Calcium and Parathyroid Disorders Hussain Mahmud, MD Clinical Assistant Professor of Medicine Division of Endocrinology, Diabetes, and Metabolism University of Pittsburgh Butler Memorial Hospital November 11, 2017
None Disclosures
Outline Physiology of calcium, parathyroid hormone and vitamin D Hypercalcemia Primary hyperparathyroidism Hypocalcemia
PHYSIOLOGY AKA HOW THINGS WORK
Physiologic Roles of Calcium Maintains electrochemical gradient across cell membranes Excitation contraction coupling in cardiac and other muscles Coagulation, synaptic transmission Hormone release and intracellular messenger: Calcium acts as a second messenger Transforms extracellular signals into intracellular responses
Physiologic Roles of Calcium Extracellular (ionized) calcium is tightly regulated Hypercalcemia => raises potential across cell making it difficult to excite Hypocalcemia => reduced membrane potential making cell hyperexcitable
==> 150 mg Filtered Ca = 10,000 mg Reabsorbed Ca = 9,850 mg
NIH Office of Dietary Supplements Fact Sheet
Dietary Calcium Sources NIH Office of Dietary Supplements Fact Sheet
Elemental Calcium ==> needs acidic environment
Parathyroid Glands Size = 3-4 mm Weight = 40 mg Number = 4, but ~10% people have one supernumerary gland & 2% have three parathyroid glands Location = neck, but ectopic locations include 6.3% in mediastinum and 2% in atypical locations in the neck
Parathyroid Hormone Secretion is predominantly regulated by serum calcium concentrations serum Ca = PTH secretion serum Ca = PTH secretion Cleared within 2-4 minutes
Parathyroid Hormone Regulation Calcium sensing receptor (CaSr) cell surface receptor that senses extracellular calcium found in parathyroid glands and kidney Binding of Ca to CaSR inhibits PTH secretion and level of PTH mrna Familial Hypocalciuric Hypercalcemia (FHH): inactivating mutation of the CaSR higher set point for calcium sensing
Actions of PTH Kidney: Stimulate 1,25(OH) 2 D production Stimulate Calcium Reabsorption Block Phosphate Reabsorption Bone: Activate Osteoclastic Resorption (acute) Activate Osteoblastic Bone Formation (subacute, chronic) Intestine:Activate Calcium Transport (indirect via 1,25(OH) 2 D) Modified from Stewart AF, Cecil Essentials of Medicine 8 th ed, 772-778
resorption absorptio n (indirectly) reabsorption Vit D hydroxylation
Vitamin D
Vitamin D Wide range of other biologic actions: inhibits cellular proliferation and angiogenesis, stimulates insulin production, inhibits renin production, stimulates macrophages 25 (OH) D major circulating form best indicator of vitamin D status 1,000 X > concentration than 1,25 (OH) 2 D Deficiency: children => rickets, adults => Osteomalacia
Vitamin D Supplementation Vitamin D 2 (ergocalciferol) => plant source Vitamin D 3 (cholecalciferol) => animal source Recent data that D 3 is more effective at raising serum vitamin D levels compared to D 2
How Much Vitamin D Do We Need? Depends on who you ask IOM provides guidance for dietary standards in the general public, used by government to set dietary regulations Endocrine Society Practice guidelines intended for use by clinicians who have patients who are at risk for deficiency Goal: Serum 25 Vitamin D > 30 ng/ml
Hyperparathyroidism
HYPERCALCEMIA AKA DOC I M TIRED ALL THE TIME
Hypercalcemia Corrected total or ionized calcium > 2 SD above normal mean (10.2-10.5 mg/dl or 1.13-1.29 mm) No formal grading criteria for severity: <12.0 mg/dl => mild 12-14 mg/dl => moderate > 14.0 mg/dl => severe
Hypercalcemia Serum Calcium: 40-50 % ionized (active) 40-45% bound to albumin 10 % bound to citrate Total calcium varies with alterations in binding proteins, specifically albumin Corrected calcium should be used for decision making Corrected Total Ca + = Measured Ca + mg/dl + 0.8 ( 4.0 measured albumin)
Manifestations of Hypercalcemia Signs and symptoms depend on severity and rapidity of onset electrical gradient across a cell depolarization potential response to chemical or neural stimulus
Manifestations of Hypercalcemia Neurologic: Fatigue => obtunded => coma Influenced by rate of onset, age, baseline MS Seizures (cerebral vasoconstriction) Renal: Polyuria => thirst and dehydration Calcium directly inhibits H2O reabsorption due to osmotic diuresis Calcium inhibits ADH effect on distal nephron = nephrogenic DI Nephrocalcinosis = deposition of Ca-Phos salts in renal interstitium Hypercalciuria => nephrolithiasis Renal insufficiency or failure over time
Manifestations of Hypercalcemia Cardiovascular: Shortened QTc interval: deposition of Ca-Phos in cardiac conduction system Arteriolar vasoconstriction Musculo-skeletal: Skeletal muscle weakness: contractility Gastrointestinal: Constipation, nausea, vomiting, ileus (due to smooth muscle hypoactivity) Pancreatitis: calcium deposits within pancreas
Differential Diagnosis of Hypercalcemia Check PTH PTH PTH Primary Hyperparathyroidism Tertiary Hyperparathyroidism Parathyroid Carcinoma FHH Everything Else
Differential Diagnosis of Hypercalcemia
Primary Hyperparathyroidism Primary Disorder Abnormality SCa SPO 4 TMP FCaE CaE* 25-D 1,25 (OH) 2 D PTH Primary Increased PTH N, N hyperparathyroidism secretion Most common cause of hypercalcemia in the outpatient setting Used to be disease of bones, stones, groans, and psychic moans but now usually discovered incidentally high normal or Ca + with inappropriately normal or PTH
Primary Hyperparathyroidism Caused by over secretion of PTH by parathyroid gland loss of normal feedback of PTH by serum calcium 85% benign solitary parathyroid adenoma 15% hyperplasia of two or more parathyroid glands Consider hereditary endocrine disorders: MEN I and MEN II Rare parathyroid carcinoma (1.25 cases per 10 million)
Primary Hyperparathyroidism Most patients are asymptomatic with mild elevated Ca + = 10.2-10.8 mg/dl Symptoms => same as Ca, bone pain Evaluation: Serum calcium, albumin, phosphorous, creatinine, PTH, 25 OH vitamin D (correct if low) 24 urine calcium and creatinine DXA scan (with forearm BMD) Imaging: Order sestamibi scan (+/- SPECT) only after diagnosis is confirmed biochemically
Primary Hyperparathyroidism: Definitive treatment is surgical Refer to an experienced surgeon! Who is a surgical candidate? Any symptomatic patient Asymptomatic patients with any of the following: Age <50 Management Serum total calcium 1.0 mg/dl above ULN T-score -2.5 SD at any site or vertebral fracture Cr clearance < 60cc/min, Ur Ca >400 mg/d and high biochemical stone risk, presence of nephrolithiasis or nephrocalcinosis Bilezikian JP, JCEM 2014.
Primary Hyperparathyroidism: Medical Management Antiresorptives (bisphosphonates) for low bone density Calcimimetic (cinacalcet) symptomatic or severe hypercalcemia in non-surgical candidate Yearly monitoring for those with mild disease S Calcium, albumin, phosphorous, PTH, 25 OH Vit D Urine calcium and creatinine if indicated BMD every 1-2 years (include distal radius)
Differential Diagnosis of Hypercalcemia Check PTH PTH PTH Primary Hyperparathyroidism Tertiary Hyperparathyroidism Parathyroid Carcinoma Everything Else
Non-PTH Mediated Hypercalcemia Familial Hypocalciuric Hypercalcemia Malignancy associated hypercalcemia Granulomatous disorders (lymphoma, sarcoidosis) Endocrine disorders (hyperthyroidism, Addison s, Pheochromocytoma) Milk alkali syndrome Immobilization (among adolescents, Paget s) Acute Renal Failure TPN/hyperproteinemia End Stage Liver Disease Medications
Malignancy Associated Hypercalcemia Most common cause of hypercalcemia in inpatient setting Common cause of death among cancer patients: severe hypercalcemia leads to coma and renal failure Breast, lung, renal, ovarian, hematologic Secretion of Parathyroid hormone-related protein (PTHrP) causing humoral hypercalcemia of malignancy Skeletal metastases cytokine mediated osteoclastic bone destruction Lymphomas can make 1,25 (OH) 2 Vitamin D Rare tumors make ectopic PTH
Malignancy Associated Hypercalcemia: Treatment Treat underlying malignancy Acute management: Vigorous intravenous hydration Loop diuretics only to prevent CHF Calcitonin Often responds acutely to meds that block bone resorption IV Bisphosphonates: Zoledronate or Pamidronate
Sarcoidosis Granulomatous disease: giant granuloma cells multiple organs Prototype of hypercalcemia associated with granulomatous diseases Occurs in 10% of sarcoid patients 1,25 (OH) 2 D production by macrophages and giant cells => intestinal hyperabsorption of calcium Lesser extent renal calcium absorption and osteoclastic bone resorption Treatment: Glucocorticoids
Medications Hypervitaminosis A Hypervitaminosis D Thiazide diuretics Lithium Estrogens, androgens Tamoxifen
HYPOCALCEMIA AKA DOC I M TINGLING ALL OVER
Hypocalcemia Corrected total or ionized calcium < 2 SD below normal mean (<8.5 mg/dl = <1.16 mm) As with hypercalcemia, total calcium needs to be corrected for albumin when assessing hypocalcemia Evaluation includes measurement of: Serum calcium, albumin Serum ionized Ca, Mg, Phos, PTH, and 25 OH Vit D
Manifestations of Hypocalcemia Signs and symptoms depend on severity and rapidity of onset electrical gradient across a cell depolarization potential response to chemical or neural stimulus => hyperexcitability
Manifestations of Hypocalcemia Neurologic: Fatigue, seizures, perioral numbness, tingling Basal ganglia and intra-cerebral calcifications Cardio-vascular: Prolonged QTc interval, arrhythmias CHF Cardiomyopathy
Manifestations of Hypocalcemia Musculo-skeletal: Muscle twitches, cramps, tetany Chvostek s sign => twitching of facial muscle Trousseau s sign => spasms of forearm with BP cuff > systolic Gastrointestinal: Cramping Other: Bronchospasm Cataracts
Differential Diagnosis of Hypocalcemia Hypoparathyroidism Psuedohypoparathyroidism Vitamin D Disorders Hypoalbuminemia Magnesium disorders Rapid Bone formation Hyperphosphatemia Medications Pancreatitis
Hypoparathyroidism Rare, results from no or little PTH low ionized calcium with low PTH Phos often elevated early in disease Low 1,25 (OH) 2 vitamin D Result is hypocalcemia that is often symptomatic at onset Etiology Surgical Idiopathic/Autoimmune Infiltrative diseases Wilson s, hemochromatosis Congenital
Hypoparathyroidism: Treatment One of the few endocrine disorders that has previously not been treated with replacement hormone 2 main components of therapy: Calcium supplementation (~2 gm a day) 1,25 (OH) 2 vitamin D (rocaltrol, calcitriol) Important to monitor serum and urine calcium closely to avoid calcium-phosphate precipitation Recombinant PTH 1-84 recently (2015) approved for treatment of long-standing severe hypoparathyroidism
Severe Hypocalcemia Among Inpatients Treat with IV calcium if: Symptomatic (carpopedal spasm, tetany, seizures) QT prolongation Acute hypocalcemia, corrected Ca <7.5 mg/dl Administer IV calcium gluconate (mix 1 amp with 50 ml D5 to avoid hypotension and bradycardia) Start calcium gluconate infusion (11 amps in 890mL NS = 1 mg/ml elemental Ca) 50 ml/hr Start oral calcium carbonate 2 gm TID Start calcitriol 0.25 mcg BID Treat hypomagnesemia and monitor Ca closely
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