An unusual case of hypercalcemia in a patient of concomitant hypoparathyroidism and celiac disease

Summary

Milk alkali syndrome has shown resurgence with increase in use of (prescription or non prescription) calcium supplements. Cases of iatrogenic vitamin D intoxication has also increased due to increasing use of high doses of injectable vitamin D formulations by physicians, surgeons, orthopaedicians, gynecologists and other specialties inadvertently. Here, we present an unusual case of a 17-year-old boy who presented with iatrogenic hypercalcemia as a result of combination of milk alkali syndrome with vitamin D intoxication despite being a case of hypoparathyroidism and concomitantly suffering from celiac disease.

Introduction

Hypoparathyroidism is characterized by hypocalcemia and hyperphosphatemia due to deficiency of parathyroid hormone. Treatment with oral calcium and activated vitamin D is rarely able to achieve target calcium levels and most patients continue to have frequent symptomatic exacerbations. Concomitant celiac disease may further worsen hypocalcemia by interfering with intestinal calcium absorption. Hypercalcemia in a patient with hypoparathyroidism has rarely been described (1). Here we discuss a case of primary hypoparathyroidism with celiac disease who presented with hypercalcemia as a result of combined milk-alkali syndrome and vitamin D intoxication.

Case report

A 17-year-old boy presented with complaints of insidious onset, unintentional weight loss (~12 kg), anorexia and easy fatigability for last 2 months. There was no history of fever, cough, diarrhea, constipation, tremulousness, palpitations, headache, rash, pedal edema, polyuria, polydipsia, decreased urine output, dyspnoea on exertion or postural dizziness. He was diagnosed with primary hypoparathyroidism 1 year back when he presented with repeated episodes of carpopedal spasms and was on calcium supplements ever since. There was no history of blood transfusion, high risk sexual behavior or significant family history.

On examination he was visibly pale, thin built, lean patient, well oriented in time, place and person. Anthropometry revealed height – 168 cm, weight – 42 kg, BMI – 14.89 kg/m²; upper segment/lower segment ratio – 0.85 and arm span –170 cm. Vital examination revealed tachycardia (pulse –110/min) and hypotension (systolic BP/diastolic BP – 90/62 mm Hg) with no postural fall. He had pallor with signs of dehydration. There was no icterus, clubbing, lymphadenopathy, pedal edema, goiter, tremors, vitiligo, candidiasis or cutaneous/mucosal hyperpigmentation. Systemic examination was unremarkable.

Preliminary investigations revealed microcytic hypochromic anemia, azotemia, metabolic alkalosis with hypercalcemia (haemoglobin – 7.5 g/dl, total WBC count – 18.000/cumm, differential count: neutrophils – 84%, lymphocytes – 14%; platelet count – 3.9 X 10⁵/cmm, MCV – 66 fl, ESR – 140 mm in 1 hour, blood urea nitrogen – 42 mg/dl, serum creatinine –2.2 mg/dl, blood gas analysis: pH – 7.55, pCO2 – 36, HCO³⁻- 28, serum calcium – 13.4 mg/dl, corrected calcium – 14.4 mg/dl, phosphorus – 4 mg/dl, alkaline phosphatase – 45 IU/L, total protein – 8.5 g/dl, albumin – 2.8 g/dl, 24 hr urinary protein – 1.4 gm. Rest of the biochemical studies (Na+/K+ - 134/3.6 mmol/L, S. bilirubin – 0.9 mg/dl, ALT/AST – 14/26 U/L, random blood glucose – 95 mg/dl), urine examination, ECG & chest X-ray were normal. Further evaluation revealed serum iron – 30 (60–160) μg/dl, TIBC – 438 (250–380) μg/dl, Ferritin – 30 (10–150) ng/ml, iPTH was low - 2.4 (10–65) pg/ml and 25(OH) vitamin D was high - 288 (75–250) nmol/L. There were no lytic lesions on skeletal survey, normal LDH –598 U/L, negative Mantoux test (5 mm induration). Ultrasound abdomen showed altered cortico-medullary differentiation of kidneys bilaterally, periportal and mesenteric lymphadenopathy. Sputum examination was negative for acid fast bacilli. Non contrast CT of chest and abdomen revealed diffuse lymphadenopathy. FDG whole body PET scan showed FDG avid right supraclavicular, mediastinal, hilar, paratracheal and abdominal lymphadenopathy. Associated autoimmune diseases were screened that revealed elevated anti – tTG IgA antibody (190 U/L;N < 15) and endoscopic duodenal biopsy confirmed diagnosis of celiac disease. Anti TPO antibody assay, thyroid function tests (T4 – 9.4 μg/dl, TSH – 3.5 uIU/ml) and basal serum cortisol (15.9 μg/dl) were normal. Thus, a presumptive diagnosis of primary hypoparathyroidism with celiac disease and hypercalcemia due to milk alkali syndrome was made.

He was started on gluten free diet (GFD). Serum calcium, BUN and creatinine improved with saline diuresis (corrected calcium – 12.4 mg/dl, BUN – 14 mg/dl, creatinine – 1.2 mg/dl). Treatment and dietary history was revisited and revealed that apart from daily 3 tablets of 500 mg calcium carbonate, patient had received 8 weekly intramuscular injections of calcitriol 6,00,000 units in past 3 months (total −48,00,000 units) and was consuming around 800 – 1000 ml of milk with plenty of curd daily, as advised by his treating physician. Thus, his hypercalcemia was ascribed to be due to combined effects of milk-alkali syndrome (MAS) and vitamin D intoxication. After his creatinine was normalized, in view of persistent hypercalcemia, he was given injection zoledronic acid 4 mg intravenously. Calcium levels and appetite gradually improved over next 10–15 days and prior to discharge he had gained about 3 kg weight. Lymphadenopathy improved spontaneously without active management. He was discharged on hematinics and was advised for strict GFD with dietary restriction of calcium. He continued to show gradual improvement on subsequent follow up and remained asymptomatic, however, vitamin D levels continued to be elevated for about 9 months. Table 1 shows evaluation at 3, 6 & 12 months of follow up. After about 12 months of primary admission, he started having peripheral tingling, numbness & muscular spasms again. Evaluation showed hypocalcemia with low PTH which was concurrent with his primary diagnosis (S. Ca+ - 6.8 mg/dl, phosphorus – 5.2 mg/dl, iPTH – 5.4 pg/ml, 25(OH)vit D – 158 nmol/L). He has been restarted on oral calcium, continued on GFD and is under regular follow-up.

Table 1.

Clinical and biochemical parameters at baseline, 3, 6 and 12 month follow-up.

Time	Wt. (kg)	Hb (g/dl)	Corrected Calcium (mg/dl)	Phosphorus (mg/dl)	ALP (IU/L)	iPTH (pg/ml)	25(OH)vit D (nmol/L)	1,25(OH)vit D (pmol/L)
Normal range	-	13–15	8.4–10.4	2.5–4.5		10–65	75–250	39–193
On admission	42	7.5	14.4	4.0	45	2.4	288	19
On discharge	44	9.0	10.2	3.8	56	1.9	-	-
3 month follow-up	50	10.6	9.1	3.7	74	< 0.23	>375	-
6 month follow-up	54	11.3	8.9	4.0	52	2.5	359	-
12 month follow-up	54	10.2	6.8	5.2	126	5.4	158	-

Discussion

Primary hypoparathyroidism is characterized by recurrent tetany, hypocalcemia, hyperphosphatemia & low iPTH. Treatment includes oral/parenteral calcium and activated vitamin D supplementation, however, recently PTH(1–34) and PTH(1–84) have also been used as replacement therapy. The doses required to avoid tetany in most patients varies greatly ranging from 1–9 gm/day of oral calcium and 0.25–2 μg of activated vitamin D (2). However, even with diligent therapy normocalcemia is rarely achieved and emergency room visits for tetanic spasms are common. After postoperative hypoparathyroidism, autoimmune process is the most common etiology causing hypoparathyroidism (2) and it is frequently associated with other autoimmune disorders like Addisons’ disease, Type 1 diabetes mellitus, primary hypothyroidism, vitiligo, celiac disease. Screening of other autoimmune disorders is recommended in each patient suspected of autoimmune hypoparathyroidism as some of them may be completely asymptomatic (2, 3). On autoimmune screening our patient was found to have celiac disease and was subsequently advised for GFD.

Hypercalcemia can occur in the setting of either high or low PTH (Table 2). Milk-alkali syndrome (MAS) is characterized by triad of hypercalcemia, metabolic alkalosis and renal insufficiency associated with ingestion of large amounts of calcium and absorbable alkali. It was classically described in patients with peptic ulcer disease treated with Sippy’s diet (milk and sodium bicarbonate). With widespread availability of drugs like H2 blockers and proton pump inhibitors, MAS became rare. However, in recent years there has been resurgence in the occurrence of MAS due to inadvertent intake of prescription or sometimes non-prescription calcium preparations (4). MAS was the third most common cause of hypercalcemia, after hyperparathyroidism and malignancy, in non-ESRD hospitalized patients and it was second most common cause of severe hypercalcemia (5). Pathogenesis of MAS is not completely understood. Excess intake of oral calcium and absorbable alkali and associated renal insufficiency are prerequisites for its development. However, milk-alkali may develop without renal insufficiency; on the other hand, ingesting large amounts of calcium and alkali does not necessarily results into MAS. Hypercalcemia impairs renal concentrating capacity, causes diuresis, dehydration, impairs renal excretion of alkali aggravating metabolic alkalosis. Impaired renal function further worsens hypercalcemia and alkalosis (6). Similarly in our case, patient was advised to take oral calcium preparations (1500 mg/day) along with plenty of milk and milk products, presence of altered renal functions and large doses of injectable vitamin D therapy probably resulted MAS with vitamin D toxicity to cause hypercalcemia.

Table 2.

Causes of hypercalcemia.

PTH-dependent

PTH-independent

Parathyroid adenoma Parathyroid hyperplasia Parathyroid carcinoma Tertiary hyperparathyroidism Lithium therapy Familial hypocalciuric hypercalcemia

Malignancy - CA Breast - metastasis - CA Lung, Kidney - PTHrP - Multiple myeloma. Leukemia Milk-alkali syndrome Granulomatous disorders (Increased 25α-hydroxylase activity) - Tuberculosis - Sarcoidosis - Lymphoma Endocrine disorders - Addison’s disease - Hyperthyroidism Vitamin D intoxication Vitamin A intoxication Prolonged immobilization Thiazide diuretics Williams Syndrome Jansen’s Metaphyseal Dysplasia

The Institute of Medicine (IOM) has defined the “tolerable upper intake level” (UL) for vitamin D as 100 mcg (4000 IU) daily for healthy adults and children 9–18 years (7). In studies determining vitamin D safety and efficacy, considering hypercalcemia as a critical effect, the adverse effect occurring at the lowest intake, there were no increases in mean calcium levels with higher vitamin D intakes tested in controlled trials up to 100,000 IU per day (8). Common circumstances of vitamin D intoxication are wrong formulations, prescriptions, self medications, increasing use of activated vitamin D formulations for replacement and inadvertent high doses of vitamin D for musculoskeletal and joint problems (9–13). Factors predisposing an individual to vitamin D toxicity include elderly, increased calcium intake, parenteral vitamin D therapy, decreased renal function, diminished estrogen levels, presence of granulomatous diseases (14). The usual manifestations of vitamin D toxicity are due to hypercalcemia and include polyuria, polydipsia, anorexia, nausea, vomiting, headache, confusion, dehydration, hypercalciuria, kidney stones (13). Similarly in our case, the patient received mega doses of injectable activated vitamin D (total – 48,00,000 IU) preparation weekly over 8 weeks resulting in vitamin D intoxication and hypercalcemia. Treatment of vitamin D intoxication includes usual management of hypercalcemia with saline diuresis, bisphophonates and glucocorticoids. Recovery from vitamin D toxicity is variable and prolonged, as vitamin D is stored in fat, and recurrent toxicity even after stopping exposure has been seen (9). Similar pattern of delayed normalization of serum vitamin D levels was seen in our patient. Thus, inspite of presence of concomitant hypoparathyroidism and celiac disease that should cause severe hypocalcemia, inadvertent high doses of injectable vitamin D and overzealous prescription of calcium resulted in severe life threatening hypercalcemia. Uniquely our patient showed simultaneous features of two uncommon causes of hypercalcemia – milk-alkali syndrome and vitamin D toxicity. Physicians should be aware of this increasingly common cause of hypercalcemia and a thorough history of use of any form of calcium and vitamin D formulations should be obtained in each case of hypercalcemia.