A complex case of clinically diagnosed tuberculosis with hypercalcemia: Not missing the tree for the forest!

Abstract

The management of tuberculosis in elderly patients often portends unexpected challenges due to multimorbidity. Although tuberculosis in endemic regions such as India may have varied manifestations, this may sometimes be misleading, and physicians may try to explain all symptoms and signs in a patient by tuberculosis, following the classical medical teaching of Occam’s razor. Here we describe the case of an elderly gentleman with clinically diagnosed central nervous system tuberculosis and co-existent advanced chronic liver disease. The presence of comorbidities impaired the prescription of usual effective antitubercular therapy. In addition, the patient had hypercalcemia, which could have been mistakenly attributed to tuberculosis, but additional workup revealed a co-existing parathyroid adenoma, whose management plan was deferred.

Introduction

Tuberculosis is a major infectious cause of morbidity and mortality worldwide. India accounts for more than 25% of global tuberculosis cases [1]. India, being a tuberculosis-endemic country, the clinical manifestations of tuberculosis are extremely diverse, and the disease affects almost every organ. Once a diagnosis of tuberculosis is made, it is common primary care practice to explain most clinical findings in light of it, and this approach is usually successful. Nevertheless, here we present the case of an older gentleman, where we had to deviate from the traditional medical teaching of Occam’s razor, and successfully evaded the possibility of missing out on an additional clinical entity in the presence of clinically diagnosed tuberculosis. Our case also highlights the challenges of managing tuberculosis in a multimorbid older patient.

Case report

A 61-year-old gentleman with diabetes was referred to our center from a secondary care hospital where he was initially admitted, with generalized body swelling, dry cough, intermittent fever with evening rise of temperature of two months duration, and fluctuating sensorium for 15 days. There were no falls, focal neurological deficit, seizures, or substance abuse. He had been on metformin- glimepiride for the past 5 years. At admission in our Geriatric inpatient unit, the patient was febrile (102⁰F), had a Glasgow Coma Scale score of 12 (E3V4M5), with pallor, bilateral pitting pedal edema, and stable vitals. Shifting dullness was detected in the abdomen.

Baseline hematological and biochemical investigations were performed (Table 1) and showed reduced hemoglobin (8.25 g/dL) and hypercalcemia (ionic calcium: 1.3 mmol/L) with normal serum phosphate (2.6 mg/dL). Magnetic resonance imaging (MRI) of the brain, performed at the referring hospital two days earlier, showed abnormal leptomeningeal enhancement along the sulci, mild vasogenic edema, and tiny enhancing tuberculoma-like lesions. Although central nervous system tuberculosis is the likeliest diagnosis in endemic regions such as India, other differentials considered included fungal meningoencephalitis and brain abscesses with bacterial meningitis. Two blood cultures sent at admission were sterile. Cerebrospinal fluid (CSF) analysis done at our center showed elevated protein (121 mg/dL) and lymphocytic pleocytosis (176 cells/mm³, 60% lymphocytes) (details in Table 1). Abdominal ultrasonography showed splenomegaly and gross ascites, and ascitic fluid analysis revealed a high serum-ascitic albumin gradient (SAAG). Further, a hepato-portal venous Doppler was suggestive of portal hypertension with dilated portal and splenic veins. A contrast-enhanced computed tomographic (CT) scan of the thorax revealed consolidation with collapse of the left upper lung lobe, a few calcified hilar lymph nodes, and bilateral pleural effusion. Based on history and available positive investigations, he was clinically diagnosed with disseminated tuberculosis (pulmonary and brain) with chronic liver disease (Child-Pugh B, Score 8).

Table 1.

Biochemical and radiological investigations of the patient.

	Laboratory Reference range		Systemic steroid started	ATT started					INH stopped
Parameters		Day 1	Day 3	Day 4	Day 7	Day 8	Day 15	Day 19	Day 21	Day 23	Day 24
Hemoglobin (g/dL)	13-17	8.25		10.58				10.4			11.2
Total leukocyte count (/µL)	4000-10000	4610 (Neutrophils, N-78%, Lymphocytes, L- 11%)		12300 (N-95%, L-3%)				15000 (N-88%, L-5%)			15600 (N-94%, L-2.7%)
Platelet count (x103/µL)	150-450	49		144				177			158
Serum creatinine/urea (mg/dL)	0.7-1.2/ 12.8-42.8	0.34/33.8		0.84/26.38				0.6/43.8
Serum sodium/potassium (meq/L)	135-145/ 3.5-5.3	133/3.2					126/3.9	127/4.4
SGOT/SGPT (U/L)	<40/ <45	42/22		38/24		68/41		105/130	134/185	100/152	80/142
Serum alkaline phosphatase (IU/L)	<270	157		178		666		477	624	655	616
Serum total protein/ Serum albumin (g/dL)	6.4-8.3/ 3.5-5.2	5.4/3.1		6.5/3.4				5.9/3	5.8/3.1
Serum total bilirubin/ direct bilirubin (mg/dL)	0-2.0/ <0.4	0.46 / 0.18		1.04/0.48				0.8/0.38	1/0.4	0.9/0.4	0.9/0.4
PT/INR	Control: 11-15	16/1.26
Serum procalcitonin (ng/mL)	<0.5			24.07			0.24				0.14
C-reactive protein (mg/L)	0-6		17.63
Serum total calcium (mg/dL)/ ionized calcium (mmol/L)/ serum phosphate (mg/dL)	8.6-10.3/ 1.15-1.27/ 2.5-4.5	10.6 /1.3/2.6				10.6/1.4/5.5
HBsAg/ Anti-HCV/ Anti- HIV-1 and 2		Non-reactive
Autoimmune liver profile							No antibodies positive
Serum electrophoresis						No M spike
Blood culture and sensitivity						Sterile
Urine routine microscopy		2-4 pus cells/high power field
Urine culture			Sterile
Intact PTH (pg/mL)	10-55				166.4
25-OH-Vitamin D3 (ng/mL)	30-100					72.57
Ultrasonography of the neck								Well-defined oval hypoechoic lesion of size 1.8 ×1.6 ×1.6 cm on the right side, posterolateral to the thyroid- likely parathyroid adenoma
MRI of the Brain (two days before admission)		Abnormal leptomeningeal enhancement along the cortical sulci of the right frontal lobe and insula with hyperintense gyral swelling, mild vasogenic edema, and tiny enhancing nodular lesions, likely tuberculoma
Cerebrospinal fluid analysis			Glucose- 97.3 mg/dL (corresponding blood glucose- 218 mg/dL) Protein- 121 mg/dL Cells- 176/µL (L-60%, N-40%) Acid fast bacilli- Not seen CBNAAT- Negative for MTB Fungal culture- Negative
Ascitic Fluid Analysis			Cytology- Negative for malignant cells ADA- 10.5 U/L Cells- 177/mm3 (88% lymphocytes) Albumin- 0.55 g/dL SAAG- High Culture- Sterile
Color Doppler ultrasound of hepato-portal venous system			Portal hypertension, moderate ascites, dilated portal vein and splenic vein

Abbreviations: ADA: Adenosine deaminase, ATT: Anti tubercular therapy, CBNAAT: Cartridge-based nucleic acid amplification test, INH: Isoniazid, INR: International normalized ratio, PTH: Parathyroid hormone, MRI: Magnetic resonance imaging, MTB: Mycobacterium tuberculosis, PT: Prothrombin time, SAAG: Serum ascitic fluid albumin gradient, SGOT: serum glutamate oxaloacetate transaminase, SGPT: Serum glutamate pyruvate transaminase

The patient was managed in the general geriatric inpatient unit, with access of non-invasive vital-sign monitoring and a continuous oxygen line, as intensive care unit beds are limited, given the large number of referred patients. Hypercalcemia was initially thought to be due to chronic tubercular granulomatosis. Intravenous normal saline (2.5 L) was administered to treat hypercalcemia, and furosemide was added after adequate hydration was achieved. For the management of neurotuberculosis, intravenous (IV) dexamethasone 8 mg q8h was administered, and considering his chronic liver disease, we initiated a modified anti-tubercular therapy (ATT) consisting of once-daily oral isoniazid 300 mg, ethambutol 800 mg, levofloxacin 750 mg, and intramuscular streptomycin 750 mg. Over the next four days, although the patient’s sensorium improved rapidly, we observed a rising trend in the serum alkaline phosphatase. Since serum calcium also remained high, further workup was performed, and serum intact parathyroid hormone (iPTH) was found to be significantly elevated. Ultrasonography of the neck showed a right-sided parathyroid adenoma of size 1.8 cm× 1.6 cm× 1.6 cm. Our management plan was focused on adequate ATT and management of the parathyroid enlargement after bacteriologic cure. An IV infusion of 4 mg zoledronate in normal saline was administered on day−13 of admission for correction of hypercalcemia. Unfortunately, the patient's sensorium again declined, and a repeat MRI of the brain showed an acute frontal lobe ischemic infarct. Other metabolic abnormalities were ruled out as possible causes of delirium. Oral aspirin-atorvastatin (75/20 mg) and IV levetiracetam were initiated with improvement in sensorium over the next 2 days.

On day−19 (day−16 of ATT), a significant elevation in hepatocellular enzymes occurred; isoniazid was stopped, and we continued the other drugs. Improvement in liver function was noted over the next few days, and the patient was discharged on day−26 in a hemodynamically and clinically stable condition. We added oral cinacalcet 30 mg twice daily, as definitive surgical management of the parathyroid adenoma had to be delayed in view of active neurotuberculosis. Follow-up was advised, but caregivers confirmed the sudden death of the patient within weeks of discharge. No autopsy was performed in accordance with prevailing social norms for non-medicolegal cases, and the exact cause of death could not be confirmed, as it happened outside our unit. Considering the fact that the patient had at least four potentially life-threatening conditions- neurotuberculosis, advanced chronic liver disease, recent cerebrovascular accident, and hyperparathyroidism, any of these could have contributed to his death.

Discussion

The case highlights multiple challenges faced by our team. Cases of suspected tuberculosis in endemic areas are often clinically diagnosed with supportive evidence from brain and lung imaging, cerebrospinal fluid analysis, or other tests, without definite microbiological or molecular proof. Since disseminated fungal infections can sometimes mimic tuberculosis, initial blood cultures are often helpful even if the patient has previously received antibiotics. This may detect not only systemic fungal infections but also secondary bacterial infections to which such patients are predisposed [2].

Hypercalcemia prevalence in tuberculosis ranges from 2.3% to 28% and is often attributed to increased 1-α-hydroxylase activity in macrophages and lymphocytes [3], [4], [5]. The risk may be higher in the presence of diabetes, renal failure, and disseminated tuberculosis [3]. The present case, however, highlights that hypercalcemia in such settings is not always attributable to tubercular disease, and other etiologies need exclusion, especially in the elderly, where multi-morbidity may be the norm. In the current case, the elevated iPTH levels and detection of an adenoma on imaging confirmed hyperparathyroidism, and not tuberculosis, as the etiology of hypercalcemia.

Interestingly, in a few cases, tubercular granulomatous inflammation of the parathyroids may result in or coexist with parathyroid enlargement and hypercalcemia [6], [7], [8], [9], [10]. All cases we identified from a literature search involved adult females, all of whom had positive histopathological diagnoses, with or without microbiological/ molecular confirmation, and most improved with antitubercular therapy [6], [7], [8], [9], [10]. Histopathology of the parathyroid was, however, not performed in our patient in view of his poor general condition and burden of comorbidities, and hence it cannot be ascertained whether our patient had tubercular involvement of the parathyroids.

Tubercular exudates blocking cortical arteries can cause stroke. However, zoledronate infusion has also been linked with a modestly increased risk of new-onset atrial fibrillation in older cohorts and has produced ischemic stroke in isolated elderly patients [11], [12]. Although we identified no atrial fibrillation or zoledronate-induced metabolic abnormality in the current case, it highlights vigilance for stroke risk with zoledronate in older patients vulnerable to ischemic brain insults due to a thrombotic pathology, such as but not limited to neurotuberculosis. The case also highlights challenges in optimizing ATT in elderly patients with compromised liver function. The dearth of safe antitubercular options continues to persist in patients with advanced liver dysfunction.

There is often a tendency in medical care to overlook hidden major pathology in favor of evident minor illnesses. Conversely, in this case, central nervous system tuberculosis, which is a major pathology, could have been easily thought to be the cause of hypercalcemia, but a focused workup ensured not missing out on a parathyroid adenoma, which is admittedly not as serious a condition, but nevertheless needed management at a later date. A reversal of the common proverb, our patient was a case of ‘not missing a tree for the forest’.

CRediT authorship contribution statement

Shreya Barnawal: Writing – original draft, Data curation. Abhishek Singhal: Resources, Investigation. Upinder Kaur: Writing – original draft, Supervision, Conceptualization. Sankha Shubhra Chakrabarti: Writing – review & editing, Conceptualization. Akshar Patel: Writing – original draft, Visualization.

Consent to publish

Written informed consent was received from the legal guardian of the patient for publication of the case. However, consent to publish images was not provided.

Ethical statement

No human experimentation performed. All procedures were performed in accordance with the Declaration of Helsinki and subsequent modifications.

Funding

The authors did not receive any funding support for the submitted work.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability

All necessary data are contained in the manuscript.