|Year : 2020 | Volume
| Issue : 1 | Page : 7-11
Risk factors for hypercalcemia in patients with tuberculosis
Sujith Mathew John, Sheeba Sagar, Joshi Krishnakumari Aparna, Sharon Joy, Ajay Kumar Mishra
Department of Internal Medicine, Christian Medical College, Vellore, Tamil Nadu, India
|Date of Submission||25-Dec-2019|
|Date of Decision||24-Jan-2020|
|Date of Acceptance||01-May-2020|
|Date of Web Publication||6-Mar-2020|
Ajay Kumar Mishra
Department of Internal Medicine, Christian Medical College, Vellore - 632 004, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Background: Tuberculosis (TB) is prevalent worldwide and causes significant morbidity and mortality. TB is known to cause hypercalcemia. We aimed to assess the prevalence and risk factors for developing hypercalcemia among patients with TB. Methods: In this retrospective case–control study, patients with microbiological evidence of TB and an available serum calcium value were included between 2005 and 2016. The demographic, clinical, and laboratory details were recorded. Various risk factors were compared in TB patients with and without hypercalcemia. Results: A total of 129 patients fulfilled the inclusion criteria. Twenty percent were found to have an elevated serum calcium level, 65% of them had clinical features of hypercalcemia. In comparison, the odds of developing hypercalcemia in the presence of disseminated TB, diabetes and renal failure was 1.83, 1.60, and 7.33, respectively. Conclusion: One-fifth of patients with TB have hypercalcemia. Risk factors of the same are renal failure, diabetes, and disseminated TB.
Keywords: Hypercalcemia, risk factors, tuberculosis
|How to cite this article:|
John SM, Sagar S, Aparna JK, Joy S, Mishra AK. Risk factors for hypercalcemia in patients with tuberculosis. Int J Mycobacteriol 2020;9:7-11
|How to cite this URL:|
John SM, Sagar S, Aparna JK, Joy S, Mishra AK. Risk factors for hypercalcemia in patients with tuberculosis. Int J Mycobacteriol [serial online] 2020 [cited 2021 Apr 22];9:7-11. Available from: https://www.ijmyco.org/text.asp?2020/9/1/7/280149
| Background|| |
Tuberculosis (TB) is a chronic granulomatous infectious disease caused by the bacterium Mycobacterium TB. Being the second most common infectious cause of death worldwide, TB is a huge burden world over, causing significant morbidity and mortality, and its ability to efficiently establish latent infection has enabled it to spread to nearly one-third of individuals worldwide., It is especially prevalent among those from the lower socioeconomic strata of society in developing and underdeveloped countries. Of the 9.6 million new cases diagnosed globally in 2015, 2.2 million were from India.,
Hypercalcemia with high calcitriol levels has been described as a common complication in patients with TB – both pulmonary and extrapulmonary. The incidence of hypercalcemia in patients with TB has been reported to vary from as low as 2.3%–28%.,, This difference has been attributed to variation in Vitamin D and calcium intake, amount of sun exposure, and extent of disease. However, most (88%) of these patients remain asymptomatic for hypercalcemia, and it is detected only on routine screening or after the development of complications such as neuropsychiatric disturbances, renal dysfunction, cardiovascular disease, or musculoskeletal disease. The incidence of hypercalcemia in patients with TB in India has not been documented.
In a resource-limited setup such as in most of rural India, routinely screening all patients with TB for hypercalcemia is neither practicable nor economically feasible. Therefore, knowing the risk factors for developing hypercalcemia in patients with TB would allow for select patients with risk factors to be screened for hypercalcemia and treated appropriately. In this study, we attempt to identify the risk factors for hypercalcemia in patients with TB in a tertiary care center in Vellore, India.
The objective of this study was to (1) assess the prevalence of albumin-corrected hypercalcemia in patients with TB (pulmonary and extrapulmonary) in a tertiary care center in South India and (2) identify the risk factors for developing hypercalcemia in these patients with TB.
| Methods|| |
In this single-center retrospective case–control study, all adult patients (age >18 years), with the diagnosis of TB and a concomitant available serum calcium value, were recruited from the various units of the department of general medicine. The details of these patients were obtained retrospectively from the medical records department of our hospital. All patients with the diagnosis of TB and available serum calcium between January 1st, 2005, and January 1st, 2016, were eligible to be recruited into the study. Among those who were eligible patients, who had a microbiological diagnosis of TB – either sputum smear positive for acid-fast bacilli (AFB), culture positive for AFB, biopsy showing TB granuloma with AFB, or GeneXPert polymerase chain reaction positive were included in the study as participants. From among these, we selected those patients who had an albumin value done along with the calcium value. Patients who had other known causes for hypercalcemia such as malignancy, sarcoidosis, thyrotoxicosis, and hyperparathyroidism were excluded from the study. The calcium value was corrected for albumin using Payne's formula:
Corrected calcium (mg/dL) = Total calcium + 0.8 (4 – Albumin).
The patients who fulfilled our inclusion criteria were divided based on their calcium values into cases (patients with TB and hypercalcemia) and controls (patients with TB and no hypercalcemia). According to our laboratory reference range, an albumin-corrected serum calcium ≥10.4 mg/dL was considered as hypercalcemia.
Data was collected for each of these patients. We collected data regarding the demography, type of TB, blood parameters (hemoglobin [Hb], Total blood count (TBC), prothrombin time, and activated partial thromboplastin time), inflammatory markers (erythrocyte sedimentation rate and C-reactive protein), thyroid parameters (T4 and free thyroxine), parathyroid hormone (PTH) level, renal function parameters (creatinine and urea), electrolytes, serial calcium readings, Vitamin D levels, human immunodeficiency virus (HIV) status, diagnosis of renal failure, comorbidities (hypertension and diabetes mellitus), symptoms of hypercalcemia, and TB treatment. Data were collected by three-independent investigators. The investigators underwent short training regarding the study methodology, several variables, and the pathological basis behind the study methodology. In case of any discrepancies, senior investigator's opinion was sought. The senior investigator supervised the data acquisition and monitored the accuracy of the data. A preplanned questionnaire was used by the investigators for data recruitment. The data were entered and documented using EpiData version 126.96.36.199. (Denmark) The data were analyzed using SPSS Statistics v23 (IBM, US). We used unpaired Student's t-test to compare the categorical variables, and analysis of variance was used for variables between the two groups with a significant difference. The odds ratio was calculated for the various risk factors, and P < 0.05 was considered as statistically significant. This study was approved by the Institutional Review Board of Christian Medical College, Vellore. The patient identity was concealed by assigning a unique identifier number for each patient.
| Results|| |
A total of 616 patients were included in the study. Of 616 patients who were suspected to have TB, 129 had a microbiological diagnosis of TB and had albumin values tested concomitantly with the calcium values. Of these, 26 patients (17 males and 9 females) had albumin-corrected hypercalcemia and were taken as cases. Twenty-five age- and sex-matched controls (16 males and 9 females) were selected. The details of demographic parameters and laboratory variables among the two groups are shown in [Table 1]. The mean age of the population in the study was 41, and there was a male predominance of the population. Disseminated TB, renal dysfunction, and diuretic use were more commonly seen in the cases. The mean calcium for the cases was 11.9 ± 1.2 mg/dL, whereas the mean calcium for the controls was 8.9 ± 0.75 mg/dL.
|Table 1: Baseline demographic, clinical, and laboratory details of tuberculosis patient with and without hypercalcemia|
Click here to view
The incidence of hypercalcemia (albumin corrected) in our study group was 20.15% (26/129). Of these, nine patients (34.6%) showed symptoms of hypercalcemia. Symptoms such as delirium, anorexia, nausea, weakness/lethargy, and polyuria were seen in 78%, 56%, 44%, 44%, and 33% of patients, respectively. Moderate and severe hypercalcemia was seen in 31% and 7.5% of the patients. Among the patients with moderate and severe hypercalcemia, 25% and 50% had clinical symptoms because of the same as shown in [Figure 1].
|Figure 1: The distribution of severity and clinical presentation among patients with hypercalcemia|
Click here to view
A number of risk factors were considered, and analysis was performed, as shown in [Table 2]. An elevated creatinine level, the diagnosis of renal failure was independently found to be statistically significant risk factors for hypercalcemia in patients with TB, with an odds ratio of 14.16 (P = 0.001) and 7.33 (P = 0.006), respectively. Elevated creatinine represented the patient's creatinine at the time of admission, and renal failure implied patients who had a history of chronic renal failure. The use of diuretics and severe anemia (defined as Hb of <8) were also found to be associated with hypercalcemia in patients with TB.
| Discussion|| |
TB is a chronic granulomatous infectious disease caused by the bacterium Mycobacterium TB. It is especially prevalent among those from the lower socioeconomic strata of society in developing and underdeveloped countries. Of the 9.6 million new cases diagnosed globally in 2015, 2.2 million were from India.,
Hypercalcemia with high calcitriol levels has been described as a common complication in patients with TB – both pulmonary and extrapulmonary, and the incidence of hypercalcemia varies from as low as 2.3%–28%.,, Most (88%) patients with hypercalcemia in the background of TB remain asymptomatic for hypercalcemia, and hence, it is usually detected on routine screening or after the development of complications such as neuropsychiatric disturbances, renal dysfunction, cardiovascular disease, or musculoskeletal disease.,,
In a resource-limited setup such as in most of rural India, routinely screening all patients with TB for hypercalcemia is neither practicable nor economically feasible. Therefore, knowing the risk factors for developing hypercalcemia in patients with TB would allow for selecting patients with risk factors to be screened for hypercalcemia and treated appropriately. In this study, we attempted to identify the risk factors for hypercalcemia in patients with TB in a tertiary care center in Vellore, India.
Our study demonstrated that hypercalcemia is rather common and can be seen in one in five patients with TB. Forty percent of these patients present with moderate-to-severe hypercalcemia and 35% of these have symptoms of hypercalcemia. Renal failure and elevated creatinine were found to be risk factors for developing hypercalcemia in these patients. This was a surprising finding and was contrary to studies, which have shown a high prevalence of hypocalcemia in non-TB patients with chronic kidney disease. Severe anemia and the use of diuretics were also shown to be risk factors for hypercalcemia in patients with TB. It is thus advisable to screen TB patients with renal failure, severe anemia, disseminated infection, or diuretic use for hypercalcemia.
We also compared the previous studies on the patient with TB and hypercalcemia and identified six other studies. Among these, four were prospective, one was retrospective, and one was bidirectional simultaneously. Of the four prospective studies, two had 1–2 cases and lacked a control arm [Table 3].,,,,, Our study was unique with the highest number of patients with hypercalcemia, having a control arm with TB in contrast to chronic obstructive lung disease in prior studies, and including the patient with HIV coinfection. These studies have mostly included patients with hypercalcemia and pulmonary, disseminated TB. Although predominantly reported in pulmonary TB, TB in various other sites has been reported to have hypercalcemia as shown in [Table 4].,,,, Most often, hypercalcemia is mild and asymptomatic. In 25% of patients, it can occur before the initiation of chemotherapy. The level of serum alkaline phosphatase can be normal, and most of these patients do not have data on serum PTH level. The identified risk factors for hypercalcemia were as follows: (1) degree and duration of Vitamin D intake, (2) higher exposure to sunlight, (3) extensive pulmonary disease in radiology, and (4) the presence of renal dysfunction. Hypercalcemia in most of these patients resolved with treatment and was self-limiting.
Our study had several limitations, it was a retrospective case–control study, and hence, the time relationship in the association between the risk factors and the development of hypercalcemia could not be ascertained. The sample size was small. Furthermore, the TB treatment status of the patients could not be taken into consideration. We also did not have the treatment, morbidity, and long-term follow-up details of the study participants.,, However, the strength of this study was the study design, microbiologically confirmed cases, and systematic exclusion of other causes of hypercalcemia. A further prospective study with a larger sample size would be recommended to confirm the findings of this study.
| Conclusion|| |
In conclusion one fifth of patients with TB can have hypercalcemia. hypercalcemia can occur in patients with both pulmonary and extrapulmonary TB., Reported risk factors of hypercalcemia in this study were renal failure, diabetes, and disseminated TB.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Kanabus A. Information about Tuberculosis. TB Facts | TB, Tests, Drugs, Statistics. GHE; 2017. Available from: https://www.tbfacts.org/about-us/
. Last accessed on 2020 Jan 05].
Lal A, Al Hammadi A, Rapose A. Latent tuberculosis infection treatment initiation and completion rates in persons seeking immigration and healthcare workers. Am J Med 2019;132(11):1353-5.
Rajendra A, Mishra AK, Francis NR, Carey RA. Severe hypercalcemia in a patient with pulmonary tuberculosis. J Family Med Prim Care 2016;5:509-11.
] [Full text]
Abbasi AA, Chemplavil JK, Farah S, Muller BF, Arnstein AR. Hypercalcemia in active pulmonary tuberculosis. Ann Intern Med 1979;90:324-8.
Tan TT, Lee BC, Khalid BA. Low incidence of hypercalcaemia in tuberculosis in Malaysia. J Trop Med Hyg 1993;96:349-51.
Abdullah AS, Adel AM, Hussein RM, Abdullah MA, Yousaf A, Mudawi D, et al
. Hypercalcemia and acute pancreatitis in a male patient with acute promyelocytic leukemia and pulmonary tuberculosis. Acta Biomed 2018;89:23-7.
Mishra AK, George AA, Peter D. Annular cutaneous sarcoidosis with systemic involvement. J Family Med Prim Care 2017;6:660-2.
] [Full text]
Pokharel A, Sigdel PR, Phuyal S, Kansakar PB, Vaidya P. prediction of severity of acute pancreatitis using total serum calcium and albumin-corrected calcium: A prospective study in tertiary center hospital in Nepal. Surg Res Pract 2017;2017:271-3.
Ninan F, Mishra AK, John AO, Iyadurai R. Splenic granuloma: Melioidosis or tuberculosis? J Family Med Prim Care 2018;7:271-3.
] [Full text]
Dv K, Gunasekaran K, Mishra AK, Iyyadurai R. Disseminated tuberculosis presenting as cold abscess of the thyroid gland-a case report. Oxf Med Case Reports 2017;2017:omx049. https://doi.org/10.1093/omcr/omx049
Arrais Morais M, Cardoso Teixeira LL, de Sousa Brandão Torres D, da Rocha Klautau Neto PB, Machado Kahwage A. Localized hepatic tuberculosis presenting as severe hypercalcemia. Indian J Tuberc 2018;65:172-4.
Sahu KK, Mishra AK, Lal A, Gandhi R. Fahr's syndrome: A case of unwanted calcium in the brain. Intern Emerg Med 2019;14:1359-62.
Hill Gallant KM, Spiegel DM. Calcium balance in chronic kidney disease. Curr Osteoporos Rep 2017;15:214-21.
Chan TY, Chan CH, Shek CC, Davies PD. Hypercalcemia in active pulmonary tuberculosis and its occurrence in relation to the radiographic extent of disease. Southeast Asian J Trop Med Public Health 1992;23:702-4.
Chan TY, Chan CH, Shek CC. The prevalence of hypercalcaemia in pulmonary and miliary tuberculosis-a longitudinal study. Singapore Med J 1994;35:613-5.
Roussos A, Lagogianni I, Gonis A, Ilias I, Kazi D, Patsopoulos D, et al
. Hypercalcaemia in Greek patients with tuberculosis before the initiation of anti-tuberculosis treatment. Respir Med 2001;95:187-90.
Lind L, Ljunghall S. Hypercalcemia in pulmonary tuberculosis. Ups J Med Sci 1990;95:157-60.
Ali-Gombe A, Onadeko BO. Serum calcium levels in patients with active pulmonary tuberculosis. Afr J Med Med Sci 1997;26:67-8.
Mishra AK, Aaron S, Abhilash K, Iyadurai R, Shaikh A, Lazarus E,et al
. Simple telephone call a feasible, useful and acceptable method of following up patients with cerebrovascular accidents: Prospective Cohort study in South India. Int J Stroke 2016;11:NP87-8.
Sadanshiv M, George AA, Mishra AK, Kuriakose CK. Rifampicin-induced immune allergic reaction. Trop Doct 2018;48:156-9.
Torres-Ortiz A, Acharya P, Cheungpasitporn W. Successful treatment of tuberculosis-associated hypercalcemia with denosumab in a patient with acute kidney injury. Ther Apher Dial 2019;23:484-5.
Lal A, Mishra AK, Sahu KK, Abraham GM. The return of Koch's: Ineffective treatment or re-infection. Enferm Infecc Microbiol Clin 2019. pii: S0213-005X (19) 30193-4.
Kumar KV, Unni VN, Kachare N, John N, Bipi PK, Pullockara J. Ileal tuberculosis causing hypercalcemia and renal failure. Indian J Nephrol 2019;29:53-6.
] [Full text]
Lal A, Mishra AK, Sahu KK, Davaro R. Tuberculous cold abscess eroding iliac bone. Rev Esp Patol 2020;53:71-2.
[Table 1], [Table 2], [Table 3], [Table 4]