351

CASE REPORT
Acute hypercalcemia and hypervitaminosis D associatedwith pulmonary tuberculosis in an elderly patient :A case report and review of the literature.
Toshihiro Wada1, Masaki Hanibuchi2, and Atsuro Saijo2
Department of Internal Medicine, 2Department of Respiratory Medicine, Shikoku Central Hospital of the Mutual Aid Association of Public
School teachers, 2233 Kawanoe-cho, Shikoku-Chuo, 799-0193, Japan
1

Abstract : An 80-year-old man was referred to our hospital for further examination of fever, cough and left pleural effusion. The laboratory findings showed acute inflammation, and the elevation of albumin-corrected serum
calcium and 1,25-dihydroxyvitamin D3. A chest CT revealed centrilobular particulate opacity in the bilateral lungfields and left pleural effusion, indicating acute hypercalcemia and hypervitaminosis D associated with pulmonary tuberculosis. By the confirmation of Mycobacterium tuberculosis on polymerase chain reaction and culturesof the sputum and pleural effusion, a diagnosis of pulmonary tuberculosis was made. The patient successfullycompleted a 9-month course of the anti-tuberculosis treatment, and bilateral infiltrative shadows and left pleural
effusion in chest X-ray disappeared. Symptoms progressively improved and serum level of albumin-corrected calcium and 1,25-dihydroxyvitamin D3 eventually normalized. While pulmonary tuberculosis is an infrequent causeof hypercalcemia, it should be considered in patients with hypercalcemia and elevated serum level of 1,25-dihydroxyvitamin D3. J. Med. Invest. 66 : 351-354, August, 2019
Keywords : pulmonary tuberculosis, hypercalcemia, 1,25-dihydroxyvitamin D3INTRODUCTION
The most important causes of hypercalcemia in the elderly are
hyperparathyroidism, malignant disease and prolonged immobilization. Medications, such as thiazide diuretics and lithium,
as well as excessive supplementation with calcium/vitamin D,
may precipitate hypercalcemia (1). Granulomatous disorders,such as sarcoidosis and tuberculosis, can also potentially present
with hypercalcemia. Although hypercalcemia is known to be associated with pulmonary tuberculosis, it is relatively uncommon(2, 3). We herein report an elderly case of pulmonary tuberculosis
with hypercalcemia and hypervitaminosis D. In the present report, we highlight pulmonary tuberculosis as a potential causeof hypercalcemia and hypervitaminosis D, as well as discuss theprevalence and the putative mechanisms of tuberculous hypercalcemia through the review of the literature.

CASE REPORT
An 80-year-old man was referred to our hospital for further
examination of left pleural effusion. On admission, low grade
fever and productive cough had persisted for approximately ninemonths. His medical history included hypertension, vibrationdisease and fracture of left clavicle. No significant social or family
history was reported. His body temperature was 36.7 ℃, a bloodpressure of 110/74 mmHg, a pulse of 60 beats per minute andan oxygen saturation of 97% on room air. There were no evident
cervical, supraclavicular and axillar lymphadenopathies. The
Abbreviations
corrected Ca, albumin-corrected calcium ; 1,25-(OH)2D3 , 1,25-dihydroxyvitamin D3 ; PTH, parathyroid hormone ; INH, isoniazid ; RFP,rifampicin ; EB, ethambutol ; IFN-γ, interferon gamma

cardiovascular examination was unremarkable. Respiratory
sounds were decreased in the left lower lung field. The remainder of the physical examination was normal. The laboratory
findings on admission indicate acute inflammation (white blood
cell count 6500/μL, C-reactive protein 4.35 mg/dL) and renal
dysfunction (urea nitrogen 27.8 mg/dL, creatinine 2.94 mg/dL). The albumin-corrected serum calcium (corrected Ca) and
1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) were elevated at 12.4
mg/dL and 151.0 pg/mL, respectively, but intact parathyroid hormone (PTH), PTH-related protein and angiotensin converting
enzyme were within normal range. The remainder of laboratory
test results is shown in Table 1. A chest X-ray demonstrated
bilateral infiltrative shadows and left massive pleural effusion(Fig. 1A). A chest CT revealed centrilobular particulate opacities
and consolidations in the bilateral lung fields and left massive
pleural effusion (Fig. 1B). Several differential diagnoses wereconsidered at this juncture. In our patient, there was neither
a reported history of excessive calcium/vitamin D intake nor
consumption of thiazides. Laboratory tests and systemic radiological scans excluded any malignancies and endocrinopathies.
In view of the radiological findings, a diagnosis of hypercalcemia
and hypervitaminosis D secondary to pulmonary tuberculosis
was formulated. By the confirmation of Mycobacterium tuberculosis on polymerase chain reaction and cultures of the sputum
and pleural effusion, a diagnosis of pulmonary tuberculosis(bIII2, lPl ; The classification of The Japanese Society for Tuberculosis) was made. The isolated strain was susceptible to allanti-tuberculosis drugs. Immediately after diagnosis, the patient
received an anti-tuberculosis treatment comprising daily dosing
Received for publication April 26, 2019 ; accepted June 9, 2019.
Address correspondence and reprint requests to Masaki Hanibuchi,
Department of Respiratory Medicine, Shikoku Central Hospital of the
Mutual Aid Association of Public School teachers, 2233 Kawanoe-cho,
Shikoku-Chuo, 799-0193, Japan and Fax : +81-896-58-3464.

The Journal of Medical Investigation Vol. 66 2019

T. Wada, et al. Pulmonary tuberculosis with hypercalcemia

352

Table 1. Laboratory data on admissionHematology

Na

136 mEq/L

PR3-ANCA< 1.0 U/mL

WBC

6,500 /μL

K

4.4 mEq/L

MPO-ANCA< 1.0 U/mL

Neu

80.9 %

Cl

410 mEq/L

Lymph

9.8 %

Ca

11.6 mg/dL

Mono

7.6 %

P

4.1 mg/dL

pH

Eos

1.1 %

CRP

4.35 mg/dL

specific gravity

0.6 %HbA1c (NGSP)

5.9 %

Sugar

－BS

129 mg/dL

Occult blood

±

Baso
RBC

368×104 /μL

Urinalysis

Hb

10.3 g/dL

1,25(OH)2D3

151 pg/mL

ProteinHt

30.8 %

intact PTH

7 pg/mL

Sediment

Plt

43.2×104 /μL

BiochemistryPTHrP

6.51.009－
W.N.L.

< 1.0 pmol/L

ACE

3.1 IU/L

Analysis for acid-fast bacilli

AST

48 IU/L

KL-6404 U/mL

SputumALT

44 IU/L

β-D-glucan< 5.0 pg/mL

Smear

−

ALP

214 IU/L

Culture＋LDH

299 IU/L

TB-PCR＋γ-GTP

24 IU/L−Immunology
IgG

1,177 mg/dL

MAC-PCR
Pleural effusion

T-bil

0.59 mg/dL

IgA

334 mg/dL

CK

261 U/L

IgM

79 mg/dL

Smear−

TP

6.5 g/dL

C3113 mg/dL

Culture＋Alb

3.2 g/dL

C438 mg/dL

TB-PCR＋

BUN27.8 mg/dL

CH5045.8 U/mL

MAC-PCR−Cre

2.94 mg/dL

anti-nuclear antibody< 40ACE, angiotensin-converting enzyme ; KL-6, krebs von den lungen-6 ; ANCA, antineutrophil cytoplasmic antibody ; TB, tuberculosis ;MAC, Mycobacterium-avium complex

Figure 1A

Figure 1B

Figure 1. Chest X-ray and Chest CT on admission. Bilateral infiltrative shadows and left massive pleural effusion were evident in chest
X-ray (Figure 1A). A chest CT revealed centrilobular particulate opacities and consolidations in the bilateral lung fields and left massive pleuraleffusion (Figure 1B).

of isoniazid (INH) 300 mg and rifampicin (RFP) 450 mg, andalternate-day administration of ethambutol (EB) 750 mg fortwo months followed by daily dosing of INH and RFP for sevenmonths. The dose of EB was adjusted according to the degreeof renal dysfunction. In terms of treatment for hypercalcemia,
intravenous saline was also administered. After receiving thesetreatments, the patient’s symptoms progressively improvedand serum level of corrected Ca and 1,25-(OH)2D3 eventuallynormalized at 9.0 mg/dL and 29.6 pg/mL, respectively. Finally,
the patient successfully completed a 9-month course of theanti-tuberculosis treatment, and bilateral infiltrative shadows
and pleural effusion in chest X-ray and chest CT disappeared(Fig. 2A, B).

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The Journal of Medical Investigation Vol. 66 August 2019

Figure 2B

Figure 2A

Figure 2. Chest X-ray and Chest CT after a 9-month course of the anti-tuberculosis treatment. Bilateral infiltrative shadows and left pleural
effusion disappeared in both chest X-ray (Figure 2A) and chest CT (Figure 2B).

DISCUSSION
The present case reminds us of the importance of pulmonary
tuberculosis as a cause of hypercalcemia especially in elderly
patients. While pulmonary tuberculosis is an infrequent causeof hypercalcemia (4), it should be considered in patients withhypercalcemia and elevated serum level of 1.25-(OH)2D3. Whenever pulmonary tuberculosis is suspected, timely diagnosis andtreatment are mandatory.
Main causes of hypercalcemia include primary hyperparathyroidism, malignancies, drugs and granulomatous diseases,
although relative frequency is different between various regions(5). Primary hyperparathyroidism is the most frequent cause,
but cancer and drugs have been recently identified as the causes
with increased frequency, especially in elderly patients becauseof the greater risk for malignancy and increased use of vitamin
D supplements. However, following these three major causesof hypercalcemia, granulomatous diseases remain importantcauses for hypercalcemia and these include sarcoidosis, histoplasmosis, coccidioidomycosis and candidiasis in addition totuberculosis. Finally, other rare causes include hyperthyroidism.
Investigations for causes of hypercalcemia include detailed history-taking, physical examination and logical use of laboratory
tests. The use of vitamin D or calcium should be sought andphysical examination should be performed for looking for a cluesuggestive of possible malignancy or granulomatous diseases.

The prevalence of hypercalcemia in patients with tuberculosis
is quite variable between countries, varying from approximately
2.3% in some studies (3) to 14.7-50.6% in other studies (6-14)(Table 2). This variation has been largely attributed to disparity
in vitamin D and calcium intake, the degree of sunlight exposure
as well as the criteria for the diagnosis for hypercalcemia (4).
Generally, studies using the albumin-adjusted serum calcium
concentration have reported higher prevalence rates comparedwith patients who did not use correction (7, 9). In the elderly patient with tuberculosis, the frequency of hypercalcemia has notbeen well documented. Although clinically significant hypercalcemia from tuberculosis is relatively uncommon, the elderly patient seems to be particularly susceptible, given their advanced
age, comorbidities, polypharmacy as well as the frequent use ofcalcium/vitamin D supplements. In the present case, serum levelof corrected Ca and 1,25-(OH)2D3 eventually normalized with acontinued treatment of tuberculosis, as reported previously (1).
Although hypercalcemia associated with pulmonary tuberculosis is relatively uncommon and is rarely symptomatic, prompt
diagnosis and appropriate treatment is very important.
The mechanism of tuberculous hypercalcemia remains unclear, but has been largely attributed to vitamin D dysregulation. Patients presenting with tuberculosis tend to have lower
levels of vitamin D than healthy individuals (15). In patientswith tuberculosis, extrarenal synthesis of active vitamin D,
1,25(OH)2D3, occurs via 1-α-hydroxylase produced by interferon

Table 2. Summary of the prevalence of hypercalcemia in pulmonary tuberculosis
Author

YearCountry

N

Prevalence

Methodology*Abbasi AA1979

U.S.A.

79

27.8%

Ionized calcium

Reference No.
6

Need AG1980Australia

89

50.6%

Albumin-adjusted calcium

7

Sharma SC

1981

India

94

15.5%

Ionized calcium

8

Kitrou MP

1983

Greece50

48.0%Albumin-adjusted calcium

9Lind L1990

Sweden67

25.4%

Ionized calcium

10Tan TT

1993

Malaysia

43

2.3%

Ionized calcium

3

Chan TY

1994

China

34

5.9%

Ionized calcium

11

Chan TY

1994

China

34

14.7%

Albumin-adjusted calcium

11

Liam CK1998

Malaysia

120

27.5%

Albumin-adjusted calcium

12

Roussos A

2001

Greece8825.0%Albumin-adjusted calcium

13

Dosumu EA

2006

Nigeria

120

27.5%

Albumin-adjusted calcium14*Methodology for the diagnosis of hypercalcemia

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T. Wada, et al. Pulmonary tuberculosis with hypercalcemia

gamma (IFN-γ)-activated T lymphocytes and alveolar macrophages (16, 17), which results in increased enteric absorptionof calcium. In vitro, vitamin D promotes mycobacterial killing inmacrophages through production of nitric oxide (18), as well as
the antimicrobial peptide cathelicidin LL-37, after activation ofmacrophages via either Toll-like receptor or IFN-γ release (19,20), and by inducing phagolysosyme fusion and autophagy (20,21). These effects have been shown to be local (22) and does notnormally affect overall calcium homeostasis. In addition, 1,25(OH)2D3 induces 24-(OH) hydroxylase expression, which deactivates 1,25-(OH)2D3 to calcitroic acid. However, it is believed that
if large quantities of 1,25-(OH)2D3 are produced, a ‘spillover’
effect may occur in the circulation and potentially result in
hypercalcemia (23). It should be also kept in mind that RFPand INH may alter concentrations of serum 25-hydroxyvitamin
D3 and 1,25-(OH)2D3 and thereby reduce the degree of hypercalcemia. RFP induces several enzymes (CYP3A4, CYP24A1,and uridine 5’-diphospho-glucuronyltransferases) that degrade
25-hydroxyvitamin D3 and, by reducing substrate, reduce 1,25(OH)2D3 concentrations (24). In contrast, INH inhibits 1,25(OH)2D3 synthesis (13). Further study is warranted to elucidate
the appropriate mechanism of tuberculous hypercalcemia.
In conclusion, we herein report a case of pulmonary tuberculosis with hypercalcemia and hypervitaminosis D and discuss theprevalence and the putative mechanisms of tuberculous hypercalcemia through the review of the literature. While pulmonary
tuberculosis is an infrequent cause of hypercalcemia, it should beconsidered in patients with hypercalcemia and elevated serum
level of 1.25-(OH)2D3 especially in the elderly.

CONFLICT OF INTEREST DISCLOSURE
The authors have stated that we have no conflicts of interest.

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