Idiopathic Hypercalcemia in Decompensated Cirrhosis: Reexploring an Entity in Oblivion

Abstract

Hypercalcemia is a rare metabolic abnormality seen in patients with cirrhosis and is usually considered a paraneoplastic manifestation of hepatocellular carcinoma. Idiopathic hypercalcemia in cirrhosis is a diagnosis of exclusion, which is considered when all the causes of hypercalcemia have been ruled out. Here, we report a rare case of idiopathic hypercalcemia presenting as acute kidney injury in a case of decompensated cirrhosis, managed with adequate hydration and injection of ibandronate and intranasal calcitonin, leading to the normalization of serum calcium and resolution of acute kidney injury.

Case report

A 52-year-old gentleman, a diagnosed case of ethanol-related decompensated cirrhosis, with mild ascites and large esophageal varices was admitted with complaints of generalized weakness, progressive increase in abdominal distension, and decreased urine output for two weeks. There was no history of intake of calcium, vitamin D supplements, or complementary medicine intake. On examination, the patient had facial puffiness, pedal edema, and gross ascites. The laboratory investigations revealed acute kidney injury (serum creatinine of 2.5 mg/dl) and hypercalcemia (serum calcium levels of 12.8 mg/dl) with normal serum albumin (4.6 g/dl). The urine examination was normal without any active sediment. The initial evaluation of hypercalcemia was suggestive of a hypercalcemic state independent of parathyroid harmone (PTH) without changes in vitamin D levels (Table 1). An extensive etiological workup of the cause of hypercalcemia including multiple myeloma, granulomatous diseases, and occult malignancy turned out to be negative (Table 1). Hence, a possibility of idiopathic hypercalcemia, with hypercalcemia-induced tubulointerstitial nephritis, was kept. The patient was managed with adequate hydration and injection of ibandronate and intranasal calcitonin, leading to the normalization of serum calcium (S. calcium 9.1 mg/dl) and resolution of acute kidney injury (serum creatinine 0.9 mg/dl). The patient continues to be on follow-up and is on weekly long-term albumin infusions and diuretics.

Table 1.

Laboratory Investigations and Aetiological Workup.

Investigations	Values
Hemoglobin (g/dl)	8.3
Total leukocyte count(/mm3)	6500
Platelet count (/mm3)	1,20,000
Prothrombin index/international normalized ratio (PTI/INR)	20.2/1.4
Liver function tests (LFTs)
•Bilirubin (mg/dl)	1.9
•AST (IU)	33
•ALT (IU)	12
•Protein (g/dl)	8.4
•Albumin (g/dl)	4.6
•SAP (IU)	83
Renal function tests
•Urea (mmol/L)	101
•Creatinine (mg/dl)	2.5
S. calcium (mg/dl)	12.8
S. phosphorus (mg/dl)	3.4
25 (OH) Vitamin D3 (ng/ml) (11–42)	40
Parathyroid hormone (pg/ml) (15–65)	11.1
Parathyroid hormone–related peptide (PTH rp) - (normal<2)	0.9
Multiple myeloma workup •Skeletal survey (low dose whole-body computer tomography [CT]) = no lytic lesion •Serum protein electrophoresis (SPEP) = moderate hypergammaglobulinemia, no M band seen •Urine protein electrophoresis (UPEP) = very faint band in the albumin region •Serum immunofixation (SIFE) = polyclonal gammopathy •Serum free light chain assay (SFLC) = kappa light chain = 147 (3.3–19.4), lambda light chain = 113 (5.7–26.3), kappa lambda ratio = 1.3 (0.26–1.65)	Granulomatous Diseases & occult malignancy workup •Chest X-ray – normal •High resolution computer tomography (HRCT) chest – no mediastinal lymphadenopathy •S.angiotensin-converting enzyme levels – 38 IU/L •Activated vitamin D3 levels – 20 ng/mL (19.9–79.3) •Triple phase computer tomography (TPCT) abdomen – suggestive of cirrhosis with portal hypertension, no arterial hypervascular lesion suggestive of hepatocellular carcinoma •Whole-body Fluorodeoxyglucose (FDG) PET scan – non-FDG avid gross ascites, no definite PET e/o clinically significant hypermetabolism noted anywhere else in the body Tumor markers: Alpha fetoprotein (AFP)- 3.09 ng/mL Carcinoembryonic antigen (CEA)- 3.50 ng/mL CA 19-9- 20.94 units/mL Prostate-specific antigen (PSA)- 0.104 ng/mL

AST, aspartate transaminase; ALT, alanine transaminase; SAP, serum alkaline phosphatase; PET, positron emission technology.

Discussion

Hypercalcemia is defined as serum calcium levels more than 11 mg/dl. The most common cause of hypercalcemia is parathyroid adenoma (PTH dependent) accounting for 40% of cases.¹. In cases where PTH levels are within the normal range (PTH independent), causes Like multiple myeloma, vitamin D intoxication, granulomatous disorders, occult malignancy, prolonged immobilization, and milk-alkali syndrome are considered.¹

Hypercalcemia is a rare phenomenon in patients with cirrhosis in the absence of hepatocellular carcinoma. The possible etiologies for hypercalcemia in cirrhosis include malignancies (hepatocellular carcinoma and squamous cell carcinoma), primary hyperparathyroidism, granulomatous disorders, vitamin D intoxication, and in rare case due to prolonged immobilization.² Hypercalcemia due to immobilization is rare and is seen primarily in a younger age-group due to restricted mobility, due to trauma, and consequent immobilization.³ Since in our case of an ambulatory patient, hypercalcemia was PTH independent and an extensive evaluation for the cause of hypercalcemia did not reveal any etiology, a diagnosis of idiopathic hypercalcemia was considered.

The exact pathogenesis of hypercalcemia in cirrhosis is still obscure. In the setting of an acute decompensation of cirrhosis which leads to a state of heightened inflammation, resultant inflammatory mediators may lead to resorptive changes in bone and consequent hypercalcemia.⁴ In a series of sixteen patients of hypercalcemia by Gerhardt et al⁵ in the setting of chronic liver disease, five had hepatocellular carcinoma and eleven patients had idiopathic hypercalcemia. Meyrier et al⁶ have previously demonstrated that hypercalcemia in chronic liver disease is resorptive and can be seen as a metabolic feature in such patients independent of the etiology of chronic live disease.

The management of idiopathic type of hypercalcemia attributed to the liver disease per se is relatively easy and requires minimal intervention. This type of hypercalcemia responds well to hydration, bisphosphonates, and calcitonin therapy.⁴

To conclude, in patients with chronic liver disease, hypercalcemia is a diagnosis of exclusion. Treatment of this condition is simple with excellent response. However, more research is needed to dissect this clinical condition and decipher its exact pathogenesis in patients with chronic liver disease.

CRediT authorship contribution statement

Divya C. Ragate: Writing - original draft. Sunil Taneja: Writing - review & editing. Akash Roy: Writing - original draft, Writing - review & editing. Ajay K. Duseja: Writing - review & editing. Radha K. Dhiman: Writing - review & editing. Virendra Singh: Writing - review & editing.

Conflicts of interest

The authors have no conflict of interest to declare.

Acknowledgment

None.

Funding

None.

Informed consent

Informed consent was obtained for the study from the participant.