (4)

Preparation of botulinum toxin

Botulinum toxin is harvested from a culture medium after fermentation of producing strain of a botulinum c toxin. It is extracted, precipitated, purified and finally crystallized with ammonium sulfate. Toxin A should be diluted with preservation free saline. It should be diluted with preservative free saline. It should be prepared with in four hours of its reconstitution. The solution should be include pH 4.2-6.8 for stamility. Its temperature should be less than 20c .This solution can be inactivated easily.

Scientific background-botulinum toxin

Botulinum toxin is a potent neurotoxin that block cholinergic nerve terminals, symptoms of botulism include cessation of sweating. Therefore, intracutaneous injections have been investigation as a treatment of gustatory hyperhidrosis and focal primary hyperhidrosis, most frequently involving the axillae or palms. Askew and colleagues reported on the outcomes of 19 patients with gustatory hyperhidrosis treated with botulinum toxin injected with every 4 cm 2 of involved skin. (20In all cases, gustatory sweating ceased within two days, with a mean duration of effect of 17 months. There is a considerable body of published literature regarding outline toxin injecting for the treatment of auxiliary hyperhidrosis, all of which substantiates its effectiveness. Two of these were double-blind, randomized trials that de palmer hyperhhidrosis. The drawback of this approach is the need for repeated injections, which has led some to consider surgical approaches to treatment.(5)

Toxicity and Botulism

Very small amount of Botulism toxin can lead to botulism, a descending paralysis and often affecting the autonomic system. .Clinical features of Botulism;
Food born botulism is caused by ingestion of performed toxin produced in food by c botulism. The most frequent source in home-canned foods, in which spores that survive an inadequate cooking and canning process germinate and produce toxin in the anaerobic environment of the canned food. In the event of intentional food borne poisoning with botulism toxin, the signs and symptoms developing after ingestion would probably resemble those of naturally occurring food borne botulism. If aerosolized toxin was inhaled the incubation period might be slightly longer and gastrointestinal symptoms might not occur The clinical syndrome of food borne botulism is dominated by neurological symptoms resulting (cont.p.16-Botox) (Botox-fromp.15) from a toxin-induced block of the voluntary motor and autonomic cholinergic junctions. With food borne botulisum, symptoms begin within 6 hours to 2 weeks (most commonly between 12 and 36 hors ) after eating toxin-containing food. Although the syndrome is similar for each toxin type ,type A toxin has been associated with more severe disease and a higher fatality rate than type or type E toxin.Symptoms from any toxin type may range from subtle motor `weakness or cranial nerve palsies to rapid respiratory arrest. The initial symptoms of food borne botulism may be gastrointestinal and can include nausea ,vomiting ,abdominal cramps ,or diarrhea, after the onset of neurology symptoms, constipation is more typical. Dry mouth ,blurred vision, and diplopia are usually the earliest neurologic symptoms. These initial symptoms may be followed by dysphonia ,dysarthria, dysphagia, and peripheral muscle weakness symmetric decending paralysis is characteristic he of botulism paralysis begins with the cranial nerves ,the upper extremities in a proximal-to-distal pattern. Onset usually occurs 18 to 36 hours after exposure . In severe cases extensive respiratory muscle paralysis leads to ventilator failure and death unless supportive care is provided. Patients have required ventilator support for up to 7 months before the return of muscular function, but ventilator support is most commonly needed for 2 to 8 weeks. Clinical recovery generally occurs over weeks to months; electron microscopic evidence suggests that clinical recovery correlates with the formation of new presynaptic end plates and neuromuscular junctions (26). Before mechanical ventilation and intensive supportive care. Up to 60% of patient’s deed. Death now occurs in 5% to 10% of cases of food borne botulism ; early deaths result from a failure to recognize the severity of disease, whereas deaths after 2 weeks result from complications of long- term mechanical ventilator management .
The demonstration of the toxin in serum is definitive, but the test may be negative, particularly in infant or wound botulism. The demonstration of toxin or the organism in vomit, gastric fluid, or stool is strongly suggestive, because intestinal carriage is rare. Isolation of the organism from food without the toxin is insufficient for the diagnosis. Wound cultures showing the organism are suggestive. Cerebrospinal fluid examination is normal, unless dehydration or starvation are present. The electromyography may demonstrate a defect in neuromuscular transmission, and a typical finding is facilitation (potentiation) of the evoked muscle action potential at high frequency stimulation (6)

Food-born:botulism After the ingestion of contaminated food, the illness varies from mild, which needs no medical attention; to severe disease, which can result in death in less than 24 hours. The incubation period is usually 18 to 36 hours, but may range from a few hours to many days depending on the amount of toxin ingested. The shorter the incubation period, the more severe the clinical manifestations are. The onset of the symptoms is characterized by cranial nerve involvement, mainly in those innervating the bulbar musculature. This results in the appearance of diplopia, difficulty in close-range focusing, dysphonia, dysartria, and dysphagia. The weakness progresses rapidly to involve the neck, shoulder, thorax, abdomen, arms, and legs. Nausea, vomiting, and abdominal pain may appear before or after the onset of paralysis. The weakness is usually symmetric, but may be asymmetric as well. Autonomic involvement may cause dizziness, blurred vision, dry mouth, very dry and sore throat, ileus, and salivary retention. The tendon reflexes may be normal, but are usually diminished. The pupillary reflexes are depressed, and the pupils may be fixed and dilated. The patient is alert and conscious, and mentation is spared. The gag reflex is also diminished or abolished. Typically there is no fever, but the descending paralysis also attacks the respiratory muscles. This, along with bulbar paralysis and secondary infections, is the main cause of death together.(7)
Wound botulism : This form of botulism appears after a wound is contaminated by the spores of C. botulinum, which is found in soil. The spores then germinate into vegetative forms that produce toxin The period of incubation for this form of botulism is longer, ranging from 4 to 14 days, with a median average of 10 days. The clinical manifestations are identical to the food-borne, botulism with the exception of gastrointestinal symptoms. The illness occurs even after preventative antibiotics are administered.(8)
Infant : This usually differs in apparent initial symptoms of the illness, simply because infants cannot verbalize them. Almost invariably, the first indication of illness is constipation, defined as three or more days without defecation. Parents usually notice lethargy, listlessness, poor appetite, a weak cry, and diminished movements. Dysphagia may be seen as “drooling” from the mouth. Gag, suck, and corneal reflexes diminish as paralysis advances. Oculomotor palsies also occur. The pupillary reflex may be spared until the child is severely ill. Loss of head control is a prominent sign, and respiratory arrest may occur suddenly.(9)
Adult-infant: In this form of botulism the clinical manifestations are the same as mentioned above. The disease affects adults and children, who are older than 12 months old, by the C. botulinum colonization of the intestines. It is there that the disease-causing toxin is produced.
Diagnosis
botulism should be suspected in any mentally intact patient who has an afebrile, descending paralysis without sensory manifestations. In these cases analysis (searching for C. botulinum or it toxin ) of serum, stool, gastric contents or vomit, food, and wounds is necessary.(10)
Treatment
Any patient suspected of having botulism should be hospitalized and monitored closely-both clinically and by spirometry, pulse oximetry, and measurement of arterial blood gases to prevent respiratory failure. Intubation and mechanical ventilation should be considered when vital capacity falls below 30% of prediction-especially when paralysis is progressing rapidly and hypercarbia is present.
In food-borne illness, trivalent antitoxin should be administered as soon as possible after material for laboratory analysis is obtained. Since toxin may persist in the blood for extended periods, the antitoxin should be given irrespectively to the time of progression of the illness. One should not wait for laboratory confirmation before initiating treatment . After testing for horse serum hypersensitivity, two vials of trivalent antitoxin, containing 7500I of type A, 5500I of type B, and 8500I of type E should be administered; one intravenously, and another intramuscularly. This dose may be repeated 2 to 4 hours later. Hypersensitivity reactions may occur since the antitoxin is made of horse serum. Anaphylaxis and serum sickness are feared reactions, and allergic patients should be desensitized prior to the administration. If there is no ileus, cathartics and enemas should be given to eliminate toxin from the gut. Emetics and gastric lavage are also used if the ingestion of the contaminated food has been recent within a few hours. Other therapeutic considerations are the use of guanidine hydrochloride (15 to 50mg/kg daily), to enhance acetylcholine release, and antibiotics (penicillin), to eliminate the bacteria from the intestine.(11)

Botulinism toxin Use as.

Introduction :- The role of botulinum toxin as a therapeutic agent for several conditions is expanding. We sought to determine if botulinum toxin is safe and effective in treating patients with cervical dystonia and maxillofacial conditions. Our purpose was to establish a safety and efficacy profile to determine whether or not this treatment may be used prophylactically in patients undergoing dental implant therapy,
Methods- We performed a systematic search of the literature to identify randomized clinical trials evaluating patient treated with botulinum as an adjunct to dental implant
therapy, maxillofacial conditions including TM disorders (TMD) and cervical dystonia.

Results: – For randomized controlled trials (RCTS) met our search criteria in the area of cervical dystonia and chronic facial pain. No RCTS were identified evaluating dental implant therapy. Patient with chronic facial pain improved significantly from baseline in terms of pain compared to placebo. Rates of adverse events were less than 1% .

Conclusion; Botulinum toxin appears relatively safe and effective in treating cervical dystonia and ohronic facial pain associated with masticatory hyperactivity. No literature exists evaluating its use in dental implantology. Randomized clinical trials are warranted to determine its safety and efficacy in dental implantology and other maxilliaryfacial conditions such as bruxism
Migraine is a chronic headache disorder manifesting in attacks lasting 4-72 hours .Characteristics of headache are unilateral location pulsative quality, moderate , or severe intensity ,aggravation by routing physical activity ,and association with nausea ,photophobia and phonophobia. The migraine aura is a complex of neurological symptoms, which occurs just before or at the onset of migraine headache. Botulinum toxin A represents a completely new option for patients with chronic pain conditions. Numerous retrospective open-label chart reviews and 4 double-blind, placebo –controlled studies have demonstrated that botulinum toxin type A is significantly effective in migraine prophylaxis and reduces the frequency, severity, and disability associated with migraine headache. Studies have generally reported a good and consistent efficacy. The differential therapeutic use of botulinum toxin appears to be worth attempting in migraine patients with the following characteristic features.

1. muscular stress as migraine trigger. e.g. in craniocervical dystonia, pericranial painful muscular trigger points or tender points ,oromandibular dysfunctions.
2. concurrent chronic tension.- type headache with the aggravating factors of muscular stress or oromandibular dysfunction.
3. chronic migraine with frequent migraine attacks on more than 15 days per month for longer than three months and if other therapeutic options have been either ineffective of have not been tolerated. The use of agent does not cause CNS side effects. Migraine patients in particular , often suffer the drugs used , frown fatigue, dizziness, reduced
concentration , loss of appetite, weight gain, hairless and changes in libido. These sideeffects are not known in association with botulinum toxin A. To date neither organic damage nor allergic complications have been reported. Thus both the tolerability and the safety of this therapeutic measure are high. The mode of action by which outline toxin is effective in migraine prophylaxis is not fully understood and is order investigation .
Tension type Headaches;
Tension type headaches are described as a band-like pain that encompasses the frontal to occipital region. Associated with this type of headache ,there m ay be an associated cervical Myofacial pain syndrome (MPS).MPS is characterized by acute pain in one or more trigger point located within the affected muscles. The goal for treatment of these conditions is to provide relaxation to the affected muscles. Standard therapies have included non-steroidal anti-inflammatory drugs, corticosteroids, and antidepressants, injections of local anesthetic in combination with or without corticosteroids. Additional therapies have included dry needing and physical therapy.

Migraines; Recently botulinum toxin has come into vague as a treatment for facial wrinkles, it was discovered that people who suffered from migraines had a decrease in the frequency and severity of these types of headaches. Since then several authors have described the treatment of migraines with Botulinum toxin.
Botulinum toxin has demonstrated its efficacy in a number of conditions associated with dysregulated muscle contractions. In addition to the muscle relaxation, secondary effects include release of entrapped nerve and pain relief physiotherapy associated with this treatment will assist in breaking the cycle of pain and spasm. This combination of effects is designed to achieve neuromuscular re – education improving posture & restoring normal muscle and tendon movement.

(1)Tennis elbow (lateral epicondylitis) is a frequent cause of elbow pain. Repetitive use of arm, especially repeated extension of the wrist and elbow causes strain and inflammation of muscles and tendons. These movements are common in many activities besides tennis. Commonly used treatments include nonsteroidal anti-inflammatory drugs physical therapy corticosteroid injections and surgery. Researchers do not know if any of these therapies are really effective because tennis elbow eventually improves by itself. Botulinum toxin (Botox) is another potential treatment. Botulinum toxin is a protein produced by bacteria that blocks conduction of nerve impulses. It may reduce pain by blocking the nerve impulses that cause painful muscle spasms small studies suggest that botulinum toxin is an effective treatment for tennis elbow but studies are not definitive.
References
(1) Hackett R, kam Pc, Botulinum toxin: pharmacology and clinical developments, a literature review. Medic hem 3rd July 2007
(2) Animals of internal Medicine.
Established in 1927 by the .American collage of physicians
. Botulinum toxin as a treatment for Tennis Elbow.
6, Dec, 2005
(3) J Cutan Med Surg . 2005 Jan 6; {Epub ahead of print

(4) Nature, 2004 Dec 16, 432(7019), 925 – 9 Epub 2004 Dec 12
(5) Botulinum toxin in migrane prophylaxis Gobel H
Neurologists-Verhaltenseidizinische Scherzklini Kiel ,Heikendorfer Weg 9-27,
(6) Department of Epidemiology, Military Medical Academy, Hradec Kralove, Czech Republic.
The ASA Newsletter
www.asanltr.com/ newsletter/ 02-1/ articles/ Botulinum htm-371 cached

(7).ABUTYN, Elias. In: ISSELBACHER, Kurt; BRAUNWALD, Eugene et al. Harrison`s Principles of Internal Medicine. 13th ed. McGraw-Hill Inc, 1994.

(8).ADAMS, Raymond; VICTOR, Maurice & ROPPER, Allan H. Principles of Neurology. 6th ed. McGraw-Hill Inc, 1997.

(9).ARNON, Stephen S. botulism In: BEHRMAN, Richard E; KLIEGMAN, Robert M & ARVIN, Ann M. Nelson Textbook of Pediatrics. 15th ed. W.B. Saunders Co., 1996.

(10).BARTLETT, John G . In: BENNET, J Claude & PLUM, Fred. Cecil Textbook of Medicine. 20th ed. W.B. Saunders Co., 1996.

(11) Trakads Ramachandran, MD, chief Department of Neurology, university of Newyork
Medicine
From webMD

• RUM 2006/3377.

What is Emphysema?
Emphysema is characterized by destruction of gas exchanging airspaces, i.e. the respiratory bronchiol,alveolar ducts, and alveolai. Their walls become perforated and later obliterated with airspaces.1
Classifications
Emphysema is classified into distinct pathologic types, 1
1. Centriacinar emphysema.
2. Panacinar emphysema.
Centriacinar emphysema
The type most frequently associated with cigarette smoking is characterized by enlarged airspaces found (initially) in association with respiratory bronchioles. Centriacinar emphysema is most prominent in the upper lobe and superior segments of lower lobes and is often quite focal .1 ,2
Panacinar emphysema.
Panaicinar emphysema refers to abnormally large airspaces evenly distributed within and across acinar unites.Panacinar emphysema is usually observed in patients with Alpha-1-antitrypsin deficiency, with has a predilection for the lower lobes .1, 2

Pathogenesis of emphysema.
It is important to know pathogenesis in order to prevent, and having treatments.
The pathogenesis of emphysema can be dissected into three interrelated events,
1. Chronic exposure to cigarette smoke may lead to inflammatory cell recruitment within the lung,
2. Those inflammatory cells release electrolytic proteinases that damage the extracellular matrix of the lungs,
3. Ineffective repair of elastin and perhaps other extracellular matrix components results in pulmonary emphysema.2

Cigarette Smoking.
Cigarette smoking causes a number of changes to occur in the lung, many of which are still poorly understood. Among these are changes in the number and character of immune cells in the alveolar spaces and in the function and composition of pulmonary surfactant. The latter is becoming an increasingly significant issue given the abundance of recent findings that surfactant regulates immune cell function in the lungs.3
The most accepted theory for the pathogenesis of emphysema involves an imbalance between proteases and antiproteases.3
Historically, neutrophils and neutrophil proteaseshave been thought to play a major part in the development of this disease; however, evidence is emerging that macrophages also play an important role in the pathogenesis of smoking-related emphysema .4 Cells of the monocyte/macrophage lineage have the ability to secrete several members of the matrix metalloproteinase (MMP) family, including MMP-1 (collagenase 1), MMP-3 (stromelysin), MMP-7 (matrilysin), MMP-9 (gelatinase B), MMP-12 (macrophage metalloelastase), and MMP-14.5 It has been demonstrated that patients with emphysema and/or chronic obstructive pulmonary disorder (COPD) have elevated levels of MMP-9 and that alveolar macrophages were the major source of the MMP-9. 6, 7

Despite the fact that MMP-9 is also known as gelatinase B, it has been shown to have substantial elastolytic activity as well .Although most attention has been paid to the matrix degrading and remodeling functions of the MMPs, recent evidence suggests that they are also involved in the regulation of the inflammatory response and other biological processes.8,9
Surfactant protein A (SP-A) is a member of a family of C-type lections recently termed “collections” because of the presence of a caliginous domain. This molecule is the most abundant surfactant protein in the alveolar space and plays roles in the structure, metabolism, and function of surfactant. It is also an important regulator of local host defense mechanisms that make up the innate immune system .10
SP-A levels in the alveolar spaces are altered by a variety of factors and circumstances. 8 Among these are increased oxygen, ozone, and nitrogen dioxide .Often, these changes in SP-A levels are accompanied by changes in the levels of various surfactant lipids. SP-A modulates a number of immune cell functions, including cell proliferation, cytokine production, the expression of cell surface markers, and the generation of oxidative activity.11 SP-A may also participate in adaptive immune responses .The mechanism of action is still unclear, but it is possible that many of its functions may be mediated via cell surface receptors.9
Cigarette smoking accelerates the progression of emphysema in patients with AAT deficiency. Symptoms develop about 10 years earlier in AAT-deficient individuals who smoke regularly.

Nrf2-deficient mice are highly susceptible to cigarette smoke-induced emphysema.
Inflammation, protease/anti-protease imbalance and oxidative stress play important roles in the pathogenesis of emphysema.12 Nrf2 counteracts oxidative tissue damage and inflammation through transcriptional activation via the anti-oxidant responsive element (ARE).
To clarify the protective role of Nrf2 in the development of emphysema, the susceptibility of Nrf2-knockout mice to cigarette smoke induced emphysema was examined. In Nrf2-knockout mice, emphysema was first observed at 8 weeks and exacerbated by 16 weeks following Cigarette Smoke-exposure, whereas no pathological abnormalities were observed in wild-type mice. Neutrophilic lung inflammation and permeability lung damage were significantly enhanced in Nrf2-knockout mice 8 weeks after Cigarette Smoking exposure.12
Importantly, neutrophil elastase activity in bronchoalveolar lavage fluids was markedly higher in Nrf2-knockout mice preceding the pronounced neutrophil accumulation.12 The expression of secretory leukoprotease inhibitor, a potent inhibitor of neutrophil elastase, was inducible in wild-type, but not in Nrf2-knockout mice.
This protease/anti-protease imbalance, together with the lack of inducible expression of ARE-regulated anti-oxidant/anti-inflammatory genes, may explain the predisposition of Nrf2-knockout mice to neutrophilic inflammation. Indeed, specific activators of Nrf2 induced the expression of the SLPI gene in macrophages. These results indicate that Nrf2 protects against the development of emphysema by regulating not only the oxidant/ anti-oxidant balance, but also inflammation and the protease/anti-protease balance.12

Lung histology and quantification of emphysema
The trachea and lung of terminally anesthetized mice were removed and inflated with 4% paraformaldehyde in PBS to a pressure of 25 cm H2O. The tissues were then embedded in paraffin was stained with hematoxylin and eosin. Air space enlargement was quantified by the mean linear intercept in 20 randomly selected fields of tissue sections. The density of the alveolar surface area per unit volume of lung parenchyma was also calculated as previously described.10, 12
Bronchoalveolar lavage (BAL)
The lungs of terminally anesthetized mice were lavaged with six sequential 1 mL aliquots of PBS. The supernatant of the first BAL was used for determining the albumin concentration.The NE activity of the supernatant was measured by spectrophotometry at 405 nm using the synthetic substrate N-methoxysuccinyl-Ala-Ala- Pro-Val-paranitroanilide .13The remaining pool of BAL was centrifuged and resuspended in PBS. Cells were counted using a hemocytometer and a differential cell count was performed by standard light microscopy based on staining.12
Lung mechanics
Terminally anesthetized mice were tracheostomized and the trachea was cannulated. After opening the chest wall, the cannula was connected to a computer-controlled small animal ventilator.14 The compliance was determined by recording the relaxation pressures during inflation and deflation in 0.1 mL steps between 0 and 25 cm H2O.11 Due to variation in the weight of each animal, the lung volumes were normalized by body weight. Pressures from the normalized compliance curves were then extrapolated at 0.1 mL increments and used to establish the mean static lung compliance in each group.8,11

Measurement of alpha-1 anti-trypsin activity
The activity of alpha-1 anti-trypsin was calculated by determining the trypsin inhibitory capacity against bovine trypsin in the serum as previously described.15

Discussion
In the present study, mice lacking Nrf2 developed overt emphysema within 16 weeks of Cigarette Smoke exposure, while wild-type Balb/c mice were resistant to Cigarette Smoke-induced emphysema. During the development of emphysema, NE activity in the BAL was significantly higher in Nrf2–/– mice. Furthermore, neutrophil accumulation in the BAL was increased, at least partly because of the decreased clearance of neutrophils. These results indicate that Nrf2 protects against the development of emphysema by regulating not only the oxidant/anti-oxidant balance, but also inflammation and the protease/anti-protease balance.12

What is alpha-1 antitrypsin deficiency emphysema?
Alpha-1 related emphysema is caused by an inherited lack of a protective protein called alpha-1 antitrypsin (AAT) that is produced by the liver.

In normal and healthy individuals, AAT protects the lungs from natural enzymes such as neutrophil elastase. Neutrophil elastase is an enzyme that normally serves a useful purpose in lung tissue , it digests damaged or aging cells and bacteria in order to provide for healing. However, once it is done digesting those proteins, it does not stop, and attacks the lung tissue. Alpha-1-antitrypsin, in sufficient amounts, will trap and destroy the neutrophil elastase before it has a chance to begin damaging the delicate lung tissue. Without enough AAT, the lung tissue continues to be destroyed.15
If allowed to progress, this form of emphysema becomes chronic and eventually fatal. Symptoms of alpha1-antitrypsin (AAT) deficiency emphysema are limited to the respiratory system.
The initial symptoms of AAT deficiency include cough, sputum production, and wheezing. Symptoms are initially intermittent, and, if wheezing is the predominant symptom, patients often are told they have asthma. If recurrent episodes of cough are most prominent, patients may be treated with multiple courses of antibiotics and evaluated for sinusitis, postnasal drip, or gastroesophageal reflux.Dyspnea is the symptom that eventually dominates AAT deficiency.
Similar to other forms of emphysema, the dyspnea of AAT deficiency is initially evident only with strenuous exertion. Over several years, it eventually limits even mild activities.
Patients with AAT deficiency frequently develop dyspnea 20-30 years earlier (at age 30-45 y) than do smokers with emphysema and normal AAT levels.17
Cigarette smoking accelerates the progression of emphysema in patients with AAT deficiency. Symptoms develop about 10 years earlier in AAT-deficient individuals who smoke regularly.
By the time dyspnea becomes the dominant manifestation and a diagnosis is established, most patients will have seen several physicians over several years. Efforts to improve the interval between the onset of symptoms and the diagnosis of AAT deficiency have been disappointing. Between 1968 and 2003 a significant improvement has not been noted in the average interval (approximately 8 y), although improvement has been shown in the AAT deficiency detection in older individuals.11

Physical:
No single physical sign confirms a diagnosis of AAT deficiency emphysema. Signs characteristic of increased respiratory work, airflow obstruction, and hyperinflation eventually develop but are dependent on the severity of emphysema at the time of diagnosis.
Increased respiratory work is evident as tachypnea, scalene and intercostal muscle retraction, and tripod position.
Airflow obstruction manifests as pursed-lip breathing, wheezing, and pulsus paradox.
Hyperinflation results in barrel chest, increased percussion note, decreased breath sound intensity, and distant heart sounds.
Patients with mild emphysema generally have no abnormal findings on physical examination.
Even moderate disease may be evident only when a complicating acute infection occurs.
Most of the signs generally considered a part of emphysema (from any cause) are signs of moderate-to-severe disease.
Mild-to-moderate disease is easily missed if the physician relies solely on physical findings.

Causes:
AAT deficiency is an uncommon medical problem. The responsible genetic defect affects 1 in 3000-5000 individuals, making it 1 of the 3 most common lethal genetic diseases among whites. (The other 2 common fatal genetic defects are cystic fibrosis and Down syndrome.) Fortunately, not every individual with AAT deficiency develops clinically significant disease. 2,3
The major biochemical activity of the AAT molecule is inhibition of several neutrophil-derived proteases (e.g., trypsin, elastase, proteinase 3, cathepsin G). Therefore, the protein is more accurately termed alpha1-antiprotease. However, most physicians, and virtually all patients, refer to the disease as AAT deficiency, and doctors and patients often refer to those who are affected as “alphas.”12
Hepatocytes synthesize alpha1-antiprotease. After its release from the liver, alpha1-antiprotease circulates unbound and diffuses into interstitial and alveolar lining fluids. Its principle function in the lung is to inactivate neutrophil elastase, an enzyme that is released during normal phagocytosis of organisms or particulates in the alveolus.
Alpha1-antiprotease constitutes about 95% of all the antiprotease activity in human alveoli, and neutrophil elastase is considered the protease largely responsible for alveolar destruction.
In healthy persons, alpha1-antiprotease serves as a protective screen that prevents alveolar wall destruction. Individuals with the AAT genetic defect do not release alpha1-antiprotease from the liver, and serum and alveolar levels of the protein are low. Consequently, alveoli lack antiprotease protection. The imbalance of proteases-antiproteases in the alveolus leads to unimpeded neutrophil elastase digestion of elastin and collagen in the alveolar walls and progressive emphysema. 7, 9
Alveolar cell apoptosis may also play an important role in emphysema pathogenesis. Recent evidence suggests that alpha1-antiprotease may inhibit alveolar cell apoptosis and protect against emphysema in the absence of neutrophilic inflammation. Cigarette smoking accelerates the onset of symptomatic disease by approximately 10 years by increasing the number of neutrophils (and neutrophil elastase) in the alveolus and inactivating the remaining small amounts of antiprotease. Other factors that can accelerate the onset or worsen symptoms of disease include infections and exposures to dust and fumes, which can also cause the recruitment of neutrophils to the alveoli.15
The production of alpha1-antiprotease is controlled by a pair of genes at the protease inhibitor locus.
Nearly 24 variants of the alpha1-antiprotease molecule have been identified, and all are inherited as codominant alleles. The most common (90%) allele is M (PiM), and homozygous individuals (MM) produce normal amounts of alpha1-antiprotease (serum levels of 20-53 mol/L or 150-350 mg/dL).16
The most common form of AAT deficiency is associated with allele Z, or homozygous PiZ (ZZ). Serum levels of AAT in these patients are about 3.4-7 mol/L, 10-15% of normal serum levels. Serum levels greater than 11 mol/L appear to be protective. Emphysema develops in most (but not all) individuals with serum levels less than 9 mol/L .
Patients with the PiSZ phenotype have a 20-50% increased likelihood of developing emphysema compared with MM homozygotes. Serum levels of patients with PiSZ AAT deficiency are 75-120 mg/dL.13
Patients with the null gene for AAT will not produce any AAT and are high risk for emphysema (100% by the age of 30 y). None with the null gene develop liver disease because of a lack of production, and thus accumulation, of AAT in the hepatocytes. The null gene is the least common of the known alleles associated with AAT deficiency.
Carriers or heterozygotes (MZ, MS or M/Null) have levels approximately 35% of normal levels, but they do not develop disease.
People who have Alpha-1 antitrypsin deficiency will pass on one abnormal gene to their children, who will become “carriers” and will not have Alpha-1 unless they receive another abnormal gene from their other parent.12, 17

Who is most at risk?
It is estimated that there are 100,000 Americans today who were born with Alpha-1 antitrypsin deficiency.2 AAT related emphysema may afflict a majority of these individuals. However, AAT deficiency is often under diagnosed or misdiagnosed. As many as 3% of individuals with chronic obstructive pulmonary disease (COPD) may have undiagnosed Alpha-1 antitrypsin deficiency.3 If AAT deficient individuals also smoke, their risk of developing emphysema is greatly increased.18

AAT deficiency related emphysema can lead to liver diseases. The most serious liver disease are cirrhosis and liver cancer.4

Worldwide, it is estimated that 116 million people (25 million Americans) are carriers of the disease.5 The World Health Organization (WHO), The American Thoracic Society (ATS) and the European Respiratory Society (ERS) recommends that all individuals with COPD, as well as adults and adolescents with asthma (an estimated 20 million Americans) be tested for AAT deficiency or Alpha-1.11

How does emphysema develop?
While there are different causes of emphysema (such as smoking and Alpha-1 antitrypsin deficiency), the physical signs and symptoms in each case are similar.

Emphysema begins with the destruction of alveoli, small sac-like structures (resembling bunches of grapes) in the lungs where oxygen from the air is exchanged for carbon dioxide in the blood. The walls of the alveoli are thin and fragile, and are easily damaged.2,3

The damage is irreversible and results in permanent “holes” in the tissues of the lower lungs. As alveoli are destroyed, the lungs are able to transfer less and less oxygen to the bloodstream, causing shortness of breathe during exercise and eventually even at rest.3

The lungs also lose their elasticity, so the patient experiences great difficulty exhaling. The bronchial tubes leading to the air sacs may collapse, which traps air in the lungs. This is the condition known as emphysema.11
What are the signs and symptoms?
The onset of Alpha-1 related emphysema symptoms often appear between ages 32 and 41 but may appear later. The most common signs and symptoms of the disease are:

* Shortness of breath
* Wheezing
* Chronic cough and sputum (phlegm) production (chronic bronchitis)
* Recurring chest colds
* Eyes and skin turning yellow (jaundice)
* Swelling of the abdomen or legs
* Decrease exercise tolerance
* Non-responsive asthma or year-round allergies
* Unexplained liver problems or elevated liver enzymes
* Bronchiectasis. 8

The early age at which the disease is present and the fact that the disease most frequently appears in the lower rather than the upper lung regions helps distinguish Alpha-1-related emphysema from other types of emphysema.

How is alpha-1 related emphysema treated?
In December 1987, the first specific treatment for Alpha-1 related emphysema was approved. Replacement therapy (also called augmentation therapy) raises the level of AAT in the blood and provides the lungs with a protective shield against neutrophil elastase, the destructive enzyme.18

The replacement therapy is derived from human plasma that has been screened and tested for viral markers. During the manufacturing process the product is heat-treated to minimize the risk of viral transmission.

Therapy must be taken throughout a patient’s life for its protective effect. If a patient chooses to stop therapy, his or her lungs will return to the prior imbalanced state of neutrophil elastase and AAT.

Replacement therapy is intended only for AAT deficient patients who have begun to show symptoms of emphysema. It is not recommended for those without AAT deficiency who develop emphysema as a result of cigarette smoking or other environmental factors.

While replacement therapy does not cure Alpha-1 related emphysema, it does appear to slow the progression of this disease.
References
1. David A.Warrel etal. Chronic obstructive pulmonary disease.Oxofrd Text book of Medicine . ( vol 2 , 4 th edi ) ,1381-1383 ,2005
2. Dennis L. Kasper etal Harrison’s Principles of Internal Medicine. (Vol 2,16th edi )1547-1551.
3. Gadek JE and Pacht ER. The protease-antiprotease balance within the human lung: implications for the pathogenesis of emphysema. Lung 168, Suppl: 552–564, 1990.
4. Tetley T. Matrix metalloproteinases: a role in emphysema? Thorax 52: 495–497, 1997.
3 .Christoper Haslet.ectal Davidson’s principles and Practice of Medicine (19th
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5. Shapiro SD and Senior RM. Matrix metalloproteinases: matrix degradation and more. Am J Respir Cell Mol Biol 20: 1100–1102, 1999.
6. Finlay GA, O’Driscoll LR, Russell KJ, D’Arcy EM, Masterson JB, Fitzgerald MX, and O’Connor CM. Matrix metalloproteinase expression and production by alveolar macrophages in emphysema. Am J Respir Crit Care Med 156: 240–247, 1997.
7. Lim S, Roche N, Oliver BG, Mattos W, Barnes PJ, and Chung KF. Balance of matrix metalloprotease-9 and tissue inhibitor of metalloprotease-1 from alveolar macrophages in cigarette smokers. Am J Respir Crit Care Med 162: 1355–1360, 2000.
8. Opdenakker G, Van den Steen PE, and van Damme J. Gelatinase B: a tuner and amplifier of immune functions. Trends Immunol 22: 571–579, 2001.
9. Shapiro SD and Senior RM. Matrix metalloproteinases: matrix degradation and more. Am J Respir Cell Mol Biol 20: 1100–1102, 1999.
10. Uthaisangsook S, Day NK, Bahna SL, Good RA, and Haraguchi S. Innate immunity and its role against infections. Ann Allergy Asthma Immunol 88: 253–264, 2002.
11. Phelps DS. Surfactant regulation of host defense function in the lung: a question of balance. Pediatr Pathol 20: 269–292, 2001.
12. Shapiro, S.D., Goldstein, N.M., Houghton, A.M., Kobayashi, D.K., Kelley, D. & Belaaouaj, A. (2003) Neutrophil elastase contributes to cigarette smoke-induced emphysema in mice. Am. J. Pathol. 163, 2329–2335.
13. Sakamaki, F., Ishizaka, A., Urano, T., et al. (1996) Effect of a specific neutrophil elastase inhibitor, ONO-5046, on endotoxininduced acute lung injury. Am. J. Respir. Crit. Care Med. 153, 391–397.
14. MacNee, W. & Rahman, I. (2001) Is oxidative stress central to the pathogenesis of chronic obstructive pulmonary disease? Trends Mol. Med. 7, 55–62.
15. Lim S, Roche N, Oliver BG, Mattos W, Barnes PJ, and Chung KF. Balance of matrix metalloprotease-9 and tissue inhibitor of metalloprotease-1 from alveolar macrophages in cigarette smokers. Am J Respir Crit Care Med 162: 1355–1360, 2000.
16. Mecham RP, Broekelmann TJ, Fliszar CJ, Shapiro SD, Welgus HG, and Senior RM.
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antileucoprotease on experimental emphysema. Eur. Respir. J. 4, 31–39.
18. Parveen Kumar and Michael Clark . Clinical Medicine. 5th edi 863-864 2002.

MD / 2006 / 3389

Myocardial diseases are due to a specific heart muscle disorder or a known infiltrative metabolic or toxic or neuromuscular disorder. But may be caused by;
• An acute or chronic inflammatory disease (Myocarditis)
• Idiopathic myocardial disease ( Cardiomyopathy)
Cardiomyopathy is a series of disorders causing primary heart muscle dysfunction that is often leading to heart failure or sudden death. There are three main types of cardiomyopathy;
• Dilated Cardiomyopathy
• Hypertropic Cardiomyopathy
• Restrictive Cardiomyopathy
Roles of gene in cardiomyopathy
There are some genes which synthesis some certain proteins which form structure and do some certain function of heart muscle. But some defects of genes caused for the dysfunctions of the heart scientist. The following Table 1.1 gene proteins have been linked to Cardiomyopathy.
Gene proteins Function Defects
Actin Basic structure of muscle function. Hypertropic Cardiomyopathy
Desmin Intermediate filament between cardiac and skeletal muscle. Inherited Cardiomyopathy
Dystrophin Regenerating muscle fibers. Cardiomyopathy, Muscular dystrophy & other disorders
Tafazzin Musculoskeletal function Inherited Cardiomyopathy
β-myosin Family of creating myosin, involve in contraction & relaxation. Inherited Cardiomyopathy
Table 1.1 – Link between gene protein & cardiomyopathy
Other causes for primary dysfunction of cardiomyopathies are results from hypertension, valvular disease, congenital heart disease, obvious myocardities, systemic metabolic disturbances, nutritional disorders (e.g., wet beriberi),and hypersensitivity diseases (e.g., acute rheumatic fever). Deficiency of frataxin, which is an essential mitochondrial protein, leads to progressive neurodegeneration and cardiomyopathy. Progressive heart failure is due to diastolic resection and / or valvular dysfunction is caused by eosinophilic endomyocardial disease2. CoQ10 (Coenzyme Q (ubiquinone) 10) depletion during statin therapy which is used to treatment of hypercholesterolemia might be associated with subclinical cardiomyopathy and this situation can be reversed by treating CoQ103. Ion channels, such as those encoded by the potassium channel genes KCNQ and HERG which are contribute to normal heart function in humans and when they are malfunctioning, cardiomyopathies or arrhythmias is caused in humens12.

Clinical features of Cardiomyopathies
Some people who develop cardiomyopathy which may have no signs and symptoms in the early stages of the disease. But with the advancing the disease, signs and symptoms usually appear. These signs and symptoms which are most commonly associated with the syndrome called as congestive heart failure. They may include: 18

• Shortness of breathing
• dyspnoea
• Cardiac arrhythmias
• Dizziness & fainting
• Syncope due to the cardiac arrhythmias.
• Ejection fraction is les than 25 %( normal- 50%-65%) due to the ineffective ventricular contraction.
• Swelling in the lower limbs
• Chest pain is due to the reduced blood supply to the myocardium; Angina pectoris.
• tachycardia
• Elevated jugular venous pulse.
• Cardiomegaly
• Emboli formation
• Weakness and reduced activities are due to the low energy.
• Sudden death is due to the severe heart failure. Most of time this may be first symptom.
Investigation of cardiomyopathy
The investigations are use to differential diagnosed of cardiomyopathy. These investigations include a diligent clinical history and examination, blood tests, and ophthalmologic, otologic, dermatological, gastroenterological, nephrological, hematological, and neurological examinations7. The transthoracic, transesophageal and stress echocardiography, contrast echocardiography (CE) are used to improve the diagnostic accuracy of technically when used in combination with harmonic imaging13. Demonstrated benefits of CE include improvement in the accuracy of left ventricular (LV) measurements which are endocardial border marking out and LV opacifiication, regional wall motion assessment, and assessment of noncompaction cardiomyopathy, thrombus detection, Doppler signal enhancement and conjunctive use with stress echocardiography13.

Electrocardiography is used to differential diagnoses and that demonstrate the characteristic features of different types of cardiomyopathy. Changes in ST segment, T wave and Q wave can be shown.
As well as there should be analyzed the whole blood, coagulation, electrolyte parameters, and inflammatory and enzyme values will be within the normal range7, 16.
Regular pulmonary function tests should be done in addition to the routine biopsy controls and the laboratory tests as well as electrocardiography, echocardiography and radiography.
Chest X ray is used to demonstrate the generalized cardiac enlargement.
Blood flow per unit of myocardial volume is calculated using 3D surface-based registration between the imaging of heart wall thickness from cardiac magnetic resonance imaging (MRI) and from myocardial perfusion from single –photon emission computed tomography (SPECT) 8.
Transesophageal echocardiogram (TEE).

Cardiac catheterization
24 hours Holter monitor (heart monitor)
Physical examinations- Listen to the heart and lungs with stethoscope, abnormal heart sounds or murmurs and abnormal heart beats.
Pedigree analysis which generally shows the autosomal dominant inheritance and that may provide prognostic information, (e.g. – history of sudden death). Genetic analysis where available confirms the diagnosis, may provide prognostic information and facilitates assessment of relatives21.
Exercise test and ECG ambulatory recordings provide prognostic information21.
Treatments of cardiomyopathy
The treating management involves the conventional treatment of heart failure and arrhythmias. The goals of management are to reduce symptoms, retard disease progression and prevent complications.
Sevoflurane postconditioning is as effective as preconditioning in protecting myocardial function after global ischemia11. The combination of sevoflurane preconditioning and postconditioning therapy is accessible no additional benefit over either intervention alone11.
Carvedilol and metropolis succinate treatments are efficient in chronic heart failure ;( CHF) 9, 15. The improvement is more significant in patients with non-ischemic CHF, but as well as this treatment therapy improve subjective and submaximum parameters of the functional status of patients with CHF without changing maximal physical ability9. Therapy with beta-adrenoblockers may be resulted in a significant decrease in CHF9, 15.
Anticoagulant treatment is used to a history of embolization, a severe ventricular dilation and dysfunction, or documented atrial fibrillation21.
Diuretics agents are highly effective for the relief of congestive symptoms but should not be used in isolation because of they aggravate activation of neurohormones that may be contribute to progression of disease21.
Angiotensin converting enzyme (ACE) inhibitors are antagonizing activation of the renin-angiotensin- aldosterone, (RAAS) 17, 21. That is useful in relief of patient with hypertension.
Beta blockers which are antagonizing activation of sympathetic nervous system that helps to prevent arrhythmias21.
Permanent pacing, anti-arrhythmic therapy or implantable cardioverter-defibrillators may be obtainable21.
Corticosteroid therapy
Prolong bed rest.
Avoidance of alcohol.
Nutritional supplement
Cardiac transplantation is done in severe congestive cardiomyopathy in relatively young adult.

Dilated Cardiomyopathy (DCM)
Definition: – A condition in which the heart’s ability to pump blood is reduced because of the left ventricle; (one of two pumping chambers of heart) is enlarged or dilated.
This is the most common form of the Cardiomyopathy. Responding for 10,000 deaths of each year in the United State is dilated cardiomyopathy. The dilated cardiomyopathy may represent a late stage of myocardities. DCM is characterized by dilatation and systolic dysfunction of the left ventricle or right ventricle, in the absence of loading conditions, (hypertension, and valve disease) 2, 21.
One of the causes of degenerative heart disease is idiopathic dilated cardiomyopathy that is 7.6% of the patients1. The myocardial infraction (MI) in 36.6%, ischemic heart disease in 25.4%, and Barlow’s disease in 17.8% are the other major causes of patients with degenerative heart disease1.

Causes for dilated Cardiomyopathy
• Autoimmune response- An autoimmune response occurs immune system of own body mistakes body cells as foreign materials and attacks them. Therefore own body cells can cause severe damage to the attached tissue.
• A large number of different myocardial insults; viral nucleic acids from coxsackievirus B and other enteroviruses.
• Alcohol abuse- Due to the raising of ethanol toxicity and coronary artery disease or hypertention19.
• Myocardial injury caused by cobalt and certain chemotherapeutic agents, including doxorubicin, cyclophosphamide and other anthracyclines.
• Late in pregnancy or several weeks to months post partum. That is known as peripartum cardiomyopathy, which is a special form of dilated cardiomyopathy19.
• Defects in sarcomere protein genes- e.g. – β myosin, cardiac troponin T. Sarcomere forms the basic functional structure of the muscle. Therefore defects of gene causes for heart failure with inherited dilated Cardiomyopathy due to the poor contraction of muscle fibers19.
• Abnormal cytoskeleton proteins – e.g. – desmin, Dystrophin associated protein. This is associated with muscular dystrophies and inherited cardiomyopathy19.
• Primary heart muscle disease- e.g. – amyloidosis.
• Cardiovascular disease- e.g. – ischemia, rheumatic, systemic hypertension.
• Connective tissue disorders- e.g. –systemic lupus erythematosus, systemic sclerosis.
• Glycogen storage disease- e.g. – pompé’s disease.
• Presence of hepatitis C virus causes the chronic infections and idiopathic dilated cardiomyopathy as well.

Clinical features
Symptoms depend on the relative degree of heart failure (right or left heart failure) and occurrence of cardiac arrhythmias and emboli.
• Syncope is due to the ventricular arrhythmias or conduction disease or with pulmonary or systemic embolism21.
• Appearing third or fourth heart sound and basal crackles.
• Mitral or tricuspid valvular regurgitation.
• Death results from severe heart failure conditions.
Investigation
• The echocardiogram reveals dilation of the left ventricle or right ventricle with poor global contraction.
• ECG changes- diffuse non-specific ST segment and T wave changes in conduction disturbances, sinus tachycardia, conduction abnormalities and sinus arrhythmias, (atrial fibrillation, ventricular premature conduction or ventricular tachycardia)21.
• Cardiac biopsy which shows variable fibrosis and nonspecific leucocytes infiltration. –e.g. – amyloid. Generally there is not indicated outside specialist career21.
• Angiography is performed to eliminate coronary artery disease in all individual at risk21.

Treatment
In treating management, the causes of cardiomyopathy should be treated.
• The dilated left ventricular (LV) base can be reshaped by undersized mitral annuloplasty (MAP) in patients with dilated cardiomyopathy and MAP is used in functional mitral regurgitation (MR) as well14.

Hypertropic Cardiomyopathy (HMC)
Alternative names20
• IHSS- Idiopathic Hypertropic Subaortic Stenosis.
• ASH- Asymmetric Septal Hypertrophy.
• HOCM- Hypertropic Obstructive Cardiomyopathy
Definition
HMC is a cardiac disorder in which heart muscles become markedly thick. That is most prominent in the left ventricle and interventricular septum.
Because of this thick –walled ventricle, diastolic filling is impaired and it is also characterized by myocardial hypertrophy, intermittent ventricular outflow obstruction, and by a powerful, hyperkinetic contraction that rapidly eject blood from the ventricular cavities19, 20. The most of HMCs cases are inherited; (50%) 20. HMC is associated with Noonan’s syndrome, Friedreich’s ataxia, glycogen storage disease and mitochondrial myopathies21.
Hypertrophic cardiomyopathy can develop at any age, but the condition tends to be more severe among those diagnosed during childhood
Causes for hypertropic cardiomyopathy
• Abnormalities in cytoskeletal proteins19.
• Mutation involving the heavy chains of β-myosin, α-tropomyosin, and troponins I and T19.
• As a result of an alcohol septal ablation, there is an improvement of symptoms and a reduction in dynamic obstruction in most patients with hypertrophic obstructive cardiomyopathy.4
Clinical features
• Some patients have no symptoms and may not recognize that they have the hypertropic cardiomyopathy until it is found during a regular medical exam. A double apical pulsation- Forceful contraction produces a palpable forth heart sound.
• A jerky carotid pulse- Because of sudden obstruction to the left ventricular outflow and rapid ejection during diastole.
• An ejection systolic murmur- Due to the left ventricular outflow obstruction late in systole that can be increased by physical manoeuvres that decrease after load, e.g. – valsalva, or standing, can be decreased by manoeuvres that increase after load and venous return, e.g.- squatting21.
• A pan systolic murmur due to the mitral regurgitation (secondary to systolic anterior motion; (SAM)) 21.
• Appearing the fourth heart sound21.
• Dyspnoea is due to impaired relaxation of the cardiac muscle. Therefore left ventricular filling and empting are impaired. Systolic ventricular function remains good until the very late stages of disease when progressive dilation may occur.
• Light –headedness – especially after activity or exercise.
• Shortness of breathing occurs when lying down position. Sometimes the first symptom of hypertropic cardiomyopathy is sudden death, caused by severe cardiac arrhythmias among the young patients21. As well as hypertropic cardiomyopathy is major caused for death of young athletes who seem completely healthy, but die during serious exercise.
Investigation
• The ECG is can be used to demonstrates the left ventricular hypertrophy by changing ST segment and T wave, abnormal Q waves, most commonly in the inferolateral leads occur in 25-50% of patients21.
• The echocardiogram with Doppler ultrasound- This is the most common test for diagnose. It shows septal hypertrophy than the posterior wall hypertrophy, abnormal mitral valve movement and very strongly contracting ventricle.
• The calculated blood flow per unit of myocardial volume of HMC group is 1/7 times that of normal in the apex8.

Treatment
Firstly, sudden death must be avoided by anti-arrhythmic treatment.
• Beta blockers and versapamil, either along or in combination to use as treatment of chest pain and dyspnoea21.
• Disopyramide which is second line therapy for patient with obstructive hypertrophic cardiomyopathy21.
• Dual chamber pacing used with significant left ventricular obstruction and refractory symptoms.
• Occasionally resection of septal myocardium may be indicated.
• Surgical myectomy can be performed as a treatment of alcohol ablation with hypertropic obstructive cardiomyopathy and that was successful in researching4.

Restrictive cardiomyopathy (RCMP)
This is least common form of cardiomyopathy. The heart muscle becomes rigid and less elasticity, interfering with the expansion and filling of chambers of the heart with blood between heartbeats or contractions20, 21. This prevents the heart from enough blood. But filling of ventricles is rapid but ends abruptly when the stiff heart stops expanding. Because of the “inflow” of blood in to the heart is compromised, symptoms of heart failure can result. This restrictive cardiomyopathy usually affects older people.
The conditions associated with the restrictive cardiomyopathy are amyloidosis ;( commonest), sarcoidosis, Loeffler’s endocardities and endomyocardial fibrosis, there is myocardial and endocardial fibrosis associated with eosinophilia. In the restrictive cardiomyopathy thrombus formation is common condition.
• Idiopathic restrictive cardiomyopathy is familial that is associated with mutation in sarcomeric protein, troponin I. left ventricular thrombectomy in a patient with acute hypereosinophilia and congestive heart failure associated with severe mitral regurgitation and restrictive cardiomyopathy21.
• It may occur idiopathically or as a cardiac manifestation of systemic diseases such as scleroderma, amyloidosis, Churg-Strauss syndrome, cystinosis, sarcoidosis, lymphoma, Gaucher’s disease, hemochromatosis, Fabry’s disease, pseudoxanthoma elasticum, hypereosinophilic syndrome, carcinoid, Noonan’s syndrome, reactive arthritis, or Werner’s syndrome and various neuromuscular disorderses7, 20, 21.
• The patient with amyloidosis has a worse prognosis than those with other forms of deseases often recur after transplantation.
Clinical features
• Dyspnoea, fatigue and embolic symptoms.
• Restrictive to ventricular filling (e.g. Right ventricle) cause in persistently increased venous pressures and consequent hepatic enlargement, ascites and dependent edema.
• Physical sings are similar to those of constrictive pericardities21.
• An elevated JVP with diastolic collapse (Friedreich’s sing) 21.
• An elevation of venous pressure with inspiration ;( kussmual’s sing) 21.
• Fourth heart sound is common in early disease21.
• A cardiac enlargement. But in idiopathic condition, cardiac size may remain normal.
• Third heart sound may be present in advanced disease as well.
Investigation
Investigations of RCMP include a helpful clinical history, physical examination and as well as other common clinical an extracardiac tests
• Chest X-ray which demonstrates the pulmonary venous congestion, cardiac shape can be normal or cardiomegaly, and arterial enlargement21.
• ECG which usually has low- voltage and ST segment and T wave abnormalities.
• The echocardiogram which shows symmetrical myocardial thinking and an often a normal systolic ejection fraction, but impaired ventricular filling21.
• Cardiac catheterization which heamodynamic studies help dysfunction from constrictive pericardities.
• Endomyocardial biopsy in contact with other cardiomyopathies is often useful in this condition and may permit a specific diagnosis such as amyloidosis to be made. When there is no revealed possible caused of extracardiac examinations for RCMP, endomyocardial biopsy is indicated as well7, 21.

Treatment
• There is no special treatment for restrictive cardiomyopathy but in idiopathic RCMP effective, therapeutic option are only treatments of cardiac congestion and a causal therapy can be obtainable21.
• Cardiac failure and embolic manifestation treatment should be prescribed.
• Cardiac transplantation occurs in some severe cases.
• Treating causes for the restrictive cardiomyopathy; e.g.-in primary amyloidosis uses combination therapy with melphalan plus prednisolone with or without colchicines that improves survival of patient.
• Liver transplantation may be effective in familial amyloidosis due to the production of mutant prealbumin can lead to reversal of the cardiac abnormalities21.
Other types of cardiomyopathies
Arrhythmogenic right ventricular cardiomyopathy (ARVCM)
This is characteristic by progressive fibro fatty replacement of myocardium of right ventricle21. This is lead to ventricular arrhythmias and risk of sudden death of early stages and right ventricular or biventricular failure in its later stages.
At least 50% of cases are familial that is most commonly with an autosomal dominant pattern of inheritance21.
A rare form of arrhythmogenic right ventricular cardiomyopathy is associated with dermatological abnormalities such as Naxos disease is caused by a mutation in a gene encoding a myocyte structural protein (plakoglobin) found in desmosomes and gap junction21.

Clinical features
• Severe symptomatic ventricular arrhythmias or syncope.
• Present with right heart failure, later stage of disease in which left ventricular dilation and severity of arrhythmias may paradoxically diminish.
• This is often asymptomatic but first symptom may be sudden death.
Investigation
• ECG which most commonly demonstrates the T wave inversion in precordial related to the right ventricle (V1-V3 leads). A small amplitude potentials occurring at the end of the QRS complex (epsilon waves) may be present. Incomplete or complete right bundle branch block (RBBB) is seen21.
• Signal averaged ECG which indicates the presence of late potentials, delayed depolarization of individual muscle cell.
• Echocardiogram is in low normal and in more advanced cases may demonstrate right ventricular dilatation and aneurysm formation associated in some case with related left ventricular dilation.
• MRT scan in which demonstrate the morphological abnormalities of right ventricle and capable of demonstrating fatty infiltration21.
• Right ventricular angiography which demonstrates enlargement and abnormal motion of myocardium of R ventricle.
• Right ventricular biopsy demonstrates the fibro fatty replacement.
• Holter monitoring in which demonstrates regular extra systole of right ventricular origin and runs of none continuous or continuous ventricular tachycardia21.
• Genetic testing.
Treatment
• β- Blockers use in first line treatment for patient with non-life threatening arrhythmias21.
• Amiodarone or sotalol for symptomatic arrhythmias, refractor or life threatening arrhythmias and ICD may be required.
• Cardiac transplantation occurs in intractable arrhythmias or cardiac failure.

Ischemic cardiomyopathy
Ischemia is the localized blood deficiency caused by constriction or destruction of blood vessels that supply to that area. Myocardial ischemia happens when a coronary artery supply to the part of the heart becomes narrowed or blocked for a short time and leads to hypoxia by unable to reach oxygen-rich blood that part of the heart. In most cases of ischemia, this temporary blood shortage to the heart causes the accumulation of “P factor” and pain in the chest called angina pectoris. In certain other cases, there is no pain. These cases are called silent ischemia. If the myocardial ischemia is severe and prolonged, there can irreversible changes occur in the heart muscle and result is the MI.
Ischemic cardiomyopathy is the loss or weakening of heart muscle tissue caused by ischemia or silent ischemia. The ischemia usually results from coronary artery disease and heart attacks.
Treatment for ischemic cardiomyopathy is similar to that for other forms of cardiomyopathy, with special concentration given to treating coronary artery disease. For patients whose hearts have been seriously damaged by ischemic cardiomyopathy, there may be recommend that a heart transplant.
Ampulla (takotsubo) cardiomyopathy
This type of cardiomyopathy is caused by secondary adrenal insufficiency resulting mainly deficiency of ACTH and cortisol in the blood10. Activation of the sympathetic nervous system, adrenocortical failure, and hypoglycemic attack are also trigged with the takotsubo cardiomyopathy10. The development of some of the case of tokotsubo cardiomyopathy is associated with septal ventricular hypertrophy and intraventricular obstruction6.
Electrocardiography showed ST segment elevation; prolong QT interval and T wave inversion in leads V (1-6)6,10.Other investigations are included the insulin tolerance tests, ventriculogram and ultra sound studies of the heart.
Cardiac dysfunction due to both cardiomyopathy and adrenal cortical failure can be recovered by careful monitoring of cardiac function and appropriate treatments10. Taxonomic confusion occurs as well5.
Stress- induced cardiomyopathy (SICMP)
Stress induced cardiomyopathy is an imitated acute coronary syndromes (ACS) that is often associated with sings of cardiac failure5. There is significance correlation among the female gender with a short height (<158cm), a small body surface area (<1.9m2) and a hypoplastic branching coronary arteries mainly in the apical region of the heart.5 By researching there is found out that more tendency to get this SICMP for Mediterranean and Indo-Asian women, who represent 85% of cases5.
In the most of cases, the symptoms become chronic and medical treatments of SICMP rarely improve dyspnea and chest pain. Because of that the quality of life is reduced5.

List of references
References
1) Gatti G, Pugliese P, Preliminary experience in mitral valve repair using the Cosgrove-Edwards annuloplasty ring Department of Cardiac Surgery, Villa Torri Hospital, viale Filopanti, 12-40126 Bologna, Italy,2003 Sep. giusep.gatti@tiscali.it
2) Reis FJ, Viana M, oliveira M, Sousa TA Parana R ,Prevalence of hepatitis C and B virus infection in patients with idiopathic dilated cardiomyopathy in Brazil: a pilot study, 2007 Jun, Bahiana School of Medicine and Public Health
3) Littarru GP, Langsjoen,Coenzyme Q10 and statins: biochemical and clinical implication, Institute of Biochemistry, Polytechnic University of the Marche, Via Ranieri, 60131 Ancona, Italy, 2007 Jun. G.littarru@univpm.it
4) Nagueh SF,Buergler JM, Quinones MA, Spencer WH 3rd, Lawrie GM,Outcome of surgical myectomy after unsuccessful alcohol septal ablation for the treatment of patients with hypertrophic obstructive cardiomyopathy, 2007 Aug, Methodist DeBakey Heart Center and Department of Cardiology, Methodist Hospital, Houston, Texas, USA. snagueh@tmh.tmc.edu
5) Cocco G, Chu D, Stress-induced cardiomyopathy: A review, 2007 Jul, Marktgasse 10a, Postfach 119, CH-4310 Rheinfelden 1, Switzerland.
6) Azzarelli S, Galassi AR, Amico F, Giacoppo M, Argentino V, Fiscella A, Intraventricular obstruction in a patient with tako-tsubo cardiomyopathy, 2007 Aug, Division of Cardiology, “Cannizzaro” Hospital, Catania, Italy.
7) Stöllberger C, Finsterer J, Extracardiac medical and neuromuscular implications in restrictive cardiomyopathy, 2007 Aug, Medizinische Abteilung, Krankenanstalt Rudolfstiftung. Fukami T, Sato H, Wu J, Lwin TT, Yuasa T, Kawano S, Iida K, Akatsuka T, Hontani H, Takeda T, Tamura M, Yokota H, Quantitative evaluation of myocardial function by a volume-normalized map generated from relative blood flow, Department of Bio-system Engineering, Faculty of Engineering, Yamagata University, Yonezawa, Yamagata 992-8510, Japan,2007 Jul. fukami@yz-yamagata-u.ac.jp.
9) Poltavskaia MG, Syrkin AL, Andreev DA, Svet AV, Sarkisova EA, Kalashnikov VIu, The effects of beta-adrenoblocker therapy on the physical working capacity of patients with chronic heart failure of various origin, [Article in Russian], 2007.
10) Sakihara S, Kageyama K, Nigawara T, Kidani Y, Suda T, Ampulla (Takotsubo) Cardiomyopathy Caused by Secondary Adrenal Insufficiency in ACTH Isolated Deficiency, 2007 Jul Department of Endocrinology and Metabolism, Hirosaki University School of Medicine.
11) Deyhimy DI, Fleming NW, Brodkin IG, Liu H Anesthetic preconditioning combined with postconditioning offers no additional benefit over preconditioning or postconditioning alone, 2007Aug, Department of Anesthesiology and Pain Medicine, University of California, Davis, CA, USA.
12) Ocorr K, Perrin L, Lim HY, Qian L, Wu X, Bodmer R,Genetic control of heart function and aging in Drosophila,2007 Jul, Burnham Institute for Medical Research, Program for Systems and Developmental Biology, Center for Neurosciences and Aging, La Jolla, CA 92037, USA
13) Honos G, Amyot R, Choy J, Leong-Poi H, Schnell G, Yu E, Contrast echocardiography in Canada: Canadian Cardiovascular Society/Canadian Society of Echocardiography position paper, 2007 Apr, Sir Mortimer B Davis Jewish General Hospital, Montreal, Quebec, Canada. ghonos@cardio.jgh.mcgill.ca
14) Koyama T, Soga Y, Unimonh O, Nishimura K, Komeda M, Mitral annuloplasty as a ventricular restoration method for the failing left ventricle: a pilot study, 2007 Mar, Department of Cardiovascular Surgery, Kyoto University, Graduate School of Medicine, Kyoto, Japan.
15) Brixius K, Lu R, Boelck B, Grafweg S, Hoyer F, Pott C, Mehlhorn U, Bloch W, Schwinger RH, Chronic treatment with carvedilol improves Ca2+-dependent ATP consumption in triton X-skinned fiber preparations of human myocardium, 2007 Jul, Department of Molecular and Cellular Sport Medicine, German Sport University, Cologne, Germany .
16) Strecker T, Zimmermann I, Wiest GH, Pulmonary and cardiac recurrence of sarcoidosis in a heart transplant recipient, [Article in German], 2007 May, Zentrum für Herzchirurgie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany. thomas.strecker@herz.imed.uni-erlangen.de
17) Lefebvre HP, Brown SA, Chetboul V, King JN, Pouchelon JL, Toutain PL, Angiotensin-converting enzyme inhibitors in veterinary medicine, 2007, UMR 181 INRA-ENVT Physiopathologie et Toxicologie Expérimentales, National Veterinary School, Toulouse cedex 03, France. h.lefebvre@envt.fr
18) Diseases and Conditions, cardimyopathy, 2006 march, MayoClinic.com.
19) J.C.F Underwood, General and systemic pathology, 319-21, 322b, 4th edition.
20) Parakrama Chandrasoma, Clive. R.Taylor, Concise pathology, 175-6, 248, 355, 360, 374, 2nd edition.
21) Fraveen .J. Kumar & Michal Clark, Clinical medicine, 848-53, 6th edition.

MD/2006/3461

Introduction

Adrenal Insufficiency (AI) defines an inadequate secretion of cortisol or aldosterone or both hormones. At the same time the clinical picture can be highly variable and anyone presented with unexplained fatigue, hyponatraemia or hypertension should be subjected to suspicion of AI by the clinician(1). The disease is classified in such a way that the hypofunction of the adrenal gland is divided in to primary and secondary by cause (2). Either way all types of AI’s are only concerned with the adrenal cortex as the adrenal medullary hormones are not essential for life(3). The patterns of the disease are usually considered as three main conditions (2).
(i) Primary acute adrenocortical insufficiency also known as adrenal crisis.
(ii) Primary chronic adrenocortical insufficiency or Addison’s disease (AD).
(iii) Secondary AI or a decreased stimulation of adrenals owing to a deficiency of Adrenocorticotrophic hormone (ACTH).

The Adrenal Gland
Adrenal Anatomy
Adrenal gland is an important endocrine gland in the body weighing 8-10gm s. It contains a steroid-producing cortex which (4, 5) has a mesodermal origin from the peritoneal lining. The other part is the catecholamine producing medulla, which originate from neural crest cells and resemble modified sympathetic ganglion cells (4, 5). The gland is located on the superomedial surface of the corresponding kidney and is covered by the same fascial sheath that covers the kidney known as the renal fascia. The kidney is separated from it by a little fatty connective tissue layer. The right gland is pyramidal in shape and the left is crescent shaped. The renal arteries, aortic branches and inferior phrenic arteries supply it, first the cortex then through the cortex to the medulla. The right is drained directly to inferior vena cava as the right suprarenal vein, and the left to the left renal vein (5). The cortex consist of 3 zones (4)

The outermost Zona glomerulosa which principally secretes mineralocorticoids, mainly aldosterone(6). It is also the sole aldosterone producer in the body (4) aldosterone secretions is independent of ACTH (Adrenocorticotrophic hormone) produced by the anterior pituitary in response to CRH (corticotrophin releasing hormone) produced in the hypothalamus (6)

The next zone is zona fasciculata the middle and broadest of the zones. Secretes glucocorticoid hormones of which the main form is cortisol. Its secretion unlike aldosterone which is independent at ACTH, is solely regulated by hypothalmopituitary adrenal axis. This layer also secretes a small amount of adrenal androgens and estrogens (7)

The innermost zone is zona reticularis and it produces some amount of glucocorticoid and also adrenal androgens. Though its width is the thinnest of the 3 zones, varies under different physiological conditions to which it is subjected (6)
Physiology of Adrenocortical hormone secretion

The anterior pituitary hormone ACTH is a principal stimulator of the adrenocortical hormone out put. About 20% anterior pituitary cells are corticotropes that secrete ACTH (8). The main ACTH activity is aimed at the production at Glucocorticoids. The levels of cortisol have a negative feed back action on the anterior pituitary and the hypothalamus. Reduced levels of blood cortisol will stimulate the hypothalamus to produce CRH. CRH is also released in response to the circadian rhythm and stress. In response to CRH and also direct stimulation of anterior pituitary by a low cortisol level in blood causes ACTH to be released (4). Circulating ACTH stimulates cortisol production in the adrenals. Cortisol will in turn cause negative feed back on both hypothalamus and pituitary that will regulate the release of CRH and ACTH accordingly. The set point of this system has a direct variation pattern to the circadian rhythm which can be overridden by stress (4, 3, 9). Secretion of Aldosterone and mineralocorticoids is mainly regulated by the renin angiotensin system. But ACTH is also needed though is not of notable influence (7).But Adrenal sex steroid production is largely independent of pituitary action. (4)

Primary Acute AI

Primary Acute AI or the adrenal crisis can occur in conditions where a patient with chronic AI is subjected to stress thereby precipitating AI and creating a state in which immediate increase in steroid out put is required. But due to chronic AI already suppressing corticosteroid out put, will create the so called crisis. (2) Prolonged administration of anti-inflammatory glucocorticoids suppress the ACTH production of pituitary (3). In patients maintained on such exogenous corticosteroids, a rapid withdrawal or failure to increase the doses in response to acute stress may also precipitate primary acute AI (2) In cases of prolonged glucocorticoid treatment, even if the responsiveness is stimulated by exogenous ACTH, the pituitary may still need as long as a month to reach normal ACTH production (3). Massive adrenal hemorrhage that occurs in cases of newborns, following difficult delivery, in patients under anticoagulant therapy or patients who develop disseminated intravascular coagulation post surgically will cause hemorrhagic infarction of the adrenals and develop primary acute AI (2). It is also noted in a special case where bilateral adrenal hemorrhage causing primary acute AI should also be considered in patients with systemic lupus erythematosus (10). In an over whelming bacterial infection usually associated with Neisseria meningitidis or occasionally by pseudomonas or pneumococci, direct bacterial seeding of small adrenal vessels, development of disseminated intravascular coagulation and endotoxin induced vasculitis (or hypersensitivity vasculitis) will cause adrenal hemorrhage that will develop primary acute AI . This especial condition is called Waterhouse Friderichsen syndrome (2). A normal healthy subject when exposed to a single intra or periarticular injections of corticosteroid for posttraumatic or micro traumatic articular injuries are also at the risk of hypothalmopituitary adrenal axis suppression that can in turn create an acute adrenal crisis (11)

Primary Chronic AI

Primary Chronic AI is called Addison’s disease after Thomas Addison who in 1855 published a paper about some individuals with several symptoms of languor, debility, feebleness of heart action, and peculiar change in the colour of skin. It is an uncommon disease and adrenal cortex is subjected to progressive destruction but clinical manifestations arise when at least 90% of the cortex is demolished (2). Some define it as a destruction of the entire adrenal cortex (4). Pathogenesis of the cortical destruction in more than 90% of all cases is by autoimmune adrenalitis, tuberculosis (TB), the acquired immune deficiency syndrome (AIDS) or metastatic cancer, (2) but lymphomas, amyloidosis, sarcoidosis, hemochromatosis, fungal infections and adrenal hemorrhage can also be the cause. In the U.K. there is marked female preponderance by autoimmune disease (>90% of AI cases) rather than TB (4). In the case of autoimmune adrenalitis adrenal cortex is subjected to organ specific auto antibodies. (eg. 21 hydroxylase as the common antigen). There are also incidents associated with autoimmune conditions like poly glandular autoimmune syndromes type I and II (2, 4 , 12) Type I is inherited as an autosomal recessive condition causing Addisons disease, chronic mucocutaneous candidiasis and hypoparathyroidsm. Type II is more common and apart from developing Addisons disease it may lead to autoimmune thyroid disease, diabetes mellitus and hypogonadism. It is inherited with linkage to the HLA major histocompatibility complex, mainly HLA – DR 3 and DR 4 (12)

In especial cases Addisons disease (AD) was shown to have a positive association with Celiac disease (CD). A study indicates that patients with AD or CD should be independently screened for the other (13). An important factor of primary AI is that usually both glucocorticoid and mineralocorticoid deficiency does not arise in secondary adrenal insufficiency in which an intact renin angiotension aldosteron system will keep up the secretary process intact. (14) The major actions at glucocorticoids are increasing or stimulating :Gluconeogenesis, glycogen deposition, protein catabolism, fat deposition, sodium retentions potassium loss, free water clearance, Uric acid production and circulating neutrophil count. But they inhibit or decrease protein synthesis, host response to infection, lymphocyte transformation, delayed hypersensitivity, circulating lymphocyte count and circulating eosinophil count (4) In AD, glucocoticoid & mineralocorticoid reduction will lead to symptoms such as weight loss, Anorexia, malaise, weakness, fever, depression, impotence, amenorrhoea, nausea, vomiting, diarrhea, confusion ,syncope from postural hypotension , abdominal pain, constipation, myalgia, joint or back pain and muscle cramps. Signs of AD include pigmentation, buccal pigmentation postural hypo tension, weight loss, wasting dehydration and vitiligo (4) The adrenal crisis is often precipitated by other disease, surgery and infections(1). In AD mineralocorticoid deficiency is mainly the lack of aldosterone so renal tubular sodium reabsorption decreases and Na+ water and chloride ions are greatly lost in urine. So there will be a general decrease in extra cellular fluid volume, thus the plasma volume falls with and increase of red cell concentration and a decrease of cardiac out put. Death can arise by hypovolemic shock. If untreated death arises within 4 days to 2 weeks after aldosterone levels have depleted (7). But Glucocorticoid deficiency is mainly based on the lack of Cortisol which means the normal blood glucose concentration between nutritional intake is not maintainable by Gluconeogenesis. The mobilization of protein & fat is also reduced by the lack of Cortisol. Therefore there is a general slowing of metabolism throughout the body (7). The most significant differentiating factor of AD from secondary AI is skin pigmentation (12). Pigmentation occurs in scars that developed after the onset of the disease, in skin creases and nipple areolas, at pressure points and also in gums (3) .The pigmentation can be detectable in the form of diffuse tanning and also in a form at spotty pigmentation.(3) This is a general symptom of chronic glucocorticoid deficiency (3). The reason is based on the fact that ACTH shares the precursor prehormone which is proopiomelanocortin, with several other endocrine peptides including melanocyte stimulating hormone (MSH), β – lipoprotein and β – endorphin (7). Therefore when AD causes a decrease in Blood cortisol levels the negative feed back loop stated earlier (4) will act on both hypothalamus and pituitary so that as a final result of the feed back stimulation, ACTH level will be greatly increased. As the cortex has been considerably destroyed or totally demolished by AD, the feed back stimulation to produce ACTH will continue. Thus ACTH will start acting in a MSH like manner. Melanocytes will be stimulated. This melanin is not always deposited, but the deposition will occur in the areas mentioned above (3) where thin skin maybe found. But some point out that this pigmentation also occur because CRH will not only stimulate ACTH but also MSH. Therefore to a lesser degree of pigmentation is due to actual MSH but mainly due to MSH like activity of elevated ACTH. (7, 14). When primary AI strikes an individual morphological impact varies according to the pathogenesis. For example if it is due to primary autoimmune adrenalitis the glands are shrunken and will be difficult to identify within suprarenal adipose tissue. A variable lymphoid invasion may reach the medulla but usually it is preserved. (2) But if the case is due to tuberculosis and fungal disease the adrenal composition is challenged by a granulomatous inflammatory reaction, which is usually seen in sites of infections. Or if it is a case of metastatic carcinoma the infiltrating neoplasm will rather enlarge the adrenals contrary to primary autoimmune adrenalitis in which case the glands are shrunken .(2)

Secondary hypoadrenalism

Secondary AI or secondary hypoadrenalism is most often due to a sudden cessation of exogenous glucocorticoids used as therapy. (4, 12) As mentioned earlier primary acute AI can also be precipitated by abrupt withdrawal of exogenous glucocorticoids (9) But in the case of secondary AI the AI is totally due to the lack of ACTH but not a disorder concerned with the actual steroid production of the adrenal cortex (12) Such therapy of exogenous glucocorticoid suppress the hypothalamic pituitary adrenal axis and with the lack of ACTH will lead to adrenal atrophy which sometimes last for months after withdrawal of glucocorticoid treatment (4, 12) This can be expected in anyone who has taken more than the equivalent amount of 30 mg of oral hydrocortisone per day (7.5 mg /day of prednisolone or 0.75 mg/day of dexamethasone) for longer than a month (12) With reference to the circadian rhythm (3, 4, 9) the timing of the dose may also affect the degree at adrenal suppression (12) So prednisolone 5 mg at night and 2.5 mg in the morning will be extremely more prominent in hypothalmopituitary suppression than that caused by the 5 mg in the morning and 2.5 mg at night. (12) Most patients with this form of suppressed hypothalmopituitary axis may also have panhypopituitarism and will need Thyroxin replacement as well as cortisol. But cortisol replacement should be started earlier than Thyroxin replacement. (4). Any disorder of the hypothalamus and pituitary can generate secondary AI. Common disorders are metastatic cancer, infection, infarction or irradiation and the general cause of secondary AI is the reduction in the ACTH out put. (2) Contrary to AD there is no skin pigmentation. Also notable is the fact that aldosterone out put is normal or near normal owing to the fact that there is a zona glomerulosa in the cortex to respond to the renin angiotensin system. (2) Therefore in secondary AI marked hyponatraemia and hyperkalemia is not seen. (2) The ATCH deficiency as stated above can (4) be isolated or associated with panhypopituitarism or rather multiple primary trophic hormone deficiencies (2) Another factor of differentiating AD form secondary AI is the fact that ACTH exogenously administered can increase plasma levels at cortisol (9) The differences in salt and water balance in the two groups of AI is a significant factor that changes the clinical presentation (12). Therefore in the case of Secondary AI due to hypopituitarism the ACTH deficiency is also associated with the deficiencies of Luteinizing hormone (LH) follicle stimulating hormone (FSH) Thyroid stimulating hormone (TSH) and growth hormone(GH) Therefore the deficiencies of GH will cause hypoglycemia and of TSH will cause weight gain and cold intolerance and of FSH, LH will cause infertility, oligo/amenorrhoea and poor libido. But if it is isolated ACTH deficiency like in the case of exogenous glucocorticoid withdrawal, then the features are more of chronic AI or AD without any signs of pigmentation. (12). The size of the adrenals will vary according to the lack of ACTH (2) It could be a moderate or marked reduction . Even if reduced to small flattened structures the cortex retains the yellow colour because an amount of lipid will be left over. The main composition of the active cortex at this stage will be the glomerulous zone where the renin angiotensin axis will maintain aldosterone production (2).

Investigation of AI

There are several main investigations aimed at AI which are routine biochemical profiles which involves assessment of plasma, potassium, blood urea and blood glucose. Then more specific AI oriented investigations like plasma cortisol /ACTH test, testing mineralocorticoid status and stimulation tests. (12)

Routine biochemical profile

Measurement of plasma electrolytes may give the first clue of diagnosis in AD that has been there for an established period of time. Hyponatraemia can be expected in 90% of the cases. But Hyperkalemia is found in 65%. The blood urea level is increased. In secondary AI dilutional or low blood urea maybe found. When diagnosing secondary AI in this way a rise in Eosinophil count and an elevated ESR may also assist as pointers. In more than half of those who suffer from primary or secondary AI , hypoglycemia is detected (12, 14)

Plasma Cortisol / ACTH

Basal plasma cortisol and urinary free cortisol levels are often in the low normal range and cannot be used to exclude the diagnosis. The test directly aimed at primary AI or AD is simultaneous measurement at plasma cortisol and ACTH, so that a disproportionate elevation of ACTH to cortisol can be observed. Then the cortisol response to exogenous ACTH is also useful. (This will be disused later) (12, 14) A random cortisol level below 100 n mol/L is suggestive of AI but > 550 n mo/L is unlikely (4) A 0900h in plasma ACTH > 80 ng/L with low or low normal cortisol confirms primary AI (4)

Mineralocorticoid status

The difference of aldosterone level in the case of Primary and secondary AI is of great value in differentiating the disease condition (2) Therefore in the case of primary AI the renin activity in Plasma is elevated and the plasma aldosterone is low or normal (12)

Stimulation Tests

The stimulation test is most commonly ACTH stimulation. This involves intravenous or intramuscular injection of 250 mg of tetracosactrin (Synacthen) Then the Plasma cortisol level is measured immediately, after half and hour and also after one hour. During the half hour measurement a normal person will indicate at least 550 nmol/L of cortisol. In all forms of AI, less than the 550 mark can be found after acute administration of Synacthen. Measuring ACTH as discussed earlier can differentiate the two forms of AI. Another way to differentiate between the two forms of AI is by performing prolonged stimulation test. This test is performed by administrating an intramuscular dose of 1 mg de pot tetracosactrin with measurement of plasma cortisol at 0, 4 and 24 h. Normally at the mark of 4 h, cortisol is > 1000nmol/L and 24 h is a little increased than that. People with AD will show instead a significant increase in the 24 h mark. (14) The insulin tolerance test is also a useful investigation on assessing both ACTH and GH reserves. But it cannot be performed on people with ischemic heart problems, epilepsy or hypopituitarism (severe) (14). The test is performed by intravenously administering soluble insulin 0.1 to 0.15 U/kg of body weight, than plasma cortisol is measured at 0, 30, 45, 60, 90, 120 min. Hypoglycemia with blood glucose <2.2mmol/L and neuroglycopenia, sweating, tachycordia is essential. Normally the cortisol peak exceeds 500 nmol/L. This test is useful to be performed after an ACTH stimulation test that showed a positive of AI and not otherwise. (14) This is because some patients hold an inadequate response to ACTH but normal response to hypoglycemia and does not require corticosteroid replacement therapy. (14)

Other tests

Antibodies against 21 hydroxylase antigen can be detected via radioimmunoassay in order to confirm AD. Also in AD it is important to look for signs of organ specific autoimmune disease (14). Chest and abdominal x-rays may show evidence of tuberculosis and calcified adrenal glands (4) CT and MRI scanning is useful in detecting adrenal hemorrhage or neoplasm, but CT is better in making out the difference between an inflamed adrenal from a metastasized (14)

Treatment for AI

If a patient is suspected of AD investigation is a prompt action. A seriously afflicted individual with hypertension, an intramuscular hydrocortisone (100 mg) with intravenous saline is a good protective measure (4). An acute AI patient is for the emergency room. If his/her cardiovascular function is normal 1L of normal saline over 30-60 min with 100 mg of intravenous bolus hydrocortisone is the standard 1st approach. The next step is administering several liters of saline up to the next day, with six hourly hydrocortisone
(100mg) intramuscularly, till the individual is stable. The hypoglycemic, need glucose infusion. Then an oral replacement can be started, firstly hydrocortisone 20 mg, then reducing over a few days. (4,14). As hydrocortisone also holds sufficient mineralocorticoid activity mineralocorticoids are not necessary at this stage but when hydrocortisone dose is reduced in cases of acute AI then fludrocortison acetate is useful in doses of 0.05 – 0.1 mg daily(14). As noted before those with primary AI may require both glucocorticoid and mineralocorticoid replacement. But when it comes to secondary AI only glucocorticoids are needed. In case of chronic replacement therapy for both AI conditions the daily glucocorticoid dose is 30 mg of hydrocortisone per day in such a way that 20 mg on waking up and 10 mg at six noon. The actual amount may vary from individual to individual. If inadequate then primary AI patient (AD) will still hold pigmentation and elevation of ACTH. In events of intercurrent febrile illness, trauma, mental stress, the dose of glucocorticoids must be doubled. In cases of vomiting, paraentaral infusion is urgent. In case of surgery 100 mg hydrocortisone hemisuccinate is given with the premedication. Even in major operations this is conducted together with the procedure taken for acute AI. If an individual is given enzyme inducing drugs like Rifampicin or Phenytoin then the hydrocortisone dose need increasing. The same goes with pregnancy. This is because in gestation estrogen increase cortisol binding globulin thus free cortisol will decrease(14). A famous clinical practice on patients with glucocorticoid therapy is to get them registered for a Medic-Alert bracelet or necklace and making them carry a Steroid Card (5,3) In case of postural hypotension and hyperkalaemia, “fludrocortisone” is useful and it’s need can be monitored simply by measuring blood pressure or plasma electrolytes.(4, 14)

Discussion
All forms of AI hold a considerable risk of death and impairment of a normal lifestyle.
( 4 , 7 , 12) So as suggested above the patient who shows up with typical signs of AI should be screened immediately while the first hand treatment line is commenced. AIDS, TB and other forms of pathological conditions are also capable of generating AI. So screening such an individual for AI is important. (2, 4, 12, 10, 13) when it comes to treating an individual for AI the administration of medications should be carefully regulated and in the case of an adrenal crisis, prompt action is essential. (4). In the process of diagnosis utmost importance rest on the differentiation of one form of AI from another . The physiologic regulation and the influence of the adrenal gland in general can always be applied to classify, diagnose, investigate and finally treat all forms of AI. (4, 3, 9).

References

1. Strachan MWJ, Walker BR, Endocrine disease. Boon NA, Colledge NR , Walker BR, Hunter JAA, editors. Davidson’s principles & practice of medicine. 20th ed. Philadelphia: Churchill Livingstone; 2006 P 782-784.

2. Maitra A, Abbas AK, The Endocrine System. Kumar V, Abbas AK, Fausto N, editors. Robbins and Cotran Pathologic basis of disease 7th Ed. Pennsylvania: Elsevier; 2004 P 1214 –1217.

3. Ganong WF, Review of medical physiology 22nd ed. Boston Burr Ridge: McGraw –Hill; 2005 P. 356-381

4. Drury PL, Howlett TA, Endocrine disease Kumar P, Clark M, editors. Clinical Medicine 5th Ed. Edinburgh: WB Sanders, Elsevier Science 2002. P 1047 –1052

5. Romanes GJ, Cunningham’s Manual of Practical Anatomy – Volume two Thorax and abdomen 5th Ed. New York: Oxford University Press Inc: 2002 P 165 –166.

6. Young B, Heat JW, Wheater’s functional histology – A text and color atlas. 4th ed. Edinburgh: science limited: 2002 P 321.

7. Guyton AC, Hall JE, Text Book of medical physiology 11th ed. Philadelphia: Elsevier: 2006 P. 944 –960

8. Guyton AC, Hall JE, Text Book of medical physiology 11th ed. Philadelphia: Elsevier: 2006 P. 918 –919

9. Ganong WF, Review of Medical physiology 22nd ed. Boston Burr Ridge McGraw Hill; 2005 P 327

10. Jakobsen AS, Cvitanich VB, Kirkegaard BC, 2007 Acute Addisonian crisis in a patient with SLE and Secondary antiphospholipid syndrome. Ugeskr Laeger. 2007 Jun 4; 169 (23) 2224-5

11. Duclos M, Guinot M, Colsy M, Merle F, Baudot C, Corucuff JB, Lebouc Y. 2007 High risk of AI after single articular steroid injection in athletes. Med Sci Sports Exerc. 2007 Jul; 39(7) 1036-43

12. Stewark PM, disorders at the adrenal cortex. Warell DA, Cox TM, Firth JD, Benz Jr. EJ, editors. Oxford text book of medicine 4th ed. Oxford: Oxford University Press; 2005 P. 251-254

13. Elfstrom P, Montgomery SM, Kampe O, Ekbom A, Ludvigsson JF. 2007 Risk of primary AI in patients with celiac disease. J. Clin Endocrinol Metab. 2007 Jun 26; [Epub, ahead of print] (PMID: 17595243)

14. Ledingham JGG, Warrell DA, editors consise oxford text book of Medicine. 1st edn. New York: Oxford University Press Inc: 2000 P 861-863

MD/2006/3479.

Autoimmune Diseases
The autoimmunity is a mechanism that the immune system utilizes to destroy
extra cellular pathogens or host cells. The harbor intracellular foreign bodies such as mycobacterium or viruses must be appropriately targeted damage to normal host tissue is to be avoided.2 Under most inflammatory circumstances; some bystander tissue damage is unavoidable. In most circumstances, this damage is self limited. It is due to efficient clearance of exogenous nitrogen source and appropriate down modulation of immune response.2
Immune reactions against self antigens autoimmunity are an important cause of certain diseases in humans. Autoimmune disease occurs when a sustained, specific adaptive immune response is generated against self-components, and results in tissue damage or dysfunction.1 There are three requirements should be met before a disorder is categorized as truly due to autoimmunity.4
1) The presence of an autoimmunity reaction.
2) Evidence that such a reaction is not secondary to a tissue damaged. E.g. resulting from infection, but it is of primary pathogenic significances.
3) The absence of another well-defined cause of the disease.
Although a single immune effecter pathway may predominate in generating tissue dysfunction and damage in some autoimmune disease. It is much more frequent for multiple effectors pathways to participate in generating the final phenotype. Those pathways which generate tissue damage or dysfunction include autoantibody binding to target cells. There is immune complex –mediated activation of complement and Fc receptor pathways, cytokine pathways, and lymphocyte meditated cytotoxicity of target cells.4 The nature and sites of the tissue damage are what determine the pathological and clinical features of the specific diseases. Autoimmune disorders may results from tissue damage caused by T cells or antibodies that react against self antigens. The autoimmune disorders form a spectrum, on one end of which are conditions in which the immune response is directed against a single organ or tissue, resulting in organ-specific disease and on the other end are diseases in which the autoimmune reaction is against widespread antigens, resulting in generalized or systemic disease.4
Autoimmune diseases may affect individuals at all stage of life, in general diseases have a predilectation for beginning after the second decade with peak incidence in the third to sixth decades.5 In many instances female are predominate. The magnititudes of this sex difference varying among the different diseases. So for the systermic autoimmune disease such as systermic lupus erythomatosus, rheumatoid arthritis, sjogren’s syndrome, scleroderma, autoimmune myosities and autoimmune thyroid disease the female male ratio is 4:1 to9:1, whilst for insulin dependent diabetes mellitus, multiple sclerosis and myasthenia gravis the female predominance is much less prominent.5 The female: male ratio is les than 2:1. The extract mechanisms underlying this female predominance remain unknown.5 But this striking biological difference provides a major clue to pathway understanding susceptibility to autoimmunity.
It is obvious that autoimmunity results from the loss of self- tolerance. But there are mechanisms of immunological tolerance to self antigens.
Immunological tolerance
An immunological tolerance is a stage in which the individual is incapable of developing an immune response to a specific antigen.1 Self- tolerance refers to lack of responsiveness to an individuals own antigens, and it underlies our ability to live in our cells and tissues. The immunological tolerance can be broadly classified into 2 groups.1
1) Central tolerance
2) Peripheral tolerance
Central tolerance
This refers to death (deletion) of self reactive T and B lymphocyte clones during their maturation in the central lymphoid organs, the thymus for T cells and the bone marrow for B cells.6 This process is most active in fetal life, but continuous thought life as immature lymphocytes are generated.
There are several mechanisms of T cell tolerance. Once occurs in the thymus by means of a complicated, multistep selection mechanism. In the first stage of this process, immature T cells which do not bear either of the CD 4 and CD 8 molecules (double-negative) enter the sub capsular region of the thymus.8 And also divide and proliferate T cell receptors, CD 4 and CD8 molecules, are then co- expressed simultaneously; these cells are termed double-positive.8 Maturing cells are migrating towards the cortex of the thymus where the selection process occurs. T cells that can engage with MHC class I or 11 molecules on the thymus cortex are said to be positively selected and they undergo further processing. They will lose either the CD 4 or CD 8 co-receptor, depending on which particular MHC molecule they engage.8 Cells that do not interact with the MHC undergo programmed cell death (apoptosis).9 Thus after positive selection, only cells that can recognize MHC molecules (and thus antigenic peptides presented in association with these structures) remain.
However, another step is necessary to remove cells that can react with self-peptides, and this occurs through negative selection. This part of the selection process occurs in the corticomedulary junction, which is rich in dendrite cells and macrophages. If either CD 4 or CD 8 cells engage with cells bearing MHC class 1 or 2 molecules containing self-peptide (i.e. auto reactive T cells) they undergo apoptosis and are clonally deleted.7 The remaining cells pass through the thymus and become part of the mature T-cells pool. Negative selection is probably the most significant aspect of tolerance induction. The loss of thymocytes through the positive and negative selection process is high, with over 90% of cells undergoing apoptosis.4, 5
Peripheral tolerance
Those self reactive T-cells that escape intrathymic negative selection can inflict tissue injury unless they are deleted or muscles in the peripheral tissues.1 There is a prolonged or irreversible functional inactivation of lymphocytes induced by encounter with antigens under certain conditions. Apart from anergy there are also suppressions by regulatory T cells.3 Regulatory T cells may develop in the thymus as a result of recognition of self antigens, or they may be induced in the periphery. The best defined regulatory T cells are CD4+ cells that constitutively express CD 25, the chain of the IL-2 receptor, but some CD4+ cells lacking CD 25 may serve the same function.8
And also there is a colonel deletion by activation-induced cell death: CD4+ T cells that recognize self-antigens may receive signals that promote their death by apoptosis.7 This process has been called activation-induced cell death, because it is a consequence of T-cell activation.
In antigen sequestration some antigens are hidden from the immune system because the tissues in which these antigens are located do not communicate with the blood and lymph. This is believed to be the case for the testis, eye and brain all of which are also called immune – privileged sites. Because it is difficult to induce immune responses to antigen in this sites.4
Prevention of autoimmunity is so vital to survival that several mechanisms have evolved to protect us from our “protectors”. There is firm evidence in experimental animals for both central & peripheral mechanisms, but their relative importance in maintaining self-tolerance in humans is not established and may well very with the nature of the auto antigen.
Etiology of autoimmune disease
In autoimmune disease interactions between genetic and environmental factor are critically important.17
Genetic factors
Twin and family studies have confirmed a genetic contribution in all autoimmune diseases studied multiple autoimmune diseases may cluster within the same family.1 And sub clinical autoimmunity is common among family members. The genetic contribution to autoimmune disease usually involves multiple genes but some single gene defects involve defect in apoptosis.17
The strongest and best characterized associations involve alleles of the major histocompatibility com (MITC) as might be expected from the central role of the products of many of these genes in T-cell function, and in involvement of other MHCgenes in control of immunity and inflanmatic.7
Environmental factors.
Environmental triggers in autoimmunity include
• Hormones
• Infections
• Drugs
• Ultra violet radiation
Hormone
Female are more likely than males to develop autoimmune disease. While this has an obvious genetic basis. Hormonal factors must play a major role in this gender difference.
Most autoimmune diseases their peak age of onset within the reproductive years and evidence implicates estrogens as triggering factors. Removal of ovaries inhibits
the onset of spontaneous autoimmunity in animal models of SLE, while administration of estrogen accelerates the onset of disease. 17
Infection
The relationship between infection and autoimmunity is clearest in the situation of molecular mimicry.3 Autoimmune diseases tend to be less common in parts of the world that carry a high burden of parasitic diseases and other infections. In some animal models of autoimmunity, the development of disease can be dramatically inhibited by weeping the animals in a laboratory environment with high prevalence of infection.3 Keeping the same animals in germ free of conditions promotes the development of autoimmunity for reasons that are not clear. Attempts to identify hidden infections in autoimmune diseases such as rheumatoid arthritis and multiple sclerosis have been unsuccessful.4
Drugs
Drug-induced autoimmunity may involve mechanisms comparable to molecular mimicry, whereby the drugs or a drug -self- molecule complex has a structural similarity to self and hence allows bypass of peripheral tolerance. Some drugs (e.g. penicillamine) have the ability to bind directly to the peptide-containing groove in MHC molecules and a direct capacity to induce abnormal T-cell responses. 17
Drug – mediated autoimmunity affects only as mall proportion of those treated and is probably genetically determined. For e.g., HLA- DR 2 is associated with penicillamine induced myasthenia graves, whereas DR3 is associated with nephritis. Genetic variation in drug metabolism is important. The best example is the relationship between drug-induced systermic lupus erythomatosus and the rate of acetylating of the triggering drug: slow acetylators are prone SLE. It seems likely that this partial defect in metabolism may allow the formation immunogenic conjugates between drug and self molecules. 17
Ultraviolet radiation
Exposure to ultra violet (UV) is a well defined trigger for skin inflammation and sometimes systemic involvement in systemic lupus erythematosus.4 UV radiation can modify self-antigens, so enhancing their immunogenicity, or lead to apoptotic death of cells within skin. Apoptosis is associated cell surface expression of auto- antigens usually found only within cells which are then able to bind related auto-antibodies and trigger tissue damage.5
Mechanisms of autoimmune diseases
The development of autoimmunity is related to the inheritance of susceptibility genes, which may influence the maintenance of self-tolerance, and environmental triggers, particularly infections, which promote the activation of self reactive lymphocytes.3
Most autoimmune diseases show a strong genetic predisposition among the genes known to be associated with autoimmunity, the best defined are HLA genes. It is postulated that the presence of particular MHC alleles affect the negative selection of T-cells in the thymus or the development of regulatory T-cells. Many normal individual inherit the MHC, alleles that are disease associated in patient populations, and normal molecules are capable of presenting self antigens.9 The presence of particular MHC alleles is not, by it self the cause of autoimmunity. In several autoimmune diseases such as systemic lupus erythomatosus and type I diabetes mellitus many non MHS genetic loci have been shown to be associated with autoimmunity.9
Many autoimmune diseases are associated with infections, and clinical flare-ups are often proceeding by infectious proteomes there are two mechanisms have been linked between infection and autoimmunity. First, infections may up regulate the explanations of costimulaters an antigen presenting cells. If these cells are presenting self antigens the result may be a brake down of colonel anergy and also there is an activation of T cells specific for the self antigens.9 Second, some microbes may express antigens that have same amino acids sequences as self antigens. Immune responses against the microbial antigens may result in the activations of self reactive lymphocytes. This phenomenon is called molecular mimicry. The clear example of such mimicry is rheumatic heart disease. In this case an antibody against streptococcal proteins cross-react with myocardial proteins and cause myocarditist.10
Once an autoimmune disease has been induced, it tends to be progressive. An important mechanism for the persistence and evolution of autoimmune disease in the phenomenon of epitope spreading. Infections and even the initial autoimmune response may release and damage self-antigens and expose epitopes of the antigens that are normally concealed from the immune system.4
Tissue-specific autoimmune diseases
These occur where immune-meditated is restricted to a particular tissue or organ that specifically expresses the targeted antigen. 2 Graves disease (where auto antibodies bind to and stimulate the thyroid-stimulating hormone receptor, resulting in thyrotoxicosis). Myasthenia gravis (where auto antibodies target the acetylcholine receptor at the neuromuscular junction, resulting in muscular weakness and fatigue due to the inefficient transmission of the acetylcholine signal), and insulin- dependent diabetes mellitus (where a cytotoxic T-cell response to the B-cells of the pancreatic islets results in destruction of the insulin producing cells.)

Systemic autoimmune diseases
These are frequently characterized by simultaneous damage in multiple tissues (such as kidney, lung, skeletal muscle, nervous system, and skin)4.Unlike tissue-specific autoimmune diseases are frequently directed against molecules expressed ubiquitously in multiple tissue examples include the RNA syntheses targeted in autoimmune myosities the small nuclear ribonucleoproteins targeted in systemic lupus erythomatosus, and topoisomerase -1 targeted in scleroderma, each of these molecules is expressed in all cells, where they play critical roles in essential cellular processes ( such as protein translation, m RNA splicing, and DNA replication and remodeling, respectively ).4 Recent studies have suggested that novel forms of these ubiquitously expressed antigens are generated when cells undergo some forms of apoptotic death, and that apoptotic cells may represent an important source of immunogens in this group of disorders. While tissue damage is frequently mediates by numerous mechanisms in systemic autoimmune diseases, deposition of immune complexes at sensitive sites (such as shin, joints, and kidney) represents a prominent mode of tissue damage.4
Systemic lupus erythomatosus (SLE)
It is a prototype of a multi-system disease of autoimmune origin. Virtually every other organ in the body however may also be affected. SLE is fairly common disease, with a prevalence that may be as high as in 2500 in certain populations. Similar too much autoimmune disease, SLE is predominantly a disease of women.5 The fundamental defect in SLE is a failure of the mechanisms that maintain self-tolerance. A variety of immunologic abnormalities affecting both T cells and B cells have been defected in patients with SLE. It had been thought that an intrinsic B cell hyperactivity is fundamental to the pathogenesis of SLE. 6 Polygonal B-cell activation can be readily demonstrated in patients with SLE and murine models of this disease.6
Sjogren’s syndrome
Is a chronic disease characterized by dry eyes and dry mouth resulting from immunological mediated destruction of the lacrimal and salivary glands.3 The characteristic decrees in tears and salivary is the result of lymphocytes infiltration and fibrosis of the lacrimal and salivary glands.3 The infiltrate contains predominantly activated CD helper T cells and some B cells. It is including plasma cells that secrete antibody locally. Sjogren’s syndrome is in all likelihood initiated by CD4 + T cells. Molecular analysis of the T- cell receptors of the T cells expands clonally, Suggesting antigen-driven stimulation.8
Occurs most commonly in older women, typically between ayes 50 and 60 as might be expected, symptoms results from inflammatory destructions of the exocrine glands.5
Systemic scleroderma
Systemic sclerosis is a chronic disease. It is characteristized by abnormal accumulation of fibrous tissue in the skin and multiple organs.11 And also kidneys heart, muscles and lungs are frequently involved.4 In some patients, the disease appears to remain confined to the skin for many years, but in the majority, it progresses to visceral involvement with death from renal failure, cardiac failure, pulmonary insufficiency or intestinal malabsoption.4
The likely trigger for excessive fibrosis is a combination of abnormal immune responses and vascular damage resulting in local accumulation of growth factors that act on fibroblast, and stimulation collagen production.11 There is abnormal immune responses play a role in the pathogenesis of systemic sclerosis.3 It is proposed that CD 4+T-cells responding to an as yet unidentified antigen accumulate in the skin and release cytokines that recruit and activate inflammatory cells, including mast cells and macrophages.
Molecular analysis of the antigen receptors of the infiltrating T cells suggests that the accumulated CD4+ cells are oligoclonal, and their expansion is antigen driven. In the skin and other affected tissues the accumulated T cells and other inflammatory cells release a variety of mediators, such as histamine, heparin, IL-1, IL-2, IL-3, TNF, several of these mediators can stimulate transcription of genes that encode collagen and other extracellulor metrics proteins in tibroblased.6 Fibroblasts from patients may also be hyper responsive to cytokines and may respond to excessive collagen production.6
Rheumatoid arthritis (RA)
Is a chronic systemic inflammatory disorder that may affect many tissues and organs such as skin blood vessels, heart, lungs and muscles.16 But it is principally attach to the joints. That producing a non supportive proliferactive and inflammatory synovites that offen progress to distraction of the auricular cartilage and ankylosis of the joints.16
About 1% of the world’s population is afflicted by RA. The women 2 to 3 times more often than men.16
RA is an autoimmune disease triggered by exposure of a genetically susceptible host to an unknown arthritogenic antigen. It is the continuing autoimmune reaction, with activation of CD4+cells and other lymphocytes and local release of inflammatory mediators and cytokines that ultimately destroys the joint.4
The autoimmune reaction in RA consists of activated CD4+ T cells, and probably B lymphocytes, as well.
The T cells apparently function mainly by stimulating other cells in the joint to produce cytokines that are central mediators of the synovial reaction.4
Wegener granulomatosis
Wegener granulomatosis is a necrotizing vacuities characterized by the triad of acute necrotizing granulomas of the upper respiratory tract, the lower respiratory tract or both. 4The glaucomatous vacuities affecting small to medium-sized vessels, most prominent in the lungs and upper airways but affecting other sites as well.4 The renal disease in the form of focal necrotizing often crescent, glomerulitis.4 The Wagener granulomatosis may represent some form of hypersensitivity, possibly to an inhaled infectious or other environmental agent. The presence of granulomas and dramatic response to immunosuppressive therapy also strongly support an immunologic mechanism, perhaps of the cell-mediated type, 4
Pernicious anemia
It is believed to result from immunological mediated, possibly autoimmune, detraction of gastric mucosa.3 The resultant chronic atrophic gastritis is marked by a loss of parietal cells, a prominent infiltrate of lymphocytes and plasma cells. 3 types of antibodies are present in many but not all patients with pernicious anemia. About 75% of patients have a type 1 antibody that blocks binding of vitamin B12 to intrinsic factor.3 Type 1 antibodies are found in both plasma and gastric juice. Type 2 antibodies prevent binding of the intrinsic factor-Vitamin B12 complex to its ileal receptor.3 These immunoglobulin are also found in a large proportion of patients with pernicious anemia. Despite the presence of these auto antibodies it is not established that they are the primary cause of gastric changes. The auto reactive T cell response initiates gastric mucosal injury, triggering the formation of auto antibodies, which may exacerbate epithetical injury.3
Myasthenia gravis
Is a muscle disease caused by immune-mediated loss of ach receptors? And having characteristic temporal and anatomic patterns as well as chug responses the disease has a prevalence of about 3 in 100,000 persons.13
In most cases the auto antibodies against the AchR lead to loss of functional AchRs at the neuromuscular junction by fixing complement and causing direct injury to the post synaptic membrane. Increasing the internalization and degradation of the receptors and inhibiting binding and function of Ach.14 Electrophysiological studies are notable for decrement in motor responses with repeated stimulation. Nerve conduction studies findings are normal.13 Sensory as well as autonomic functions are not affected. Despite the evidence that anti-AchR antibodies play an artificial pathogenic role in the disease, there is not always a correlation between antibody levels and neurological deficit.12
Graves’ disease
Graves’ disease is peak incidence between the ages between ages of 20-40.women being affected up to 7 times more frequently than men. Graves’ disease is a disorder in which a variety of antibodies may be present in the serum.15
Long acting thyroid stimulator (LATS) so named because it stimulated thyroid function more slowly than TSH, LATS proved to be an IgG antibody that binds to the TSH receptor and mimics the action of TSH. It leads to stimulating adenyl cyclase, with resultant increased release of thyroid hormones.15 Almost all patients with Graves ’ disease in contrast to thyroglobuling and thyroid peroxides antibodies.15
Multiple sclerosis
Is an autoimmune demyelinating disorder characterized by distinct episodes of neurological deficits. It is the most common of the demyelinating disorders, having a prevalence of 1 per 1000 person.3 The disease becomes clinically apparent at any age. Although onset in childhood or after age 50 years is relatively rare.4
The lesions of multiple sclerosis are caused by a cellular immune response that is inappropriately directed against the components of the myelin sheath. The like hood of developing this autoimmune process is influenced by genetic and environmental factors.14 The available evidence indicate that the disease is initiated by CD4+T1+I T cells that react against self myelin antigens and secrete cytokines. These are IFN-R, which activates macrophage. 3
Treatments
Often, in organ specific Aug disorders the symptoms can be corrected by metabolic control. 2
E.g. hypothyroidism can be controlled by administration of thyroxin and thyrotoxicosis by antithyroid drugs.
In pernicious anemia metabolic correction is achieved by injection of VIT B and in myasthenia graves by administration of cholinesterase inhibiters.3. In the case of tissue grafts, protection from the immunological process, which necessitated the transplant may required.4
Conventional immunosuppressive therapy with ant mitotic drugs can be used to damp down the immune response but, because of the dangers involved, tends to be used only in life-threatening disorders such as SLE and dermatomyosities.17
The potential of cyclosporine and related drugs has get to be fully realized, but quite dramatic results have been reported in the treatment of type 1 diabetic mellitus.3,4
In particular, some experimental autoimmune diseases have been treated successfully with auto antigenic peptides and their analogues, and by vaccination with auto reactive T cells this suggests that stimulating normally suppressive functions.1

References
1) Kumar & Clark, Clinical immunology, 5th edition, (216-220)
2) John Stewars, Donald M, Weir Immunology7 th edition
3) D.P.Stites, J.D.Stobo, Basic & Clinical immunology.4th edition, (156-187)
4) Yoshisugi Hokama, Robert M., Immunology & Immunopathology
5) Roitt, Brostoff, Immunology, 4th edition, (chapter 27)
6) Wiesel f., Wellmann, Winkler, Auto reactive B cells get activated in cellular sites, Eur I Immune 2007 Nov. 29extra
7) Mackay IR, Autoimmunity since the clonal selection theory Immunal cell bio 11 2007 Nov. 27 Thewissen M., Somers, CD4+ CD28, null T cells in auto immune diseases
T immunol 2007 Nov. 15
9) Muller A., Lamprecht, Interleukin 17 in chronic Inflammatory and autoimmune disease, Z.Rheumatoid 2007 Nov. 16
10) Leyngold., Baughman. Kasper E., Comparison of survival among patients with connective tissue disease & cardiomyopathy, Am T. cardio 2007 Aug. 1-100
11) Williams HJ, Alarcon GS Early infiltration connective tissue J. Rheumatoid 1998 Feb
12) Ben David, H Sharan., The role of CD 8+, CD 28 regulatory cells
13) Apostaliski S, Larrinic D, Srp Arth Celok 2007 March, Apr. 135
14) Wakata N. Konno S., Interm Med 2007 46 (11) 747-750
15) Saiton O., Abiru N, Nakanara M, Nagayamoy, CD8+ CD 122 + T cells
16) T. Gibson, Rheumatic disease, an introduction for medical students
17) J. C. G. Underwood General & systemic Pathaphysiology4th edition
MD/2006/3486

Introduction

Caffeine is a methylxanthine whose primary biologic effect is

antagonism of the adenosine receptor.That can also acts as a mild central nervous

system stimulant. Caffeine is the most widely consumed drug in Western society. It belongs to a class of organic compounds called alkaloids, which also include morphine, codeine, LSD, cocaine and nicotine.{1}
.
1. Carbon.
2. Hydrogen.
3. Nitrogen.
4. Oxygen.

Structure of caffeine,(1,3,7-trimethylxanthine ,C8H10N4O2)
Coffee was first discovered around 850 A.D. Caffeine sensitivity varies

from person to person. Several factors may be involved in increased sensitivity to

caffeine.They are Body mass , age, smoking habits, medication or hormone use, and

health conditions such as anxiety disorders. . Although age may play some role in a

person’s sensitivity to caffeine, most studies have shown that caffeine affects children

and adults in a similar manner.The intake of caffeine-containing beverages in many

Derivation of caffein

Its presence in coffee, tea, soda beverages, chocolate, and many

prescription and over-the-counter drugs makes it the most commonly consumed stimulant

drug.Below table shows other foods which containing caffeine.

Caffeine
Dark (semi-sweet) chocolate, 1 oz. 5 to 35
Unsweetened chocolate, 1 oz. 26
Milk chocolate, 1 oz. 1 to 15
Coffee flavored yogurt, 6 oz. 35
Coffee ice cream, 1/2 cup 20 to 30
Chocolate ice cream, 1/2 cup 2
Beverage Caffeine
Brewed coffee, 8 oz. 60 to 160
Instant coffee, 8 oz. 30 to 120
Espresso, 2 oz. 100
Brewed imported tea, 8 oz. 25 to 110
Brewed American tea, 8 oz. 20 to 90
Energy drinks, 8 oz. 35 to 90
Functional waters, 8 oz. 20
Iced tea, 8 oz. 6 to 60
Caffeinated water, 8 oz. 30 to 60
Soft drinks or soda, 8 oz. 15 to 50
Instant tea, 8 oz. 24 to 31
Chocolate milk, 8 oz. 2 to 7
Decaffeinated coffee, 8 oz. 2 to 4
Medication Caffeine
Aspirin, 1 tablet 0
Appetite suppressant, 1 tablet
200
Medication to help people stay alert,
1 tablet 100 to 200
Phenylpraponolanine Hcl 30
acetominophen 32
Propoxyphene Hcl 32.4

The medical literature dealing with developmental and reproductive risks of caffeine was

reviewed, and the biological plausibility of the epidemiological and animal findings, as

well as the methods and conclusions of previous investigators, were evaluated.Also The

the effect of caffeine level in tea and coffee on acute physiological responses and mood

In addition to that Coffee is often perceived as producing greater pharmacological effects

than cola. The present study compared the magnitude and rapidity of peak caffeine levels

and subjective effects between coffee and cola.

Epidemiologic risk of caffeine .
Coffee and/or caffeine consumption has been linked to {8}many human diseases in

epidemiologic studies. Causal relationships have been difficult to substantiate. Initial

investigations, showing an association between coffee and{2}coronary heart disease,

suffer from confounding variables and have been difficult to replicate. Recent studies,

showing a significant effect over long follow-up periods and with high coffee intake,

have again raised the question of a role for coffee and/or caffeine consumption in the

pathogenesis of atherosclerotic heart disease. Contrary to common belief, the published

literature provides little evidence that coffee and/or caffeine in typical dosages

increases the risk of infarction, sudden death or arrhythmia.

Also; The epidemiological studies describe exposures of women to caffeine during
pregnancy, as well as the occurrence of congenital malformations, fetal growth
retardation, small-for-date babies, miscarriages (spontaneous abortions), behavioral
effects, and maternal fertility problems that presumably resulted from the caffeine
consumption. A few epidemiological studies were concerned with the genetic effects of
preconception exposures to caffeine. Animal studies, conducted mostly in pregnant rats
and mice, were designed to produce malformations. The objectives of the present review
are to summarize the findings from the various clinical and animals studies, objectively
discuss the merits and/or faults inherent in the studies and establish a global
reproductive risk assessment for caffeine consumption in humans during pregnancy. It
should be noted that evaluation of the developmental risks of caffeine based solely on
epidemiological studies is difficult because the findings are inconsistent. Even more
important, is the fact that caffeine users are subject to multiple confounding factors that
make analyses difficult and prevent investigators from reaching definitive conclusions.
For example, the caffeine content of foods and beverages can vary considerably, which
can interfere with obtaining valid interpretations from many human studies. Isolated
epidemiological studies dealing with the risk of abortion, without evaluating other
developmental and reproductive effects, are the most difficult to interpret, because they
present special problems that are sometimes ignored in epidemiological studies. The
results of animal studies are probably most helpful in solving some of the dilemmas
created by the epidemiological studies. An animal study reported in 1960 first focused
our attention on the potential developmental effects of caffeine. However, the exposure
reported by Nishimura and Nakai (‘60) was an intraperitoneal dosage of 250 mg/kg in

the mouse, an extremely high dosage that would result in a blood plasma level that
could never be obtained from consuming caffeine containing products. More recent
animal studies have demonstrated, that depending on the method of administration and
species, the developmental NOEL in rodents is approximately 30 mg/kg per day, the
teratogenic NOEL is 8,100 mg/kg per day, and the reproductive NOEL approximately
80-120 mg/kg per day. Lack of biological plausibility to support the concept that
caffeine has been responsible for human malformations is another important part of this
analysis. For example, no one has described the Caffeine “teratogenic syndrome,” a
cluster of malformations associated with caffeine ingestion. Proven human teratogens
have an identifiable syndrome. The malformations described in the animal studies at
very high doses fit the description of vascular disruptive types of malformations.
.Advers effect of the caffein

Ninety-nine percent of ingested caffeine is absorbed and distributed to all tissues and

organs. The effects of caffeine intake differ greatly according to acute or chronic intake,

level of intake, and the development of tolerance. Caffeine administered acutely to non-

users or recent abstainers can induce hypertension, arrhythmias, altered myocardial{5}

function, increased plasma catecholamine levels, plasma renin activity, serum cholesterol

levels, increased production of urine, gastric acid secretion, and alterations in mood and

sleep patterns.Tolerance to chronic caffeine intake develops in most individuals,with the {4}
cessation of its effects on the renal system, the cardiovascular system, the gastrointestinal

system and, to some extent, the central nervous system. Moderate caffeine consumers

probably need to have little concern for the effect of caffeine intake on their health if their

other life-style habits are also moderate.

Caffeine is probably the most frequently ingested pharmacologically active substance in
the world.. Because of its wide consumption at different levels by most segments of the
population, the public and the scientific community have expressed interest in the
potential for caffeine to produce adverse effects on human health. The possibility that
caffeine ingestion adversely affects human health was investigated based on reviews of
(primarily) published human studies obtained through a comprehensive literature search.
Based on the data reviewed, it is concluded that for the healthy adult population,{3}
moderate daily caffeine intake at a dose level up to 400 mg day(-1) (equivalent to 6 mg
kg(-1) body weight day(-1) in a 65-kg person) is not associated with adverse effects such
as general toxicity, cardiovascular effects, effects on bone status and calcium balance
(with consumption of adequate calcium), changes in adult behaviour, increased incidence
of cancer and effects on male fertility. The data also show that reproductive-aged women
and children are ‘at risk’ subgroups who may require specific advice on moderating their
caffeine intake. Based on available evidence, it is suggested that reproductive-aged
women should consume day(-1) for a 65-kg person) while children should consume Coffee is consumed in large quantities worldwide and any adverse effects would likely
have important public health consequences. Because of the widespread exposure to
coffee and other caffeine-containing beverages and because teratogenic effects of
caffeine have been recorded in several species since 1960, women are concerned that
there may be reason to limit their intake of coffee when pregnant. Several human studies
on birth defects have been conducted and the overall results do not implicate coffee as a
likely human teratogen. However, there is some evidence that consumption of three or

more cups of coffee per day may have a modest effect on lowering infant birth weight.
Studies of coffee consumption and increased rates of spontaneous abortion and delayed
time to conception are inconsistent and conclusions cannot yet be drawn.

The health effects of caffeine have been examined in a review of its toxicological and

pharmacological properties together with its effect on children. Caffeine commonly

causes symptoms of an acute overdose and withdrawal symptoms. These may be

identified as anxiety in moderate consumers and can lead to severe central nervous

system effects in heavy consumers. Pharmacological effects occur even at low doses but

their severity is influenced by wide individual variation and the development of

tolerance. Nevertheless, chronic consumption of caffeine is implicated in various minor

symptoms of ill health and is associated with elevated serum cholesterol levels. At the

doses that are consumed by humans, there is little evidence at present to suggest effects

on reproduction, teratogenesis, tumour formation or the incidence of myocardial

infarction. A reduced consumption of caffeine is advocated for all age groups.{7}

In addition to that ;Initially caffeine increases blood pressure, plasma catecholamine

levels, plasma renin activity, serum free fatty acid levels, urine production, and gastric

acid secretion. Its long-term effects have been more difficult to substantiate. Most of the

caffeine consumed is in coffee, which contains many other chemicals that may have other

biologic actions. The consumption of coffee is a self-reinforcing behavior, and caffeine

dependence and addiction are common. Coffee and caffeine intake have been linked to

many illnesses, but definitive correlations have been difficult to substantiate. Initial trials

showing coffee’s association with coronary disease and myocardial infarction have been

difficult to reproduce and have many confounding variables. Recent studies showing a

larger effect over long follow-up periods and with heavy coffee consumption have again

brought the question of the role of coffee in disease states to the fore. Caffeine in average

dosages does not seem to increase the risk of arrhythmia{6}. At present there is no

convincing evidence that caffeine or coffee consumption increases the risk for any solid

tumor. The intake of coffee and caffeine has clearly been decreasing in this country over

the past two decades, largely brought about by the increasing health consciousness of

Americans. Although there have been many studies that hint that the fears of increased

disease with coffee drinking may be warranted, many questions have yet to be answered

about the health effects of coffee and caffeine use.
coffee or caffeine dose, despite a fourfold variation in the Increasing beverage strength
was associated with greater increases. in DBP and energetic arousal. In study 2,
caffeinated beverages increased SBP, DBP, and skin conductance and lowered heart rate
and skin temperature compared to water. Significant dose-response relationships to
caffeine were seen only for SBP, heart rate, and skin temperature. There were
significant effects of caffeine on energetic arousal but no consistent dose-response
effects. Caffeinated beverages acutely stimulate the autonomic nervous system and
increase alertness. Although caffeine can exert dose-dependent effects on a number of
acute autonomic responses, caffeine level is not an important factor. Factors besides
caffeine may contribute to these acute effects,
It alters the electroencephalographic spectrum, mood, and sleep patterns of normal
volunteers. Chronic caffeine consumption has no effect on blood pressure, plasma
catecholamine levels, plasma renin activity, serum cholesterol concentration, blood
glucose levels, or urine production. Caffeine does not appear to be useful for increasing
the motility of hypomotile sperm in artificial insemination or in the therapy of minimal

brain dysfunction, cancer, or Parkinson’s syndrome, but it may be effective as a topical
treatment of atopic dermatitis and as systemic therapy for neonatal apnea. Caffeine does
not seem to be associated with myocardial infarction; lower urinary tract, renal, or
pancreatic cancer; teratogenicity; or fibrocystic breast disease. The role of caffeine in
the production of cardiac arrhythmias or gastric or duodenal ulcers remains uncertain.
Sprint and power performance

Research evidence on the effects of caffeine ingestion on sprint and power performance

is limited and inconclusive by comparison with the large volume supporting its use with

endurance athletes. And any beneficial effects on power performance are likely to be

most marked in trained athletes.{8}

A precise explanation for the ergogenic effects of caffeine remains elusive. It is likely

that the enhancement in endurance capacity results from caffeine’s ability to facilitate the

use of fat as an exercise fuel, thus sparing the body’s limited carbohydrate reserve.{9}

Caffeine’s facilitating effect on neuromuscular activity is thought to be responsible for

any improvement in short duration, high intensity exercise.{11}

Irrespective of the mode of exercise, many research subjects have reported lower levels

of perceived exertion and localised muscular fatigue following caffeine ingestion, which

will undoubtedly have boosted their performance capacity.{10}

It would be remiss not to mention at this stage that athletes who normally avoid

caffeine may experience adverse effects if they start using it as an ergogenic aid. Many

of these side effects are well known and include anxiety, gastrointestinal disturbances,

restlessness, insomnia, tremors and heart arrhythmias. The scientific literature suggests

that the risk of such side effects is increased if caffeine is taken in doses higher than 9mg

per kg of body mass.{12}

In addition, caffeine can act as a diuretic, which could lead to an unnecessary pre

exercise loss of fluid, with negative knock-on effects on thermal balance and exercise

performance, particularly in hot environments. However, this diuretic effect is reduced

when caffeine is consumed during exercise, which helps to explain why some athletes

rely on defizzed cola during events.The ergogenic effects of caffeine vary greatly, but

are most predictable in trainedathletes.{12}

Athletes should also be aware that beneficial effects do not occur consistently in habitual

caffeine users, suggesting a level of ‘caffeine tolerance’. One way round this may be for

caffeine users to shun all caffeinated foods and drinks for a period of 4-6 days prior to

pre-event supplementation in order to optimise its benefits.{10}
Physiological and Pharmacological effects

The largest sources of caffeine are from the plants used to make coffee, tea, cocoa and

kola (the basis of cola beverages), although it is also found in Latin America as mate’ and

guarana. Caffeine particularly has a profound effect on the central nervous system, but it

also affects, to a lesser degree the heart muscle, gastric secretion and diuresis.

Interestingly, caffeine is ingested daily by a vast number of people and is unique in that

it is a potent drug, considered to be part of our normal diet.

Caffeine stimulates the central nervous system first at the higher levels, the cortex and

medulla, and finally the spinal cord at higher doses. Mild cortex stimulation appears to be

beneficial resulting in more clear thinking and less fatigue. Caffeine has been shown to

improve attention in a study which simulated night driving {19} The onset of

the effect of caffeine occurs within one hour and lasts for three to four hours {17}

The equivalent of one or two cups of coffee (150 to 250 mg of caffeine) is sufficient to

induce adverse effects. The occurrence of hyperesthesia, an unpleasant sensory sensation,

can be stimulated by large doses of caffeine.

The medullary, respiratory, vasomotor and vagal centers are stimulated by caffeine. This

effect is due to an increased sensitization to carbon dioxide but needs large doses to elicit

this effect, 150 to 250 mg, parenterally. The spinal cord is stimulated at higher doses and

convulsions and death may result. More than 10 g are needed for such toxicity to occur in

man {20}

Stimulation of the CNS is followed by depression{25}, although the effect is small at low

doses e.g. a single cup of coffee. After two hours, Klein reported that males (but not

females) showed a lower CNS stimulation compared to placebo. The post stimulation “let

down” with caffeine results in fatigue and lethargy and the constant stimulation caused by

chronic caffeine dosing could be disastrous{13};

Children, because of their smaller size, are more susceptible to caffeine. One report noted

that hyperactivity and ir~somnia observed in children could be attributed to excess

caffeine intake from cola drinks.

“There is no doubt that children should be kept from using coffee and the popular

caffeine containing soft drinks.” {13}

Caffeine’s effect on the cardiovascular system is less profound than its central nervous

system action. Its direct stimulatory effect on the heart may be neutralized by its central

vagus stimulation. The direct effect predominates at very large doses with tachycardia

and, eventually, arrythmias resulting. Caffeine’s ability to potentiate cyclic AMP can

explain its ability to potentiate ionotropic responses to B-adrenergic agonists and

glucogon {20}Although caffeine dilates blood vessels by a direct action, its central effect

is one of constriction. At higher doses, the dilating effect is apparent {26}

Similarly, because its direct and central effects are antagonistic, the resultant effect of

caffeine on blood pressure is unpredictable. The net effect is usually of less than 10 mm

of Hg in blood pressure {20} Caffeine’s purported efficacy in hypertensive headaches

may be due to a decrease in blood flow as a result of the increased cerebral resistance {20}
Caffeine also stimulates releases of catecholamines from the adrenal medulla and

norepinephrine is released from nerve endings in the isolatA heart {18}

It has been shown that prolonged augmentation of gastric ’secretion results from caffeine

administration and that ulcer patients have sustained elevation of acid as opposed to

normals {20}Although a dose of approximately 10 g or more taken orally can be fatal, an

oral (3.2 g IV) one gram dose will cause adverse effects The toxic effects are

due to CNS and circulatory system stimulation and include some well recognized

prominent symptoms in addition to those which can result at high doses or in

hypersensitive persons: insomnia, restlessness, excitement, tinnitus, flashes of light,

quivering muscles, tachycardia, extrasystoles, and even low grade fever and mild

delirium have been observed.

Although caffeine is well absorbed when taken orally, its absorption may be erratic

because of its low solubility and because it may cause gastric irritation. Caffeine is

principally metabolized with only 10 percent excreted in the urine unchanged{20}

Caffeine has a physiological half-life of three and a half hours to six hours {16} Its

physiological effects are observed in less than one hour{24}. Infants do not metabolize

caffeine as well as adults and thus have a half-life of about four days {16}Certainly,

continuous ingestion of caffeine by infants can be dangerous. If a cup of coffee is

consumed by an adult six or seven times a day it would result in a high steady

concentration of caffeine in the blood. As little as four cups a day can result in

appreciable omnipresent amounts of caffeine in the body.

Caffeine can accumulate in severe liver disease {23}when its half-life can

increase to 96 hours. If these patients drink coffe(~ they should be closely monitored.

Caffeine is known to interact with other drugs resulting in a modified effect. For

example, caffeine administered with nardil (an MAO inhibitor) caused headaches and

high blood pressure{22}. This potentially dangerous interaction was first noted

by Berkowitz et al., and implicated serotonin in the mechanism.

Caffeine and barbitol are antagonistic, with caffeine (in coffee) reducing the sleeping

time induced by barbitol. Decaffeinated coffee had no effect {14}

In another study, caffeine resulted in reduced sleeping time which was counteracted by

pentobarbitol in hospitalized patients {21};Recent investigations of caffeine abuse have

questioned the indiscriminant use of this commonly accepted drug. In some individuals,

chronic excessive caffeine consumption leads to the development of caffeinism, a

syndrome which includes increased anxiety, depression, frequency of

psychophysiological disorders, and possibly degraded performance. research

demonstrating the abuse potential of caffeine. Special attention
has been given those factors which mediate the wide individual differences in
consumption patterns, susceptibility to abuse, and the varied psychological and
physiological responses to this drug. While the development of caffeine abuse is
probably best viewed as an idiosyncratic process, general guidelines for the recognition
of potential abuse, and caffeinism proper, are offered.

Thank you

References
1 Coffee and health (1984), Branbury report 17: macmahon B, sugimura T.
2 Health consequences of caffeine. Ann inter med 1983; 98:641-653, Curatolo pw, Robertson D.
3. Pathologic steepness induces by caffeine, Am J med 1981:87 (586-588), Regestein QR.
4. Caffeine induces changes in cerebral circulation, 1985; 16:814-817 Mathew RJ, Wilson WH.
5 Caffeine and hypertension, Am J med (1984) 77:54-60, Robertson D , Hollister AS, Kincaid S, workman R, Goldberg MR.
6 the genesis of ventricular extrasystoles under chloroform; with special reference to consecutive ventricular fibrillation, heart (1914);5:219-234.levy AGG
7 Coffee and health, Engl J Med, (1984) ;310:783-784,Goldman P.
8 J Sports Med Phys Fitness, 31, 42
9 Can J Appl Physiol, 20, 168
10 nt J Sports Med, 16, 225
11 Eur J Appl Physiol, 73, 358
12 Med Sci Sports Exerc, 32, 1958-63
13 ABRAMS, L.H.: Consumers Research 21, May, 1977.
14 AESCHBACHER. H.V. et al.: The Effect of Caffeine on Barbiturate Sleeping Time and Brain Level. J. Pharmacol. Exp. Ther. 192. 3, 635-641. 1975.
15 ALDRIDGE, A. at al.: Caffeine Metabolism in the Newborn. Clin. Pharm. and Ther. 25, 4, 447, 1979.
16 ARANDA. J.V. at al.: Pharmacokinetic Profile of Caffeine in the Premature Newborn Infant with Apnea. J. Pediatr. 94, 4, 663-666,1979.
17 BAKER, W.J. et al.: Effects of Caffeine on Visual Monitoring. J. Appl. Psych. 56, 5, 422-427,1972.
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