Parathyroid Disorders PDF

Parathyroid Disorders Hypoparathyroidism & Hyperparathyroidism Misty T. Justus,DMSc, PA-C Anatomy  Parathyroid Gland Function Produce: Parathyroid Hormone (PTH) ↓ Maintains: Calcium & Phosphate balance ↓ Allows: Nervous & muscular systems...

Parathyroid Disorders Hypoparathyroidism & Hyperparathyroidism Misty T. Justus,DMSc, PA-C Anatomy  Parathyroid Gland Function Produce: Parathyroid Hormone (PTH) ↓ Maintains: Calcium & Phosphate balance ↓ Allows: Nervous & muscular systems to function properly & Controls: Bone physiology Parathyroid Hormone Actions Raises serum calcium level by Stimulating vitamin D production (important for GI absorption of calcium) & Increasing renal reabsorption of calcium by decreasing renal tubular reabsorption of phosphate  Normal Physiology The four parathyroid glands are mainly composed of chief cells which secrete parathyroid hormone (PTH) Parathyroid gland activity is controlled by the level of free (ionized) calcium (Ca2+) & Phosphate (PO4)3- Low levels of free Ca2+ stimulate PTH which in turn: Increases osteoclast activity (releasing Ca++and PO43-) Increases small bowel Ca2+& PO43- absorption (through vitamin D) Increases renal resorption of Ca++ (distal tubule) & PO43- excretion (proximal tubule) This results in increased free Ca++ levels, which then inhibit PTH secretion (feedback loop) Parathyroid Hormone Actions Increase in levels of circulating ionized calcium -> inhibit PTH production Except for Parathyroid Adenoma which will autonomously make PTH despite high levels of circulating ionized calcium thereby causing primary hyperparathyroidism HYPOPARTHYROIDISM Hypoparathyroidism Definition/Pathophysiology PTH deficiency leading to low levels of serum calcium What causes PTH deficiency? Causes of Low PTH/ HYPOPARATHYROIDISM Surgical Removal of the Parathyroid Glands Most Common Cause Occurs as a complication of subtotal thyroidectomy Radical neck dissection in cases of cancer of the neck Ischemic Injury to the glands during surgery (may be temporary & recover in weeks to months) Idiopathic Cause of Hypoparathyroidism Much less common Diagnosed in childhood Can be familial Genetic Disorders: Associated defects in parathyroid development DiGeorge syndrome: Congenital absence of parathyroid glands in association with other malformations (thymic aplasia, cardiovascular defects) Autoimmune Other: Destruction by radiation therapy, infiltrative diseases of the parathyroid glands, Hypomagnesemia  Clinical Features of Hypoparathyroidism Clinical Manifestations are due to hypocalcemia Tetany: Hallmark of acute hypocalcemia (neuromuscular irritability). Produces acute symptoms: Perioral numbness Paresthesia of the hands & feet Muscle cramps Carpopedal spasm Laryngospasm Focal or generalized seizures Neuromuscular fatigue & weakness Clinical Features of Hypoparathyroidism  Chronic Manifestations of Hypoparathyroidism & Hypocalcemia Calcifications of the basal ganglia & eye Over time basal ganglia calcifications can lead to parkinsonism, other movement disorders like dystonia Ocular: Cataracts, keratoconjunctivitis Dental: Abnormalities seen if hypocalcemia is during early development. (Dental hypoplasia, defective enamel, & root formation) Skeletal abnormalities Ectodermal Manifestations: Brittle nails, ridging of nails Dryness & skin scaling  Chvostek sign: Tapping along facial nerve induces contractions of eye, mouth, or nose Classic signs of muscles Hypocalcemia Trousseau sign: Carpal spasms elicited by filling of a blood pressure cuff  Signs of Hypocalcemia Chvostek Sign Trousseau Sign https://www.youtube.com/watch?v=kvmwsTU0InQ Hypoparathyroidism: Diagnostic Evaluation Lab findings: Serum Ca2+ Normal or PTH Phosphorus Must Verify normal Magnesium & Vit. D levels Measuring Serum Calcium Normal: 8.4-10.2 mg/dl Critical value: 13.5 mg/dl The plasma level varies with the rate of Ca2+ absorption from the small intestine & the proximal renal tubular reabsorption rate under the control of PTH Serum Calcium Correction for Low Albumin Calcium is present in the three forms: Ionized or free Ca2+ that is physiologically active Protein-bound or non-diffusible Ca2+, most of which is loosely bound to plasma albumin Complexed or complex-bound Ca2+, which forms relatively soluble fractions complexed with carbonates, citrates, or phosphates. Calcium must be corrected for low albumin states: Measured calcium+0.8 (4-serum albumin) Differential Diagnosis Hypomagnesemia Hypomagnesemia (serum magnesium concentration below 0.8 mEq/L) causes hypocalcemia decreasing production of PTH & inhibiting the actions of PTH on the bone It is therefore a reversible cause of hypocalcemia associated with low or inappropriately normal PTH. Hypoparathyroidism should resolve within minutes or hours after restoration of normal serum magnesium concentrations if hypomagnesemia was the cause.  Differential Diagnosis of Hypocalcemia Causes of hypocalcemia with increased PTH levels - Kidney disease: Hypocalcemia multifactorial (e.g. Renal phosphate retention, Decreased production of 1,25-dihydroxyvitamin D3 by the diseased kidneys, bone resistance to the calcemic action of PTH) Vitamin D deficiency (as diagnosed by low 25-hydroxyvitamin D [25(OH)D]) Pancreatitis: Rapid intraabdominal precipitation of calcium sops in areas of fat necrosis of the pancreas Hypoalbuminemia Osteoblastic metastatic disease (Breast, lung, & prostate cancer produce hypocalcemia due to rapid bone uptake of cancer) Pseudohypoparathyroidism: Hereditary disease - causes end organ resistance to PTH & hypocalcemia Prone to skeletal abnormalities (Short stature, shortening of the metacarpal bones (Albrights hereditary osteodystrophy)), mental deficits Treatment Goals of Hypocalcemia Relieve symptoms Raise & maintain the serum calcium concentration in the low-normal range, e.g. 8.0 to 8.5 mg/dL Attainment of higher serum calcium values is not necessary & is usually limited by the development of hypercalciuria (due to the loss of renal calcium-retaining effects of parathyroid hormone (PTH)) Avoid hypercalciuria & iatrogenic development of nephrocalcinosis & kidney stones Avoid hyperphosphatemia Treatment of Hypocalcemia Calcium Supplementation Combined with vitamin D to enhance absorption Calcium Supplements: 1-2 g of elemental calcium per day Three types: Calcium Carbonate (tums) , calcium citrate, & calcium gluconate. Dose in 3-4 divided doses per day Raise or lower the dose depending on the calcium level Hypocalcemia Treatment - Calcium Supplements Calcium carbonate (Tums) 40% elemental calcium Best absorbed at the low gastric pH that occurs with meals Calcium citrate 21% elemental calcium Absorbed with or without meals & is a better choice for patients taking PPIs or H2-blockers Causes less GI intolerance than calcium carbonate Calcium supplements are given orally in divided doses to provide 800–1200 mg elemental calcium daily Hypocalcemia Treatment - Calcitriol Biologically active form of Vitamin D Vitamin D is needed to absorb & utilize the calcium A typical starting dose of is 0.25 mcg twice daily Increase with weekly dose increments of 0.25 mcg/day to achieve a low-normal serum calcium Many adults require up to 2 mcg daily Treatment of Severe Hypocalcemia Patients who develop severely symptomatic acute hypocalcemia (eg, laryngospasm, carpopedal spasm, seizures, markedly prolonged QT intervals on electrocardiogram) - First treated with IV calcium + oral calcitriol supplementation Also use IV calcium in asymptomatic or mildly symptomatic patients who have a rapid decline in serum corrected calcium to ≤7.5 mg/dL These patients may develop severe symptoms if hypocalcemia is not treated quickly  Hypoparathyroidism: Treatment IV Calcium replacement +/- IV magnesium (check & replace magnesium as needed) 1-2 10ml ampules 10% Ca Gluconate in 100ml D5, infuse intravenously over 10 min Treat alkalosis (alkalosis = ↑ Ca2+ & albumin binding) Cardiac monitoring & ABGs Laboratory monitoring: Albumin-corrected serum total Calcium, Magnesium, & phosphate levels  Hypoparathyroidism: Treatment IV calcium (gluconate & chloride) Causes tissue necrosis (chloride > gluconate) Administer slowly in large vein (central venous catheter preferred) Continuous cardiac monitoring Alkalosis (treat) Reduces serum Ca2+ availability by favoring Ca2+ binding to albumin Can cause worse clinical presentation than albumin-corrected Ca2+ level may suggest Calcitriol Biologically active form of Vit. D Vit. D enables cells to absorb & utilize Ca2+ Rapid onset & shorter half-life = less toxicity Preferred over Vit. D2/Vit. D3 PTH (human recombinant) Adjunct Tx when unsatisfactory response to calcium supp. & calcitriol Complications of Treatment/Hypercalciuria The major side effects of calcium & active vitamin D therapy in patients with hypoparathyroidism are hypercalcemia & hypercalciuria Chronically this can cause nephrolithiasis, nephrocalcinosis, & chronic kidney disease Management: Reduce Calcium & Vit D dose if urinary calcium >300 mg Perform renal ultrasounds to check for calcifications Add thiazide diuretics when urine calcium approaches 250 mg Use HCTZ with K supplements & monitor Mg. Replete as needed Clinical Medicine Endocrinology Primary Hyperparathyroidism Due to the oversecretion of Results in parathyroid Hypercalcemia hormone Primary Hyperparathyroidism Etiology Single Parathyroid Adenoma causes 80-90% of cases Parathyroid hyperplasia of all 4 glands causes 10- 20% Parathyroid Cancer (rare) Predisposing Factors to History of Head & Neck Hyperparathyroidism Irradiation Familial Occurrence of parathyroid hyperplasia in MEN syndrome Often involves parathyroid adenoma, hyperplasia Indicates genetic factors are important Hyperparathyroidism Pathophysiology PTH Actions Under Normal Circumstances Raises serum calcium by stimulating vitamin D production This increases GI reabsorption of calcium Decreases renal tubular reabsorption of phosphate Promotes calcium movement from the bone Under normal circumstances, increased serum ionized calcium levels will inhibit PTH production. A parathyroid producing adenoma can function autonomously & produce excessive PTH despite high ionized calcium levels This causes the abnormalities of primary hyperparathyroidism Primary Hyperparathyroidism Clinical Features 01 02 03 04 May be diagnosed Common to only Occasionally Patients with high based on routine have mild patients can serum calcium measurement of symptoms present with levels of 11-12 calcium advanced kidney & mg/dl may have GI bone disease & neurologic symptoms  Manifestations by Organ System Renal Although PTH increases renal calcium reabsorption The resulting hypercalcemia and increased glomerular filtration can lead to the formation of kidney stones Calcium deposits within the renal parenchyma can cause nephrocalcinosis & eventual renal failure Manifestations by Organ System Skeletal PTH increases osteoclastic bone resorption & can lead to osteitis fibrosa cystica Symptoms include: Bone pain Fractures Swelling and Deformities Areas of demineralization in the bone can lead to bone cysts and brown tumors (localized area of proliferating osteoclasts, osteoblasts, & fibrosis Radiographs show osteopenia & osteoporosis Loss of lamina around the teeth Subperiosteal resorption of cortical bone seen in the phalanges Similar problems skull can cause to salt & pepper appearance Manifestations by Organ System Gastrointestinal Symptoms Include: Anorexia Weight loss Nausea & vomiting Abdominal pain Constipation Increased incidence of peptic ulcer disease Increased incidence of pancreatitis Manifestations by Organ System Neurologic Symptoms Include: Fatigue & muscle weakness Emotional changes Abnormal mentation Hyperparathyroidism Labs Elevated serum calcium is the hallmark of primary hyperparathyroidism Serum phosphate may be lowered in many, but not all Serum alkaline phosphatase level will be elevated in patients with bone disease Urine calcium elevated (hypercalcuria) common (not all patients due to calcium resorption with elevated PTH) Elevated PTH level (should be measured in conjunction with calcium level) Other Hyperparathyroidism Labs 25- Serum 24-hour urine hydroxyvitamin creatinine calcium D  Bone Mineral Density Dexa Scan  Diagnostic Imaging in Primary Hyperparathyroidism Localizing the Parathyroid Gland/Adenoma Tc-sestamibi scanning, CT scanning (including 4-D CT) Magnetic resonance imaging Ultrasound with color flow doppler Individually, each has a sensitivity of 60% to 80% in experienced hands Used in combination, they are successful in at least 80% Tc-sestamib/SPECT CT scan Parathyroid Adenoma  The definitive treatment is parathyroidectomy & is indicated for symptomatic patients Surgical approach minimally invasive vs bilateral neck exploration depends on the ability of the localizing studies to detect one clearly abnormal gland Treatment of Primary Hyperplasia-may show multiple enlarged glands on Hyperparathyroidism scans, double adenomas also can occur. Multiple glands may require excision With experienced surgeons the cure rate for a single adenoma is 95% Success rate for hyperplasia is lower because missed glands can occur Transient hypocalcemia can occur post op  No definitive Medical Treatment Asymptomatic persons >50 with serum Primary calcium level no greater than 11-12 mg /dl, Hyperparathyroidism often have no progression of disease for 10 Medical Treatment or more years These patients can be followed & operated on if calcium rises  INCREASED FLUIDS CAN HELP MINIMIZE HYPERCALCEMIA Primary ORAL PHOSPHATE 1-2 G/DAY Hyperparathyroidism Medical Treatment CAN HELP LOWER CALCIUM ESTROGEN DECREASES BONE RESORPTION  Emergency Treatment of Hypercalcemia Calcium Level >14 mg/dl Hydration with 4-6 L of NS & large doses of furosemide to increase renal calcium excretion & lower serum sodium SQ/IM calcitonin (Effect limited to first 48 hours) IV Bisphosphonates block dissolution of bone & inhibit osteoclast activity (takes 2-4 days to see be effective but more sustained) If the 25-hydroxyvitamin D level is less than 20 ng/dL, vitamin D should be cautiously replaced (eg, 400 to 800 international units daily Denosumab if bisphosphonates are contraindicated (severe renal disease/allergy) Hemodialysis as last resort EKG monitoring - Shortening QT interval (hypocalcemia prolongs QT)  Malignant tumors & tumors with bone metastasis Tumors that cause Differential hypercalcemia in the absence of bone metastases make PTH Diagnosis of related peptide (PTHrP) Hypercalcemia PTHrP - Acts like PTH & binds to PTH receptors; may produce similar biochemical effects as PTH Differential Diagnosis of Hypercalcemia Sarcoidosis - Causes hypercalcemia via production of 1, 25-dihydroxyvitamin D3 by granulomatous tissue. This will respond to a therapeutic trial of glucocorticoids (prednisone 40 mg daily). **More to come in pulmonology Familial Hypocalciuric hypercalcemia - Genetic disorder ~ mildly elevated calcium; rarely has complications Clue: Family history & low urine calcium levels Vitamin D intoxication Usually in people receiving vitamin D with hypocalcemia Milk-Alkali-syndrome: Ingestion of large dose of calcium & absorbable alkali (calcium carbonate >5 g/d) Causes renal damage/nephrocalcinosis Hypercalcemia & systemic alkalosis Differential Diagnosis of Hypercalcemia Other Causes: Hyperthyroidism due to increased bone turnover Thiazide Diuretic: Decreases urinary calcium excretion - rare Avoid thiazides in patients with primary hyperparathyroidism Prolonged immobilization: Continuous bone resorption in the absence of normal posture Paget’s disease: Due to increased bone turnover Recovery from acute renal failure from rhabdomyolysis  Chronic kidney disease - Mineral & bone disorder (CKD-MBD) Systemic disorder characterized by biochemical abnormalities: Calcium Secondary Phosphate Hyperparathyroidism PTH Vitamin D Abnormalities in bone turnover Extra skeletal calcification Secondary hyperparathyroidism refers to the biochemical abnormalities that characterize CKD- MBD Tertiary Hyperparathyroidism Refractory (autonomous) hyperparathyroidism Increased PTH & resulting from chronic increased calcium kidney disease Nomogram for Parathyroid Disorders