INTRODUCTION AND AIMS

Drug-induced liver injury (DILI) is an uncommon cause of liver disease in the general population.¹ DILI in most cases is detected with mild to moderate elevations of liver tests. However, in rare cases it may lead to liver failure and mortality.² Also, hepatotoxicity is one of the important causes of termination of clinical trials and withdrawal of drug after marketing.³ The real incidence of DILI remains unknown due to difficulty in establishing diagnosis and the subclinical nature of injury in many cases. Its annual incidence in general population ranges from 14 to 19 per 100,000 inhabitants, with approximately 30% exhibiting jaundice.^{1 , 4} Overall mortality from 10 to 17.3% has been observed in several series.^{2 , 5 - 7}

The major etiologic agents for DILI include antibiotics, anti-epileptics, complementary and alternative medicine (CAM) and non-steroidal anti-inflammatory drugs (NSAIDS).^{2 , 5} However, there is limited data from developing countries including Indian subcontinent, on etiology and outcome of DILI. As tuberculosis remains a very common infectious disease in these regions, most commonly implicated drugs for DILI are anti-tuberculous therapy (ATT).⁵

The spectrum of clinical presentation of DILI is wide, from asymptomatic liver test abnormalities to symptomatic acute liver disease or liver failure. This study was conducted to evaluate various causes, clinical features and outcomes of DILI in India. Also, the clinical and laboratory parameters associated with mortality were studied.

MATERIAL AND METHODS

The study was designed as a single centre prospective observational cohort study. It was conducted in the Department of Gastroenterology in a large tertiary care hospital of a metropolitan city in western India. Patients were enrolled during the study period of two years from January 2014 to December 2015. Inpatients as well as outpatients presenting by themselves and satisfying the study criteria were included. Informed consent was taken from all the patients. The criteria for DILI were those established by the Indian Network for DILI (INDILI) in 2012. DILI was defined as (a) aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels greater than 5 times the upper limit of normal (ULN), regardless of symptoms or (b) total bilirubin greater than 2 mg/dL and rise in AST or ALT or alkaline phosphatase (ALP) levels greater than 2 times the ULN or (c) AST or ALT greater than 3 times ULN, if symptomatic with nausea, vomiting, abdominal pain, anorexia, skin rash, etc. Exclusion of other competing causes such as viral hepatitis, bile duct obstruction or congestive heart failure was done with serological tests and imaging.

Clinical and laboratory details of the patients were recorded as per the INDILI proforma. Clinical variables included age, gender, symptoms, duration of hospitalization and drug intake, concomitant drugs and illness, and cause of death. Laboratory tests included liver function tests, serum creatinine, complete hemogram, international normalized ratio, and viral serology to exclude viral hepatitis (IgM anti-hepatitis A virus, IgM anti-hepatitis E virus, hepatitis B surface antigen, IgM anti-hepatitis B core antigen, anti-hepatitis C virus antibody, Human Immunodeficiency Virus ELISA). If clinically indicated, studies were undertaken to exclude malaria, enteric fever, leptospirosis, dengue, and Wilson’s disease. Tests for autoimmune hepatitis like antinuclear antibodies and smooth muscle antibodies or anti- LKM1 antibody were done if indicated. Acute kidney injury was defined as per the Kidney Disease Improving Global Outcomes (KDIGO) criteria.⁹ Abdominal ultrasound was done to rule out biliary obstruction. All patients were followed up for at least 6 months or until normalization of liver biochemistry. Injury was considered as chronic if serum biochemistry values or imaging remained abnormal at 6 months.² Patients with pre-existing chronic liver injury were not excluded if they were considered to have developed superimposed DILI. If their basal liver tests were abnormal the DILI-induced increase was based on that basal value and the ULN was calculated from that value.¹ MELD score was calculated by the formula: 9.6 x log_e (creatinine mg/dL) + 3.8 x log_e (bilirubin mg/dL) + 11.2 x log_e (international normalized ratio) + 6.4.

RESULTS

DISCUSSION

Drug induced liver injury still remains a challenge in modern day hepatology. Although it is relatively rare cause of liver injury, the overall mortality associated with DILI is significant across all regions of the world. In our series, overall mortality was 15.85%. Overall mortality from 10 to 17.3% has been observed in several series.^{1 , 2 , 5 - 7} However, in the study from Iceland, out of 11 deaths, only 1 patient died as consequence of DILI.¹ In our series, 8 deaths were related to liver injury. A study from Thailand¹³ reported 26% mortality with DILI caused by antimicrobial agents. In this study, 21 out of 26 deaths due to all causes (76%) were observed in patients with ATT DILI. This is similar to our study in which 70% of deaths due to all causes was seen in ATT DILI patients. Also, the liver related mortality was significantly higher in ATT group as compared to non-ATT group (17.5% vs. 2.4%), which was also reported in the previous study from India.⁵ However, there was no significant difference in overall mortality between the two groups, as also observed in the study from Thailand.¹³

Similar to our study, other studies from different regions of the world including Indian subcontinent, antimicrobial agents remained the commonest cause of DILI.^{1 , 2 , 8 )} However, different class of antimicrobials was found to be causative in these studies, probably reflecting the differences in common infectious diseases seen in these regions. Tuberculosis being one of the most common infectious diseases in our country, ATT was amongst the most commonly implicated drugs, as observed by other studies from this region.^{5 , 13} Although CAM is increasingly being reported worldwide to cause DILI, our series reported 10% of patients due to CAM.

In contrast to several previous studies^{1 , 14 , 15} older age and female gender were not associated with increased risk of DILI in our study. The median age in previous studies was 58 years^{14 , 15} and 56% patients were females.^{1 , 15} The male-to-female gender ratio was 1:1 in our series similar to that observed by the Spanish group.⁸ The median age in our study was 38 years, as also observed in the previous study from India.⁵ Thus, in our series, with comparatively younger patients and equal gender ratio, it appears that neither older age nor female sex is predisposing factors for DILI. Similar observation was reported by the Lucena, et al. in the Spanish group.¹⁶ Symptoms of nausea, vomiting, and abdominal pain could be related to DILI or merely reflect general adverse effects related to the drug intake. It could not be differentiated. However, the criteria for DILI required laboratory parameters regardless of symptoms for inclusion in the study.

We also analyzed if different patterns of liver injury could predict severity and outcome in DILI patients. However, although patients with cholestatic liver injury appeared to have higher proportion of moderate and severe injury as compared to hepatocellular or mixed type (P value 0.06), there was no significant difference in overall as well as liver related mortality in these groups. Similarly, in the DILIN prospective study,² authors found that hepatocellular cases had higher proportions that were mild, as found in our series. Although hepatocellular cases had a higher frequency of fatal cases (liver related deaths or transplantation), there was no significant difference in overall as well as liver related mortality between the 3 types of liver injury. In the study from China, 9.9% mortality was reported in patients with hepatocellular damage and 9.5% in patients with cholestatic/mixed damage (P < 0.05).¹⁷ However, the difference was very small. Similarly, in the Spanish and Swedish studies hepatocellular type of liver injury was associated high but variable mortality rate, depending on the presence of jaundice or drug involved.^{8 , 14} The differences in observations made by several authors could be due the fact that these patterns of liver disease are not mutually exclusive¹⁸ and the pattern of liver disease may change from one type to another as injury progresses.¹⁹ Hence, the usefulness of different patterns of liver injury in predicting severity and outcome of DILI is questionable and needs further evaluation.

There are few studies that have reported predictors of outcome in DILI.^{5 , 8 , 13 , 14 , 17 , 20 , 21} In all these studies, various independent risk factors for acute liver failure or mortality were identified. These included hepatocellular damage, high bilirubin and female sex,⁸ high MELD score or a combination of encephalopathy, ascites, high bilirubin, prothrombin time and leucocyte count,⁵ presence ofjaundice,¹³ age, AST and bilirubin in the hepatocellular group, whereas bilirubin in the cholestatic/mixed liver injury group,¹⁴ hepatic encephalopathy, ascites, jaundice, alcohol abuse and direct bilirubin,¹⁷ female gender, high total bilirubin and high AST:ALT ratio,²⁰ high MELD and low hemoglobin.²¹ Similar to these studies, our study also found jaundice and encephalopathy as independent clinical predictors of mortality. However, laboratory variables at one week predicted mortality better than those at initial recognition of DILI. This is a unique finding in our study. The probable explanation to this finding is due to the fact that in some instances, bilirubin, ALT or ALP may continue to rise for several days even after the drug is stopped.²² Besides, the R value may advance towards cholestatic type of liver injury (i.e. R < 2) with progression of the disease.²³ The other reason for this could be, delay in access to tertiary care centers and in recognition of DILI. This is the limitation of the study and needs further evaluation in larger studies.

In our study, baseline alkaline phosphatase (ALP) in the patients receiving ATT was normal. Gamma glutamyl transferase (GGT) was done only in few patients with borderline ALP, to exclude pretreatment cholestatic liver damage or bone disease due to the tuberculosis. Hence, GGT values were not included in the analysis of final data. Also, the natural outcome of DILI would be affected by interventions like liver transplantation which is not easily available for the patients from low middle income country like ours. The risk for DILI involves several interrelated factors. However, there is little data available to support the validity of these factors.²⁴ The natural course of DILI without transplantation would help to predict actual factors that are associated with mortality. This would help us identify those patients who would benefit the most from referral to centers with transplantation facility in a country with financial constraints like India.

Limitations of the study include a relatively small sample size of the study, study based in single tertiary care center and non-availability of transplantation facility.

CONCLUSIONS

DILI results in significant overall mortality (15.85%). ATT, anti-epileptic drugs, CAM and antiretroviral drugs are leading causes of DILI in India. Presence ofjaundice, encephalopathy, MELD score at one week, and alkaline phosphatase at one week are independent predictors of mortality. The unique finding in our study was that the laboratory variables at one week predicted mortality better than those at initial recognition of DILI, however, it needs further evaluation in larger studies.