GRANULOMATOUS DISEASE OF UNUSUAL SITES CAUSING HYPERCALCEMIA: TWO CASE REPORTS

Abstract

Objective:

Hypercalcemia with suppressed parathyroid hormone (PTH) levels is mostly due to granulomatous disease (GD) or neoplastic disease. In GD, autonomous activity of extra-renal 1α-hydroxylase enzyme is usually the underlying cause. We describe a pair of cases where hypercalcemia resulted from GD of unusual sites posing significant diagnostic challenges.

Methods:

We describe 2 cases of PTH-independent hypercalcemia due to GD of the prostate gland and the stomach.

Results:

Both cases presented with marked hypercalcemia and suppressed PTH levels. Case 1 is an elderly male who presented with marked symptomatic hypercalcemia on multiple occasions. Investigations revealed elevated levels of 1,25-dihydroxyvitamin D3 and prostate-specific antigen but normal PTH-related protein. Transrectal biopsy of the prostate gland confirmed the presence of chronic granulomatous prostatitis. The patient responded very well to steroids which entirely normalized his calcium level. Case 2 is a male who presented similarly with significant hypercalcemia but had upper gastrointestinal symptoms and anemia at onset. Endoscopy and biopsy established the presence of granulomatous gastritis likely due to Crohn disease which responded to steroids resulting in normalization of calcium levels within a short span of time.

Conclusion:

While the majority of PTH-independent hypercalcemia cases are due to GDs of lymph nodes or malignancy, our cases indicate that in uncertain cases, granulomatous processes involving unusual sites should be considered in the evaluation of hypercalcemia with suppressed PTH.

INTRODUCTION

Hypercalcemia is commonly encountered in clinical practice and once identified it is useful to associate it with either parathyroid hormone (PTH)-dependent or PTH-independent processes. The former is most commonly due to primary or tertiary hyperparathyroidism but the latter is usually associated with malignancy or granulomatous diseases (GDs). Among the GDs, sarcoidosis is most often associated with hypercalcemia with an estimated incidence of 11% (1), however altered calcium homeostasis has been also noted in infections like tuberculosis (2), leprosy (3), disseminated candidiasis (4), and in non-infective conditions like inflammatory bowel disease (5) and silicone-induced granulomas (6). GDs of unusual sites (7–9) have been reported to cause marked hypercalcemia due to increased expression of 1α-hydroxylase enzymatic activity in tissue macrophages leading to inappropriately elevated levels of 1,25-dihydroxyvitamin D3 (1,25(OH)₂D) which is resistant to feedback control. Here, we describe 2 cases of non PTH-mediated hypercalcemia due to granulomatous processes involving rare sites which posed significant diagnostic challenges.

CASE REPORT

Case 1

A 60-year-old man presented to the acute medicine department in November of 2015 with a 2-week history of intermittent abdominal pain, constipation, and confusion. His past medical history included undifferentiated spondyloarthropathy, stage 3 chronic kidney disease, and chronically raised prostate-specific antigen. At presentation, his physical examination was normal but he was profoundly dehydrated and mildly confused. His initial blood results are presented in Table 1.

Table 1.

Initial Biochemical Investigations of Case 1

Parameter	Patient's value (reference range)	Parameter	Patient's value (reference range)
Calcium	3.59 mmol/L (2.13–2.55 mmol/L)	Thyroid-stimulating hormone	3.21 mU/L (0.27–4.20 mU/L)
Albumin	45 g/L (35–50 g/L)	Hemoglobin	127 g/L (130–180 g/L)
Adjusted calcium	3.6 mmol/L (2.2–2.6 mmol/L)	Immunoglobulins	Normal
Urea	19.4 mmol/L (2.5–7.8 mmol/L)	Serum protein electrophoresis	Normal
Creatinine	436 μmol/L (58–110 μmol/L)	Light chains (kappa and lambda)	Elevated
Parathyroid hormone	0.9 pmol/L (1.6–6.9 pmol/L)	Urine Bence Jones proteins	Normal
25-hydroxyvitamin D	69 nmol/L (>50 nmol/L)	Autoimmune screen	Normal
Angiotensin-converting enzyme	114 U/L (8–65 U/L)	Prostate-specific antigen	7 μg/L (<3 μg/L)
24-hour urine calcium	4.8 nmol/24 hours (2.5–7.5 nmol/24 hours)	Tumor markers (HCG, CEA, CA 19-9, CA 15-3)	Normal
Free thyroxine	13 pmol/L (11–25 pmol/L)

He was commenced on aggressive fluid resuscitation which continued for 48 hours followed with 2 doses of intravenous pamidronate (30 mg each). Further investigations showed a normal appearance on chest X-ray and ultrasound of the renal tract but computed tomography (CT) scan of the thorax, abdomen, and pelvis demonstrated a small volume of lymphadenopathy along the small bowel mesentery, inguinal, and retrocrual regions. Lymphoproliferative disorder was considered, prompting a review by the hematology team. A nuclear bone scan showed bilaterally patchy uptake in the mid and upper hemithorax. A bone marrow examination confirmed a normocellular marrow with normal trilineage hemopoiesis and tissue lymphoma immunotyping by flow cytometry was normal. He also had a biopsy of the inguinal lymph nodes which was normal.

While these investigations were carried out, his hydration was maintained with intravenous fluids and over the course of days his adjusted calcium levels (average from 2.55 to 2.65 mmol/L) and renal function improved. He was discharged with outpatient follow-up with the endocrinology, nephrology, and urology teams.

Over the course of the next few months he attended multiple clinics and his calcium levels were checked on several occasions and it remained stable (average from 2.69 to 2.85 mmol/L) and the PTH remained suppressed (average from 0.8 to 1.9 pmol/L). Magnetic resonance imaging of the pelvis showed no evidence of prostate enlargement or malignancy, but a biopsy showed evidence of prostatitis. He had 2 further admissions in 2016 with marked hypercalcemia (>3.5 mmol/L) which were treated with intravenous fluids and pamidronate, but unfortunately the endocrinology team was not involved on either occasion.

He was readmitted in March of 2017 with multiple systemic symptoms and was found be hypercalcemic (2.84 mmol/L) again with an acute kidney injury (urea of 16.6 mmol/L; creatinine of 456 μmol/L). He was treated again with fluids and pamidronate but the endocrine team was promptly involved this time. A repeat set of tests were organized which showed normal levels of immunoglobulins, serum protein electrophoresis, and urine Bence Jones protein. On this occasion his 24-hour urine calcium excretion was found to be elevated (8.78 mmol/24 hours) but PTH level remained suppressed (1.3 pmol/L). Further tests showed elevated levels of angiotensin-converting enzyme (101 U/L) and 1,25(OH)₂D (218 pmol/L; reference range is 43 to 143 pmol/L) but normal levels of PTH-related protein (<1 pmol/L; reference range is <1.8 pmol/L).

A further CT scan of the thorax, abdomen, and pelvis confirmed the presence of multifocal lymphadenopathy that was noted earlier but there were additional flecks of calcification in the liver and spleen. Lymph node biopsy of the inguinal region was repeated but found no evidence of lymphoma or GD. We suspected the possibility of an extra-nodal granulomatous process driving a PTH-independent hypercalcemia. His medical notes and previous tests were revisited and we identified that the transrectal prostate biopsy results had actually reported “There is chronic granulomatous prostatitis with basal cell hyperplasia” (Fig. 1).

Fig. 1.

Histology of the prostate gland showing chronic granulomatous changes with inflammation and loss of glands.

We started him on prednisolone at 40 mg once daily which was gradually tapered down to 10 mg over the next few weeks. He had multiple visits to clinics subsequently and was found to have settled adjusted calcium levels (average from 2.22 to 2.40 mmol/L) with stable renal function (average creatinine from 218 to 285 μmol/L). He is currently under active follow up and remains on a maintenance dose of prednisolone but will be commenced on azathioprine soon by the rheumatology team.

Case 2

A 79-year-old man was admitted to the hospital in May of 2015 with several months' history of progressive weight loss, intermittent upper abdominal pain, recurrent nausea, vomiting, and loss of appetite. His medical background included history of stage 3 chronic kidney disease, prostate cancer, gout, hypertension, dyslipidemia, hypothyroidism, and benign splenic hemangiomas. He was only on levothyroxine and folic acid prior to admission. His physical examination was normal but he was markedly dehydrated. His initial blood tests are presented in Table 2.

Table 2.

Initial Biochemical Investigations of Case 2

Parameter	Patient's value (reference range)	Parameter	Patient's value (reference range)
Calcium	3.06 mmol/L (2.13–2.55 mmol/L)	Thyroid-stimulating hormone	4.11 mU/L (0.27–4.20 mU/L)
Albumin	37 g/L (35–50 g/L)	Hemoglobin	131 g/L (130–180 g/L)
Adjusted calcium	3.3 mmol/L (2.2–2.6 mmol/L)	Autoimmune screen	Normal
Urea	18.3 mmol/L (2.5–7.8 mmol/L)	Immunoglobulins	Normal
Creatinine	183 μmol/L (58–110 μmol/L)	Light chains (kappa and lambda)	Normal
Parathyroid hormone	1.2 pmol/L (1.6–6.9 pmol/L)	Serum protein electrophoresis	Normal
25-hydroxyvitamin D	36 nmol/L (>50 nmol/L)	Urine Bence Jones proteins	Normal
24-hour urine calcium	6.6 mmol/24 hours (2.5–7.5 mmol/24 hours)	Prostate-specific antigen	9 μg/L (<3 μg/L)
Angiotensin-converting enzyme	89 U/L (8–65 U/L)	Tumor markers	Normal

He was admitted for intravenous rehydration and over the next 4 to 7 days his calcium remained elevated (average from 2.78 to 2.92 mmol/L). He received intravenous pamidronate on 3 occasions which eventually settled his calcium into a normal range (2.57 mmol/L). A nuclear bone scan only showed evidence of scattered osteoarthritis in different joints. A CT scan of the thorax, abdomen, and pelvis was normal except the presence of 3 splenic hemangiomas that looked benign. Ultrasound of the kidneys, ureters, and bladder showed an enlarged prostate gland.

Over the next few days, his blood results improved. Average calcium levels remained normal (2.44 to 2.56 mmol/L) but PTH remained low (1.6 pmol/L) and kidney function returned to baseline (140 μmol/L). He was discharged with outpatient follow-up appointments in the endocrinology, urology, nephrology, and gastroenterology (he was also diagnosed with iron-deficiency anemia during his inpatient stay) clinics. As part of the investigation for the iron-deficiency anemia, he had a virtual CT colonogram which showed evidence of moderate calcification of the pancreas. An upper GI endoscopy showed evidence of esophagitis, gastritis, and a large duodenal ulcer.

He was admitted electively from the endoscopy unit for intravenous infusion of proton pump inhibitors and then was subsequently discharged after a few days on a high dose of oral proton pump inhibitors. The histology of the stomach biopsy confirmed evidence of mildly active chronic gastritis with the presence of multiple non-caseating epithelioid granulomas including multi-nucleated giant cells (Fig. 2). Both the Ziehl-Neelsen stain and Finkelstein's stain were negative. Plans were made to assess fecal calprotectin levels and repeat the upper GI endoscopy over the next few weeks to confirm the diagnosis.

Fig. 2.

Histology of the stomach showing non-caseating epithelioid granulomas.

Over the next few months, he persisted to have intermittent hypercalcemia (from 2.66 to 2.80 mmol/L) with one record of 3.08 mmol/L. His renal function gradually worsened (average creatinine from 269 to 292 μmol/L). He attended the renal clinic on multiple occasions and a suggestion was made for a renal biopsy which the patient declined. As planned, fecal calprotectin was assessed and found elevated (185.3 μg/g; reference range is <50 μg/g) and a repeat upper GI endoscopy showed normal macroscopic appearance of the esophagus, stomach, and duodenum but the histology confirmed the presence of a single crypt abscess with marked lymphoplasmocytic infiltrate, focal gland loss, and fibrosis (Fig. 3). The most likely differential diagnosis was chronic granulomatous gastritis due to Crohn disease.

Fig. 3.

Histology of the stomach showing lymphoplasmocytic infiltration with focal gland loss.

The patient continued to have poor appetite and lost >11 kg over the course of a year. In one of his visits to the gastroenterology clinic, he was commenced on prednisolone at 30 mg/day for 2 weeks and then was tapered down by 5 mg every week. He responded to the steroid treatment with improvement in weight by (gaining >13 kg within 4 to 5 months) and his calcium level settled down completely (average from 2.36 to 2.58 mmol/L). In due course his prednisolone tablets were changed to budesonide at 3 mg taken 3 times daily. At present, he remains well on budesonide and is completely asymptomatic and remains under follow up in multiple clinics.

DISCUSSION

We have described 2 cases where GD of unusual sites has contributed to PTH-independent hypercalcemia. In both cases, the severity of hypercalcemia was significant and needed extensive investigation to establish a diagnosis. Although hypercalcemia due to common GDs like sarcoidosis, tuberculosis, and systemic fungal infections are well established (10), in recent years systemic GD leading to hypercalcemia involving muscles (7,8), skin (11), or kidneys (12) are being reported more frequently. In addition, there has been also a significant rise in cases of hypercalcemia where granulomatous reactions have been identified with injections of silicone (6), methacrylate (13), or talc (14). Hypercalcemia due to granuloma formation in unusual sites such as our cases are usually mediated by elevated levels of 1,25(OH)₂D. A full list of rare causes is presented in Table 3.

Table 3.

Rare Causes of Hypercalcemia Associated with Granuloma Formation and Elevated 1,25-Dihydroxyvitamin D3 ^*

Crohn disease Wegener granulomatosis Hepatic granulomas in chronic dialysis Granulomatous interstitial nephritis Langerhans cell histiocytosis Cat-scratch fever Acute granulomatous pneumonia Lipoid pneumonia Granulomatous myositis Lymphomatoid/angiocentric granulomatosis Plasma cell granuloma Subcutaneous fat necrosis of newborn Talc granulomatosis Silicone granulomatosis Paraffin granulomatosis Bacillus of Calmette-Guerin (BCG) therapy 8-Cl-cAMP therapy Methyl methacrylate therapy

^*For more information see references 7–9, 12, and 15.

In case 1, the levels of 1,25(OH)₂D were markedly elevated and contributed to rapid diagnosis. Unfortunately, 1,25(OH)₂D was not estimated in case 2 which probably delayed diagnosis. Activated macrophages within granulomas exhibit increased 1α-hydroxylase activity, which is responsible for increased enzymatic activation of 25-hydroxyvitamin D to 1,25(OH)₂D (15). Excessive levels of 1,25(OH)₂D enhance intestinal absorption of calcium and promote osteoclast-mediated calcium resorption from bone leading to hypercalcemia. The distinguishing feature of extra-renal 1α-hydroxylase is that it is independent of normal feedback mechanisms, including failure to upregulate the enzyme 1,25 dihydroxyvitamin D 24-hydroxylase (16).

In some cases, hypercalcemia has been also reported with granulomatous pathology where 1,25(OH)₂D levels were normal or low (17,18). Certain malignancies like non-Hodgkin lymphoma, seminoma, dysgerminoma, and squamous cell bronchogenic carcinoma may also be associated with elevated levels of 1,25(OH)₂D. Hypercalcemia in these circumstances is usually due to granulomatous inflammatory response surrounding the tumor or in adjacent lymph nodes, implicating tissue macrophages rather than the tumor itself in elevated 1,25(OH)₂D production (7,19).

In 1,25(OH)₂D-mediated hypercalcemia, the most effective therapy should be targeted towards the underlying cause. Glucocorticoids are very useful as an adjunct to the primary disease treatment as the extra-renal 1α-hydroxylase within granulomatous tissue is sensitive to suppression by glucocorticoids (16). Steroids cause a fall in serum 1,25(OH)₂D and calcium within 3 to 5 days (20), but long-term maintenance with glucocorticoids is usually required for ongoing suppression of 1α-hydroxylase activity and to maintain normocalcemia. Other agents like chloroquine and hydroxychloroquine have also been found to be effective in lowering calcium levels in these circumstances (10,21).

CONCLUSION

Our cases highlight the diagnostic challenges that clinicians may face when hypercalcemia is driven by a non PTH-mediated autonomous 1α-hydroxylase activity in GD involving rare and unusual sites. We have developed a simple algorithm (Fig. 4) which clinicians might find helpful when evaluating patients with similar presentations. Measurement of vitamin D metabolites like 1,25(OH)₂D would be key in making a diagnosis in such difficult cases, and prompt initiation of glucocorticoid therapy would be very effective in lowering calcium concentrations.

Fig. 4.

Algorithm for diagnosis of hypercalcemia with suppressed parathyroid hormone. ACE = angiotensin converting enzyme; CT = computed tomography; IGF1 = insulin-like growth factor 1; MRI = magnetic resonance imagery; PTH = parathyroid hormone; PTHrp = parathyroid hormone related protein; 1,25(OH)₂D = Calcitrol; TFT = thyroid function test.

Abbreviations:

1,25(OH)₂D

1,25-dihydroxyvitamin D3

CT

computed tomography

GD

granulomatous disease

GI

gastrointestinal

PTH

parathyroid hormone