ENDOCRINOLGYDIABETES MELLITUS1. Definition:Diabetes mellitus (DM) is a chronic metabolic disorder caused by an absolute or relative deficiency of insulin with hyperglycaemia as a cardinal biochemical feature2. Classification:1. Type 1 Diabetes Mellitus : insulin dependent; ketoacidosis is common2. Type 2 Diabetes Mellitus : non insulin dependent; ketoacidosis is uncommon3. Secondary diabetes mellitus: Cystic fibrosis; Cushing syndrome4. Impaired glucose tolerance: intermediate between normal and diabetic state; risk factor for future diabetes and coronary disease3. Type 1 Diabetes Mellitus :1. Overall incidence is .2 to .3 %2. 10% of all cases of DM3. 40% of them are < 20 years old4. Annual rate of increase of cases is 3-4%5. Peak presentation: 5-7 years ( exposure to infectious agents) and at puberty ( increased GH)6. Genetics:i. Immune mediated damage to the insulin producing B cells due to genetic predispositionii. Association with HLA-DR3 and DR4iii. Association with DQ 1 gene (absence of aspartic acid in HLA DQ chain responsible for activating autoimmune cascade)7. Environment:i. Increasing prevalence of autoimmune provactive factors:eg. Frequent childhood infectionsii. Decreasing prevalence of protective factors:eg. Breastfeedingiii. Viral infections of cells: Coxackie B3 and B48. Pathogenesis:i. T cell mediated autoimmune disease leading to destruction of cells over a period of time9. Clinical manifestations:i. Symptoms steadily increases with decreasing cell massii. Worsening insulinopenia progressive hyperglycemiaeventual ketoacidosisiii. Polyuria, nocturia, plydipsia, glycosuria (caloriuria) and hyperphagia but with weight lossiv. Monilial vaginitis in female childv. Ketoacidososis: DKA10. Diagnosis:i. Non fasting blood glucose > 200 gm/dl with polyuria, glycosuria and ketonuriaii. HbA1ciii. Tests for other autoimmune disorders:1. IgA: celiac disease2. Antithyroid peroxidase, antithyroglobulin antibodies: Thyroiditis11. Treatment:i. Patient and family education: regarding symptoms, drug dosing and diet and glucose monitoringii. Insulin:1. Facilitates cellular entry of glucose; decreases neoglucogenesis; turns off ketone production2. Dose: a. Prepubertal: 0.7 U/kg/dayb. Midpuberty: 1 U/kg/dayc. Postpuberty: 1.2 U/kg/day3. Dosing:a. Twice-daily combinations of short-acting and intermediate-acting insulin.b. Dosage adjusted over a trial period to cover before meal and after the meal4. Insulin pump: Continuous subcutaneous insulin infusion (CSII) using an insulin pump5. Inhaled insulin therapy:a. Preprandial inhaled insulin and bed time long acting insulins are being tried with promising results6. Oral insulin: oralin; promising trial are underway12. Diabetic Ketoacidosis:i. Commonest cause of death due to DMii. Induced by stress, infection, omitting insulin doseiii. Ketoacidosis: DKA1. 20% of present with symptom before diagnosis2. Very low insulin levels3. Ketoacids produce abdominal discomfort, nausea, vomiting and further dehydration4. Signs of dehydration are masked as intravascular volume is maintained at the expense of intracellular volume 5. Deep heavy rapid breathing: Kussmauls respiration6. Fruity odor due to acetone7. Increased ion gap, decreased sodium bicarbonate and pH8. Confusion leading to comaiv. Complications:1. Cerebral edema2. Hypokalemia3. Septic shock4. Hypoglycemia5. Cerebral hemorrhage6. Pancreatitisv. Problems to be managed:1. Dehydration/shock2. Acidosis 3. Hypokalemia4. Hypoglycemia5. Hyperosmolality 6. Cerebral edema7. infectionvi. Diagnosis:1. Hyperglycemia (BG > 200mg/dL or 11 mmol/l) 2. pH < 7.3 3. Bicarbonate < 15 mmol/l 4. More than 3% dehydration 5. Clinical:a. Vomiting b. Drowsiness c. Clinical acidosisvii. Management: Milwaukee protocol1. Insulin therapy2. Fluid replacement3. Treatment of underlying causeviii. Insulin:1. Insulin to drive glucose into cells; it is given as infusion 0.1U/kg/hourix. Intravenous fluids to correct dehydration: PhaseType of managementType of fluidAmount ml/kgDuration

1Shock treatment0.9 % NaCl or RL 10-20 ml /kg0-1 hour

2Treatment for dehydration0.45% NaClEg: 5% dehydration:50 ml x Kg body weight minus shock fluid already given1-48 hours

3Maintenance0.45%100 ml/kg first 10 kg; plus 50 ml/kg for next 10 kg; plus 25 ml/kg for remaining wt

a. Total Requirement for 24 hours = Maintenance + Deficit shock fluid already givenb. 5% GDW added when glucose level falls below 250 mg/dlc. Potassium 20 mEq/L as K.phosphate and 20 mEq/L as K acetate in maintenance fluid.d. Bicarbonate is not necessary as fluid and insulin correct acidosis1. Hourly rate = 48 hr maintenance + deficit resuscitation fluid already given48

13. Nutrition in DM:i. Food :1. 20% breakfast; 20% lunch; 30% dinner; 10% in between snacks2. Carbohydrate: 55%(70% complex Carbohydrate;) more fibers3. Fat: 30% polyunsaturatyed: saturated 1.2:2; vegetable fat4. Protein: 15%ii. Wight in normal range to be maintained14. Self monitoring:i. Blood glucose- 4 times daily to monitor glycemic control and insulin doseii. HbA1c It is an index of long term glycemic control. values 6 to 7.9% represent good metabolic control15. Exercise: helps utilization of glucose by muscles and glucoregulation; planned exercise decreases insulin requirement by 10-15% and prolonged exercise by 50%; exercise induced hypoglycemia is avoided by carbohydrate exchange16. Somogyi phenomenon:i. Early morning hypoglycaemia due to exaggerate counteregulatory response17. Brittle diabetes: refers to fluctuating blood glucose levels due to environmental factors such family stress in young girls

HYPOTHYROIDSM1. Physiology1. Circulating T4 is predominantly bound to T4-binding globulin (TBG). 2. Free T3 and T4 are less than 1%3. T4 is deiodinated in peripheral tissue to T3, the more bioactive thyroid hormone. 4. T3 exerts profound effects on the regulation of gene transcription. Thyroid hormone actions include:a. Differentiation of theCNS b. Maintenance of muscle mass. c. Skeletal growth and differentiation d. Metabolism of carbohydrates, lipids, vitamins. 4. Physiology of Iodine1. Thyroid hormone synthesis absolutely requires iodine. The recommended dietary allowance of iodine is 40-50 mcg daily in infants, 70-120 mcg daily for children, and 150 mcg daily for adolescents and adults. 5.Physiology - synthesis1. Iodide oxidized by thyroidal peroxidase 2. Iodination of tyrosine forms mono-iodotyrosine and di-iodotyrosine.3. Two molecules of di-iodotyrosine combine to form t4, and one molecule of mono-iodotyrosine combines with one molecule of di-iodotyrosine to form t3. 4. TSH stimulates uptake and organification of iodide as well as liberation of t4 and t3 from thyroglobulin.6. Classification1. Congenital hypothyroidism: a. Agenesis, b. Dysplasia, c. Ectopy d. Autosomal recessive defects :i. Organification of iodine ii. Enzymatic steps in T4 synthesis and release.2. Acquired hypothyroidism is most commonly caused by autoimmune destruction (hashimoto thyroiditis).3. Congenital resistance to throxine 4. Seondary: hypopituitarism7.Epidemiology1. Congenital hypothyroidism: 1 per 3500 live births.2. Thyroid dysgenesis: 1 per 4000 newborns 3. Secondary hypothyroidism: 1 per 60,000-140,000 newborns worldwide.4. Autoimmune thyroid disease: 10% of young females are estimated to have some signs of, usually chronic lymphocytic thyroiditis (CLT). 8.Familial thyroid dyshormonogenesis: Rare autosomal recessive inborn errors of thyroid hormone synthesis, secretion, or uptake 9. Autoimmune thyroiditis: Chronic lymphocytic thyroiditis: CLT (ie, autoimmune thyroiditis, Hashimoto thyroiditis) is the most common cause of acquired hypothyroidism 10. Congenital Hypothyroidism1. It is due to dysgenesis or agenesis of the thyroid 2. Congenital hypothyroidism is twice as common in girls as in boys 3. Clinical features in Infancy:1. Birthweight and length are normal, but head size may be slightly increased because of myxedema of the brain.2. Prolongation of physiologic icterus, caused by delayed maturation of glucuronide conjugation, may be the earliest sign. 3. Respiratory difficulties, due to the large tongue 4. Affected infants cry little, sleep much, have poor appetites, and are generally sluggish. 5. There may be constipation that does not usually respond to treatment. 6. The abdomen is large, and an umbilical hernia is usually present. 7. The temperature is subnormal and the skin may be cold and mottled. 8. Edema of the genitals and extremities may be present. 9. The pulse is slow, and heart murmurs, cardiomegaly are common. 10. Anemia is often present and is refractory to treatment with hematinics. 11. The anterior and posterior fontanels are open widely; 12. The eyes appear far apart, and the bridge of the broad nose is depressed. 13. The palpebral fissures are narrow and the eyelids swollen. 14. The mouth is kept open, and the thick and broad tongue protrudes from it.4. Older children:1. Dentition is delayed. 2. The skin is dry and scaly, and there is little perspiration. 3. The scalp is thickened, and the hair is coarse, brittle, and scanty. 4. Development is usually retarded. Hypothyroid infants appear lethargic and are late in learning to sit and stand. 5. The voice is hoarse, and they do not learn to talk. The degree of physical and mental retardation increases with age.6. Sexual maturation may be delayed or may not take place at all.7. The muscles are usually hypotonic, but in rare instances generalized muscular pseudohypertrophy occurs (Kocher-Debr-Smlaigne syndrome). Affected children may have an athletic appearance because of pseudohypertrophy, particularly in the calf muscles. 11.Acquired hypothyroidism: 1. Clinical features are insidious in onset. 2. Goiter 3. Slow growth, short stature4. Delayesd tendon reflexes13.Lab1. TSH: sensitive test; it is elevated; Normal is less than 6 mIU/L. 2. T4 is present in both the free State and bound to TBG. Total T4 assays are useful to establish the diagnosis of primary hypothyroidism 3. Measurement of serum T3 concentration, free or total, is not required to confirm the diagnosis of hypothyroidism4. In infants, if the serum total T4 is less than 85 nmol/L ( 6 yersd. Familial short stature (FSS) is associated with normal skeletal maturatione. Bone age is usually delayed in children with constitutional growth delay, malnutrition, and endocrine causes of short stature (eg, hypothyroidism, cortisol excess, GH deficiency)5. Body proportions:a. The upper-to-lower body segment (U/L) ratio: i. The ratio:1. At birth: 1.72. 3 years: 1.33. 6 years: 1.14. 10 yeras: 1ii. Decreased U/L ratio for age:1. Skeletal dysplasias involving primarily the spine (eg, spondylodysplasias) 2. Eunichoidism3. Delayed or incomplete puberty (eg, Klinefelter or Kallmann syndrome)iii. Increased U/L ratio 1. Those dysplasias involving especially the long bones (eg, achondroplasia) 2. Because puberty is associated with relatively greater truncal than limb growth, an increased U/L ratio for age may be seen in precocious puberty. 6. Classification of short stature:a. Physiological:i. Familial short statureii. Constitutional growth delayb. Pathological:i. Endocrine disorders:1. Growth hormone deficiencya. Genetic causes:i. Gene deletionii. GH resistanceb. Congenital: associated with septo-opic dysplacia and ectopic pituitaryc. Acuired:i. Parental deprivation syndromeii. Craniopharyngeomad. Idiopathic:i. Isolated GH deficiencyii. Combined pituitary hormone deficiency2. Insulin like growth factor-1 deficiency3. Hypothyroidism4. Cushing syndrome5. Precocious puberty6. Diabetes mellitus7. Psuedo hypoparathyroidismii. Ricketsiii. IUGRiv. Inborn errors of metabolism:1. Mucopolysachharidoses2. Other storage disordersv. Intrinsic disease of bone:1. Achondroplasia2. Fibrous dysplasiavi. Chromosomal:1. Autosomal:a. Down b. Prader-Willi c. Noonan2. Sex chromosome:a. Turnervii. Chronic illness:1. CHD2. Inflammatory bowel disease3. Hematologic: Thalassemia4. Pulmonary : cystic fibrosis; Bronchial asthma5. Renal disease7. Practical Classification of short stature:a. Proportional: i. Equal height weight ratio: GHDii. Weight more than height: Cretinism, GH deficiency,GH insensitivity, hypothyroidism, or glucocorticoid excess,iii. Height more than weight: Chronic illness, mal nutritionb. Disproportional:i. Short limb: achondroplasia and other chondrodysplasiasii. Short trunk: Hurler, Morquio8. Familial Short stature:a. Short parentsb. Normal weight and length at birthc. Growth velocity is decreased in first two years and then resumes normal growthd. Bone age and puberty are normale. Adult height is appropriate for the family9. Constitutional growth delay:a. Normal parentsb. Normal weight and length at birthc. Growth pattern is similar to FSSd. Delay in bone agee. Delay in onset of pubertyf. Growth is decreased in first 3 years g. But growth continues beyond the average period of growthh. Finally reaches the target height10. Growth Hormone Deficiency:a. Hypopituitarism :i. Incidence is 1 in 4000-10,000ii. Multiple hormone deficiency- 20%iii. Isolated growth hormone deficiency- 13%b. Growth hormone:i. Deficiency is due to:1. Mutation : Septo optic dysplasia: 2. Isolated pituitary hypoplasia3. Acquired pituitary defects:i. Craniopharyngeomaii. Germinomaiii. Histiocytosisiv. Tuberculosisv. Meningitis4. Isolated GHD and insensitivity:a. Genetic defectb. Acquired: Radiation; meningitisc. Clinical manifestations:i. Congenital hypopituitorism:1. Normal length at birth2. Growth rate below 25% 3. Hypoglycaemia, prolonged jaundice and apnoea and cyanosis and seizures at birth4. Microphallus in boys5. Round head, broad and short face6. Small saddle shaped nose; nasolacrimal folds7. Bulging eyes8. Small chin9. Crowded teeth10. High pitched voice11. Proportional extremities12. Delay or absent sexual maturation13. Delayed skeletal age14. Normal intelligenced. Lab findings:i. Low levels of GH in response to stimulation by insulin, argentine, clonidine, glucagonii. Levels of IGF1iii. Levels of TSH, ACTH, e. X-Ray:i. CT: supracellar calcification- craniopharyngeomaii. Bony erosion: histiocytosisiii. MRI: Triad: small ant pituitary, hypolastic pituitary stalk, ectopic post pituitary bright spotiv. Delay in bone agef. Treatment:i. Subcutaneous recombinant GH for 7 days- total dose .1 to.3 mg?kgii. IGF 1 for resistant cases

CUSHINGS SYNDROME

a. Introduction:a. Cushing syndrome is the result of abnormally high blood levels of cortisol or other glucocorticoids. b. Hypersecretion of corticotropin (adrenocorticotropic hormone [ACTH]) by the pituitary is called Cushing diseaseb. Causes:a. Exogenous: Steroid induced: b. Endogenous Cushing syndrome:i. Adrenocortical tumour:

ii. Excessive ACTH:1. pituitary adenoma 2. Ectopic ACTH secretion: neuroblastoma or ganglioneuroblastoma, hemangiopericytoma, Wilms tumor, etciii. ACTH-independent Cushing syndrome:1. McCune-Albright syndrome: nodular hyperplasia and adenoma formation occurs in adrenal cortex which functions independant of ACTH iv. MEN syndrome: multiple endocrine neoplasia type 1 syndrome, an autosomal dominant disorderc. Clinical features:a. Young children:i. The face is rounded, with prominent cheeks and a flushed appearance (moon facies).ii. Generalized obesity is common in younger children. iii. In children with adrenal tumors, signs of abnormal masculinization occur frequently; accordingly, there may be hirsutism on the face and trunk, pubic hair, acne, deepening of the voice, and enlargement of the clitoris in girls. iv. Growth is impaired, with length falling below the 3rd percentile v. Hypertension is common and may occasionally lead to heart failure. vi. An increased susceptibility to infection may also lead to fatal sepsisb. Older children:i. In older children, in addition to obesity, short stature is a common presenting feature. ii. Purplish striae on the hips, abdomen, and thighs are common. iii. Pubertal development may be delayed, or amenorrhea may occur in girls past menarche. iv. Weakness, headache, and emotional lability may be prominent. v. Hypertension and hyperglycemia usually occur; vi. Hyperglycemia may progress to frank diabetes. vii. Osteoporosis is common and may cause pathologic fracturesd. Diagnosis:a. Cortisol levels in blood are normally elevated at 8 am and decrease to less than 50% by midnight. Night time salivary cortisol levels are elevated and may be a screening test in obese childrenb. Urinary excretion of free cortisol is increased. c. Dexamethasone suppression test: a dose of 25-30 g/kg (maximum of 2 mg) given at 11 pm results in a plasma cortisol level of less than 5 g/dL at 8 am the next morning in normal individuals but not in patients with Cushing syndromed. A glucose tolerance test is often abnormal despite elevated levels of insulin.e. f. After the diagnosis of Cushing syndrome has been established, it is necessary to determine whether it is caused by a pituitary adenoma, an ectopic ACTH-secreting tumor, or a cortisol-secreting tumor:i. The two-step dexamethasone suppression test consists of administration of dexamethasone, 30 and 120 g/kg/24 hr in four divided doses, on consecutive days. In children with pituitary Cushing syndrome, the larger dose, but not the smaller dose, suppresses serum levels of cortisol. Typically, patients with ACTH-independent Cushing syndrome do not show suppressed cortisol levels with dexamethasoneg. CT: detects virtually all adrenal tumors larger than 1.5 cm in diameter. h. MRI: may detect ACTH-secreting pituitary adenomas, but many are too small to be seen; the addition of gadolinium contrast increases the sensitivity of detection. e. Differential diagnosis:a. Simple obescity:i. Cushing syndrome is frequently suspected in children with obesity, particularly when striae and hypertension are present. ii. Children with simple obesity are usually tall, whereas those with Cushing syndrome are short or have a decelerating growth rate. iii. Although urinary excretion of cortisol is often elevated in simple obesity, salivary night time levels of cortisol are normal and cortisol secretion is suppressed by oral administration of low doses of dexamethasonef. Treatment:a. Transsphenoidal pituitary microsurgery is the treatment of choice in pituitary Cushing disease in children. b. Cyproheptadine, a centrally acting serotonin antagonist that blocks ACTH release, has been used to treat Cushing disease in adults; remissions are usually not sustained after discontinuation of therapy. This agent is rarely used in children. c. If a pituitary adenoma does not respond to treatment or if ACTH is secreted by an ectopic metastatic tumor, the adrenal glands may need to be removed. This can often be accomplished laparoscopically. Adrenalectomy may lead to increased ACTH secretion by an unresected pituitary adenoma, evidenced mainly by marked hyperpigmentation; this condition is termed Nelson syndrome.d. Benign cortical adenomas are treated with unilateral adrenalectomy e. Management of patients undergoing adrenalectomy requires adequate preoperative and postoperative replacement therapy with a corticosteroid.

MUCOPOLYSACCHARIDOSES

1. Mucopolysaccharidoses are hereditary, progressive diseases caused by mutations of genes coding for lysosomal enzymes needed to degrade glycosaminoglycans (acid mucopolysaccharides). 2. Failure of this degradation due to reduced activity of mutated lysosomal enzymes results in the intralysosomal accumulation of GAG fragments.3. Distended lysosomes accumulate in the cell, interfere with cell function, and lead to a characteristic pattern of clinical, radiologic, and biochemical abnormalities4. Mutations of the gene encoding L-iduronidase may result in severe Hurler disease with early death or in mild Scheie disease manifesting only with limited joint mobility, mild skeletal abnormalities, and corneal opacities. 5. Mucopolysaccharidoses are autosomal recessive disorders, with the exception of Hunter disease, which is X-linked recessive. 6. Their overall frequency is between 3.5/100,000 and 4.5/100,000. The most common subtype is MPS-III, followed by MPS-I and MPS-II. YPEEPONYMDEFECTIVE ENZYMEMAIN CLINICAL FEATURES

I-H Hurler-L-iduronidaseSevere Hurler phenotype, mental deficiency, corneal clouding, death usually before age 14 years

IIHunter-X-linked recessiveIduronate sulfate sulfataseSevere course similar to I-H but clear corneas. Mild course: less pronounced features, mild mental deficiency

III-ASanfilippo AHeparan-S-sulfamidaseBehavioral problems, sleeping disorder, aggression, progressive dementia, mild dysmorphism, coarse hair, clear corneas, survival to adulthood possible

IV-AMorquio AN-ac-galactosamine-6-sulfate sulfataseShort-trunk dwarfism, fine corneal opacities, characteristic bone dysplasia; final height 20 mg/dL, excess phenylalanine is metabolized to phenylketones (phenylpyruvate and phenylacetate) that are excreted in the urine, giving rise to the term phenylketonuria (PKU). 5. Clinical Manifestations. a. The affected infant is normal at birth. Mental retardation may develop gradually b. Vomiting, sometimes severe enough to be misdiagnosed as pyloric stenosis, may be an early symptom. c. Older untreated children become hyperactive, with purposeless movements, rhythmic rocking, and athetosis and hypertonic with hyperactive deep tendon reflexes; 25% of children have seizuresd. Microcephaly, prominent maxilla with widely spaced teeth, enamel hypoplasia, and growth retardation are other common findings in untreated children. e. These infants are lighter in their skin and hair color with an unpleasant odor of phenylacetic acid (bronze skin and musty odour) f. Some may have a seborrheic or eczematoid rash 6. Mild type :a. Child with phenylalanine