Pediatric Endocrinology

PEDIATRIC ENDOCRINOLOGY PART 2 Dr. Ruby Ann Punongbayan January 19, 2009

(Adrenals na dapat ang start ng trans namin pero isinama ko ulit ung Calcium Homeostasis kasi may ilang slides na hindi naisama sa part na un)

PTH & Vit.D are the principal regulators of calcium homeostasis



In the parathyroid gland, pre-pro-PTH & a proparathyroid hormone are synthesized--- pre-pro-PTH converted to pro-PTH- converted to PTH (rapidly cleaved in the liver & kidney into smaller fragments) PTH has C-terminal, mid-region & N-terminal fragments o N-terminal – assay most useful for detecting acute secretory changes o C-terminus & mid-region – inert & represent 80% of plasma immunoreactive PTH o C-terminal assay – detects hyperparathyroidism When serum Ca falls, secretion of PTH increases.





  











Calcitonin & PTH-related peptide (PTHrP) – important primarily in the fetus

PTH stimulates 1-a-hydroxylase in the kidney--enhances production of 1,25-OH2D3-- induces synthesis of a Ca-binding protein (calbindin-D) in the intestinal mucosa with Ca absorption PTH mobilizes Ca by directly enhancing bone resorption Hypocalcemia induces increased PTH secretion; hypercalcemia depresses PTH secretion.





Calcitonin – 32-AA polypeptide; secreted in parafollicular cells (C cells) of the TG o In the fetus, high levels augment bone metabolism & skeletal growth stimulated by the normally high fetal Ca levels. o Main biologic effect: inhibition of bone resorption by decreasing the number & activity of bone-resorbing osteoclasts.



HYPOPARATHYROIDISM Hypocalcemia is common from 12-72 hrs of life esp.in premature infants, in infants with asphyxia at birth & in infants of diabetic mothers Clinical Manifestations o Muscular pain and cramps – early o Numbness, stiffness, tingling of the hands & feet o (+)Chvostek or Trosseau sign or laryngeal & carpopedal spasm o Convulsions with loss of consciousness o Chronic: late teeth eruption, irregular enamel formation, soft teeth o Dry & scaly skin o Horizontal lines in nails of the fingers & toes o Mucocutaneous candidiasis o Cataracts o Permanent mental & physical deterioration occur if initiation of treatment is delayed. Serum Calcium o About 50% of calcium is ionized o 40-45% is bound to albumin o 5-10% is bound to other anions (sulfate, PO4, lactate, citrate) o Only ionized fraction is physiologically active & can be rapidly measured o Blood pH should always be performed with ionized Ca (increased in acidosis; decreased in alkalosis) Laboratory Findings o Serum calcium <5-7 mg/dL o Serum phosphorus >7-12 mg/dL o Serum ionized calcium (45% of the total) is low o Serum alkaline phosphatase is normal or low



Marias

4th Shifting

Low level of 1,25 OH2D3 Normal serum magnesium Low serum PTH X-ray of the bones: increased density limited to the metaphyses o X-ray and CT of the skull: calcifications in the basal ganglia o ECG: prolonged QT interval o EEG: widespread slow activity Management o Emergency treatment for neonatal tetany: 5-10 ml of 10% solution of calcium gluconate IV at a rate of 0.5-1 mL/min while HR is monitored o 1,25-dihydroxycholecalciferol (calcitriol) should be given – initial dose 0.25 ug/day & MD 0.01-0.1 ug/kg/day; given in 2 equal divided doses o Management o Supplemental calcium gluconate or glubionate to provide 800 mg of elemental calcium daily o Reduce high phosphorus content in diet such as milk, eggs & cheese o Frequent monitoring of serum calcium levels o o o o

CALCIUM HOMEOSTASIS

 

Pediatrics 2

 





HYPERPARATHYROIDISM Excessive production of PTH due to primary defect of the parathyroid glands such as adenoma or hyperplasia; may also be due to vitamin D excess Increased PTH production is compensatory aimed at correcting hypocalcemic states of diverse origins Childhood occurrence is rare; usually due to a single benign adenoma manifested after 10 yrs of age Some occur as part of multiple endocrine neoplasia (MEN) syndrome (AD) characterized by hyperplasia or neoplasia of the endocrine pancreas, the anterior pituitary & parathyroid glands Clinical Manifestations o Muscular weakness, anorexia, nausea, vomiting, constipation, polydipsia, polyuria, loss of weight, fever o Progressively diminished renal function in chronic cases o Osseous changes may produce pain in the back or extremities, gait disturbances, fractures o Abdominal pain o Parathyroid crisis: serum calcium >15 mg/dL, progressive oliguria, azotemia, stupor, coma o Infants: failure to thrive, poor feeding, hypotonia o Chronic cases: mental retardation, convulsions, blindness Laboratory Tests o Serum calcium should always be measured at the same time as PTH. o Primary case: increased serum Ca; increased serum PTH; increased serum chloride; decreased serum phosphorus in 50% of cases o Serum & ionized calcium elevated o Serum phosphorus is low <3 mg/dL o Serum magnesium is low o Low specific gravity of urine o Serum nonprotein nitrogen & uric acid inc. o Elevated serum PTH o Most consistent X-ray finding is resorption of subperiosteal bone best seen along the margins of the phalanges of the hands o Skull X-ray: gross trabeculation or a granular appearance due to focal rarefaction o Abdominal X-ray: renal calculi or nephrocalcinosis Management

1 of 7

PEDIATRICS 2 Pediatric Endocrinology Part 2 o o o o o

 

Surgical exploration is indicated in all instances. All glands should be carefully inspected. Removal of the adenoma Total parathyroidectomy for infants with severe hypercalcemia Good prognosis if recognized early & there is appropriate surgical treatment

ADRENAL GLANDS Adrenal gland: 2 endocrine systems: medullary gland & cortical system Adrenal cortex: 1. Zona glomerulosa – aldosterone (15%) 2. Zona fasciculata – cortisol & androgens 3. Zona reticularis – androgens (10%)

Renin-Angiotensin-Aldosterone System  Major regulators of aldosterone secretion are the R-A system & potassium  Renin produced by the JG apparatus reacts with renin substrate --angiotensin I--angiotensin-converting enzyme cleaves-- angiotensin II---angiotensin III (potent stimulators of aldosterone secretion)  Both angiotensin & K act by IC signal transduction mechanisms to stimulate conversion of cholesterol to pregnenolone. Adrenal Steroids  Glucocorticoids: o Regulate RNA & protein synthesis o Catabolic effect in muscles, skin, connective, adipose & lymphoid tissues: increased degradation of protein o Anabolic in the liver: increase protein & glycogen content, enhances gluconeogenesis o Effects of insulin & androgens are antagonistic to those of glucocorticoids  Mineralocorticoids o Aldosterone maintains electrolyte balance-blood volume & BP stabilization o Controls Na & H20 reabsorption in the distal tubules  Androgens o inc. retention of N, K, P, S04 o Promote growth & have androgenic effects o DHEAS levels begin to rise before the other hormonal changes of puberty occur

  

 Hypothalamic-Pituitary-Adrenal Axis  Pulses of ACTH & cortisol occur every 30-120 minutes, are highest at about the time of waking, are low in late afternoon & evening, and reach their lowest point an hour or two after sleep begins.  In the hypothalamus (paraventricular nucleus): CRH is synthesized which is the most important stimulator of ACTH secretion.  AVP augments CRH action--neural stimuli from the brain cause the release of CRH & AVP-- pulsatile release in the hypophyseal-portal circulation--pulsatile release of ACTH

  



 Role of ACTH  Acute effects of ACTH: o Stimulates cholesterol release o Transport of cholesterol into mitochondria o Binds cholesterol to P450 cytochrome o Releases newly synthesized pregnenolone  Long-term effects of ACTH stimulation: o increase the uptake of LDL cholesterol o Formation of the steroidogenic enzymes Marias



ADRENAL MEDULLA Catecholamines: dopamine, norepinephrine, epinephrine Synthesis occur in the brain, sympathetic nerve endings & in chromaffin cells Metabolites are excreted in the urine: VMA, metanephrine, normetanephrine Both epi- & norepinephrine raise the mean arterial BP, increase PVR-inc.systolic & diastolic BP Epinephrine increases the PR-dec.PVR ACTH INSUFFICIENCY Addison’s disease Deficient production of cortisol or aldosterone due to congenital or acquired lesions of the hypothalamus, pituitary gland or adrenal cortex Etiology: congenital hypo- or aplasia of the pituitary (abnormalities of skull & brain, craniopharyngioma), adrenal hypoplasia congenita, inborn defects of steroidogenesis, autoimmune destruction of the glands, CNS demyelination, etc. Laboratory Tests o Low serum Na & Cl, increased K o Inc. urinary excretion of Na & Cl o Nonprotein nitrogen plasma level is high, hypoglycemia o Most definitive test: measurement of plasma or serum level of cortisol before & after administration of ACTH Clinical Manifestations o S/Sx begin shortly after birth (adrenal hypoplasia, steroidogenesis defects): failure to thrive, vomiting, lethargy, anorexia, dehydration 2 of 7

PEDIATRICS 2 Pediatric Endocrinology Part 2

Older children: gradual, muscular weakness, lassitude, anorexia, weight loss, general wasting, hypotension, intense craving for salt o Increased skin pigmentation on face & hands, most intense around the genitals, umbilicus, axilla, nipples, joints o Failure of suntan to disappear may be the first clue Management o D5 0.9 NSS IV – to correct hypoglycemia & the Na loss o Hydrocortisone succinate IV (25 mg for infants & 75 mg for children) every 6 hrs for the 1st 24 hrs o After 48 hrs, may discontinue fluids & shift to oral cortisol in 5-20 mg every 8 hrs o Further reduction until maintenance levels & a stable clinical situation are achieved. o May add Florinef ( flurohydrocortisone) 0.05-0.3 mg daily o



C0NGENITAL ADRENAL HYPERPLASIA



  1.

2.



AR disorders of adrenal steroidogenesis leading to a deficiency of cortisol-- inc. secretion of corticotropin-- adrenocortical hyperplasia & overproduction of intermediary metabolites Deficiency of 21-hydroxylase accounts for 90% of affected patients Clinical Manifestations NON-SALT-LOSING CAH o Normal at birth but signs of sexual & somatic precocity appear within the 1st 6 months of life o Well developed muscles & BA > CA o Stunted adult stature o Small testes and enlarged penis o Usually normal mental development o Females: pseudohermaphroditism; enlarged clitoris, labial fusion; internal genital organs are those of a normal female o Masculinization progresses after birth o Tall for age with advanced ossification SALT-LOSING CAH o Severity of virilization is generally greater in this type o Symptoms begin shortly after birth: failure to regain birthweight, progressive weight loss, dehydration, prominent vomiting, anorexia o Females: virilization of external genitals o Males: genitals appear normal Laboratory Findings o Salt-losing type: low serum Na & Cl; inc. K; low serum cortisol o Inc.plasma renin; serum aldosterone o 21-hydroxylase deficiency: increased serum 17-OHP o Pelvic ultrasound to visualize presence of uterus in female pseudohermaphrodites o Urinary 17-ketosteroid excretion & plasma levels of DHEAS elevated with CAH & cortical tumors but very high values favor the diagnosis of neoplasm o Management o Glucocorticoids inhibit excessive production of androgens & prevents progressive virilization o Hydrocortisone 10-20 mg/m2/day orally in 2-3 divided doses o Monitor growth & hormonal levels Marias

Flurohydrocortisone (0.05-0.3 mg daily) & NaCl 1-3 gms given to normalize plasma renin activity o Hydrocortisone continued indefinitely in all patients with classic forms of CAH Management o Adequate indices of control: monitor serum 17-OHP, androstenedione, testosterone, renin preferably measured at 8-9 am prior to taking the morning medication o Surgical correction of enlarged clitoris at 6-12 months old o Outcome: short stature, disordered puberty, menstrual irregularity, infertility o





 







 

     

CUSHING SYNDROME Characteristic pattern of obesity with associated hypertension which is the result of abnormally high blood levels of cortisol resulting from hyperfunction of the adrenal cortex; ACTH –dependent or independent Etiology: functioning adrenocortical tumor (infants); pituitary adenomas; hyperplasia of adrenals Clinical Manifestations o More severe in infants o Rounded face, prominent cheeks, moon facies, buffalo hump, generalized obesity, abnormal masculinization, impaired growth, hypertension, inc. susceptibility to infection o Older children: purplish striae on hips, abdomen & thighs, delayed puberty, emotional lability, weakness, headache, renal stones Laboratory Findings o Serum cortisol levels are normally elevated at 8 am & decrease to <50% by 8pm--- diurnal rhythm is lost o Urinary excretion of free cortisol & 17hydroxycorticosteroids are increased Management o Unilateral adenalectomy for benign cortical adenomas o Bilateral tumors: subtotal adenalectomy o Trans-sphenoidal pituitary microsurgery for children o Adequate preoperative & postoperative replacement therapy o Substantial catch-up growth; abnormal bone density PHEOCHROMOCYTOMA Catecholamine-secreting tumor arising from the chromaffin cells Most common site of origin is the adrenal medulla Tumors may develop anywhere along the abdominal sympathetic chain, likely to be located near the aorta at the level of the IMA or at its bifurcation. Periadrenal area, urinary bladder, ureteral walls, thoracic cavity, cervical region Occur in children 6-14 yrs old Tumors found more often on the right side, about 1-10 cm in diameter Bilateral in >20% affected children Inherited as AD trait May be associated with other syndromes such as neurofibromatosis, part of MEN syndromes, tuberous sclerosis, Sturge-Weber syndrome, ataxia-telangiectasia

Biosynthesis & Metabolism 3 of 7

PEDIATRICS 2 Pediatric Endocrinology Part 2

Phenylalanine

Tyrosine

Dopamine Norepinephrine 3-Methoxy-dopamine Homovanillic acid











Dihydroxyphenylalanine



Epinephrine Normetanephrine Metanephrine

3-Methoxy-4-hydroxy mandelic acid (VMA)

Clinical Manifestations o S/Sy result from excessive secretion of epinephrine & norepinephrine o May be symptom-free in between attacks of hypertension o Headache, palpitations, abdominal pain, dizziness, pallor, vomiting, sweating, convulsions o Severe: precordial pain radiate into the arms, pulmonary edema, cardio- & hepatomegaly o Good appetite but does not gain weight due to hypermetabolism o Polyuria, polydipsia, growth failure, papilledema, hemorrhages, exudates & arterial constriction on ophthalmoscopy Laboratory Findings o Urine contains protein & few casts o Gross hematuria suggests that the tumor is in the bladder wall o Dx: demonstration of elevated blood or urinary levels of catecholamines & their metabolites o Predominant catecholamine in children is norepinephrine derived from the adrenal gland & adrenergic nerve endings o Total urinary catecholamine excretion >300 ug/day o Urinary excretion of vanillylmandelic acid (major metabolite of epi-, norepi- & metanephrine) is increased o Vanilla-containing foods & fruits can produce falsely elevated levels of VMA o Ultrasound, CT scan, MRI: tumors o I-metaiodobenzylguanidine taken up by chromaffin tissue is useful for localizing small tumors Management o Surgical removal of tumors o Preoperative a- & B-adrenergic blockers o Thorough transabdominal exploration of all the usual sites o Accurate indicators of malignancy – presence of metastatic disease or local invasiveness that precluded complete resection or both o Pediatric malignant tumors – rare o Prolonged follow-up is indicated because functioning tumors at other sites may become manifested many years after the initial operation DEVELOPMENT OF GONADS The undifferentiated, bipotential fetal gonad arises from a thickening of the urogenital ridge 6 wks of gestation – gonad contains germ cells & stromal cells -- Leydig cells in testes; theca, interstitial or hilar cells

 

in the ovary; supporting cells --- Sertoli cells in testes or granulosa cells in ovaries In the absence of a testis-determining factor (SRY or sexdetermining region on the Y chromosome), the gonad develops into an ovary. 46,XX – needed for the development of normal ovaries Development of the testis requires a Y chromosome (short arm of the Y is critical for sex determination)

Function of the Testes  During the 1st trimester of pregnancy – levels of placental chorionic gonadotropin peak (8-12 wks) & stimulate the fetal Leydig cells to secrete testosterone; critical period for normal virilization of the XY fetus  Shortly after birth, transient increase of gonadotropins (LH) occurs- sharp inc. in serum testosterone which peak at 1-3 months old-- 6 mos.old levels dec. to low prepubertal levels that persist until the beginning of puberty  Within specific target cells, 6-8% of testosterone is converted by 5-reductase to dihydrotestosterone & 0.3% is acted on by aromatase to produce estradiol  Half of circulating testosterone is bound to sex-hormonebinding globulin (SHBG) & half to albumin; only 2% circulates in the free form  Mullerian-inhibiting substance (MIS) – earliest secreted product of the Sertoli cells of the fetal testis; causes involution of the embryologic precursors of the cervix, uterus & fallopian tubes during sexual differentiation; secreted in males by Sertoli cells both during fetal & postnatal life’ in females, it is secreted by granulosa cells only postnatally  Inhibin – glycoprotein secreted by the Sertoli cells of the testes & granulosa & theca cells of the ovary; inhibits FSH secretion  Activin – stimulates pituitary FSH secretion



Follistatin – protein produced by gonads that inhibits FSH secretion

Function of the Ovaries  Oocytes are present from the 4th mo of gestation; need granulosa cells to form primordial follicles  Most important estrogens produced by the ovary are: estradiol-17 (E2) & estrone (E1); estriol is a metabolic product of these two & all three may be found in the urine of mature females  Estrogens also arise from androgens in the adrenal glands & in the testis.  Ovary also synthesizes progesterone, a progestational steroid; the adrenal cortex & testis synthesize progesterone as a precursor for other adrenal & testicular hormones.  Estrogens, like androgens, inhibit secretion of LH & FSH.  In females, estrogens also provoke the surge of LH secretion that occurs in midmenstruation. Conversion of Androgens to Estrogens Androstenedione

P450 Aromatase Estrone (E1)

Marias

Testosterone

17B-Estradiol (E2) 4 of 7

PEDIATRICS 2 Pediatric Endocrinology Part 2

  



Noonan Syndrome  Boys & girls have normal karyotypes  Occurs in ½,000 live births  Autosomal dominant  Short stature, webbing of the neck, pectus carinatum/excavatum, cubitus valgus, right-sided CHD, hypertelorism, downward slanted palpebral fissures, ptosis, micrognathia, moderate MR in 25%, SNHL; hepatosplenomegaly; delayed puberty, cryptorchidism  Human growth hormone has been used. KLINEFELTER SYNDROME  1/500-1/1,000 newborn males have 47,XXY chromosome – most common sex chromosomal aneuploidy in males  Due to meiotic nondisjunction of an X chromosome during parental gametogenesis; the extra X chromosome is maternal in origin in 54% & paternal in 46% of patients.  Clinical Manifestations o Dx rarely made before puberty due to paucity of s/sy in childhood o Considered in all boys with MR & in children with psychosocial, learning, or school adjustment problems o Anxious, immature, excessively shy, aggressive, antisocial acts o Tall, slim, underweight, long legs, small testes & penis, gynecomastia, azoospermia, associated with leukemia & lymphoma (15-30 yrs old)  Management o Normal basal plasma levels of FSH & LH before 10 yrs old. o Midpuberty – testicular growth stops & testosterone levels are low o Replacement therapy with a long-acting testosterone preparation at 11-12 yrs old o Enanthate ester 25-50 mg IM every 3-4 wks with 50-mg increments every 6-9 mos until a maintenance dose for adults is achieved (200-250 mg every 3-4 wks) TURNER SYNDROME  45,X chromosomal complement  Unknown mechanism of chromosome loss  Risk does not increase with maternal age  Recognizable at birth: edema of the dorsa of the hands & feet, loose skin folds at the nape, LBW, decreased length, webbed neck, low posterior hairline, small mandible, prominent ears, epicanthal folds, high arched palate, widely spaced nipples, hyperconvex fingernails, delayed sexual maturation  Short stature – cardinal finding in all girls  Hypofunction Of The Ovaries

postnatal Caused by congenital failure of development, destruction (primary hypogonadism), or lack of stimulation by the pituitary (secondary hypogonadism) o Hypergonadotropic hypogonadism in the female o Diagnosis before puberty is difficult o Nonstenotic bicuspid aortic valves, horseshoe kidney, complete absence of one kidney, idiopathic hypertension, IBD o Ultrasound of the heart, kidneys & ovaries is indicated after the dx is established o Most common skeletal abnormalities: shortening of the 4th metatarsal & metacarpal bones, epiphyseal dysgenesis in the joints of the knees & elbows Plasma level of gonadotropins (FSH) are elevated--decrease from 2-8 yrs old--by 10-11 yrs old rise to adult levels Tx: recombinant GH increases height velocity & ultimate stature in most but not all children (starting dose 0.375 mg/kg/wk) Replacement therapy with estrogens is indicated (little consensus re: initiation) Premarin (conjugated estrogen) 0.3-0.625 mg given daily for 3-6 mos – effective in inducing puberty Estrogen is then cycled (taken on days 1-23) & Provera (progestin) is added taken on days 10-23 in a dose of 5-10 mg daily Withdrawal bleeding occurs in the remainder of the calendar month Psychosocial support o

PRIMARY HYPOGONADISM Hypergonadotropic hygonadism in the male Congenital anorchia occurs in 0.6% of boys with nonpalpable testes (1/20,000 males) Have normal external genitals; noxious factor damaged the fetal testes of the genetic male fetus after sexual differentiation took place Chromosomal aberrations

 

  

 

47,XXX FEMALES  Most frequent X chromosome abnormality occurring in about 1/1,000 liveborn girls  Due to maternal meiotic nondisjunction  Phenotype is of a normal female; normal sexual development  By 2 yrs old, delays in speech is evident, lack of coordination, poor academic performance, immature behavior  Tall & gangly, well coordinated, academically superior, socially outgoing



 

DIABETES MELLITUS Syndrome of metabolic disease characterized by hyperglycemia due to deficiency of insulin secretion or insulin action or both resulting in abnormal metabolism of CHO, CHON & fat Most common endocrine-metabolic disorder of childhood & adolescence Etiologic Classification o Type I – B-cell destruction leading to absolute insulin deficiency: immune-mediated or idiopathic o Type II – insulin resistance with relative deficiency or a secretory defect with insulin resistance o Drug- or chemical-induced – glucocorticoids, thyroid hormone, diazoxide, thiazides, dilantin, B-adrenergic agonists o Infections – congenital rubella, CMV o Gestational DM o Neonatal DM

Impaired Glucose Tolerance Marias

5 of 7

PEDIATRICS 2 Pediatric Endocrinology Part 2

  

Refers to a metabolic stage that is intermediate between normal glucose homeostasis & diabetes Fasting glucose concentration of 109 mg/dL – upper limit of “normal” Many individuals are euglycemic; manifest hyperglycemia only when challenged with oral glucose load

Insulin  Insulin is synthesized in the RER of the B cells of the pancreas- transported to the Golgi apparatus --packaged in membrane-bound granules-- move to the cell wall & their membranes fuse expelling the insulin to the exterior-- insulin crosses the basal lamina of the B cell & the fenestrated epithelium of the capillary to reach the bloodstream  Effects of Insulin • Adipose tissue o Increase glucose entry o Increase FA synthesis o Increase glycerol phosphate synthesis o Increase triglyceride deposition o Activation of lipoprotein lipase o Increase K uptake o Inhibition of hormone-sensitive lipase •

•

•



 



 



Muscle o Increase glucose entry o Increase glycogen synthesis o Increase amino acid uptake o Increase protein synthesis in ribosomes o Decrease protein catabolism o Decrease release of gluconeogenic amino acids o Increase ketone uptake o Increase K uptake Liver o Decrease ketogenesis o Increase protein synthesis o Increase lipid synthesis o Decrease glucose output due to decrease gluconeogenesis & increase glycogen synthesis General o Increase cell growth

TYPE I DM Girls=boys; peaks at 5-7 yrs old & puberty Basic cause of the initial clinical findings is the sharply diminished insulin secretion Mechanisms that lead to failure of pancreatic B-cell function point to the likelihood of autoimmune destruction of pancreatic islets in predisposed individuals Associated with increased frequency of HLA-B8, -DR3, -BW15, -DR4 About 80-90% of newly diagnosed patients have islet –cell antibodies (ICAs) directed at cell surface. Some evidence of abnormal T-cell function with an alteration in the ratio of suppressor to killer T cells at the onset Tissue damage of pancreatic B cells is mediated by T lymphocytes-- produce cytokines-- induce destruction of islet cells

Effects of Insulin Deficiency Marias











With progressive deficiency--excessive glucose production & impairment of its utilization--hyperglycemia w/ glucosuria---resultant osmotic diuresis produces polyuria, urinary losses of electrolytes, dehydration, polydipsiahypersecretion of epinephrine, glucagon, cortisol & GH which amplifies & perpetuates metabolic derangements & accelerates metabolic decompensation Combination of insulin deficiency & inc. counterregulatory hormones is responsible for accelerated lipolysis & impaired lipid synthesis- inc.plasma total lipids, cholesterol, TG, FFA ketone body formation w/c exceeds the capacity for peripheral utilization & renal excretion--metabolic acidosis & rapid deep breathing Clinical Manifestations o Classic: polyuria, polydipsia, polyphagia, weight loss (often in a less than a month) o Clue to polyuria: onset of enuresis in a previously toilettrained child o Pyogenic skin infections & monilial vaginitis in adolescent females o Lethargy & weakness Diagnosis o Dependent on the demonstration of hyperglycemia in association with glucosuria with or w/o ketonuria o Postprandial determinations of blood glucose or screening oral glucose tolerance tests yield low detection rates in children Diagnostic Criteria o Symptoms of diabetes plus a random plasma glucose >200 mg/dL or fasting plasma glucose >126 mg/dL or a 2-hr plasma glucose during the OGTT >200 mg/dL o Polyuria, polydipsia, & unexplained weight loss with glucosuria & ketonuria

DIABETIC KETOACIDOSIS  Glucose >300 mg/dL, ketonemia, acidosis (pH <7.3 & HCO3 <15 mEq/L), glucosuria, ketonuria  Precipitating factors like trauma, infections, vomiting, psychologic disturbances NONKETOTIC HYPEROSMOLAR COMA  Blood glucose >600 mg/dL, absence of or only slight ketosis, nonketotic acidosis, severe dehydration, depressed sensorium or coma, various neurologic signs  Serum osmolarity is >350 mOsm/kg  Pre-existing neurologic damage  Management 6 of 7

PEDIATRICS 2 Pediatric Endocrinology Part 2

3 phases: ketoacidosis, postacidotic or transition period for establishment of metabolic control, continuing phase of guidance of the diabetic child o Ketoacidosis: expansion of intravascular volume, correction of deficits in fluid, electrolyte & acid-base status; initiation of insulin therapy o Blood pH & electrolytes; ECG; blood culture; monitoring I&O o Initial hydrating fluid is isotonic saline (hypotonic relative to the patient’s serum osmolality) o Rate of fluid replacement is adjusted to provide 50-60% of the calculated deficit within the 1st 12 hrs; the remainder is given during the next 24 hrs o Administration of glucose (5% solution in 0.2 N saline) is initiated when blood glucose approaches 300 mg/dL to limit the decline of serum osmolality & reduce cerebral edema o Give potassium added after the initial 20 ml/kg if UO is adequate. o Bicarbonate only if pH <7.2 given slowly o Anticipate cerebral edema – limit rate of fluid to 4 L/m2/day or less o Insulin 0.1 U/kg of regular insulin followed by constant infusion of 0.1 U/kg/hr o When acidosis has been corrected, the continuous infusion may be discontinued & insulin given subcutaneously at 0.2-0.4 U/kg every 6-8 hrs while maintaining the glucose infusion until the child can fully tolerate food. o Monitor blood glucose before & 2 hrs after each meal & the insulin dose adjusted to maintain the blood glucose in the range of 80-180 mg/dL. Nutritional Management o CHO 55%, fat 30%, CHON 15% o 70% of CHO content should be derived from complex CHO & intake of sucrose & highly refined sugars should be limited. o Polyunsaturated:saturated fat ratio 1.2:1 o Total daily caloric intake divided to provide 20% at breakfast, 20% at lunch, 30% at dinner with 10% for each of the midmorning, midafternoon & evening snacks. Monitoring o Reliable index of long-term glycemic control – measure glycosylated Hgb o Glycohemoglobin (HbA1c) represents the fraction of Hgb to which glucose has been nonenzymatically attached in the bloodstream o The higher the blood glucose & the longer the RBC’s exposure to it, the higher will be the fraction of HbA1c- reflects the average blood glucose concentration of the preceding 2-3 months o





Glycohemoglobin  Glucose combines with Hgb continuously & nearly irreversibly during the life span of RBC (120 days)  Glycated Hgb is proportional to the mean plasma glucose level during the previous 6-12 weeks  Glycated Hgb predicts risk of progression of diabetic complications  HbA1c measurements obtained 3-4x/yr to get a profile of long-term glycemic control Marias



 

The more consistently lower the level, the better the metabolic control, the more likely it is that microvascular complications will be less severe, delayed in appearance or avoided. Use: monitor diabetic patients’ compliance with therapeutic regimen & long-term blood glucose level control In known diabetics: 7% indicates good diabetic control; 10% indicates fair diabetic control; 13-20% indicates poor diabetic control

Somogyi Phenomenon  Hypoglycemic episodes manifest as late nocturnal or early AM sweating, night terrors & headaches alternating rapidly within 4-5 hrs with ketosis, hyperglycemia, ketonuria & glucosuria suggest the possibility of Somogyi phenomenon.  Due to an outpouring of counterregulatory hormones in response to insulin-induced hypoglycemia. Dawn Phenomenon  Elevations of blood glucose occur between 5-9 am without preceding hypoglycemia  Normal event; reflects the waning effects of insulin probably due to increased clearance of insulin & nocturnal surges of GH that antagonize insulin’s metabolic effects Brittle Diabetes  Implies that control of blood glucose fluctuates widely & rapidly despite frequent adjustment of insulin doses  Somogyi & dawn phenomena are the most common cause of “brittleness”.  To distinguish: measure blood glucose at 3,4,7 am. If blood glucose >80 mg/dL in the 1st 2 samples & markedly higher in the last ---dawn (tx: inc. evening dose of intermediate insulin 10-15%)  If the 3 or 4 am blood glucose level is 60 mg/dL or less followed by rebound hyperglycemia at 7 am- Somogyi (tx: reduction of the evening intermediate-acting insulin of 1015% or a delay in its injection until about 9 pm is indicated)

FILLER! FILLER!FILLER! FILLER!FILLER! FILLER! FILLER! Here’s a poem by E. E. Cummings (cited in one of Cameron Diaz’s films)… Para kay: Rej at Jen, Aiza at Patrick…patience is a virtue... To real-life lovers: Dhess & Pats, Sheng & Myron, Roche & Fluffy, Khaye & Pau… more power to you guys! To my inspiration & bestfriend, ‘til we meet again… Para sa mga in-lurv jan!

i carry your heart with me (i carry it in my heart) i am never without it (anywhere i go you go, my dear; and whatever is done by only me is your doing, my darling) i fear no fate (for you are my fate, my sweet) i want 7 of 7

PEDIATRICS 2 Pediatric Endocrinology Part 2

no world (for beautiful you are my world, my true) and it's you are whatever a moon has always meant and whatever a sun will always sing is you here is the deepest secret nobody knows (here is the root of the root and the bud of the bud and the sky of the sky of a tree called life; which grows higher than soul can hope or mind can hide) and this is the wonder that's keeping the stars apart i carry your heart (i carry it in my heart) …owww… how sweet…

MOTTO OF THE WEEK: “Ang point kasi dun ay…. “ “It’s not what you say that matters, it’s how you say it”

The End

Marias

8 of 7