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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 6  |  Issue : 2  |  Page : 149-155

Cholecalciferol for prophylaxis against antituberculosis therapy-induced liver disorders among naïve patients with pulmonary tuberculosis: A randomized, comparative study


1 Department of Tropical Medicine and Gastroenterology, Assiut University, Assiut, Egypt
2 Department of Chest Diseases, Assiut University, Assiut, Egypt
3 Department of Internal Medicine, Assiut University, Assiut, Egypt
4 Department of Microbiology, Assiut University, Assiut, Egypt

Date of Web Publication19-May-2017

Correspondence Address:
Ahmad Farooq Alsayed Hasanain
Department of Tropical Medicine and Gastroenterology, Assiut University, Assiut
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmy.ijmy_19_17

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  Abstract 

Background: Patients in countries endemic for chronic viral hepatitis are more vulnerable to antituberculosis therapy-induced liver disorders (ATT-LDs). The aim of this study was to explore the role of cholecalciferol in prophylaxis against ATT-LD among patients with pulmonary tuberculosis (TB) receiving ATT. Material and Methods: We conducted a hospital-based, prospective, randomized, comparative study which included 300 consecutive, naïve patients with pulmonary TB eligible for ATT. The patients were randomly allocated to Group A (150 patients who received ATT) and Group B (150 patients who received ATT with cholecalciferol) who had clinical evaluation, laboratory investigations, and imaging studies. Statistical analysis used student's t-test and Chi-square test were used as appropriate to compare the variables between the study groups. Results: The study population mean age was 35.6 ± 15.3 years. The overall incidence rate of ATT-LD among the study population was 9.3%; the incidence rate was significantly higher among Group A patients compared to those of Group B (13.3 vs. 5.3%;P = 0.001). The onset of ATT-LD was significantly earlier among patients of Group A compared to those of Group B (31.4 vs. 58.7 days,P = 0.027), while the duration of ATT-LD was significantly longer among patients of Group A compared to those of Group B (34.8 vs. 16.9 days,P = 0.009). No adverse effects related to cholecalciferol use were observed. Conclusions: Adjuvant cholecalciferol supplementation may be protective against ATT-LD without extra adverse effects. Before recommending the routine use of cholecalciferol supplementation for prevention of ATT-LD, larger scale studies are recommended.

Keywords: Antituberculosis therapy, cholecalciferol, liver disorders


How to cite this article:
Hasanain AF, Zayed AA, Mahdy RE, Nafee AM. Cholecalciferol for prophylaxis against antituberculosis therapy-induced liver disorders among naïve patients with pulmonary tuberculosis: A randomized, comparative study. Int J Mycobacteriol 2017;6:149-55

How to cite this URL:
Hasanain AF, Zayed AA, Mahdy RE, Nafee AM. Cholecalciferol for prophylaxis against antituberculosis therapy-induced liver disorders among naïve patients with pulmonary tuberculosis: A randomized, comparative study. Int J Mycobacteriol [serial online] 2017 [cited 2021 Oct 28];6:149-55. Available from: https://www.ijmyco.org/text.asp?2017/6/2/149/206594


  Introduction Top


In developing countries including Egypt, tuberculosis (TB) is an endemic disease and is recognized with increasing incidence, mainly among the immunocompromised patients.[1] Antituberculosis therapy (ATT) including isoniazid (INH), rifampin (RIF), and pyrazinamide (PZA), although effective for treatment, carries the risk of liver disorders; it may be severe enough to result in discontinuation of therapy or exacerbation of underlying liver disease. The spectrum of ATT-induced liver disorders (ATT-LDs) encompasses a range of elevated levels of aminotransferases to acute liver failure.[2],[3] The prevalence of ATT-LD is up to 4.28% in Western countries;[4] its risk factors include extensive TB, older age, polymorphism and reduced activity of liver N-acetyl-transferase-2 genes and glutathione-S-transferase, slow acetylation, inappropriate use of drugs, underlying liver disease, severe malnutrition (including baseline hypoalbuminemia), alcohol excessive intake, and human immunodeficiency virus (HIV) infection.[5],[6],[7],[8],[9]

Relation of Vitamin D to the severity of liver disease has been reported among liver disorders other than ATT-LD. Patients with nonalcoholic steatohepatitis (NASH) have significantly lower levels of Vitamin D.[10] In addition, Vitamin D deficiency is associated with the histopathological severity of NASH.[11] Animal studies demonstrate that elevated level of Vitamin D using phototherapy results in lower severity of nonalcoholic fatty liver disease (NAFLD) as indicated by less necroinflammation, fibrosis, and apoptosis.[12] Vitamin D receptor (VDR) gene polymorphisms involved in Vitamin D synthesis and activation are associated with Vitamin D status and the severity of liver disease.[13] In Egypt, VDR BsmI genotype distribution among healthy individuals is 57% for genotype Bb, 34% for bb, and 9% for BB, with b allele among 62.5% compared to 37.5% for B allele.[14]

The only measure to manage ATT-LD is discontinuation of the ATT; it is reintroduced after normalization of the aminotransferases levels.[15] There is no standard recommendation for prophylaxis against ATT-LD. The contribution of Vitamin D to prevention of ATT-LD has not been studied before. The aim of this study was to explore the role of cholecalciferol (Vitamin D3) supplementation in prophylaxis against ATT-LD among naïve patients with pulmonary TB receiving ATT. The study objective was to compare incidence rate of ATT-LD among patients receiving ATT with cholecalciferol supplementation to that of a matching group receiving ATT only.


  Materials and Methods Top


Study design

We conducted a hospital-based, prospective, randomized, comparative study.

Study location

We recruited the study population in the inpatient sectors and outpatient clinics of the Departments of Chest Diseases, Tropical Medicine, and Internal Medicine.

Study duration

We recruited the study population during the period from October 2014 to May 2016.

Study population

The study included 300 consecutive, naïve patients with pulmonary TB eligible for ATT. The patients were randomly allocated to two groups. Group A included 150 patients who received ATT only while Group B included another 150 patients who received ATT with cholecalciferol supplementation.

Pulmonary TB was diagnosed based on positive sputum culture on Lowenstein–Jensen medium performed by an experienced microbiologist, with or without the radiological evidence on chest radiography.[16] ATT-LD was diagnosed according to the International Union Against TB and Lung Disease based on the presence of one or more of the following criteria: (1) a rise to more than two times the upper limit of normal (ULN) of alanine transaminase (ALT; ULN is 41 IU/L) level and/or aspartate transaminase (AST; ULN is 38 IU/L) level; (2) a rise in total serum bilirubin level to more than 25.7 µmol/L or 1.5 mg/dl; (3) any increase in AST and/or ALT levels above pretreatment levels together with anorexia, nausea, vomiting, and jaundice. In addition, normalization of laboratory abnormalities and resolution of signs and symptoms of liver disease after discontinuation of ATT were needed for diagnosis.[17]

Inclusion criteria

The study included adult (18 years or more) patients with pulmonary TB eligible for ATT who accepted to be enrolled in the study.

Exclusion criteria

Pregnant female patients or those with previous ATT were excluded from being enrolled. In addition, patients with pre-existing elevated liver chemistry (ALT, AST, and bilirubin), hepatitis C virus (HCV) infection, hepatitis B virus infection, Human immunodeficiency virus (HIV) infection, evidence of fatty liver disease, liver cirrhosis or portal hypertension, any alcohol intake, receiving hepatotoxic drugs other than ATT, renal disorder (elevated serum creatinine level), and hemolytic anemia were excluded as well as those receiving corticosteroids or antimetabolites for any other indication.

Methods

All the patients enrolled had pretreatment evaluation including clinical evaluation (medical history and physical examination with estimation of weight and height), imaging studies (chest radiography and abdominal ultrasonography), and laboratory investigations (liver chemistry panel, virology panel, kidney chemistry panel, and complete blood count). Body mass index (BMI) was calculated as the following: body weight (kg)/(height [m])2. Liver chemistry panel included estimation of serum levels of ALT, AST, and bilirubin. Virology panel included testing for serum antibody to HCV, hepatitis B surface antigen, antibody to hepatitis B core, and anti-HIV. For patients with criteria of ATT-LD, the following were performed to confirm the diagnosis: testing for serum antibody to hepatitis A virus of immunoglobulin-M type and markers of autoimmune hepatitis (antinuclear and anti-smooth muscle antibodies).

All the study patients received the World Health Organization (WHO)-recommended therapy: INH (5 mg/kg/day; maximum dose was 300 mg/day), RIF (10 mg/kg/day; maximum dose was 600 mg/day), PZA (30 mg/kg/day; maximum dose was 2000 mg/day), and ethambutol (EMB) (20 mg/kg/day; maximum dose was 1600 mg/day) for 2 months, followed by INH and RIF for four more months.[18] Group B patients, in addition to ATT, received cholecalciferol supplementation during the whole treatment period (600 IU/day, orally, immediately after lunch). The dose of cholecalciferol was determined according to the recommended dietary allowances for persons 19–70 years old.[19] Taking Vitamin D with the largest meal improves its absorption.[20] Cholecalciferol supplementation was produced by the same pharmaceutical company.

Follow-up included clinical evaluation and laboratory investigations. Daily clinical evaluation during the period of hospital admission and weekly clinical and laboratory evaluation (liver chemistry panel) at the outpatient clinic for the first 2 months of the treatment period and then monthly for rest of the period were carried out. Therapeutic failure of ATT was defined as positive sputum culture at the 4th month or later during the treatment period.[21]

For the study patients with elevated levels of ALT and/or AST (three times the ULN or more with symptoms or five times the ULN with or without symptoms) during the first 2 months of ATT, RIF and PZA were discontinued immediately. Liver-friendly drugs (EMB and streptomycin [SM]) were used in addition to INH until RIF and PZA were resumed after decrease of ALT and/or AST levels to less than two times the ULN. The dose of SM was 15 mg/kg/day by intramuscular injection with a maximum daily dose of 1000 mg. For patients with the same criteria but after the first 2 months of ATT, RIF was replaced by EMB temporarily until it was be resumed according to the previously mentioned rules.[18]

Statistical analysis

Data were collected in a specialized data collection form and then entered and analyzed using the Statistical Package for Social Sciences (SPSS, version 22.0; SPSS Inc., Chicago, IL, USA) for Windows. Results were expressed as mean ± standard deviation or frequency (percentage) as appropriate. Student's t-test and Chi-square test were used as appropriate to compare the variables between the study groups. P < 0.05 was considered statistically significant.

Ethical considerations

The study was approved by the Faculty of Medicine Clinical Research Ethical Committee (Assiut University) and was carried out in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki). Before enrollment in the study, all participants signed a consent certificate. Before signing, they were able to discuss in detail with investigators the certificate subjects and the study aim. Participants were clearly informed that refusing to participate in the study will not affect having full benefit of the available medical service and treatment. Data were collected by personal interview of investigators with participants taking in consideration data confidentiality.


  Results Top


The study included 300 naïve patients with pulmonary TB. Their mean age was 35.6 ± 15.3 years; female patients represented 57% of them.

Pretreatment characteristics of the study population

Pretreatment demographic, clinical, radiological, and laboratory characteristics of the two groups of the study population with pulmonary TB are shown in [Table 1]. No statistically significant difference was observed between the patients of Group A and Group B; the two groups were matching.
Table 1: Pretreatment demographic, clinical, radiological, and laboratory characteristics of the study population

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Antituberculosis therapy induced liver disorders among the study population

Out of 300 patients with pulmonary TB, 28 (9.3%) developed ATT-LD. [Table 2] shows the pattern of ATT-LD among the two groups of the study population with pulmonary TB. Out of 28 patients with ATT-LD, 20 (71.4%) were of Group A patients [Figure 1]. The incidence rate of ATT-LD was significantly higher among patients of Group A compared to patients of Group B (13.3 vs. 5.3%; P = 0.001). The most frequent type of ATT-LD among patients who developed ATT-LD was elevated level of ALT more than two times of the UNL (18 out of 28, 64.3%), which also was the most frequent among Group B patients with ATT-LD (5 out of 8, 62.5%). All patients with elevated levels of AST and/or bilirubin had concomitant ALT level elevation. Symptoms associated with elevated aminotransferases levels were anorexia, nausea, and vomiting, which were more common among patients of Group A with ATT-LD (10 out of 20, 50%) compared to those of Group B (3 out of 8, 37.5%). Interestingly, patients of Group B with ATT-LD had no single case of elevated bilirubin. Even among Group A patients with elevated bilirubin level, jaundice was not detected.
Table 2: Pattern of antituberculosis therapy induced liver disorders among the study population

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Figure 1: Relative distribution (percentage) of antituberculosis therapy induced liver disorders among the two groups of the study population. Group A: patients with antituberculosis therapy only; Group B: patients with antituberculosis therapy and cholecalciferol supplementation.

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The onset of ATT-LD was significantly earlier among patients of Group A compared to those of Group B (31.4 vs. 58.7 days, P = 0.027) while the duration of ATT-LD was significantly longer among patients of Group A compared to those of Group B (34.8 vs. 16.9 days, P = 0.009). Complete cure was ultimate for all the patients who developed ATT-LD.

The mean peak serum levels of ALT, AST, and bilirubin among the study population of the two groups are shown in [Table 3]. The aminotransferases levels were significantly higher among patients of Group A compared to those of Group B, especially for ALT (62.5 vs. 36.9 IU/L, P = 0.024).
Table 3: Peak levels of alanine aminotransferase, aspartate aminotransferase, and bilirubin among the study population with antituberculosis therapy.induced liver disorders

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Therapeutic outcome of pulmonary tuberculosis among the study population

Discontinuation of the WHO-recommended ATT temporarily due to elevation of ALT and/or AST of triple the ULN or more with symptoms was inevitable in 5 out of 20 patients (25%) of Group A with ATT-LD while no single patient of Group B patients with ATT-LD had to. Hepatotoxic drugs (RIF and PZA) were replaced by liver-friendly ones (SM and EMB). Therapeutic failure among the study population with pulmonary TB was 23% (69 out of 300 patients). Therapeutic failure was more frequent among Group A patients compared to those of Group B (27.3% vs. 18.7%); however, it did not reach the statistical significance level although it was close to P = 0.057 [Table 4]. No adverse effects related to cholecalciferol supplementation were observed among Group B patients. [Figure 2] shows the therapeutic outcome according to the presence or absence of ATT-LD.
Table 4: Therapeutic outcome among the study population

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Figure 2: Therapeutic outcome of the study population. TB: tuberculosis, ATT: antituberculosis therapy, n: number, ATT-LD: antituberculosis therapy-induced liver disorder, TF: therapeutic failure.

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  Discussion Top


We believe that the use of cholecalciferol with ATT should be considered. Based on our results, cholecalciferol needs to be incorporated as an adjuvant therapy for patients receiving ATT although not being recommended by the currently available studies. Patients with TB in areas endemic for chronic viral hepatitis are rendered more vulnerable to ATT-LD with higher risk of liver-related morbidity and mortality and more chance of mycobacterial resistance due to discontinuation of the standard of care-ATT.

The overall incidence rate of ATT-LD among our study population receiving the WHO-recommended ATT for pulmonary TB was 9.3%. This incidence rate was lower than that reported by Makhlouf et al. (15%) among 100 Egyptian patients with TB who were followed up for the same period.[22] The lower incidence rate of ATT-LD among our study patients could be attributed to the study population; while our study was restricted to patients with pulmonary TB, theirs included patients with both pulmonary and extrapulmonary TB. Furthermore, the nutritional status might have played a role; the mean BMI of their study population was 20 which was lower than that of ours (26), reflecting more potential for malnourishment among their study patients. Globally, the incidence rate of ATT-LD is variable with higher rates among patients in developing countries as a consequence of endemicity of chronic viral hepatitis, medications abuse, especially antimicrobials and nonsteroidal anti-inflammatory drugs, and worse nutritional conditions.[23],[24] In Africa, the reported incidence of ATT-LD was 16.4% among Nigerian patients [25] with worldwide variation between 4%[26] and 20%,[27] approximately, due to different study populations, medications, monitoring methods, and definitions of ATT-LD.[7] Regarding the pattern of ATT-LD, the most frequent disorder was elevated ALT level regardless of the degree of elevation or the presence or absence of symptoms among our study patients (9.3%) as well as those of the study by Makhlouf et al. (15%). No serious ATT-LD was reported among our study population compared to a single case of mortality due to fulminant liver failure reported by Makhouf et al. The onset of ATT-LD among our study population was after 46 days, in agreement with the reported range among Egyptian (15–60 days)[22] and Nepalese patients receiving ATT (12–60 days).[28] Regarding the duration of ATT-LD, it was 26 days among our study population which was also within the reported range among Egyptian patients with TB (15–45 days).[22]

Among our study population, Group B patients who received adjuvant cholecalciferol supplementation had significantly lower incidence rate of ATT-LD compared to those of Group A without the supplementation (5.3% vs. 13.3%, P = 0.001), near to the lowest reported globally (4%).[26] Moreover, patients of Group B had significantly more late onset (59 vs. 31 days, P = 0.027) and shorter duration (17 vs. 35 days, P = 0.009) of ATT-LD compared to those of Group A. Regarding the liver chemistry panel, Group B patients had significantly lower levels of ALT (37 vs. 63 IU/L, P = 0.024) and AST (~36 vs. 57 IU/L, P = 0.046) compared to those of Group A. Considering both groups of our study were matching, we can suggest that adjuvant cholecalciferol supplementation for Group B patients has contributed to less development, later onset, and shorter duration of ATT-LD among such patients compared to Group A patients who did not receive the supplementation, reflecting a potential hepatoprotective property of cholecalciferol. Although it was not reported previously, several studies described the role of Vitamin D in liver disease severity and progression. The prevalence of Vitamin D deficiency (serum 25-hydroxycholecalciferol concentrations <20 ng/mL) among the general population is 20%–100%[29] while it is 64%–92% among patients with chronic liver disease where it is inversely correlated to liver disease progression.[30],[31] In addition to the role of Vitamin D in calcium and bone metabolism, its extraskeletal effects associated with chronic disease have been discovered.[32] Regardless of the etiology of chronic liver disease, it was found that Vitamin D deficiency is highly prevalent [33] and is associated with liver dysfunction and liver-related mortality.[34] It has been suggested that Vitamin D deficiency can aggravate liver damage;[35],[36] Vitamin D plays a pivotal role in the progression of liver necroinflammation and fibrosis.[32] Vitamin D deficiency (25-hydroxycholecalciferol <10 ng/mL) was a predictor of advanced liver fibrosis among patients with chronic liver disease.[37] Among patients with genotype-1 chronic HCV infection, a significant inverse correlation between 25-hydroxycholecalciferol serum level and stage of fibrosis has been reported. Moreover, low level of 25-hydroxycholecalciferol was a predictor of higher necroinflammation grade and fibrosis stage.[38] This observation was corroborated by the finding that lower 25-hydroxycholecalciferol concentration was associated with hepatic steatosis, necroinflammation, and fibrosis among patients with NAFLD.[39],[40] Oral administration of 1α-hydroxycholecalciferol for 6 weeks in rat model with diet-induced NASH showed dose-dependent amelioration of NASH progression, suggesting that the active form of Vitamin D may be beneficial as an adjunctive therapy for NASH.[12]

The potential hepatoprotective effect of Vitamin D could be explained by its significant role in immune system response. Vitamin D has been demonstrated to modulate the activation of lymphocytes toward a Th2 anti-inflammatory profile.[41] In addition, activated macrophages produce 1,25-dihydroxycholecalciferol and express VDR. Thus, 1,25-dihydroxycholecalciferol produced by the liver can practice a negative feedback effect on inflammation contributing to its suppression.[42] Moreover, Vitamin D inhibits monocytes activation and subsequent expression of the key inflammatory markers of NAFLD-related liver injury (tumor necrosis factor alpha and interleukin-1) while its deficiency promotes NAFLD progression through the activation of Toll-like receptor 2, 4, and 9 leading to more severe necroinflammation.[43] It has been suggested that the active form of Vitamin D could suppress the activation of stellate cells based on in vitro and in vivo models.[44] In experimental model, it was found that Vitamin D inhibits proliferation of primary hepatic stellate cells, suppresses the expression of collagen, and prevents thioacetamide-induced liver fibrosis.[45]

The overall therapeutic failure rate among out study population was 23%. This rate was lower than previously reported (29%) among 133 Egyptian patients with pulmonary TB who received the WHO-recommended ATT. This may be attributed to the absence of some potential risk factors of therapeutic failure (liver cirrhosis and renal failure) among our study patients compared to those recruited by Hasanain et al.[46] Although it was not statistically significant, our study Group B patients had a less frequent therapeutic failure rate compared to those of Group A (19% vs. 27%). This may point to a potential, additional, beneficial role of adjuvant cholecalciferol supplementation among patients with TB receiving ATT. 1,25-dihydroxycholecalciferol promotes the antimicrobial properties of macrophages and monocytes; this may play a role in combatting pathogens such as Mycobacteriumtuberculosis indirectly through Toll-like receptor signaling, monocytes-induced cytochrome (CYP27B1), inflammatory response in macrophages with enhanced secretion of cytokines, enhanced capacity of monocyte-derived macrophages,[47] and VDR activity, or directly by modulating gene expression in favor of cathelicidin production.[48] Production of human cathelicidin is upregulated in response to infection to destroy lipoprotein membranes of microbes.[49]

Our study has a weakness; estimation of Vitamin D level was not performed to assess the pretreatment Vitamin D status of the study population due to financial limitations. Lower pretreatment level of Vitamin D among patients of Group A might have contributed to the higher incidence rate of ATT-LD. However, this study is unique in being the first one to explore the potential role of Vitamin D3 supplementation for protection against ATT-LD.


  Conclusions Top


Adjuvant cholecalciferol supplementation may be protective against ATT-LD without extra adverse effects. Before recommending the routine use of cholecalciferol supplementation for prevention of ATT-LD, larger scale studies are recommended. The potential contribution of cholecalciferol supplementation to ATT therapeutic response needs further studies to be explored. Being inexpensive and safe, the use of Vitamin D supplementation within the recommended dietary allowance range cannot be discouraged among patients with TB receiving ATT.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]


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