1. Pediatric Clinical Chemistry Main Reference Bishop M.L. Clinical Chemistry 1

2. Diabetes Blood glucose homeostasis and hepatic metabolism of glucose are maintained by the concerted actions of several hormones. Following a meal, the level of glucose in the circulation rises, which triggers increased synthesis and release of insulin. Increased levels of insulin in the circulation cause glucose to be taken up by certain cells, such as hepatocytes and muscle cells, and to be converted into glycogen as a future source of energy. Glucagon, a hormone secreted by alpha cells of the pancreas hasan opposing effect to that of insulin. Other hormones; cortisol, epinephrine and insulin-like growth factor,IGF affect glucose levels. 2

3. Type 1 diabetes(insulin dependent) is the most common in pediatrics. It is immune mediaied or idiopathic. In the immune mediated, the most common form, the insulin-secreting beta cells are destroyed by a T-cell-mediated autoimmune response. This form of diabetes was previously termed”juvenile diabetes” because it is the predominant form in children. A patient typically presents with diabetic ketoacidosis, with profound hyperglycemia and metabolic acidosis due to increased fatty acid metabolism and production of excess ketone bodies. 3

4. Type 2 diabetes(non-insulin dependent) is normally associated with increased resistance to normally secreted insulin in obese individuals. During the past 30 years, the number of children diagnosed as being overweight has increased by >100% and this epidemic of childhood obesity is causing children to suffer from chronic complications that were previously only seen in adults. Type 2 diabetes now accounts for a considerable proportion of newly diagnosed cases of diabetes in the pediatric population. 4

5. Urbanization, unhealthy diets, and indreasingly sedentary lifestyles have contributed to increase the prevalence of childhood obesity. In children and adolescents, a number of studies have demonstrated a link between childhood metabolic syndrome and elevated cardiovascular risk in later life. Chronic hyperglycemia can be distinguished from acute cases(due to other hormones) by measuring blood concentration of HbA1C. 5

6. Nitrogen Metabolism The liver plays a central role in nitrogen metabolism. It is involved with the metabolic Interconversions of amino acids and the synthesis of nonessential amino acids. The liver synthesizes many body proteins, including most proteins found in the circulation, such as albumin, transferrin and clotting factors. The liver is also responsible for complete metabolism of the breakdown products of nitrogen turnover, such as ammonia and urea through the urea cycle and creatinine and uric acid from energy stores and nucleic acids, respectively. 6

7. Blood ammonia levels are higher in the newborn period than in later life, presumably due to immaturity of urea cycle enzymes and the portal circulation. A blood ammonia level of 100 umol/L in a newborn would be regarded as less significant than the same level in a 1-year-old. Persistently elevated ammonia levels should alert the investigator to possible liver damage and secondary failure of the urea cycle. 7

8. Nitrogenous End Products as Markers of Renal Function In contrast to the high neonatal ammonia levels, creatinine and uric acid levels are lower in newborns. Creatinine concentrations in blood increase with muscle mass and are independent of diet, it is filtered at the glomerulus and not extensively reabsorbed by the renal tubules. Its measurement as a clearance ratio in blood and in a 24-hour urine sample has been used as a marker for the GFR for many years. Serum cystatin C is more sensitive marker since it is independent of muscle mass and recent meat ingestion. It is freely filtered at the glomerulus and reabsorbed by the tubular epithelial cells. 8

9. Liver Function Tests serum albumin and conjugated bilirubin are true tests of liver function because they measure the synthetic and metabolic pathways for these compounds. Very low levels of albumin indicate a long exposure to protein restriction, and its measurement in blood is often used as a guide to nutritional status and chronic liver disease of other causes. other tests, as liver enzymes reflect tests of liver cell integrity. Large elevations in aminotransferases indicate hepatocellular damage and subsequent leakage of cellular contents into the serum. An elevated ALP suggests hepatic biliary damage. 9

10. Calcium and Bone Metabolism in pediatrics Normal bone growth, which parallels body growth, requires integration of calcium, phosphate, and magnesium metabolism with endocrine regulation from vitamin D, parathyroid hormone(PTH), and calcitonin. The active metabolite of vitamin D is 1,25-dihydroxy vitamin D. Hydroxylation of vitamin D from the diet takes place in the liver and in the kidneys and requires normal functioning of these organs. 10

11. Absorption of vitamin D from GIT, conversion to its active form in the kidney, and incorporation of calcium and phosphate into growing bone requires normally active PTH. Secretion of PTH, in turn, modulated by serum calcium and magnesium levels. Low levels of both divalent cations inhibit PTH secretion, while calcitonin has an antagonistic effect on PTH. 11

12. Vitamin D deficiency can result from inadequate nutritional intake of vitamin D coupled with inadequate sunlight exposure or use of sunscreens, disorders that limit vitamin D absorption and conditions that impair the conversion of vitamin D into active metabolites including certain liver and kidney diseases. Deficiency results in impaired bone mineralization And leads to rickets in children and osteoporosis and osteomalacia in adults. Vitamin D can help in preventing other diseases including several types of cancer, diabetes, multiple sclerosis, obesity, and hypertension. 12

13. Vitamin d deficiency is common in children. The American Academy of Pediatrics has recently doubled the amount of vitamin D recommended for all infants from 200- 400IU/d. this dose is required to prevent rickets. The serum concentration of 25- hydroxyvitamin D is typically used to determine vitamin D status. It reflects vitamin D produced in the skin as well as that acquired from diet and has long circulating half-life. Immunoassay is used for its determination. 13

14. Approximately 98% of total body calcium content is present in bone and less than 1% is measurable in blood. Serum calcium is present as the unbound ionized fraction(about 50% of total in blood), with the rest bound to protein(40%) or chelated to anions in the circulation, such as citrate and phosphate. serum ionized and bound calcium levels are strictly regulated. Abnormal regulation has profound clinical effects 14

15. Hypocalcemia and Hypercalcemia hypocalcemia is defined as total serum calcium below 7.0 mg/dl or ionized calcium below 3.0 mg/dl. hypocalcemia can result in irritability, twitching and seizures. Prolonged hypocalcemia can result in reduced bone growth and rickets. Hypercalcemia is defined as total serum calcium of greater than 11.0 mg/dl. Patients with hypercalcemia have poor muscle tone, constipation, and failure to thrive and may develop kidney stones leading to renal failure. 15

16. causes of hypocalcemia: prematurity, metabolic acidosis, vitamin D deficiency, liver disease, renal disease, hypoparathyroidism, low calcium intake, high phosphorous intake, diuretic use, hypomagnesemia, exchange transfusion(anticoagulants in transfused blood). caucses of hypercalcemia: hyperparathyroidism, acute renal failure, excessive intake of vitamin D, idiopathic hypercalcemia of infancy. * hypercalcemia is less common than hypocalcemia in infants 16

17. Endocrine Function in Pediatrics Hypothalamic-Pituitary-Thyroid System The hypothalamus secretes thyrotropin-releasing hormone(TRH), a 3-amino acid peptide into the portal blood system between the hypothalamus and the anterior pituitary. TRH binds to a receptor on specialized cells in the anterior pituitary that stimulates the secretion of thyroid-stimulating hormone(TSH), a polypeptide made up of two chains α and β. The α chain is common to human chorionic gonadotrophin, follicle- stimulating hormone and leutinizing hormone and the β chain confers specificity to all of these hormones. 17

18. TSH is released into the circulation and targets its end organ, the thyroid gland where it stimulates the synthesis and release of thyroid hormones into the circulation. T3 and T4 are bound to specific transporter proteins called thyroid-binding globulins. Free T3 is the active form and reacts with receptors on many peripheral tissues to cause increased metabolism and stimulate normal growth and development. 18

19. Dysfunction of hypothalamic- Pituitary-Thyroid System Primary hypothyroidism: It results from any defect that causes failure of the thyroid gland to synthesize and secrete thyroid hormone. This results in a congenital hypothyroidism which is present in 1 of 4000 births and is screened for in all newborns in the developed world. Untreated patients have severe mental retardation with unusual face appearance. Treatment by thyroid replacement, The best diagnostic test is to measure TSH levels in blood spots from newborns or serum if the disease is suspected in later childhood. TSH is high as a result of failure of the feedback loop. Total T4 and free T4 levels are very low in untreated patients. 19

20. Secondary Hypothyroidism It is a result of the failure of the pituitary gland to secrete TSH followed by lack of thyroid gland stimulation and subsequent low production of thyroid hormone. Diagnosis: low TSH levels Because the pituitary is involved with all major endocrine systems, it is important to study the other pituitary pathways to determine if hypothyroidism is the result of isolated TSH defect or due to panhypopituitarism involving all other pathways. Panhypopituitarism is clinically complex and may include hypoglycemia, salt loss, poor somatic and bone growth, failure to thrive, and later in childhood, failure to develop secondary sexual characteristics. 20