Evaluation of Drug Induced Liver Injury in Tuberculosis and Hepatitis Coinfection by Liver Fibrosis Index Score

Research Article

Austin J Gastroenterol. 2017; 4(3): 1086.

Evaluation of Drug Induced Liver Injury in Tuberculosis and Hepatitis Coinfection by Liver Fibrosis Index Score

Alkady OA¹*, Yousef LY², Elkady AA³ and Elkady AA4

¹Department of Chest Diseases and Tuberculosis, Sohag University, Egypt

²Department of Clinical Pathology, Sohag University, Egypt

³Department of Clinical Pathology, South Valley University, Egypt

4Department of Medical Microbiology and Immunology, Assiut University, Egypt

*Corresponding author: Alkady OA, Department of Chest Diseases and Tuberculosis, Faculty of Medicine, Sohag University, Sohag, Egypt

Received: May 26, 2017; Accepted: June 19, 2017; Published: July 05, 2017


Background: Egypt has high Tuberculosis (TB), Hepatitis C (HCV) prevalence and intermediate Hepatitis B (HBV) prevalence with unclear Dug Induced liver injury (DILI) risk in chronic viral hepatitis patients.

Objective: To evaluate DILI incidence in tuberculous patients suffered from viral hepatitis co-infection compared to non hepatitis patients.

Methods: Newly diagnosed pulmonary TB patients under TB therapy were evaluated none invasively for DILI before and after treatment by liver function tests and liver fibrosis index (FIB-4 index).

Results: 195 tuberculous patients, age (19-61) years old. Of those, 62% (non hepatitis) were control, 31% HCV, 5% HBV, 2% were both (HB-C). Average baseline fibrosis indices in groups respectively were 0.81, 1.41, 0.70, and 1.47. Overall DILI respectively was 7%, 31%, 30%, 75%. FIB-4 index was significantly increased after treatment in all groups with significant difference between control and (HCV) group (p=0.04). The number of patients with FIB-4 index above 1.45 was 12%, 43%, 50%, 100% of all groups respectively with statistically significant difference in time lag to develop hepatotoxicity.

Conclusion: HCV, HBV, HB-C increases DILI risk after anti TB therapy. Meticulous follow up is advised. FBI-4 is a promising tool for liver damage evaluation. More studies are required to validate FIB-4 score.

Keywords: Tuberculosis; Drug induced liver injury; Liver fibrosis index


TB: Tuberculosis; HBV: Hepatitis B Virus; HCV: Hepatitis C Virus; DILI: Drug Induced Liver Injury; FIB4- index: Liver Fibrosis Index Score


Tuberculosis (TB) is a major global infectious disease caused by mycobacterium tuberculosis. It affects millions of people each year. In 2015 was ranking above HIV/AIDS as one of the leading causes of death from an infectious disease [1]. In Egypt, TB is considered the third most important public health problem after schistosomiasis and hepatitis C. WHO defined TB estimated rate in 2015 was 15 per 100,000 patients in Egypt [2].

Standard four-drug anti-TB therapy for active disease is associated with many side effects. Drug Induced liver injury (DILI) is the most dangerous. Majority of the reports have used an elevated alanine (ALT) or aspartate transaminase (AST) of 3 times upper limit of normal range (ULN) with symptoms (abdominal pain, nausea, vomiting, unexplained fatigue or jaundice) attributable to liver injury or 5 times ULN of ALT or AST without symptoms to define hepatotoxicity. Drug induced liver injury (DILI) accounts for 5% mortality rate [3]. It can be caused by all anti TB medications and it’s incidence during standard anti-TB treatment ranges from 2% to 28% depending on the definition of hepatotoxicity and the population studied [4,5]. When patients develop DILI, additional modes of anti- TB treatment are used. Once DILI occurs, all anti-TB drugs should be withheld until a complete resolution of the hepatotoxicity is accomplished [6]. Among the anti-TB agents, isoniazid (INH) is the primary drug which induces hepatotoxicity in TB patients with DILI. On the other hand, one recent report proved that rifampicin (RF) high plasma levels compared to control group, independently predicted subsequent development of DIH [7]. Reported risk factors for development of DILI during anti TB treatment were female gender, advanced age, alcohol abuse, malnutrition, underlying chronic liver disease [8].

Hepatitis C virus (HCV) is a serious global health problem. WHO estimates that 3% of the world’s population is infected with HCV and that more than 170 million chronic carriers are at risk of developing liver cirrhosis and/or liver cancer [9]. In Egypt, chronic hepatitis C virus (HCV) infection is a major cause of liver cirrhosis and liver cancer [10]. Hepatitis B is also one of the major health problems. In 2010 and 2014 resolutions of the World Health Assembly, have ranked HBV as the 15th cause of death in all cause global mortality [11]. Some recent studies have suggested that HCV infection is a significant risk factor for developing either DILI or transient liver dysfunction during anti-TB treatment [12,13].

The aim of the study is to evaluate the incidence of drug induced liver injury in tuberculous patients who suffered from viral hepatitis co-infection compared to non hepatitis infected patients. DILI will be evaluated none invasively.

Patients and Methods

This study included newly diagnosed pulmonary TB patients who were enrolled at the department of chest diseases and tuberculosis, Sohag faculty of medicine, Sohag University, Egypt, in the period between January 2013 to December 2014. Institutional research ethics review Board has approved the study and patient’s consent for the study was obtained from entire patients.

Patients who suffered from symptoms suggestive of TB such as cough, weight loss, night sweat, abnormal chest x ray findings, Acid-fast Bacilli (AFB) smear microscopy was performed using the Ziehl Neelson staining method. Culture was performed using solid (Lowenstein-Jensen) and liquid (MGIT BACTEC 960) media using standard methodologies [14,15].

Exclusion criteria of the study were children >16 years and extrapulmonary TB, miliary TB, acute active hepatitis at time of diagnosis and decompensated liver cirrhosis or patients with liver malignancy. The treatment regimen was done according to WHO guidelines for management of TB 4th edition that consisted of intensive therapy regimen for newly diagnosed TB. It consisted of a full 6 months treatment starting by 2 months of the following isoniazid, rifampicin, pyrazinamide, ethambutol followed by 4 months regimen of isoniazid and rifampicin [16].

The data collected from patient’s medical records included: socio-demographic data (age, sex, alcohol consumption, smoking drug abuse), features of symptomatic hepatotoxicity (such as fatigue, loss of appetite, nausea, vomiting, right hypochondrial pain/ tenderness, fever, and jaundice), pulmonary or extrapulmonary TB, laboratory data including alanine transaminase ((IU/L), aspartate transaminase (IU/L), total bilirubin (μ mol/L), total serum protein and albumin (g/L), hepatitis B surface antigen (HBsAg), and HCV antibody (anti-HCV),platelets counts and calculated liver fibrosis index FIB4 and cutline of FIB4 [17,18]. The FIB-4 index is calculated using the formula: FIB-4 = Age (years) × AST (U/L)/ [PLT (109/L) ×ALT1/2 (U/L)].

Liver functions tests were followed up on monthly basis. At the baseline visit, serum sample was collected and tested for HIV, Hepatitis B surface antigen and hepatitis B core antibody (HBsAg by the Auszyme Monoclonal and Corzyme assays (Abbott Laboratories, Abbott Park, IL, USA) and for HCV (HCV-Ab) by Ortho HCV Version 3.0 ELISA (Ortho Diagnostics Systems, Raritan, NJ, USA). HBV, HCV virus DNA-PCR detection was not done. Patients with symptoms suggestive of hepatitis or with an elevated ALT more than twice the upper limit of normal were referred to hepatologist for specific management but the patients didn’t receive liver protective drugs. Abdominal ultrasound exam was done and medical treatment was carried out during this stage and the offending anti TB treatment was replaced by non hepatotoxic medication and resumption of classic regimen was obtained serially when liver functions tests returned to the base line or normalized. Rifampicin was first reintroduced at progressively increasing dose then isoniazid. The regimen included rifampicin, isoniazide and ethambutol without pyrazinamide.


Medical records showed that 361 patients were diagnosed with TB. one hundred sixty six patients were excluded from the study, 102 were children, 44 patients had extra-pulmonary TB, 9 had acute active hepatitis at time of diagnosis of pulmonary TB, 6 had end-stage liver disease with jaundice and ascites, 5 patients has liver malignancy, 3 of them had hepatocellular carcinoma and 2 had metastatic liver disease from colorectal cancer and neuroendocrine tumor of pancreas. The study included 195 patients who were recently diagnosed with pulmonary TB and antituberculous therapy was commenced. Their age ranged from 19 to 61 years old with average of 36.7 years, males constituted 63% of study population (n=123) while as 37% were females (n=72).

All the patients were HIV negative. Majority of our patients (n=120) were non infected with hepatitis (62%) and considered as control for our study, while hepatitis C was diagnosed in 61 patients (31%) and hepatitis B was seen in 5% (n=10) and infection by both hepatitis B and C was seen in 2% (n=4) patients. There were no significant differences among control group and hepatitis C and hepatitis B and hepatitis B and C groups as regards smoking or alcohol consumption (Table 1).