Some Specific Causes of Hypercalcemia
Primary Hyperparathyroidism
Primary hyperparathyroidism (PHPT) is the most underlying and leading cause of hypercalcemia in the general population
More common in elderly women than men. Postmenopausal women are at increased risk for hypercalcemia
PHPT is due to a single adenoma in 80–85 %, and hyperplasia of four glands in 15–20 %
Clinically, PHPT presents as mild hypercalcemia (60–80 %) with minimal or no symptoms, moderate hypercalcemia (20–25 %) with nephrolithiasis and recurrent stones, or severe hypercalcemia (5–19 %) with symptoms such as renal disease, bone disease, or GI tract problems
Diagnosis is made by measuring serum parathyroid hormone (PTH) and electrolytes. PTH is at times normal, but commonly elevated. Hypercalcemia, hypophosphatemia, hyperchloremic metabolic acidosis, elevated alkaline phosphatase, and occasionally elevated uric acid are observed. Elevated levels of creatinine and blood urea nitrogen (BUN) are common in untreated patients for many years. Hypercalciuria, hyperphosphaturia, and elevated urinary cyclic adenosine monophosphate (cAMP) levels are characteristics of PHPT
Bone disease, called osteitis fibrosa cystica, is due to generalized increase in osteoclastic activity with mobilization of Ca2+ and phosphate from bone (bone resorption). Pathologic fractures of bones are frequently seen
Standard therapy for severe and symptomatic (renal stones, bone disease, and severe hypercalcemia) PHPT is still surgery. However, surgery versus medical therapy for asymptomatic patients remains unclear
Preoperative localization of parathyroid glands is usually done with sestamibi scan, which has a specificity of 90 %. Ultrasonography of the neck is also useful in some patients
Some asymtomatic patients with PHPT may have evidence of reduced bone mass and masked neurocognitive abnormalities. Such patients may benefit from surgery. The indications for surgery in asymptomatic patients have been revised and published [1]. Table 19.2 shows these indications :
Table 19.2
Indications for surgery in asymptomatic primary hyperparathyroidism
Serum Ca2+ level > 1 mg/dL above normal
GFR < 60 ml/min
Reduced bone mineral density (T-score < − 2.5 at any site)
History of fracture
Age < 50 years
Hypercalciuria is deleted from previous indications because it is not considered a risk factor for stone formation
Asymptomatic patients older than 50 years of age should get bone density measurements for 1–2 years with follow-up of renal function and serum Ca2+ levels. Their hydroxyvitamin D level should be maintained > 25 ng/ml
For those who are not surgical candidates or refuse surgery, medical therapy is indicated. Four classes of medications are available:
1.
Ca2+-sensing receptor (CaSR) agonist—cinacalcet. Activation of CaSR inhibits PTH secretion
2.
Bisphosphonates. Many drugs are available, which do not influence PTH secretion, but maintain bone mineral density by inhibiting osteoclast activity
3.
Estrogens and progestins. Many drugs are available, which reduce serum and urinary Ca2+ levels and bone resorption. Adverse effects are major concern for their infrequent use
4.
Selective estrogen modulator—raloxifene. It reduces serum Ca2+ level and bone turnover, but side effects may limit its use
Determination of PTH by appropriate assay is extremely important in patients with PHPT and chronic kidney disease (see Study Questions)
Multiple Endocrine Neoplasia Type 1 and Type 2a
Multiple endocrine neoplasia (MEN) Type 1
Includes tumors of the parathyroid, anterior pituitary, and pancreas
Of these tumors, parathyroid tumors are more prevalent
It is caused by mutations in the tumor suppressor gene encoding menin
Hypercalcemia due to hyperparathyroidism develops in the 2nd and 3rd decades of life. Parathyroidectomy improves hypercalcemia
MEN Type 2a
Includes medullary carcinoma of the thyroid, pheochromocytoma, and hyperparathyroidism due to hyperplasia and adenoma of parathyroid glands
It is caused by mutations in the RET proto-oncogene
Clinically, patients with MEN type 2a-associated hyperparathyroidism behave similarly as patients with PHPT
Removal of the thyroid and/or parathyroid glands improves hyperparathyroidism
Jansen’s Disease
A rare hereditary disorder caused by activating mutations of the gene for PTH receptor. The disease is characterized by dwarfism, hypercalcemia, hypophosphatemia, and metaphyseal chondrodysplasia. It is also called pseudohyperparathyroidism
Familial Hypocalciuric Hypercalcemia
Familial Hypocalciuric Hypercalcemia (FHH) is characterized by mild hypercalcemia, hypermagnesemia, hypocalciuria (calcium/creatinine clearance ratio < 0.01), hypophosphatemia, and normal to slightly elevated PTH levels
Higher Ca2+ levels are needed to inhibit PTH secretion
Patients are always asymptomatic even from childhood to adulthood
FHH is caused by inactivating mutations of CaSR, and is inherited as an autosomal dominant disease
No treatment is necessary for asymptomatic patients with FHH. However, possible parathyroidectomy is considered in adult patients with relapsing pancreatitis, and serum [Ca2+] > 14 mg/dL
Neonatal Severe Hyperparathyroidism
A homozygous form of FHH (born to both parents with FHH) is a disease of life-threatening hypercalcemia with massive hyperplasia of the parathyroid glands. It is a lethal disease unless total parathyroidectomy is done
Renal Failure
Secondary Hyperparathyroidism
Appropriate increase in PTH secretion in response to hypocalcemia is called secondary hyperparathyroidism. It usually occurs in chronic kidney disease (CKD) stages 4–5. Mechanisms include hyperparathyroidism due to hyperplastic parathyroid glands, bone disease, calcium supplements, and vitamin D administration
Tertiary Hyperparathyroidism
Occurs in a subset of CKD patients and following renal transplantation. Hyperparathyroidism persists despite adequate treatment with calcium salts and active vitamin D compounds
Polyclonal parathyroid cell proliferation and monoclonal hypertrophy of adenematous-like tissue, leading to an increase in parathyroid mass and continuous secretion of PTH seems to be the underlying mechanism for hyperparathyroidism
Following renal transplantation, serum Ca2+ levels follow a biphasic pattern with hypocalcemia during the postoperative period followed by hypercalcemia.
Hypercalcemia persists due to slow regression of hyperplastic parathyroid gland and generation of calcitriol by the transplanted kidney. It improves slowly in 6 months
Acute Kidney Injury
Hypercalcemia is seen during the diuretic phase of acute kidney injury (AKI)
Although hypercalcemia is common with rhabdomyolysis, other causes of AKI may also be associated with its development
Mechanisms of hypercalcemia include release of Ca2+ from myonecrosis, improved renal function, synthesis of calcitriol, and bone resorption due to decreased PTH resistance
Milk (Calcium)-Alkali Syndrome
This syndrome was initially described in patients with peptic ulcer disease who consumed calcium salts and milk for many years. With the introduction of new drugs for peptic ulcer disease, the use of calcium salts and milk has decreased substantially. However, calcium salts alone or in combination with vitamin D are being used to prevent and/or treat osteoporosis. Thus, the incidence of milk-alkali syndrome is increasing recently
Since milk is not consumed to prevent peptic ulcer or bone disease, and calcium supplements are recommended, the preferable term may be calcium-alkali syndrome
Calcium-alkali syndrome is characterized by the triad of hypercalcemia, metabolic alkalosis, and some degree of renal insufficiency
The generation and maintenance of hypercalcemia is dependent on several factors: (1) sufficient intake of Ca2+ over several days to weeks with increase in intestinal absorption; (2) decreased glomerular filtration rate (GFR) with decreased filtered load of Ca2+, resulting in hypercalcemia and hypocalciuria; (3) hypercalcemia-induced nephrogenic diabetes insipidus (DI) and volume depletion; and (4) increased renal reabsorption of Ca2+ in the proximal tubule due to volume depletion. The latter two factors with metabolic alkalosis tend to maintain hypercalcemia
It is of interest to note that hypercalcemia develops even in the presence of suppressed PTH and 1,25(OH)2D3
Hydration with normal saline initially will improve both calcium and metabolic alkalosis, but elevated creatinine may persist
Malignancy
Malignancy is the second leading cause of hypercalcemia, which occurs in 20–30 % of patients. The most common malignancy associated with hypercalcemia is the lung (35 %), followed by breast (25 %), hematologic (14 %), and other organs (3–7 %). The mechanisms for malignancy-induced hypercalcemia are classified into four types (Table 19.3) .
Table 19.3
Types of hypercalcemia associated with malignancy
Type
Occurrence (%)
Bone metastases
Causative factors
Associated tumors
Humoral hypercalcemia of malignancy
80
Minimal or absent
PTH-related protein (PTHrP)
Squamous cell cancers (lung, head and neck, esophagus, and cervix), breast cancer, renal cell cancer, ovarian and endometrial cancers, HTLV-associated lymphoma
Local osteolytic hypercalcemia
20
Extensive
Cytokines, PTHrP, chemokines
Breast cancer, multiple myeloma, lymphoma
1,25(OH)2D3 (calcitriol)-secreting lymphomas
< 1
Variable
1,25(OH)2D3
Lymphomas (all types)
Ectopic hyperparathyroidism
< 1
Variable
PTH
Variable
PTH-Related Protein and Hypercalcemia
A major factor that is responsible for hypercalcemia in > 80 % of tumors
PTH-related protein (PTHrP) is similar to PTH because the initial eight amino acids at the N-terminus are identical. In bone, PTHrP interacts with PTH-PTHrP receptor and activates bone resorption. In renal tubules, PTHrP occupies the PTH-PTHrP receptor as well and increases Ca2+ reabsorption. Both of these mechanisms maintain hypercalcemia
PTHrP also causes hypophosphatemia and an increase in urinary excretions of phosphate and cAMP
Circulating levels of PTHrP are negligible in normal individuals, and they are high in Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (HHH)
Unlike PTH, PTHrP reduces 1,25(OH)2D3 production so that GI absorption of Ca2+ is decreased
Cytokines and Hypercalcemia
Many tumors such as breast and prostate cancers as well as hematologic malignancies (multiple myeloma) cause hypercalcemia by generating osteoclast-activating cytokines such as IL-1, IL-6, IL-8, tumor necrosis factor-α (TNF-α), macrophage inflammatory-peptide (chemokine), and PTHrP. These cause bone resorption. PTHrP and the other cytokines induce receptor activator of nuclear factor κB (RANK) ligand, which mediates osteoclast bone resorption with resultant hypercalcemia
1,25(OH)2D3 and Hypercalcemia
All types of lymphoma cells increase 1α-hydroxylase and then conversion of 25-hydroxyvitamin D3 to 1,25(OH)2D3 (calcitriol) . As a result, intestinal Ca2+ absorption is increased. Hypercalcemia results from intestinal and bone resorption of Ca2+
Granulomatous Diseases
Sarcoidosis and other granulomatous diseases, including silicone-induced granulomas secrete 1,25(OH)2D3 with resultant hypercalcemia
Note that 1,25(OH)2D3 may be normal in certain granulomatous diseases
1α-hydroxylase is elevated in those with high 1,25(OH)2D3
Steroids improve hypercalcemia by decreasing 1,25(OH)2D3 levels
Chloroquine and ketoconazole also decrease1,25(OH)2D3 by inhibiting 1α-hydroxylase activity
Vitamin D Intoxication
Doses > 100,000 units/day of 25-hydroxyvitamin D are required to cause hypercalcemia, which is due to intestinal absorption of Ca2+ and 1,25(OH)2D3-induced bone resorption
Thus, most of the cases of vitamin D intoxication are iatrogenic
PTH levels are low and 25(OH)D3 levels are elevated. However, 1,25(OH)2D3 levels may be slightly elevated, low, or normal. Low levels may be due to suppressed 1α-hydroxylase by low PTH and high levels may be related to displacement of calcitriol by weaker vitamin D metabolites from the vitamin D receptors
Discontinuation of vitamin D, hydration, bisphosphonates, and low calcium diet improve hypercalcemia
Clinical Manifeststions
As Ca2+ is needed for functions of all organs, hypercalcemia affects all organ systems. The signs and symptoms of hypercalcemia depend on the severity and rate of rise of Ca2+ levels. Depending on serum Ca2+ levels, hypercalcemia is classified into mild (10.5–11.9 mg/dL), moderate (12–13.9 mg/dL), and severe (> 14 mg/dL) hypercalcemia. Renal and neurologic manifestations worsen with increasing severity of hypercalcemia. Also, a rapid development of mild to moderate hypercalcemia results in severe neurologic dysfunction. In contrast, chronic hypercalcemia may cause minimal neurologic signs and symptoms. Mild hypercalcemia may be asymptomatic in younger individuals, but may have profound effect in the elderly because of preexisting neurologic and cognitive dysfunction. Table 19.4 lists signs and symptoms of hypercalcemia.
Table 19.4
Clinical manifestations of hypercalcemia
General | Weakness, malaise, and tiredness |
Neuromuscular (psychiatric) | Confusion, impaired memory, lethargy, stupor, coma, muscle weakness, and hypotonia |
Cardiac | Short QT interval, arrhythmias, bundle branch blocks, and hypertension
Related posts: Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
Get Clinical Tree app for offline access
|
