Abstract and Introduction
Abstract
Background: Idisyncratic drug-induced liver injury (DILI) is a rare instance of liver injury after exposure to an otherwise safe drug or herbal or dietary supplement. DILI can be associated with significant morbidity and mortality. Furthermore, it is an important consideration in drug development due to safety concerns.
Aims and Methods: To highlight pearls and pitfalls to aid clinicians in diagnosing DILI and surmising the management options. We also share the best practices from personal insights developed from decades long participation in the causality assessment committee meetings of the DILI Network.
Results: DILI lacks a diagnostic test and is currently diagnosed through a process of exclusion of competing aetiologies of liver injury. This requires a high degree of suspicion to consider the possibility of DILI, skill in ruling out the obvious and less obvious competing liver insults, and an understanding of the expected phenotypes of DILI. The facets of DILI cover multiple aspects, including the latency, liver injury pattern, course of injury, and associated autoimmune or immuno-allergic features. Care for patients with DILI is geared towards stopping the offending drug and symptom management that include the use of corticosteroids in select cases.
Conclusion: The diagnosis of DILI is challenging and is primarily made through a carefully crafted patient interview, temporal relationship with the implicated drug or supplement, and exclusion of competing aetiology. LiverTox is a useful resource for clinicians to review the literature and recognise the likelihood of the implicated agent in causing DILI.
Introduction
Case Narrative
A 55-year-old woman was referred for enrollment into drug-induced liver injury network (DILIN) prospective study after discharge from her recent hospital stay. She was hospitalised for acute liver injury with no rash or fever (peak AST 2210 U/L, ALT 1447 U/L, ALP 74 U/L and total bilirubin 2.2 mg/dl) that occurred approximately 6 weeks after her use of Augmentin (amoxicillin and clavulanate). Her serologic workup was negative for acute viral and autoimmune hepatitis. Imaging studies revealed patent hepatic vasculature without any biliary tree abnormalities or mass lesions. She also underwent a liver biopsy that revealed a largely preserved hepatic architecture. There was moderate portal inflammation in a chronic hepatitic pattern. The interlobular bile ducts revealed mild diffuse injury with extensive ductular reaction with no florid duct lesions. There was Kupffer cell hyperplasia with no significant steatosis or fibrosis. The overall impression was drug-induced liver injury (DILI), possibly from amoxicillin and clavulanate. At the study visit, we recognised that the pattern of liver injury was hepatocellular and wondered if she had been on any other competing medications or herbal or dietary supplements (HDS). She reported consuming a glass of wine with dinner on most days of the week. During her hospital stay, she had reported taking some vitamins and supplements for her joint pain and was instructed to get the vitamin and supplement bottles by the study nurse. She was taking three supplements (two in capsule form and one as a drink), and a review of the product label revealed that there were multiple ingredients (Figure 1), with two of the supplements containing green tea.
Figure 1.
Product label of supplements that the patient brought for our review. Multiple ingredients with some ingredients overlapping in different supplements.
Drug-induced liver injury (DILI) is a term commonly used in clinical practice to indicate unanticipated liver injury. Health care providers are very familiar with intentional and unintentional acetaminophen overdose. The current review is focused on non-acetaminophen-related DILI and its clinical assessment and management. Idiosyncratic DILI, by definition, is unpredictable.[1] It is also infrequent and general not considered to be dose-related.[1] It may occur from exposure to a multitude of causative agents such as prescription drugs, non-prescription over-the-counter drugs, herbal and dietary supplements (HDS) and rarely vaccines.[2–5]
Several studies reported an association between the risk of DILI and non-genetic factors such as the drug's properties (metabolism, solubility, and lipophilicity) and host-related factors such as age, disease state or alcohol use.[12–15] It appears that idiosyncratic DILI is largely immunologic, and risk factors include certain HLA alleles (often different for different agents) and possibly, and to a lesser extent, other genes important in modulating immune responses.[6–11] More recently, however, there has been a lot of interest in genetic susceptibility and the risk of DILI after the association between the gene HLA-B*5701 and the risk of DILI from flucloxacillin was reported.[16] The study showed that individuals who carry this allele had an 80-fold increased risk of DILI compared with those who did not.[16] Despite the high risk, it should be appreciated that individuals with this specific HLA allele had only 1 in 500 chance for flucloxacillin DILI, suggesting that factors beyond the HLA allele determine the ultimate risk. The genetic susceptibility is mediated through single-nucleotide polymorphism (SNP), that is, a positional difference of the nucleotide, and is known to be responsible for about 90% of individual human differences.[17] These SNPs account for inter-individual differences in drug response and risk of toxicity. Therefore, genetics, particularly in HLA has become very important to the study of DILI. In the recent reports including those from DILIN, HLA-B*35:01 was found in the majority of individuals with liver injury from polygonum multiflorum, green tea, Garcinia Cambogia and also turmeric.[10,11,18] HLA-B *35:02 was associated with a 30-fold increased risk of minocycline hepatotoxicity.[19] In addition to the HLA, genes involved with immune signalling such as PTPN22 and ERAP2 have also been reported to be associated with an increased risk of DILI.[7,20] Finally, genetic variants in genes involved with drug disposition have been reported, but the strength of association and risk of DILI are typically not as high as those reported with HLA alleles.[21–23]
The lack of a reliable biomarker has led to the use of multiple Omics, that is, genomics, transcriptomics, proteomics and metabolomics to investigate the underlying mechanisms involved in DILI. Genomics includes the various HLA and non-HLA polymorphisms (for example HLA-B*35:01 with green tea and Garcinia cambogia). Transcriptomics examines the changes in the genetic expression that occur at the time of the DILI event primarily using RNA sequencing (RNA-seq). This technology is currently limited to pharmaceutical industry and academia, but we anticipate that this technology may eventually make it to patient care when there is a validated signature. Currently, it is unclear if this signature would be drug specific or pattern of injury specific. Proteomics is the study of proteins using an approach that includes mass spectrometry. Using serum proteins to detect liver injury may help improve the accuracy and sensitivity in diagnosing DILI. A notable example is the acetaminophen-protein adducts that can be detected in serum may days after the levels of acetaminophen are undetectable.[24] The acetaminophen adduct testing has been instrumental in correctly classifying many cases of acute liver failure of indeterminate aetiology.[25,26] Finally, metabolomics helps with identification of small molecular biomarkers and allows for understanding the mechanistic insights of DILI. Lipidomics is a version of metabolomics that characterises the lipid profile by examining the total triglycerides, diglycerides and various phospholipids. All of the Omics either alone or in combination have been subject of some good reviews.[27–30] Recently, a public–private consortium, SAFE-T (Safer And Easter Evidence-based translation) project was established for biomarker qualification process and its validation in clinical biomarker studies designed for the translation, performance testing and eventual regulatory qualification of drug-DILI. The committee identified nine new liver safety biomarkers supported by the European Medicines Agency (EMA) and/or Food and Drug Administration (FDA) for exploratory use in clinical drug development.[31] These biomarkers are associated with various aspects of DILI that include necrosis, immune activation, apoptosis, hepatocyte leakage and mitochondrial injury. These biomarkers include total high mobility group box 1 (HMGB1), hyperacetylated HMGB1, osteopontin, total keratin 18, K-18 fragments, macrophage colony-stimulating factor receptor 1 (M-CSFR1), microRNA-122 (miR-122), glutamate dehydrogenase (GLDH) and sorbitol dehydrogenase (SDH).[31]
The severity of DILI may vary and ranges from asymptomatic liver enzyme abnormalities to acute liver injury progressing to fulminant liver failure.[2,3] Cases of chronic DILI with progression to cirrhosis with select drugs are also well characterised.[2,3] While the most common scenario encountered in clinical practice is the referral for new onset liver test abnormalities or new onset jaundice, there are some uncommon scenarios where some drugs may manifest as drug-induced AIH (minocycline, nitrofurantoin), bland cholestasis (anabolic steroids), granulomatous hepatitis (allopurinol, trimethoprim-sulfamethoxazole, hydralazine, diltiazem) or vanishing bile duct syndrome (amoxicillin-clavulanate, carbamazepine, chlorpromazine) (Table 1). Some other atypical and uncommon manifestations include drug-induced steatohepatitis, hepatoportal sclerosis, secondary sclerosing cholangitis (sevoflurane), nodular regenerative hyperplasia (azathioprine, mercaptopurine, trastuzumab emtansine, oxaliplatin, didanosine, some chemotherapy combinations) and sinusoidal obstruction syndrome (busulfan, alkaloids, gemtuzumab, palbociclib) (Table 1). During drug development, hepatic safety signals are set at a threshold starting as low as >3 times the upper limit of normal (ULN) to 5 times ULN and >10 times ULN.[32] The proportion of patients who meet these criteria is compared between the study drug and the placebo arms.[32] A concern for DILI arises if there is an imbalance between the two arms.[32] Of particular interest is an event where a subject meets the criteria of Hy's law that is based on an observation described by Hyman Zimmerman.[33–37] According to this observation, hepatocellular injury with jaundice, without a significant cholestatic component, leads to death or liver transplantation in >10% of cases.[33–37] In general, the diagnosis of DILI requires that a confirmed and clinically significant liver injury has occurred. In the Drug-induced Liver Injury Network (DILIN) prospective study, inclusion criteria required two consecutive determinations with abnormal values of serum aspartate transaminase (AST) or alanine aminotransferase (ALT) ≥5 times the ULN or serum alkaline phosphatase (ALP) ≥2 times ULN (or baseline if the baseline levels were abnormal).[2,3,38] In addition, individuals who develop a serum total bilirubin of greater than 2.5 mg/dl or an INR above 1.5, with any degree of elevation in ALT, AST or ALP levels, in the absence of competing causes were also considered to have experienced a clinically significant liver injury event.[2,3,38]
Over the last decade, the clinical phenotypes and outcomes of several drugs and HDS have been systematically characterised with prospective follow-up from several consortia across the world.[2,4,39–42] A review of the top 10 implicated agents across these consortia reveal that amoxicillin-clavulanate is the most common implicated agent (Table 2). Other common implicated drugs across the consortia include isoniazid, nitrofurantoin and ibuprofen (Table 2). Although we cannot formally comment on the temporal trends due to data from different consortia, it is interesting to note that more recent consortia data report HDS and immune checkpoint inhibitors (CPIs) are more commonly implicated agents. The HDS associated with liver injury have been varied and seem to be changing with time. Notable reports in the United States that have at times led to FDA recall include black cohosh,[43] hydroxycut,[44–46] Herbalife,[47] Oxy-Elite Pro in 2015,[48] anabolic steroids, green tea,[10] Ashwagandha,[49] Garcinia Cambogia,[11] Kratom[50] and more recently turmeric.[51] Lastly, the contents of HDS may be mislabeled and adulterants not listed on the label may be present.[52] In one study from DILI, a patient with liver injury attributed from taking a combination of Garcinia cambogia and green tea had discrepancies between label and chemical profiling of the product consumed by the patient.[11]
In addition to identifiable competing causes of liver injury and acetaminophen hepatotoxicity, important exclusionary criteria in DILIN and other prospective registries included pre-existing autoimmune liver disease (autoimmune hepatitis, primary biliary cholangitis or primary sclerosing cholangitis [PSC]) and prior liver or bone marrow transplantation.[2,3,38] Ascertaining DILI in patients with these conditions is very challenging due to abnormal liver tests from underlying liver disease. The data from these consortia, particularly DILIN, immensely helped to establish LiverTox (https://www.ncbi.nlm.nih.gov/books/NBK547852/), as the 'go to' resource for a busy clinician to easily navigate unbiased and carefully curated literature on DILI.
Making a diagnosis of DILI can be challenging due to varied presentations necessitating careful and deliberate exclusion of competing etiologies. Particularly challenging are patients taking multiple drugs or dietary supplements (polypharmacy), those with pre-existing liver disease, and liver or bone marrow transplant recipients. In this clinical practice review, we reflect on a decade of our personal experience as members of the DILIN causality committee and share our opinions on the best practices in the causality assessment and management of DILI.
Aliment Pharmacol Ther. 2022;56(11):1516-1531. © 2022 Blackwell Publishing
