Dear Editor,
Hypercalcemia is a common metabolic abnormality in tuberculosis. It is usually mild
and asymptomatic. We report a patient presenting with severe hypercalcemia and renal
failure secondary to pulmonary tuberculosis.
Presenting a 41 year old daily labourer presented with the complaints of being unwell
for a year. He also complained of low-grade fever, chronic productive cough, loss
of appetite, and weight loss of 20 kg during the same time. Two months before the
presentation, he had developed extreme tiredness and fatiguability and on evaluation
was found to be anemic requiring two units of packed red cell transfusions elsewhere.
On general examination, he was emaciated, dehydrated, and pale. His vitals were normal
except a temperature of 100.2 F. Chest examination revealed bronchial breath sounds
in the right infraclavicular and mammary regions with generalized hollowing of the
supraclavicular and infraclavicular region suggesting a fibrocavitary lesion in the
right upper lobe. Rest of the systemic examination was unremarkable. On admission,
his blood investigations revealed hemoglobin of 5.3 mg/dl (mean curpuscular volme:
61.4 fL, reticulocyte: 0.80%), total white cell count of 5400 with 83% neutrophil,
9% lymphocytes, 8% monocytes, and platelets 4.27 lakh. Biochemical investigations
revealed a serum calcium of 14.2 (is it 14.2 or 14.6) (8.3–10.4 mg/dl), phosphate
of 2.5 (2.5–4.6 mg/dl), parathyroid hormone of 11.7 (8.0–74 pg/ml), alkaline phosphatase
of 87 (40–125 U/L), serum creatinine of 2.55 mg%, and serum urea 68 mg/dl. The urine
24 h measured 4980 ml with a 24 h urinary calcium of 408 mg/24 h (<240 mg/24 h). Blood
urea nitrogen/creatinine ratio was 9.55 suggesting an intrinsic renal pathology. Urine
analysis was normal. Chest radiograph revealed a fibrocavitary lesion involving the
right and left upper lobe [Figure 1]. On ultrasonography of abdomen, kidneys were
of normal shape and volume with no evidence of nephrocalcinosis or nephrolithiasis.
3 sets of sputum smears were positive for acid-fast bacilli (1+, 3+, 1+), a diagnosis
of pulmonary tuberculosis was established, and the patient was initiated on appropriate
antitubercular therapy based on culture susceptibility. Evaluation of hypercalcemia
was suggestive of a parathyroid independent mechanism of hypercalcemia. He also had
an elevated Vitamin D. Hence, the cause of the hypercalcemia was attributed to extra-renal
1-alpha hydroxylase activity in the alveolar macrophages.
Figure 1
Posterior anterior chest X-ray showing the right upper lobe fibrocavitatory lesion
and left upper lobe fibrosis
Parathyroid independent hypercalcemia can occur in patients with disseminated malignancy,
multiple myeloma, and other granulomatous disorders. Hypercalcemia with new onset
renal failure could also be explained by paraproteinemias. In our patient, serum electrophoresis,
urine bence jones protein, skeletal survey, and bone marrow did not show any evidence
to suggest paraproteinemias. In view of his microcytic and hypochromic anemia with
an elevated red cell distribution width, a disseminated malignancy or lymphoproliferative
disorder could also have presented with such severe hypercalcemia. However, our patient's
tumor marker levels, malignancy workup including a bone marrow were normal. As hypercalcemia
is well documented with granulomatous disorders, it was hence attributed to tuberculosis.
He was initiated on weight-based antitubercular therapy for pulmonary tuberculosis.
With vigorous saline hydration and diuresis with frusemide, there was a serial decline
in the serum calcium [Figure 2] in the subsequent 10 days. There was also a serial
decline in the serum creatinine.
Figure 2
Decrease in calcium during hospitalization with pulmonary tuberculosis and acute kidney
injury
He was discharged in a stable condition following the management of acute severe hypercalcemia,
and is on follow-up for completion of antitubercular therapy. He was advised to avoid
excessive sun exposure, decrease oral Vitamin D, or calcium supplements and to avoid
milk products.
Hyperparathyroidism and malignancy account for 80–90% of cases of hypercalcemia.[1]
The first step in the evaluation of a patient with hypercalcemia is to assess whether
it is parathyroid dependent or independent. A normal or low parathyroid hormone level
would mean a parathyroid independent pathology. Various causes which needs to be considered
are parathyroid hormone related peptide (PTHrP) mediated hypercalcemia, activation
of extra-renal 1-alpha hydroxylase, osteolytic bone metastasis, and Vitamin D intoxication.[2]
Hypercalcemia is known to occur in granulomatous disease most commonly sarcoidosis
and tuberculosis.[3
4] The incidence of hypercalcemia in tuberculosis varies from 2% to 25% depending
on the geographical area where the study was conducted and is depended on multiple
other factors such as the intake of calcium, Vitamin D, and exposure to the sun.[5
6
7
8
9] In a study carried out in Jabalpur Military Hospital, in 94 patients with active
tuberculosis, only 5 had hypercalcemia.[10] Mechanism of hypercalcemia in tuberculosis
is considered to be due to the extra-renal production of 1,25(OH)2D3 by alveolar macrophages
and T lymphocytes possibly CD8 T lymphocytes.[11] However, hypercalcemia independent
of the following mechanism is also reported. Activated Vitamin D plays an important
role in the regulation of granulomatous inflammation and influences the cell-mediated
immunity to tuberculosis. If produced in large quantities, there may be spillage into
the systemic circulation causing severe hypercalemia.[12] Our patient also had absorptive
hypercalciuria further substantiating the presence of increased activated Vitamin
D in the circulation.[13] In the incidence studies mentioned above, it was found that
patients with granulomatous disorders and hypercalcemia were from areas where there
was increased calcium and Vitamin D consumption in their daily diet.[5
6
7
8
9] Our patient, a daily laborer also was a gentleman who used to work in the sun,
which could explain the elevated circulating activated Vitamin D causing severe hypercalcemia.
Our patient also had renal failure at presentation which could be one of the presentations
of hypercalcemia. Renal complications of hypercalcemia will depend on the degree and
duration of hypercalcemia. Severe hypercalcemia of 12–15 mg/dl can cause acute renal
failure by direct renal vasoconstriction and volume contraction causing a decrease
in glomerular filtration rate.[13] Longstanding hypercalcemia can lead to chronic
hypercalciuria causing nephrolithiasis.[13
14] In our patient, renal functions started to improve with hydration and starting
of antitubercular therapy, but it did not normalize till the last follow-up. The presence
of hypercalemia in patients with pyrexia of unknown origin requires meticulous evaluation
for tuberculosis.[14]
Conclusion
Severe hypercalcemia can be a manifestation of pulmonary tuberculosis even though
its rare. Hypercalcemia in pulmonary tuberculosis is due to excessive extra-renal
1-alpha hydroxylase activity, and hence, limiting oral Vitamin D and calcium supplements
is one of the major interventions in the treatment of hypercalcemia due to tuberculosis.
Among tuberculosis patients presenting with renal failure hypercalcemia must be looked
for and managed promptly.
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Conflicts of interest
There are no conflicts of interest.