Diagnosing Drug‐Induced Liver Injury

Diagnosing Drug‐Induced Liver Injury

Guruprasad P. Aithal1,2

1Nottingham University Hospitals NHS Trust, Nottingham, UK

2University of Nottingham, Nottingham, UK

Acute onset of liver injury attributable to the exposure to a drug taken in its therapeutic dose is referred to as . The term “drug” includes non‐prescription medicinal products, herbal remedies, and dietary supplements unless specified. Overdoses, whether intentional or inadvertent, are not discussed in this chapter. Distinction between intrinsic and idiosyncratic is hypothetical, as a subtle dose relationship (within the therapeutic range) exists in relation to DILI secondary to a number of drugs.

Challenges in the Diagnostic Approach

Identifying a particular drug as the etiology of an acute liver injury early is of critical importance, as its prompt withdrawal can reduce the risk of serious consequences. On the other hand, interruption of antituberculosis, antiepileptic, or antineoplastic agents may reduce the effectiveness of the treatment regimen. The general approach to diagnosis in clinical practice, as with other conditions, involves pattern recognition, assessing the pretest probabilities, and performing suitable tests to support or refute the diagnosis. However, confident diagnosis of DILI has remained a challenge because of a number of factors. First, over 650 medicinal products have been associated with adverse liver reactions; medications that accounted for DILI in consecutive patients enrolled into a cohort study are listed in Table 20.1. Polypharmacy has risen with the prevalence of multimorbidity. Truly distinct “signature patterns” of liver injury attributable to a particular drug or group of drugs are exceptions than a rule. Although lack of specific tests is highlighted as a barrier, specialist tests such as liver biopsy and genetic tests are underused.

We make rapid decisions, deemed necessary while managing medical emergencies or when evaluating many patients in a time‐limited manner. Our approach is aided by “heuristics,” strategies that provide short cuts to quick decisions, which in turn are pitfalls in diagnosis. In a large European study involving over 10 000 patients presenting with jaundice, doctors had an overall diagnostic accuracy of 77% at the time of initial assessment compared with the final diagnosis. However, diagnostic accuracy was 49% for DILI and it was ranked 15th of 18 categories of diagnoses considered in the study. Systematic evaluation would be able to overcome some of these limitations.

Be Aware of the Base Rates

Knowledge of how frequently particular condition occurs in different clinical contexts informs the pretest probability of a diagnosis. Considering DILI as a differential diagnosis in all acute presentation of liver injury is the first step in the systematic evaluation.

Raised Liver Enzymes

An international expert working group established the threshold for defining DILI, which includes any one of the three criteria: alanine transaminase elevation fivefold or more above the ULN, alkaline phosphatase twofold or more above ULN or ALT threefold or more above ULN with elevation of bilirubin twofold or more above ULN [1]. Aspartate amino transaminase (AST) is a substituted for ALT when the latter is not a part of the available panel of tests. Unexplained elevation of ALT five or more times ULN unrelated to the drug exposure have been observed in 0.3–0.4% of large population monitored regularly over one year. In a recent study involving 3155 patients on standard regimen of antituberculosis treatment, 218 (6.9%) developed ALT elevation between three and five times ULN [2]; of these, 193/218 (88.5%) resolved without significant (more than seven days) interruption in the treatment, while none of the 25/218 (11.5%) who developed DILI (ALT ≥ fivefold ULN) in this group progressed to acute liver failure. Lower thresholds of ALT elevation may be suitable for monitoring adverse liver reactions in clinical trials, where knowledge about the efficacy and safety of a medication is yet to be confirmed. However, unexplained elevation of ALT between above threefold ULN has been observed in 0.26% of people per year in the placebo group of a clinical trial and most were not explained by diagnosable liver disease. However, six of these who had raised bilirubin greater than twofold ULN all had liver disease requiring hospitalization. In a group of patients with atrial fibrillation attending routine outpatient care, 0.2% had new persistent elevation of ALT greater than twofold ALT. Cohort studies describing etiology underlying ALT/AST elevation of greater than 10‐fold ULN or greater than 20‐fold ULN have found 9% of these are due to DILI [3, 4].

Table 20.1 Etiological agents of consecutive 78 cases of drug‐induced liver injury (DILI) presenting to secondary care hospitals in the UK.

Drug group Drug Cases (n) Total DILI (%) Pattern of DILI
Antimicrobial Co‐amoxiclav 13 16.46 Eight hepatocellular; three mixed; two cholestatic
Flucloxacillin 12 15.19 Five hepatocellular; five mixed; two cholestatic
Nitrofurantoin 4 5.06 Three hepatocellular; one cholestatic
Doxycycline 2 2.53 Two cholestatic
Pivmecillinam 1 1.27 Hepatocellular
Isoniazid 1 1.27 Hepatocellular
Total 33 41.77
Immune checkpoint inhibitors Ipilimumab/nivolumab 11 13.92 All hepatocellular
Nivolumab 1 1.27 Mixed
Total 12 15.19
Statin Atorvastatin 9 11.39 Four hepatocellular; five cholestatic
Antimetabolites Azathioprine 3 3.80 Two mixed; one cholestatic
Methotrexate 2 2.53 Hepatocellular
Gemcitabine 1 1.27 Cholestatic
Total 6 7.59
Antineoplastic Asparaginase 2 2.53 One hepatocellular; one mixed
Temozolomide 1 1.27 Hepatocellular
Docetaxel 1 1.27 Mixed
Total 4 5.06
Biologics Infliximab 2 2.53 Hepatocellular
Vedolizumab 1 1.27 Hepatocellular
Total 3 3.80
Tyrosine kinase inhibitor Zanubrutinib 1 1.27 Hepatocellular
Panzopanib 1 1.27 Hepatocellular
Total 2 2.53 Hepatocellular
NSAIDS Ibuprofen 1 1.27 Hepatocellular
Naproxen 1 1.27 Hepatocellular
Total 2 2.53
Angiotensin ii receptor antagonists Irbesartan 1 1.27 Cholestatic
Anesthetics Propofol 1 1.27 Hepatocellular
Anabolic steroids SD matrix 1 1.27 Cholestatic

DNP (2,4‐dinitrophenol) 1 1.27 Hepatocellular
Estrogens Tibolone 1 1.27 Hepatocellular
Antispasmodics Alverine citrate 1 1.27 Hepatocellular

Promethazine/dextromethorphan (supplement) 1 1.27 Hepatocellular

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Dec 15, 2022 | Posted by in GASTROENTEROLOGY | Comments Off on Diagnosing Drug‐Induced Liver Injury
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