Idiosyncratic drug‐induced liver injury associated with bile duct loss and vanishing bile duct syndrome: Rare but has severe consequences
Authors: Einar S. Björnsson, Jon Gunnlaugur Jonasson
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. See Article On Page 1267 Destruction and loss of small bile ducts are frequently observed in chronic cholestasis of different etiologies. An important differential diagnosis is cholestatic drug‐induced liver injury (DILI).1 If the bile duct loss is severe with extensive loss of bile ducts or even diappearance, the syndrome is referred to as vanishing bile duct syndrome (VBDS).2 VBDS is rare and has been considered to occur in only 0.5% of small duct biliary disease.2 In this issue of Hepatology, Bonkovsky et al. in the Drug‐Induced Liver Injury Network (DILIN) publish a relatively large cohort of patients with bile duct loss and VBDS.3 The contribution of the DILIN group to the knowledge on DILI since it was initiated in 2004 is impressive.4 In the total DILIN cohort during the first 10 years, 1,056 fulfilled the predetermined criteria for DILI, of whom 363 (34%) had a liver biopsy undertaken. In all, 26 of 263 (7%) had bile duct loss: 14 had severe bile duct loss (<50% of portal areas with bile ducts) and 12 mild bile duct loss.3 It has to be taken into consideration that the DILIN network consists of several tertiary referral centers and is likely to recruit more‐severe cases than observed in population‐based studies. In a prospective study from Iceland over a 2‐year period with approximately 100 DILI patients, no VBDS cases were identified and all patients with severe cholestatic reaction recovered with time.5 In this interesting article,3 there seems to be several different features in the patients with bile duct loss compared with the overall DILIN cohort, as recently reported.4 Overall, the patients with bile duct loss presented in 25 of 26 (96%) with jaundice versus 70% in the overall DILIN cohort and 77% with itching versus 54% in the total cohort.4 Thus, if a patient with DILI does not present with cholestatic jaundice and itching, the diagnosis of VBDS is unlikely. Immunoallergic features, such as peripheral or hepatic eosinophilia, were not more common in the patients with bile duct loss than in other patients with available histology in the current study or patients in the largest DILIN cohort.4 Interestingly, the most common histopathological pattern was shown to consist of mild inflammatory infiltrates, with no or little interaction with the remaining ducts. In some of the biopsies, marked ductular reaction was observed. The outcome, based on these histopathological patterns, was not reported by the researchers. However, the only predictor of poor outcome was degree of bile duct loss on biopsy. It is unclear whether or not the presence of marked ductular reaction is a marker for reversibility. A patient who developed VBDS, who had complete loss of bile ducts after a 3‐week course of the antiepileptic drug, zonisamide, had complete restoration of bile ducts shown on serial liver biopsies during follow‐up.6 In that case, ductular reaction was not observed in the index biopsy.6 Ten or more portal tracts are thought to be needed for an adequate liver biopsy in estimating bile ducts for VBDS, defined as absense of interlobar bile ducts in >50% of portal areas (Fig. 1).7 In the article by Bonkovsky et al.'s article,3 these criteria inevitably could not be strictly fulfilled, with portal tracts ranging from 6 to 21. This drawback is well recognized in the article, and the study has to be evaluated with this in mind. An important strength factor is that all the biopsies were estimated, double blinded, by a single, experienced liver pathologist. It would, however, have been useful to state the histologial stains used. An interesting observation is that the necroinflammatory (hepatic activity index) index was not significantly different between patient outcome groups (in Table 4). The numbers, if at all of importance, would rather indicate that there was less inflammation in the poor outcome group as compared to the benign outcome group. Perhaps the most interesting statistical information in this study is that bile ducts were present in 64% of portal areas in biopsies from patients with benign outcome, in contrast to only 17% of portal areas having bile ducts in the biopsies from patients with poor outcome.Figure 1: Portal area of a liver biopsy demonstrating the lack of a bile duct. The arrows point at an artery (yellow arrow) and a vein (red arrow). The bile duct that normally should accompany is missing.The overall outcome in the cohort with bile duct loss was unfavorable. There was approximately 19% liver‐related mortality among patients with bile duct loss, either as the primary or contributing cause of death. This high mortality can be compared with the overall 6.2% mortality in the 899 DILI patients, half of which was liver related.4 The need for liver transplantation was observed in 2 of 26 (8%) in the current study and 4% in the overall cohort.4 Furthermore, “chronicity,” defined as elevation of liver tests at 6 months of follow‐up, was observed in 94% of the patients with bile duct loss versus 47% in patients with other histopathological patterns.3 The almost 50% of patients with chronicity in other patients undergoing a liver biospy might be attributed to selection of patients with slow recovery from liver injury who are more likely to undergo a biopsy. There is a long list of drugs associated with VBDS, such as chlorpromazine, carbamazepine, and flucloxacillin, to name a few.8 The quality of some of these reports has though been very variable, and in most cases, the drug is only a suspected, not proven cause of the liver injury. Recently, categorization of drugs has been published, illustrating which are the well‐documented hepatotoxic drugs and by causality assessment of those which are not.9 However, a separate analysis of case reports on VBDS was not undertaken.9 Among the drugs associated with VBDS in the current study, only in 5 (23%) cases, the drug belonged to category A of the major hepatotoxic drugs with >50 cases reported.9 The rest of the drugs belonged to category B and C and one (metoclopramide) from category E, that did not have a published case report fulfilling causality assessment.9 Common causes of pure (bland) cholestasis, such as oral contraceptives and anabolic steroids, were not associated with a single case of VBDS.3 Interestingly, liver‐related mortality in oral‐contraceptive–induced liver injury has not been reported and liver failure attributed to anabolic steroids leading to death or liver transplantation has very rarely been reported.9 Although the liver damage of the VBDS was irreversible in 38% of the patients, resulting in liver‐related death or liver transplantation in the current report, the prognosis in drug‐induced VBDS seems to be more favorable than in other causes of VBDS.2 The pathogenesis behind VBDS associated with drugs is largely unknown, and there is no proven therapy to reverse this condition once established. Given the potentially severe consequences, it therefore cannot be overemphasized that drugs with known serious adverse effects should only be given to patients with a clear indication for the medication.