Hepatology Snapshot: JOURNAL

Drug-induced chronic liver injury OF HEPATOLOGY The Home of Liver Research

Lara Dakhoul, Marwan Ghabril, Naga Chalasani

Indiana University School of Medicine, Division of Gastroenterology & Hepatology, Indianapolis, Indiana
(Pathology images are adapted from Zhang et al. Clin Liver Dis. 2013;1 Kleiner DE. Gastroenterol Clin North Am. 2017;2 Goodman ZD. Clin Liver Dis. 2017.3 Copyright permissions were obtained to use them.)

Autoimmune Granulomatous hepatitis Sinusoidal obstruction Peliosis Hepatis

DILI Allopurinol syndrome
Danazol
Nitrofurantoin Diltiazem Busulfan Oxaliplatin
Minocycline TMP-SMX Alkaloids Vinyl chloride
Hydralazine Gemtuzumab Sinusoidal dilation

Hepatic
Sinusoidal
Autoantibody vein
Hypersensitivity dilation
formation thrombosis
Reaction? ●

Vanishing bile duct Drug-induced steatosis

syndrome + steatohepatitis
Amoxicillin-clavulanate Lomitapide
Carbamazepine Mipomersen APO-B
Chlorpromazine

X
Flucloxacillin
TG VLDL

X
MTP
Bile ducts
injury/loss

Bland cholestasis Drug-Induced

Anabolic steroids steatosis +
steatohepatitis
Amiodarone Respiratory
Valproic acid chain

X
Tamoxifen

β-oxidation

Hepatic neoplasms* Hepatocellular Hepatoportal Nodular regenerative

deposits ♦ sclerosis hyperplasia
OCP
Vinyl Chloride Amiodarone Hypervitaminosis A Mercaptopurine
Thorotrast Hypervitaminosis A Vinyl chloride Azathioprine
Danazol Phenobarbital Arsenicals Oxaliplatin
Didanosine
Obstructive
Ischemic hepatopathy
Hypersensitivity portal
with compensatory
reaction?* venopathy
hypertrophy

Abbreviations: APO-B, apolipoprotein B; DILI, drug-induced liver injury; MTP, microsomal triglyceride transfer protein; OCP, oral contraceptive pill; TG, triglyceride; TMP-SMX, trimethoprim-sulfamethoxazole; VLDL, very low-density lipoprotein.
* Include hepatic adenoma and angiosarcoma. ♦ Include hepatic glycogenosis, phospholipidosis, lipofuscin pigment and ceroid-laden macrophages.
● The mechanism is poorly understood. Pathogenesis might be due to an immunoallergic response.
Journal of Hepatology 2018 vol. x | xxxx-xxxx
Received 7 September 2017; received in revised form 1 December 2017; accepted 2 January 2018
Hepatology Snapshot

Table 1. Pathology of drug-induced liver injury by causative agents.

Phenotype Selected causative agents Histological findings Clinical pearls
Chronic hepatocellular injury
Hepatic steatosis Amiodarone, valproic acid, tamoxifen, Macro and microvesicular steatosis due to Subclinical, minimal or no elevation of
4,5 5
± steatohepatitis lomitapide, mipomersen, methotrex- mitochondrial dysfunction.6,7 May or may liver enzymes (AST or ALT up to 250 U/L).
ate, glucocorticoids, tetracycline, zidovu- not be accompanied by steatohepatitis fea- Prolonged exposure to these agents can
dine, didanosine, irinotecan. tures (ballooning, inflammation, etc.). cause cirrhosis.
Autoimmune like Nitrofurantoin, minocycline, methyldopa, Prominent plasma cells infiltration, portal Clinically immunologically and
drug-induced liver interferon-beta, statins, tumor necrosis neutrophils, and piecemeal necrosis pathologically similar to autoimmune
injury factor-alpha antagonists.8 including interface hepatitis.3,9 hepatitis; however, it carries a better
prognosis.
Hepatocellular Amiodarone, Hypervitaminosis A, Cytoplasmic inclusion bodies and ground- Can present with hepatomegaly with or
deposits phenobarbital, phenytoin, glass change, lipofuscin deposits,3 pigment without other organ involvement (lungs,
corticosteroids. containing macrophages (gold and thyroid and skin). ALT and AST are only
thorotrast).9 moderately increased (<5x ULN).
Chronic cholestatic injury
Bland cholestasis Anabolic steroids, amoxicillin- Bile accumulation within hepatocytes and/ Chronic intrahepatic cholestatic pattern
clavulanate,8 oral contraceptives. or canaliculi, but little inflammation. Must (bilirubin and alkaline phosphatase
be distinguished from other intracellular elevation >6 months) with jaundice and
pigments. pruritus.7 Modest elevation in serum
aminotransferases.10
Vanishing bile Trimethoprim-sulfamethoxazole, Bile ducts injury ranging from interlobular Can lead to fibrosis. Might be reversible
duct syndrome erythromycin, terbinafine, bile duct loss (ductopenia)11 to near com- with bile ducts restoration.1 If unresolved
carbamazepine, phenytoin, clindamycin, plete absence of bile ducts. on long term follow-up, the mortality rate
amitriptyline. is very high without liver transplantation.
Chronic vascular injury
Sinusoidal Busulfan, pyrrolizidine alkaloids, Occlusion or loss of central veins,11 throm- Manifests with a sudden onset of ascites,
obstruction actinomycin, cyclophoshamide, bosis, with or without central hemorrhage tender hepatomegaly and elevated liver
syndrome (hepatic gemcitabine. and necrosis.2,3 enzymes. Can lead to fatal congestive
veno-occlusive hepatopathy.
disease)
Nodular Azathioprine, 6-mertcaptopurine, Multiple nodular expansions around the Can be clinically mistaken with cirrhosis,
regenerative oxaliplatin, didanosine, Hypervitaminosis portal vein bounded by compressed atrophic needs pathological diagnosis.13
hyperplasia A. liver plates.12
Peliosis hepatis Anabolic steroids, danazol, oxaliplatin, Sinusoidal dilation and fibrosis, formation of Found incidentally, presentation is usually
tamoxifen, vinyl chloride. small cystic spaces filled with blood.1 due to a complication such as
hemoperitoneum due to rupture of cysts
which can be fatal.7
Hepatoportal Allopurinol, carbamazepine, hydralazine, Portal fibrosis and disappearance of small Clinically presents as non-cirrhotic portal
sclerosis phenytoin, quinidine. and medium branches of the portal vein.9 hypertension. May present with
(obliterative splenomegaly, ascites and varices.7
portal venopathy)
Other types of injuries
Granulomas Allopurinol, hydralazine, carbamazepine, Non-necrotizing microgranulomas ± Other causes of granulomas should be
formation ± etanercept, lithium, phenytoin, quinidine. inflammation. Can be seen in the portal ruled out such as sarcoidosis, primary
hepatitis tracts or within the lobule. biliary cholangitis, and infectious
etiologies.2,9 Sometimes may need steroid
therapy.
Hepatic Vinyl chloride, thorotrast, danazol, oral Findings differ by type of neoplasm. Fat and Often asymptomatic until complications
neoplasms contraceptives, phenobarbital, glycogenated nuclei are present within the occur, causing abdominal pain or
androgens, arsenicals. lesion in adenomas and areas of hemorrhage rupture.7
can be seen.1
ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal.

Conflict of interest
The authors declare no conflicts of interest that pertain to this Supplementary data
work. Supplementary data associated with this article can be found, in
Please refer to the accompanying ICMJE disclosure forms for the online version, at https://doi.org/10.1016/j.jhep.2018.01.001.
further details.

References
Authors’ contributions Author names in bold designate shared co-first authorship
Lara Dakhoul, MD: conceptualizing the figure and manuscript
[1] Zhang X, Ouyang J, Thung SN. Histopathologic manifestations of drug-
preparation.
induced hepatotoxicity. Clin Liver Dis 2013;17:547–564, Vii–viii.
Marwan Ghabril, MD: conceptualizing the figure and critical [2] Kleiner DE. Drug-induced liver injury: the hepatic pathologist’s
input in manuscript preparation. approach. Gastroenterol Clin North Am 2017;46:273–296.
Naga Chalasani, MD: conceptualizing the study and critical [3] Goodman ZD. Phenotypes and pathology of drug-induced liver disease.
input in manuscript preparation. Clin Liver Dis 2017;21:89–101.

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