Introduction
Tuberculosis can present in different ways which may pose difficulties in diagnosis. Extra pulmonary tuberculosis infections often lack typical clinical symptoms and imaging features. It can potentially be easily misdiagnosed leading to a delay in treatment.
Case Presentation
A 72-year-old female, with no known comorbidities, presented with complaints of 8kg weight loss in the last two months, loss of appetite, generalised fatigue and a recent onset of altered sensorium which lasted for one week. The patient did not report fever, cough, shortness of breath, haemoptysis, swelling of legs or abdominal symptoms. On clinical examination, the patient was confused (Mini mental state examination score of 14; normal score 24-30), but haemodynamically stable. A respiratory system examination revealed dull note and decreased breath sounds in both lung bases.
Initial investigations showed total leukocyte count 5.7K/ul (normal range 4-10K/ul), raised ESR of 100 mm/hr (normal range 20-35mm/hr), raised serum protein 9.2g/dl (normal range 6.4-8.3g/dl), hypoalbuminemia of 2.8g/dl (normal range 3.6-5.1 g/dl ), hyperglobulinemia of 6.0g/dl (normal range 2-3.5 g/dl) with albumin/globulin (A/G) ration reversal of 0.5. Serum Lactate dehydrogenase of 162 U/L (normal range 135-214 U/L). Serum Calcium was elevated at 13.5 mg/dl (normal range 8.6 -10.2mg/dl) and CT Thorax shows bilateral pleural effusion (Figure 1). A diagnostic thoracentesis and pleural fluid analysis showed protein 5.7g/dl (normal range 1-2 g/dl), sugar 104 mg/dl (normally similar to plasma), Lactate dehydrogenase 167.3 U/L (normally less than 50% of serum LDH). Pleural fluid adenosine deaminase level (ADA) level was of 20.8 U/L (normal range 0-40U/L). Cytology revealed 85% lymphocytes (normal less than 50%). This low ADA was inconclusive to consider the possibility of tuberculosis despite being a lymphocytic exudative effusion. Thus further evaluation was carried out.
Figure 1 CT thorax (axial plane) showing bilateral pleural effusion (black arrows)
As serum intact PTH was low at 7.3pg/ml (normal range 14.0-72pg/ml), hyperparathyroidism was ruled out. Her hypercalcaemia was managed with intravenous hydration and Zoledronic acid. Serum electrophoresis showed polyclonal gammaglobulinemia but no paraproteins. Multiple myeloma panel (by FISH technique) was negative for any chromosomal abnormalities. Bone marrow biopsy showed trilineage haematopoiesis with few scattered plasma cells. Urine Bence Jones proteins was negative. Serum free kappa/lambda ratio was normal. The patient underwent a whole body PET scan which revealed FDG avid multiple supra and infra-diaphragmatic, paracardiac lymph nodes and diffuse peritoneal uptake with multiple pericolic necrotic lymph nodes with circumferential wall thickening and luminal narrowing of terminal ileum (Figure 2). CT guided biopsy from PET avid lesion from juxtaphrenic lymph nodes was performed. Examination of biopsy specimen showed features of granulomatous inflammation with extensive necrosis (Figure 3). Rapid molecular test for tuberculosis, Xpert MTB/RIF assay of lymph node biopsy also detected mycobacterium tubercle bacillus which was sensitive to rifampicin. We initiated anti-tubercular treatment (two months of intensive phase with Isoniazid 300mg, Rifampicin 450mg, Pyrizinamide 1200mg, Ethambutol 800mg and four months of continuation phase with Isoniazid 300mg, Rifampicin 450mg and Ethambutol 800mg).
Figure 2 PET scan showing uptake in diaphragmatic nodes (green arrow), terminal ileum (red arrow)
After six weeks, AFB culture of the biopsy specimen by Mycobacterial Growth Indicator Tube (MGIT) liquid culture technique also showed the growth of Mycobacterium Tuberculosis. The patient showed good clinical response to antitubercular treatment. Her altered sensorium can be attributed to hypercalcaemic status, which showed improvement in two weeks with correction of serum calcium. Her appetite improved in four weeks with a weight gain of 6kg with six months of antitubercular treatment.
Figure 3 Histopathologic examination of lymph node showing granulomatous inflammation (yellow arrow) with necrosis (black arrows).
Discussion
Disseminated tuberculosis is defined as having two or more non-contiguous sites resulting from lympho-haematogenous dissemination of Mycobacterium tuberculosis. Extrapulmonary involvement occurs in one-fifth of all Tuberculosis cases and it may occur in the absence of histological and radiological evidence of pulmonary infection.
In this case, the patient had hypercalcaemia as a metabolic abnormality and minimal pleural effusion as a radiological abnormality. As pleural fluid results were of low ADA and a lymphocytic exudative effusion, it presented a diagnostic dilemma. Measurement of the ADA level in pleural fluid is diagnostically useful because it tends to be higher in pleural effusion of tubercular origin. In this case, a negative ADA report would have justified abandoning further diagnostic procedures for TB, and pursuing alternative diagnoses.
The evaluation for hypercalcaemia was suggestive of a parathyroid independent hypercalcaemia. Possibility of paraproteinemia was ruled out. Though the PET scan was carried out with the aim of ruling out malignancy, the unexpected detection of suspicious lesions and a timely intervention with biopsy resulted in confirmatory diagnosis of TB.
The Xpert MTB/RIF is a cartridge based nucleic acid amplification test for simultaneous rapid tuberculosis diagnosis and a rapid antibiotic sensitivity test. It is an automated diagnostic test that can identify mycobacterium tuberculosis DNA and resistance to rifampicin. The diagnostic accuracy of Xpert in lymph node samples showed sensitivities ranging from 83 to 96% and specificities ranging from 86 to 94%1. This test has higher specificity for the diagnosis in smear negative and extrapulmonary specimens.
Hyperparathyroidism and malignancy account for 80–90% of cases of hypercalcaemia. Hypercalcaemia is known to occur in granulomatous disease, most commonly in sarcoidosis and has also been reported in tuberculosis2,3. The incidence of hypercalcaemia in TB has been variably reported as ranging from 2% to 25% depending on multiple factors including geographical area, Vitamin D and calcium intake and exposure to sunlight4. Hypercalcaemia in TB is usually mild and asymptomatic. Mechanism of hypercalcaemia in TB is considered to be due to the extra-renal production of 1,25(OH)2D3 by alveolar macrophages and T lymphocytes possibly CD8 T lymphocytes5. However hypercalcaemia independent of the aforementioned mechanism has also been reported. Activated Vitamin D plays an important role in the regulation of granulomatous inflammation and influences the cell-mediated immunity to tuberculosis. Treatment of hypercalcaemia in patients with TB is aimed at controlling tuberculosis infection to decrease calcitriol synthesis and directly lower blood calcium levels. Initial treatment should involve aggressive hydration with a loop diuretic such as furosemide, avoidance of thiazide diuretics, use of calcitonin and bisphosphonates. Low-dose glucocorticoid therapy also plays a role in hypercalcaemia treatment especially if it is severe or refractory hypercalcaemia associated with mycobacterium tuberculosis6.
Conclusion
Tuberculosis is a common disease with various atypical presentations. Hypercalcaemia is commonly caused by hyperparathyroidism and malignancy. However, granulomatous diseases, especially tuberculosis, must be considered as one of the probable causes in patients who present with hypercalcaemia with coexistent pleural effusion. This case report highlights the need to consider rare presentations of a common disease in difficult case scenarios.
References
1 Seo, Y.S., Kang, J., Kim, D.S. et al. Xpert MTB/RIF assay for diagnosis of extra pulmonary tuberculosi in children: a systematic review and meta-analysis. BMC Infect Dis 20, 14 (2020)
2 Gkonos PJ, London R, Hendler ED. Hypercalcemia and elevated 1, 25-dihydroxyvitamin D levels in a patient with end-stage renal disease and active tuberculosis. New England Journal of Medicine. 1984 Dec 27;311(26):1683-5.
3 Shai F, Baker RK, Addrizzo JR, Wallach S. Hypercalcemia in mycobacterial infection. The Journal of Clinical Endocrinology & Metabolism. 1972 Feb 1;34(2):251-6.
4 Lind L, Ljunghall S. Hypercalcemia in pulmonary tuberculosis. Upsala Journal of Medical Sciences. 1990 Jan 1;95(2):157-60.
5 Cadranel J, Garabedian M, Milleron B, Guillozo H, Akoun G, Hance AJ. 1,25(OH) 2D2 production by T lymphocytes and alveolar macrophages recovered by lavage from normocalcemic patients with tuberculosis. J Clin Invest. 1990;85:1588–93.
6 Lai RP, Nakiwala JK, Meintjes G, Wilkinson RJ. The immunopathogenesis of the HIV tuberculosis immune reconstitution inflammatory syndrome. European Journal of Immunology. 2013 Aug;43(8):1995-2002.
