Objectives

• 2. 3. 4. 5. 6. 7. To understand the pathophysiology & recognize the common manifestations of the following conditions: Hypopituitarism / Hyperpituitarism Diabetes insipidus Precocious puberty Hypothyroidism / Hyperthyroidism Thyroiditis Hypoparathyroidism / Hyperparathyroidism

Objectives
7. ACTH insufficiency 8. Congenital adrenal hyperplasia 9. Cushing syndrome 10. Pheochromocytoma 11. Hypogonadism (testes & ovaries) 12. Diabetes mellitus • To devise an appropriate diagnostic & therapeutic plan for each endocrinologic condition.

Hormones

Hormones of the Hypothalamus & Pituitary
Anterior pituitary gland produce the ff: Somatotropes – produce GH Lactotropes – prolactin Thyrotropes – TSH Corticotropes – pro-opiomelanocortin, the precursor of corticotropin (ACTH) 6. Gonadotropes – LH & FSH • 2. 3. 4. 5.
• • TSH, LH, FSH – glycoproteins ACTH, prolactin, GH - polypeptides

Hormones of the Hypothalamus & Pituitary
Protein hormones produced by the anterior pituitary act on other endocrine glands to affect almost every organ • Neurohypophysis produce the ff: 3. Arginine vasopressin (ADH) 4. Oxytocin • Produced by neurosecretion in the hypothalamic nuclei •

General Approach • Hyper states – suppression test • Hypo states – stimulation test

GROWTH HORMONE
• Polypeptide metabolized rapidly in the liver • Synergize with ACTH in increasing adrenal size and with androgens in increasing the size of accessory reproductive organs • Increases hepatic glucose output & exerts an anti-insulin effect in muscle (ketogenic)  increase circulating FFA levels

Somatomedins
Polypeptide growth factors secreted by the liver and other tissues in response to stimulation by GH • Interacts with GH and has effects on growth, bone, cartilage and protein metabolism 3. Insulin-like GF I (somatomedin C) – secretion is stimulated by GH 4. Insulin-like GF II – role in the growth of fetus •

HYPOPITUITARISM
Deficiency of growth hormone with or without a deficiency of other pituitary hormones • Congenital or acquired • Clinical manifestations: 4. Of normal size & weight at birth 5. Atrophy of adrenal cortex, thyroid & gonads result in weight loss, asthenia, sensitivity to cold, absence of sweating •

Hypopituitarism
3. Tendency to hypoglycemia 4. Short & broad face, prominent frontal bone, depressed nasal bridge, underdeveloped mandible, short neck, high-pitched voice, well proportioned extremities but small hands & feet, delayed sexual maturity

HYPOPITUITARISM
• Laboratory findings:  Diagnosis of classic type is suspected in cases of profound postnatal growth failure (height > 3 SD below the mean for age & gender)  Definitive diagnosis: absent or low levels of GH in response to stimulation * Use of L-dopa, insulin, arginine, clonidine or glucagon: peak level of GH < 10 ug/L in each of 2 provocative tests – GH deficiency

HYPOPITUITARISM
• Examine other pituitary functions: levels of TSH, T4, ACTH, cortisol, DHEA, gonadotropins may provide evidence of other pituitary hormonal deficiencies • X-ray/MRI findings: destructive or spaceoccupying lesions: enlargement of the sella or erosions & calcifications within or above the sella turcica; delayed skeletal maturation

Differential Diagnosis of Short Stature
1. Congenital pathologic short stature – prenatal onset; infant is born small and growth slowly tapers off throughout infancy; due to chromosomal abnormalities, infections, teratogens, alcohol, extreme prematurity

Differential Diagnosis of Short Stature
2. Constitutional growth delay- normal weight & length at birth; weight & height decrease near the end of infancy, parallel the norm through middle childhood, and accelerates toward the end of adolescence; normal adult size; bone age is low and comparable to height age
* Height age is the age at which the standard (median) height equals the present height

Differential Diagnosis of Short Stature
3. Familial short stature- both infant and parents are small; growth runs parallel to and just below the normal curves; bone age is normal comparable to chronologic age

Differential Diagnosis of Short Stature
4. Endocrine causes of decreased linear growth/postnatal onset- length decrease first or at the same time as the weight; weight for height is normal or elevated

Management
• Guidelines for GH treatment: 1. hGH 0.18-0.3 mg/kg/wk SC in 6-7 divided doses 2. Add LHRH agonist – interruption of puberty will delay fusion & prolong growth 3. Therapy until near final height is achieved

* Criteria for stopping tx: growth rate < 1 in/yr & BA > 14 yrs in girls & > 16 yrs in boys

HYPERPITUITARISM
• Primary type is rare in children • Secondary type: seen in conditions in which deficiency of a target organ gives decreased hormonal feedback • Pituitary hyperplasia – occurs in response to stimulation by ectopic production of releasing hormones or systemic tumors

Pituitary Gigantism
• Young persons with open epiphyses, overproduction of GH results in gigantism • Persons with closed epiphyses – acromegaly • Cardinal clinical feature of gigantism: longitudinal growth acceleration due to GH excess • Coarse facial features, enlarged hands & feet, broad nose, enlarged tongue, visual field defects

Diagnosis of GH excess
• Serum somatomedin C (IGF-I) is uniformly increased in untreated cases; more precise & cost-effective than serum GH because GH levels fluctuate & have short serum half-life (22 mins) • All patients with acromegaly should have baseline serum prolactin measured because <40% of adenomas may secrete both prolactin & GH.

Diagnosis of GH excess
• Gold standard: failure to suppress serum GH levels to <5 ng/dL after a 1.75 g/kg oral glucose challenge (measures the ability of IGF-I to suppress GH secretion because the glucose load results in insulin secretion leading to IGFBP-I suppression, leading to acute increase in free IGF-I) • Serum IGF-I – sensitive screening test for GH excess

Treatment of GH Oversecretion
• Goals of therapy: 2. to remove or shrink the pituitary mass 3. to restore GH & secretory patterns to normal 4. to restore IGF-I & IGFBP-3 levels to normal 5. to retain the normal pituitary secretion of other hormones 6. to prevent recurrence of disease

Treatment of GH Oversecretion
• If with well-circumscribed pituitary adenomas: transsphenoidal surgery (complete removal of the tumor) • Biochemical cure: GH level <1 ng/mL within 2 hrs after a glucose load and serum IGF-I (age adjusted normal range) • Pituitary radiation & medical therapy • Somatostatin analog (Octreotide)

DIABETES INSIPIDUS
• Presents clinically with polyuria & polydipsia and may result from either vasopressin deficiency (central DI) or vasopressin insensitivity (nephrogenic DI)

DIABETES INSIPIDUS
• Vasopressin, secreted from the posterior pituitary, is the principal regulator of tonicity; has both antidiuretic & vascular pressor activity & synthesized in the paraventricular & supraoptic nuclei of the hypothalamus

DIABETES INSIPIDUS
• Vasopressin exerts its principal effect on the kidney via V2 receptors located in the collecting tubule, the thick ascending limb of the loop of Henle & the periglomerular tubules • Activation of V2 receptor increase in IC cAMP insertion of the aquaporin-2 water channel into the apical membrane

DIABETES INSIPIDUS
• Atrial natriuretic peptide (ANP) – stimulates natriuresis (excretion of excessive Na in the urine), inhibits Na resorption & vasopressin secretion • ANP is expressed in endothelial cells & vascular smooth muscle where it relaxes arterial smooth muscles

DIABETES INSIPIDUS
• As plasma osmolality increases, patient becomes thirsty & drinks fluids-- plasma is diluted before it reaches the higher set level to stimulate ADH release--- initiates cycle of polyuria & polydipsia

Central DI
Genetic (autosomal dominant) Acquired: Trauma (surgical or accidental) Congenital malformation Neoplasms (germinoma or pinealoma) Infiltrative, autoimmune & infectious disease 7. Drugs (ethanol, phenytoin, opiate antagonists, halothane, alpha-adrenergic agents) • • 3. 4. 5. 6.

Nephrogenic DI
Genetic (X-linked, AR, AD): more severe • Acquired  Hypercalcemia, hypokalemia  Drugs (lithium, foscarnet, amphotericin, methicillin, rifampicin)  Kidney disease (ureteral obstruction, CRF, •
polycystic kidney disease)

Approach to DI
• Serum osmolality, Na, K, BUN, creatinine, glucose, Ca, urine osmolality, urine SG • Diagnosis: serum osmolality >300 mOsm/L; urine osmolality <300 mOsm/L • Differentiate central vs nephrogenic type: water deprivation test: serum osmolality 270-300 mOsm/L; with pathologic polyuria & polydipsia

Diagnosis of Central DI
• Urine is inappropriately dilute (low specific gravity <1.005) & osmolality (50-200 mOsm/kg) in the presence of serum osmolality (295 mOsm/kg) & increased or normal serum sodium • After Pitressin, urine osmolality doubles.

Diagnosis of Nephrogenic DI
• Urine SG <1.010, urine osmolality of 100-200 mOsm/kg (increased) • Increased plasma osmolality 310-320 mOsm/kg • After Pitressin, no change in urine osmolality is noted.

Treatment of DI
• Central DI:  Patients can maintain plasma osmolality & Na in the high normal range  Often best treated solely with fluid therapy (3 L/m2/day)  Long-acting vasopressin analog dDAVP (desmopressin) intranasal (10 ug/spray) & tablet (25-300ug every 8-12 hrs)  Post-surgery: synthetic aqueous vasopressin (Pitressin) – 1.5 mU/kg/hr

Treatment of DI
• Nephrogenic DI:  Elimination of underlying disorder  Ensure intake of adequate calories for growth & to avoid severe dehydration  Use of thiazides with indomethacin & amiloride to further reduce polyuria

Physiology of Puberty
• Prepubertal stage (between early childhood and 8-9 yrs old): hypothalamicpituitary-gonadal axis is dormant; the activity of the hypothalamus & pituitary is thought to be suppressed by poorly characterized neuronal restraint pathways • Peripubertal stage (1-3 yrs before the onset of puberty): low serum levels of LH during sleep • LH secretion occurs in a pulsatile fashion & reflects episodic discharge of GnRH.

Physiology of Puberty
• Nocturnal pulses of LH – responsible of enlargement & maturation of the gonads & the secretion of sex hormones • Early puberty – appearance of secondary sex characteristics is the culmination of the sustained active interaction among the H-P-G axis • Midpuberty – LH pulses become evident during the daytime & occur at about 90120 min interval

Physiology of Puberty
• Mid- to late adolescence – (+)feedback mechanism wherein increasing levels of estrogen in midcycle causing LH rise • GnRH is the major hormone responsible for the onset & progression of puberty.

PRECOCIOUS PUBERTY
• • 3. Onset of secondary sexual characteristics before 8 yrs old in girls & 9 yrs old in boys Conditions causing precocious puberty: Gonadotropin-dependent puberty (true precocious puberty) – increased sex hormone secretion & progressive sexual maturation Idiopathic Brain tumors, severe head trauma, hydrocephalus Prolonged & untreated hypothyroidism

  

PRECOCIOUS PUBERTY
2. Combined gonadotropin-dependent & gonadotropin-independent puberty 3. Gonadotropin-independent (precocious pseudopuberty) – no activation of the normal HPG interplay & some sexual chars.appear  Ovarian tumors  Exogenous estrogens/androgens  Congenital adrenal hyperplasia  McCune-Albright syndrome  Adrenal tumors

PRECOCIOUS PUBERTY
4. Incomplete (Partial) precocious puberty  Premature thelarche – breast development in the first 2 yrs of life, regress after 2 yrs & rarely progressive  Premature adrenarche – pubic hair; early maturational event of adrenal androgen production  Premature menarche

PRECOCIOUS PUBERTY
• Laboratory Findings: 2. Immunometric assay for LH (serum)serial blood samples obtained during sleep & shows pulsatile LH secretion 3. GnRH stimulation test or an agonist (leuprolide stimulation test) – diagnostic tool esp.for boys where a brisk LH response (LH peak >5-10 IU/L) with predominance of LH over FSH that occurs in the early phase

Laboratory Findings
3. Pelvic ultrasound – progressive enlargement of the ovaries & uterus 4. Cranial CT scan/cranial MRI – physiologic enlargement of the pituitary gland; pedunculated mass attached to the tuber cinereum of the floor of the 3rd ventricle

Treatment
• Leuprolide acetate – 0.25-0.3 mg/kg IM once every 4 wks (true precocious puberty) • If treatment is effective, serum sex hormones decrease to prepubertal levels (testosterone <20 ng/dL; estradiol <10 pg/mL); serum LH & FSH decrease to <1 IU/L • Menarche & ovulatory cycles appear within 6-18 months of cessation of therapy

THYROID GLAND
• Development & Physiology:  Fetal thyroid is seen at 7 wks of gestation  Thyroid follicle cell & colloid formation at 10 wks of gestation  Thyroglobulin synthesis occurs from 4 wks gestation onwards; iodine trapping by 8-10 wks; T4 & T3 synthesis by 12 wks; TSH secretion by 12 wks

Development & Physiology
• Hypothalamic neurons synthesize TRH by 6-8 wks of gestation • Maturation of the hypothalamicpituitary-thyroid axis occurs occurs over the 2nd half of gestation • Normal feedback mechanisms mature about 1-2 months postnatal life

Feedback control of thyroid secretion

Development & Physiology
• Functions of thyroid hormones:  Increase oxygen consumption (increased basal metabolic rate via inc. Na-K-ATPase activity)  Stimulate protein synthesis  Affect CHO, lipid, vitamin metabolism  Influence growth & differentiation (bone growth, CNS maturation)

HYPOTHYROIDISM
• • •
4. 5. 6. 7. 8.

Due to deficient production of hormone or a defect in hormonal receptor activity congenital or acquired Etiology of congenital hypothyroidism:
Thyroid dysgenesis Thyrotropin receptor-blocking antibody Defective synthesis of thyroxine Defect of iodide transport Thyroid peroxidase defects of organification & coupling

Etiology of Congenital Hypothyroidism 6. Defects of thyroglobulin synthesis 7. Defects in deiodination 8. Radioiodine 9. Thyrotropin deficiency 10. Thyroid hormone unresponsiveness

Clinical Manifestations
• Birthweight & length are normal • Prolonged physiologic jaundice * • Feeding difficulties, sluggishness, lack of interest, somnolence • Respiratory difficulties due to large tongue • Frequent constipation • Large abdomen; usually with umbilical hernia

Clinical Manifestations
• Hypothermic; cold & mottled skin; dry & scaly • Edema of the genitals & extremities • Retardation of physical & mental development progresses • Stunted growth, short extremities, depressed nasal bridge, narrow palpebral fissures, swollen eyelids, delayed dentition, short & thick neck, deposits of fat above the clavicles & between the neck & shoulders, coarse hair • Delayed sexual maturation, motor & language skills

Diagnostics & Therapeutics
• Low serum T4 & T3; elevated serum TSH • X-ray: epiphyseal dysgenesis, deformity of T12 or L1-2; large fontanels & wide sutures; large sella turcica; cardiomegaly • Tx: Sodium-L-thyroxine 10-15 ug/kg/day • Monitor hormone levels & maintain • Better prognosis if it occurred >2 years old

THYROIDITIS
• Lymphocytic / Hashimoto / Autoimmune • Most common cause of thyroid disease in children & adolescents; also the most common cause of acquired hypothyroidism with or without goiter • Etiology: organ-specific autoimmune disease is characterized histologically by lymphocytic infiltration between the thyroid follicles (lymphoid follicle formation with germinal centers)

THYROIDITIS
• HLA-DR4, HLA-DR5 associated with an increased risk of goiter & thyroiditis • Thyroid antiperoxidase antibodies (TPOAbs) seen in the sera of 90% of children; inhibit enzyme activity & stimulate natural killer cell cytotoxicity

THYROIDITIS
• Girls > boys; more common >6 y/o with peak during adolescence • Most common manifestations are goiter & growth retardation • Thyroid is diffusely enlarged, firm & nontender in most patients • Most of the affected children are euthyroid & asymptomatic

THYROIDITIS
• Variable clinical course (become small, disappear, remain unchanged for years) • Incidence in siblings or parents of affected children 25%; autosomal dominant • Definitive dx: biopsy (rarely indicated) • Thyroid function tests (normal) • TSH may be slightly increased (subclinical)

THYROIDITIS
• Thyroid scan: 50% reveal irregular & patchy distribution of the radioisotope • Thyroid UTZ: scattered hypoechogenicity • (+) Serum Ab titers to TPO • Tx: if with evidence of hypothyroidism, give sodium-L-thyroxine (50-150 ug/day) • May be self-limited; periodic re-evaluation • (+)nodules – biopsy (identify CA)

GOITER
• An enlargement of the thyroid gland • May have normal function (euthyroid), thyroid deficiency (hypothyroidism) or overproduction of hormones (hyperthyroidism) • May be congenital or acquired; sporadic or endemic

GOITER
• Results from increased pituitary secretion of thyrotropic hormones in response to decreased circulating levels of thyroid hormones • May also result from infiltrative processes that may be inflammatory or neoplastic • Congenital form: due to fetal T4 synthetic defect or the administration of antithyroid drugs or iodides during pregnancy for the treatment of thyrotoxicosis

GOITER
• Iodine deficiency – endemic goiter is rare in populations living along the sea • RDA of iodine for infants is > 30 ug/kg/day (cow’s milk > breast milk)

HYPERTHYROIDISM
• Results from excessive secretion of thyroid hormone and due to diffuse toxic goiter during childhood • Germ line mutations of the TSH receptor were reported in familial (AD) cases • May also be due to toxic uninodular goiter (Plummer disease) or hyperfunctioning thyroid carcinoma

Graves Disease
• Occurs in 1:5000 children with peak incidence in the 11-15 y/o and a 5:1 female to male ratio • (+)family hx of autoimmune thyroid disease • Enlargement of the thymus, splenomegaly, lymphadenopathy, infiltration of the thyroid gland & retro-orbital tissues • Ophthalmopathy appears to be due to antibodies against antigens shared by the thyroid & eye muscle (TSH receptors identified in retro-orbital adipocytes & may be a target for antibodies)

Graves Disease
• Abs that bind to the extraocular muscles & orbital fibroblasts stimulate the synthesis of glycosaminoglycans & produce cytotoxic effects on muscle cells

Graves Disease
• Postulated failure of T suppressor cells allows expression of T helper cells, sensitized to the TSH Ag, which interacts with B cells---- differentiate into plasma cells --- produce TRSAb --bind to TSH receptor & stimulates cAMP • In whites, associated with HLA-B8 & HLA-DR3

Graves Disease
• Peaks in adolescence • Variable clinical course & thyroid size • Interval between onset & diagnosis is 6-12 months • Earliest sign may be emotional disturbance with motor hyperactivity • Tremor of fingers; voracious appetite with loss or no increase in weight

Graves Disease
• Lagging of the upper eyelid, impaired convergence, retraction of the upper eyelid, infrequent blinking • Flushed skin with excessive sweating • Tachycardia, palpitations, dyspnea, cardiomegaly, increased systolic & pulse pressure, may have (+)apical systolic murmur (MR) due to papillary muscle dysfunction

Graves Disease
• Thyroid “crisis” or “storm” – acute onset, hyperthermia, severe tachycardia, restlessness, rapid progression to delirium, coma & death • “Apathetic” or “masked” hyperthyroidism – extreme listlessness, apathy, cachexia • Both variants are rare in children.

Graves Disease
• Increased T4, T3; low TSH • (+)TRSAb; its disappearance predicts remission of the disease • TSH receptor Abs are generally not necessary for diagnosis but may be useful in equivocal cases • Radionuclide study: palpable nodule and increased T3

Graves Disease
• Tx: preference of antithyroid drugs over RAI or subtotal thyroidectomy • PTU & Methimazole – both inhibit incorporation of trapped inorganic iodide into organic compounds; may also suppress levels of TRSAb by directly affecting intrathyroidal autoimmunity

Graves Disease
• Methimazole 10x more potent than PTU and has a longer serum half-life • PTU is protein-bound and has a lesser ability to cross the placenta & to pass into breast milk; inhibits extrathyroidal conversion of T4-T3 • Transient leukopenia as side effect of Methimazole (asymptomatic)

Graves Disease
PTU initial dose 5-10 mg/kg/day TID Methimazole 0.25-1 mg/kg/day OD or BID Careful surveillance needed Rising serum TSH to greater than normal indicates overtreatment & leads to increased size of the goiter • Clinical response apparent in 2-3 wks; adequate control evident in 1-3 months; dose is decreased to the minimal level needed to maintain a euthyroid state • • • •

Graves Disease

2. 3. 4.

Indications for surgery or RAI treatment:
When adequate cooperation for medical management is not possible When adequate trial of medications has failed to result in permanent remission Severe side effects preclude further use of antithyroid drugs

Subtotal thyroidectomy – only when the patient is in a euthyroid state

Graves Disease
• Radioiodine > 10 y/o; effective and relatively safe; major consequence is hypothyroidism which occurs in 10-20% of patients after the 1st year & in 3% per year thereafter

CALCIUM HOMEOSTASIS
• PTH & Vit.D are the principal regulators of calcium homeostasis • Calcitonin & PTH-related peptide (PTHrP) – important primarily in the fetus • 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)

CALCIUM HOMEOSTASIS
• PTH has C-terminal, mid-region & Nterminal fragments
 N-terminal – assay most useful for detecting acute secretory changes  C-terminus & mid-region – inert & represent 80% of plasma immunoreactive PTH  C-terminal assay – detects hyperparathyroidism

• When serum Ca falls, secretion of PTH increases.

CALCIUM HOMEOSTASIS
• 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

CALCIUM HOMEOSTASIS
• Hypocalcemia induces increased PTH secretion; hypercalcemia depresses PTH secretion.

CALCIUM HOMEOSTASIS
• Calcitonin – 32-AA polypeptide; secreted in parafollicular cells (C cells) of the TG
 In the fetus, high levels augment bone metabolism & skeletal growth stimulated by the normally high fetal Ca levels.  Main biologic effect: inhibition of bone resorption by decreasing the number & activity of boneresorbing 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
• Muscular pain and cramps – early • Numbness, stiffness, tingling of the hands & feet • (+)Chvostek or Trosseau sign or laryngeal & carpopedal spasm • Convulsions with loss of consciousness • Chronic: late teeth eruption, irregular enamel formation, soft teeth

Clinical Manifestations
• Dry & scaly skin • Horizontal lines in nails of the fingers & toes • Mucocutaneous candidiasis • Cataracts • Permanent mental & physical deterioration occur if initiation of treatment is delayed.

Serum Calcium
• About 50% of calcium is ionized • 40-45% is bound to albumin • 5-10% is bound to other anions (sulfate, PO4, lactate, citrate) • Only ionized fraction is physiologically active & can be rapidly measured • Blood pH should always be performed with ionized Ca (increased in acidosis; decreased in alkalosis)

Laboratory Findings
• Serum calcium <5-7 mg/dL • Serum phosphorus >7-12 mg/dL • Serum ionized calcium (45% of the total) is low • Serum alkaline phosphatase is normal or low • Low level of 1,25 OH2D3 • Normal serum magnesium • Low serum PTH

Laboratory Findings
• X-ray of the bones: increased density limited to the metaphyses • X-ray and CT of the skull: calcifications in the basal ganglia • ECG: prolonged QT interval • EEG: widespread slow activity

Management
• 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 • 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

Management
• Supplemental calcium gluconate or glubionate to provide 800 mg of elemental calcium daily • Reduce high phosphorus content in diet such as milk, eggs & cheese • Frequent monitoring of serum calcium levels

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

HYPERPARATHYROIDISM
• 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
• Muscular weakness, anorexia, nausea, vomiting, constipation, polydipsia, polyuria, loss of weight, fever • Progressively diminished renal function in chronic cases • Osseous changes may produce pain in the back or extremities, gait disturbances, fractures

Clinical Manifestations
• Abdominal pain • Parathyroid crisis: serum calcium >15 mg/dL, progressive oliguria, azotemia, stupor, coma • Infants: failure to thrive, poor feeding, hypotonia • Chronic cases: mental retardation, convulsions, blindness

Laboratory Tests
• Serum calcium should always be measured at the same time as PTH. • Primary case: increased serum Ca; increased serum PTH; increased serum chloride; decreased serum phosphorus in 50% of cases

Laboratory Findings
Serum & ionized calcium elevated Serum phosphorus is low <3 mg/dL Serum magnesium is low Low specific gravity of urine Serum nonprotein nitrogen & uric acid inc. • Elevated serum PTH • • • • •

Laboratory Findings
• Most consistent X-ray finding is resorption of subperiosteal bone best seen along the margins of the phalanges of the hands • Skull X-ray: gross trabeculation or a granular appearance due to focal rarefaction • Abdominal X-ray: renal calculi or nephrocalcinosis

Management
• 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: 3. Zona glomerulosa – aldosterone (15%) 4. Zona fasciculata – cortisol & androgens 5. Zona reticularis – androgens (10%) •

Hypothalamic-PituitaryAdrenal 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.

Hypothalamic-PituitaryAdrenal Axis
• 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:  Stimulates cholesterol release  Transport of cholesterol into mitochondria  Binds cholesterol to P450 cytochrome  Releases newly synthesized pregnenolone

Role of ACTH
• Long-term effects of ACTH stimulation:  increase the uptake of LDL cholesterol  Formation of the steroidogenic enzymes

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:  Regulate RNA & protein synthesis  Catabolic effect in muscles, skin, connective, adipose & lymphoid tissues: increased degradation of protein  Anabolic in the liver: increase protein & glycogen content, enhances gluconeogenesis  Effects of insulin & androgens are antagonistic to those of glucocorticoids

Adrenal Steroids
• Mineralocorticoids
 Aldosterone maintains electrolyte balance- blood volume & BP stabilization  Controls Na & H20 reabsorption in the distal tubules

• Androgens
 inc. retention of N, K, P, S04  Promote growth & have androgenic effects  DHEAS levels begin to rise before the other hormonal changes of puberty occur

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
• Low serum Na & Cl, increased K • Inc. urinary excretion of Na & Cl • Nonprotein nitrogen plasma level is high, hypoglycemia • Most definitive test: measurement of plasma or serum level of cortisol before & after administration of ACTH

Clinical Manifestations
• S/Sy begin shortly after birth (adrenal hypoplasia, steroidogenesis defects): failure to thrive, vomiting, lethargy, anorexia, dehydration • Older children: gradual, muscular weakness, lassitude, anorexia, weight loss, general wasting, hypotension, intense craving for salt

Clinical Manifestations
• Increased skin pigmentation on face & hands, most intense around the genitals, umbilicus, axilla, nipples, joints • Failure of suntan to disappear may be the first clue

Management
• D5 0.9 NSS IV – to correct hypoglycemia & the Na loss • Hydrocortisone succinate IV (25 mg for infants & 75 mg for children) every 6 hrs for the 1st 24 hrs • After 48 hrs, may discontinue fluids & shift to oral cortisol in 5-20 mg every 8 hrs • Further reduction until maintenance levels & a stable clinical situation are achieved. • May add Florinef ( flurohydrocortisone) 0.05-0.3 mg daily

C0NGENITAL ADRENAL HYPERPLASIA
• 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
 Normal at birth but signs of sexual & somatic precocity appear within the 1st 6 months of life  Well developed muscles & BA > CA  Stunted adult stature  Small testes and enlarged penis  Usually normal mental development  Females: pseudohermaphroditism; enlarged clitoris, labial fusion; internal genital organs are those of a normal female  Masculinization progresses after birth  Tall for age with advanced ossification

Clinical Manifestations
• SALT-LOSING CAH
 Severity of virilization is generally greater in this type  Symptoms begin shortly after birth: failure to regain birthweight, progressive weight loss, dehydration, prominent vomiting, anorexia  Females: virilization of external genitals  Males: genitals appear normal

Laboratory Findings
• Salt-losing type: low serum Na & Cl; inc. K; low serum cortisol • Inc.plasma renin; serum aldosterone • 21-hydroxylase deficiency: increased serum 17-OHP • Pelvic ultrasound to visualize presence of uterus in female pseudohermaphrodites

Laboratory Findings
• Urinary 17-ketosteroid excretion & plasma levels of DHEAS elevated with CAH & cortical tumors but very high values favor the diagnosis of neoplasm

Management
• Glucocorticoids inhibit excessive production of androgens & prevents progressive virilization • Hydrocortisone 10-20 mg/m2/day orally in 2-3 divided doses • Monitor growth & hormonal levels • Flurohydrocortisone (0.05-0.3 mg daily) & NaCl 1-3 gms given to normalize plasma renin activity • Hydrocortisone continued indefinitely in all patients with classic forms of CAH

Management
• Adequate indices of control: monitor serum 17-OHP, androstenedione, testosterone, renin preferably measured at 8-9 am prior to taking the morning medication • Surgical correction of enlarged clitoris at 6-12 months old • Outcome: short stature, disordered puberty, menstrual irregularity, infertility

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
• More severe in infants • Rounded face, prominent cheeks, moon facies, buffalo hump, generalized obesity, abnormal masculinization, impaired growth, hypertension, inc. susceptibility to infection • Older children: purplish striae on hips, abdomen & thighs, delayed puberty, emotional lability, weakness, headache, renal stones

Laboratory Findings
• Serum cortisol levels are normally elevated at 8 am & decrease to <50% by 8pm---diurnal rhythm is lost • Urinary excretion of free cortisol & 17-hydroxycorticosteroids are increased

Management
• Unilateral adenalectomy for benign cortical adenomas • Bilateral tumors: subtotal adenalectomy • Trans-sphenoidal pituitary microsurgery for children • Adequate preoperative & postoperative replacement therapy • 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

PHEOCHROMOCYTOMA
• 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, SturgeWeber syndrome, ataxia-telangiectasia

Biosynthesis & Metabolism
Phenylalanine Dopamine Dihydroxyphenylalanine Norepinephrine 3-Methoxy-dopamine Homovanillic acid Normetanephrine Epinephrine Metanephrine Tyrosine

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

Clinical Manifestations
• S/Sy result from excessive secretion of epinephrine & norepinephrine • May be symptom-free in between attacks of hypertension • Headache, palpitations, abdominal pain, dizziness, pallor, vomiting, sweating, convulsions • Severe: precordial pain radiate into the arms, pulmonary edema, cardio- & hepatomegaly

Clinical Manifestations
• Good appetite but does not gain weight due to hypermetabolism • Polyuria, polydipsia, growth failure, papilledema, hemorrhages, exudates & arterial constriction on ophthalmoscopy

Laboratory Findings
• Urine contains protein & few casts • Gross hematuria suggests that the tumor is in the bladder wall • Dx: demonstration of elevated blood or urinary levels of catecholamines & their metabolites • Predominant catecholamine in children is norepinephrine derived from the adrenal gland & adrenergic nerve endings

Laboratory Findings
• Total urinary catecholamine excretion >300 ug/day • Urinary excretion of vanillylmandelic acid (major metabolite of epi-, norepi- & metanephrine) is increased • Vanilla-containing foods & fruits can produce falsely elevated levels of VMA • Ultrasound, CT scan, MRI: tumors • I-metaiodobenzylguanidine taken up by chromaffin tissue is useful for localizing small tumors

Management
• Surgical removal of tumors • Preoperative a- & B-adrenergic blockers • Thorough transabdominal exploration of all the usual sites • Accurate indicators of malignancy – presence of metastatic disease or local invasiveness that precluded complete resection or both

Management
• Pediatric malignant tumors – rare • 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

DEVELOPMENT OF GONADS
• In the absence of a testis-determining factor (SRY or sex-determining 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

Function of the Testes
• Within specific target cells, 6-8% of testosterone is converted by 5reductase to dihydrotestosterone & 0.3% is acted on by aromatase to produce estradiol • Half of circulating testosterone is bound to sex-hormone-binding globulin (SHBG) & half to albumin; only 2% circulates in the free form

Function of the Testes
• 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

Function of the Testes
• 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.

Function of the Ovaries
• 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 Testosterone

P450 Aromatase Estrone (E1) (E2) 17B-Estradiol

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

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
• Dx rarely made before puberty due to paucity of s/sy in childhood • Considered in all boys with MR & in children with psychosocial, learning, or school adjustment problems • Anxious, immature, excessively shy, aggressive, antisocial acts • Tall, slim, underweight, long legs, small testes & penis, gynecomastia, azoospermia, associated with leukemia & lymphoma (1530 yrs old)

Management
• Normal basal plasma levels of FSH & LH before 10 yrs old. • Midpuberty – testicular growth stops & testosterone levels are low • Replacement therapy with a long-acting testosterone preparation at 11-12 yrs old • 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)

HYPOFUNCTION OF THE OVARIES
• Caused by congenital failure of development, postnatal destruction (primary hypogonadism), or lack of stimulation by the pituitary (secondary hypogonadism) • Hypergonadotropic hypogonadism in the female • Diagnosis before puberty is difficult

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

Turner Syndrome
• Short stature – cardinal finding in all girls • Nonstenotic bicuspid aortic valves, horseshoe kidney, complete absence of one kidney, idiopathic hypertension, IBD • Ultrasound of the heart, kidneys & ovaries is indicated after the dx is established • Most common skeletal abnormalities: shortening of the 4th metatarsal & metacarpal bones, epiphyseal dysgenesis in the joints of the knees & elbows

Turner Syndrome
• Plasma level of gonadotropins (FSH) are elevated---decrease from 2-8 yrs old--by 1011 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)

Turner Syndrome
• 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 123) & 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

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

• Type I – B-cell destruction leading to absolute insulin deficiency: immune-mediated or idiopathic • Type II – insulin resistance with relative deficiency or a secretory defect with insulin resistance • Drug- or chemical-induced – glucocorticoids, thyroid hormone, diazoxide, thiazides, dilantin, B-adrenergic agonists • Infections – congenital rubella, CMV • Gestational DM • Neonatal DM

Etiologic Classification

Impaired Glucose Tolerance
• 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
       Increase glucose entry Increase FA synthesis Increase glycerol phosphate synthesis Increase triglyceride deposition Activation of lipoprotein lipase Increase K uptake Inhibition of hormone-sensitive lipase

Effects of Insulin
• Muscle
        Increase glucose entry Increase glycogen synthesis Increase amino acid uptake Increase protein synthesis in ribosomes Decrease protein catabolism Decrease release of gluconeogenic amino acids Increase ketone uptake Increase K uptake

Effects of Insulin
• Liver
    Decrease ketogenesis Increase protein synthesis Increase lipid synthesis Decrease glucose output due to decrease gluconeogenesis & increase glycogen synthesis

• General
 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

TYPE I DM
• 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
Insulin deficiency (& glucagon excess) Dec.glucagon uptake Hyperglycemia, FFA, glycosuria, osmotic ketogenesis, diuresis, E-disturbance ketonuria, CHON synthesis plasma AA; N loss in urine Lipolysis plasma

Dehydration, acidosis Coma

-nemia

Effects of Insulin Deficiency
• 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

Effects of Insulin Deficiency
• 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
• Classic: polyuria, polydipsia, polyphagia, weight loss (often in a less than a month) • Clue to polyuria: onset of enuresis in a previously toilet-trained child • Pyogenic skin infections & monilial vaginitis in adolescent females • Lethargy & weakness

Diagnosis
• Dependent on the demonstration of hyperglycemia in association with glucosuria with or w/o ketonuria • Postprandial determinations of blood glucose or screening oral glucose tolerance tests yield low detection rates in children

Diagnostic Criteria
• 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 • 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
• 3 phases: ketoacidosis, postacidotic or transition period for establishment of metabolic control, continuing phase of guidance of the diabetic child • Ketoacidosis: expansion of intravascular volume, correction of deficits in fluid, electrolyte & acid-base status; initiation of insulin therapy • Blood pH & electrolytes; ECG; blood culture; monitoring I & O

Management
• Initial hydrating fluid is isotonic saline (hypotonic relative to the patient’s serum osmolality) • 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 • 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

Management
• Give potassium added after the initial 20 ml/kg if UO is adequate. • Bicarbonate only if pH <7.2 given slowly • Anticipate cerebral edema – limit rate of fluid to 4 L/m2/day or less • Insulin 0.1 U/kg of regular insulin followed by constant infusion of 0.1 U/kg/hr

Management
• 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. • 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
• CHO 55%, fat 30%, CHON 15% • 70% of CHO content should be derived from complex CHO & intake of sucrose & highly refined sugars should be limited. • Polyunsaturated:saturated fat ratio 1.2:1 • 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
• Reliable index of long-term glycemic control – measure glycosylated Hgb • Glycohemoglobin (HbA1c) represents the fraction of Hgb to which glucose has been nonenzymatically attached in the bloodstream • 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

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

Glycohemoglobin
• HbA1c measurements obtained 34x/yr to get a profile of long-term glycemic control • 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.

Glycohemoglobin
• 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%)

Brittle Diabetes
• 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 10-15% or a delay in its injection until about 9 pm is indicated)

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