Calcium Booklet

Calcium,the greatest case report ever told

Joel M. Topf, M.D.Attending Nephrologist

Cell: 248.470.8163www.pbfluids.com

IntroductionThe perfect case report for calcium

The patient I am using for this chapter on Calcium and Phosphorus is a real patient who was admitted to St John Hospital and Medical Center in 2005. While usually residents can learn one or two aspects of medicine from any single admission. This patient taught the team about 20 lessons on electrolytes and metabolic bone disease.The interesting case of M.M. is a poignant reminder of the unspoken contract between residents and patients, ''I’ll treat you and at the same time I will learn the craft of medicine.'' Every talented physician owes more of his knowledge to scores of patients than to Tinsley Harrison, Burton “Bud” Rose or the residents of Wash U.This chapter is dedicated to the patients and to the debt of knowledge we owe them.

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Case Report 5

Calcium Balance 66Total body calcium

Physiology of Calcium Regulation 8

Hypercalcemia 1212

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Primary hyperparathyroidism Hypercalcemia of malignancy Granulomatous disease Milk-alkali syndrome Diagnosis of Hypercalcemia Symptoms of Hypercalcemia Treatment of hypercalcemia 15

Hyperparathyroidism 16Primary vs Secondary vs. Tertiary hyperparathyroidism 16

Renal Osteodystrophy 19Treating secondary hyperparathyroidism/ROD 21Treatment options 21

Hypocalcemia 23Etiologies: 23

Tissue deposition 23

Increased renal loss 23

Decreased intake and mobilization of skeletal reserves 24

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Hypocalcemia of critical illness Consequences of hypocalcemia Treatment 26

Case ReportRoutine admission for trauma or something more

A 26 year old African American dialysis patient, MM, with a history of non-com-pliance and anti-social behavior presents with knee pain. X-rays showed avulsion of the patellar tendon. The patient had been on dialysis for 3 years due to reflux nephropathy induced FSGS. Past medical history was otherwise unremarkable.

No old records were available in the hospital information system.

Initial labs: Ca: 10.8 Phos: 6.6 PTH: 1012 Albumin: 2.8

A call to his dialysis unit reveals that over the last four months his calcium has been between 10 and 11, his phos has been floating between 4.8 and 7.8. The albumin has been falling from 4.0 to 3.0. His most recent PTH was 880.

Questions:What is this patient’s adjusted calcium? What is the most common cause of hypercalcemia in hospitalized patients. Among outpatients? What is this patient’s diagnosis?

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Gauci C, Moranne O, Fouqueray B, et al. Pitfalls of measuring total blood calcium in patients with CKD. J Am Soc Nephrol. 2008;19(8):1592-8.

Calcium BalanceTotal body calciumCalcium is distributed in the body among 2 main compartments. 99% of total body calcium is stored in bone and teeth with 1% distributed in solution between the intracellular compartment and extracellular compartment. The intracellular concentration of calcium is very low, typically being one ten thousandths the concentration of the extracellular calcium. The normal extracellular calcium is: 8.4- 10.4 mg/dL.

Calcium in the serum is 45% ionized, 40% protein bound (mainly albumin) and 15% complexed to anions, such as phosphate, bicarbonate and citrate.

Ionized calcium is the physiologically active fraction and the fraction which is actively regulated by the body. Changes in albumin and phosphorus may alter the total calcium and briefly change the ionized calcium but the regulatory mechanisms will bring the ionized calcium back to its preset point even if it leaves patients with an abnormal total calcium.

Though the adjusted calcium compensates for changes in albumin, other factors which affect ionized calcium are phosphorus and pH.

Increasing pH (alkalosis) decreases the ionized calcium and decreased pH (acidosis) increases the ionized calcium. The higher hydrogen ion concentration displaces calcium from albumin, increasing the fraction which is ionized.

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Adjusting calcium for albuminAn adjusted calcium compen-sates for an abnormal albumin. The adjusted calcium gives the clinician an idea of what the total calcium would be if the albumin was 4.

CaAdj = Ca + [ (4 – Albumin) x 0.8]

This behavior was demonstrated in a controlled trial of bicarbonate for lactic acidosis. Though there was no survival benefit from treating the acidosis, the investigators did find a drop in the ionized calcium. (Cooper, DJ et al, Ann Intern Med 1990;112:492-8.)

Questions: In the following patients will they behave as if they have hypercalcemia, hypocalcemia or eucalcemia.

45 y.o. patient being treated for Burkitt’s Lymphoma

Ca: 8.8 Phos 16.4 Albumin 4.0 pH 7.4

! hypercalcemia ! hypocalcemia ! eucalcemia

8 y.o. with congenital nephrotic syndrome (Finnish type)

Ca: 6.2 Phos 3.5 Albumin 1.2 pH 7.4

! hypercalcemia ! hypocalcemia ! eucalcemia

28 y.o. getting pimped on the nephrology service and hyperventilatingCa: 8.6 Phos 4.4 Albumin 4.0 pH 7.8! hypercalcemia ! hypocalcemia ! eucalcemia

Patients with altered phosphorus and pH will have an altered relationship of ionized calcium and total calcium. There is no validated way to adjust for changes in phosphorus and pH so these patients need to have a measured ionized calcium.

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Normal Range

0.8

1.0

1.2

1.4

Before After

Bicarbonate

Saline

Physiology of Calcium RegulationTotal body calcium, like all electrolytes is regulated by balancing intake and excretion. The primary difference is the massive skeletal calcium store which can absorb excess calcium or replenish a calcium deficit. The skeletal store is slow and can safely be ignored in acute hospitalized patients but when looking at long-term out-patient management it needs to be addressed.

The regulation of calcium is controlled by adjusting the absorption (via 1,25 di-hydroxy-vitamin D), excretion (via PTH) of calcium into and out of the body and regulating the movement of calcium into and out of the bone (via PTH and 1,25 dihydroxyvitamin D).

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Ionized calcium is measured at the cell membrane of the parathyroid chief cell by a transmembrane protein logically called the Calcium Sensing Receptor (CaSR).

In addition to calcium, PTH is regulated by magnesium and 1,25 dihydroxyvitamin D. High magnesium and 1,25 dihydroxyvitamin D both suppress PTH.

PTH acts to raise calcium by:

1. Minimizing urinary calcium excretion by increasing calcium resorption in

the thick ascending limb of the loop of Henle and distal convoluted tubule

2. Stimulating the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D (calcitriol) by the kidney

3. In conjunction with calcitriol, mobilizing calcium and phosphorus from

boneNote that the first two mechanisms depend on functioning kidneys.

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Increases in calcium at the CaSR suppresses the production and release of PTH while, decreases in Ca stimulate the production and release of PTH.

Vitamin D is ingested or synthesized in the skin. In order for vitamin D to become metabolically activate it must be hydroxylated, first in the liver and then in the kidney, to form 1,25 dihydroxyvitamin D. 1,25 dihydroxyvitamin D increases dietary absorption of calcium and phosphorus and is active in bone metabolism and renal handling of calcium.

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�Holick MF. N Engl J Med. 2007 Jul 19;357(3):266-81

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HypercalcemiaMM had an adjusted calcium of 11.8. The differential diagnosis of hypercalcemia is long but, as residents, you should have 4 diagnosis on the tip of your tongue:

1. Primary hyperparathyroidism

2. Hypercalcemia of malignancy

3. Granulomatous diseases

4. Milk-Alkali syndrome

Primary hyperparathyroidismPrimary hyperparathyroidism is the number one cause of outpatient hypercalcemia. It is due to autonomous oversecretion of PTH by a benign adenoma of the parathyroids. The adenoma does not respond to the typical negative feedback for PTH secretion such as increased calcium or 1,25 dihydroxyvitamin D. Patients have increased Ca and PTH, and decreased phosphorus. Despite the increased reabsorption of urinary calcium they have increased urinary calcium and often present with kidney stones. Treatment is surgical removal of the functioning adenoma.

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Indications for parathyroidectomy in primary HPTHSerum Ca ≥1.0 mg/dL above the upper limit of normal Hypercalciuria (urinary Ca > 400 mg/dayCreatinine Cl decreased by 30%Osteoporosis (T score <-2.5)Age less than 50 years Periodic follow-up anticipated to be difficult

Hypercalcemia of malignancyHypercalcemia of malignancy is the number one cause of hypercalcemia among hospitalized patients. There are 3 different mechanisms for hypercalcemia:

1. Humoral hypercalcemia. Here a normal hormone used in cartilage formation is produced out of control. This protein, PTH related protein (PTHrP), has PTH like properties due to the fact that the first 13 amino acids are almost identical. Like PTH, PTHrP increases calcium reabsorption in the distal tubule and decreases phosphorus reabsorption in the proximal tubule. It also promotes skeletal mobilization of calcium. The primary difference from PTH is that it does not stimulate the production of 1,25 dihydroxyvitamin D. It is produced in non-metastatic solid tumors. PTH and phosphorus are low while calcium and PTHrP are elevated.

Direct invasion of the bone causing increased osteoclast activity is seen primarily non-small cell lung cancer and breast cancer following bone metastasis. Multiple myeloma can also cause bone invasion and cause hypercalcemia by this mechanism. These patients will have increased calcium and decreased PTH, PTHrP and variable phosphorus.

Increased and unregulated hydroxylation of 25 hydroxyvitamin D. Hodgkin’s and non-hodgkin’s lymphoma cause activation of the storage form of vitamin D outside of the normal regulation by the kidney and PTH. These patients will have suppressed PTH, increased Ca and phosphorus and increased 1,25 vitamin D levels.

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2.

3.

Causes of unregulated production of 1,25 dihydroxyvitamin D

sarcoidosistuberculosisHodgkin lymphomanon-Hodgkin's lymphomaberylliosiscoccidioidomycosishistoplasmosiscandidiasisCrohn's diseaseLangerhans-cell histiocytosissilicone-induced granulomascat-scratch diseaseWegener's granulomatosisPneumocystis carinii pneumonia

Granulomatous diseaseThis cause of hypercalcemia is identical to the third mechanism of hypercalcemia of malignancy. Unregulated production of 1,25 vitamin D.

Milk-alkali syndromeAn interesting cause of hypercalcemia is milk-alkali syndrome. The syndrome consists of renal failure, hypercalcemia and metabolic alkalosis. It is due to ingestion of alkali and calcium and is now most often seen in woman taking calcium carbonate for osteoporosis.

Diagnosis of HypercalcemiaConfirm the diagnosis with an ionized calcium in edge cases. Check PTH.While waiting for the PTH, check the medication list for nutritional and pharmaceutical vitamin D, calcium supplements, thiazide diuretics and lithium.

High PTH? Hyperparathyroidism is the diagnosis. Use your brain to differentiate primary from tertiary HPTH.

Low PTH? Think malignancy, granulomatous disease or milk-alkali syndrome. Tests to consider include 1,25 OH D, PTHrp, and a skeletal survey. Exogenous calcium intake is common and should be associated with alkalosis. Otherwise, look for unregulated 1,25 OH D production (common) or PTHrp (uncommon).

Symptoms of HypercalcemiaMild hypercalcemia is associated with relatively mild, non-specific symptoms. Patients with primary hyperparathyroidism are generally asymptomatic but may complain of weakness, fatigue, anorexia, depression, vague abdominal pain and constipation. Gastrointestinal side effects become more severe at higher calcium levels. Hypercalcemia has been associated with increased gastrin secretion and may predispose patients to peptic ulcers. Severe hy-percalcemia can cause pancreatitis. The hypothesized mechanism is inap-propriate activation of trypsinogen within the pancreatic parenchyma.

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Hypercalcemia can cause multiple forms of renal dysfunction:

Long-standing hypercalcemia predisposes patients to nephrolithiasis.

Hypercalcemia causes nephrogenic diabetes insipidus by reducing sodium reabsorption in the thick ascending limb of the loop of Henle and decreasing the renal response to ADH. These changes predispose patients to volume depletion.

Hypercalcemia also causes renal insufficiency. Primarily this is due to volume deficiency but calcium induced vasoconstriction reduces renal blood flow. If the hypercalcemia is long standing, calcification and ischemia results in irre-versible renal insufficiency.

Mental status changes from mild confusion to psychosis or coma can occur in severe cases of hypercalcemia. Mental status impairment can persist for one to two days following correction of hypercalcemia.

Shortened QT-interval occurs with hypercalcemia and is generally consid-ered a benign finding. Bradycardia, responsive to atropine, has been report-ed.

Treatment of hypercalcemiaThe best treatment for hypercalcemia is to correct the underlying etiology. In situations where this is not possible or specific hypocalcemic therapy is needed, the treatment should focus on the three legs of calcium physiology: calcium reabsorption in the kidney, calcium mobilization by the bones and calcium absorption by the gut.

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Complete the figure by drawing the CaSR on the basolateral membrane and drawing it’s effect on the ROMK channel and Ca, Na and Mg resorption.

This is representation of the thick ascending limb of the loop of Henle. The ba-solateral side has CaSR that respond to increases in serum calcium by shutting down the ROMK channel. This decreases the positive tubular charge which drives the reabsorption of Ca, Mg and Na. This is partly re-sponsible for the nephro-genic DI in hypercalcemia.

Calcium reabsorption is tied to sodium reabsorption so that interventions that reduce sodium reabsorption also reduce calcium reabsorption. The most ef-fective way to do this is to infuse saline. Saline also treats the volume deple-tion found with hypercalcemia. Following volume repletion, loop diuretics can further reduce calcium reabsorption. The goal of therapy is a brisk diuresis of 250-300 mL/hr; however this may be difficult to achieve and poses significant risk to patients. Significant hypercalcemia usually requires additional therapy.

In hypercalcemia due to granulomatous diseases conservative therapy con-sists of minimizing sun exposure, avoiding supplemental vitamin D and dis-couraging calcium rich diets. Corticosteroids are highly effective in granulo-matous disorders. If prednisone 40-60 mg/day for two weeks fails to correct the calcium you probably have the wrong diagnosis. Chloroquine and hy-droxychloroquine can be used as steroid-sparing agents.

The bisphosphonates are effective at correcting hypercalcemia of malignan-cy regardless of the etiology. Pamidronate and zolendronate are commonly used to treat hypercalcemia of malignancy.

Salmon calcitonin can rapidly lower serum calcium by inhibiting osteoclastic bone resorption. It also increases renal excretion of calcium. It can be given IV or SQ and reduces serum calcium by 1-2 mg/dL within hours of adminis-tration. Unfortunately, it only works in just over half of patients with hypercal-cemia of malignancy and tachyphylaxis is common after 2-3 days.

HyperparathyroidismPrimary vs Secondary vs. Tertiary hyperparathyroidismWe have already talked about primary hyperparathyroidism, which causes hypercalcemia. The other two forms of hyperparathyroidism are secondary and tertiary hyperparathyroidism.

Secondary hyperparathyroidism is an increase in PTH due to a low calcium. This increase in PTH is physiologic rather than pathologic. While short term secondary hyperparathyroidism is adaptive, long term increases in PTH cause a variety of problems. This long term secondary hyperparathyroidism is found in chronic kidney disease:

1. Decreased GFR results in increased FGF-23 and increased phosphorus

2. Increased FGF-23 inhibits 1-alpha-hydroxylase decreasing 1,25 OH Dformation.

3. Decreased 1,25 OH D triggers an increase in PTH

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4. Increased PTH decreases phosphorus absorption in the proximal tubulereturning serum phosphorus to normal.

5. The end result is a normal phosphorus atthe expense of an increased PTH andFGF-23.

This system works with ever increasing PTH as the GFR falls. The cycle can be interrupted by decreasing the phosphorus load either by diet or use of phosphorus binders.

Unfortunately this neat little system of increas-ing PTH in exchange for a normal Phos com-pletely fails when the patient progresses to ESRD. At this point regardless how high the PTH is, the kidney is unable to excrete the phosphorus. Patients are left with increased phosphorus and in-

creased PTH.

Long standing secondary hyperparathyroidism causes hypertrophy of the parathyroid gland. This initially manifests as simply an increase in size of the gland. Later the gland changes from a smooth to a nodular appearance. This nodularity is associated with a decrease in responsiveness to the normal regulation of PTH secretion. In essence the secretion of PTH ceases to be secondary to hypocalcemia, hyperphosphatemia and low vitamin D. The se-cretion becomes autonomous in much the same way as in patients with pri-mary hyperparathyroidism. A sign of this transition is hypercalcemia. This transition is called tertiary hyperparathyroidism and like primary hyper-parathyroidism it is treated by surgery.

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This is representation of the relative size increase seen in hyperparathy-roidism. A change from 40 mg to 1,000 mg

Type of HPTH

Calcium Phos Treatment

Primary High Low Surgery

Secondary Low to normal

High in CKD

Low in other types of 2° HPTH

Decrease phos load, Active vitamin D, Calcimimetics

Tertiary High Normal to high Surgery

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Renal OsteodystrophyBone disease due to renal disease

MM was admitted. The hypercalcemia was relatively asymptomatic. The ortho service did an open reduction and internal fixation of the avulsed patellar tendon. On the nephrology service we determined that his avulsion with minimal trauma was due to osteitis fibrosa cystica. On further questioning, the patient reports dif-fuse bone pain and severe itching.

Renal osteodystrophy (ROD) are skeletal disorders seen in CKD or ESRD patients. The bone pathology in ROD comes in two basic flavors, high turnover disease with increased osteoblast activity and low-turn over disease where there is a lack of osteoclast activity. Both conditions are bad for the bones. The specific pathologies are below:

1. Osteitis fibrosa cystica - due to secondary hyperparathyroidism withconcomitant increase in resorption of bone. This condition leads toincrease in bone pains, fractures and skeletal deformities.

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2. Osteomalacia – due to Vitamin D Deficiency which results in lowbone turnover in combination with increased volume of unmineral-ized bone (osteoid)

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3. Adynamic bone disorder – due to PTH levels less than target whichresults in low bone turnover.

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4. Mixed osteodystrophy – mixed elements of both high and low boneturnovers.

Regardless of the specific bone pathology found, renal osteodystrophy re-sults in weak bones, bone pain and other extra-osseous manifestations of diease:

• Anemia

• Itching (uremic pru-ritis)

• Myopathy

• Increased Ca xPhos product

• Calciphylaxis

• Vascular calcifica-tion

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Treating secondary hyperparathyroidism/RODPrevention and management of ROD revolves around maintenance of calci-um, phosphate and PTH balance. Researchers are just beginning to perform prospective studies to look at the proper target levels of calcium, phosphorus and PTH. For now physicians are relying on opinion based guidelines.

The Kidney Disease Improving Global Outcomes (KDIGO) recommendations are international consensus guidelines that purport to provide more evidence based, rather than opinion based, guidelines.

Phosphorus

➡In patients with CKD stages 3–5, we suggest main- taining serum phosphorus in the normal range (2C). In patients with CKD stage 5D, we suggest lowering elevated phosphorus levels to-ward the normal range (2C).

Calcium

➡In patients with CKD stages 3–5D, we suggest maintaining serum cal-cium in the normal range (2D). Avoid hypercalcemia.

intact PTH

➡In patients with CKD stages 3–5 not on dialysis, the optimal PTH level is not known. However, we suggest that patients with levels of intact PTH (iPTH) above the upper normal limit of the assay are first evaluat-ed for hyperphosphatemia, hypocalcemia, and vitamin D deficiency (2C).

➡In patients with CKD stages 3–5 not on dialysis, in whom serum PTH is progressively rising and remains persistently above the upper limit of normal for the assay despite correction of modifiable factors, we sug-gest treatment with calcitriol or vitamin D analogs (2C).

➡In patients with CKD stage 5D, we suggest maintaining iPTH levels in the range of approximately two to nine times the upper normal limit for the assay (2C).

Treatment optionsDecrease Phosphorus AbsorptionControlling phosphorus can help patients get the Phos, the Ca-Phos product and PTH to goal. There are two strategies for lowering the phosphorus, de-creasing the phosphorus in the diet and decreasing phosphorus absorbed from the diet. All dialysis patients are advised to ingest no more than 800 mg of phosphorus per day. High phosphorus foods include dairy products, whole grains, and nuts.�21

Phosphorus binders are effective at lowering the absorption of phosphorus. The current options are sevelamer, calcium carbonate, calcium acetate, and lanthium carbonate. These medications need to be administered with food to be effective.

The primary side effects are all GI related. There is a concern that the calci-um containing binders may promote vascular calcification by increasing the calcium burden and suppressing the PTH. This has been shown in two un-blinded trials (Treat To Goal and RIND) but use of sevelamer failed to reduce mortality in the pivotal DCOR trial.

Intact PTHIn addition to using phosphorus binders to lower PTH, activated vitamin D (1,25 dihydroxyvitamin D and its synthetic analogs) and cinacalcet can lower the intact PTH.

The parathyroid gland uses 1,25 dihydroxyvitamin D as a negative inhibitor to decrease the release of PTH. In renal failure, the kidneys do not produce dihydroxyvitamin D so this negative feedback for PTH release is lost. Provid-ing exogenous vitamin D lowers the PTH. The primary problem with vitamin D is that in addition to lowering PTH they increase the GI absorption of both calcium and phosphorus. The synthetic analogs of dihydroxyvitamin D, pari-calcitol (Zemplar) and doxercalciferol (Hecterol) have less GI activity and so are less prone to cause hypercalcemia and hyperphosphatemia.

Cinacalcet (Sensipar) is the only commercially available member of a novel class of medications called the calcimimetics. Cinacalcet binds the calcium binding receptor and makes it bind calcium more tightly. This makes the re-ceptor behave like the serum calcium level is significantly higher than it actu-ally is. This perceived elevation in calcium inhibits the release of PTH. In clin-ical trials cinacalcet reduces PTH, calcium and phosphorus. Cincalcet was approved based on the ability to get patient to the K/DOQI bone and mineral guidelines.

If patients have increased calcium and hyperparathyroidism they have ter-tiary hyperparathyroidism. Tertiary hyperparathyroidism is treated by parathy-roidectomy, the last method of reducing PTH.

Parathyroidectomy should be recommended in patients with severe hyper-parathyroidism (persistent serum levels of intact PTH >800 pg/mL [88.0 pmol/L]), associated with hypercalcemia and/or hyperphosphatemia that are refractory to medical therapy.

Indications for parathyroidectomy are:

• Severe hypercalcemia

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• Progressive and debilitating hyperparathyroid bone disease

• Pruritus that does not respond to medical or dialytic therapy

• Progressive extra-skeletal calcification or calciphylaxis

• Otherwise unexplained symptomatic myopathyMM goes for a parathyroidectomy due to the bone pain, persistent hyper-parathyroidism and hypercalcemia. Following the surgery MM develops hypocalcemia, hypokalemia and hypomagnesemia. He is diagnosed with severe hungry bone syndrome. His total calcium falls as low as 5 mg/dL. He is started on a calcium drip.

HypocalcemiaIs it pathology or physiology

Etiologies: Hypocalcemia is a pervasive finding among acutely ill patients. Various stud-ies have found a prevalence of 70-90% among patients in the ICU. Hypocal-cemia occurs when calcium leaves the vascular space faster than it is replet-ed. It can leave the vascular space by either by renal losses or deposition in the bones or soft tissues. Repletion normally occurs through diet or mobiliza-tion of skeletal stores.

Tissue depositionAcute deposition in the tissues occurs with acute hyperphosphatemia as seen with tumor lysis syndrome or with pancreatitis in which the calcium is absorbed by free fatty acids produced by the increase in lipase. Citrate expo-sure can also do this and occurs with blood transfusions, continuous dialysis and plasmapheresis. Liver disease, renal failure and hypothermia all de-crease the metabolism of citrate and contribute to this risk.

Hungry bone syndrome is a special case of tissue deposition, where long-standing hyperparathyroidism (primary, secondary or tertiary) has demineral-ized large amounts of the bone leaving osteoid. When the PTH is removed the bone begins to rapidly remineralize and can absorb tens of grams of cal-cium. The hypocalcemia can persist for months.

Increased renal lossRenal loss of calcium is due to hypoparathyroidism. Decreased PTH is pri-marily due to surgical intervention on the neck which can stun the parathyroid glands (usually temporarily). Additionally high magnesium levels can trigger the CaSR and suppress release of PTH. The release of PTH, like insulin, is a

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magnesium dependent process, so hypomagnesemia can also suppress PTH release and decrease end-organ PTH responsiveness.

In addition to the increased renal losses, the loss of PTH prevents the mobi-lization of skeletal reserves.

Decreased intake and mobilization of skeletal reservesAcute hypocalcemia with vitamin D deficiency occurs because of the inability to mobilize skeletal reserves of calcium. Vitamin D deficiency is very common with a measured prevalence among nursing home patients of 40-100%. Pre-adolescent white girls have a 50% rate of insufficiency (Sulli-van SS, Rosen CJ, et al. J Am Diet Assoc 2005; 105:971-974.). Even among health conscious (daily vitamin and glass of forti-fied milk plus weekly salmon) adults the rate of deficiency was 32% (Tangpricha V, Pearce EN, et al. Am J Med 2002;112:659-662.).

Increased hepatic metabolism of vitamin D occurs in patients on phenytoin and phenobarbital. The nephrotic syndrome is commonly associated with hypocalcemia, though most of this is due to hypoalbuminemia. Ionized hypocalcemia occurs with the nephrotic syndrome and may be due to the loss of 25-hydroxyvitamin D and its binding protein in the urine. Decreased activation of 25-hydroxyvitamin D occurs with renal failure and hypoparathy-roidism.

Hypocalcemia of critical illnessHypocalcemia is a pervasive disorder in the ICU. While hypocalcemia was thought to be limited to patients with sepsis, Zivin et al. have shown hypocal-cemia to be frequent in all patients with severe illness.(Zivin JR, Gooley T, et al. Am J Kidney Dis 2001 37:689-698.) Despite careful assessment however, a definitive etiology can be found in less than half of the patients. Some au-thors believe that ICU associated hypocalcemia (ICU-H) is an adaptive, ben-eficial, response to critical illness as it may prevent intracellular hypercal-cemia and associated tissue damage.

This concept of adaptive hypocalcemia gained credence initially from in-vitro studies that showed that intracellular calcium was a mediator of injury. Addi-tionally calcium infusions enhanced reperfusion injury. In vitro evidence came from a series of studies on septic rats that showed that the correction of

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Interpreting 25-OH Vitamin D levels

• 30-40 ng/mL: optimal

• 20-29 ng/mL: insufficient

• <20 ng/mL: deficient

hypocalcemia improved hemodynamics but increased mortality.

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One other cautionary tale about the consequences of calcium replacement comes from a 2008 article. (Bolland MJ, Barber PA, et al. Brit Med J 2008; 336: 262-6) This was an additional analysis of a 5 year study of calcium sup-plementation in post-menopausal women to look at fracture risk and BMD. This paper however looked at the randomized cohort to see if their was a risk of increased cardiovascular events.

"CaInduce sepsis

#Ca

"Ca "BP

$BP

• Zaloga G, Sager A, Black KW, Low dose calcium administration increases mor-tality during septic peritonitis in rats., Circulatory Shock (1992) 37:226-229.

• Malcolm D, Zaloga G, Holaday J, Calcium administration increases the mortali-ty of endotoxic shock in rats., Critical Care Med (1989) 17:900-903.

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Consequences of hypocalcemiaThe primary manifestation of hypocalcemia is neuromuscular irritability. This can range from perioral numbness and acral paresthesias to severe tetany and seizures.

Tetany can cause laryngospasm or bronchospasm resulting in respiratory failure. The classic signs of latent tetany are Trouseau’s sign (carpal spasm after inflation of a blood pressure cuff on the arm for 3 minutes) and Chvostek’s sign (facial spasm induced by tapping on the facial nerve at the temple). The sensitivity of both is poor and the specificity of Chvostek’s is particularly poor (a partial Chvostek’s sign is found in 25% of eucalcemic in-dividuals).

Acute hypocalcemia can cause heart failure. Even modest hypocalcemia can precipitate heart failure and hypotension in patients with latent cardiac dam-age. The classic electrocardiogram findings of hypocalcemia are bradycar-dia, prolonged QT interval and inversion of the T wave. The electrocardio-gram is not sensitive and may be normal during life threatening hypocal-cemia.

Hypotension can occur following loss of vascular tone. In one ICU study de-creased ionized calcium correlated with decreased mean arterial pressures.

Digitalis acts by increasing intracellular calcium. Hypocalcemia is a cause of digitalis resistance. Patients can sometimes tolerate toxic digitalis levels with concurrent hypocalcemia. Correction of this protective hypocalcemia can precipitate symptomatic digitalis toxicity.

TreatmentUnique to calcium among all electrolyte disorders is the theory that hypocal-cemia may be an adaptive response to critical illness and because of this,

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the treatment of ICU associated hypocalcemia (ICU-H) is controversial. Care must be made not to extrapolate this controversy to patients in which the eti-ology of their hypocalcemia is understood (e.g. acute hypoparathyroidism, tumor lysis syndrome, acute renal failure). Patients with chronic hypocal-cemia and myocardial dysfunction should be given a trial of calcium supple-mentation.

Calcium should be repleted in cases of seizures, tetany, laryngospasm and hyperkalemia. Among asymptomatic patients, the risk of significant clinical symptoms rises as the ionized calcium falls below 3 mg/dL and treatment is warranted in these patients.

National guidelines call for active treatment of patients with hungry bone syndrome.

Mild hypocalcemia can be treated with increases in oral calcium of 1000 mg/day.

Acute symptomatic hypocalcemia should be treated with IV calcium. Two forms of IV calcium are available: calcium gluconate and calcium chloride. The chloride preparation has more calcium but is sclerosing to the veins and should only be used in patients with central access.

Calcium Preparation

Elemental Calcium

Pill Size

Calcium carbonate 250 mg 650 mg

Calcium gluconate 90 mg 1000 mg

Calcium citrate 200 mg 950 mg

Calcium lactate 60 mg 300 mg

Calcium Preparation

Elemental Calcium per gram (ampule)

Calcium gluconate 94 mg

Calcium chloride 272 mg (equivalent to 3 amps of Ca Gluconate)

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Symptomatic patients should get 1-2 ampules of calcium gluconate followed by a calcium infusion. I use 5 grams of calcium gluconate in 500 mL of D5W and run this at 10-100 mL/hour to normalize the calcium.

Following the parathyroidectomy M.M. lingered on the floor for days on a calcium infusion, receiving regular potassium and magnesium supple-ments. He never had symptomatic hypocalcemia. Then Alonzo Mourning came to the hospital on a promotional tour for Johnson and Johnson. As part of the tour he met M.M. and ac-tually spent 15 minutes alone with the patient talking to him. I was Alonzo’s physician guide and about 10 minutes after I left the ward with him I re-ceived a frantic call from my fellow that M.M. was stridorous and in respi-ratory distress. We gave an amp of calcium gluconate, increased calcium drip and transferred him to the ICU. The ABG done in the ICU showed:

7.46 / 24 / 88. Our conclusion was that M.M. hyperventilated in response to meeting Alonzo and developed respiratory alkalosis. This lowered his ionized calcium and precipitated the symptomatic hypocalcemia.

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Joel M. Topf, MDNephrology

248.470.8163http://pbfluids.com/