Calcium Metabolism and Disorders Seminar.pptx

Calcium Metabolism and Disorders

1. Calcium Metabolism and its D isoders Presenter Eyosiyas (IMR1) Mahder A.(IMR2) Moderator Dr. Tedla (Consultant Internist, Endocrinologist)

2. Outline Introduction Etiology Clinical Presentation Diagnosis Treatment Reference

3. Introduction The major factors that influence the serum calcium concentration are PTH, vitamin D, FGF23, calcium ion itself, and phosphate. Other causes of hypocalcemia include disorders that result in a decrease in serum ionized calcium concentration by binding of calcium within the vascular space or by its deposition in tissues, as can occur with hyperphosphatemia .

4. CALCIUM HOMEOSTASIS Serum calcium concentrations are normally maintained within the very narrow range that is required for the optimal activity of the many extra- and intracellular processes calcium regulates. Calcium in the blood is transported partly bound to plasma proteins (40-45%), notably albumin ; Partly bound to small anions such as phosphate and citrate (15%); and partly in the free or ionized state (40-45%)

5. Although only the ionized calcium is metabolically active ( ie , subject to transport into cells), most laboratories report total serum calcium concentrations . Concentrations of total calcium in normal serum generally range between 8.5 and 10.5 mg/ dL (2.12 to 2.62 mmol /L), and levels below this are considered to be consistent with hypocalcemia . The normal range of ionized calcium is 4.65 to 5.25 mg/ dL (1.16 to 1.31 mmol /L).

6. Hypoalbuminemia  — When protein concentrations (particularly albumin) fluctuate substantially, total calcium levels may vary, whereas the ionized calcium (whose level is hormonally regulated) remains relatively stable . The serum total calcium concentration falls approximately 0.8 mg/ dL (0.25 mmol /L) for every 1 g/ dL (10 g/L) reduction in the serum albumin concentration. Thus, in patients with hypoalbuminemia , the measured serum calcium concentration should be corrected for the abnormality in albumin, or for standard units

7. Acid-base disturbances  — Even in the presence of a normal serum albumin, changes in blood pH can alter the equilibrium constant of the albumin-calcium complex, with acidosis reducing the binding and alkalosis enhancing it. When major shifts in pH are present, it is most prudent to directly measure the ionized calcium level in order to determine the presence of hypocalcemia .

8. Hormone regulation  — The major hormones that regulate serum calcium are PTH and vitamin D via effects on bone, kidney, and the GIT. The hormone FGF23 can inhibit renal phosphate reabsorption and thus affect serum calcium by lowering the serum phosphate. However, it can also inhibit conversion of vitamin D to its active form, 1,25-dihydroxyvitamin D ( calcitriol ) and, therefore, reduce calcium absorption from the GIT. Additionally, FGF23 has been reported to inhibit PTH production. Calcium itself acts to regulate its own blood levels by acting via a calcium-sensing receptor ( CaSR ) in the parathyroid gland to inhibit PTH secretion and on a CaSR in the loop of Henle to stimulate renal calcium excretion.

9. PTH is secreted almost instantaneously in response to very small reductions in serum ionized calcium, which are sensed by the CaSR . The increase in PTH release raises the serum calcium concentration toward normal via three actions: ●Decreased urinary calcium excretion due to stimulation of calcium reabsorption in the distal tubule ●Increased intestinal calcium absorption mediated by increased renal production of 1,25-dihydroxyvitamin D ●Increased bone resorption

10. Hypocalcemia may occur when PTH secretion is insufficient to act on kidney, bone, and intestine to normalize serum calcium ( hypoparathyroidism ). When the parathyroid glands and PTH are functioning normally, then other causes of hypocalcemia , such as vitamin D deficiency, are characterized by high PTH (secondary hyperparathyroidism). Thus, it is useful to characterize hypocalcemia broadly as associated with low PTH or high PTH.

11. HYPOCALCEMIA WITH LOW PTH ( HYPOPARATHYROIDISM) Occurs when there is decreased secretion of PTH due to destruction of the parathyroid glands (autoimmune, postsurgical), abnormal parathyroid gland dev’t , or altered regulation of PTH production and secretion. The most common cause of hypoparathyroidism is surgical.

12. Destruction of the parathyroid glands Surgical  — Surgical hypoparathyroidism can occur after thyroid, parathyroid, or radical neck surgery for head and neck cancer. It may be transient, with recovery in days, weeks or months; permanent; or even intermittent. Transient hypoparathyroidism occurs in up to 20% of pts after surgery for thyroid ca and permanent hypoparathyroidism occurs in 0.8-3.0% of pts after total thyroidectomy.

13. Autoimmune - Permanent hypoparathyroidism can result from immune-mediated destruction of the parathyroid glands. Alternatively , hypoparathyroidism may result from activating antibodies to the calcium-sensing receptor ( CaSR ) that decrease PTH secretion. The antibodies are not destructive and may remit spontaneously. Autoimmune hypoparathyroidism is a common feature of polyglandular autoimmune syndrome type I, which is a familial disorder (the most common features are chronic MC candidiasis , and adrenal insufficiency).

14. Other - include irradiation and storage or infiltrative diseases of the parathyroid glands (hemochromatosis, Wilson disease, granulomas, or metastatic cancer ). Symptomatic hypoparathyroidism has also been described in association with human immunodeficiency virus (HIV) infection. 

15. HYPOCALCEMIA WITH HIGH PTH Vitamin D deficiency or resistance  —  Causes of vitamin D deficiency include poor intake or malabsorption coupled with reduced exposure to ultraviolet light, decreased 25-hydroxylation of vitamin D to form 25-hydroxyvitamin D ( calcidiol ) in the liver increased metabolism to inactive metabolites, decreased 1-hydroxylation of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D in the kidney, decreased 1,25-dihydroxyvitamin D action.

16. Chronic kidney disease   - The most common cause of an acquired decrease in renal production of 1,25-dihydroxyvitamin D is CKD. H ypocalcemia in CKD is also due to the occurrence of hyperphosphatemia (due to reduction in the filtered phosphate load and a reduction in the fractional excretion of phosphorus ). Hypocalcemia typically does not occur until end-stage CKD (G5, estimated glomerular filtration rate [ eGFR ] <15 mL/min or treatment by dialysis). 

17. PTH resistance (impaired PTH action)  —  Pseudohypoparathyroidism , which presents in childhood, refers to a group of heterogeneous disorders defined by target organ (kidney and bone) unresponsiveness to PTH due to an alteration in the postreceptor PTH signaling pathway. It is characterized by hypocalcemia , hyperphosphatemia , and, in contrast to hypoparathyroidism , elevated rather than reduced PTH concentrations . PTH resistance has also been associated with a recessive missense mutation in the mature PTH (1-84) sequence, resulting in resistance to PTH because of reduced PTH-receptor binding. It is characterized by hypocalcemia and hyperphosphatemia and, depending on the assay used to measure PTH, either elevated or low-normal concentrations of circulating PTH.

18. Extravascular deposition  — Ionized calcium can be lost from the extracellular fluid either by deposition in tissues or by binding within the vascular space. Hyperphosphatemia - In pts with impaired renal excretion or in AKI, increased phosphate intake or excess tissue breakdown ( rhabdomyolysis , TLS) can cause acute hypocalcemia . In hyperphosphatemia , calcium is deposited mostly in bone, but also in extraskeletal tissue. 

19. Osteoblastic metastases - pts with widespread osteoblastic metastases, particularly those with breast or prostate ca , have hypocalcemia . The presumed cause is deposition of calcium in the newly formed bone around the tumor. In a study of 131 men with advanced prostate cancer, 34%had elevated serum PTH concentrations, and of these, 56% had a low serum ionized calcium.

20. Acute pancreatitis -  Hypocalcemia is also a frequent finding in pts with acute pancreatitis, where it is associated with precipitation of calcium soaps in the abdominal cavity. The actual mechanism remains unclear. Although PTH concentrations are variable, they are typically elevated in response to hypocalcemia .

21. Sepsis or severe illness - I ncidence of hypocalcemia in critically ill or postsurgical pts approaches 80-90%. The cause appears to be a combination of impaired secretion of PTH coupled with reduced calcitriol production and end-organ resistance to the action of PTH; The probable underlying mechanisms include hypomagnesemia and actions of inflammatory cytokines on the parathyroid glands, kidneys, and bone . Hypocalcemia is common in the toxic shock syndrome. In addition to the above mechanisms high serum calcitonin concentrations (w/c inhibit bone resorption ) have been found in some pts

22. Surgery -   Hypocalcemia can occur during and soon after surgery, most often in patients who received large volumes of blood, because the citrate used as an anticoagulant chelates calcium . In these cases, total calcium is normal, while ionized calcium is reduced as a result of citrate binding. It can also occur during and after major surgery in patients who do not receive transfusions. Most of the reduction in serum calcium is due to volume expansion and hypoalbuminemia and does not affect the ionized calcium concentration .

23. DISORDERS OF MAGNESIUM METABOLISM M agnesium depletion can cause hypocalcemia by producing PTH resistance, which occurs when serum Mg concentrations <0.8 mEq /L (1 mg/ dL or 0.4 mmol /L) or by decreasing PTH secretion, w/c occurs in pts with more severe hypomagnesemia . Malabsorption , chronic alcoholism, and  cisplatin  therapy are the most common causes of hypomagnesemia ; others include prolonged parenteral fluid administration, diuretic therapy, and the administration of aminoglycosides. Despite PTH resistance or PTH deficiency, most patients with hypomagnesemia have normal or low serum phosphate concentrations, probably because of poor intake.

24. Severe hypermagnesemia , a very rare disorder, can also cause hypocalcemia , by suppressing the secretion of PTH. This requires a serum Mg concentration > 5 mEq /L (6 mg/ dL or 2.5 mmol /L), a concentration encountered only when Mg is given to women with eclampsia .

25. DRUGS Calcium chelators - Substances such as citrate (used to inhibit coagulation in banked blood or plasma), lactate,  foscarnet , and sodium EDTA chelate calcium in serum, thereby reducing serum ionized calcium concentrations but not serum total calcium concentrations . Symptomatic hypocalcemia during transfusion of citrated blood or plasma is rare, b/c normal subjects rapidly metabolize citrate in the liver and kidney. However , a clinically important fall in serum ionized calcium concentration can occur if citrate metabolism is impaired due to hepatic or renal failure or if large quantities of citrate are given rapidly ( eg , during plasma exchange, leukapheresis , or massive blood transfusion). A similar effect can occur in patients with lactic acidosis due to shock or sepsis For this reason, serum ionized calcium should be measured periodically in patients with these disorders.

26. Chemotherapy - cisplatin  causes hypocalcemia by causing hypomagnesemia . Combination therapy with  fluorouracil  and  leucovorin  caused hypocalcemia in 65% of patients in one series, possibly by decreasing calcitriol production. Bisphosphonates -   Hypocalcemia may result from the treatment of hypercalcemia , skeletal metastases, Paget disease of bone, or osteoporosis with bisphosphonates, which act to reduce osteoclastic bone resorption . Hypocalcemia is more likely to occur when high doses of especially potent bisphosphonates, such as  zoledronic acid , are used and in patients with underlying vitamin D deficiency, unrecognized hypoparathyroidism , or impaired renal function. 

27. Denosumab - It  is a fully human monoclonal antibody to the receptor activator of nuclear factor kappa-B ligand (RANKL), an osteoclast differentiating factor . It inhibits osteoclast formation, decreases bone resorption , increases bone mineral density (BMD), and reduces the risk of fracture . In pts with conditions that predispose to hypocalcemia , such as CKD, malabsorption syndromes or other causes of vitamin D deficiency, or hypoparathyroidism , symptomatic hypocalcemia may occur.

28. Clinical M anifestations Hypocalcemia may be associated with a spectrum of clinical manifestations, ranging from few (if any) symptoms if the hypocalcemia is mild to life-threatening seizures, refractory heart failure, or laryngospasm if it is severe. In addition to severity, the rate of development of hypocalcemia and chronicity determine the clinical manifestations. Among the symptoms of hypocalcemia , tetany , papilledema, and seizures may occur in patients who develop hypocalcemia acutely. By comparison, ectodermal and dental changes, cataracts, basal ganglia calcification, and extrapyramidal disorders are features of chronic hypocalcemia .

29. ACUTE MANIFESTATIONS Tetany - Acute hypocalcemia directly increases peripheral neuromuscular irritability. The symptoms of tetany may be: mild (perioral numbness, paresthesias of the hands and feet, muscle cramps) or severe ( carpopedal spasm, laryngospasm, and focal or generalized seizures, which must be distinguished from the generalized tonic muscle contractions that occur in severe tetany ). Tetany is uncommon unless the serum ionized calcium concentration falls below 4.3 mg/ dL (1.1 mmol /L ), w/c usually corresponds to a serum total calcium concentration of 7.0-7.5 mg/ dL ( 1.8-1.9 mmol /L). Patients in whom the onset of hypocalcemia is gradual tend to have fewer symptoms at the same serum calcium concentration.

30. Hypocalcemia and alkalosis act synergistically to cause tetany . Although alkalosis can directly reduce serum ionized calcium, the ability of alkalosis to enhance tetany is only partly due to this effect since the decrease is relatively small . Respiratory alkalosis alone ( eg , hyperventilation) can cause tetany , even in the absence of underlying hypocalcemia . By contrast, tetany is unusual among patients with chronic renal failure and hypocalcemia (occasionally severe) because of the protective effect of concurrent metabolic acidosis.

31. Trousseau's sign - It is the induction of carpal spasm by inflation of a sphygmomanometer above systolic blood pressure for three minutes. Carpal spasm is characterized by adduction of the thumb, flexion of the metacarpophalangeal joints, extension of the interphalangeal joints, and flexion of the wrist. It may also be induced by voluntary hyperventilation for one to two minutes after release of the cuff . Trousseau's sign depends upon the effect of ischemia to increase excitability of the nerve trunk under the cuff, rather than at the motor endplate; excitability is maximal at three minutes and returns to normal even if ischemia is maintained for a longer period.

32. Chvostek's sign - It is contraction of the ipsilateral facial muscles elicited by tapping the facial nerve just anterior to the ear. The response ranges from twitching of the lip to spasm of all facial muscles and depends upon the severity of the hypocalcemia . Chvostek's sign occurs in approximately 10% of normal subjects.

33. Seizures -  GTC, generalized absence, and focal seizures can occur in hypocalcemia and may be the sole presenting symptom. The presence of seizures without tetany in pts with hypocalcemia may be explained by the observation that low CSF ionized calcium concentrations may have a convulsive but not a direct tetanic effect. In patients with seizures caused by hypocalcemia , the EEG shows both spikes ("convulsive effect") and bursts of high-voltage, paroxysmal slow waves.

34. Cardiovascular - Although the mechanism is undefined, calcium plays a critical role in excitation-contraction coupling and is required for epinephrine-induced glycogenolysis in the heart . Hypocalcemia characteristically causes prolongation of the QT interval in the ECG. Prolongation of the QT interval is associated with early after- depolarizations and triggered dysrhythmias. Torsades de pointes can potentially be triggered by hypocalcemia but is much less common than with hypokalemia or hypomagnesemia . S erious hypocalcemia -induced dysrhythmias, such as heart block and ventricular dysrhythmias, are infrequent .

35. Papilledema -  It occurs only when hypocalcemia is severe, and it usually improves with reversal of hypocalcemia . It may or may not be accompanied by high CSF pressure (benign intracranial hypertension). Rarely , optic neuritis (distinguished by decreased visual acuity) rather than papilledema is present. Psychiatric manifestations -  Hypocalcemia can cause psychological symptoms, particularly emotional instability, anxiety, and depression . Less common are confusional states, hallucinations, and frank psychosis. All are reversible with treatment.

36. Diagnostic Approach to H ypocalcemia It involves confirming, by repeat measurement, the presence of hypocalcemia & distinguishing among the potential etiologies. The diagnosis may be obvious from the patient's history; examples include CKD and postsurgical hypoparathyroidism . When the cause is not obvious or a suspected cause needs to be confirmed, other biochemical tests are indicated.

37. CONFIRM HYPOCALCEMIA In most pts with normal serum albumin concentrations, the total serum calcium concentration can be used for both the initial and repeat serum calcium measurements. If the diagnosis of hypocalcemia is in doubt, due to hypoalbuminemia , atypical or absent symptoms, or a minimally reduced serum calcium concentration, we obtain a serum ionized calcium for the repeat measurement . If ionized calcium is not available, the total calcium should be repeated and corrected for any abnormality in serum albumin, using a calcium correction formula.

38. Ionized calcium -   remains the gold standard for assessing calcium status b/c it measures the biologically active (or free) calcium. However , It is not performed routinely, ( more costly & must be handled carefully & stored under appropriate conditions to preserve a sample pH of 7.4). It is important to note that the affinity of calcium for albumin is increased in the presence of alkalosis.

39. Hypoalbuminemia : Calcium correction -  the total serum calcium concentration will change in parallel to the albumin concentration and may not accurately reflect the physiologically important ionized calcium concentration . Traditionally , one of the most widely utilized equations to estimate the total calcium concentration in clinical practice assumes: the serum calcium to fall by 0.8 mg/ dL (0.2 mmol /L) for every 1 g/ dL (10 g/L) fall in the serum albumin concentration or for standard units.

40. DETERMINING THE ETIOLOGY Clinical clues-  The etiology of hypocalcemia may be obvious from the clinical history. A family history of hypocalcemia suggests a genetic cause. Chronic familial hypocalcemia is often seen in pts with an activating mutation of the CaSR (ADH type 1) or, less frequently, of a downstream signaling molecule of the calcium-sensing receptor, GNA11 ( ADH type 2), and in pseudohypoparathyroidism . On the other hand, acquired hypoparathyroidism is most often the result of postsurgical or autoimmune damage to the parathyroid glands. Thus , a history of head and neck surgery or the presence of a neck scar suggests postsurgical hypoparathyroidism . Autoimmune hypoparathyroidism can occur as an isolated abnormality and is also a common feature of polyglandular autoimmune syndrome type I, which is a familial disorder. The presence of chronic mucocutaneous candidiasis and adrenal insufficiency suggests a polyglandular syndrome. 

41. There are several drugs that also may cause hypocalcemia . Other causes of hypocalcemia that may be apparent from the H x , P/E & routine lab data include: Acute or chronic kidney disease, acute pancreatitis, rhabdomyolysis , and marked increases in tissue breakdown with the release of phosphate from cells, as occurs in the TLS. The P/E may reveal findings of latent tetany , such as Chvostek's and Trousseau's signs, which are strongly suggestive of hypocalcemia . 

42. Laboratory evaluation : Serum PTH concentrations -  Hypocalcemia is the most potent stimulus of PTH secretion; as a result, a low or even normal serum PTH concentration in a patient with hypocalcemia is strong evidence of hypoparathyroidism . The serum PTH concentration varies with the cause of the hypocalcemia : ● Serum PTH is reduced or inappropriately normal in patients with hypoparathyroidism . ● Serum PTH is elevated in patients with acute or chronic kidney disease, vitamin D deficiency , and pseudohypoparathyroidism . ● Serum PTH is typically normal or low in patients with hypomagnesemia or ADH .

43. Magnesium - Serum magnesium should be measured in any patient with hypocalcemia in whom the cause is not obvious . Hypocalcemia should resolve within minutes or hours after restoration of normal serum magnesium concentrations if hypomagnesemia was the cause of the hypocalcemia . A few patients with magnesium-responsive hypocalcemia have  normal  serum magnesium concentrations. These patients are presumed to have tissue magnesium deficiency. Thus , magnesium supplementation may be indicated in patients with unexplained hypocalcemia who are at risk for hypomagnesemia , such as patients with chronic malabsorption or alcoholism.

44. Phosphate - Phosphate levels may be elevated, low, or normal depending upon the etiology of hypocalcemia . Elevated - In the absence of kidney disease or increased tissue breakdown, virtually diagnostic of either hypoparathyroidism or pseudohypoparathyroidism . Low - indicates either excess PTH secretion, w/c in the context of hypocalcemia means 2o hyperparathyroidism (some abnormality in vitamin D intake or metabolism), or low dietary phosphate intake, which is uncommon. Normal - Normal serum phosphate in the setting of hypocalcemia may be consistent with hypomagnesemia or mild vitamin D deficiency.

45. Vitamin D metabolites - Vit D deficiency increases PTH secretion by causing hypocalcemia (due to the reduction in intestinal calcium absorption) & to a lesser degree, by removing the normal inhibitory effect of calcitriol on PTH production. Vit D deficiency also diminishes intestinal phosphate absorption. Excess PTH enhances phosphate excretion and lowers the serum phosphate . Measurement of serum 25(OH)D ( calcidiol ) provides more information about vit D deficiency than does measurement of serum 1,25-dihydroxyvitamin D ( calcitriol ) b/c the hypocalcemia -induced increase in PTH secretion stimulates renal 1,25-dihydroxyvitamin D production (in pts without underlying renal insufficiency). Thus, in individuals with vitamin D deficiency, serum 25(OH)D is low, whereas 1,25-dihydroxyvitamin D is typically normal or high, but it may subsequently decrease because of limited availability of its substrate, 25(OH)D. In contrast, pts with hypoparathyroidism may have normal serum 25(OH)D and low 1,25-dihydroxyvitamin D concentrations.

46. Patterns of vitamin D metabolites and phosphate : A low serum 25(OH)D in a pt with hypocalcemia and hypophosphatemia usually indicates that vit D intake or absorption (usually coupled with decreased production in skin) is low. Other possibilities include therapy with antiseizure medications, glucocorticoids, or other drugs; hepatobiliary disease; the nephrotic syndrome (in which vitamin D-binding protein is lost in the urine); or a rare familial disorder characterized by inability to 25-hydroxylate vitamin D in the liver (vitamin D-dependent rickets, type 1B). The combination of normal or low serum 25(OH)D and low serum 1,25-dihydroxyvitamin D, with high-normal or elevated serum phosphate, indicates the presence of CKD. CKD is the only condition in which hypocalcemia and secondary hyperparathyroidism are not associated with low or low-normal serum phosphate (as a result of the inability of the diseased kidney to respond to the high PTH ).

47. The combination of normal or low serum 25(OH)D, low serum 1,25-dihydroxyvitamin D & low serum phosphate suggests the presence of vit D-dependent rickets, type 1A (renal 1-alpha-hydroxylase deficiency ),-pseudo- vit D deficient rickets . Hereditary vit D-resistant rickets ( vit D-dependent rickets, type 2) presents in early childhood & is associated with a defect in the vitamin D receptor . It should be suspected in hypocalcemic pts if serum phosphate is low and serum 1,25-dihydroxyvitamin D concentrations are high .

48. Other - Other tests that may be helpful in determining the cause of hypocalcemia include- An elevared ALP is common in osteomalacia (as a result of severe vit D deficiency & secondary hyperparathyroidism) & can occur with osteoblastic bone metastases, w/c can cause hypocalcemia due to rapid deposition of calcium in bone metastases Serum amylase is elevated in acute pancreatitis but only slightly in chronic pancreatitis .  Low urinary calcium occurs in patients with untreated hypoparathyroidism or vit D deficiency. Ass’t of urinary Mg may be helpful in individuals with hypomagnesemia . In this setting, an elevated value is consistent with renal losses.

49. Treatment T he management of hypocalcemia depends upon the severity of symptoms. In patients with acute symptomatic hypocalcemia , intravenous IV calcium gluconate  is the preferred therapy, whereas chronic hypocalcemia is treated with oral calcium and vitamin D supplements.

50. IV calcium dosing - Initially, IV calcium (1 or 2 g of  calcium gluconate , equivalent to 90 or 180 mg elemental calcium, in 50 mL of D5W or NS) can be infused over 10-20min. The bolus may be repeated after 10 to 60 minutes, if needed to resolve symptoms. The bolus dose of calcium gluconate will raise the serum calcium for only 2-3hrs; as a result, it should be followed by a slow infusion of calcium in pts with persistent hypocalcemia . A dding 11 g of  calcium gluconate  (equivalent to 1000mg elemental calcium) to NS  or 5% D5W to provide a final volume of 1000mL .

51. The infusion should be prepared with the following considerations : The calcium should be diluted in D5W or  NS   b/c concentrated calcium solutions are irritating to veins. The IV solution should not contain bicarbonate or phosphate, which can form insoluble calcium salts. If these anions are needed, another IV line (in another limb) should be used . IV calcium should be continued until the patient is receiving an effective regimen of oral calcium and vitamin D.

52. For pts with acute hypoparathyroidism ,  calcitriol   (0.25-0.5mcg BID) & oral calcium ( 1-4 g of elemental  calcium carbonate  daily in divided doses) should be initiated as soon as possible . Calcitriol is the preferred preparation of vitamin D for patients with severe acute hypocalcemia because of its rapid onset of action (hours).

53. Concurrent hypomagnesemia - In pts with hypomagnesemia , hypocalcemia is difficult to correct without first normalizing the serum magnesium concentration . Thus , if the serum magnesium concentration is low, 2 g (16 mEq ) of  magnesium sulfate  should be infused as a 10% solution over 10-20min, followed by 1gm in 100 mL of fluid per hour. Persistent hypomagnesemia , as occurs in some patients with ongoing GI ( eg , malabsorption ) or renal losses, requires supplementation with oral magnesium, typically 300-400 mg daily divided into three doses .

54. DISEASE-SPECIFIC APPROACH Hypoparathyroidism : Most pts with hypoparathyroidism require lifelong calcium and vitamin D supplementation. The goals of therapy in patients with hypoparathyroidism i s to raise and maintain the serum calcium concentration in the low-normal range, eg , 8.0 to 8.5 mg/ dL (2.0 to 2.1 mmol /L). Attainment of higher values is not necessary and is usually limited by the development of hypercalciuria due to the loss of renal calcium-retaining effects of PTH. 

55. Vitamin D deficiency- Hypocalcemia due to vit D deficiency is typically treated with   ergocalciferol  (vitamin D2) or  cholecalciferol  (vitamin D3). In the setting of uncomplicated vitamin D deficiency, vitamin D2 or D3 corrects the deficiency and returns the patient's physiology to normal. We typically treat nutritional vitamin D deficiency with 50,000IU of vitamin D2 or D3 weekly for 6-8weeks. Vitamin D metabolites ( calcitriol , dihydrotachysterol , calcidiol ) can be used to treat hypocalcemia , particularly when there is abnormal vitamin D metabolism (renal or liver disease). The major advantage of vitamin D over vitamin D metabolites is its low cost, which is approximately 20% that of the vit D metabolites. Disadvantages include the necessity for hepatic and renal metabolism and slow onset and long duration of action.

56. Chronic kidney disease - Few patients with CKD have symptomatic hypocalcemia . Such asymptomatic patients are often treated with oral calcium to bind intestinal phosphate and to prevent bone disease rather than hypocalcemia per se. The addition of an active form of vitamin D is required in some of these patients.

57. Chronic liver disease - Calcidiol (25-hydroxyvitamin D [25(OH)D]) does not require hepatic 25-hydroxylation and is therefore most useful in patients with liver disease. Its action is more rapid and not as prolonged as that of vitamin D, but slower in onset and more prolonged than that of  calcitriol .

58. Autosomal dominant hypocalcemia - Increased activity of CaSR in the renal tubules results in normal or high urinary calcium excretion despite hypocalcemia ; raising the patient's serum calcium with calcium and vit D can result in more hypercalciuria , nephrocalcinosis , and renal insufficiency. Recombinant human PTH, which enhances calcium absorption in the tubules, may be an alternative if therapy is needed. It can raise the serum calcium concentration in this disorder with a low risk of exacerbating hypercalciuria . Alternatively , calcilytics , a class of drugs in development that inhibit the CaSR , may provide a useful therapeutic approach in the future. 

59. Hypercatabolic state - Unless they are symptomatic from hypocalcemia ( eg , tetany or cardiac arrhythmia ): pts with acute hypocalcemia and hyperphosphatemia due to a hypercatabolic state such as the TLS or massive trauma should  not  be treated with calcium until the hyperphosphatemia is corrected to prevent calcium-phosphate precipitation . Hemodialysis is often indicated in such patients who have symptomatic hypocalcemia . 

60. Pseudohypoparathyroidism - The long-term treatment of hypocalcemia in adults with PHP is similar to the treatment of hypocalcemia caused by other forms of hypoparathyroidism . However , patients with PHP infrequently develop hypercalciuria with calcium and vitamin D therapy. Therefore , the goal of treatment with calcium and vitamin D is to maintain normocalcemia (rather than low-normal serum calcium as for other forms of hypoparathyroidism ). A typical starting dose of  calcitriol  is 0.25mcg BID. The dose should be increased weekly to achieve a normal serum calcium. Many patients require up to 2 mcg daily. Approximately 1-2 g of elemental calcium daily (in divided doses) is recommended . Patients with PHP may also require screening for other endocrinopathies , particularly hypothyroidism and hypogonadism .

61. Vitamin D Deficiency

62. INTRODUCTION DEFINING VITAMIN D SUFFICIENCY- The optimal serum 25(OH)D concentration for skeletal health is controversial. Based upon the trials of vit D supplementation and National Academy of Medicine, systematic review, maintaining the serum 25(OH)D concentration b/n 20-40 ng /mL (50 to 100 nmol /L ) is favored. Experts agree that levels <20 ng /mL are suboptimal for skeletal health. The optimal serum 25(OH)D concentrations for extraskeletal health have not been established. Other experts (NOF, IOF, AGS) suggest that a minimum level of 30 ng /mL (75 nmol /L) is necessary in older adults to minimize the risk of falls and fracture

63. The systematic review by the NAM concluded there are insufficient data to determine the safe upper limit of serum 25(OH)D. However, there was some concern at serum 25(OH)D concentrations > 50 ng /mL (125 nmol /L ). These concerns were based upon the increase in fracture in patients treated with high-dose vitamin D and conflicting studies describing a potential increased risk for some cancers ( eg , pancreatic, prostate) and mortality with levels above 30 to 48 ng /mL (75 to 120 nmol /L).

64. Given the controversy surrounding optimal serum 25(OH)D concentrations , t he majority of groups currently use the following values to categorize the vitamin D status in adults. Vitamin D sufficiency is defined as a 25(OH)D concentration ≥20 ng /mL (50 nmol /L) Vitamin D insufficiency is defined as a 25(OH)D concentration of 12 to <20 ng /mL (30 to 50 nmol /L) Vitamin D deficiency is defined as a 25(OH)D level <12 ng /mL (30 nmol /L) A "risk" of vitamin D toxicity is defined as a 25(OH)D level >100 ng /mL (>250 nmol /L) in adults ingesting substantial amounts of calcium

65. Prevalence - The prevalence of vit D deficiency depends upon the definition used. In a systematic review of vitamin D status in different regions of the world, vitamin D levels <20 ng /mL (50 nmol /L) were prevalent in a majority of the regions studied. Data from the NHANES showed no change in the prevalence of vitamin D deficiency (defined as <12 ng /mL) and a decline in prevalence of vitamin D insufficiency (defined as 12 to 19 ng /mL [30 to 49 nmol /L]) between 2003 to 2014 . In the 2011-2014 survey, the prevalence in the US of vitamin D <12 ng /mL was 5%, and for vitamin D of 12-19 ng /mL, 18%.  

66. Groups at high risk- Vitamin D insufficiency appears to be common among several other populations, including those who are : ● Taking medications that accelerate the metabolism of vit D ( eg ,  phenytoin ) ● Hospitalized on a general medical service ●Institutionalized And those who have : ● Increased skin pigmentation ● Obesity ● Limited effective sun exposure due to protective clothing or consistent use of sun screens ●Osteoporosis ● Hyperparathyroidism ● Malabsorption , including inflammatory bowel disease and celiac disease

67. Clinical M anifestations   It depends upon the severity & duration of the deficiency. The majority of patients with moderate to mild vitamin D deficiency (serum 25[OH]D b/n 15-20 ng /mL [37.5 to 50 nmol /L]) are asymptomatic. Serum calcium, phosphorus, and alkaline phosphatase are typically normal. Patients with low vitamin D and secondary elevations in PTH are at increased risk for having accelerated bone loss, as evidenced by low bone mass on bone densitometry (DXA) and fractures.

68. With prolonged, severe vit D deficiency, there is reduced GI absorption of calcium and phosphorus and hypocalcemia occurs, causing 2o hyperparathyroidism , which leads to phosphaturia , demineralization of bones, and when prolonged, osteomalacia in adults & rickets & osteomalacia in children. Associated symptoms may then include bone pain and tenderness, muscle weakness, fracture, and difficulty walking.

69. There are a large number of epidemiologic data indicating that the risks of cancer and infectious, autoimmune, and CVD are higher when 25[OH]D levels are <20 ng /mL and that risks decrease with higher 25(OH)D concentrations. However , there are no convincing randomized trial data that vitamin D supplements can decrease cancer risk or prognosis, decrease the risk or severity of infections or autoimmune diseases, or decrease cardiovascular risks or metabolic diseases.

70. EVALUATION The majority of healthy adults with serum 25-hydroxyvitamin D (25[OH]D) levels of 12 to <20 ng /mL do not require any additional evaluation. Patients with serum 25(OH)D levels <12 ng /mL are at risk for developing osteomalacia . In such pts , measure serum calcium, phosphorus, alkaline phosphatase, PTH, electrolytes, BUN, Cr, and tissue transglutaminase antibodies (to assess for celiac disease ). Radiographs are necessary in certain settings, such as the presence of bone pain.

71. VITAMIN D REPLACEMENT Many pts with subclinical vit D deficiency have relative hypocalcemia & high serum PTH concentrations, w/c may contribute to the dev’t of osteoporosis & to an increased risk of fractures & falls in older adults. This secondary hyperparathyroidism can be attenuated by the administration of vitamin D supplements. In pts with normal absorptive capacity, for every 100IU (2.5 mcg) of added  vitamin D3 , serum 25(OH)D concentrations increase by ~ 0.7-1.0 ng /mL, with the larger increments seen in pts with lower baseline 25(OH)D levels. The increment declines as the 25(OH)D concentration increases above 40 ng /mL

72. S erum 25(OH)D <12 ng /mL, not infrequently associated with hypocalcemia and osteomalacia , typically treated with 25,000-50,000IU ( 625-1250mcg) of  Vit D2/D3 orally once/week for 6-8wks , & then 800IU (20 mcg) daily thereafter. S erum vit D levels of 12-20 ng /mL, initially supplement with 800-1000IU(20-25mcg ) daily . A repeat serum 25(OH)D level should be obtained after approximately 3months of therapy to assure obtaining the goal serum 25(OH)D level. If goal level is not achieved, higher doses may be necessary. 

73. S erum 25(OH)D levels of ≥ 20-30ng/mL, 600-800IU (15 -20mcg) of  vit D3 daily may be sufficient to maintain levels in the target range.  For pts with malabsorption , oral dosing & duration of tx depend upon the vit D absorptive capacity of the individual pt . High doses of vitamin D of 10,000-50,000IU ( 250-1250mcg) daily may be necessary to treat pts with gastrectomy or malabsorption . Pts who remain deficient or insufficient on such doses will need to be treated with hydroxylated vit D metabolites b/c they’re more readily absorbed .

74.  Although large, intermittent ( eg , monthly, yearly) doses of  Vit D3  increase serum 25(OH)D levels, we do not use them in p ts with normal absorptive capacity. In one trial, a large, annual oral dose of 500,000IU of vitamin D3 had the undesirable effect of increasing falls and fractures in older adults. Additionally , monthly dosing with 60,000IU and 100,000IU has had the undesirable effect of increasing risk of falling in older adults and nursing home residents .

75. Special populations Pregnancy - The optimal serum 25(OH)D level in pregnancy is unknown but should be at least 20 ng /mL (50 nmol /L). For routine supplementation, NAM report suggests a recommended daily allowance of 600IU vit D for all reproductive-age women, including during pregnancy and lactation. ACOG recommended routine supplementation with the dose in a standard prenatal vitamin until more evidence is available to support a different dose. Most prenatal vits contain 400IU ( 10mcg) of vit D, but some preparations contain as little as 200 or as much as 1000-1200IU

76. In pregnant women with vitamin D deficiency, the safety of 50,000IU(1250 mcg) of vit D weekly for 6-8weeks has not been adequately studied. S o some treat vitamin D-deficient and insufficient pregnant women more slowly by giving a total of 600-800IU ( 15-20mcg) of  vit D3 daily . ACOG- 1000-2000IU of vit D daily is safe and may be necessary to maintain a blood level of 25(OH)D >30 ng / mL. Urinary calcium excretion increases in pregnancy, and it should be monitored when treating vitamin D deficiency, especially in women with a history of renal stones.

77. There are a growing number of trials examining the efficacy and safety of vitamin D supplementation in pregnant women. In one trial of vitamin D supplementation (400, 2000, or 4000IU D3 daily) in 192 pregnant Arab women ( 12-16wks gestation) with severe vit D deficiency (mean serum 25[OH]D 8.2 ng /mL), all doses were safe, and the highest dose was most effective in increasing vitamin D levels to 32 ng / mL. There were no significant differences in the mean birth weight, length, head circumference, and gestational age among the groups.

78. CKD -   Pts with an eGFR >30 mL/min who have no biochemical evidence CKD-MBD ( eg , hyperparathyroidism, hyperphosphatemia ) should have similar vit D supplementation as pts with normal renal function. As renal failure progresses ( eGFR <30 mL/min),  calcitriol  (1,25 dihydroxyvitamin D) production may be low due to diminished GFR, loss of the 1-alpha-hydroxylase enzyme 2o to structural renal compromise, and suppression of enzyme activity 2o to hyperphosphatemia . The net result is a tendency to hypocalcemia , secondary hyperparathyroidism, and bone disease .

79. Malabsorption   - oral dosing & duration of treatment depend upon the vitamin D-absorptive capacity of the individual patient. High doses of vitamin D of 10,000-50,000IU daily may be necessary to treat pts with gastrectomy or malabsorption . Patients who remain deficient or insufficient on such doses will need to be treated with hydroxylated vitamin D metabolites ( eg , calcidiol or  calcitriol ) because they are more readily absorbed. Calcidiol (25[OH]D),which is more hydrophilic than   cholecalciferol  or  ergocalciferol , If available , a typical initial dose is 20-40mcg daily.

80. Coexisting primary hyperparathyroidism - may not recognized until vitamin D is supplemented. Hypercalcemia may not be evident initially if the vitamin D deficiency is severe . Vit D replacement in these individuals should be provided cautiously as hypercalcemia and hypercalciuria may develop. Urinary calcium will be extremely low in pts with vit D deficiency and 2o hyperparathyroidism , & it may not normalize for weeks to months as skeletal healing occurs . Urinary calcium may be low or normal in individuals with vitamin D deficiency and primary hyperparathyroidism, but it will increase rapidly with vitamin D repletion.

81. Calcium - All pts should maintain a daily total calcium intake (diet plus supplement) of 1000mg (for ages 19-70yrs ) to 1200mg (for women ages 51-70yrs & all adults >71yrs). The Upper Level of intake for calcium in most adults is 2000-2500mg daily. However, a higher calcium dose (up to 4 g/day) may be necessary in patients with malabsorption . Ultraviolet B exposure   - Artificial UVB radiation exposure from tanning beds (sunbeds, sunlamps) is effective in increasing and maintaining serum 25(OH)D levels. However , b/c there are no defined safe exposure limits for UVB exposure, we do not typically use UVB radiation to treat vitamin D deficiency . One possible exception is pts with malabsorption who remain vitamin D deficient even with high-dose, oral supplementation ( 50,000IU daily).

82. Thank you!