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There are three types of hyperparathyroidism and should be differentiated between each other. Hyperparathyroidism should be differeniated from other causes of hypercalcemia. Causes of hypercalcemia include:

  • Parathyroid related
    • Primary hyperparathyroidism
      • Typical primary hyperparathyroidism
      • Familial hypocalciuric hypercalcemia
    • Secondary hyperparathyroidism
    • Tertiary hyperparathyroidism
  • Non-parathyroid related
    • Malignancy
      • Para-neoplastic syndrome: Parathyroid hormone related peptide
      • Hypercalcemia due to bone destruction
    • Medication induced
      • Thiazide diuretics
      • Lithium
    • Nutritional
      • Milk alkali syndrome
      • Vitamin D toxicity
    • Granulomatous disease
      • Sarcoidosis
    • Surgical
      • Immobilization
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypercalcemia
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Related to Parathyroid gland
 
 
 
 
 
 
 
 
 
 
 
Unrelated to parathyroid gland
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary hyperparathyroidism
 
 
Secondary hyperparathyroidism
 
 
Tertiary hyperparathyroidism
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Typical primary hyperparathyroidism
 
Familial hypocalciuric hypercalcemia
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Malignancy
 
 
 
 
 
Medication induced
 
 
 
Nutritional
 
 
 
 
Granulomatous disease
 
 
Surgical
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Para-neoplastic syndrome: Parathyroid hormone related peptide
 
Metaplasia: Hypercalcemia due to bone destruction
 
Thiazide diuretics
 
Lithium
 
Milk alkali syndrome
 
Vitamin D toxicity
 
Sarcoidosis
 
 
Immobilization
 

Differential diagnosis

Differential diagnosis of hyperparathyroidism on the basis of hypercalcemia
Disorder Mechanism of hypercalcemia Clinical features Laboratory findings Imaging & diagnostic modalities
Hyperparathyroidism Primary hyperparathyroidism Increase in secretion of parathyroid hormone (PTH) from a primary process in parathyroid gland. Parathyroid hormone causes increase in serum calcium.
  • Usually asymptomatic
  • Hypercalcemia detected on routine biochemical panel
  • ↑ PTH
  • ↑ Calcium
  • ↓/N Phosphate
  • N/↑ calcitriol
 Findings of bone resorption:
  • X-ray
  • DXA

Preoperative localization of hyperfunctioning parathyroid gland:

  • Non-Invasive
    • Tc-99m sestamibi scintigraphy
    • Neck ultrasound
    • 4D-CT
    • SPET(P-SPECT)
    • PET
    • MRI
  • Invasive:
    • Super sensitive venous sampling
    • Selective arteriography
    • Angiography

Predicting post-operative success:

  • Intraoperative parathyroid hormone monitoring
Secondary hyperparathyroidism Increase in secretion of parathyroid hormone (PTH) from a secondary process. Parathyroid hormone causes increase in serum calcium.
  • May present with history of:
    • Chronic renal failure
    • Vitamin D deficiency
  • ↑ PTH
  • ↓/N Calcium
  • ↑ Phosphate
Tertiary hyperparathyroidism Continuous elevation of parathyroid hormone (PTH) even after successful treatment of the secondary cause of elevated parathyroid hormone. Parathyroid hormone causes increase in serum calcium.
  • Usually present with history of:
    • Kidney transplant
  • Usually hyperplasia of all four parathyroid glands
  • ↑ PTH
  • ↑ Calcium
  • ↑ Phosphate
Malignancy[1] Humoral hypercalcemia of malignancy[2][3][4] Tumor cells secretes parathyroid hormone related protein (PTHrP) which has similar action as parathyroid hormone.
  • Most common cause of malignancy related hypercalcemia.
  • Usually present in solid tumors
  • ↑ PTHrP
  • ↑ Calcium
  • ↓/N Phosphate
  • N/↑ Calcitriol
  • Chest X-ray
  • CT scan
  • MRI
Osteolytic tumors Multiple myeloma produces osteolysis of bones causing hypercalcemia. Osteolytic metastasis can cause bone resorption causing hypercalcemia.
  • Most commonly present in multiple myeloma and breast cancer.
  • ↓ PTH
  • ↑ Calcium
  • DXA
  • X-ray
  • Mammography
  • Ultrasound
  • ESR
  • Serum protein electrophoresis
Production of calcitirol Some tumors has ectopic activity of 1-alpha-hydroxylase leading to increased production of calcitriol. Calcitriol is active form of vitamin D and causes hypercalcemia.
  • Most commonly present in lymphomas and in some ovarian germ cell tumors.
  • ↑ Calcium
  • ↑ Calcitriol
  • CT scan
  • MRI
Ectopic parathyroid hormone[5] Some tumors leads to ectopic production of parathyroid hormone.
  • In rare instances, small cell carcinoma of lung may produce hypercalcemia by this process.
  • ↑ PTH
  • ↑ Calcium
  • ↓/N Phosphate
  • N/↑ Calcitriol
  • Chest X-ray
  • CT scan
  • MRI
Medication induced Lithium[6] Lithium lowers urinary calcium and causes hypercalcemia. Lithium has been reported to cause an increase in parathyroid hormones and enlargement if parathyroid gland after weeks to months of therapy.
  • History of mood disorder
  • ↑ PTH
  • ↑ Calcium
  • Lithium levels
Thiazide diuretics Thiazide diuretics lowers urinary calcium excretion and causes hypercalcemia
  • History of cardiac disorder
  • Rarely causes hypercalcemia
  • ↑ Calcium
 --
Nutritional Milk-alkali syndrome Hypercalcemia is be caused by high intake of calcium carbonate
  • History of
    • High milk intake
    • Excess calcium intake for treating:
      • Osteoporosis
      • Dyspepsia
  • May lead to metabolic alkalosis and renal insufficiency.
  • ↑ Calcium
  • Renal function test
Vitamin D toxicity Excess vitamin D causes increased absorption of calcium from intestine causing hypercalcemia.
  • History of:
    • Excess intake vitamin D
    • Excess milk fortified with vitamin D[7]
    • Topical application of vitamin D analogue analogue calcipotriol[8]
  • ↑ Calcium
  • ↑ Vitamin D (calcidiol and/or calcitriol)
 --
Granulomatous disease Sarcoidosis[9] Hypercalcemia is causes by endogeous production of calcitriol by disease-activated macrophages.
  • History of:
    • Cough
    • Dyspnea
    • Chest pain
    • Tiredness or weakness
    • Fever
    • Weight loss
  • ↑ Calcium
  • ↑ Calcitriol
  • ↑ ACE levels
  • Chest X-ray
  • Biopsy
  1. ↑ Mirrakhimov AE (2015). "Hypercalcemia of Malignancy: An Update on Pathogenesis and Management". N Am J Med Sci. 7 (11): 483–93. doi:10.4103/1947-2714.170600. PMC 4683803. PMID 26713296.
  2. ↑ Ratcliffe WA, Hutchesson AC, Bundred NJ, Ratcliffe JG (1992). "Role of assays for parathyroid-hormone-related protein in investigation of hypercalcaemia". Lancet. 339 (8786): 164–7. doi:10.1016/0140-6736(92)90220-W. PMID 1346019.
  3. ↑ Ikeda K, Ohno H, Hane M, Yokoi H, Okada M, Honma T, Yamada A, Tatsumi Y, Tanaka T, Saitoh T (1994). "Development of a sensitive two-site immunoradiometric assay for parathyroid hormone-related peptide: evidence for elevated levels in plasma from patients with adult T-cell leukemia/lymphoma and B-cell lymphoma". J. Clin. Endocrinol. Metab. 79 (5): 1322–7. doi:10.1210/jcem.79.5.7962324. PMID 7962324.
  4. ↑ Horwitz MJ, Tedesco MB, Sereika SM, Hollis BW, Garcia-Ocaña A, Stewart AF (2003). "Direct comparison of sustained infusion of human parathyroid hormone-related protein-(1-36) [hPTHrP-(1-36)] versus hPTH-(1-34) on serum calcium, plasma 1,25-dihydroxyvitamin D concentrations, and fractional calcium excretion in healthy human volunteers". J. Clin. Endocrinol. Metab. 88 (4): 1603–9. doi:10.1210/jc.2002-020773. PMID 12679445.
  5. ↑ VanHouten JN, Yu N, Rimm D, Dotto J, Arnold A, Wysolmerski JJ, Udelsman R (2006). "Hypercalcemia of malignancy due to ectopic transactivation of the parathyroid hormone gene". J. Clin. Endocrinol. Metab. 91 (2): 580–3. doi:10.1210/jc.2005-2095. PMID 16263810.
  6. ↑ Mallette LE, Khouri K, Zengotita H, Hollis BW, Malini S (1989). "Lithium treatment increases intact and midregion parathyroid hormone and parathyroid volume". J. Clin. Endocrinol. Metab. 68 (3): 654–60. doi:10.1210/jcem-68-3-654. PMID 2918061.
  7. ↑ Jacobus CH, Holick MF, Shao Q, Chen TC, Holm IA, Kolodny JM, Fuleihan GE, Seely EW (1992). "Hypervitaminosis D associated with drinking milk". N. Engl. J. Med. 326 (18): 1173–7. doi:10.1056/NEJM199204303261801. PMID 1313547.
  8. ↑ Hoeck HC, Laurberg G, Laurberg P (1994). "Hypercalcaemic crisis after excessive topical use of a vitamin D derivative". J. Intern. Med. 235 (3): 281–2. PMID 8120527.
  9. ↑ Dusso AS, Kamimura S, Gallieni M, Zhong M, Negrea L, Shapiro S, Slatopolsky E (1997). "gamma-Interferon-induced resistance to 1,25-(OH)2 D3 in human monocytes and macrophages: a mechanism for the hypercalcemia of various granulomatoses". J. Clin. Endocrinol. Metab. 82 (7): 2222–32. doi:10.1210/jcem.82.7.4074. PMID 9215298.
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