Histopathological Challenges in Suspected Drug-induced Liver Injury

David E. Kleiner

Liver International. 2018;38(2):198-209.

Abstract and Introduction

Abstract

When a patient with suspected drug-induced liver injury (DILI) undergoes liver biopsy, the pathologist is confronted with two major challenges. The first and most important is to establish the pattern(s) of injury which are present. Patterns of injury represent stereotypical responses of an organ to injury and relate to specific aetiologies of liver damage. The pattern of injury and the histological details of that injury can then be analysed with respect to the patient's intercurrent diseases and medication history. The specific expertise of the pathologist can be used to weigh the prospect of DILI against the likelihood of other explanations of injury. The second challenge is to characterize specific types of injury and the severity of injury, both of which may have importance for clinical decision-making and prognosis. The pathologist's report should convey both an accurate description of the pathology as well its interpretation.

Introduction

Liver biopsy is not an obligate part of the evaluation of patients with suspected drug-induced liver injury (DILI), but it is a frequently performed procedure. In the U.S. Drug-Induced Liver Injury Network (DILIN), a multicenter prospective registry of suspected and confirmed cases of DILI, liver biopsy was performed in about 50% of patients.^[1] Although the utility of liver biopsy in the evaluation of DILI has not been rigorously evaluated, as a single clinical test it has the potential to provide a wealth of direct information about the character of the liver injury. In the broadest sense, a liver biopsy provides information about both the severity of injury and the overall morphological changes, generally termed the pattern of injury (Table 1).

The pathologist faces several challenges in the interpretation of liver biopsies from patients with suspected DILI. First, DILI is uncommon—population-based studies have identified an incidence rate that varies from 8.1 per 100 000 in a 3-year study from the Nièvre district of France^[2] to 19.1 per 100 000 identified in a 2-year survey in Iceland.^[3] To put these numbers in perspective, the overall incidence of DILI is about 10 times that of autoimmune hepatitis (AIH) (1.9 per 100 000),^[4] primary biliary cholangitis (0.2–2.4 per 100 000)^[5,6] and primary biliary sclerosis (1.3 per 100 000),^[4] three uncommon diseases that often enter into the differential diagnosis in suspected DILI. Of course, DILI is not a single entity, but many different drug-specific injuries, which will lower the incidence of any one type of drug injury to far less than 1 per 100 000. As the use of liver biopsy to evaluate these diseases is limited, the opportunity for any pathologist to gain wide experience in the histological evaluation of uncommon liver disease is further limited. The pathologist must develop a systematic approach to the pathology to overcome this limitation of practical experience.

Additional challenges are apparent in Table 1. Patients with known underlying liver disease—most often fatty liver disease or viral hepatitis—may develop an acute injury suspected to be DILI. The challenge to the pathologist involves distinguishing histological features that can be explained by the underlying disease and those that may be related to DILI. If the suspected drug causes an injury like that of the underlying disease (eg, suspected minocycline injury in a patient with chronic hepatitis C), it may be impossible to define a contribution to the injury by the drug. Nevertheless, there may be histological changes, like zonal necrosis or cholestasis, that would not be expected in pathology owing to the underlying disease, allowing the suggestion of superimposed DILI to be made. Examination of prior biopsies, if available, may become very important in the distinction of additional injury. Similarly, patients who are acutely ill, on multiple medications or in the intensive care unit present a different kind of challenge. Patients may be at risk for sepsis or hypoxic/ischaemic injury, which have their own distinctive patterns of injury. In cases of polypharmacy the pathologist may need to sort through the medication list to identify the most likely candidates for DILI. Finally, the pathologist may be asked for their opinion on whether the degree of injury would permit the continued careful use of a medication that cannot be replaced and is providing a clear, life-sustaining benefit. It is important that both the pathologist and the clinician maintain open communications during and after the biopsy evaluation. Severe or unusual injury may require immediate contact of the clinician. Information from additional clinical testing indicated by changes in the biopsy or from longer follow-up may provide the opportunity for deeper interpretation of the biopsy.

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Next Section

Abstract and Introduction
Defining the Pattern of Injury
Histological Changes Related to Age and Gender
Liver Biopsy and Outcome
Summary and Conclusions
References
Sidebar

Table 1. The role of liver biopsy in the evaluation of suspected DILI
• Characterize the Pattern of Injury ○ Morphological changes may help to confirm drug injury by matching known/reported patterns of DILI ○ Pattern of injury is related to the non-DILI differential diagnosis and may therefore exclude or suggest alternate diagnoses ○ Overlapping patterns of injury may be dissected by careful clinical-pathological correlation ○ Morphological changes may suggest mechanism of injury • Assess the degree of injury ○ Severe injury, for example, extensive necrosis or marked ductopenia, may have prognostic implications ○ The injury may be mild, permitting the continued use of a necessary drug (eg, methotrexate)

Table 2. Frequency of histopathological patterns of injury observed in the drug-induced liver injury network
Pattern	Characteristic features	Nuances and Caveats	Frequency in DILIN¹⁰
Necroinflammatory patterns
Zonal Coagulative Necrosis	Zone 3 or 1 coagulative necrosis, usually without significant inflammation	Steatosis may be seen in the non-necrotic parenchyma; veins should be examined for changes in veno-occlusive disease	3%
Submassive to Massive Necrosis	Extensive pan-acinar necrosis, variable inflammation	Often a consequence of severe acute hepatitis	0.4%
Acute (Lobular) Hepatitis	Lobular-dominant inflammation with/without confluent or bridging necrosis; no cholestasis	Mild presentations will overlap with non-specific reactive hepatitis	21%
Chronic (Portal) Hepatitis	Portal-dominant inflammation, interface hepatitis (also includes mononucleosis pattern), with or without portal-based fibrosis; no cholestasis	Mild presentations will overlap with non-specific reactive hepatitis	14%
Granulomatous Hepatitis	Inflammation dominated by granulomas (usually non-necrotizing), portal or lobular	Granulomas are usually non-fibrogenic and may be mixed with lymphocytes or oeosinophils	1%
Cholestatic injury patterns
Acute Cholestasis (Intrahepatic, Canalicular)	Hepatocellular and/or canalicular cholestasis in zone 3; may show duct injury, but little inflammation	Hepatocytes may be complete normal or may be ballooned in areas of cholestasis.	9%
Chronic Cholestasis	Periportal cholate-stasis, periportal fibrosis, copper accumulation, duct sclerosis or injury, duct loss	Zone 3 cholestasis may also be seen	10%
Cholestatic Hepatitis	Acute or chronic hepatitis pattern plus zone 3 cholestasis	Often an inverse relationship between the severity of inflammation and severity of cholestasis	29%
Steatotic injury patterns
Steatosis, microvesicular	Predominantly microvesicular steatosis, inflammation variable	Small groups of hepatocytes with microvesicular steatosis may be seen in the context of other injury patterns	0.4%
Steatosis, macrovesicular	Predominantly macrovesicular steatosis without significant portal or lobular inflammation, no cholestasis	Vacuoles may be variably sized but cells should not have a foamy appearance
Steatohepatitis	Zone 3 ballooning injury, sinusoidal fibrosis, Mallory bodies, variable inflammation and steatosis, no cholestasis	Ballooning should not be the cell swelling sometime seen with cholestasis	2.4%
Vascular injury patterns
Sinusoidal Obstruction syndrome/Veno-occlusive disease	Occlusion or loss of central veins, thrombosis, with or without central haemorrhage and necrosis	Masson trichrome stains useful to identify occluded central veins	1%
Hepatoportal sclerosis	Disappearance of portal veins	Often a subtle finding unless there are clear occlusive changes in the portal veins
Nodular regenerative hyperplasia	Diffuse nodular transformation, with or without mild inflammation and sinusoidal fibrosis	Should always be in the differential when minimal changes are apparent on the routine stain	0.4%
Sinusoidal Dilation/Peliosis	Sinusoidal alterations with/without mild lobular inflammation, sinusoidal fibrosis	Sinusoidal dilation may be associated with atrophic hepatocyte plates
Cytoplasmic alterations
Glycogenosis	Diffuse hepatocyte swelling with very pale bluish-gray cytoplasm		1%
Ground-glass change	Diffuse homogenization of cell cytoplasm caused by induction of smooth endoplasmic reticulum		1%

Approximately 5% of cases had complex injury pattern not easily categorized. Frequencies adapted from Kleiner et al ¹⁰

Table 3. Common and uncommon aetiologies of liver disease in the differential diagnosis of DILI
Pattern	Common Aetiologies	Uncommon Aetiologies
Zonal necrosis	Hypoxic-ischaemic injury
Non-zonal necrosis		Herpetic or adenoviral hepatitis
Acute Hepatitis	Acute viral or autoimmune hepatitis	Graft-vs-host disease
Chronic Hepatitis	Chronic viral or autoimmune hepatitis	Early PBC, EBV hepatitis, CVID, Hepatitis A
Granulomatous Hepatitis	Sarcoidosis, PBC, infection
Acute Cholestasis	Sepsis, acute large duct obstruction (LDO), postsurgical cholestasis	Benign recurrent intrahepatic cholestasis
Chronic Cholestasis	PBC, sclerosing cholangitis, chronic LDO	Ischaemic cholangitis, idiopathic ductopenia, PFIC
Cholestatic Hepatitis	Acute viral hepatitis (acute form), acute LDO	Graft-vs-host disease, PFIC
Microvesicular Steatosis		Alcoholic foamy degeneration, fatty liver of pregnancy
Macrovesicular Steatosis	Obesity, diabetes, alcohol	Lipodystrophy
Steatohepatitis	Obesity, diabetes, alcohol	Lipodystrophy
VOD/SOS		Environmental toxins
Nodular regenerative hyperplasia and hepatoportal sclerosis	Collagen vascular diseases, CVID, lymphoproliferative diseases
Glycogenosis	Type 1 diabetes

PBC, Primary biliary cholangitis; CVID, Common variable immunodeficiency; LDO, Large duct obstruction; PFIC, Progressive familial intrahepatic cholestasis.