TABLE 4. Clinical and histological phenotypes of idiosyncratic DILI.
| Clinical phenotype | Histological phenotype | ||
|---|---|---|---|
| Pattern | Characteristic histology | Examples of associated drugs | |
| Hepatocellular | Acute hepatitis | Spotty necrosis, apoptosis, lobular inflammation, with or without portal inflammation and interface hepatitis | Phenytoin, dapsone, para‐aminosalicylate, isoniazid, sulfonamides |
| Panlobular hepatitis | Spotty or focal necrosis, acidophil bodies scattered throughout the lobule, hepatocytes with degenerative changes and lytic necrosis, lymphocytic infiltrates | Immune checkpoint inhibitors (e.g., ipilimumab, nivolumab) | |
| Zonal or nonzonal (confluent) necrosis | Coagulative necrosis in zone 3 or panlobular involvement with either submassive or massive necrosis | Acetaminophen, halothane, CCL4, cocaine, ferrous sulfate | |
| Granulomatous hepatitis | Noncaseating granulomas accompanied by significant inflammation; fibrin‐ring granulomas | Sulfonamides, sulfonylurea, phenytoin, carbamazepine, quinidine, hydralazine, interferon‐α, etanercept, ipilimumab | |
| Chronic hepatitis | Similar to chronic viral hepatitis or autoimmune hepatitis with portal inflammation, interface hepatitis, fibrosis, or cirrhosis | Atorvastatin, HDS, methotrexate, vinyl chloride | |
| Drug‐induced AIH | More prominent portal neutrophils than plasma cells along with cholestasis concurrently with the typical AIH histology of portal inflammation, interface hepatitis, rosette formation | Nitrofurantoin, diclofenac, α‐methyldopa, hydralazine, minocycline, HMG‐CoA reductase inhibitors, TNF inhibitors | |
| Cholestatic | Acute cholestasis/bland cholestasis | Bile accumulation in hepatocytes and/or bile canaliculi with little or no inflammation or hepatocyte injury | Anabolic and oral contraceptives |
| Chronic cholestasis | Bile accumulation, possibly bile duct loss/ductopenia, cholate stasis | Amoxicillin‐clavulanate, flucloxacillin, enalapril, antifungal terbinafine | |
|
Acute cholestatic hepatitis Mixed hepatocellular/cholestatic |
Bile accumulation in hepatocytes and/or bile canaliculi with more prominent inflammation and hepatocyte injury | Antibiotics (erythromycin, amoxicillin‐clavulanate), ACE inhibitors, phenothiazine neuroleptics | |
| Sclerosing cholangitis | Bile duct injury with intraepithelial lymphocytic infiltration and periductal fibrosis | Nivolumab | |
| Fatty liver (drug‐induced steatosis, drug‐induced steatohepatitis) | Pure microvesicular | Numerous small droplets, foamy cytoplasm, hepatocyte nuclei retained in the center | Acetylsalicylic acid (Reye syndrome), valproic acid, glucocorticoids, aspirin, NSAIDS, tetracycline, NRTI, cocaine |
| Macrovesicular | Medium‐sized or large‐sized fat droplets with hepatocyte nuclei displaced to the periphery | Glucocorticoids, methotrexate, NSAIDs, metoprolol, chlorinated hydrocarbons (e.g., CCL4 and chloroform), 5‐fluorouracil, cisplatin, irinotecan, tamoxifen | |
| Mixed macrovesicular and microvesicular | Combination of small and large droplet | Amiodarone, valproic acid, methotrexate | |
| Steatohepatitis | Presence of ballooning, inflammation, Mallory‐Denk hyalines, and fibrosis, in a background of steatosis | Amiodarone, methotrexate, 5‐floururacil, cisplatin, irinotecan, tamoxifen | |
| Vascular | Sinusoidal obstruction syndrome | Sinusoidal congestion with hepatocyte necrosis, red blood cells trapped in Disse spaces, perisinusoidal fibrosis, fibrous obliteration of terminal hepatic venules; sloughing of endothelial cells | Busulfan, cyclophosphamide, plants containing pyrrolizidine alkaloids |
| NRH and OPV | Small (1 mm) hyperplastic nodules bordered by atrophic hepatocyte plates (NRH); may require a reticulin stain. OPV will show either dilated and herniated portal veins or sclerotic lumina | Arsenic, copper sulfate, azathioprine, methotrexate, 6‐mercaptopurine, oxaliplatin, didanosine, stavudine | |
| Peliosis hepatis | Blood‐filled sinusoidal spaces | Androgens and oral contraceptives | |
| Chronic DILI | Fibrosis/cirrhosis | Progression of fibrosis similar to chronic viral hepatitis | Methotrexate, valproic acid, HDS, oral contraceptives, isoniazid, trimethoprim‐sulfamethoxazole, nitrofurantoin, methotrexate, diclofenac, fenofibrate, amoxicillin‐clavulanate |
| Miscellaneous | Ground‐glass cytoplasm (induction hepatocytes), Lafora body‐like inclusions | Homogeneous light pink cytoplasmic inclusions with displacement of the nuclei | Barbiturates, phenytoin, polypharmacy; immunosuppressive agents, antibiotics |
| Phospholipidosis | Enlarged, granular, or foamy cytoplasm; may require electron microscopy to check for lamellar bodies | Antibiotics, antipsychotic, antidepressants, antianginal, antimalarial, antiarrhythmic, cholesterol‐lowering agents; amiodarone | |
| Pigment deposition | Ceroid‐containing macrophages; lipofuscin | 6‐mercaptopurine, phenothiazine, aminopyrine, phenacetin, | |
| Neoplastic | Hepatocellular adenoma | All subtypes possible; most common are inflammatory and HNF‐1‐alpha mutated | Oral contraceptives, anabolic and male hormone steroids, danazol |
Abbreviations: ACE, angiotensin‐converting enzyme; AIH, autoimmune hepatitis; HCA, hepatocellular adenoma; HMG‐CoA, 3‐hydroxy‐3‐methyl‐glutaryl‐coenzyme A reductase; HNF, hepatocyte nuclear factor; NRH, nodular regenerative hyperplasia; NRTI, nucleoside/nucleotide reverse transcriptase inhibitor; NSAID, nonsteroidal anti‐inflammatory drug; OPV, obliterative portal venopathy.