22: Hypercalcemia

In general, hypercalcemia is detected in 1 of 3 clinical circumstances. First, hypercalcemia may be discovered during routine laboratory work-ups in patients with no symptoms. These patients may or may not have a risk factor for hypercalcemia, such as malignancy. Most cases of hypercalcemia are diagnosed in these asymptomatic people. Second, hypercalcemia may be found during evaluation of patients with symptoms or findings that can be related to hypercalcemia, such as constipation, weakness, fatigue, depression, nephrolithiasis, or osteopenia. Third, severe hypercalcemia may present as altered mental status.

Although most cases of hypercalcemia are due to only a handful of conditions (primary hyperparathyroidism, hypercalcemia of malignancy, chronic kidney disease (CKD), and the milk-alkali syndrome), the complete differential diagnosis is extensive. The most commonly used framework for the differential is organized by pathophysiology. What follows is a somewhat abbreviated list organized by etiology.

1. Parathyroid hormone (PTH)–related

   1. Primary hyperparathyroidism

   2. Secondary hyperparathyroidism (with calcium supplementation)

   3. Tertiary hyperparathyroidism

   4. Lithium therapy (causes hypercalcemia in about 10% of patients)

   5. Familial hypocalciuric hypercalcemia

2. Hypercalcemia of malignancy

   1. Secretion of parathyroid hormone–related protein (PTHrP)

      1. Squamous cell carcinomas

      2. Adenocarcinoma of lung, pancreas, kidney, and others

   2. Osteolytic metastasis

      1. Breast cancer

      2. Multiple myeloma

   3. Production of calcitriol (Hodgkin disease)

3. Vitamin D–related

   1. Hypervitaminosis D

   2. Granulomatous diseases

4. Other relatively common causes of hypercalcemia

   1. Milk-alkali syndrome (mainly seen in patients with CKD who are taking calcium carbonate)

   2. Hyperthyroidism

   3. Thiazide diuretics

   4. Falsely elevated serum calcium (secondary to increased serum binding protein)

      1. Hyperalbuminemia

      2. Hypergammaglobulinemia

Clinically, the differential diagnosis is most commonly organized by the pivotal findings of whether or not the PTH is elevated and whether the patient has a known malignancy. A useful clinical algorithm is presented in Figure 22-1.

Before returning to the case, it is worthwhile to briefly review the basics of calcium metabolism. Calcium levels are dictated by the actions of PTH, calcitonin, and calcitriol (1,25-dihydroxyvitamin D). PTH levels rise and fall in response to serum calcium levels. High levels of PTH stimulate a rise in serum calcium by increasing both renal tubular calcium reabsorption and bone resorption. PTH also stimulates the conversion of calcidiol to calcitriol in the kidneys. Calcitriol leads to a further increase in serum calcium via increased absorption of calcium in the small intestine. Phosphate metabolism is also controlled by PTH and calcitriol; PTH generally lowers phosphate levels through its effects on the kidney, while calcitriol generally raises phosphate levels through its effects on the intestine and inhibitory effects on PTH levels. Calcitonin lowers calcium by suppressing calcium release from bones by inhibiting the function of osteoclasts.

In healthy ambulatory patients with hypercalcemia, primary hyperparathyroidism is, by far, the most common diagnosis. This disease is often asymptomatic or minimally symptomatic. The chronicity of this patient’s hypercalcemia, as well as her relatively good health, are pivotal points that make this diagnosis even more likely. Hypercalcemia related to thiazide use is also possible. Although thiazide diuretics generally cause chronic hypercalcemia in patients with other abnormalities in calcium metabolism, they occasionally do cause mild hypercalcemia in patients with no other cause. Familial hypocalciuric hypercalcemia (FHH) is another cause of chronic, usually asymptomatic hypercalcemia. Although it is usually diagnosed early in life, it can present similarly to primary hyperparathyroidism. Most patients with hypercalcemia due to a malignancy have a known malignancy when presenting with hypercalcemia. Sarcoidosis is not a common cause of hypercalcemia but should probably be considered, given the patient’s race, if another diagnosis is not made. Table 22-1 lists an appropriately limited differential diagnosis for this patient.

Leading Hypothesis: Primary Hyperparathyroidism

Textbook Presentation

Primary hyperparathyroidism usually presents with hypercalcemia found during routine laboratory screening. Occasionally, it is detected during the evaluation of nonspecific symptoms, such as fatigue or constipation.

Disease Highlights

1. Primary hyperparathyroidism most commonly presents with a modestly elevated calcium and few (if any) symptoms rather than the classic presentation of "stones, bones, groans, and psychiatric overtones."

   Primary hyperparathyroidism accounts for more than 90% of cases of hypercalcemia in otherwise healthy ambulatory patients.

2. Etiology of primary hyperparathyroidism

   1. 85% of the cases of primary hyperparathyroidism are due to solitary parathyroid adenomas.

   2. Parathyroid hyperplasia, multiple adenomas, and the rare carcinoma, cause the other 15% of cases.

      1. Parathyroid hyperplasia can be sporadic or inherited.

      2. Inherited syndromes of parathyroid hyperplasia include the multiple endocrine neoplasia (MEN) type I and IIA syndromes. Patients with other relevant diagnoses such as pituitary tumors, islet cell tumors, medullary thyroid carcinomas, and pheochromocytomas should be evaluated for these syndromes.

3. Clinical manifestations of primary hyperparathyroidism

   1. Nonspecific symptoms such as fatigue, irritability, and weakness are more common among patients with primary hyperparathyroidism.

   2. Decreased bone density is common in patients with primary hyperparathyroidism while classic osteitis fibrosis cystica is exceedingly rare today.

   3. Nephrolithiasis is present in 15–20% of patients with primary hyperparathyroidism.

   4. Other symptoms of primary hyperparathyroidism probably include increased frequency of hypertension, gout, and calcium pyrophosphate deposition disease.

Evidence-Based Diagnosis

1. Hypercalcemia should be confirmed before evaluating a patient for primary hyperparathyroidism.

   1. The calcium level should be remeasured.

   2. Ideally, the ionized calcium should be measured. Alternatively, a corrected calcium can be calculated to account for the plasma protein binding of calcium. The corrected calcium = Total calcium (mg/dL) + 0.8(4-albumin [g/dL]).

2. Other effects of elevated PTH levels (hypercalciuria, hypophosphatemia, hyperphosphaturia) are seldom useful in differentiating primary hyperparathyroidism from hypercalcemia of malignancy—the second most common cause of hypercalcemia.

3. The diagnosis of primary hyperparathyroidism is usually straightforward.

   1. The diagnosis is extremely likely in an otherwise healthy patient with chronic hypercalcemia.

   2. An elevated PTH level is confirmatory, distinguishing primary hyperparathyroidism from hypercalcemia of malignancy which has low serum PTH levels.

   3. About 10% of patients with primary hyperparathyroidism have normal PTH levels (a finding that is in fact inappropriate given the hypercalcemia). In these patients, FHH must be excluded.

Treatment

1. Definitive treatment for primary hyperparathyroidism is surgical parathyroidectomy.

2. Who needs surgery?

   1. Because of the generally benign course of primary hyperparathyroidism, not everyone needs surgery.

   2. Recommendations from consensus panels are based on who is most likely to progress to symptomatic disease and who would benefit most from surgery.

   3. Indications for surgery

      1. Symptoms of hypercalcemia

      2. Elevated serum calcium > 1 mg/dL above normal

      3. Creatinine clearance < 60 mL/min

      4. Osteoporosis (bone density with T score < 2.5 at any site) or fragility fracture

      5. Age younger than 50

      6. Patient preference or patient inability to comply with long-term monitoring

3. This approach to deciding which patients undergo surgery appears to be effective. A recent study observing 52 asymptomatic people for up to 10 years demonstrated the disease is usually not progressive.

   1. 38 (73%) had no progression of disease

   2. Patients who required surgery did so for the following reasons:

      1. Hypercalcemia worsened in 2 patients

      2. Hypercalciuria developed in 8 patients

      3. Low bone density developed in 6 patients

4. Parathyroidectomy

   1. Parathyroidectomy is markedly effective at inducing normocalcemia (95–98%), improving bone density (100%), and improving symptoms (82%).

   2. Preoperative nuclear imaging of the parathyroid glands is very helpful in identifying abnormal glands, thus decreasing the need for detailed neck exploration. The data below is for the identification of abnormal glands.

      1. Sensitivity, 69%; specificity, 98%

      2. LR+, 34.5; LR–, 0.32

   3. Intraoperative PTH assays also serve to improve the surgical success rates.

5. Monitoring (for patients not undergoing surgery)

   1. Assessment of symptoms, calcium level, and kidney function yearly.

   2. Biyearly bone density screening of the hip, spine, and wrist.

   3. Initial screening for nephrolithiasis with radiographs or CT scans.

6. If surgery is indicated but the patient declines or is unfit for surgery, medical therapy is indicated.

   1. Patients should be encouraged to remain active, stay well hydrated, and maintain moderate calcium and vitamin D intake in order to retain bone health and reduce the risk of kidney stones.

   2. Thiazide diuretics and lithium carbonate, both of which can exacerbate hypercalcemia, should be avoided.

   3. Bisphosphonates are often used to maintain bone density.

   4. Cinacalcet is probably a good option for patients with primary hyperparathyroidism who cannot or will not undergo surgery.

Other than primary hyperparathyroidism, the differential diagnosis of hypercalcemia in a patient with an elevated PTH is lithium use, MEN syndromes, secondary or tertiary hyperparathyroidism, or familial hypocalciuric hypercalcemia. Given the patient’s medications, normal kidney function, age at presentation, and lack of a family history of hypercalcemia, primary hyperparathyroidism is clearly the most likely diagnosis. FHH would remain a possibility if not for the markedly elevated PTH level. Thiazide diuretic use does not cause hypercalcemia via hyperparathyroidism and thus does not explain the patient’s hypercalcemia. It could have been a contributing factor in the initial presentation.

Alternative Diagnosis: Familial Hypocalciuric Hypercalcemia

Textbook Presentation

The diagnosis of FHH is usually made in childhood during evaluation of asymptomatic hypercalcemia or during screening because of a positive family history. The condition may also present during adulthood as hypercalcemia with a normal to slightly elevated PTH.

Disease Highlights

1. The mutation in FHH makes the calcium sensing receptor, found on various tissues throughout the body, less sensitive to calcium. In the parathyroid glands, this means that higher serum calcium levels are needed to suppress PTH release. The defect leads to:

   1. Secretion of PTH inappropriate to calcium levels

   2. Renal absorption of calcium inappropriate to calcium levels

2. Most patients with FHH are asymptomatic at the time of presentation.

Evidence-Based Diagnosis

1. FHH is usually easily distinguished from primary hyperparathyroidism as the former usually has mildly elevated calcium levels and a normal PTH level while the latter has an elevated PTH level.

2. Differentiation can be difficult because patients with FHH sometimes have a mildly elevated PTH, and patients with primary hyperparathyroidism often have mild hypercalcemia and have a normal PTH 10% of the time.

3. Three important distinguishing features are:

   1. Patients with FHH usually have family members with FHH. The genetic defect is inherited in an autosomal dominant manner.

   2. Urinary calcium excretion is reduced (> 99% reabsorption vs < 99% in primary hyperparathyroidism).

      1. A urinary calcium < 200 mg/day suggests FHH.

      2. A fractional excretion of calcium < 0.01 is nearly diagnostic of FHH. Patients with primary hyperparathyroidism usually have results > 0.02. (Fractional excretion of calcium = (urine calcium × serum creatinine)/(serum calcium × urine creatinine)

   3. Serum magnesium is often increased in FHH.

   4. Genetic testing is available when the diagnosis is difficult to make.

Treatment

Treatment for FHH is not necessary because the hypercalcemia is mild and only very rarely leads to complications.

Alternative Diagnosis: Thiazide-Induced Hypercalcemia

Textbook Presentation

Thiazide-induced hypercalcemia usually occurs transiently after starting a thiazide diuretic. It is generally mild and is not associated with hyperparathyroidism.

Disease Highlights

1. Thiazide diuretics cause hypocalciuria.

   1. Sodium depletion causes increased sodium and calcium retention in the proximal tubule.

   2. Thiazides probably also augment the effect of PTH.

2. Hypercalcemia is generally mild and short lived because reduced PTH secretion will normalize calcium levels.

3. Some patients may have persistently, although still only mildly, elevated calcium levels.

4. Patients with underlying hyperparathyroidism, or other causes of increased bone turnover, are more likely to have persistent and more pronounced degrees of hypercalcemia.

Evidence-Based Diagnosis

1. The diagnosis of thiazide-induced hypercalcemia depends on documenting hypercalcemia temporally related to beginning a diuretic.

2. Resolution of the abnormality with cessation of the drug is diagnostic.

3. Patients taking a thiazide who have persistent elevations of calcium of > 0.5 mg/dL above normal should be evaluated for other causes of hypercalcemia.

Treatment

Because the hypercalcemia is almost always mild and short lived, no treatment is necessary.

As discussed above, the patient’s symptoms are an indication for surgery. However, since the patient’s symptoms were nonspecific, there was no guarantee that they were related to the hyperparathyroidism.

This is an elderly woman with abdominal pain and marked hypercalcemia. Although primary hyperparathyroidism is a possibility, there are multiple pivotal points that suggest other diagnoses. These include the degree of hypercalcemia and the abnormalities found on physical exam and laboratory studies. Hypercalcemia of malignancy needs to be considered given the patient’s age and hepatomegaly. Most patients with hypercalcemia of malignancy have a previously diagnosed cancer, but it is possible for symptoms of cancer and hypercalcemia to present simultaneously or for symptoms of hypercalcemia to be the presenting symptoms of the malignancy. Malignancy usually leads to hypercalcemia through the elaboration of PTHrP or through osseous metastasis.

The milk-alkali syndrome should be considered. This syndrome is often caused by ingestion of large amounts of calcium carbonate in an effort to treat dyspepsia. This syndrome typically presents with hypercalcemia, metabolic alkalosis, and acute kidney injury. The presence of only 1 of the syndrome’s 3 features (hypercalcemia) makes this diagnosis less likely. The presence of other illnesses or medication use may suggest less common causes of hypercalcemia, such as granulomatous disease. Table 22-2 lists the differential diagnosis for this patient.

Leading Hypothesis: Humoral Hypercalcemia of Malignancy

Textbook Presentation

Hypercalcemia of malignancy is most commonly detected in patients with previously diagnosed cancers. It is uncommon for symptomatic hypercalcemia to be the presenting symptom of a malignancy. Hypercalcemia of malignancy carries a horrendous prognosis with 50% 30-day mortality.

Disease Highlights

1. Hypercalcemia of malignancy is a heterogeneous process.

   1. The most common pathophysiology behind hypercalcemia in malignancy is elaboration of PTHrP by tumor cells. This is referred to as humoral hypercalcemia of malignancy (HHM).

   2. Tumors metastatic to bone may also cause hypercalcemia through local osteolytic effects on the bones, sometimes via local elaboration of PTHrP. This syndrome is discussed below.

   3. It is likely there is a great deal of overlap between these first 2 causes.

   4. Rarely, tumors can cause hypercalcemia by elaborating vitamin D (seen most commonly with lymphoma).

2. The malignancies that commonly cause hypercalcemia are (in approximate order of frequency):

   1. Lung

   2. Breast

   3. Multiple myeloma

   4. Lymphoma

   5. Head and neck

   6. Renal

   7. Prostate

3. PTHrP is a normal, physiologic, protein that is produced by many non-neoplastic tissues.

   1. The protein shares considerable sequence homology to PTH and binds to the same receptor.

   2. PTH and PTHrP affect the bones and kidneys in the same way.

   3. Certain malignancies elaborate the protein in relatively large amounts.

      1. PTHrP is detectable in 80% of patients with hypercalcemia and malignancy.

      2. The most common tumors that produce PTHrP are squamous cell carcinomas and adenocarcinomas of the lung, pancreas, and kidney.

   4. In hypercalcemia of malignancy secondary to PTHrP, hypercalcemia commonly precedes bony metastasis.

Evidence-Based Diagnosis

1. Similar to primary hyperparathyroidism, hypercalcemia of malignancy seldom presents significant diagnostic confusion.

2. In patients with a known malignancy, the diagnosis is made by detecting high PTHrP and low PTH levels.

Treatment

1. Patients with hypercalcemia of malignancy benefit from treatment of the underlying disease.

2. Beyond treatment of the malignancy, treatment aimed directly at hypercalcemia depends on its severity.

3. The mainstays of treatment for moderate and severe elevations of calcium are the bisphosphonates.

   1. Bisphosphonates work by inhibiting osteoclast activity.

   2. Pamidronate and zoledronic acid are both approved for the treatment of hypercalcemia of malignancy in the United States.

4. For patients with severe, symptomatic hypercalcemia, therapy must be more rapidly effective than treatment of the underlying disease or bisphosphonate therapy (which takes about 48 hours to reach full effectiveness).

   1. Saline hydration treats the dehydration that frequently accompanies hypercalcemia and decreases reabsorption of calcium in the proximal tubule of dehydrated, hypercalcemic patients.

   2. Once hydration is attained, a loop diuretic can further assist in achieving calciuresis.

   3. While calcitonin rapidly decreases hypercalcemia, it also decreases bone resorption.

   4. While immediate therapy for hypercalcemia is instituted, a bisphosphonate should be given and long-term treatment of the malignancy should be planned.

5. In all patients being treated for hypercalcemia of malignancy, care should be taken to institute other measures known to decrease serum calcium. Calcium supplements should be stopped, drugs that lead to hypercalcemia (lithium, thiazides) should be held, hypophosphatemia should be treated and weight-bearing exercise should be encouraged.

Given the results of the patient’s ultrasound, it is highly likely that she has a malignancy that is causing the hypercalcemia. The next step is to make a definitive diagnosis of the malignancy so that specific treatment can be instituted. Determining how the malignancy is causing hypercalcemia will be part of this evaluation; is the hypercalcemia a result of osseous metastasis or of PTHrP?

Alternative Diagnosis: Local Osteolytic Hypercalcemia of Malignancy

Textbook Presentation

Similar to hypercalcemia of malignancy caused by PTHrP, hypercalcemia due to malignancies metastatic to bone generally presents in patients with previously diagnosed cancer. Breast cancer and multiple myeloma (discussed in detail here) are the most common causes.

Multiple myeloma commonly presents with bone pain (often back pain), anemia, hypercalcemia, or acute kidney disease in patients in their 60s. Plain radiographs commonly demonstrate osteolytic lesions and the diagnosis is made by the demonstration of paraproteinemia and increased plasma cells on bone marrow exam.

Disease Highlights

1. Multiple myeloma (and breast cancer) only cause hypercalcemia after metastasizing to bone.

2. The hypercalcemia is caused by local osteolytic effects on bone.

3. Multiple myeloma is caused by a malignant proliferation of plasma cells. The plasma cells usually secrete a single immunoglobulin, or fragment of immunoglobulin, called the M component (monoclonal component).

4. Multiple myeloma most commonly affects patients in the seventh decade of life. Blacks are affected at twice the rate as whites.

5. Symptoms are varied and result from the effect of plasma cell proliferation on multiple systems.

   1. Anemia: Secondary to plasma cell infiltration of the bone marrow.

   2. Infections: When the M component is excluded, patients with myeloma usually have hypogammaglobulinemia.

   3. Bone pain and hypercalcemia: Proliferation of plasma cells in the bone cause osteolytic lesions.

   4. Kidney disease: Multiple myeloma can cause kidney disease in multiple ways:

      1. Light chains may injure the kidney via toxicity to the renal tubules or through obstruction secondary to the heavy burden of filtered protein.

      2. Hypercalcemia

      3. Amyloid deposition in the kidney

      4. Urate nephropathy

   5. Serum hyperviscosity may occur from hypergammaglobulinemia; the most common symptoms are headache and visual disturbances.

6. Symptoms at presentation as reported in 1 study of over 1000 patients:

   1. Anemia was present in 73% of patients. The anemia was usually mild, normochromic, normocytic.

   2. 58% of patients had bone pain at presentation and 67% had lytic bone lesions on radiographs.

   3. 19% had renal disease

   4. 13% had hypercalcemia > 11 mg/dL

   5. M component

      1. 82% of patients had an abnormal serum protein electrophoresis. Of the 18% with a normal serum electrophoresis, 97% had an abnormal urine protein electrophoresis.

      2. The M component most commonly appears in the gamma range and is most commonly IgG.

      3. 16% have only free light chains.

   6. A sizable minority (36%) had a history of or presence of another plasma cell abnormality present at the time of diagnosis (monoclonal gammopathy of unknown significance, plasmacytoma, amyloidosis).

7. Monoclonal gammopathy of unknown significance (MGUS)

   1. Commonly seen in older patients (≈ 3% of patient > 50)

   2. MGUS is diagnosed when there is M component present on serum protein electrophoresis but the patient does not fulfill criteria for myeloma (listed below).

   3. The M component is generally small, < 3 g/dL

   4. Patients with MGUS have an elevated risk of developing multiple myeloma (≈ 1%/year)

Evidence-Based Diagnosis

1. The diagnosis of multiple myeloma is based on the identification of:

   1. Marrow plasmacytosis (> 10%)

   2. Lytic bone lesions

   3. M component detected on serum or urine electrophoresis.

2. Clues to the diagnosis are the presence of normocytic anemia, bone pain, and elevated immunoglobulins.

3. There are a few important issues that may confuse the diagnosis.

   1. Filtered light chains are not detected on traditional urine dipsticks. A patient with light chain only myeloma may have normal amounts of serum protein, a normal serum protein electrophoresis and, apparently, no proteinuria. The presence of a monoclonal gammopathy will be detected only by urine protein electrophoresis.

   2. The bone lesions of multiple myeloma are almost exclusively osteolytic. They will usually be missed on bone scans but are seen on radiographs.

Treatment

The treatment of hypercalcemia of malignancy due to local osteolytic metastases is the same as that for HHM discussed above.

Alternative Diagnosis: Milk-Alkali Syndrome

Textbook Presentation

There can be many presentations of the milk-alkali syndrome. Acute cases often present as hypercalcemia in women who use calcium carbonate for dyspepsia or osteoporosis.

Disease Highlights

1. The milk-alkali syndrome is a syndrome of hypercalcemia, metabolic alkalosis, and acute kidney injury caused by the ingestion of calcium and an absorbable alkali.

2. The syndrome was first described as a complication of a proposed ulcer therapy that included high doses of magnesium carbonate, sodium bicarbonate, bismuth subcarbonate, and about 1 liter of a milk/cream mixture daily.

3. The pathogenesis likely involves hypercalcemia secondary to the ingestion followed by a resultant decrease in glomerular filtration rate. The combination of acute kidney injury, hypercalcemia, and alkali ingestion then causes the metabolic alkalosis.

4. The modern presentation of the milk-alkali syndrome includes a wide range of calcium values, low to normal phosphate levels, moderate acute kidney injury (average creatinine 4.2 mg/dL in a review of modern, published cases), and calcium carbonate as the source of calcium and absorbable alkali.

5. The milk-alkali syndrome is a distant third among the leading causes of hypercalcemia in hospitalized patients, after malignancy and primary hyperparathyroidism.

Evidence-Based Diagnosis

The diagnosis of milk-alkali syndrome is based on history with supporting laboratory test results (hypercalcemia, metabolic alkalosis, and normal to low PTH).

Treatment

1. Cessation of calcium carbonate intake and hydration is usually sufficient treatment of milk-alkali syndrome.

2. Caution should be taken when treating patients with severe milk-alkali syndrome with fluid and loop diuretics. These patients appear to be at particular risk for subsequent, transient, hypocalcemia.

3. A subset of patients, possibly those with more prolonged or severe disease complicated by hypovolemia, may never recover normal renal function.

Because the patient had metastatic squamous cell lung cancer, her rapid decline was expected. The average life expectancy of patients with squamous cell carcinoma and extensive disease is a little less than 1 year and, as mentioned above, the presence of hypercalcemia worsens the prognosis of a malignancy.

Secondary & Tertiary Hyperparathyroidism

Disease Highlights

1. Secondary and tertiary hyperparathyroidism occur in patients with CKD.

2. Secondary hyperparathyroidism is usually associated with hypocalcemia. It is most commonly caused by the chronic hypocalcemia of CKD leading to parathyroid hyperplasia. Therapy for the hyperphosphatemia associated with secondary hyperparathyroidism, however, can lead to hypercalcemia.

   1. Hyperphosphatemia develops in patients with CKD as the renal clearance of phosphate falls.

   2. Early in the course of CKD, hypocalcemia, hypovitaminosis D, and hyperphosphatemia lead to (secondary) hyperparathyroidism. The elevated PTH is adaptive, increasing calcium release from bones and enhancing renal phosphate excretion.

   3. As CKD worsens, hyperparathyroidism becomes counterproductive as the kidneys no longer respond to PTH by excreting phosphate while phosphate continues to be released, with calcium, from the bones.

   4. Treatment of hyperphosphatemia in CKD

      1. Calcium carbonate and calcium acetate have been the traditional first-line therapy for hyperphosphatemia in CKD.

         • (1) Calcium carbonate and calcium acetate are effective phosphate binders, decreasing the GI absorption of phosphate.

         • (2) Calcium-based phosphate binders rarely bring phosphate into the normal range and may cause hypercalcemia.

         • (3) This hypercalcemia (and hyperphosphatemia) may be exacerbated by exogenous calcitriol, also used to treat secondary hyperparathyroidism.

         • (4) High levels of calcium and phosphate have deleterious cardiovascular effects.

      2. Newer therapies offer alternatives for lowering phosphate more effectively without leading to hypercalcemia.

         • (1) Sevelamer is a synthetic phosphate-binding polymer.

         • (2) The calcium mimetic cinacalcet targets the calcium-sensing receptor in the parathyroid glands, lowering PTH levels.

         • (3) Newer vitamin D analogues may be able to lower PTH levels with less of a tendency to cause hypercalcemia and hyperphosphatemia.

      3. It is important to realize that we do not yet have robust clinical data supporting the use of these new medications over the more traditional phosphate binders.

      4. Tertiary hyperparathyroidism occurs when the parathyroid hyperplasia of secondary hyperparathyroidism becomes so severe that PTH production becomes autonomous, causing hypercalcemia beyond that expected by calcium and calcitriol therapy.

Evidence-Based Diagnosis

1. In patients with CKD, an elevated calcium level, in the setting of calcium carbonate use and an elevated PTH, is diagnostic of secondary hyperparathyroidism.

2. Tertiary hyperparathyroidism is diagnosed when PTH reaches higher levels and does not respond to calcium supplementation and vitamin D.

Treatment

1. The treatment of secondary hyperparathyroidism is very complicated and is predicated on treating the factors that stimulate PTH secretion in CKD: hypocalcemia, hypovitaminosis D, and hyperphosphatemia.

2. Treatment involves phosphate binders, calcium and/or calcimimetics, and vitamin D analogues all used in an effort to control the levels of PTH, calcium, and phosphate.

3. If tertiary hyperparathyroidism occurs and is symptomatic (based on hypercalcemia, bone disease, metastatic calcifications) parathyroidectomy is often required.