If the PTH level is increased (or “inappropriately normal”) in the setting of elevated calcium and low phosphorus, the diagnosis is almost always primary hyperparathyroidism.



Because individuals with FHH(?) may also present with mildly elevated PTH levels and hypercalcemia, this diagnosis should be considered and excluded because parathyroid surgery is ineffective in this condition.

A calcium/creatinine clearance ratio (calculated as urine calcium/serum calcium divided by urine creatinine/serum creatinine) of <0.01 is suggestive of FHH, particularly when there is a family history of mild, asymptomatic hypercalcemia. In addition, sequence analysis of the CaSR gene is now commonly performed for the definitive diagnosis of FHH, although in some families, FHH may be caused by mutations in G proteins that mediate signaling by the CaSR. Ectopic PTH secretion is extremely rare.


Primary Hyperthyroidism

In primary hyperparathyroidism, secretion of PTH is increased and is independent of [Ca2+].

In contrast, in secondary hyperparathyroidism (chronic renal failure or malabsorption), the elevated PTH levels are in response to chronic hypocalcemia. Prolonged secondary hyperparathyroidism, however, can occasionally result in autonomous secretion of PTH, resulting in a normal or elevated [Ca2+] (tertiary hyperparathyroidism).

Mid-upper or minimally elevated (Serum PTH ranging from 35 to 65 pg/mL in an assay whose normal range is 10 to 60 pg/mL.)

Low (<20 pg/ml)


Causes of Hypercalcemia.

  • Malignancy
    • Patients with cancer ( lymphoma)can present with hypercalcemia whether or not bone metastases are present. Most often this is due to direct bony destruction, or secretion of humoral mediators of hypercalcemia (PTH-like substances, cytokines, or prostaglandins), or both.
  • Excessive vitamin D intake
    • hypervitaminosis D
  • Paget’s disease of bone
    • Hypercalcemia due to increased turnover of calcium from bone can also be encountered in patients with benign conditions such as Paget’s disease and chronic immobilization.
  • Granulomatous disorders (sarcoidosis, tuberculosis) due to (enhanced sensitivity to vitamin D. Serum 1,25(OH)2D levels are increased in granulomatous disorders
  • Chronic immobilization
  • Milk-alkali syndrome
    • Increased gastrointestinal absorption of calcium can lead to hypercalcemia in patients with the milk-alkali syndrome (marked increase in calcium intake),
  • Adrenal insufficiency
  • Drug-induced
    • Thiazide diuretics
    • Lithium

A suppressed PTH level in the face of hypercalcemia is consistent with non-parathyroid-mediated hypercalcemia, most often due to underlying malignancy. Although a tumor that causes hypercalcemia is generally overt, a PTHrP level may be needed to establish the diagnosis of hypercalcemia of malignancy.


[Hypertension is often present initially before hypovolemia supervenes. ECG signs include a shortened ST segment and a shortened QT interval. Hypercalcemia increases cardiac sensitivity to digitalis. Pancreatitis, peptic ulcer disease, and kidney failure may also complicate hypercalcemia.}

Acidosis should be avoided so as to not worsen the elevated plasma [Ca2+].

Parathyroid mediated
Primary hyperparathyroidism (sporadic)
Inherited variants
Multiple endocrine neoplasia (MEN) syndromes
Familial isolated hyperparathyroidism
Hyperparathyroidism-jaw tumor syndrome
Familial hypocalciuric hypercalcemia
Tertiary hyperparathyroidism (renal failure)
Non-parathyroid mediated
Hypercalcemia of malignancy
Activation of extrarenal 1 alpha-hydroxylase (increased calcitriol)
Osteolytic bone metastases and local cytokines
Vitamin D intoxication
Chronic granulomatous disorders
Activation of extrarenal 1 alpha-hydroxylase (increased calcitriol)
Thiazide diuretics
Excessive vitamin A
Theophylline toxicity
Adrenal insufficiency
Parenteral nutrition
Milk alkali syndrome
PTHrp: PTH-related peptide.


The causes of hypercalcemia can be understood and classified based on derangements in the normal feedback mechanisms that regulate serum calcium.

1. Excessive PTH production

Primary hyperparathyroidism (adenoma, hyperplasia, rarely carcinoma)

Tertiary hyperparathyroidism (long-term stimulation of PTH secretion in renal insufficiency)

Ectopic PTH secretion (very rare)

Inactivating mutations in the CaSR or in G proteins (FHH)

Alterations in CaSR function (lithium therapy)

Hypercalcemia of malignancy
 Overproduction of PTHrP (many solid tumors)
Cancer that started in the bone (Osteosarcoma),  

Lytic skeletal metastases (breast, myeloma)

Excessive 1,25(OH)2D production
 Granulomatous diseases (sarcoidosis, tuberculosis, silicosis)
 Vitamin D intoxication


Primary increase in bone resorption
Excessive calcium intake
 Milk-alkali syndrome
 Total parenteral nutrition
Other causes
 Endocrine disorders (adrenal insufficiency, pheochromocytoma, VIPoma)
 Medications (thiazides, vitamin A, antiestrogens)



  • Abbreviations: CaSR, calcium sensor receptor; FHH, familial hypocalciuric hypercalcemia; PTH, parathyroid hormone; PTHrP, PTH-related peptide.

    Excess PTH production, which is not appropriately suppressed by increased serum calcium concentrations, occurs in primary neoplastic disorders of the parathyroid glands (parathyroid adenomas; hyperplasia; or, rarely, carcinoma) that are associated with increased parathyroid cell mass and impaired feedback inhibition by calcium. Inappropriate PTH secretion for the ambient level of serum calcium also occurs with heterozygous inactivating calcium sensor receptor (CaSR) or G protein mutations, which impair extracellular calcium sensing by the parathyroid glands and the kidneys, resulting in familial hypocalciuric hypercalcemia (FHH). Although PTH secretion by tumors is extremely rare, many solid tumors produce PTH-related peptide (PTHrP), which shares homology with PTH in the first 13 amino acids and binds the PTH receptor, thus mimicking effects of PTH on bone and the kidney. In PTHrP-mediated hypercalcemia of malignancy, PTH levels are suppressed by the high serum calcium levels. Hypercalcemia associated with granulomatous disease (e.g., sarcoidosis) or lymphomas is caused by enhanced conversion of 25(OH)D to the potent 1,25(OH)2D. In these disorders, 1,25(OH)2D enhances intestinal calcium absorption, resulting in hypercalcemia and suppressed PTH. Disorders that directly increase calcium mobilization from bone, such as hyperthyroidism or osteolytic metastases, also lead to hypercalcemia with suppressed PTH secretion as does exogenous calcium overload, as in milk-alkali syndrome, or total parenteral nutrition with excessive calcium supplementation.
  • Paget's disease of the bone.
  • Some medications cause hypercalcemia such as: alkaline antacids, diethylstilbesterol (DES), long-term use of diuretics, estrogens and progesterone.








 Increases in PTH are often accompanied by hypophosphatemia.

In addition, serum creatinine should be measured to assess renal function; hypercalcemia may impair renal function, and renal clearance of PTH may be altered depending on the fragments detected by the assay.



Content 3

Content 13

A 70-year-old woman is brought to the emergency department with right flank pain, nausea, vomiting, and blood in her urine. She has no fever. She has recurrent kidney stones, vague abdominal pain, muscle weakness, and atrophy.

On examination, she is in moderate distress secondary to her flank pain. Other than right back pain, her physical examination is normal. Urinalysis reveals large amounts of blood but no signs of infection. An intravenous pyelogram (IVP) is performed and reveals numerous kidney stones. A metabolic panel shows an extremely elevated calcium level. Further workup demonstrates that the patient has hyperparathyroidism from a parathyroid adenoma.

Summary: A 70-year-old woman who presents to the emergency department with kidney stones, abdominal pain, and muscle weakness is found to have hyperparathyroidism.


How does parathyroid hormone (PTH) increase intestinal calcium absorption?

  • PTH Increases absorption by increasing the production of 1,25-dihydroxycholecalciferol (1 α-hydroxylase activity is increased).

What effect do elevated levels of PTH have on renal phosphate reabsorption?

What are three factors that increase the activity of 1 α-hydroxylase in the kidney?

Answers to Case 38: Calcium Metabolism



  • Elevated levels of PTH and effect on phosphate: Inhibits renal phosphate reabsorption in proximal tubule, resulting in phosphate excretion.

  • Three factors that increase 1 α-hydroxylase activity: Increased PTH, decreased serum calcium and phosphate levels.

Clinical Correlation

Hypercalcemia can be caused by a variety of conditions, including those which increase calcium absorption (milk-alkali syndrome), decrease calcium excretion (thiazide use), increase mobilization of the bone (hyperparathyroidism), and involve metastatic cancer (breast, prostate, etc.). A patient's symptoms depend on the level of hypercalcemia. With a mild elevation, a patient may be asymptomatic. With increasing levels, patients may have constipation, anorexia, nausea, vomiting, abdominal pain, nephrolithiasis, renal failure, emotional lability, confusion, psychosis, or coma.


Question 1 of 10

A 43-year-old male is admitted to the emergency room for severe pain in his left flank, radiating to the groin. The pain is intermittent and initiated after running a marathon on a hot summer day. The patient is asked for a urine specimen and blood is detected in the urine. He is hydrated, and additional diagnostic procedures are done. Laboratory values show serum Ca2+of 12 mg/dL, and PTH values of 130 pg/mL. Which of the following findings would be predictable in this patient?

The correct answer is B.

The precipitating factor in this young otherwise healthy patient is dehydration. He has high parathyroid hormone (PTH) levels (probably a problem that had been ongoing). High PTH is associated with increased bone resorption resulting in increased serum calcium (and consequently filtered calcium), which with dehydration, precipitated and formed kidney stones (reason for the pain and the blood in the urine when he passed them). You would expect low serum inorganic phosphate (Pi) because PTH promotes Pi excretion. High PTH would stimulate vitamin D synthesis and thus intestinal calcium absorption. The urinary calcium excretion likely reflects a reabsorption process that has been overwhelmed by the excess calcium filtered. The increase in bone resorption and turnover would be expected to be associated with increased serum alkaline phosphatase.



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