A curious case of hypercalcemic crisis in sarcoidosis: The missing link beyond 1,25(OH)₂D

ABSTRACT

Sarcoidosis is a chronic granulomatous disease affecting various organs and is one of the causes of parathyroid hormone (PTH)-independent hypercalcemia. However, sarcoidosis per se presenting with severe hypercalcemia is very rare. We present a case with an initial presentation of hypercalcemic crisis (corrected calcium of 16.8 mg/dl) and suppressed iPTH (7.2 pg/ml). Upon thorough evaluation, including biochemical, radiology, and histopathology, of the right inguinal lymph node biopsy, extrapulmonary sarcoidosis was diagnosed. The patient was initiated on glucocorticoid therapy, leading to clinical and biochemical improvement. This case is characterized by hypophosphatemia and inappropriately normal 1,25-dihydroxy vitamin D level, a finding rarely reported in the literature. Hypercalcemia may be due to the overproduction of bone-resorbing cytokines, INF-α, IL-6, IL-1β, and PTHrP.

Introduction

Sarcoidosis is a multisystem granulomatous disorder that affects people worldwide, affecting various organs like the lungs, liver, and lymph nodes. It presents with chronic cough, breathlessness, skin lesions, anterior uveitis, optic neuritis, arthropathy, and cranial nerve palsy. It is pathologically characterized by the development of noncaseating granulomas in the affected organs. Although it is commonly seen at a young age,[1] it usually occurs in women at an older age.[2] The lung is the most common organ involved; however, about 30% of patients present with extrathoracic manifestations[3] like liver, lymph nodes, and spleen. Sarcoidosis constitutes about 1% of the causes of hypercalcemia.[4] However, 10–30% of patients with sarcoidosis have asymptomatic hypercalcemia. Severe hypercalcemia, or hypercalcemic crisis, is defined as albumin-corrected serum calcium >14 mg/dl[5] as initial presentation is rare in sarcoidosis.[6] Increased exogenous vitamin D from diet or sunlight may worsen this problem.

Case Presentation

A 40-year-old male with underlying Type 2 diabetes mellitus for 7 years was on Tab Teneligliptin 20 milligram (mg) and Metformin (1 gram), historically optimally controlled, and presented in our medical emergency department with a history of polyuria and polydipsia for the past 3 months. There was an associated history of anorexia, constipation, and easy fatigability. There is no history of epigastric pain, altered sensorium, or fracture in the past. On clinical exam, the patient was conscious, cooperative, and well oriented with time, with blood pressure = 130/80, pulse rate = 84 beats per minute, and no cervical lymphadenopathy. The lymph node of size 2 × 3 cm was palpable in the right inguinal region, which was soft, nontender, and not adherent to the underlying skin. Abdominal examination revealed hepatomegaly (liver span 2–3 cm below the costal margin) and mild splenomegaly. The fundus was unremarkable.

Investigations

On initial evaluation, he was found to have severe hypercalcemia (corrected calcium 16.8 mg/dl) (8.8–10.8) as shown in Figure 1 and low phosphorus (PO4), 1.42 mg/dl (3.5–4.5). The biochemical evaluation revealed normal hemoglobin level, creatinine, and liver enzymes except elevated alkaline phosphate (ALP) and suppressed iPTH = 7.2 pg/ml with normal 25(OH) vitamin D = 37 ng/ml (30–100). Serum iPTH and 25-hydroxyvitamin D [25(OH) D] levels were analyzed using the DXI 800 random access chemiluminescence analyzer (Beckman Coulter, Brea, CA), in accordance with the manufacturer’s instructions. The reference range for iPTH was 12–88 pg/ml. The assay demonstrated intra-assay and interassay coefficients of variation of 2.1% and 3.9% for iPTH and 3.6% and 6.5% for 25(OH)D, respectively. Ultrasonography of the abdomen revealed hepatosplenomegaly with hypoechoic lesions in the liver. Chest X-ray revealed hilar lymphadenopathy. Given suppressed iPTH, the possibility of PTH-independent hypercalcemia was made. Erythrocyte sedimentation rate (ESR) =50 mm/hour, the angiotensin-converting enzyme (ACE) level was >130 U/L, serum electrophoresis revealed no monoclonality, thyroid function test (TFT), 1,25 dihydroxy vitamin D = 58.2 pg/ml (48–90), and tumor markers were normal as shown in Table 1. Contrast-enhanced computed tomography (CECT) of the chest and abdomen showed diffuse hypoenhancing nodularity in both liver lobes and hilar lymphadenopathy, as shown in Figure 2. The rest was normal. The patient was subjected to a right inguinal lymph node excision biopsy, which revealed a noncaseating granuloma suggestive of sarcoidosis, as shown in Figure 3. Because of severe hypercalcemia, intravenous fluids with normal saline at 130 ml/hour were started, and calcitonin injections in 6 IU/kg/day divided doses were started. His calcium normalized within 6 days, as shown in Figure 1. The patient was discharged on tablet prednisolone 40 mg/day.

Figure 1.

Serum calcium level during admission

Table 1.

Biochemical profile of the patient

Parameter	Value	Parameter	Value
Hemoglobin	12.2 gm/dl	24-hour urinary calcium	680 mg/day
Total leucocyte count	7.5 x103	1,25 dihydroxy vitamin D	58.2 pg/ml (48-90)
Platelet count	2.04 lac/microliter	ACE (Angiotensin converting enzyme)	>130 IU/L (8-52)
MCV	84 fl	CB NAAT lymph node *	Negative
MCH	28 pg per cell	Sr iron	41.91 ug/dl
Urea	12 mg/dl	Calcium	16.8 mg/dl (8.8-10.8)
Creatinine	0.68 mg/dl	Phosphorus (PO4)	1.42 mg/dl (3.5-4.5)
ESR	50 mm/hour	TIBC (total iron binding capacity)	368.91 ug/dl
Bilirubin	1.06 mg/dl	Transferrin saturation	11.36%
Aspartate aminotransferase	20 U/L (0-45)	Serum electrophoresis	No M band seen
Alb (Albumin)	3.56 g/dl	CEA 2 (Carcinoembryonic antigen)	1.30 ng/ml (0-3)
ALP (Alkaline Phosphate)	296 U/L (30-141)	PSA (Prostate-specific antigen)	0.75 ng/ml (0-4)
25(OH) vitamin D	37 ng/ml(30- 100 ng/ml)	AFP (Alpha-fetoprotein)	1.24 IU/ml (0-20)
iPTH (intact parathyroid hormone)	7.2 pg/ml (12-88 pg/ml)	LDH (Lactate dehydrogenase)	133 U/L (25-248)
TSH	3.9(0.27- 4.20) uIU/ml	T4	9.2 (5.10-14.10) ug/dl
T3	1.13(0.80-2) ng/ml

*CB NAAT: Cartridge-based nucleic acid amplification test, fl: femtoliters, pg: picograms

Figure 2.

Diffuse hypo-enhancing nodularity in both lobes of the liver

Figure 3.

Lymph node infiltrated by epithelioid cell granuloma (noncaseating) with a foreign body and Langhans-type giant cells

Outcome and follow-up

The patient is on a tapering prednisolone dose, and his serum calcium has normalized, with the latest being 9.8 mg/dl (albumin corrected).

Discussion

Diagnosis of sarcoidosis in hypercalcemia is very challenging in our Endocrine clinic as the most common cause of hypercalcemia is primary hyperparathyroidism. The definitive diagnosis of sarcoidosis relies on clinical compatibility and the presence of noncaseating granulomas on histopathology, while ruling out other granulomatous diseases.[7] Although elevated ACE levels support our diagnosis, it is not a sensitive marker. Fetzer et al.[8] reported ACE level elevation in 65.5% of 39 patients with hepatic sarcoidosis. Upon evaluation of this patient, iPTH was suppressed, which rules out hyperparathyroidism. Our case was diagnosed with extra-pulmonary sarcoidosis, predominantly involving hepatosplenomegaly with no cholestatic symptoms, with high ALP. The diagnosis was established based on a right inguinal lymph node biopsy showing noncaseating granulomas and CECT abdomen revealing granulomas in both liver lobes. Hepatic granulomas can be found in 50–65% of cases, but they are usually asymptomatic,[3] with patients having predominantly elevated ALP suggestive of a cholestatic pattern with normal enzymes, making elevated ALP an intriguing finding. About 20% of patients with sarcoidosis have palpable hepatomegaly or splenomegaly. Ungprasert et al.[9] reported that none of the patients experienced cholestatic symptoms, although the majority had elevated ALP.

The etiology of hypercalcemia is broadly classified into PTH-dependent (iPTH >20 pg/ml) and PTH-independent (iPTH <20 pg/ml), based on iPTH levels and the assay used.[5] The most common causes of hypercalcemia are primary hyperparathyroidism and malignancy, accounting for approximately 90% of cases.[7] Chronic granulomatous diseases, such as tuberculosis (TB) and sarcoidosis, are relatively rare causes of hypercalcemia. In sarcoidosis, hypercalcemia is classically attributed to increased activity of 1α-hydroxylase within activated macrophages in granulomas. This leads to excessive conversion of 25-hydroxy vitamin D (25(OH) D) to its active form, 1,25-dihydroxy vitamin D (1,25(OH)₂D), which in turn enhances intestinal calcium absorption and bone resorption. However, evidence suggests that parathyroid hormone-related peptide (PTHrP) can also mediate hypercalcemia in sarcoidosis. Only two cases have been reported in the literature where PTHrP-mediated hypercalcemia was identified in sarcoidosis.[10,11] PTHrP shares structural homology with PTH and exhibits similar physiological effects, including stimulation of bone resorption and increased renal calcium reabsorption, thereby contributing to hypercalcemia. Additionally, PTHrP activates 1α-hydroxylase, leading to increased 1,25(OH)₂D levels, albeit not as markedly as PTH. Under normal physiological conditions, hypercalcemia suppresses PTH and 1,25(OH)₂D levels via negative feedback mechanisms.[12] However, this feedback is disrupted in sarcoidosis, possibly due to increased interferon-gamma (IFN-γ) production, which enhances macrophage-mediated 1α-hydroxylase activity. In our patient, 1,25(OH)₂D levels were inappropriately normal despite severe hypercalcemia. This finding suggests an alternative mechanism, such as PTHrP-mediated or cytokine-induced bone resorption, rather than classic 1,25(OH)₂D-driven hypercalcemia. Also, malignancy-related hypercalcemia was ruled out. If 1,25(OH)₂D had been the primary driver, we would have expected hyperphosphatemia or normal phosphorus due to increased intestinal phosphate absorption. However, our patient exhibited hypophosphatemia, which is more consistent with PTHrP-like effects or cytokine-mediated phosphaturia. Due to logistical and financial constraints, PTHrP levels could not be measured, which remains a limitation of our study. The patient’s dramatic response to steroids further supports an inflammatory or PTHrP-mediated mechanism of hypercalcemia. Since 1,25(OH) ₂D levels were normal in this case, it indirectly supports our hypothesis. Patients with sarcoidosis often demonstrate exquisite sensitivity to vitamin D and may develop hypercalcemia in response to ultraviolet (UV) radiation or even small doses of vitamin D supplementation. Thus, careful monitoring of calcium levels, avoidance of excessive sun exposure, and cautious vitamin D supplementation are crucial in these patients. Therapeutic options in severe hypercalcemia include rehydration to correct volume depletion, loop diuretics to promote calcium excretion, and corticosteroids. Corticosteroids are very effective in sarcoidosis because of their effect on vitamin D metabolism[13]; they are potent inhibitors of enzyme 1 alpha-hydroxylase in macrophages and reduce activated macrophages. They also reduce PTHrP production by binding to the cytokine promoter region in the macrophage nucleus, downregulating IL-2 and IFNÝ production.[13] This could explain the response to glucocorticoids in our patient.

Conclusion

Although due to the nonavailability of PTHrP, because of reasons already explained, this case highlights an atypical presentation of hypercalcemia in sarcoidosis, where bone-resorbing cytokines and possible PTHrP overproduction contributed to hypercalcemia, rather than the classic 1,25(OH)₂D-mediated mechanism. Our findings suggest that not all sarcoidosis-related hypercalcemia is driven by 1,25(OH)₂D excess, and alternative pathways such as PTHrP-mediated hypercalcemia or cytokine-induced bone resorption should be considered. The patient’s excellent response to corticosteroids further reinforces the role of inflammation-driven hypercalcemia in sarcoidosis. Importantly, this case underscores the need for primary care physicians to recognize nonparathyroid and extra-renal causes of hypercalcemia early, particularly in resource-limited settings, to prevent serious complications such as renal failure. The diagnostic and therapeutic approach demonstrated here is directly relevant to the scope of family medicine and highlights the importance of maintaining a broad differential when evaluating hypercalcemia.

Consent

Written informed consent was obtained from the patient for the publication of this case report in accordance with the journal’s patient consent policy.

Ethics statement

This case report did not require prior ethical approval as per institutional guidelines. The patient provided informed consent and waived the requirement for further ethical review before publication.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.