Calcium Homeostasis and Hypercalcemia Resident Conference Robert B

Calcium Homeostasis and Hypercalcemia Resident Conference Robert B. Kamali, M. D. Nov. 4, 2003

Overview Calcium Homeostasis: PTH and Calcitriol n Mechanisms of Hypercalcemia n Causes of Hypercalcemia n Clinical Manifestations of Hypercalcemia n Diagnosis of Hypercalcemia n Treatment of Hypercalcemia (Medical and Surgical) n

Calcium Homeostasis n Two major hormones modulating calcium and phosphate homeostasis: n n PTH and Calcitriol PTH: n maintainins serum ionized calcium concentrations within a narrow range

Calcium Homeostasis PTH n Raises calcium by: Accelerating osteoclastic bone resorption n Increasing renal tubular resorption of calcium n Increases calcitriol, indirectly raising serum calcium n

Calcium Homeostasis PTH n Stimulates the conversion of calcidiol [25(OH) D] to calcitriol [1, 25 -(OH)2 D] in renal tubular cells n Its secretion regulated by serum ionized calcium acting via a sensitive calcium-sensing receptor on the surface of parathyroid cells

Calcium Homeostasis PTH n With small increase in serum ionized calcium-sensing receptor activated PTH secretion is inhibited n A small decrease in serum ionized calcium deactivation of the receptor stimulating PTH secretion

Calcium Homeostasis PTH synthesized as a 110 -aa polypeptide cleaved to pro-PTH (90 -aa) PTH (84 -aa) n Intact PTH: The major storage, secreted, and biologically active form of the hormone n Biosynthetic process takes less than one hour n Within seconds after hypocalcemia PTH 184 secreted by exocytosis n Calcium regulates release, synthesis and degradation of PTH n

Calcium Homeostasis PTH n n PTH rapidly cleared from plasma through uptake by liver and kidney PTH 1 -84 cleaved into amino- and carboxyl-terminal fragments cleared by the kidney Intact PTH has a plasma half-life of 2 -4 min Circulating immunoreactive PTH in normal subjects comprises: n n n Intact PTH 5 -30% C-term fragment 70 -95% N-term fragment a small percentage

Calcium Homeostasis PTH n Biologic activity of PTH resides in its aminoterminus n The amino terminus of PTHr. P structurally similar to PTH hypercalcemia in patients with PTHr. P-secreting tumors

Calcium Homeostasis Vitamin D Synthesis n n n Dermal synthesis major source of the vitamin D Synthesized nonenzymatically in skin from 7 dehydrocholesterol during exposure to the UVB rays in sunlight Dietary vit D absorbed in the small intestine as a fat soluble vitamin Travels to the liver, bound to vitamin D-BP Hepatic enzyme 25–OHase places an OH group in the 25 position of the vitamin D molecule, resulting in the formation of 25 -hydroxyvitamin D or calcidiol

Calcium Homeostasis Vitamin D Synthesis Calcidiol only about 1% as potent as calcitriol n Calcidiol enters circulation and travels to the kidney, bound to vit-D-BP n 1 -alpha-OHase in the tubular cells synthesizes calcitriol n

FUNCTIONS OF CALCITRIOL [1, 25 -(OH)2 D 3] Calcitriol binds to intracellular receptors in target tissues and regulates gene transcription n Its most important biological action: n n Promoting enterocyte differentiation and intestinal absorption of calcium n Other effects include: n Stimulation of intestinal phosphate absorption n Direct suppression of PTH release from the parathyroid gland

FUNCTIONS OF CALCITRIOL Contributes to the maintenance of normal plasma concentrations of calcium and phosphate n Allows mineralization of newly formed bone to take place n Prevents symptomatic hypocalcemia or hypophosphatemia n

Actions of the Hormones Involved in Calcium Homeostasis Hormone PTH ↑Ca ++ , ↓PO 4 levels in blood Vitamin D ↑Ca++ , ↑PO 4 levels in blood Calcitonin ↓Ca++ , ↓PO 4 levels in blood when hypercalcemia present Effect on bones Supports osteoclast resorption Effect on kidneys Effect on GI Supports Ca++ Indirect effects via ↑calcitriol resorption and PO 4 excretion, activates from 11 -hydroxylation No direct effects ↑Ca++ and PO 4 No direct effects Supports osteoblasts absorption Inhibits osteoclast resorption No direct effects Promotes Ca++ and PO 4 excretion

Overview n Calcium Homeostasis: PTH and Calcitriol n Mechanisms of Hypercalcemia Causes of Hypercalcemia n Clinical Manifestations of Hypercalcemia n Diagnosis of Hypercalcemia n Treatment of Hypercalcemia (Medical and Surgical) n

Mechanisms of Hypercalcemia 1)Increased GI Absorption n 2)Bone Resorption n 3)Renal Reabsorption n Vitamin D: Predominant control in GI absorption n PTH: Principal one at bone surface and in the kidney n

Underlying Disorders Increasing GI Absorption n Major Physiologic Control: Vitamin D n n n Sarcoidosis Lymphoma Vitamin D intoxication Milk Alkali syndrome Hyperparathyroidism n n n 1, 25 -(OH)2 D 3 Vitamin D GI Absorption PTH increased D

Underlying Disorders Increasing Bone Resorption n Hyperparathyroidism n n n n n Adenoma Hyperplasia Cancer Metastatic Cancers Myeloma Humoral hypercalcemia of malignancy Hyperthyroidism Paget’s disease Mediated by n n n n PTH PTHr. P Cytokines PTHr. P Thyroxine ?

Underlying Disorders Increasing Renal Reabsorption n Hyperparathyroi dism n Thiazides n FHH n Adrenal Insufficiency n PTH n?

ne resorption (right), or renal reabsorption (bottom) leads to an increased serum calcium level. Several underlying disorders may affect each system and

Overview Calcium Homeostasis: PTH and Calcitriol n Mechanisms of Hypercalcemia n n Causes of Hypercalcemia Clinical Manifestations of Hypercalcemia n Diagnosis of Hypercalcemia n Treatment of Hypercalcemia (Medical and Surgical) n

Causes of Hypercalcemia Related to PTH n Vitamin D-related n Malignancy n Medications n Other endocrine n Genetic n Other n

Causes of Hypercalcemia PTH n Primary hyperparathyroidism n Sporadic, familial, associated with MEN I or II n Tertiary hyperparathyroidism associated with CRF or vitamin D deficiency

Tertiary Hyperparathyroidism. CRF generally causes hypocalcemia n Untreated hypocalcemia, prolonged high phosphate and low vitamin D levels can lead to increased PTH secretion and subsequent hypercalcemia n

Causes of Hypercalcemia Vitamin D-related Vitamin D intoxication: Usually 25 hydroxvitamin D in OTC supplements n Granulomatous disease n n sarcoidosis n berylliosis n Tuberculosis n Hodgkin’s lymphoma

Causes of Hypercalcemia Malignancy n Humoral hypercalcemia of malignancy (mediated by PTHr. P) n Solid tumors, especially lung, head, and neck squamous cancers, renal cell tumors n Local osteolysis (mediated by cytokines) n multiple myeloma

Causes of Hypercalcemia n Medications Thiazide diuretics (usually mild) n Lithium n Milk-alkali syndrome (from calcium antacids) n Vitamin A intoxication (including analogs used to treat acne) n

Causes of Hypercalcemia n Other endocrine disorders Hyperthyroidism n Adrenal insufficiency n Acromegaly n Pheochromocytoma n

Causes of Hypercalcemia n Genetic disorders Familial hypocalciuric hypercalcemia: mutated calcium-sensing receptor n Nl PTH in 80 -85% of patients n Benign inherited condition n

Causes of Hypercalcemia n Other Immobilization, with high bone turnover (e. g. , Paget’s disease, bedridden child) n Recovery phase of rhabdomyolysis n

Causes of Hypercalcemia n n Hyperparathyroidism and Malignant neoplasms account for majority of hypercalcemia Neoplasms most frequently associated with hypercalcemia: breast cancer, lung cancer (10% of squam lung Ca) , and multiple myeloma Most hypercalcemias in the setting of malignancy caused by humoral hypercalcemia of malignancy Single adenomas of the parathyroid gland account for 75% of primary hyperparathyroidism associated with hypercalcemia

Overview Calcium Homeostasis: PTH and Calcitriol n Mechanisms of Hypercalcemia n Causes of Hypercalcemia n n Clinical Manifestations of Hypercalcemia Diagnosis of Hypercalcemia n Treatment of Hypercalcemia (Medical and Surgical) n

Clinical Manifestations of Hypercalcemia “stones” n “bones” n “abdominal moans” n “psychic groans” n Neuromuscular n Cardiovascular n Other n

Clinical Manifestations of Hypercalcemia n Renal “stones” Nephrolithiasis n Nephrogenic DI: polydipsia and polyuria n Dehydration n Nephrocalcinosis n

Clinical Manifestations of Hypercalcemia n Skeleton “bones” Bone pain, arthralgias n Osteoporosis of cortical bone such as wrist n In primary hyperparathyroidism: Subperiosteal resorption, leading to osteitis fibrosa cystica with bone cysts and brown tumors of the long bones n

Clinical Manifestations of Hypercalcemia n Gastrointestinal “abdominal moans” Nausea, vomiting n Anorexia n weight loss n Constipation n Abdominal pain n Pancreatitis n Peptic ulcer disease n

Clinical Manifestations of Hypercalcemia n “psychic groans” Impaired concentration and memory n Confusion, stupor, coma n Lethargy and Fatigue n

Clinical Manifestations of Hypercalcemia n Neuromuscular Reduced neuromuscular excitability and muscle weakness n Easy fatigability and muscle weakness more common in hyperparathyroidism than other hypercalcemic conditions n n Clinical features of hyperparathyroid myopathy: n Proximal muscle weakness, wasting and mild nonspecific myopathic features on electromyogram and muscle biopsy

Clinical Manifestations of Hypercalcemia n Cardiovascular Shortened QT interval on electrocardiogram n Cardiac arrhythmias n Vascular calcification n

Clinical Manifestations of Hypercalcemia n Other Itching n Keratitis n Conjunctivitis n Corneal calcification, band keratopathy n Carpal tunnel syndrome has occasionally been associated with hyperparathyroidism n

Clinical Manifestations of Hypercalcemia n n n AMS common in hypercalcemia (particularly when Ca> 14 mg/d. L) and generally consist of progressive lethargy, confusion, and ultimately coma These reversible symptoms directly related to the degree of hypercalcemia HA, elevated CSF protein, and rare convulsions also occur Hyperparathyroidism been rarely associated with severe CNS dysfunction, including ataxia, internuclear opthalmoplegia, corticospinal tract dysfunction, dysarthria, and dysphagia Hypercalcemia been associated with apnea in children

Overview Calcium Homeostasis: PTH and Calcitriol n Mechanisms of Hypercalcemia n Causes of Hypercalcemia n Clinical Manifestations of Hypercalcemia n n Diagnosis of Hypercalcemia n Treatment of Hypercalcemia (Medical and Surgical)

Diagnosis Serum Calcium, PO 4 n Intact PTH (10 -60 pg/ml) n Serum PTHr. P n 24 hr urine Ca excretion n Urinary nephrogenous c. AMP excretion n 99 m. Tc sestamibi scans to predict the location of abnormal gland n

Diagnosis Accurate Hx of constitutional symptoms suggesting malignancy, Accurate FH (MEN, FHH) n Elevated PTH and concern for FHH: n Take an accurate Hx n Renal Ca reabsorption: n n Primary hyperparathyroidism: <99% n FHH: >99% reabsorption

Overview Calcium Homeostasis: PTH and Calcitriol n Mechanisms of Hypercalcemia n Causes of Hypercalcemia n Clinical Manifestations of Hypercalcemia n Diagnosis of Hypercalcemia n n Treatment of Hypercalcemia (Medical and Surgical)

Who should be treated? If severe hypercalcemia and primary hyperparathyroidism Surgery mandatory as soon as Dx can be confirmed by PTH n Most patients with hyperparathyroidism, mild hypercalcemia Do not require urgent surgical or medical Rx n Which patients with asymptomatic hyperparathyroidism should be treated? n

Criteria for Surgery in Primary Hyperparathyroidism NIH Consensus Conference on Management of Asymptomatic Hyperparathyroidism in 1991 n n n n Age younger than 50 Serum total calcium level >12 mg/d. L (3 mmol per L) at any time Hyperparathyroid crisis (Hx of discrete episode of life -threatening hypercalcemia) Marked hypercalciuria (urinary calcium excretion >400 mg/d) Nephrolithiasis (presence of kidney stone on Xray even if asymptomatic) Impaired renal function Osteitis fibrosa cystica

Criteria for Surgery in Primary Hyperparathyroidism n Reduction of bone mass more than 2 SD below age-matched controls n Classic neuromuscular symptoms Information from NIH conference: diagnosis and management of asymptomatic primary hyperparathyroidism: consensus development conference statement. Ann Intern Med 1991; 114: 593– 7. *—Guidelines from the National Institutes of Health Consensus Development Conference.

Natural History of Primary Hyperparathyroidism Many have benign clinical course without significant progression n Most asymptomatic patients do not have progression n Most asymptomatic patients who have parathyroidectomy have normalization of the biochemical values as well as increased bone density studies n

How Do You Treat Hypercalcemia? Depends on the cause… n 1 st principle of Rx: Restoration of Nl hydration n In patients with mild hypercalcemia, adequate hydration should be encouraged and immobilization discouraged n

How Do You Treat Hypercalcemia? n Mainstay of management in severe hypercalcemia: Aggressive IV rehydration. NS: to achieve a UO of 200 m. L/hr: If life-threatening circumstances: 6 L of NS/d plus Lasix 100 mg q 2 hr might be needed n Repletion of K and Mg as needed n n Combined use of above increase urinary Ca excretion to 500 mg/d

Treatment of Malignancy-Associated Hypercalcemia n IV pamidronate (Aredia), 60 to 90 mg, by 4 -hr infusion n n Often will normalize the serum calcium level, with peak effects of 24 -48 hours after infusion In severe hypercalcemia refractory to saline diuresis, calcitonin 2 -8 U/kg q 6 hrs. (Rapid onset but short duration of effect) Tacyphylaxis can occur

What Are Some of The Other Antiresorptive Agents? n Now used rarely: Plicamycin (Hepatic necrosis, coagulopathy) n Gallium nitrate (Nephrotoxic) n

Where Do You Use Glucocorticoids in Rx of Hypercalcemia? n In hypercalcemia mediated by vitamin D and in hematologic malignancies (May be effective in MM, Leukemia, Hodgkin’s disease and other lymphomas), Also vitamin D intoxication and sarcoidosis n glucocorticoids are the first line of therapy after fluids n Increase urinary Ca excretion n Decrease intestinal Ca absorption n Dose: 40 -100 mg of prednisone or equivalent divided qid

How Do You Treat Resistant or Hypercalcemia Complicated by RF? HD with Ca-free dialysate more effective than PD n Large amounts of PO 4 lost can aggrevated hypercalcemia Phosphate supplements n Therapy for the underlying condition n Hypercalcemic crisis from primary hyperparathyroidism: urgent parathyroidectomy potentially curative n

XII-19 n A person with hypercalcemia caused by sarcoidosis would have which of the following findings? n (A) A normal chest x-ray (B) Increased absorption of calcium from the GIT (C) Normal urine calcium excretion (D) Increased serum parathyroid hormone level (E) Hypogammaglobulinemia n n

XII-37 n n n 37. A 55 -year-old woman presents to her physician with mild fatigue. Her PMH is unremarkable. She is taking no medication. No abnormalities are detected on PE. The only abnormality detected on routine blood testing is an elevated calcium 11. 9 mg/d. L and a serum inorganic phosphorus of 2 mg/d. L. An immunoreactive PTH level is undetectable. The most likely etiology for this patient's high serum calcium is (A) primary hyperparathyroidism (B) malignancy (C) hypervitaminosis (D) hyperthyroidism (E) familial hypocalciuric hypercalcemia

XII-47 n n n During a routine checkup, a 67 -year-old man is found to have a level of serum alkaline phosphatase three times the upper limit of normal. Serum calcium and phosphorus concentrations and liver LFTs are normal. He is asymptomatic. The most likely diagnosis is (A) metastatic bone disease (B) primary hyperparathyroidism (C) occult plasmacytoma (D) Paget's disease of bone (E) osteomalacia

XII-48 n The most important regulator of serum 1, 25(OH)2 vitamin D concentration is (A)serum calcium n (B) serum magnesium n (C) serum 25 (OH) vitamin D n (D)parathyroid hormone n (E) prolactin n

XII-55 n The most common presentation of primary hyperparathyroidism is (A) bone fracture n (B) increased serum creatinine n (C) osteitis fibrosa cystica n (D) calcium kidney stones n (E) asymptomatic hypercalcemia n

XII-56 n A 34 -year-old woman has had three hospital admissions during the last year because of nephrolithiasis. The rate of 24 -h urinary calcium excretion has been above the normal range on all three occasions, and serum calcium concentrations were between 10. 2 and 11. 5 mg/d. L. The serum phosphorus concentration was 2. 4 mg/d. L, and the PTH level was 229 n. L eq/m. L (normal, less than 150 n. L eq/m. L). The most appropriate management at this time would be:

XII-56 n n n (A) to begin administration of prednisone, 40 mg daily, and taper the dose over a period of 4 weeks (B) to administer thiazide diuretics to decrease calcium excretion (C) symptomatic treatment of renal lithiasis only (D) calcium supplementation to prevent progressive bone loss (E) surgical exploration of the neck

XII-60 n A 60 -year-old woman has lower-back pain. Radiographic examination reveals diffuse demineralization and a compression fracture of the fourth lumbar vertebra. The serum calcium concentration is 11. 5 mg/ d. L. CBC and SPEP are normal. This clinical picture is most compatible with the presence of which of the following conditions? n (A) (B) (C) (D) (E) n n Postmenopausal osteoporosis Paget's disease Primary hyperparathyroidism Multiple myeloma Osteomalacia

XII-61 n Which of the following conditions is MOST likely to be associated with a normal serum 25(OH) vitamin D level? n (A) Dietary deficiency of vitamin D (B) Chronic severe cholestatic liver disease (C) Chronic renal failure (D) Anticonvulsant Rx with phenobarb or phenytoin (E) High-dose glucocorticoid therapy n n

XII-70 n A 41 -year-old previously healthy woman presents to an emergency room complaining of N/V. Her calcium is found to be 11. 7 mg/ d. L with an albumin of 4. 0 g/d. L. Hyperparathyroidism is diagnosed, and an exploration of her four parathyroid glands reveals one large parathyroid tumor, which is removed. One day after the operation the patient complains of paresthesia in her hands and around her mouth. Her calcium is 7. 3 mg/d. L. Her phosphorus is 1. 8 mg/d. L. Four months later she still requires aggressive calcium and vitamin D supplementation. The most likely etiology of her hypocalcemia is

XII-70 (A) hypoparathyroidism secondary to inadvertent surgical removal of all 4 parathyroid glands n (B) hypoparathyroidism secondary to atrophy of the 3 remaining parathyroid glands n (C) hungry bone syndrome n (D) parathyroid cancer n (E) magnesium deficiency n

XII-109 n Correct statements concerning hypervitaminosis D include which of the following? n (A) It may result from prolonged sun exposure. (B) It usually results from a single excessive dose of vitamin D 2 or D 3. (C) The consequences include hypercalcemia, hypercalciuria, and renal impairment. (D) Anephric patients cannot develop vitamin D toxicity (E) Serum 1, 25 (OH) vitamin D levels are elevated. n n