UPDATED 2024

General Characteristics

Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycemia with or without glycosuria, resulting from an absolute or relative deficiency of insulin. This is brought about by an impairment of insulin production or its release by the beta cells of the islets of Langerhans. More often it is due to a resistance to the action of insulin either due to a receptor/post receptor defect or an imbalance between insulin and its counter regulatory hormones. Clinically diabetes is characterized by a wide spectrum of disorders ranging from asymptomatic hyperglycemia to abnormalities in the various organs.

PANCREAS

The endocrine component of the pancreas consists of different types of cells: α-cells, β-cells, δ-cells and PP cells contained in the islets of Langerhans which constitute 1% of its weight. There are 100,000 islets in the pancreas, and each islet contains 1000-3000 cells. Thus altogether there are 100-300 million β-cells in the pancreas.

Pancreatic beta cells can store 200 units of insulin and can release 30-50 units of insulin per day. 95% of cells of the pancreas have exocrine function and 5% have endocrine function. The beta cells produce insulin, alpha cells produce glucagon, delta cells produce somatostatin and the PP cells produce pancreatic polypeptide.

CLASSIFICATION

The Classification suggested by American Diabetes Association (ADA) is called as the etiological classification of diabetes and has the two main types of diabetes labeled as type 1 and type 2, along with gestational diabetes mellitus and the other specific types where a precise etiological factor is identified.

The revised diagnostic criteria give equal importance to the fasting and 2 hours post glucose load plasma glucose (2h PG) for the diagnosis of diabetes, thereby eliminating the need for a routine oral glucose tolerance test (OGTT) for the diagnosis of diabetes. The cut-off level of fasting plasma glucose (FPG) for diagnosis of diabetes has been fixed as 126 mg/dl, since this reflects the same degree of hyperglycemia as a 2hr-PG of 200 mg/dl in terms of susceptibility for the development of microvascular and macrovascular complications. These criteria are expected to rationalize and simplify the diagnosis of diabetes and a larger number of people could be screened due to the simplification of the procedure of doing only fasting plasma glucose rather than an OGTT.

ETIOPATHOGENESIS

Type 1Diabetes:

Type-1 diabetes mellitus has been classified into type-1A in which cell-mediated autoimmune attack on the beta cells is more prominent and type-1B in which the mechanism is less clear. Type1B is less frequent of the two.

Classification of type-1 diabetes mellitus

1. Preclinical

a. Autoantibodies + / OGTT normal.

b. Autoantibodies + / OGTT abnormal.

c. Autoantibodies + / fasting hyperglycemia

2. Clinical – with diabetes

1a. Autoantibodies present (autoimmune)

1b. Autoantibodies absent (idiopathic)

3. Explosive onset / fulminent onset

4. Rapid onset

5. Late onset (LADA).

ETIOLOGICAL CLASSIFICATION OF DIABETES MELLITUS

1. Type 1 diabetes (cell destruction, usually leading to absolute insulin deficiency)

• Immune mediated

• Idiopathic

2. Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance)

3. Other specific types

A. Genetic defects of cell function

• Chromosome 12, HNF-1 (MODY 3)

• Chromosome 7, glucokinase (MODY 2)

• Chromosome 20, HNF-4 (MODY 1)

• Mitochondrial DNA

• Others.

B. Genetic defects in insulin action

• Type A insulin resistance

• Leprechaunism

• Rabson-Mendenhall syndrome

• Lipoatrophic diabetes

• Other

C. Diseases of the exocrine pancreas

• Pancreatitis, Trauma, Pancreatectomy

• Neoplasia

• Cystic-Fibrosis, Hemochromatosis

• Fibrocalculous pancreatopathy

• Others

D. Endocrinopathy

• Acromegaly/Cushing’s syndrome

• Glucagonoma, pheochromocytoma

• Hyperthyroidism, somatostatinoma

• Aldosteronoma

• Others

E. Drug or chemical induced

• Pentamidine

• Nicotinic acid

• Glucocorticoids

• Thyroid hormone, diazoxide

• Adrenergic agonists

• Thiazides, phenytoin

• Interferons

• Others. Immunosuppressive drugs, steroids, tarcrolimus, cyclosporin

F. Infections

• Congenital rubella

• Cytomegalovirus

• Others

G. Uncommon forms of immune mediated diabetes

• Stiff man syndrome

• Anti-insulin receptor antibodies

• Others

H. Genetic syndromes associated with diabetes

• Down’s syndrome, Turner’s syndrome

• Klinefelter’s syndrome

• Wolfram’s syndrome, Friedreich’s ataxia

• Huntington’s chorea

• Laurence-Moon-Biedl syndrome

• Myotonic dystrophy, porphyria

• Prader-Willi syndrome

• Others

4. Gestational diabetes mellitus

Type 2 DM

Type 2 DM (previously known as NIDDM) is considered as a ‘multifactorial’ or ‘complex’ disease due to the complex interaction between various genetic and environmental factors in its pathogenesis. Multiple evidence suggests that genetic factors play a major role in this condition. A genetic predisposition running through families is evident. Identical twins invariably develop type 2 diabetes when exposed to the same environmental factors. In genetically predisposed individuals several environmental factors precipitate the onset of diabetes.

Important among these are obesity, physical inactivity, repeated pregnancies, infections, physical or psychological stress and diabetogenic drugs. Birth of large babies weighing above 4 kg is a strong pointer to the subsequent development of diabetes in the mother.

Obesity

The current obesity epidemic due to the modern sedentary life and caloric abundance is a major factor that predisposes to type 2diabetes. Hence it is invariably seen that type 2 diabetes is closely related to obesity. Obese subjects show a relative resistance to the action of insulin due to a reduction in the number of insulin receptors on the target cells. The full complement of receptors is restored on shedding the excess weight.

There is an association between low birth weight in infancy and occurrence of IGT or DM in young adulthood. Increase in the body mass index (BMI) after the age of 2 years is also associated with the chance to develop DM.

Physical Inactivity

It seems to act as a factor favoring the onset of type 2 diabetes. Many of the diabetics are physically inactive. Physical exercise improves their exercise tolerance.

Role of Insulin antagonists: Glucose metabolism is delicately balanced by the coordinated effects of insulin antagonist hormones like glucagon, cortisol, catecholamines and growth hormone. Several other hormones also take part in the metabolism of carbohydrates. Imbalance of this hormonal profile results in carbohydrate intolerance.

Other antagonists to insulin: Antibodies to insulin may develop in individuals who are on treatment with insulins especially the animal insulins. The antibodies inactivate endogenous as well as administered insulin. Such patients show progressive insulin resistance. Fatty acids which compete with carbohydrate for metabolism in muscle lead to insulin resistance. In hyperlipidemia insulin dependent carbohydrate metabolism suffers and a relative insulin resistance develops.

Thus it would seem that persons are predisposed to develop type 2 diabetes by genetically. However lifestyle factors will determine the onset, age of onset, severity of the metabolic defect and further course.

PATHOLOGICAL CHANGES

Pancreas: In type 1 diabetes the beta cells of the islets of Langerhans show reduction in number, degranulation and hyalinization. In recent onset type 1 DM lymphocytic infiltration of the islets occurs and this may be caused by viral infection. Inflammation is seen particularly around the beta cells only and not around the other types of cells.

In type 2 DM during the early phase the beta cells are normal in number or only slightly reduced. The beta cells lose their sensitivity to the hyperglycemic stimulus for releasing insulin. As a result insulin secretion loses its smooth and fine relationship with glucose level. It tends to be erratic. In the early stages of evolution of type 2 DM—the reduction in the sensitivity of the receptors is compensated by overproduction of insulin and accompanying hyperinsulinemia. Frank diabetes results when beta cells starts failing and insulin production comes down.

Insulin resistance in muscle develops early in persons who would develop type 2 diabetes later. Beta cell function starts deteriorating about 10 years before the onset of DM, by which time the beta cell function has fallen to 30% or less. Acanthosis nigricans is a cutaneous marker of hyperinsulinemia. Both impaired fasting glucose (1FG) and

impaired glucose tolerance (IGT) lead to type 2 diabetes in a variable proportion of patients.

Several factors account for the frequency and time of onset of complications in diabetes. These include theabnormalities of glucose levels, genetic factors, smoking, obesity, hypertension, hyperlipidemia and others.

Vascular Changes

Diabetics show a predisposition to develop vascular lesions affecting both small and large blood vessels. In microangiopathy, there is specific involvement of the small blood vessels. Venules, capillaries and arterioles are affected in this process. There is deposition of PAS (periodic acid Schiff) positive material in the capillary basement membrane. Glycosylation of several proteins in the vessel wall results in increased permeability. The basement membrane is thickened. Ultimately there is vascular occlusion.

Microangiopathy is most marked in type 1, developing early in life but also occurs in type 2. Various factors like endothelial damage, increased plasma viscosity, erythrocyte aggregation, reduced red cell deformability and increased platelet adhesion lead to microangiopathy. The problem is more complex and the entire process is still not fully understood. Microangiopathy affects several organ systems. The main lesions are seen in the retina; kidneys, peripheral nerves and heart giving rise to diabetic retinopathy, nephropathy, many forms of diabetic neuropathy and cardiomyopathy.

Macroangiopathy

The diabetic is prone to develop occlusive vascular disease in medium sized arteries such as the coronary, cerebral and peripheral limb vessels. The process is one of atheroma which sets in at younger ages and is more extensive than that occurring in non diabetics. These lesions lead to increased risk of ischemic heart disease, cerebrovascular accidents and ischemia to the limbs with intermittent claudication and peripheral gangrene. Macroangiopathy largely accounts for the steep rise in mortality in middle-aged diabetics.

Retinopathy

Diabetes mellitus produces a classical retinopathy. A specific change occurs in the vessels leading to loss of mural cells (pericytes) and the formation of micro aneurysms. The occurence of retinopathy is related more to the duration of the disease than to the severity. Once initiated the fundus changes are usually progressive. The early changes are venous dilation and the appearance of small dot like micro aneurysms in the perimacular area.

Arterial blood is shunted and this leads to ischemia of the retina. Increased vascular permeability accounts for the formation of exudates. In the next stage dot and blot hemorrhages predominate. Large subhyaloid hemorrhages and vitreous hemorrhages may develop and vision is seriously impaired. Such hemorrhages are due to rupture of newly formed blood vessels. As these hemorrhages are absorbed, organization by fibrous tissue results and multiple bands of retinitis proliferans develop. These lead to permanent visual impairment. The fibrous bands may contract giving rise to retinal detachment. Leaking vessels in the retina can be demonstrated by fluorescein angiography.

Retinopathy is usually associated with advanced nephropathy. Sometimes in diabetic ketoacidosis with severe hyperlipidemia the fat gives a milky white appearance to the retinal arteries called “lipemia retinalis”

Renal Lesions

These are commonly seen in subjects who have had diabetes for over 15-20 years. Vascular changes include (i) arteriosclerosis of the renal artery, (ii) sclerosis of the arterioles and (iii) glomerulosclerosis. Glomerulosclerosis may be nodular (Kimmelstiel-wilson lesion) or diffuse. There is accumulation of PAS positive eosinophilic material within the mesangium. There is thickening of the glomerular capillary basement membrane. The establishment of glomerulosclerosis is indicated by the presence of proteinuria. Further damage to the glomeruli results in the development of chronic renal failure.

Distant stages can be defined in the evolution of diabetic nephropathy. In the initial stages, asymptomatic microalbuminuria in which up to 200 mcg/minute of albumin may be lost in the urine. Normal subjects do not lose more than 20 mcg/min or 300 mg of protein in 24 hours. Microalbuminuria is not detectable by the ordinary laboratory tests. In type 1 DM there is elevation of systotic BP during sleep preceding micro albuminuria. This rise in BP is an important contributory factor in the development of structural changes in the kidneys. It is absolutely necessary to control blood pressure also along with blood sugar to prevent deterioration.

In the early stage the kidneys are enlarged, more vascular and the glomerular filtration rate (GFR) is increased. In the second stage, there is microalbuminuria and in third stage the proteinuria is more pronounced and easily detectable by routine tests. Loss of 3.5g or more of protein in 24 hours may lead to the development of nephrotic syndrome. Hypertension develops during this stage. In the fourth stage further structural changes develop and the glomerular filtration rate comes down with gradual increase in the blood levels of metabolic waste products such as creatinine and urea. The fifth stage is one of gross reduction of glomerular filtration and overt renal failure with azotemia, severe hypertension and complications such as cardiac failure and end stage renal failure. Autonomic neuropathy may lead to functional obstruction of the bladder, retention with over flow, urinary infection and further deterioration of renal functions. Another system of classification is based on creatinine clearance.

The diabetic patient is predisposed to develop urinary infection and therefore acute and chronic pyelonephritis are very common. Fulminant urinary infection leads to ischemic necrosis of the renal papillae. This presents as acute anuric renal failure. Fleshy masses may be passed in the urine. These are the necrosed papillae and the condition is called papillitis necroticans ulcerans. Emphysematouspyelonephritis is another serious complication.

Peripheral Nerves

In the myelinated nerve fibers, axonal atrophy was considered to be the primary lesion, secondary to ineffective axonal transport. Axoglial dysfunction, and abnormalities of paranodal connections between the terminal myelin loops and the axonal membrane have also been described. This could explain the reduction in nerve conduction velocity. This improves with therapeutic inhibition of aldose reductase. More recent studies, however provide evidence for the presence of demyelination and hence Schwann’s cell involvement is the primary lesion. As the myelinated fibers degenerate, there is an attempt to regenerate, which manifests in the form of regeneration clusters. With progress of the neuropathy the density of the regeneration clusters also comes down. Structural abnormalities have also been found in the vessels supplying the nerve fibers. The epineural vessels show arteriolar attenuation, venous distension, arteriovenous shunting and new vessel formation along with intimal hyperplasia and hypertrophy, denervation and reduction in neuropeptide expression. The perineural vessels also demonstrate basement membrane thickening and endothelial cell hypertrophy and hyperplasia. There is also a reduction in capillary density and occurrence of pericyte loss with reduction of endoneural oxygen tension and blood flow to the nerves.

CLINICAL FEATURES

The clinical manifestations of diabetes are protean. Though the symptoms are similar in both types of diabetes, in type 1 they develop acutely whereas in the majority of the type 2 the onset is insidious. Type 1 patients are usually below the age of 30, thin and emaciated and unless promptly treated with insulin, they would develop ketoacidosis.

Due to the high prevalence of obesity, type 2 diabetes is occurring at earlier ages as a global phenomenon, especially in developed countries.

Type 2 patients are generally above the age of 30, obese, usually asymptomatic and may present directly with the vascular complications of diabetes. Around 50% of the cases present with the classical symptoms of polyuria, polyphagia and weight loss. These symptoms can be directly correlated with hyperglycemia and glycosuria. Other clinical presentations which warrant full investigation to exclude diabetes are (i) non-healing ulcers (ii) recurrent respiratory or urinary tract infections (iii) Rapid changes in refraction of the eyes (iv) steady and unexplained rapid weight loss (v) increased tendency for fungal infections like moniliasis, balanoposthitis and vulvitis; (vi) unexplained peripheral neuropathy (vii) premature onset of ischemic heart disease, stroke or vascular occlusions (viii) history of overweight babies and recurrent fetal loss in women (ix) premature cataract often below the age of 50 years and retinopathy (x) impotence in males, and (xi) any vague ill-health. In some cases, diabetics may present to the doctor for the first time with any of the major emergencies, without any apparent illness previously.

DIAGNOSIS

Diabetics with classic symptoms can be diagnosed clinically, but since many cases may be asymptomatic, diabetes should be suspected even in the absence of symptoms. The clinical symptoms and the biochemical alterations do not go hand in hand in many cases. Diabetes being mainly a biochemical disease with several different but inter-related biochemical and molecular abnormalities, should always be diagnosed and managed with biochemical monitoring along with clinical examination.

Fasting plasma glucose levels above 126 mg/dL (6.7 mmol/L) or postprandial plasma glucose levels above 200 mg/dL are diagnostic. It is always better to do bothestimations to confirm the diagnosis.

Estimation of FBS and PPBS has become mandatory investigations in all health check up examinations.

Urine tests: These tests can be used for initial screening and follow-up of cases under treatment. Urinary glucose does not always directly reflect the blood glucose level. The value of urine examination cannot be underestimated since protenuria, ketonuria and the microscopic abnormalities can be detected only by examining the urine.

Glucose in urine is tested by the Benedict’s test and Clinitest (Chemtab), which detect reducing substances non-specifically. While glucose is by far the most common reducing substance in urine, the possibility of other reducing substance should be kept in mind and the enzyme methods (employing glucose oxidase) which are specific for glucose (Clinistix, Diastix) should be employed. If the Benedict’s test is positive and the glucose oxidase is negative, the presence of other reducing substances such as ascorbic acid, aspirin and lactose should be suspected.

Blood glucose estimation: Various methods are employed to estimate the blood glucose. The methods using copper reduction (Folin-Wu or Nelson Somogyi) also detect the reducing substances like uric acid, creatinine and hence their values are 20-30 mg/dL higher than those obtained by the glucose oxidsae method which gives the true glucose values. Highly accurate and rapid (1-2 min) devices are now available based on immobilized glucose oxidase electrodes. Hexokinase and glucose dehydrogenase methods are used for reference. Blood sugar estimations are mandatory for confirming the diagnosis of diabetes. Both fasting and postprandial values should be estimated. In mild diabetes the fasting blood sugar values may be below 126 mg /dL and therefore the diagnosis is likely to be missed if only the fasting blood sugar is estimated.

Glucose tolerance test (GTT): The oral glucose tolerance test (OGTT) is mainly used for diagnosis of diabetes when blood glucose levels are equivocal, during pregnancy, or in an epidemiological setting to screen for diabetes and impaired glucose tolerance.

The OGTT should be administered in the morning after at least 3 days of unrestricted diet (greater than 150 g of carbohydrate daily) and usual physical activity. The test should be preceded by an overnight fast of 8-14 h. during which period only water may be drunk. Smoking is not permitted during the test. The presence of factors such as medications, inactivity and infection that influence interpretation of the results of the test must be recorded.

After collection of the fasting blood sample, the subject should drink 75 g of anhydrous glucose dissolved in 250-300 mLof water over the course of 5 minutes. For children, the test load should be 1.75g of glucose per kg of body weight, up to a maximum of 75g of glucose. Blood samples should be once again collected 2 hr after the test load.

If there is delay in estimation of glucose the blood samples should be collected in a tube containing sodium fluoride (6 mg/mL of whole blood) and immediately centrifuged to separate the plasma. In subjects having symptoms of diabetes, a single fasting value above 126 mg/dL or a 2-hour blood glucose value above 200 mg/dL after 75 g of glucose oral may be taken to be diagnostic. In asymptomatic subjects at least two abnormal blood glucose values should be insisted upon to confirm the clinical diagnosis.

TREATMENT

The aim of treatment is to achieve normal blood glucose levels throughout day and night, to alleviate symptoms and to prevent complications. The four pillars of diabetic management are diet, exercise, drugs and patient education, backed up by regular monitoring of glycemic control and early detection and treatment of complications.

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CORD BLOOD TRANSFUSION

Cord blood is the blood obtained from placenta and in the attached umbilical cord. Sources of stem cells include bone marrow, peripheral blood, umbilical cord blood, fetal organs and artificially produced human embryos in vitro.

Cord blood is a rich source of multipotent stem cells. They are less likely to mount immunological reactions. Cord blood stem cell infusion is becoming more popular.

Use of blood collected from the umbilical cord after delivery as a source of stem cells has become an established procedure within the past 15 years. Cord blood contains large number of granulocyte-macrophage progenitor stem cells, sufficient enough to re-populate marrows of irradiated subjects. This has paved the way for organized cord blood banking. There are several blood banks undertaking storage and delivery of cord blood, all over the developed countries. There are a few privately-owned cord blood banks in the world. Cord blood can be cryopreserved in the viable state for many years. The services provided include:

1. Use of cord blood as a source of stem cells and

2. Preservation of the cord blood indefinitely for long periods, for use in the same individual if a need for stem cells arises. The donor is charged for this service.

Uses of Cord Blood

1. Allogenic transplant

2. Autologous transplant

3. As a source of multipotent stem cells for reconstitution and repair of damaged tissues such as the heart, after myocardial infarction.

The immunological properties of cord blood stem cells differ from those of adult marrow or peripheral blood.

Cord blood contains a higher proportion of T-cells expressing (C D 45 R A ⁺/ C D 45 R A O^–) and CD 62 L⁺. These cells are immunologically naïve and therefore graft versus host disease is less common.

The chemokine receptor C C R5 expressed by Th-1 T lymphocytes is less abundant in cord blood T-cells compared to adult T-cells.

Cord Blood Banking

Pregnant women are recruited as donors after obtaining informed consent, and excluding common communicable diseases. Blood is collected from the placental side of the severed umbilical cord either in utero before the delivery of the placenta or ex-utero after its delivery. Long-term storage is done under temperatures below –180° C and released for use on demand after proper cross-matching.

Indications for Cord Blood Transfusions

a. Stem cell replenishment in hematological malignancies—acute leukemias, chronic myeloid leukemia and myelodysplastic syndrome.

b. Non-malignant conditions-aplastic anemia, thalassemias, hemoglobinopathies, immunodeficiency states.

ADVANTAGES AND DISADVANTAGES OF CORD BLOOD

Advantages of cord blood are its availability, lower incidence of graft versus host disease (GVHD) and good success rate even if mismatched for two antigens. The waiting period for transplantation is also shorter.

Disadvantages are the higher infection rates with cord blood stem cells, compared to preparations from bone marrow or peripheral blood from adult donors.

Future strategies for improving the service include:

1. Pooling of cord blood

2. Cord blood expansion using cytokines which stimulate stem cell proliferation

3. Combining cord blood and haplo-identical bone marrow transplants

4. Non myeloablative or reduced intensity conditioning regimen.

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ZINC

Zinc is present in many enzymes. Highest concentration occurs in the liver, voluntary muscle, bone, prostate, and ocular structures. Foods such as meat, fish, peas and cereals contain zinc. Daily requirement is not clearly known, but is around 15 mg. Dietary deficiency is very rare. Zinc deficiency leads to impairment of maturation and immunodeficiency. In malnourished subjects zinc deficiency may result in thymic atrophy.

A syndrome of dwarfism and hypogonadism seen in Egypt and Iran has been attributed to zinc deficiency. Oral zinc sulphate corrected this clinical picture. Acrodermatitis enteropathica is an inherited disorder resulting from the malabsorption of zinc, probably due to an enzymic defect.

Administration of zinc sulphate 30-150 mg/day results in complete remission. Oral zinc sulphate 100 mg/day has been found to stimulate the growth of granulation tissue in chronic ulcers. Oral supplementation of zinc 10 mg (5mg) in children less than 1 year of age for 16 months reduced overall all-cause mortality by 7%.

SELENIUM

Selenium is a constituent of selanoproteins. It has structural and enzyme roles and it acts as an important antioxidant. It is a catalyst for the production of thyroid hormone. Other functions include: (1) proper functioning of the immune system, (2) sperm motility, (3) maintenance of proper mood and mental state, (4) resistance against cancer. Selenium retards the progress of AIDS. Daily requirement is 400-450 μg/day. Dietary sources include Brazil nuts, kidney, crab, liver, shellfish, fish, meat, poultry, wheat and some vegetables. In animal foods selenium is present as sclenocystine. In vegetable sources it occurs as sclenomethionine.

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Yellow fever is an acute mosquito-borne infection of varying severity characterized by the triad of hepatitis, hemorrhagic diathesis and proteinuria.

Etiology

The causative virus is an arbo virus belonging to the genus Flavivirus, in the family Flaviviridae.

Distribution and Incidence

Yellow fever is prevalent in many parts of Africa, tropical parts of South America and Panama. The presence of the efficient vector Aedes aegypti mosquitoes and the non-immune population pose a threat of the disease spreading, if the virus is introduced.

Transmission and Epidemiology

Epidemic (urban) yellow fever is transmitted from human to human by Aedes aegypti mosquitoes. Infected monkeys and the vector mosquitoes maintain the reservoir of infection in the jungle. These act as a source of infection when the humans intrude into endemic areas.

Pathology and Pathogenesis

The incubation period after an infectious mosquito bite is 3 to 6 days. Liver and kidneys show maximal lesions but hemorrhage may occur in all organs. Hepatic changes include widespread necrosis, and degeneration of liver cells. Renal changes include acute tubular necrosis and subcapsular hemorrhages. Bleeding diathesis is due to depletion of hepatic clotting factors, intravascular coagulation, and platelet abnormalities. Direct damage to the myocardium, kidneys and other organs and the effects of vasoactive cytokines, lead to fatal complications such as multi-organ failure and shock.

CLINICAL FEATURES

In the majority of cases, the disease is a self limited with fever and myalgia. 25 to 50% of cases may develop the full syndrome with complications such as hemorrhages, jaundice, renal involvement and shock.

The first stage (i.e. period of infection) is due to the direct effect of the virus. It starts abruptly with fever, headache and myalgia. In severe illness there is nausea vomiting, abdominal pain and distressing pain in the back, and limbs. There is relative bradycardia. This stage lasts about 3 days and by 4th day the temperature comes down and the second stage (period of remission) starts.

Many cases recover without going to the third stage. Some progress to the third stage (period of intoxication). It starts after a day or a few days, with resumption of high fever, body pains, nausea, vomiting, abdominal pain and changes in the level of consciousness. Bradycardia, jaundice, wide spread hemorrhages and renal failure may supervene. Death is due to hepatic or renal failure and shock.

Diagnosis

In endemic areas, fever, leukopenia and proteinuria with or without jaundice should suggest the possibility of yellow fever. Specific diagnosis is established by the isolation of the virus from the blood in the first few days of fever or demonstration of rising titer of antibodies in serum.

Treatment

There is no specific antiviral treatment. Symptomatic and supportive measures should be instituted. Hepatic and renal failure has to be anticipated and managed accordingly.

Prevention

Vaccination using live attenuated vaccine (17D strain) is very effective. Vaccination gives immunity starting from ten days and full protection for 10 years. Though side effects are generally negligible, children below 9 months may develop encephalitis. Pregnancy is not a contraindication for vaccination. Many countries insist on yellow fever vaccination for persons entering the country or remaining during transit, if they come from endemic areas. Persons travelling to endemic areas have to take vaccination.

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Sex Chromosome Related Disorders

In all females one of the ‘X’ chromosome derived from either parent undergoes inactivation at the early period of gestation, in a random manner governed by the laws of probability Lyon’s hypothesis (1961). Females, therefore contain a mosaic of tissue cells containing either the maternal or the paternal X-chromosome. Inactivation of the X-chromosome is effected by the action of a gene called the X-inactivation specific transcript which is located in the long arm of the X-chromosomes. Since 50% of the X-chromosomes in carrier females are normal, they do not manifest signs of the disease, but male offsprings suffer from the disease.

X-linked Recessive Inheritance

1. There is ‘oblique’ transmission, i.e., in the pedigree a line drawn through the affected persons is oblique.

2. Only males are affected, females are only carriers.

3. For the offsprings of a carrier female there is a 50% chance of sons being affected and a 50% chance of daughters being carriers.

4. Among offsprings of an affected male, none of the sons will carry the trait, while all the daughters will be carriers.

A female may manifest an X-linked trait if the normal X-chromosome is inactivated during early fetal life or if she is the offspring of a carrier female and affected male, or if the unaffected X-chromosome is structurally abnormal, as in Turner’s syndrome, e.g., hemophilia, Christmas disease, pseudohypertrophic muscular dystrophy.

X-linked Dominant Inheritance

1. The number of females affected is double the number of affected males.

2. The affected male passes Y-chromosome to his sons (and not the X-chromosome). Therefore, all sons of an affected male are normal, whereas all daughters of an affected male are abnormal.

3. The affected female passes the mutant X-chromosome to half her daughters and to half her sons and, therefore, half the daughters and half the sons are affected.

The disease is usually milder in the female, because of the normal gene on the other X-chromosome, e.g. hypophosphatemic type of vitamin D resistant rickets.

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DEFINITION

The term pertussis, which means intensive cough, is an acute respiratory infection, seen more commonly in young children. The disease is also more serious in them. The term “whooping cough” is derived from the occurrence of progressive repetitive paroxysms of cough followed by inspiratory whoop. Natural pertussis infection and vaccination do not produce life-long immunity. The immunity wanes over a few decades. Since there is almost complete coverage of DPT vaccination in children, adolescents and adults may become susceptible to infection increasingly. It is therefore possible that adults develop pertussis infection.

Pertussis is caused by Bordetella pertussis which is highly infective. Bordetella parapertussis and B. bronchiseptica are members of the same genus, rarely causing disease in man. Maximum incidence is seen in children below five years and the mortality is highest for children below 1 year of age. The organisms are spread by droplet infection and the route of entry is the respiratory tract.

The infectious period is the catarrhal prodrome and for three weeks after the onset of illness. Bordetella are small gram-negative coccobacilli, exclusively pathogenic to humans. The genome of B.pertussis has been sequenced.

Pathology

The mucosal lining of the respiratory tract shows inflammation. Peribronchial lymphoid hyperplasia occurs initially and this is followed by necrosis of the midzonal and basilar layers of the bronchial epithelium. This leads to the accumulation of tenacious mucus, atelectasis and eventually bronchiectasis.

Clinical Manifestations

The incubation period is usually 7-14 days but may be prolonged to 20 days. Three stages can be distinguished—catarrhal, paroxysmal and convalescent—each lasting up to 2 weeks so that the course of the disease extends to 6-8 weeks.

The catarrhal stage manifests with rhinorrhea, mild fever, and cough. During this stage, clinical recognition of the disease is difficult. This is the most infective stage.

In the paroxysmal stage cough starts, increases in severity, and becomes repetitive and explosive. Each paroxysm is followed by a whoop produced by a sudden massive inspiratory effort through a narrowed glottis. During the paroxysms of cough the infant develops facial congestion, distension of neck and scalp veins, lacrimation, cyanosis, and clouding of consciousness. The paroxysm ends with the onset of vomiting. The whoop may not be distinctly made out in younger infants, but they may become asphyxiated and develop anoxic convulsions. Physical examination may reveal periorbital edema. In the uncomplicated cases lung signs are usually absent. Pertussis occurring in adults causes prolonged cough. With increasing age the manifestations also become more severe.

Convalescence is marked by the decrease in frequency and severity of the paroxysms. Vomiting subsides and the patient’s appetite improves. At this stage the child is very susceptible to develop superinfections by other respiratory pathogens and this may lead to recurrence of the

paroxysms of cough. When this occurs it may last for several months.

Complications

Complications are common to develop

A. Respiratory:

Otitis media, especially in infants

Bronchitis

Bronchopneumonia

Atelectasis (segmental or lobar)

Interstitial or subcutaneous emphysema or pneumothorax due to rupture of alveoli

Bronchiectasis

Flare-up of tuberculosis

Sudden death of the infant may occur

B. Central nervous system:

Convulsions may occur due to anoxia, encephalopathy or rarely intracranial hemorrhage.

C. Gastrointestinal:

Severe vomiting with dehydration, tetany, ulceration of the frenum of the tongue (due to biting during a paroxysm), prolapse rectum, hernia.

D. Hemorrhages:

Epistaxis

Subconjunctival hemorrhage

Hemoptysis, hematemesis

E. Malnutrition:

Severe emaciation occurs in most of the affected children. In poor communities it is the starting point for marasmus and kwashiorkor.

Diagnosis

The disease has to be suspected clinically, particularly in an unimmunized child with known contact with the disease. Total leucocyte count is elevated to 20,000 to 50,000/cmm with absolute lymphocytosis. A leukemoid reaction may sometimes occur. Chest X-ray may show perihilar infiltrates or segmental collapse. Bacteriological diagnosis is established by culturing the organism obtained from nasopharyngeal swabs. Fluorescent antibody staining of pharyngeal specimens provides a rapid and specific diagnosis. PCR using nasopharyngeal aspirate reveals the organisms. In cases with duration above two weeks IgG antitoxic antibody can be demonstrated in serum.

Treatment

Supportive care is important to maintain nutrition, prevent aspiration into the respiratory tract and maintain the airway. The airway is cleared by suction of the exudates. Anoxic convulsions are managed by administration of oxygen and anti-convulsants. Small, frequent feeds are tolerated if given soon after a paroxysm of cough.

Intravenous fluids may be required if the child is dehydrated. In general, administration of antibiotics does not shorten the paroxysmal stage, once it is established. Erythromycin 50 mg/kg/day given for 5-7 days will reduce the period of communicability. It may even abort or prevent the progress of the disease if given in the catarrhal stage. Ampicillin, chloramphenicol and cotrimoxazole may also be used as alternative drugs. Azithromycin 250-500 mg po, od for 7-10 days is effective in controlling the infection if started early. Clarithromycin is a suitable alternative.

Antibodies are not transferred transplacentally in the case of whooping cough. In most patients, a single attack confers life-long immunity.

Prevention

Active immunization is achieved by the administration of the pertussis vaccine, usually given in combination with diphtheria and tetanus toxoids (DPT). The vaccine contains killed B. pertussis. The initial dose is given at 2 months, with 2 more doses at 4 week intervals. The first booster is given 1 year later and the next one at school entry.

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THIAMINE (VITAMIN B₁ – ANEURINE)

Thiamine plays an essential part in the metabolism of carbohydrates by acting as a coenzyme required for the decarboxylation of pyruvate to acetyl coenzyme A. It also takes part in other steps of the Kreb’s tricarboxylic acid cycle. Cereals contain the vitamin, which is maximal subjacent to the bran. Thiamine content of rice is lost during milling and polishing. Parboiling allows the vitamin to penetrate the grain and conserves it to some extent. Other good sources of the vitamin are sprouting pulses, green leafy vegetables, liver, pork, and legumes. Part of the vitamin is lost by washing or discarding the water used for cooking. The daily requirement is 0.4 mg/1000 kcal, i.e. 1.2 mg/day. Requirement is partially influenced by the intake of carbohydrates.

Deficiency States

Pathology of deficiency

In thiamine deficiency the cells cannot utilize glucose aerobically. Nervous system is affected first. Pyruvic and lactic acids accumulate and this leads to vasodilation. The myocardium shows loss of striation, vacuolation of fibers, fragmentation and edema. Cardiomyopathy, encephalopathy and peripheral neuropathy may develop. Sensory, motor and autonomic nerves show demyelination and degeneration.

Clinical features

Cardiovascular involvement results in ‘wet beriberi’ and nervous system involvement results in ‘dry beriberi’. Cardiovascular system Peripheral vasodilation leads to high output circulatory state, myocardial failure and retention of sodium and water leading to edema. The pulse is of high volume. The extremities are warm owing to vasodilation and tender owing to neuropathy. Acute fulminant cardiac failure may be rapidly fatal. Wet beriberi may occur in breastfed infants aged 2-8 months. The child presents with edema, oliguria and an aphonic cry. If not clinically suspected, this condition may be missed. Sudden death may occur.

Neurological involvement

This manifests as symmetrical sensori-motor polyneuropathy with muscle wasting. Foot-drop and wrist-drop are common. Deep hyperaesthesia occurs and it manifests as calf tenderness.

Wernicke’s encephalopathy

This is an acute neurological manifestation which is more common in alcoholics. Pathological changes occur in the upper part of the midbrain, hypothalamus and the walls of the third ventricle which show congestion and petechial hemorrhages, most marked in the mammillary bodies. The onset is sudden with vomiting, confusion, bilateral ophthalmoplegia, loss of consciousness, nystagmus, ataxia and psychological disturbances. Confusion proceeds to coma and death. Korsakoff’s syndrome is characterized by retrograde amnesia, impaired ability to learn and confabulation. Wernicke’s encephalopathy is associated with high mortality. Prompt administration of thiamine rapidly restores normalcy.

Diagnosis of thiamine deficiency

The condition has to be suspected clinically. It can be confirmed by demonstrating raised levels of blood pyruvate. Normal blood pyruvate is 62.5 to 125 mmol/liter and it may rise to 375 mmol/liter (3.3 mg/L). Measurement of erythrocyte transketolase activity, before and after the addition of thiamine pyrophosphate gives the most reliable diagnostic test.

Treatment:

When beriberi is suspected or diagnosed, 50 mg thiamine should be given intramuscularly daily for several days. After controlling the acute symptoms 2.5-5 mg should be given orally as maintenance. Wet beriberi and Wernicke’s encephalopathy have to be treated as medical emergencies. A dose of 25-100 mg of thiamine should be given intravenously to save life. Dramatic recovery with diuresis occurring within hours of injection confirms the diagnosis.

Infants with beriberi should be given 10 mg thiamine intramuscularly followed by oral doses. The mother also should be treated with oral doses of 10 mg twice daily for several days. Since polyneuropathy and Korsakoff’s psychosis are more resistant to treatment, the vitamin has to be given for prolonged periods. Once neuropathy is established, residual paralysis persists even after therapy. Adverse side effects to thiamine include sensitization and anaphylactic shock.

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VITAMIN E (ANTI-STERILITY VITAMIN)

Vitamin E is a tocopherol. Among the tocopherols alpha tocopherol is the most easily absorbed and biologically most active compound. All vegetable oils, wheat-germ, cotton seeds, egg yolk, butter and peas contain this vitamin and the average Indian diet contains the daily requirement which is 15 IU or 5 mg. Vitamin E which is a strong antioxidant prevents the peroxidation of cellular and subcellular membrane phospholipids. It is probably involved in preserving the integrity of cell membranes.

In cattle and poultry, vitamin E deficiency may lead to infertility. Nutritional deficiency of vitamin E is rare. Excess of free fatty acids in the diet increases the requirement for vitamin E. In premature infants fed on artificial diets containing iron and high concentrations of fatty acids, conditioned deficiency may develop, leading to the production of hemolytic anemia.

In doses of 400-800 mg, vitamin E acts as an effective antioxidant, thereby retarding the development of atheromatous changes in arteries.

VITAMIN K (COAGULATION VITAMIN)

This vitamin which is chemically a substituted naphthoquinone is present in adequate amounts in vegetable oils and green leafy vegetables as vitamin K₁ (phytomenadione). Vitamin K comprises of several molecular forms that have a common 2-methyl-l, 4-naphthoquinone ring, but different side chains at the 3-position. In green leafy vegetables and legumes and vegetable oils such as rapeseed oil and soyabean oil vitamin K occurs as phylloquinone (old name K₁).

Bacteria synthesize vitamin K which is named menaquinone (MK-n) which occurs in several molecular forms. Milk is a poor source. The colonic bacteria synthesize this vitamin (Vitamin K₂) and this supplements the dietary source. Naturally occurring vitamin K is fat soluble. The synthetic form of this vitamin is vitamin K₃ which is water-soluble. This can be given intramuscularly or intravenously, unlike the oily preparations which can be given only intramuscularly. Daily requirement is not clearly known, but is probably 1 μg/kg body weight. Body sources are limited and, therefore, signs of deficiency develop within 3 to 4 weeks of dietary deprivation. Oxidative phosphorylation processes which take place in cellular mitochondria require the presence of vitamin K. Vitamin K occurs in large amounts in liver and bone. In the liver it takes part in the synthesis of precursors for coagulation factors, protein C and protein S. Vitamin Kdependent coagulation factors (factors II, VII, IX and X) are produced in the inactive form by the liver, and vitamin K is required for their biological activation. The inhibitors of coagulation—Protein C and Protein S are also produced in the liver and these are also vitamin K dependent. Coumarins inhibit the enzyme vitamin K epoxide reductase and thereby inhibit further actions of Vitamin K.

Prothrombin (factor II) is synthesized in the liver as an inert precursor, termed protein induced by vitamin K absence (PIVKA). This is carboxylated to form prothrombin by the vitamin K dependent enzyme—gamma carboxylase. In the absence of vitamin K or after

administration of vitamin K antagonists such as coumarin PIVKA appears in the plasma.

Vitamin K is needed for the formation of several proteins concerned with calcium homeostasis. Vitamin K promotes the conversion of protein-bound glutamate residues to gamma-carboxy glutamate (Gla). Proteins containing Gla are present in several tissues such as bone, kidneys, placenta, pancreas, spleen and lungs.

Vitamin K also takes part in bone metabolism—both bone formation and resorption. Two of the important Vitamin K dependent proteins are osteocalcin and matrix Gla protein.

Vitamin K Deficiency

Vitamin K deficiency occurs in conditions associated with malabsorption of fat such as obstructive jaundice and malabsorption states. Prolonged treatment with broad spectrum antibiotics destroys the colonic bacteria which synthesize this vitamin. Deficiency manifests as mild or severe bleeding tendency occurring from injection sites, mucous membranes, and skin. Injections of vitamin K in doses of 5-10 mg corrects the defect, if hepatic parenchymal function is normal. In the presence of hepatic failure, vitamin K may not be effective.

HEMORRHAGIC DISEASE OF THE NEWBORN

Hemorrhage may develop in newborn infants occasionally. Prematurity predisposes to this condition. Vitamin K deficiency in the mother and anticoagulant medication aggravate this disorder. Hemorrhagic  tendency develops on the second or third day of delivery. This is due to exaggeration of the physiological hypoprothrombinemia which develops before the colon is colonized by bacteria.

A dose of 1 mg of vitamin K1 given intramuscularly to the baby brings about relief. Synthetic vitamin K is also effective. Larger doses have to be avoided since these lead to hemolysis. Administration of 5-10 mg vitamin K to the mother in late pregnancy abolishes this risk in the newborn.

Anticoagulant therapy Use of coumarin drugs or warfarin leads to alteration in the synthesis of coagulation factors. As a result proteins antigenically similar to factors II, VII, IX and X are produced but they lack the procoagulant properties. Excess of anticoagulants leads to hemorrhagic tendency.

Bleeding occurs from injection sites, urinary tract, gastrointestinal tract and uterus. Intramuscular injection of 10 mg vitamin K is usually effective. When the bleeding tendency is severe, large intravenous doses (50-75 mg) may be required. For severe cases transfusion of fresh blood or vitamin K-dependent coagulation factors may also be necessary.

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Vitamin D is required for normal metabolism of calcium and phosphorus and for bone formation. It enhances the absorption of these minerals from the gut, their mobilization from bone and the reabsorption of phosphorus by the kidney. Vitamin D1 is the essential precursor for 1-25 alpha dihydroxy vitamin D1 which is the steroid hormone required for the development of bone, growth in children, maintenance of bone mass in adults and also for the retardation of osteoporosis and prevention of fractures in the elderly.

The two different forms of vitamin D active in man are vitamin D (calciferol) obtained by ultraviolet irradiation of ergosterol (also called ergocalciferol or provitamin D2) which is of plant origin, and vitamin D3 (cholecalciferol) which is formed by activation of 7-dehydrocholesterol present in the epidermal cells of human skin as a provitamin D2. This activation is effected by the ultraviolet rays ranging in wavelength from 296 to 310 A obtained from sunlight naturally. Exposure to sunlight for 20-30 minutes daily ensures adequate supply of Vitamin D. Excessive exposure does not lead to overdose of the vitamin. Skin damaged by burns will not be capable of producing Vitamin D on exposure to sunlight.

Vitamin D2 is obtained from the diet and vitamin D3 is formed endogenously. On an average the endogenous source supplies about 80% and diet about 20% of the total requirement. Vitamin D2 and D3 which are identical in potency, differ only in the configuration of the side chain. Vitamin D3, though formed in the skin is also absorbed through the small intestine. Further metabolism of vitamin D2 and D3 is identical and these together are referred to as vitamin D.

Biological actions of vitamin D metabolites:

1. Increase the absorption of calcium and phosphate from the small intestine by promoting active transport.

2. Increase mobilization of calcium from bone by promoting osteoclastic activity.

3. Stimulation of reabsorption of calcium and phosphate at the renal tubules.

The overall result of all these processes is to increase serum calcium and phosphate. Deficiency of vitamin D results in impairment of mineralization of bone leading to nutritional rickets in children and osteomalacia in adults.

Dietary sources of vitamin D are milk, butter, cheese, egg yolk and fish liver oils. This vitamin is heat stable. One international unit (IU) is equivalent to 0.025 μg. The daily requirement varies depending on the age.

DAILY REQUIREMENTS

Infant and children – 400 IU

Age 19-50 years – 200 IU

51-70 years – 400 IU

71 and above years – 600 IU

RICKETS

Prevalence Rickets is prevalent in India, more so in the north than in the south. Premature babies are more vulnerable. The disease is more florid during winter months when exposure to sunlight is minimal. Prevalence is more among the poor and illiterate classes. Indians who have emigrated to affluent countries still show a higher prevalence of rickets. Osteomalacia is more common in multiparous women who have nursed their babies repeatedly. Rickets has been ranked among the most frequent childhood diseases affecting children in the developing world. There is evidence that dietary deficiency of calcium may also lead to rickets.

In rickets, the arrangement and normal regenerative processes of cartilage are abnormal. Subsequent calcification of the cartilaginous matrix and osteoid do not proceed normally. The osteoid and cartilage which remain uncalcified are deposited irregularly. These give rise to a wide irregular frayed zone of non-calcified cartilage and osteoid termed rachitic metaphysis. These in turn account for many of the skeletal deformities. In the subperiosteal region also, while resorption of cortical bone continues normally, new bone is not laid down, resulting in softening and rarefaction of the bone shaft. In vitamin D deficiency, since absorption of calcium and, phosphorus from the gut is defective, serum calcium and phosphorus levels fall. Lowered level of serum calcium stimulates the secretion of parathyroid hormone which in turn, leads to mobilization of calcium from the bone. Thus, the serum calcium is usually maintained normal for considerable periods, tetany developing only rarely. Since parathyroid hormone (PTH) decreases reabsorption of phosphorus by the renal tubule, the serum phosphorus falls. The serum alkaline-phosphatase is elevated due to increased osteoblastic activity.

CLINICAL FEATURES

Florid rickets manifests by the age of 1-2 years. Early manifestations These include irritability, flabbiness of muscles, prominence of abdomen and delay in the appearance of milestones, except speech. Skeletal manifestations These are the most characteristic features. They develop several months after the deficiency is established. The bones which have the maximum rate of growth at the time of onset of the deficiency show gross abnormalities.

In children below the age of 1 year the lesion is craniotabes, characterized by abnormal softening of the skull in the occipital region. In children aged 2 years or more epiphyses of the wrists and ankles are widened and costochondral junctions are enlarged and beaded. In advanced rickets, deformities of bones are aggravated because of muscular action, gravity and weight bearing.

Head

Craniotabes disappears by 1 year of age, but the excess of osteoid and non-calcified cartilage gives rise to frontal and parietal bossing giving the skull a ‘hot cross bun’ appearance. Due to softening of the skull bones the calvarium is asymmetric. The head may be larger in size and closure of the anterior fontanelle may be delayed. The teeth erupt late; show defective enamel, and are more susceptible to develop caries. Permanent teeth also show grooving, pitting and hypoplastic enamel.

Rib-cage

Costochondral junctions are thickened (rachitic rosary) and the sternum projects forwards (pigeon chest deformity). A horizontal groove (Harrison’s sulcus) develops along the diaphragmatic attachment due to

muscular pull of the diaphragm on the softened bone.

Spine

This shows kyphosis and scoliosis when the baby starts sitting and later lordosis in the erect posture.

Pelvis

In lordotic subjects the pelvis shows a corresponding deformity. The pelvis is small and deformed (triradiate pelvis), and in female subjects the obstruction caused to the pelvic outlet gives rise to dystocia during parturition.

Extremities

The femur, tibia and fibula bend producing deformities like knock knees, coxa vara, etc. The thickened epiphyseal ends may be more prominent. Deformities of upper limbs develop if rickets sets in when the infant is crawling. Long bones may develop green stick fractures and pseudofractures. The sum total of bony deformities of the spine, pelvis, and legs leads to rachitic dwarfism.

Other general manifestations include hepatosplenomegaly, tetany, laryngysmus stridulus, convulsions and frequent respiratory infections.

Diagnosis

Rickets should be suspected in any child showing deformities of skull, long bones and ribs and in those with apathy, flabbiness, delayed milestones of development, laryngysmus stridulus or convulsions.

The clinical diagnosis is supported by the history of inadequate vitamin D in the diet or chronic diarrhea interfering with absorption of vitamin D, and it is confirmed by radiological investigations and biochemical tests. X-ray findings in active rickets Routine skiagrams of the wrists give clues in diagnosis and are helpful for following the progress. The distal ends of radius and ulna appear concave (cupping), widened (flaring) and irregular (fraying). The distance between the distal ends of the ulna and the radius and the metacarpal bones is apparently increased since the uncalcified rachitic metaphyses is translucent to X-ray. Shafts of long bones show decreased density and prominent trabeculations. Subperiosteal osteoid may give a double contour to the shaft.

With treatment, the lesions tend to heal. A line of preparatory calcification (LPC) appears. This is separated from the distal end of the shaft by a zone of translucency caused by the uncalcified osteoid. As healing progresses, the osteoid becomes calcified and shaft apparently grows towards the LPC and unites with it.

Measurement of serum 25 hydroxy vitamin D gives a reliable indication of the adequacy of the nutritional status. Normal values are above 15 ng/mL. Values below 8 mg/mL indicate severe deficiency.

Biochemical changes

In florid cases the serum phosphorus is low (1.5-3.5 mg/dL) Serum calcium may usually be normal, but in advanced cases it is reduced especially in cases with tetany. Serum alkaline phosphatase is raised to 20-60 KA units/dL (Normal 5-15). With correction of the lesion alkaline phosphatase level falls and serum phosphorus level goes up. Normal serum vitamin D levels range from 35 ± 3.5 ng/mL (80 nmol/L) and 1,25 (OH)2 D is 35 ± 3 pg/mL.

In active rickets these levels are lowered.

Prognosis for growth and cosmetic recovery is excellent if the condition is recognized early and treated before deformities develop. Intercurrent infections make the prognosis worse. If treatment is started after the bony deformities are established and the epiphyses are ossified, the deformities tend to persist.

Treatment

Oral administration of vitamin D in doses of 1500-5000 IU daily brings about rapid improvement in the vast majority of cases. Radiological improvement will be demonstrable in 2-4 weeks. A single dose of 600,000 units is preferable for advanced cases. The dose may be given orally or as in intramuscular injection. An oily preparation is available for intramuscular injection which is effective for 3 months. Three to four injections are given at intervals of two weeks. Parenteral administration is mandatory in cases showing malabsorption. If there is no improvement even after two parenteral doses of vitamin D, the case is considered to be resistant to vitamin D.

After complete healing of the lesion vitamin D should be given in doses of 400 units daily for preventing recurrence. Children should be encouraged to get exposure to sun for 20-30 minutes daily. Early bone lesions will be corrected with simple medical treatment. If treatment is started late and deformities are permanent, orthopedic correction is indicated.

Vitamin D-resistant rickets

This may be acquired, as in chronic renal failure or inherited as in congenital enzyme defects.

In chronic renal failure conversion of 25-OH D₃ into the active metabolite 1,25(OH)₂D₃ becomes defective due to the progressive deficiency of the enzyme in the renal tubules. Such patients develop features of rickets (renal rickets) forming part of renal bone diseases.

Inherited forms of rickets

Pseudo-vitamin D deficiency: Two types are known. Rickets develop early in life. Hypotonia, weakness, seizures and growth failure develop.

Vitamin D dependent rickets type I

This is an autosomal recessive trait in which the gene for expressing the renal enzyme 25 hydroxy vit D3 1-alpha hydroxylase is defective, and so this enzyme level is low or absent. Plasma levels of 25(OH)D₃ are normal, but 1,25 (OH)₂D₃ are low. The gene is located on chromosomes X 12 q 13.3.

Vitamin D dependent rickets type II

Two forms exist. In one form, the gene for vitamin D receptor is mutated. Hypocalcemic rickets develops. In the second form, also known as X-linked hypophosphatemic vitamin D resistant rickets the phosphate regulating gene (PEX gene) with homology to endopeptidoses on the X chromosome is defective. All these forms respond to 1,25(OH)₂ vitamin D.

HYPERVITAMINOSIS D

Prolonged administration of massive doses of vitamin D results in vitamin D intoxication. This causes hypercalcemia. Symptoms include nausea, vomiting, constipation, drowsiness, and signs of renal impairment. Metastatic calcification occurs in several tissues including

the kidneys, lungs, gastric mucosa and blood vessels. Renal function may deteriorate before other signs of toxicity are manifest. Subjects receiving high doses of vitamin D should have regular monitoring of serum calcium and if it is above 2.6 mmol/liter (10.5 mg/dL), the intake of the vitamin should be stopped.

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