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J R Soc Med. 2005 February; 98(2): 60–61.
PMCID: PMC1079381

Puzzling hypercalcaemia: sarcoidosis without lung involvement

A Fowler, MRCP, P Dargan, MRCP, and A Jones, FRCP

In a patient with unexplained hypercalcaemia, sarcoidosis is a possibility even if there is no overt pulmonary disease.


A Caucasoid woman of 68 was seen after three weeks of confusion, polydipsia, anorexia, general malaise and weight loss. A life-long smoker of ten cigarettes a day, she had no medical history of note. On examination she was cachectic and dehydrated. Nothing else was found—in particular, no rashes, lymphadenopathy, or respiratory or neurological signs. Routine investigations revealed a lymphopenia of 0.6 × 109/L (full blood count otherwise normal), erythrocyte sedimentation rate 34 mm/h, normal serum electrolytes with mild renal impairment (urea 12.1 mmol/L, creatinine 164 μmol/L) and hypercalcaemia with a corrected serum total calcium of 3.56 mmol/L and phosphate 1.3 mmol/L; alkaline phosphatase was 165 IU/L, alanine aminotransferase 44 IU/L, gammaglutamyltransferase 81 IU/L, and albumin 30 g/L. Her chest radiograph was normal.

The initial clinical diagnosis was hypercalcaemia secondary to malignant disease. Further testing revealed a normal mammogram, a normal parathyroid hormone (PTH) of 25 ng/L (normal range 10–65), parathyroid-related peptide (PTHrP) 1.0 pmol/L (0.1–1.8) and 25-hydroxyvitamin-D 68 nmol/L (20–100) but a raised 1,25-dihydroxyvitamin-D of 144 pmol/L (20–120). Serum protein electrophoresis was normal and urine examination was negative for Bence Jones protein. After rehydration with intravenous colloid her renal function returned to normal over four weeks. However, she remained symptomatic with a serum calcium concentration of greater than 3.7 mmol/L. She was treated with four intravenous doses of pamidronate (30 mg, 60 mg, 90 mg, 30 mg) over eight weeks, during which her calcium peaked at 4.2 mmol/L (Figure 1).

Figure 1
Serum calcium and angiotensin converting enzyme (ACE) concentration and the effect of prednisolone. [filled square] Serum calcium concentration (mmol/L); ♦ serum ACE (IU/L)

Abdominal CT revealed minimal dilatation of the left hepatic ducts and portahepatic lymphadenopathy. A CT-guided biopsy of these nodes showed non-caseating granulomata. She had a grade zero Heaf test. High-resolution CT of the chest revealed bullous emphysema in the apices but no radiological pulmonary features suggestive of sarcoidosis; however, her serum angiotensin converting enzyme (sACE) was raised at 211 IU/L (27–82).

Sarcoidosis was diagnosed and she was treated with oral prednisolone 40 mg daily. Symptoms quickly resolved; serum calcium became normal within two weeks and sACE within two months. Twenty months after discharge she was taking 5 mg prednisolone daily and symptom-free; her serum calcium was normal (2.55 mmol/L).


Hypercalcaemia, although seen in 10–20% of patients with sarcoidosis, is rare in the absence of pulmonary involvement.1 A search of EMBASE and Medline yielded only ten such cases. The present case illustrates the difficulty of distinguishing between causes of hypercalcaemia. Though not a diagnostic marker of sarcoidosis, a high ACE is a useful pointer.2

The mechanism of hypercalcaemia in sarcoidosis is not fully understood. Calcium homoeostasis is controlled mainly by levels of vitamin-D, PTH and calcitonin. 1,25-dihydroxycholecalciferol (1,25(OH)2D3), the most active form of vitamin-D, is ultimately formed in the kidney following 1α-hydroxylation of 25-hydroxycholecalciferol (25[OH]2D3) by the enzyme 1α-hydroxylase. 1,25(OH)2D3 acts to increase gastrointestinal absorption of calcium and phosphate whilst also stimulating osteoclast-mediated bone resorption.3 Studies showing increased circulating concentrations of 1,25(OH)2D3 in patients with sarcoidosis and hypercalcaemia led to the hypothesis that the cause was related to abnormal vitamin-D metabolism. One theory suggests that increased 1,25(OH)2D3 synthesis is caused by activated pulmonary macrophages in granulomatous tissue.1 This is validated by studies showing generation of 1,25(OH)2D3 from homogenates of alveolar macrophages from patients with sarcoidosis.4 Furthermore, an increase in 1α-hydroxylase mRNA expression has been reported in alveolar cells obtained from patients with sarcoidosis, with a correlation between expression and disease activity.4

If the above theories are correct, hypercalcaemia should not occur in the absence of chest disease. In cases such as ours three possible explanations have been offered. First, the granulomatous tissue responsible for 1,25(OH)2D3 production might be below the limits of standard radiographic resolution.1 Secondly, the excess 1,25(OH)2D3 might originate from extrapulmonary sarcoid granulomatous tissue. Thirdly, hypercalcaemia might be explained by production of PTHrP. PTHrP acts on 1,25(OH)2D3 in a similar manner to PTH but is regulated by tumour necrosis factor-α and interleukin-6.3 PTHrP can be found in sarcoid tissue specimens and lymph node homogenates from patients with sarcoidosis3,4 and high concentrations have been reported in some patients with sarcoid. The PTHrP was normal in our patient. Finally, there is the possibility that increased 1,25(OH)2D3 production may not be the sole cause of hypercalcaemia since 1,25(OH)2D3 is not always raised in these patients.4


1. Sander S, Buller GK, Perazella MA. Hypercalcaemia, sarcoidosis, and normal chest radiographs. Am J Med 1995;99: 437–48 [PubMed]
2. Adams JS, Gacad MA, Anders A, Enders DB, Sharma OP. Biochemical indicators of disordered vitamin D and calcium homeostasis in sarcoidosis. Sarcoidosis 1986;3: 1–6 [PubMed]
3. Conron M, Young C, Beynon H. Calcium metabolism in sarcoidosis and its clinical implications. Rheumatology 2000;39: 707–13 [PubMed]
4. Gardner DG. Hypercalcaemia and sarcoidosis—another piece of the puzzle falls into place. Am J Med 2001;110: 736–7 [PubMed]

Articles from Journal of the Royal Society of Medicine are provided here courtesy of Royal Society of Medicine Press