Lack of feedback in response to increased levels of 1,dihydroxyvitamin D leads to an enhanced calcium absorption in the small intestine and an excess of bone resorption in patients with sarcoidosis, leading to hypercalcemia. The diagnosis of sarcoidosis may be elusive, especially in atypical populations, given the variation of the presentation of the organs involved.
Hypercalcemia may be a clue to the diagnosis, especially in cases with no pulmonary symptoms or findings on chest X-ray. Sarcoidosis should be considered in patients with hypercalcemia, low PTH levels, and elevated calcitriol levels. As mentioned above, longstanding hypercalcemia and hypercalciuria can cause nephrocalcinosis and renal failure [ 2 , 6 ].
Although severe hypercalcemia is rare in sarcoidosis [ 1 , 5 ], patients may present with severe hypercalcemia, associated with renal failure, as was the case in our patients. Treatment of hypercalcemia due to sarcoidosis is beyond the scope of this paper. However, it has been reviewed by Conron et al. Therapeutic options include rehydration, a loop diuretic to promote calcium secretion, and corticosteroids [ 1 ].
Corticosteroids have been the first-line therapy in treating hypercalcemia associated with sarcoidosis because of their effectiveness in rapidly correcting hypercalcemia.
Institution of steroids causes a relatively swift decrease in circulating 1,25 dihydroxyvitamin D and serum calcium levels in 3 to 5 days [ 16 ].
Patients with asymptomatic mild hypercalcemia should be advised to avoid sun exposure and vitamin D rich diet and maintain hydration of more than 2 liters per day. The role of avoiding dairy product and low calcium diet is controversial since there is little evidence that it affects calcium balance [ 1 ]. Ketoconazole is an alternative for patients where the steroid use is contraindicated. It inhibits the cytochrome Plinked enzyme systems involved in steroid synthesis including 25 OH D 3 -1a-hydroxylase [ 17 ].
Hydroxychloroquine also causes similar effects and can be used in patients who cannot tolerate ketoconazole or who develop abnormal liver function tests [ 18 ]. Methotrexate and azathioprine may also help control hypercalcemia by reducing the granuloma formation [ 1 ].
We report two patients with sarcoidosis, where severe hypercalcemia associated with acute renal failure was the unusual presenting feature. It was only after extensive investigation that a diagnosis of sarcoidosis was confirmed. Sarcoidosis without pulmonary symptoms may pose a diagnostic challenge but should be suspected in patients with nonparathyroid-dependent hypercalcemia. Timely recognition and appropriate treatment of hypercalcemia secondary to sarcoidosis should prevent development of nephrocalcinosis and renal failure.
The authors thank Jinie Shirey for preparing this paper and James Richard, DO for his help with the pathology material. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors. Read the winning articles. Journal overview. Academic Editor: Hermann Wasmuth. Received 04 Oct Accepted 31 Oct Published 16 Dec Abstract Although hypercalcemia is a known metabolic complication of sarcoidosis, it is rarely a presenting manifestation. Introduction Although hypercalcemia is a known metabolic complication of sarcoidosis, it is rarely a presenting manifestation.
Normal value Patient no. Table 1. Figure 1. CT Chest showing mediastinal lymphadenopathy. Figure 2. Figure 3. Figure 4. References M. Conron, C. Young, and H. View at: Google Scholar A.
Berliner, M. Haas, and M. Lebacq, V. Desmet, and H. View at: Google Scholar M. Iannuzzi, B. Rybicki, and A. Taylor, H. Lynch, and W. View at: Google Scholar R. Muther, D. McCarron, and W. Nunes, D. Bouvry, P. Soler, and D. Awasthi, R. The association of ARF and hypercalcemia was studied retrospectively in eight patients based in the data in their charts.
Data are expressed as median and percentile 25th; 75th. Our results show that ARF associated with hypercalcemia was related with comorbidity in all cases cancer, multiple myeloma, hyperparathyroidism, sarcoidosis, vitamin D intoxication, and leprosy. Maximum median serum creatinine levels were 3.
Maximum total median serum calcium was Serum parathyroid hormone was almost undetectable. His lipids were normal, too and urine culture negative. Renal ultrasound was normal. Ultrasound of the parathyroid glands was normal. Computerized tomography of the abdomen showed normal findings. Bone biopsy showed osteoporosis and scattered zones with osteonecrosis.
Renal biopsy showed tubulointerstitial lesions with calcium deposits in the interstitial tissue. Chest X-ray was also normal. Endoscopy of the upper gastrointestinal tract while hospitalized showed no pathologic changes. Beta-2 microglobulin, acid phosphatase, kappa and lambda light chains were normal.
Coombs test and immunoelectrophoresis of proteins were negative. Cranial X-ray, as well as radiographs of hands and feet, was normal. He had mild metabolic alkalosis, and his ECG showed signs of hypercalcemia shortened QT interval of 0. The patient was hydrated with intravenous fluid, treated with bisphosphonates, corticosteroids and calcium antagonists for his elevated blood pressure.
Antacids were stopped promptly after admission. He was also given vitamin B 12 and folic acid upon the recommendation of a hematologist. The serum level of calcium decreased slowly to 2. After ruling out the differential diagnosis of multiple myelomas, other malignancies, primary hyperparathyroidism, hyperthyroidism or hypothyro-idism, it seemed plausible that the cause of hypercalcemia might be the ingestion of calcium containing antacids prescribed by his primary physician for his gastroesophageal reflux disease.
He was discharged from hospital after 45 days of hospitalization. Calcium is the main component of bone skeleton and serves as the intracellular and extracellular messenger in numerous cellular events such as neuronal network, immune response, muscle contraction, and hormone secretion. The kidney, intestine, and bone are the main target organs of these regulators, and the kidney plays a key role in the fine regulation of calcium excretion [ 4 ].
Hypercalcemia is common in the clinical setting and occurs in conditions when the entry of calcium into the circulation is greater than the urine excretion or bone deposition, as is the case of accelerated bone resorption or excessive gastrointestinal absorption or decreased renal excretion. Primary hyperparathyroidism and malignancy are the most common causes of hypercalcemia [ 2 ]. The pathophysiology of the milk-alkali syndrome is poorly understood, particularly because only some individuals are affected by excessive ingestion, but it has been suggested that they absorb more calcium than others.
Patients who appear to be at high risk for milk-alkali syndrome include old age, volume depletion and medication that reduces glomerular filtration rate, such as angiotensin converting enzyme inhibitors, angiotensin receptor blockers or non-steroidal anti-inflammatory agents.
Hypercalcemia causes reduced glomerular filtration rate, increased sodium excretion and depletion of total body water, leading to increased bicarbonate reabsorption and metabolic alkalosis. Alkalosis enhances calcium reabsorption in the distal nephron, thus, aggravating the hypercalcemia [ 7 ]. The modern version of the milk-alkali syndrome is now known as a calcium-alkali syndrome. It is the third most common cause of hypercalcemia in a retrospective study at a single center, where many patients reported consuming less than 2 g of elemental calcium per day in the form of calcium carbonate [ 8 ].
Whereas the traditional milk-alkali syndrome affected younger male patients with peptic ulcer disease, the demographics have changed to post-menopausal women, solid organ transplant recipients, pregnant women, bulimic patients, and those on dialysis [ 9 ]. Our patient had high levels of serum calcium, as in malignancies, thus our primary aim was to rule out malignant diseases. His PTH levels were suppressed and almost undetectable, thus in the differential diagnosis primary hyperparathyroidism was not to be considered.
He also, had normal thyroid function, no signs of hypervitaminosis D, no medical history of medications that can cause hypercalcemia, neither signs nor symptoms of sarcoidosis. As he had positive medical history on calcium containing antacids intake because of his gastroesophageal reflux, while being volume depleted for his vomiting, and having already mild metabolic alkalosis, it was plausible to make an association of his medical history and the presence of the milk-alkali syndrome.
These ECG abnormalities have been seen in other patients, too [ 10 , 11 ]. He developed transitory renal insufficiency, with a complete remission few months after discharge.
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