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The Parathyroid Glands, Hypercalcemia, and Hypocalcemia
Calcium Metabolism
A healthy adult body has a total of 1 kg of calcium, about 99% of which is within the crystal structure of bone mineral and less than 1% of which is in soluble form in the extracellular and intracellular fluid compartments. In the extracellular fluid compartment, about half of the total calcium is ionized, and the remainder is principally bound to albumin or complexed with counter-ions. Ionized calcium in the extracellular fluid plays an important role in many physiologic pathways, including muscle contraction, secretion of neurotransmitters and hormones, and coagulation pathways. The total serum calcium concentration ranges from 8.5 to 10.5 mg/dL (2.12 to 2.62 mmol/L), whereas ionized serum calcium concentrations range from 4.65 to 5.25 mg/dL (1.16 to 1.31 mmol/L). However, the usual 2 : 1 ratio of total to ionized calcium may be disturbed by disorders such as metabolic acidosis ( Chapter 104 ), which reduces calcium binding by proteins, or by changes in protein concentration, caused by cirrhosis ( Chapter 139 ), dehydration, venous stasis ( Chapter 68 ), or multiple myeloma ( Chapter 167 ). As a result, the total serum calcium concentrations may need to be adjusted, or “corrected,” to a reference albumin concentration by adding or subtracting 0.8 mg/dL (0.016 mmol/L) for every 1 g/dL (1 g/L) of albumin below or above the reference albumin concentration of 4 g/dL.
The control of body calcium involves a balance between the amounts that are absorbed from the gut, deposited into bone and into cells, and excreted from the kidney ( Fig. 227-1 ). This fine balance, which involves three organs, is chiefly under the control of parathyroid hormone (PTH), which is synthesized and secreted by the parathyroid glands. Hypocalcemia leads to an increased secretion of PTH, whereas hypercalcemia results in diminished secretion of PTH. Regulation of extracellular calcium takes place through complex interactions ( E-Fig. 227-1 ) at the target organs of the major calcium-regulating hormone, PTH, and vitamin D and its active metabolites, 1,25-dihydroxyvitamin D (1,25[OH] 2 D), which is also referred to as calcitriol.
Parathyroid Glands and Parathyroid Hormone
Humans usually have four parathyroid glands, which are located in close proximity to the superior and inferior poles of the lobes of the thyroid gland. The superior parathyroids are derived from the endoderm of the embryonic fourth pharyngeal pouches, and the inferior parathyroids are derived with the thymus from the endoderm of the third pharyngeal pouches. Extra parathyroid glands, which may be present in 3 to 5% of the population, are commonly found in aberrant locations along this migrating path and also within the thymus and thyroid.
Parathyroid cells express a G protein–coupled receptor (GPCR), referred to as the calcium-sensing receptor, that detects changes in extracellular calcium and leads to alterations in the secretions of PTH. For example, activation of the calcium-sensing receptor, which is also expressed in renal tubular cells as a result of elevated extracellular calcium concentrations, causes G protein–dependent stimulation of phospholipase C activity, which in turn leads to accumulation of inositol 1,4,5-trisphosphate and an increase in intracellular calcium concentrations. These changes then lead to reduced circulating concentrations of PTH and increased urinary excretion of calcium. Disorders of the parathyroid glands may cause hypercalcemia or hypocalcemia, which can be classified according to whether they arise from an excess of PTH, its deficiency, or insensitivity to its effects ( Table 227-1 ; see E-Fig. 227-1 ).
TABLE 227-1
PARATHYROID DISEASES AND THEIR CHROMOSOMAL LOCATIONS
| METABOLIC ABNORMALITY | DISEASE | INHERITANCE | GENE/GENE PRODUCT | CHROMOSOMAL LOCATION |
|---|---|---|---|---|
| HYPERCALCEMIA | ||||
| Multiple endocrine neoplasia type 1 | Autosomal dominant | Menin | 11q13 | |
| Multiple endocrine neoplasia types 2 and 3 | Autosomal dominant | RET | 10q11.2 | |
| Multiple endocrine neoplasia type 4 | Autosomal dominant | CDNK1B | 12p13.1 | |
| Hereditary hyperparathyroidism and jaw tumors (HPT-JT) | Autosomal dominant | CDC73 Parafibromin |
1q31.2 | |
| Familial isolated hyperparathyroidism | Autosomal dominant | Menin, CDC73, CaSR GCM2 |
11q13, 1q31.2, 3q21.1, 6p24.2 | |
| Sporadic hyperparathyroidism | Sporadic | PRAD1/CCND1, PTH Retinoblastoma Unknown |
11q13, 11p15 13q14 1p32-pter |
|
| Parathyroid carcinoma | Autosomal dominant or sporadic | Parafibromin Retinoblastoma |
1q31.2 13q14 |
|
| Familial benign hypercalcemia (FBH) | ||||
| FBH1 | Autosomal dominant | CaSR | 3q 21.1 | |
| FBH2 | Autosomal dominant | Gα11 | 19p13 | |
| FBH3 | Autosomal dominant | AP2S1 | 19q13 | |
| Neonatal severe hyperparathyroidism (NSHPT) | Autosomal recessive or autosomal dominant | CaSR | 3q21.1 | |
| Jansen disease | Autosomal dominant | PTHR/PTHrP receptor | 3p21.3 | |
| Williams syndrome | Autosomal dominant | Elastin, LIMK (and other genes) | 7q11.23 | |
| Infantile hypercalcemia | Autosomal recessive | CYP24A1, SLC34A1 | 20q13.2-q13.3, 5q35 | |
| McCune-Albright syndrome | Mutations during early embryonic development? | Gsα | 20q13.3 | |
| HYPOCALCEMIA | ||||
| Isolated hypoparathyroidism | Autosomal dominant Autosomal recessive X-linked recessive |
PTH, GCM2 PTH, GCM2 SOX3 |
11p15 ∗ 11p15 ∗ , 6p24.2Xq26–27 | |
| Autosomal dominant hypocalcemia type 1 (ADH1) | Autosomal dominant | CaSR | 3q21.1 | |
| Autosomal dominant hypocalcemia type 2 (ADH2) | Autosomal dominant | Gα11 | 19p13 | |
| Hypoparathyroidism associated with polyglandular autoimmune syndrome (APECED) | Autosomal recessive | AIRE-1 | 21q22.3 | |
| Hypoparathyroidism associated with Kearns-Sayre and MELAS | Maternal | Mitochondrial genome | ||
| Hypoparathyroidism associated with complex congenital syndromes | ||||
| DiGeorge syndrome type 1 | Autosomal dominant | TBX1 | 22q11.2 | |
| DiGeorge syndrome type 2 | Autosomal dominant | NEBL | 10p14.p13 | |
| CHARGE | Autosomal dominant | CHD7, SEMA3E | 8q12.1-12.2, 7q21.11 | |
| HDR syndrome | Autosomal dominant | GATA3 | 10p15 | |
| Blomstrand lethal chondrodysplasia | Autosomal recessive | PTHR/PTHrP receptor | 3p21.3 | |
| Kenney-Caffey syndrome type 1, Sanjad-Sakati syndrome | Autosomal dominant | TBCE | 1q42.3 | |
| Kenney-Caffey syndrome type 2 | Autosomal recessive | FAMIIIA | 11q12.1 | |
| Barakat syndrome | Autosomal recessive † | Unknown | ? | |
| Lymphedema | Autosomal recessive | Unknown | ? | |
| Nephropathy, nerve deafness | Autosomal dominant † | Unknown | ? | |
| Nerve deafness without renal dysplasia | Autosomal dominant | Unknown? | ? | |
| Pseudohypoparathyroidism (type 1a) | Autosomal dominant parentally imprinted | GNAS exons 1-3 | 20q13.3 | |
| Pseudohypoparathyroidism (type 1b) | Autosomal dominant parentally imprinted | GNAS Upstream deletion | 20q13.3 | |
| Acrodysostosis with hormonal resistance | Autosomal dominant | PRKAR1A | 17q23-24 | |
CHARGE = coloboma-heart anomaly atresia-retardation-genital-ear; HDR = hypoparathyroidism, deafness, and renal dysplasia; MELAS = mitochondrial encephalopathy, stroke-like episodes, and lactic acidosis; ? = location not known.
∗ Mutations of PTH gene are identified only in some families.
In chronic renal insufficiency, uremia ( Chapter 116 ) with low serum calcium levels and elevations in serum phosphate levels, secretion of PTH increases. This physiologic secondary hyperparathyroidism in response to hypocalcemia can progress to become an independent parathyroid adenoma—defined as tertiary hyperparathyroidism (see Chronic Hyperparathyroidism).
Parathyroid Hormone and PTH Gene
PTH is an 84–amino acid peptide encoded by the PTH gene, which is located on chromosome 11p15. The mature PTH peptide is secreted from the parathyroid chief cells as an 84–amino acid peptide; however, when the PTH mRNA is first translated, it is as pre-proPTH peptide. The “pre” sequence consists of a 25–amino acid signal peptide (leader sequence) that is responsible for directing the nascent peptide into the endoplasmic reticulum to be packaged for secretion from the cell. The “pro” sequence is 6 amino acids in length and is also essential for correct processing and secretion of PTH. After the 84–amino acid mature PTH peptide is secreted from the parathyroid cell, it is cleared from the circulation by nonsaturable hepatic uptake and renal excretion, with a short half-life of about 2 minutes.
Actions of Parathyroid Hormone
PTH and PTH-related peptide (PTHrP) share a GPCR (see E-Fig. 227-1 ), which predominantly is expressed in kidney and bone, where it enhances renal calcium reabsorption, releases stored calcium from bones into the extracellular fluid, and also acts indirectly on intestinal cells (see later) to increase calcium absorption in the gut. Expression of the PTH/PTHrP receptor also occurs in the brain, heart, skin, lung, liver, and testis, where it mediates the actions of PTHrP. Mutations involving the genes that encode these proteins and receptors in this calcium-regulating pathway (see E-Fig. 227-1 ) are associated with hypercalcemic and hypocalcemic disorders (see Table 227-1 ).
Renal Actions
Calcium is absorbed by the kidneys at multiple sites along the renal tubule and by different mechanisms, including passive paracellular or active transcellular transport. The renal actions of PTH are to: stimulate activity of the proximal tubular cell 1α-hydroxylase; increase reabsorption of calcium by the cells of the distal tubule, connecting tubules, and the thick ascending loop of Henle; and inhibit phosphate reabsorption by proximal tubular cells (see Fig. 227-1 ). PTH increases the formation of biologically active 1,25(OH) 2 D from its precursor 25-OH-D by stimulating the activity of the renal 1α-hydroxylase and inhibiting the 24-hydroxylase, which metabolizes 1,25(OH) 2 D to the inactive 24,25(OH) 2 D form (see Fig. 227-1 ). PTH regulates calcium reabsorption by distal tubular cells by upregulating expression of the transient receptor potential vanilloid 5 (TRPV5), thereby promoting calcium entry into the cell and increasing calbindin-D28K expression to enhance transcellular calcium reabsorption by increased buffering of subapical Ca 2+ ions. In the thick ascending loop of Henle, PTH may increase the active transcellular transport of calcium and the paracellular transport of calcium by augmenting the transepithelial voltage gradient. Phosphate transport in proximal tubular cells is mediated by the luminal membrane sodium-phosphate cotransporters 2a and 2c (NPT2a and NPT2c), and PTH actions lead to internalization and degradation of NPT2a and NPT2c, thereby resulting in decreased reabsorption of phosphate.
Skeletal Actions
PTH acts directly on osteoblasts and indirectly on osteoclasts to increase their numbers and activity, thereby enhancing bone turnover and the release of stored calcium. PTH increases the size of the osteoblast precursor pool, increases the bone-forming activity of mature osteoblasts, and stimulates osteoblasts to release cytokines such as colony-stimulating factor 1 and receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL), which stimulate the formation of new osteoclasts and activate mature osteoclasts. PTH also inhibits the production of osteoprotegerin, which is a decoy receptor that binds to RANKL and thereby inhibits the development of osteoblasts. The net result of persistent elevations of PTH is an increase in osteoclast activity more than osteoblast activity, thereby liberating the stores of calcium from bone into the extracellular fluid (see Fig. 227-1 ).
Intestinal Actions
Calcium is absorbed throughout the intestine by passive paracellular routes and active transcellular routes. PTH exerts indirect actions on intestinal calcium absorption by increasing the circulating 1,25(OH) 2 D concentrations (see Fig. 227-1 ). The increased 1,25(OH) 2 D concentrations facilitate enhanced calcium entry into the cell from the lumen, thereby facilitating transcellular transport of calcium.
Hypercalcemia
Definition
Hypercalcemia is defined as a serum calcium concentration greater than 2 standard deviations above the normal mean, which is usually a total serum calcium above 10.5 mg/dL (2.62 mmol/L) and an ionized serum calcium of above 5.25 mg/dL (1.31 mmol/L). No formal grading system defines the severity of hypercalcemia, but mild, moderate, and severe hypercalcemia are generally considered for total serum calcium concentrations less than 12 mg/dL (3 mmol/L), between 12 and 14 mg/dL (3 to 3.5 mmol/L), and greater than 14 mg/dL (3.50 mmol/L), respectively.
Epidemiology
The prevalence of hypercalcemia has been reported as 1% to 2% in the general population and about 2 to 5% in hospitalized patients.
Pathobiology
Hypercalcemia may arise through one of three mechanisms: increased bone resorption, increased gastrointestinal absorption of calcium, and decreased renal calcium excretion (see Fig. 227-1 ). For example, lytic bone metastases cause increased bone resorption; thiazide diuretics lead to a decrease in calcium excretion; and excessive PTH will either directly or indirectly increase the production of 1,25(OH) 2 D and stimulate bone resorption and calcium absorption from the gut and renal tubules. The causes of hypercalcemia may be classified according to whether serum PTH concentrations are elevated (i.e., primary or tertiary hyperparathyroidism due to parathyroid tumors) or reduced (i.e., not due to parathyroid tumors but instead to an excessive production of PTHrP by lytic bone metastases, multiple myeloma, drugs, or an altered set point in the calcium-sensing receptor ; see E-Fig. 227-1 ). In secondary hyperparathyroidism, by comparison, PTH levels are increased in response to a low serum calcium level (usually due to chronic renal failure or vitamin D deficiency) and, by definition, the patient cannot have hypercalcemia.
Clinical Manifestations
In developed countries, the clinical presentation of hypercalcemia is most commonly as an asymptomatic, biochemical abnormality detected during routine screening. However, it also can present as a life-threatening medical emergency, especially in developing countries and in patients with cancer ( Chapter 164 ). In general, the presence or absence of symptoms correlates with the severity of the hypercalcemia. Symptoms do not usually develop when serum calcium is below 12 mg/dL (3 mmol/L) and are nearly invariably present when the hypercalcemia exceeds 14 mg/dL (3.5 mmol/L). However, there is considerable variability, in part dependent on the rapidity of onset of mild to moderate hypercalcemia. The signs and symptoms of hypercalcemia ( Table 227-2 ) are similar, regardless of etiology. The clinical manifestations can involve the renal, musculoskeletal, gastrointestinal, neurologic, and cardiac systems, and many of these have been referred to as “moans, groans, pains, and stones.”
TABLE 227-2
CLINICAL FEATURES OF HYPERCALCEMIA
Renal
Musculoskeletal
Gastrointestinal
Neurologic
Cardiac
|
Diagnosis
Investigations should be directed at confirming the presence of hypercalcemia and establishing the cause ( Fig. 227-2 ). Hypercalcemia can be caused by a number of conditions ( Table 227-3 , and a careful initial evaluation ( Table 227-4 ) is key. Primary hyperparathyroidism and malignancy, which are the most common causes, account for more than 90% of patients with hypercalcemia. Detailed clinical history and examination will usually help to differentiate between these two diagnoses. In primary hyperparathyroidism, the hypercalcemia is often less than 12 mg/dL (3 mmol/L), asymptomatic, and may have been present for months or years. If symptoms, such as nephrolithiasis ( Chapter 111 ), are noted, then hypercalcemia usually has been present for at least several months. In malignancy, however, patients are usually acutely ill, often with neurologic symptoms; the hypercalcemia is more than 12 mg/dL (3 mmol/L), and the cancer (e.g., lung, breast, or myeloma) is often readily apparent. If bone metastases or chronic renal failure are the cause, the serum phosphate level is typically elevated, whereas it is normal or low when the PTH level is elevated. Hypercalcemia from other causes is usually suggested by a careful history (e.g., for vitamin D ingestion, drugs, renal disease) and physical examination (e.g., for thyrotoxicosis, adrenal disease, granulomatous diseases). However, appropriate laboratory investigations (see Table 227-4 and Fig. 227-2 ), are essential for establishing the diagnosis.
TABLE 227-3
CAUSES OF HYPERCALCEMIA
| HIGH PARATHYROID HORMONE LEVELS |
| Primary hyperparathyroidism ∗ (adenoma, hyperplasia, or carcinoma): nonfamilial or familial, e.g., MEN 1, MEN 2, HPT-JT, FIHP Tertiary hyperparathyroidism (hyperplasia or adenoma in chronic renal failure) |
| LOW PARATHYROID HORMONE LEVELS |
Malignancy ∗
Excess vitamin D
Drugs
Nonparathyroid endocrine disorders
|
| INAPPROPRIATE PARATHYROID HORMONE LEVELS DUE TO ALTERED SET POINT |
| Familial benign hypocalciuric hypercalcemia (FBH or FHH) types 1-3 |
FIHP = familial isolated hyperparathyroidism; HIV = human immunodeficiency virus; HPT-JT = hyperparathyroidism with jaw tumors; MEN = multiple endocrine neoplasia; TB = tuberculosis.
TABLE 227-4
INITIAL INVESTIGATIONS FOR HYPERCALCEMIA
| BLOOD |
| × 2-3 estimations of serum calcium, phosphate, albumin, urea and electrolytes, creatinine, alkaline phosphatase, liver function tests Parathyroid hormone Complete blood count Electrophoretic protein strip, serum protein electrophoresis, or immunofixation 25-OH-D 3 (and if indicated, 1,25[OH] 2 D 3 ) Thyroid function tests Magnesium Parathyroid hormone–related peptide (if malignancy suspected) |
| URINE |
| × 2-3 estimations of 24-hr urinary calcium and creatinine clearance, and clearance ratios Imaging
|
Treatment
The treatment of hypercalcemia depends on the severity of the hypercalcemia and the presence of symptoms. Asymptomatic patients with mild hypercalcemia do not usually need urgent treatment, patients with severe hypercalcemia require treatment regardless of symptoms, and patients with moderate hypercalcemia require urgent treatment if symptomatic.
Before instituting treatment, it is always important to consider the underlying causes (see Table 227-3 ) and to initiate investigations (see Table 227-4 ). In addition, drugs such as thiazides and vitamin D compounds, which cause hypercalcemia, should be discontinued and dietary calcium intake should be restricted.
Symptomatic Hypercalcemia
Dehydration owing to hypercalcemic symptoms (e.g., anorexia, nausea, vomiting, and polyuria because of defective urinary concentration) is very common, so the acute management of symptomatic hypercalcemia involves hydration and calcium diuresis, as well as specific measures using drugs to lower the serum calcium level. Saline, which enhances urinary calcium excretion by increasing glomerular filtration and reducing the proximal and distal renal tubular reabsorption of calcium and sodium, is given as required (5 to 10 L of 0.9% sodium chloride over a 24- to 48-hour period). This vigorous saline hydration, which may lower serum calcium by 1 to 3 mg/dL (0.25 to 0.75 mmol/L), may need to be combined with a loop diuretic (e.g., furosemide, 10 to 20 mg) as necessary to avoid or control complications due to volume overload, especially in elderly patients and patients who have impaired cardiovascular and renal function. The furosemide must be used carefully to avoid exacerbating volume depletion, thereby worsening the hypercalcemia. Saline diuresis may lead to hypokalemia, hypomagnesemia, and electrolyte imbalance, so these parameters must be monitored and corrected as needed.
If saline diuresis is not successful, particularly if the hypercalcemia is very severe, then more specific drugs will be required. The drugs of choice are zoledronic acid (4 mg as a single IV infusion) or pamidronate (15 to 60 mg, depending on the serum calcium concentration, in a single IV infusion or in divided doses, depending upon renal function and responses, over 2 to 4 days; maximum of 90 mg per treatment course). However, these agents should not be used if the hypercalcemia is due to primary or tertiary hyperparathyroidism; such patients ideally should be referred for surgical removal of their parathyroid tumors. Glucocorticoid therapy (e.g., hydrocortisone, 120 mg/day in three divided doses, in adults) is particularly effective when the hypercalcemia is mediated by the actions of 1,25(OH) 2 D, for example in granulomatous disease, lymphoma, or myeloma. Dialysis using a low or zero calcium dialysate should be considered if these treatments are not effective or if the patient has renal failure. When the acute management of hypercalcemia has been completed, appropriate treatment for the underlying cause must be undertaken.
Specific causes of hypercalcemia
Hyperparathyroidism
Definition
Hyperparathyroidism, which is characterized by high concentrations of serum immunoreactive PTH, can be classified as primary, secondary, or tertiary. Primary and tertiary hyperparathyroidism are essentially always associated with hypercalcemia (see Table 227-3 ). By comparison, secondary hyperparathyroidism, which is a physiological response to hypocalcemia, by definition is not associated with hypercalcemia; it may resolve when the hypocalcemia is corrected, or it may progress to tertiary hyperparathyroidism, which usually arises in association with chronic renal failure (see later).
A normocalcemic form of primary hyperparathyroidism is characterized by a normal serum calcium concentration in association with an elevated intact PTH level on at least two consecutive occasions over 3 to 6 months in the absence of any cause of secondary hyperparathyroidism. The prevalence of normocalcemic hyperparathyroidism is reported to be less than 0.2% among persons who undergo assessment of bone mineral density. The serum calcium level may remain normal, or this condition may sometimes be a prelude to the development of primary hyperparathyroidism.
Primary hyperparathyroidism usually occurs as an isolated nonsyndromic endocrinopathy and less commonly as part of complex syndromic disorders such as multiple endocrine neoplasia (MEN; Chapter 212 ) and hyperparathyroidism with jaw tumors. Syndromic and nonsyndromic forms of primary hyperparathyroidism may also occur as hereditary (i.e., familial) disorders, or as nonfamilial (i.e., sporadic) diseases.
Primary Hyperparathyroidism
Epidemiology
Primary hyperparathyroidism, which affects 3 in 1000 adults, is one of the two most common causes of hypercalcemia and is due to an excessive secretion of PTH from a parathyroid adenoma, parathyroid hyperplasia, or rarely, a parathyroid carcinoma. Studies have estimated that the global prevalence of parathyroid tumors is 4 million. Primary hyperparathyroidism usually occurs as a nonsyndromic isolated endocrinopathy between the ages of 40 and 65 years, and it is three times more common in females than males.
Pathobiology
Eighty percent of patients with primary hyperparathyroidism will have a solitary parathyroid adenoma, and 15 to 20% of patients will have hyperplasia involving all four parathyroid glands. Parathyroid carcinoma occurs in less than 0.5% of patients with primary hyperparathyroidism. The underlying causes of primary hyperparathyroidism are largely unknown. However, more than 10% of patients with clinically nonfamilial primary hyperparathyroidism occurring before 45 years of age have a germline mutation in 1 of 12 genes, including those of MEN 1 ( MEN1 ), cell division cycle 73 ( CDC73 ), and calcium-sensing receptor ( CaSR) . In addition, studies of nonfamilial sporadic parathyroid adenomas have shown that 35 to 50% have somatic mutation of the MEN1 gene; 15% have overexpression of cyclin D1; and more than 85% have an abnormality of the Wnt/β-catenin pathway.
Clinical Manifestations
Most patients with primary hyperparathyroidism have mild, asymptomatic hypercalcemia, detected by chance at the time of biochemical screening for other reasons. However, nearly 50% of these patients may have subtle neuromuscular symptoms, such as fatigue and weakness, that become apparent only in retrospect after a successful parathyroidectomy.
Symptomatic hypercalcemia (see Table 227-2 ) predominantly affects the skeletal, renal, and gastrointestinal systems. Because of early diagnosis, the classic skeletal changes of osteitis fibrosa cystica due to subperiosteal resorption of the distal phalanges, tapering of the distal clavicles, a salt-and-pepper appearance of the skull, bone cysts, and brown tumors of the long bones are now identified in less than 5% of patients. However, osteopenia, as assessed by bone mineral density, occurs in 25% of patients, primarily of the cortical bone (e.g., distal third of forearm) rather than the cancellous bone (e.g., lumbar spine). The hip bones, which are an equal mixture of cortical and cancellous bone, show intermediate reductions in bone mineral density. Overall, however, the risk for bone fractures in patients with mild primary hyperparathyroidism is similar to those in matched, normal controls. Renal stone disease (nephrolithiasis [ Chapter 111 ] and nephrocalcinosis) occurs in 20% of patients, hypercalciuria occurs in 30% of patients, and renal impairment also can occur. The gastrointestinal manifestations include peptic ulcers ( Chapter 125 ) and pancreatitis ( Chapter 130 ).
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