Quiz 1.pdf

Pathophysiology of Electrolyte Imbalance Dr. Afolayan-Oloye – Philadelphia Distribution of Body Fluids o The major fluid compartments in the body. o Total Body Water (TBW). ▪ Intracellular Fluid (ICF). ▪ Extracellular Fluid (ECF)....

Pathophysiology of Electrolyte Imbalance Dr. Afolayan-Oloye – Philadelphia Distribution of Body Fluids o The major fluid compartments in the body. o Total Body Water (TBW). ▪ Intracellular Fluid (ICF). ▪ Extracellular Fluid (ECF). Interstitial fluid (ISF) – Extravascular fluid. Plasma - Intravascular fluid (Plasma). Transcellular Fluid BODY FLUID COMPARTMENT VOLUME. PERCENTAGE OF BODY WEIGHT TOTAL BODY WATER (TBW) 42L 60% INTRACELLULAR FLUID VOLUME (ICF) 28L (2/3 OF TBW). 40% EXTRACELLULAR FLUID VOLUME (ECF) 14L (1/3 OF TBW). 20% INTERSTITIAL FLUID VOLUME (ISF) 10.5L (3/4 OF ECF). 15% PLASMA VOLUME. 3.5L (1/4 OF ECF). 5% BLOOD VOLUME 5 – 6L 7 – 8% Fluid Compartments in the body are isosmotic (isotonic) to one another Osmolality o Osmolality is an inherent property of every solution or fluid compartment. o Osmolality is defined as the osmoles of solute/Kg of water in a solution. ▪ Total number of particles of solutes per unit of solvent (concentration) within a body fluid compartment. ▪ Osmolality is measured in milliosmoles per kilogram of water (mOsm/Kg). ▪ Osmolarity is measured in milliosmoles per liter of water (mOsm/L). ▪ Both terms are used interchangeably by clinicians and are a measure of the number of particles of solutes (concentration) within a fluid compartment*. o Two solutions with the same osmolality or total number of particles of solute are described as isosmotic. o If solution A has a higher number of particles of solute than solution B, solution A is hyperosmotic to solution B, and solution B is hypoosmotic to solution A.  Effective Osmolality/Effective Osmole o The concentration of all dissolved solutes that are restricted to a fluid compartment determines the “Effective Osmolality or Tonicity” of that fluid compartment. o A solute that doesn't easily cross a membrane and is restricted to a compartment is described as an "effective osmole for that fluid compartment”. ▪ An effective osmole is able to exert an osmotic force within that compartment across a semi-permeable membrane and promote the osmosis of water. ▪ Plasma proteins are restricted to the vascular compartment and serve as the effective osmole of the vascular compartment. ▪ The major solute restricted to the ECF compartment is sodium ions, which serve as the effective osmole. To maintain the electroneutrality of the ECF, an anion remains in the ECF with sodium in the ECF (chloride/bicarbonate anions). Effective ECF (Plasma) Osmolarity o Since Na ion is the major osmotically active solute within the ECF, it is the major determinant of ECF serum osmolality. o The effective ECF (plasma) osmolality (plasma osmolality) is estimated as: ▪ 2 [plasma Na+ concentration] = 2 [142mEq/L] = 284mOsm/L. o Calculation of Effective ECF (plasma) osmolarity. ▪ 2 Plasma [Na+]mEq/L + Serum Glucose (mg/dL)/18 + Serum BUN(mg/dL)/2.8. ▪ 2 + 100/18 + 12/2.8 = 289mOsm/Kg. o Normal ECF (Plasma) Osmolality is 275 – 290mOsm/Kg. Osmolar Gap Calculation o The osmolar gap = measured ECF (plasma) osmolality – effective ECF (plasma) osmolality. ▪ Measured ECF (Plasma) Osmolality - measures all dissolved particles/solutes in the blood plasma. o Effective ECF (Plasma) Osmolality. o 2 Plasma [Na+] + Serum Glucose/18 + Plasma Blood Urea Nitrogen/2.8. o A normal osmolar gap 125mEq/L – hence, neurologic manifestations of hyponatremia are rare. o Urine Na concentration typically 20mEq/L in renal etiology due to loss of the Renin-Angiotensin- Aldosterone system activation/compensation o Summary: ▪ Volume-depleted or Dehydrated patients with hyponatremia. ▪ ETIOLOGY - Renal (Mineralocorticoid deficiency, salt-losing nephropathies, hyperglycemia with osmotic diuresis) and Non-renal etiology (vomiting, diarrhea, gastric suctioning, skin loss – Cystic fibrosis, Burns), Cerebral Salt- wasting. ▪ Appropriate Neurohumoral Activation – RAAS Activation & ADH release. ▪ Serum Na >125mEq/L – Neurological manifestations are rare. ▪ Treatment – isotonic saline. Euvolemic Hyponatremia o Hyponatremia due to inappropriate ADH release in a patient with normal ECF volume status. o Pathophysiological Mechanism: ▪ Inappropriate ADH release leads to renal water retention and a mild, transient increase in ECF volume. ▪ This subclinical transient hypervolemia suppresses the Renin-Angiotensin- Aldosterone system and stimulates the release of atrial natriuretic peptide with natriuresis. Natriuresis corrects the ECF volume and results in the development of euvolemic hyponatremia. o Etiology: ▪ 1. Syndrome of Inappropriate ADH release (SIADH) – the most common cause* Pulmonary disease – pneumonia, TB, pleural effusion, pulmonary abscess, small cell carcinoma of the lungs (paraneoplastic effect with ectopic ADH production). Central Nervous System disease – intracranial tumor, head trauma, stroke, subarachnoid hemorrhage, subdural hematoma, hydrocephalus, meningitis, encephalitis, brain abscess, MS, GBS. Medications – increase ADH release or enhance its physiologic action of ADH. o SSRIs, SNRIs, vincristine, vinblastine, carbamazepine, cyclophosphamide, ifosfamide, chlorpropamide. ▪ 2. High ADH secretion. Secondary Adrenal Insufficiency with glucocorticoid deficiency: loss of negative feedback exerted by glucocorticoids on ADH release. Hypothyroidism: increased ADH secretion secondary to decreased cardiac output in moderate to severe hypothyroidism. o The clinical evaluation shows normal volume status* (no clinical signs of volume depletion or expansion, dehydration, or edema). ▪ Serum Na concentration is typically very low, 20mEq/L. ▪ Suppression of RAAS and ANP release. ▪ Urine osmolality >300 (500) mOsm/Kg. o Elevated serum ADH levels. o Evaluate thyroid function, serum cortisol, and ACTH stimulation tests to rule out hypothyroidism and hypercortisolism. o Summary: ▪ Hyponatremia with inappropriate ADH release in patients with normal ECF volume status. ▪ ETIOLOGY-SIADH-Pulmonary causes, CNS etiology, Drugs (SSRIs, SNRIs, TCAs), Hypothyroidism, and Glucocorticoid deficiency. ▪ Transient increase in volume status suppression of RAAS and activation of ANP release.  ▪ No clinical signs of volume depletion or overload. ▪ Serum Na sodium retention). o Appropriate neurohumoral activation. o Excessive and sustained activation of the Sympathetic Nervous System, the Renin- Angiotensin-Aldosterone system, and ADH secretion. o Etiology ▪ Sodium-avid edematous states – patients with reduction in cardiac output, arterial filling, effective circulatory volume, and organ perfusion. Urine sodium concentration 125mEq/L. Hence, neurological manifestations of hyponatremia are rare. o Urine Na concentration. ▪ 20mEq/L seen in renal failure with hypervolemic hyponatremia. o Summary: ▪ Patients with hyponatremia and clinical signs of volume expansion & systemic congestion. ▪ ETIOLOGY – CHF, Nephrotic syndrome, Liver cirrhosis, Acute/Chronic Renal Failure. ▪ Appropriate Neurohumoral Activation – Appropriate but excessive RAAS activation & ADH release. ▪ Serum Na >125mEq/L – Neurological manifestations are rare. ▪ Treatment – Address underlying clinical conditions and optimize treatment. Osmotic Demyelination Syndrome  Osmotic Demyelination Syndrome is characterized by damage to brain regions and the development of neurological complications when serum Na concentration is rapidly corrected by >12mEq/L within the first 24 hours in patients with chronic hyponatremia (>48 hours). o In patients with chronic hyponatremia, the brain adapts via several mechanisms. ▪ Fluid-shift - from brain cells into the cerebrospinal fluid and systemic circulation. ▪ Efflux of intracellular solutes and water - from brain cells via ion channels to reduce brain swelling. ▪ Efflux of organic osmolytes from brain cells – efflux of creatine, betaine, glutamate, myoinositol, taurine, and glycine from brain cells to reduce the osmotic gradient (with water). These protective mechanisms are usually completed within 48 hours, and hence, in patients with chronic hyponatremia. o With rapid correction of chronic hyponatremia in these patients, a rapid increase in ECF tonicity triggers the development of osmotic demyelination syndrome in the face of delayed reaccumulation of osmolytes. o Osmotic Demyelination Syndrome has the following components: ▪ Dehydration of brain tissue. ▪ Demyelination of white matter. ▪ Degenerative loss/shrinkage/apoptosis of oligodendrocytes (Astrocytes are mainly affected). o Disruption in the integrity of the blood-brain barrier - favors entry of immune mediators that may contribute to demyelination. o The pons is the most susceptible region of the brain, hence the term "Central Pontine Myelinolysis (CPM)" - Delayed reaccumulation of osmolytes is most pronounced in the pons. ▪ However, extrapontine regions may also be affected. o Clinical manifestations of Osmotic Demyelination Syndrome follow a biphasic course. ▪ Acute phase - initial phase of acute encephalopathy presents with seizures that resolve as serum Na concentration is corrected. ▪ The phase of clinical deterioration: 3 – 5 days later with dysphagia, dysarthria, diplopia, spastic paraparesis or quadriparesis, and in the most severe cases, locked-in syndrome (LIS) and coma. o The prognosis is poor, with about 25% of patients only making a complete recovery. o To avoid osmotic demyelination syndrome during correction of serum Na concentration in patients with chronic hyponatremia. ▪ Aim for a 0.5 – 1mEq/L rise in serum sodium per hour or 8 - 12mEq/L rise per 24 hours to avoid this complication. ▪ Avoiding rapid correction of chronic hyponatremia is always recommended! Pseudohyponatremia o True hyponatremia (11.5mg/dL - symptomatic presentation ranging from: ▪ Vague neuropsychiatric symptoms - impaired concentration, decreased mental activity, lethargy, weakness, personality changes, or depression. ▪ GI symptoms (nausea, anorexia, constipation, pancreatitis from calcium precipitation). o Hypercalcemia >13mg/dL. ▪ Nephrogenic DI - impaired renal concentrating ability. ▪ Nephrolithiasis and/or nephrocalcinosis ▪ Peptic ulcer disease - hypercalcemia stimulates excessive gastric acid secretion. ▪ Cardiovascular manifestations - hypertension (30-50% of patients), bradycardia, AV block, and a short QT interval. o Severe hypercalcemia >15mg/dL. ▪ A medical emergency. ▪ Coma and cardiac arrest. ▪ Clinical Manifestations of Hyperphosphatemia o Clinical manifestations are primarily related to low serum calcium levels (secondary to high phosphate levels and calcium phosphate deposition in tissues). o Neuromuscular excitability with positive Trousseau and Chvostek sign and hyperreflexia (due to associated hypocalcemia). o Soft Tissue Calcifications. ▪ Hypophosphatemia o Etiology  ▪ Internal Redistribution. Increased insulin secretion with refeeding in malnourished patients – Refeeding Syndrome. Hungry bone syndrome – post-parathyroidectomy in patients with chronic hyperparathyroidism. Loss of PTH function leads to rapid bone formation and development of hypocalcemia, hypophosphatemia. ▪ Decreased intestinal absorption. ▪ Increased Urinary Excretion. o Refeeding Syndrome. ▪ A common cause of hypophosphatemia in patients with chronic malnourishment (associated with chronic alcohol use disorder) following reintroduction of carbohydrates (administration of dextrose containing IV fluids). o Pathophysiology ▪ Reintroduction of carbohydrates stimulates insulin secretion. ▪ Insulin secretion stimulates the redistribution of phosphate into myocytes and hepatocytes (drives phosphate intracellularly) for ATP synthesis during glycolysis and maintenance of cellular energy metabolism. o The redistribution of phosphate leads to profound hypophosphatemia – a biochemical hallmark of Refeeding Syndrome. o Hematologic Manifestations: ▪ RBCs- Hemolysis and reduced oxygen transport. ▪ Leukocytes- impaired chemotactic function and phagocytosis. ▪ Platelets- impaired platelet adhesion. o Deranged Neuromuscular Functions: ▪ Marked Muscle weakness, numbness, hyperreflexia. ▪ In severe cases, irritability, confusion, stupor, seizures, coma. ▪ Respiratory failure from diaphragmatic muscle weakness. o Bone effects - impaired bone mineralization ***TEST QUESTIONS: Dr. Sisam Hints*** Central DI (lack of ADH secretion): o Administer Desmopressin/ADH for lack of ADH from the pituitary. Hyponatremia o Patient is a 64-year-old male with shortness of breath, fatigue, paroxysmal nocturnal dyspnea, edema, JVD, rales with S3 heart sound. Bilateral pleural effusion, cardiomegaly, and interstitial pulmonary infiltrates. ▪ Na plasma concentration 5nmol/L. o Midnight Plasma Cortisol - >130nmol/L. ▪ Differentiation between ACTH-Dependent Cushing’s syndrome (Cushing’s disease and ectopic ACTH secretion), and ACTH-Independent Cushing’s syndrome (adrenal hyperplasia). o Plasma ACTH Levels. ▪ Low in ACTH-independent Cushing’s syndrome/adrenal neoplasia 15pg/ml. o ***High-dose Dexamethasone Suppression Test.*** ▪ Cortisol suppression of pituitary ACTH in Cushing’s disease. ▪ No cortisol suppression of ectopic ACTH secretion. ▪ Tumor Localization. o CT Adrenals - for Adrenal neoplasia followed by adrenalectomy. o MRI pituitary - for pituitary Cushing’s disease followed by Transphenoidal pituitary surgery. o CT scan chest – for ectopic ACTH secretion followed by resection. o Inferior petrosal sinus sampling (IPSS). o Invasive procedure for sampling of ACTH from pituitary venous drainage. o Compare ACTH levels in the pituitary venous drainage to ACTH levels in the peripheral blood to confirm the source of increased ACTH secretion (Central: Peripheral ratio). o Treatment - Surgical + Medical options (ketoconazole or metyrapone) therapy. ▪ Adrenal Insufficiency o This describes clinical conditions that arise from the deficiency of cortisol and related glucocorticoids. o Primary and Secondary Adrenal insufficiency. o Primary Adrenal Insufficiency or Addison’s disease (Associated with loss of glucocorticoid, mineralocorticoid, and adrenal androgen hormone secretion). ▪ Autoimmune destruction of the adrenal cortex – Autoimmune Polyglandular Syndrome, isolated autoimmune adrenalitis. ▪ Infections – TB adrenalitis, CMV, HIV/AIDS. ▪ Bilateral Adrenal Hemorrhage - Waterhouse-Friderichsen syndrome in meningococcal septicemia, Disseminated Intravascular Coagulation, Trauma. ▪ Adrenal infiltration - metastasis, lymphomas, sarcoidosis, amyloidosis, hemochromatosis. ▪ Medications – Ketoconazole, Etomidate. o Secondary Adrenal Insufficiency (Associated with loss of glucocorticoid and adrenal androgen hormone secretion). ▪ Abrupt withdrawal from long-term exogenous steroid use - the most common cause of adrenal insufficiency from suppression of the HPA axis.  ▪ Panhypopituitarism – Pituitary mass lesions (adenomas, craniopharyngioma, meningiomas, ependymoma), pituitary metastasis (breast, lung, colon carcinoma), inflammatory granulomatous diseases (autoimmune lymphocytic hypophysitis, sarcoidosis, TB, syphilis, eosinophilic granuloma), pituitary infiltration (hemochromatosis, amyloidosis) Sheehan syndrome, pituitary apoplexy, and pituitary surgery/trauma/irradiation. ▪ Clinical Manifestations of Adrenal Insufficiency o Fasting Hypoglycemia. Inability to handle stress. Fatigue and Myalgia. Weight loss. Normochromic anemia, neutropenia, lymphocytosis, and eosinophilia. Postural Hypotension, Hyponatremia, hyperkalemia, metabolic acidosis, and dehydration from aldosterone deficiency in primary adrenal insufficiency. Hyponatremia with SIADH in secondary adrenal insufficiency - diminished inhibition of ADH secretion by cortisol. Skin Hyperpigmentation - occurs in primary adrenal insufficiency from increased Proopiomelanocortin, (POMC - MSH & ACTH) synthesis. Slightly increased TSH secretion - loss of feedback inhibition of TSH release. ▪ Evaluation of Adrenal Insufficiency o Primary Adrenal Insufficiency. ▪ Low plasma cortisol levels, low plasma adrenal androgens, low plasma deoxy cortisol levels, ▪ Elevated plasma ACTH levels. ▪ Low plasma aldosterone levels (Elevated plasma renin levels and elevated plasma angiotensin II levels) – Mineralocorticoid deficiency. o Secondary Adrenal Insufficiency. ▪ Low plasma cortisol levels, low plasma adrenal androgens, low plasma deoxy cortisol levels. ▪ Low plasma ACTH levels. ▪ Normal plasma aldosterone levels (ACTH plays a minor role in the regulation of aldosterone synthesis) o Rapid ACTH stimulation test (COSYNTROPIN TEST) and measurement of plasma cortisol. ▪ A subnormal response 2 standard deviations Short Stature o Height that is two or more than SD below the mean for age and sex o Adult height < 4’10” o Proportionate Short Stature: limbs and trunk proportionate o Disproportionate Short Stature: limbs are disproportionately shorter than trunk (skeletal dysplasia) o Growth Failure: growth rate is lower than normal Causes of Short Stature o NON-PATHOLOGICAL (Normal Variants of Growth): ▪ Familial Short Stature ▪ Constitutional Growth Delay ▪ Idiopathic Short Stature ▪ Small for Gestational Age with Catch up Growth o PATHOLOGICAL: ▪ Undernutrition ▪ GI, Rheumatologic, Renal, Cardiac, Pulmonary, Immunologic, and Metabolic Disease ▪ Glucocorticoid Therapy  ▪ Endocrine Causes (Cushing Syndrome, Hypothyroidism, Growth Hormone Deficiency, Sexual Precocity) ▪ GENETIC: (Turner Syndrome, Noonan Syndrome, Prader-Willi, Silver- Russel Syndrome, Skeletal Dysplasias) Non-Pathological Familial Short Stature o Short parents. Final height – short but consistent with family height o Growth rate – normal/parallel to normal curve but < 5th percentile ▪ Normal puberty onset ▪ Normal bone age (=chronological age) ▪ Normal laboratory studies Constitutional Delay OF Growth & Puberty (CDGP) o Birth weight and length – normal o Growth velocity – normal pre-pubertal growth rate o Puberty – delayed (“late bloomer”) ▪ transient functional defect in production of GnRH from the hypothalamus o Parents: ▪ normal adult height ▪ delay in puberty o Delayed bone age (Bone Age < Chronologic age) o Normal LH and FSH o Will reach normal adult height Idiopathic Short Stature o Height 97th percentile)  ▪ Frontal bossing, depressed nasal bridge, midface hypoplasia ▪ Limbs - rhizomelic shortening (proximal segment is shorter) ▪ Trident hands ▪ Hypotonia ▪ Genu varum ▪ Kyphosis (thoracolumbar) Osteogenesis Imperfecta o Autosomal Dominant o Defective collagen 1 synthesis → Impaired osteogenesis (COL1A1 or COL1A2 gene) o Multiple types – type II most severe o Clinical Features: ▪ Short stature ▪ Brittle bones – skeletal deformities ▪ Blue sclerae The Short and Well-Nourished or Obese Child o *** TEST QUESTION **** ▪ RED FLAG – something is up! - Remember: children with obesity are normally TALL, NOT SHORT. o Should be evaluated with: ▪ TSH (hypothyroidism) ▪ Bone Age ▪ Karyotype (females for Turner’s Syndrome) ▪ Serum IGF-1 and IGFBP-3 (true Growth Hormone Deficiency) ▪ 24-hour urine free cortisol (Cushing’s) Tall Stature What is Too Tall? o Compare height to general population: ▪ Greater than or equal to >97th percentile or > 2SD above the mean o Determine if height is too rapid: ▪ Height crosses 2 major height percentile curves ▪ Ages 2-6: >3.5 inches per year ▪ Ages 6-puberty: >2.5 inches per year o Is growth within range for that family? ▪ Biological parents’ height ▪ Calculate mid-parental height o Is there accelerated growth? ▪ Bone age ▪ Dysmorphic features ▪ Detailed medical history including family history Maternal Diabetes o Most common cause for LGA (large-for-gestational age)  o There is an association between maternal diabetes and later development for obesity ▪ Macrosomia – shoulder dystocia, hypoglycemia *Monitor the baby for hypoglycemia* ▪ Cardiac – VSD, Transposition of Great Arteries, Truncus Arteriosus ▪ CNS neural tube defects ▪ GI situs anomalies, meconium plug syndrome ▪ Renal agenesis, hydronephrosis ▪ Polydactyly, syndactyly o Why Do They Get So Big? ▪ 1. Maternal hyperglycemia ▪ 2. Fetal hyperglycemia ▪ 3. Fetal stimulation of insulin, insulin-like growth factors, growth hormone ▪ Increased fetal growth – deposition of fat and glycogen ▪ 4. LGA or macrosomia – born with increased weight and length Sotos Syndrome/Cerebral Gigantism o Born large (>90th percentile) and grow rapidly during early childhood (>97 th percentile) o After 4-5 y/o – growth returns to normal o Early puberty – advanced bone age o Growth Hormone levels NORMAL o Usually, normal adult height o Dysmorphic – macrocephaly, high forehead, frontal bossing, hypertelorism, macrognathia, intellectual disability *** TEST QUESTION *** Beckwith-Wiedemann Syndrome o Fetal overgrowth syndrome o Similar growth as cerebral gigantism o Adult height is taller than predicted family height o Macrosomia – above average length & height o Microcephaly, Omphalocele o Advanced bone age o Likely etiology – overexpression of insulin-like growth factor 2 (IGF-2) o *** HIGH RISK Wilms tumor (Monitor with q 3-month abdominal U/S until 8 years old) and HIGH RISK hepatoblastoma (Monitor with q 6-month α- fetoprotein until 6 years old) **** Familial Tall Stature Aka Constitutional Tall Stature o Normal variant of growth o Tall parents ▪ Tall adult height- High-normal height velocity (Height is 2 SD greater than what is expected for age and sex in that population) o No dysmorphic features ▪ Normal bone age ▪ Normal puberty onset ▪ No pathologic cause for tall stature  Precocious Puberty o More common in girls o Central cause or peripheral cause o Very accelerated linear growth during childhood o Very advanced bone age o Very tall child → very short adult (secondary to early epiphyseal closure) Hyperthyroidism o Can lead to increased growth o Advanced bone age o Transient increase in vertical height when child is hyperthyroid Exogenous Obesity o 1 in 3 children in the U.S. are obese o Overweight = BMI >85 percentile – 94 percentile o Obesity = BMI>95 percentile o Tall stature for age before puberty o May have early puberty – early epiphyseal closure – normal or smaller than normal adult height ▪ Diminished growth hormone production ▪ Normal serum IGF-1 ▪ Bone age may be advanced Pituitary Gigantism o Growth hormone excess PRIOR to the fusion of the epiphyseal growth plates o Etiology – In kids – most common from GHRH excess ▪ Only in GROWING children ▪ Increased Growth Hormone and IGF-1 ▪ Excessive linear growth o Rare o Dramatic presentation – rapid, dramatic linear growth ▪ May also have mild-moderate obesity (height increase prior to weight) ▪ Progressive macrocephaly ▪ May also see coarsening of facial features, frontal bossing, prognathia, large hands & feet, excessive sweating o Treatment: ▪ Trans-sphenoidal surgery for adenoma (complication Lifelong DI) ▪ Radiation generally NOT used (Radiation → late growth failure, learning disabilities, emotional problems, obesity) ▪ Bromocriptine or Octreotide Acromegaly o Adult disease o Persistent over-secretion of growth hormone (GH) → stimulates IGF-1 secretion from the liver →excess growth o Insidious onset o No increase in vertical height  o Coarsening of facial features – nose, forehead, jaw, spreading of the upper incisors (Enlargement of the jaw, hands, feet) o Other – CV disease, sleep apnea, arthopathies, symptoms related to pituitary enlargement (headache, visual loss) o Treatment: ▪ Trans-sphenoidal resection of pituitary tumor ▪ Medical management Somatostatin analogs (octreotide) Dopamine agonists GH receptor antagonists ▪ Radiation *** TEST QUESTION **** Klinefelter Syndrome o 47, XXY - Male phenotype, extra X o Tall pre-puberty with long legs compared to trunk ▪ Gynecomastia ▪ Delayed secondary sex development ▪ Azoospermia, infertile ▪ Learning disabilities o Diagnosis: ▪ Bone age normal or delayed ▪ LH and FSH high during adolescence & adulthood ▪ Serum testosterone low o Treatment: ▪ ***Treat with testosterone*** ▪ Helps with secondary sex characteristic formation ▪ Helps with psychosocial factors ▪ May lead to diminished adult height Marfan Syndrome o Autosomal Dominant ▪ Altered fibrillin gene on chromosome 15q21.1 o 1:10,000 live births o Disorder of connective tissue ▪ Tall, thin body – excessive adult height o Normal bone age o Clinical Manifestations ▪ Arachnodactyly, Pectus excavatum, Scoliosis ▪ Ectopia lentis (upward), Dilatation of aortic root ▪ Ligamentous laxity, Joint hyperextensibility Homocystinuria o Inborn error of methionine metabolism o Deficiency of cystathionine synthetase, Autosomal recessive o Buildup of homocystine and methionine o Clinical Features:  ▪ Tall stature. Long, thin extremities ▪ Ectopia Lentis (downward) ▪ Pectus excavatum or carinatum, Intellectual disability ▪ At high risk for venous or arterial thrombi o Treatment: ▪ NO TREATMENT – goal to keep homocystine levels low Mann Kahoot Questions: 1. What is the average weight of a full-term baby at birth? a. 7 pounds 6 oz b. 8 pounds 9 oz c. 6 pounds 9 oz d. 9 pounds 1 oz 2. We expect that newborns loose __% of their birth weight? a. 5% b. 20% c. 10% d. 12% 3. What is the average WEIGHT and LENGTH of a full-term baby at birth? a. 8 pounds and 21” b. 7 pounds 6 oz and 20” c. 7 pounds 6 oz and 19” d. 8 pounds 6 oz and 23” 4. Which of the following is true about the weight of a baby/child? a. A baby should double her birth weight by 6 months old b. A baby should triple her birth weight by 1 year old c. An average 1-year-old is 25 pounds d. An average 4-year-old is 45 pounds 5. What is the condition characterized by defects in bone and cartilage development and disproportionate short stature? a. Prader-Willi b. Turner c. Osteogenesis imperfecta d. Achondroplasia 6. What is the most common cause of pituitary gigantism in growing children? a. LH and FSH excess b. GNRH excess c. Radiation Exposure d. GH receptor antagonists 7. Patient is a 45-year-old male with intellectual disability, large head, prominent forehead and jaw with 5’10” height. Diagnosis? a. Acromegaly b. Cerebral Gigantism  c. Kleinfelter d. Homocystinuria 8. Which condition is characterized by excessive endogenous production of cortisol? a. Hypothyroidism b. Marfan Syndrome c. Turner Syndrome d. Cushing Syndrome 9. Patient is a 45-year-old male who presents with bilateral peripheral vision loss and headache. What is the most likely cause? a. Hyperthyroidism b. Prolactinoma c. Inborn error of methionine metabolism d. 21-hydroxylase deficiency 10. Patient is a 10-year-old boy in special ed class presents with tall stature, long limbs, and downward displacement of the lens. Etiology? a. Additional X chromosome b. Altered Fibrillin Gene c. Deficiency of cystathionine synthetase d. Elevated growth hormone 11. Patient presents with 5th percentile height and 25th percentile weight. Mom is 4’11” and Dad is 5’4”. Onset of puberty is normal. Diagnosis? a. Growth Hormone Deficiency b. Beckwith-Weidemann Syndrome c. Constitutional Growth Delay d. Familial Short Stature 12. Growth Curve displayed. Diagnosis? a. Pituitary gigantism b. Prader-Willi c. Constitutional Growth Delay d. Obesity 13. Patient presents with IUGR, prominent forehead, triangular face, hemihypertrophy, and developmental delay. a. Turner Syndrome b. Noonan Syndrome c. Osteogenesis Imperfecta d. Silver-Russel Syndrome 14. Patient presents with short stature, thickened skin, intellectual disability, and a large tongue. Diagnosis? a. Cretinism b. Cushing Syndrome c. Beckwith-Weidemann d. Achondroplasia Clinical Perspectives of Adrenal Disorders Dr. Freeman – Philadelphia Cushinoid Appearance o Features of hypercortisolism include gynecologic, cardiovascular, musculoskeletal, and neuro/psychiatric Steroids Actions o Amino acid catabolism (muscle wasting) … gluconeogenesis in the liver. Hyperglycemia… increased insulin output… eventual beta cell failure… fat deposition… diabetes o Ca resorption, impairment of Ca absorption, increased renal Ca excretion…. osteoporosis o Increased gastric acidity… ulcer formation or aggravation o K loss and Na retention… edema and hypertension o Initially increased antibody release. Eventually decreased antibody production, lymphocytopenia, eosinopenia, neutrophilia, polycythemia… susceptibility to infections o Maintenance of arteriolar tone and blood pressure Cushing’s Disease Physical Features o Buffalo Hump o Supraclavicular Fat Pad o Central/Truncal Obesity *most common* o Hypertension o Facial Plethora o Hirsutism o Acne o Violaceous Striae Cushing’s Syndrome Major Clinical Features o Weight gain, Central obesity o Moon face and plethora o Muscular weakness, especially proximal o Malaise, Depression and psychosis o Oligomenorrhoea or amenorrhea in females o Hirsuties o Striae, acne, skin-thinning, bruising o Polyuria, nocturia, decreased libido and impotence in males o Hypertension, diabetes or impaired glucose tolerance Cushing’s Disease o Pituitary tumor o Begin screen with 1 mg dexamethasone at 11 pm o Cortisol level before 10 am next am with dexamethasone level (normal less than 1.8 mcg/dl)  o Non-suppression proceeds with low dose dexamethasone test (Cushing’s suppresses) Cushing’s Laboratory Studies o Diabetes Mellitus/Glucose Intolerance o Hypercalciuria o Renal Calculi o Hypokalemia o Erythrocytosis o Eosinophilia Petrosal Sinus Sampling o Inferior petrosal sinus sampling (IPSS) is an invasive procedure in which adrenocorticotropic hormone (ACTH) levels are sampled from the veins that drain the pituitary gland; these levels are then compared with the ACTH levels in the peripheral blood to determine whether a pituitary tumor (as opposed to an ectopic source of ACTH) is responsible for ACTH-dependent Cushing syndrome. Cushing’s Disease Treatment o ****Cushing’s Disease is diagnosed by suppression at HIGH DOSE dexamethasone suppression*** o Surgical treatment- First Choice ▪ (transsphenoidal stereoscopic hypophysectomy) o Medical treatment ▪ ketoconazole, osilodrostat (Isturisa), mitotane (Lysodren), levoketoconazole (Recorlev) ▪ metyrapone (Metopirone), Mifepristone (Korlym) o Radiation proton beam Ancillary Issues o Diabetes Mellitus o Intra and Post-Operative Cortisol Therapy o Psychiatric Disorders Ectopic Cushing’s Syndrome o ACTH levels elevated usually over 200. Even in the 1000s. o Non suppression with overnight, low dose, and high dose dexamethasone. o Recalcitrant hypokalemia and hyperpigmentation  Adrenal Insufficiency – Addison’s Disease o Hypotension o Hyperpigmentation o Hyponatremia o Hyperkalemia o Positive Anti-adrenal Antibodies Adrenal Insufficiency Clinical Features o Weakness o Skin ▪ Mucous membrane and skin pigmentation, darkening of hair freckling, vitiligo, pigment accentuation at nipples, and friction areas, pigment concentration in skin creases and in scars o Loss of weight, emaciation, anorexia, vomiting, diarrhea o Hypotension o Salt craving o Hypoglycemic episodes Causes of Adrenal Insufficiency o Primary ▪ Idiopathic (Addison disease) ▪ Tuberculosis ▪ Fungal infections ▪ Adrenal hemorrhage ▪ Congenital adrenal hypoplasia ▪ Sarcoidosis ▪ Amyloidosis ▪ Metastatic neoplasia ▪ Others o Treatment of Primary Adrenal Insufficiency ▪ Treat Dehydration ▪ Significant Salt Loss ▪ Rapid ACTH Stimulation Test ▪ Treat with IV Hydrocortisone, Florinef  21-Hydroxylase Deficiency o Most common type of congenital adrenal insuffiency (Congenital Adrenal Hyperplasia) o Hyperpigmentation, Hirsutism, Amenorrhea, Salt Wasting Adrenal Hyperplasia o Bilateral Adrenal Hyperplasia o Hypertension o Hypokalemia (milder than adenoma) o Treat with Aldactone (Antagonist to Aldosterone) Secondary Causes of Adrenal Insufficiency o After exogenous glucocorticoids o After the cure of Cushing syndrome (removing endogenous glucocorticoids) o Hypothalamic and pituitary lesions Hyperaldosteronism o Signs and Labs of Hyperaldosteronism ▪ Hypertension ▪ Hypokalemia ▪ Urine potassium wasting ▪ Increased aldosterone ▪ Low renin o ***Conn’s Syndrome*** ▪ Hypokalemia ▪ Metabolic Alkalosis ▪ Elevated Aldosterone/Renin >30 ▪ Hypertension ▪ Unilateral Adrenal Adenoma ▪ Approach with SURGICAL INTERVENTION 1. Which is true regarding Cushing’s Disease? a. Usually, ACTH independent b. Usually an adrenal adenoma c. Usually an adrenal carcinoma d. Suppresses with low dose dexamethasone test. Pathophysiology of Calcium Metabolism and Bone Disease Dr. Afolayan-Oloye – Philadelphia Background o Calcium is the most abundant mineral in the body and plays a key role in many physiological processes. o The average adult has about 1kg of calcium in the body with about 98-99% present in bone as calcium phosphate salts, a reservoir that can be drawn on quickly to buffer any significant changes in plasma calcium levels. o Dietary calcium is absorbed in the proximal part of the small intestine. o Functions: calcium plays a critical role in normal cellular function and signaling, diverse physiological processes such as neuromuscular signaling, cardiac contractility, hormone secretion, and blood coagulation. Extracellular calcium levels are therefore maintained within a narrow range by endocrine hormones. ▪ Major constituent of bone. ▪ Neuromuscular excitability. ▪ Neurotransmitter release. ▪ Signal transduction pathways – 2nd messenger. ▪ Muscle contraction. ▪ Cofactors for enzymes - Blood clotting cascade. Distribution of Plasma Calcium. o Plasma calcium (1-2%) exists in three forms: ▪ Free ionized calcium – 50%. This is the physiologically and metabolically active fraction regulated by endocrine hormones associated with calcium homeostasis (PTH, vitamin D and calcitonin). ▪ Protein-bound: 40% of plasma calcium is bound to albumin. This fraction is pH dependent – at alkaline pH more calcium is bound, and at acidic pH, less calcium is bound. ▪ Complexed fraction: 10% of plasma calcium is bound to citrate, phosphate & bicarbonate anions. o Normal plasma calcium levels - 8.5 to 10.5 mg/dL. o Normal ionized calcium levels - 4.5 to 5.6 mg/dL. Bone Cells o Osteogenic STEM Cells ▪ These are spindle-shaped mesenchymal stem. ▪ These stem cells originate from embryonic mesenchyme in the periosteum and endosteum that are capable of differentiation into osteoblasts. o Osteoblasts ▪ These are immature bone cells derived from osteogenic stem cells. ▪ They are cuboidal cells that lie on the surface of the bone matrix and appear basophilic.  ▪ Function to synthesize, transport, and lay down organic bone matrix (osteoid) during bone formation. ▪ Later, they assume a flattened shape with a decline in synthetic function and become transformed into osteocytes. ▪ They express receptors for PTH and vitamin D. ▪ Contains high amounts of alkaline phosphatase. ▪ Modulate osteoclast function, will transform into osteocytes. o Osteocytes ▪ These are mature bone cells derived from osteoblasts that have become trapped within the secreted bone matrix during bone remodeling. ▪ Osteocytes are housed within individual lacunae and communicate with each other, osteoblasts, and nutrient capillaries via gap junctions between cytoplasmic processes extending through canaliculi. ▪ Osteocytes help control calcium and phosphate levels in the microenvironment, detect mechanical forces, and translate these forces into biological activity – a process known as mechanotransduction. ▪ Osteocytes also contribute to the regulation of bone resorption and formation. o Osteoclasts. ▪ Osteoclasts are specialized multinucleated macrophages/giant cells (50 – 200um) derived from the fusion of circulating monocytes. ▪ Osteoblasts stimulate the formation and activation of osteoclasts via the release of cytokines and receptor activator of NF-kB ligand (RANK-L), which stimulates the RANK receptor on osteoclast precursors. RANK-L belongs to the TNF family of cytokines. ▪ Estrogens promote the secretion of osteoprotegerin OPG, a decoy receptor for RANK-L, therefore it is PROTECTIVE. ▪ Osteoclasts lie in shallow indentations known as Howship’s lacunae, which are small cavities formed from the digestion of underlying bone. ▪ Their cytoplasm appears faintly basophilic and granular with abundant lysosomes and an extensive ruffled border abutting on bone tissue. ▪ Osteoclasts carry out bone resorption by creating a sealed acidic microenvironment (resorption pit) on the bone surface to activate and secrete enzymes (lysosomal acid hydrolases, matrix metalloproteases, collagenous and proteolytic enzymes), demineralize bone matrix and degrade organic matrix, followed by resorption of the organic and inorganic residues into the circulation. Bone Remodeling o The adult bone appears static but undergoes continuous remodeling throughout life. o Bone remodeling is a continuous and tightly regulated process of bone formation and resorption that peaks early in life, continues throughout life, and declines later in life. o The process turns over approximately 10% of the adult skeleton each year, repairs damage and changes the shape of bones in response to mechanical stresses. o Bone remodeling is regulated by cell-to-cell interactions, cytokines, and signaling pathways. Heredity, physical activity, muscle strength, nutrition, and hormonal status (especially estrogen) play a significant role. o The process involves an interplay between bone-building cells (osteoblasts) and bone cells that carry out resorption (osteoclasts) and occurs within the bone multicellular units (BMU). o Transmembrane receptor activator for NF-kB expressed on osteoclast precursors. o RANK-Ligand (RANK-L) is expressed by osteoblasts and marrow stromal cells. ▪ The interaction between RANK and RANK-L normally activates NF-kB, which is essential for the development and activation of osteoclasts. o Osteoprotegerin (OPG) is secreted as a decoy receptor by osteoblasts and stromal cells. It functions to bind RANK-L and prevent its interaction with its receptor (RANK). OPG secretion is increased by estrogens. o Macrophage-colony stimulating factor (M-CSF) and IL-6 are produced by osteoblasts and is involved in osteoclast development. o WNT proteins produced by osteoprogenitor cells bind to LRP5 & LRP6 on osteoclasts to activate beta-catenin and OPG synthesis. o Hormonal factors of bone remodeling include PTH, vitamin D, estrogens, and glucocorticoids. ▪ Estrogens function to reduce the activity of osteoclasts by inducing the synthesis of OPG and reducing the secretion of cytokines by T- lymphocytes (IL-1, IL-6, TNF-alpha) that promote the differentiation and activation of osteoclasts. Estrogens, therefore, protect against excessive bone resorption. ▪ Glucocorticoids promote bone breakdown by inducing the synthesis and release of RANK-L and inhibiting OPG synthesis. Glucocorticoids, therefore, promote an increase in bone resorption. ▪ Weight-bearing stress promotes bone mineralization, while its absence (sedentary lifestyle, bedridden patients) promotes the demineralization of bone tissue. o Increased plasma osteocalcin and alkaline phosphatase reflect an increase in osteoblastic activity and bone formation (released from osteoblasts). o Increased urinary excretion of hydroxyproline, a breakdown product of collagen, reflects increased bone resorption. Endocrine Regulation of Plasma Calcium and Phosphate Levels Bone Diseases o Abnormalities of PTH Secretion ▪ This may arise from either the oversecretion of PTH, which results in hyperparathyroidism, or deficiency of PTH, as occurs in hypoparathyroidism. ▪ In hyperparathyroidism, the parathyroid glands secrete excess parathyroid hormone due to an inherent problem with the parathyroid glands – primary hyperparathyroidism, or due to a problem that decreases plasma calcium levels – secondary hyperparathyroidism, or loss of sensitivity to PTH in tertiary hyperparathyroidism. ▪ In hypoparathyroidism, deficiency of PTH secretion occurs due to an inherent defect of the parathyroid glands – primary hypoparathyroidism, or due to hypercalcemia secondary to excessive vitamin D ingestion - secondary hypoparathyroidism. Primary Hyperparathyroidism. ▪ This arises from excessive PTH secretion from hyperfunction of the parathyroid glands. ▪ The most common cause is a solitary parathyroid adenoma (80% of cases). ▪ The remainder of cases arise from: Parathyroid hyperplasia of all 4 glands (MEN 1 & MEN 2A – about 15 - 20% of cases) Parathyroid carcinoma (rare 50%) are asymptomatic, and hypercalcemia is discovered on routine blood testing.  ▪ Increased bone resorption leads to decreased bone mass/density, hypercalcemia, and hypercalciuria. ▪ Increased bone turnover from excessive osteoclastic bone resorption with increased alkaline phosphatase levels classically presents as osteitis fibrosa cystica. In this condition, osteoclasts are found in increased numbers in scalloped areas of surface bone, and marrow elements are replaced by fibrous tissue. The condition results in excessive bone demineralization, increased tendency for fractures, bone pain, bone cysts, and brown tumors (punched-out lesions producing a salt-and-pepper-like appearance). Brown tumors are formed from microfractures, secondary hemorrhage, macrophage/osteoclast recruitment, and ingrowth of reparative fibrous tissue inside bone cysts. The brown color results from increased vascularity, hemorrhage, and hemosiderin deposition. GI manifestations of anorexia, nausea, vomiting, thirst, abdominal pain with pancreatitis, peptic ulcer disease, weight loss, and constipation, CNS symptoms – Neuromuscular weakness, fatigue, lethargy, mild personality disturbances, confusion, coma, mental depression, neuropsychiatric disorders secondary to hypercalcemia. Cardiovascular manifestations of hypercalcemia include hypertension, short QT interval, and cardiac arrhythmias. Renal manifestations: impaired renal concentrating ability due to hypercalcemia leads to nephrogenic DI, polyuria, and dehydration. Hypercalcemia → hypercalciuria, nephrolithiasis, and nephrocalcinosis. ▪ Stones, moans, and groans – description of clinical presentation of renal calculi, increased susceptibility to fracture, and constipation. ▪ The formation of kidney stones, acute pancreatitis, or peptic ulcer disease in a patient with hypercalcemia is highly suggestive of a diagnosis of primary hyperparathyroidism. Evaluation of Patients with Primary Hyperparathyroidism. o Evaluation results in elevated serum PTH levels, elevated serum calcium levels >10.5mg/dL, decreased serum phosphate levels