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Sarcoidosis Presenting as Isolated Anasarca and Hypercalcemia

Hematoxylin-eosin stain showing patchy perivascular and interstitial granulomas (original magnification, 40×).

A 62-year-old woman presented to clinic for a second evaluation. Previously healthy, she initially presented for care several months earlier with anasarca. Initial workup was notable for normal renal function, calcium level, and liver function tests, no proteinuria, and echocardiogram demonstrating mild diastolic dysfunction and concentric left ventricular hypertrophy but preserved systolic function. One month later the patient developed severe, acute, symptomatic hypercalcemia with a calcium level of 14.7 mg/dL (corrected to 15.3 mg/dL). Parathyroid hormone (PTH) was suppressed, parathyroid hormone-related peptide (PTHrP) was negative, and 25-hydroxyvitamin D was normal. Further workup included a computed tomography (CT) of the chest, abdomen, and pelvis that was without masses or organomegaly. Serum protein electrophoresis, urine protein electrophoresis, free light chains, and thyroid-stimulating hormone were normal. The patient subsequently was tested for insulin-like growth factor 1 level (normal), cortisol (normal), follicle-stimulating hormone (normal), and luteinizing hormone (normal). Magnetic resonance imaging (MRI) of the brain, a mammogram, and a bone survey were all normal. Further workup demonstrated an elevated 1,25-dihydroxyvitamin D level (123 pg/mL) and angiotensin converting enzyme (ACE) level (152 U/L).

On presentation to our clinic we recommended cardiac MRI to evaluate for infiltrative diseases. This demonstrated preserved systolic function with nulling of the myocardium and blood pool on T1 imaging, concerning for protein deposition. There was no ventricular hypertrophy, dysfunction, or bi-atrial enlargement present, however, to support a diagnosis of amyloid. The patient subsequently underwent a fat pad biopsy which demonstrated a negative Congo Red stain and patchy perivascular and interstitial granulomatous inflammation, consistent with sarcoidosis (Figure). The patient’s hypercalcemia and anasarca resolved with steroids and hydroxychloroquine.

Common and rare etiologies of hypercalcemia are reviewed in the literature.1 While hypercalcemia in sarcoidosis is not uncommon, isolated symptomatic hypercalcemia in the absence of organ involvement is rare. A review of the literature demonstrates five cases of sarcoidosis with presentation limited to severe symptomatic hypercalcemia2; however, in each of these cases, patients had radiographic evidence consistent with sarcoidosis. There are also reports of radiographically evident sarcoidosis presenting with hypercalcemia and associated organ dysfunction, including pancreatitis and myositis.3, 4 To date there are no reported cases of sarcoidosis presenting with isolated hypercalcemia.

This case represents an atypical evaluation for and diagnosis of sarcoidosis. After the workup confirmed a PTH-independent process with a negative malignancy workup, this case highlights the importance of checking both the active and inactive form of vitamin D because a normal inactive form can hide an elevated active form. Once having confirmed an elevated 1,25-dihydroxyvitamin D, it is clinically pertinent to classify this patient as having calcitriol-mediated hypercalcemia because this narrows the differential diagnosis to a granulomatous process. Similarly, an elevated ACE level is suggestive of granulomatous disease, even in the absence of radiographic findings. Donovan et al present a retrospective case series of 101 patients presenting with hypercalcemia with low PTH and normal parathyroid hormone-related peptide and either elevated calcitriol levels or elevated ACE levels.5Sarcoidosis was the most common etiology (49%), followed by hematologic malignancy (17%) and infection (8%).5 The median ACE level was higher in sarcoidosis than in other etiologies (218 U/L).

Further review of the literature demonstrates a select number of cases of muscular sarcoidosis presenting with hypercalcemia.4 Of these nine cases, positron emission tomography/computed tomography (PET/CT) imaging was used in the initial workup and identified muscular involvement even in the absence of clinical myositis. It is possible that pursuing fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging could have facilitated earlier diagnosis.

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-Perrin E. Romine, M.D., M.Sc., Keith D. Eaton, M.D., Ph.D., Kelly G. Paulson, M.D., Ph.D., Rouba Hadi, M.D., Douglas S. Paauw, M.D.

This article originally appeared in the January issue of The American Journal of Medicine.

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