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Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 1  |  Page : 20-22

Profile of drug-induced liver injury due to antibiotics in patients with chronic liver disease


1 Department of Clinical Pharmacy, Amrita Institute of Medical Sciences, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
2 Department of Gastroenterology, Amrita Institute of Medical Sciences, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India

Date of Submission23-Jan-2020
Date of Acceptance19-Feb-2020
Date of Web Publication07-Jul-2020

Correspondence Address:
Prof. Rajesh Gopalakrishna
Department of Gastroenterology, Amrita Institute of Medical Sciences, Amrita Vishwa Vidyapeetham, AIMS Ponekkara P.O, Kochi - 682 041, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AMJM.AMJM_8_20

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  Abstract 


Background: Patients with chronic liver disease (CLD) may be more susceptible to drug-induced liver injury (DILI) through reduced drug clearance, aberrant metabolism, altered excretion, or impaired adaptive responses. The diagnosis of DILI may identify a reversible cause for acute decompensation. Aim: The aim was to study the profile and outcomes of DILI in CLD patients. Patients and Methods: A total of 400 consecutive in patients with CLD who had been received antibiotic therapy between September 2015 and April 2016 were prospectively studied for features suggestive of DILI. The Naranjo Adverse Drug Reaction (ADR) Probability Scale was used for identifying ADRs in CLD patients. Results: Sixty-three (15.8%) patients were identified by Naranjo Scale. The most common etiology of CLD in these patients was alcohol (49.2%); hepatitis C virus (7.9%), NASH (4.3%), cryptogenic (14.3%), and hepatitis B virus (5.6%) were other common causes. DILI was more common in Child class C (52.4%) as compared to Child B (30.2%) and Child A (17.4%). Thirteen (20.6%) patients had hepatitic, 17 (27%) had cholestatic, and 33 (52.45) had a mixed pattern. There were six cases with DILI due to anti-tubercular treatment. Clarithromycin (9 cases), clindamycin (9 cases), amoxicillin-clavulanate (7 cases), and co-trimoxazole (5 cases) were the most common antibiotics causing DILI in CLD patients. Forty-three (68.2%) recovered, 11 (17.4%) expired, 3 (4.7%) developed acute on chronic liver failure, and 2 (3.1%) underwent liver transplant. Conclusions: Definitive diagnosis of DILI in CLD patients is difficult, and it is often a diagnosis of exclusion. Exposure to a potentially hepatotoxic agent, the temporal profile of liver function test changes after initiation and withdrawal of antibiotics is useful pointers. Early diagnosis of DILI, even if not definitive, may help in timely intervention and affect outcomes in CLD patients.

Keywords: Drug-induced liver injury, hepatotoxicity, liver cirrhosis, Roussel Uclaf Causality Assessment method


How to cite this article:
Neethu C M, Gopalakrishna R. Profile of drug-induced liver injury due to antibiotics in patients with chronic liver disease. Amrita J Med 2020;16:20-2

How to cite this URL:
Neethu C M, Gopalakrishna R. Profile of drug-induced liver injury due to antibiotics in patients with chronic liver disease. Amrita J Med [serial online] 2020 [cited 2020 Aug 5];16:20-2. Available from: http://www.ajmonline.org.in/text.asp?2020/16/1/20/289144




  Introduction Top


Liver injury due to a drug or herbal medicines leading to liver test abnormalities or liver dysfunction where other possible causes have been reasonably excluded can be considered as drug-induced liver injury (DILI). Many cases are due to idiosyncratic or unexpected reactions when the medications are used in recommended dosages; and are distinct from liver injury secondary to a drug overdose. Antibiotics are one of the most common causes of DILI due to widespread prescription of this class of drugs.[1] Patients with chronic liver disease (CLD) may be more susceptible to DILI through reduced drug clearance, aberrant metabolism, altered excretion, or impaired adaptive responses.[2] A timely diagnosis of DILI in these patients may identify a reversible cause for acute decompensation. We prospectively studied the profile and outcomes of DILI due to antibiotics in CLD patients.


  Patients and Methods Top


A total of 400 consecutive inpatients with CLD who had been received antibiotic therapy over a 9-month period between September 2016 and April 2016, were prospectively studied for features suggestive of DILI. The medication list was screened for any other potentially hepatotoxic drugs. Viral serology was performed, and a careful history for active alcohol use or any herbal drug intake was recorded in all patients. The Naranjo Adverse Drug Reaction (ADR) Probability Scale[3],[4] was used for identifying ADRs. DILI was classified on the basis of the degree/ratio of abnormalities in the alanine aminotransferase (ALT) and alkaline phosphatase (ALP). It was considered as follows: (a) hepatocellular injury in case of isolated increase in ALT twice normal or ALT/ALP >5, (b) cholestatic injury in case of isolated increase in ALP twice normal, or ALT/ALP <2, and (c) mixed injury if ALT and ALP are increased and ALT/ALP >2 and <5.


  Results Top


Sixty-three (15.8%) patients, (53 males and 10 females), were identified by Naranjo Scale. The age group of patients was between 55 and 65 years. The most common etiology of CLD in these patients was alcohol (49.2%); hepatitis C virus (7.9%), NASH (4.3%), and cryptogenic (14.3%) were other common causes. DILI was more common in Child class C (52.4%) as compared to Child B (30.2%) and Child A (17.4%).

In our study, the mixed injury pattern was seen to be most common (52%), while 26.98% had cholestatic, and 20.63% had hepatitic pattern of liver injury [Figure 1].
Figure 1: Patterns of liver injury in drug-induced liver injury in chronic liver disease

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There were six cases with DILI due to anti-tubercular treatment. Clarithromycin (9 cases), clindamycin (9 cases), amoxicillin-clavulanate (7 cases), and co-trimoxazole (5 cases) were the most common antibiotics causing DILI in CLD patients [Figure 2]. On the assessment of outcomes, it was seen that 43 (68.2%) recovered, 11 (17.4%) expired, and 3 (4.7%) developed acute on chronic liver failure, and 2 (3.1%) underwent a liver transplant [Figure 3].
Figure 2: Drugs implicated in drug-induced liver injury in chronic liver disease

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Figure 3: Outcome of drug-induced liver injury in chronic liver disease

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  Discussion Top


Antibiotics are among the common drug class causing DILI. A Spanish population-based study involving 461 patients found out that the antibiotics were the most commonly used drugs among DILI, and amoxicillin-clavulanate was the most common at 12.8%.[5] However, in our study, the common drugs were clindamycin and clarithromycin. One reason might be due to the fact that in our study, the main indication for antimicrobials was urinary tract infections, sepsis and lower respiratory tract infections where amoxicillin-clavulanate is not the preferred agent.

A definitive clinical diagnosis of DILI can be difficult to establish, as a gold standard diagnostic test, such as a highly specific biomarker, is currently unavailable. Abnormal liver function tests (LFTs) remain the hallmark for detecting liver injury, but their use may be confounded by underlying diseases. Furthermore, there is a lack of consensus on the laboratory threshold criteria that should be used to identify DILI. Three different national DILI registries in Spain, Sweden, and the USA used different cutoff values for their inclusion criteria.[5],[6],[7] Liver histology in DILI can be nonspecific and can mimic other acute or chronic liver diseases.

Although liver biopsy is useful in grading the severity of the injury, there is no standardized histological scoring system for DILI.

Many studies have used expert opinion to adjudicate DILI cases. Various causality assessment algorithms have been developed over the years. The Naranjo ADRs Probability Scale has been widely used for DILI due to its simplicity and wide applicability but has low sensitivity and negative predictive values.[3],[4] The Roussel Uclaf Causality Assessment Method (RUCAM) has been widely used[8],[9] and has the advantage of being quantitative and logical with carefully considered variables and has disadvantages of being cumbersome to use in practice and difficult to use in case of delayed effects and where there are competing causes such as alcohol or other drugs. Some risk factors in RUCAM such as pregnancy, alcohol use, and aged > 55 years are not applicable for pediatric patients. The US DILI Network (DILIN) prospective study attempted to structure expert opinion process to minimize inter-rater variability and bias.[10],[11] Although a complete agreement was higher in the DILIN method compared to the RUCAM, there is still significant inter-rater variability in both methods.

In the setting of preexisting CLD, causality assessment requires great familiarity with the natural history of the underlying liver disease. Aithal et al. have suggested that DILI cannot be merely defined by the rise in serum aminotransferases and requires causality assessment that incorporates a temporal relationship with medication exposure, pattern of liver injury, and exclusion of alternative diagnoses to confirm cases.[12]

Current literature suggests that a clearly defined increased the risk of DILI in CLD is due to use of the anti-tuberculous medications and some antiretroviral medications.[13] However, it is unclear whether the recommendations for dose reduction of many antibiotics in hepatic impairment can protect against the development of DILI.


  Conclusion Top


The definitive diagnosis of DILI in CLD patients can be challenging. Depending on the clinical setting, by the aid of careful history taking, physical examination, and a series of serological and imaging tests, the common causes of acute liver injury such as viral hepatitis, pancreaticobiliary disease, alcohol, and ischemia which can mimic DILI have to be excluded from the study. Furthermore, some forms of CLD can present with an icteric flare (e.g. alcoholic hepatitis, autoimmune hepatitis, and chronic hepatitis B virus) that may be mistaken as DILI. Hence, detection of DILI in patients with CLD requires substantial effort, because it remains a diagnosis of exclusion. Exposure to a potentially hepatotoxic agent, the temporal profile of LFT changes after initiation and withdrawal of antibiotics are useful pointers. Early diagnosis of DILI, even if not definitive, may help in timely intervention and affect outcomes in CLD patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Robles M, Toscano E, Cotta J, Lucena MI, Andrade RJ. Antibiotic-induced liver toxicity: Mechanisms, clinical features and causality assessment. Curr Drug Saf 2010;5:212-22.  Back to cited text no. 1
    
2.
Chalasani NP, Hayashi PH, Bonkovsky HL, Navarro VJ, Lee WM, Fontana RJ, et al. ACG clinical guideline: The diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol 2014;109:950-66.  Back to cited text no. 2
    
3.
Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.  Back to cited text no. 3
    
4.
García-Cortés M, Lucena MI, Pachkoria K, Borraz Y, Hidalgo R, Andrade RJ, et al. Evaluation of naranjo adverse drug reactions probability scale in causality assessment of drug-induced liver injury. Aliment Pharmacol Ther 2008;27:780-9.  Back to cited text no. 4
    
5.
Andrade RJ, Lucena MI, Fernández MC, Pelaez G, Pachkoria K, García-Ruiz E, et al. Drug-induced liver injury: An analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 2005;129:512-21.  Back to cited text no. 5
    
6.
De Valle MB, Av Klinteberg V, Alem N, Olsson R, Björnsson E. Drug-induced liver injury in a Swedish University hospital out-patient hepatology clinic. Aliment Pharmacol Ther 2006;24:1187-95.  Back to cited text no. 6
    
7.
Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, et al. Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008;135:1924-34, 1934.e1-4.  Back to cited text no. 7
    
8.
Danan G, Benichou C. Causality assessment of adverse reactions to drugs-I. A novel method based on the conclusions of international consensus meetings: Application to drug-induced liver injuries. J Clin Epidemiol 1993;46:1323-30.  Back to cited text no. 8
    
9.
Benichou C, Danan G, Flahault A. Causality assessment of adverse reactions to drugs-II. An original model for validation of drug causality assessment methods: Case reports with positive rechallenge. J Clin Epidemiol 1993;46:1331-6.  Back to cited text no. 9
    
10.
Rockey DC, Seeff LB, Rochon J, Freston J, Chalasani N, Bonacini M, et al. Causality assessment in drug-induced liver injury using a structured expert opinion process: Comparison to the Roussel-Uclaf causality assessment method. Hepatology 2010;51:2117-26.  Back to cited text no. 10
    
11.
Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, et al. Features and Outcomes of 899 Patients With Drug-Induced Liver Injury: The DILIN Prospective Study. Gastroenterology 2015;148:1340-52.  Back to cited text no. 11
    
12.
Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H, et al. Case definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther 2011;89:806-15.  Back to cited text no. 12
    
13.
Lewis JH. The Art and Science of Diagnosing and Managing Drug-induced Liver Injury in 2015 and Beyond. Clin Gastroenterol Hepatol 2015;13:2173-89.  Back to cited text no. 13
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]



 

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