Etiology:
90% of hypercalcemia cases are caused by hyperparathyroidism (HPT) & malignancy. Other less common, but more interesting causes, include granulomatous disorders, thiazide use, vitamin A toxicity, and William-Beuren syndrome.

It occurs in about 1-2% of the population, and is usually asymptomatic, unless it is severe or the onset is acute.

Signs and symptoms:
The severity of symptoms are related to how fast the condition develops, rather than the degree of hypercalcemia. Therefore, it is not uncommon for a fairly high, but chronic hypercalcemia to be asymptomatic, but a relatively moderate, yet acute hypercalcemia to cause symptoms.

Signs and symptoms of hypercalcemia are usually combined in the mnemonic "groans bones stones moans thrones psychic overtones":
• Groans: Gastrointestinal symptoms like pain, nausea, and vomiting. Hypercalcemia can lead to peptic ulcer disease and pancreatitis.

• Bones: Bone related complications like bone pain. Hypercalcemia can lead to osteoporosis, osteomalacia, arthritis and pathological fractures.

• Stones: Renal stones causing pain.

• Moans: Refers to fatigue and malaise.

• Thrones: Polyuria, polydipsia, and constipation (sitting on the toilet as you are sitting on a throne).

• Psychic overtones: Lethargy, confusion, depression and memory loss.

Hypercalcemia also causes muscle weakness and ECG changes: prolonged PR interval, short QT interval, widened QRS complex, and bradycardia.

Prognosis:
The prognosis of hypercalcemia due to HPT is very good, and is curable and treatable.
But hypercalcemia due to malignancy is a very poor prognostic sign, and usually indicates less than 6 months survival.

Treatment:
• treating the underlying cause is the most effective way. In the case of primary HPT, this is either done with surgical removal of the pathological gland, or the use of cinacalcet (which reduces parathyroid hormone secretion).
• since too much calcium causes water loss and dehydration (because it decreases sodium reabsorption in the kidneys), the patient should be rehydrated with normal saline.
• after correcting the dehydration, use loop diuretics to decrease calcium levels.

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hypercalcemia and granulomatous diseases:

Macrophages and giant cells express high levels of 1α-hydroxylase, an enzyme that catalyzes the hydroxylation of 25-OH vitamin D to its active form, 1,25-(OH)2 vitamin D.

Granulomatous disorders (like sarcoidosis and TB) are characterized by the presence of granulomas which contain large numbers of macrophages and giant cells that lead to the overproduction of 1α-hydroxylase which is held responsible for the development of hypercalcemia in sarcoidosis patients.

Hyperparathyroidism (HPT) is divided to:

• Primary HPT: caused by excessive production of PT hormone from the PT gland. Most cases are due to a benign adenoma, only rarely it is caused by a malignant carcinoma.

• Secondary HPT: excessive PT hormone production in response to hypocalcemia (usually due to CKD, or vitamin D deficiency).

• Tertiary HPT: it's a result of long-standing secondary HPT in which the excessively high levels of PT hormone persist even after correcting the hypocalcemia.

This is caused by either of two mechanisms:

1. Humoral: in which the tumor (most commonly squamous cell, and renal carcinoma) produces something called parathyroid-related peptide (PTrP). You can guess what PTrP does from the name.

2. Bony metastasis: in which the cancer directly invades and erodes the bone (by producing osteoclast-activating factors) and thereby increasing the serum calcium levels.

To distinguish humoral hypercalcemia of malignancy (HHM) from HPT, all you need to do is to measure the level of PT hormone in the patient:

• if PT hormone is high, then it's HPT.
• if PT hormone is low or normal, then it's HHM (because HHM releases PTrP, not PT hormone).

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They are the most common cancers in infancy, and the most common extracranial cancers in childhood.
They are usually diagnosed before 5 years of age, and are classified into 3 subtypes:

• Neuroblastoma (malignant).
• Ganglioneuroblastoma (intermediate).
• Ganglioneuroma (benign).

MEN syndrome
(Multiple Endocrine Neoplasia syndrome)