Semin Liver Dis 2009; 29(4): 364-372
DOI: 10.1055/s-0029-1240005
© Thieme Medical Publishers

The Pathology of Drug-Induced Liver Injury

David E. Kleiner1
  • 1Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland
Further Information

Publication History

Publication Date:
13 October 2009 (online)

ABSTRACT

The liver biopsy is frequently used as an adjunct diagnostic test in the evaluation of drug-induced liver injury (DILI). A biopsy may be performed to confirm the diagnosis, especially when there is a complex clinical differential diagnosis that includes DILI. A biopsy can also be used to stage the severity of hepatotoxicity so that a necessary agent may be continued. Alternatively, a drug or toxin may only be implicated after a biopsy is performed, particularly in the case of subacute or chronic liver injury. The pathologist should approach the biopsy systematically by first classifying the disease and then working with the clinician to include or exclude etiologies in the pathological differential diagnosis. This article outlines a practical approach to the diagnosis of DILI on liver biopsy, including the common patterns of injury observed in drug- and toxin-induced liver pathology and prognostic pathological features that may be associated with the outcome of patients with DILI.

REFERENCES

  • 1 Lasser K E, Allen P D, Woolhandler S J, Himmelstein D U, Wolfe S M, Bor D H. Timing of new black box warnings and withdrawals for prescription medications.  JAMA. 2002;  287(17) 2215-2220
  • 2 McKenzie R, Fried M W, Sallie R et al.. Hepatic failure and lactic acidosis due to fialuridine (FIAU), an investigational nucleoside analogue for chronic hepatitis B.  N Engl J Med. 1995;  333(17) 1099-1105
  • 3 Farrell G C. Drug-Induced Liver Disease. Edinburgh, UK; Churchill Livingstone 1994
  • 4 Snover D C. Drug-Induced Liver Disease. Biopsy Diagnosis of Liver Disease. Baltimore, MD; Williams and Wilkins 1992: 164-177
  • 5 Stricker B HC. Drug-Induced Hepatic Injury. 2nd ed. Amsterdam, The Netherlands; Elsevier Science 1992
  • 6 Zimmerman H J. Hepatotoxicity: The Adverse Effects of Drugs and Other Chemicals on the Liver. 2nd ed. Philadelphia, PA; Lippincott, Williams & Wilkins 1999
  • 7 Lewis J H, Kleiner D E. Hepatic injury due to drugs, chemicals and toxins. In: Burt AD, Portmann BC, Ferrell LD MacSween's Pathology of the Liver. Philadelphia, PA; Elsevier 2007: 649-759
  • 8 Kleiner D E, Gaffey M J, Sallie R et al.. Histopathologic changes associated with fialuridine hepatotoxicity.  Mod Pathol. 1997;  10(3) 192-199
  • 9 Chariot P, Drogou I, de Lacroix-Szmania I et al.. Zidovudine-induced mitochondrial disorder with massive liver steatosis, myopathy, lactic acidosis, and mitochondrial DNA depletion.  J Hepatol. 1999;  30(1) 156-160
  • 10 Lai K K, Gang D L, Zawacki J K, Cooley T P. Fulminant hepatic failure associated with 2′,3′-dideoxyinosine (ddI).  Ann Intern Med. 1991;  115(4) 283-284
  • 11 Lewis W, Levine E S, Griniuviene B et al.. Fialuridine and its metabolites inhibit DNA polymerase gamma at sites of multiple adjacent analog incorporation, decrease mtDNA abundance, and cause mitochondrial structural defects in cultured hepatoblasts.  Proc Natl Acad Sci U S A. 1996;  93(8) 3592-3597
  • 12 Roenigk Jr H H, Auerbach R, Maibach H I, Weinstein G D. Methotrexate in psoriasis: revised guidelines.  J Am Acad Dermatol. 1988;  19(1 Pt 1) 145-156
  • 13 Khan S, Subedi D, Chowdhury M M. Use of amino terminal type III procollagen peptide (P3NP) assay in methotrexate therapy for psoriasis.  Postgrad Med J. 2006;  82(967) 353-354
  • 14 Zachariae H, Heickendorff L, Søgaard H. The value of amino-terminal propeptide of type III procollagen in routine screening for methotrexate-induced liver fibrosis: a 10-year follow-up.  Br J Dermatol. 2001;  144(1) 100-103
  • 15 Akhtar M A, Mathieson K, Arey B et al.. Hepatic histopathology and clinical characteristics associated with antiretroviral therapy in HIV patients without viral hepatitis.  Eur J Gastroenterol Hepatol. 2008;  20(12) 1194-1204
  • 16 Borghi V, Puoti M, Mussini C et al.. HIV coinfection and antiretroviral therapy enhances liver steatosis in patients with hepatitis C, but only in those infected by HCV genotype other than 3.  Antivir Ther. 2008;  13(8) 1057-1065
  • 17 Kleiner D E, Chalasani N P, Conjeevaram H S et al.. Relationship of biochemical to histologic findings and the pathological pattern of injury among cases identified in the NIH Drug-Induced Liver Injury Network (DILIN) study.  Gastroenterology. 2007;  132 A773
  • 18 Popper H, Rubin E, Cardiol D, Schaffner F, Paronetto F. Drug-induced liver disease: a penalty for progress.  Arch Intern Med. 1965;  115 128-136
  • 19 Edmondson H A, Henderson B, Benton B. Liver-cell adenomas associated with use of oral contraceptives.  N Engl J Med. 1976;  294(9) 470-472
  • 20 Ishak K G. Hepatic neoplasms associated with contraceptive and anabolic steroids.  Recent Results Cancer Res. 1979;  66 73-128
  • 21 Mays E T, Christopherson W. Hepatic tumors induced by sex steroids.  Semin Liver Dis. 1984;  4(2) 147-157
  • 22 Suh N, Liapis H, Misdraji J, Brunt E M, Wang H L. Epstein-Barr virus hepatitis: diagnostic value of in situ hybridization, polymerase chain reaction, and immunohistochemistry on liver biopsy from immunocompetent patients.  Am J Surg Pathol. 2007;  31(9) 1403-1409
  • 23 Suriawinata A A, Thung S N. Acute and chronic hepatitis.  Semin Diagn Pathol. 2006;  23(3-4) 132-148
  • 24 Kleiner D E. Granulomas in the liver.  Semin Diagn Pathol. 2006;  23(3-4) 161-169
  • 25 Medline A, Cohen L B, Tobe B A, Sellers E M. Liver granulomas and allopurinol.  BMJ. 1978;  1(6123) 1320-1321
  • 26 Mullick F G, Ishak K G. Hepatic injury associated with diphenylhydantoin therapy. A clinicopathologic study of 20 cases.  Am J Clin Pathol. 1980;  74(4) 442-452
  • 27 Cook I F, Shilkin K B, Reed W D. Phenytoin induced granulomatous hepatitis.  Aust N Z J Med. 1981;  11(5) 539-541
  • 28 Propst A, Propst T, Dietze O, Kathrein H, Judmeier G, Vogel W. Development of granulomatous hepatitis during treatment with interferon-alpha 2b.  Dig Dis Sci. 1995;  40(10) 2117-2118
  • 29 Ishak K G. Hepatic lesions caused by anabolic and contraceptive steroids.  Semin Liver Dis. 1981;  1(2) 116-128
  • 30 Lewis J H, Zimmerman H J. Drug- and chemical-induced cholestasis.  Clin Liver Dis. 1999;  3(3) 433-464, vii
  • 31 Doria Jr M I, Shepard K V, Levin B, Riddell R H. Liver pathology following hepatic arterial infusion chemotherapy. Hepatic toxicity with FUDR.  Cancer. 1986;  58(4) 855-861
  • 32 Ludwig J, Kim C H, Wiesner R H, Krom R A. Floxuridine-induced sclerosing cholangitis: an ischemic cholangiopathy?.  Hepatology. 1989;  9(2) 215-218
  • 33 Desmet V J. Vanishing bile duct syndrome in drug-induced liver disease.  J Hepatol. 1997;  26(Suppl 1) 31-35
  • 34 Ludwig J, Wiesner R H, LaRusso N F. Idiopathic adulthood ductopenia. A cause of chronic cholestatic liver disease and biliary cirrhosis.  J Hepatol. 1988;  7(2) 193-199
  • 35 Brunt E M. Nonalcoholic steatohepatitis.  Semin Liver Dis. 2004;  24(1) 3-20
  • 36 Lewis J H, Mullick F, Ishak K G et al.. Histopathologic analysis of suspected amiodarone hepatotoxicity.  Hum Pathol. 1990;  21(1) 59-67
  • 37 Murata Y, Ogawa Y, Saibara T et al.. Unrecognized hepatic steatosis and non-alcoholic steatohepatitis in adjuvant tamoxifen for breast cancer patients.  Oncol Rep. 2000;  7(6) 1299-1304
  • 38 Bissuel F, Bruneel F, Habersetzer F et al.. Fulminant hepatitis with severe lactate acidosis in HIV-infected patients on didanosine therapy.  J Intern Med. 1994;  235(4) 367-371
  • 39 DeLeve L D, Shulman H M, McDonald G B. Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease).  Semin Liver Dis. 2002;  22(1) 27-42
  • 40 Nakanuma Y, Tsuneyama K, Ohbu M, Katayanagi K. Pathology and pathogenesis of idiopathic portal hypertension with an emphasis on the liver.  Pathol Res Pract. 2001;  197(2) 65-76
  • 41 McDonald G B, Hinds M S, Fisher L D et al.. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients.  Ann Intern Med. 1993;  118(4) 255-267
  • 42 Geller S A, Dubinsky M C, Poordad F F et al.. Early hepatic nodular hyperplasia and submicroscopic fibrosis associated with 6-thioguanine therapy in inflammatory bowel disease.  Am J Surg Pathol. 2004;  28(9) 1204-1211
  • 43 Lewis J H, Tice H L, Zimmerman H J. Budd-Chiari syndrome associated with oral contraceptive steroids. Review of treatment of 47 cases.  Dig Dis Sci. 1983;  28(8) 673-683
  • 44 Lefkowitch J H, Lobritto S J, Brown Jr R S et al.. Ground-glass, polyglucosan-like hepatocellular inclusions: a “new” diagnostic entity.  Gastroenterology. 2006;  131(3) 713-718
  • 45 Vazquez J J, Guillen F J, Zozaya J, Lahoz M. Cyanamide-induced liver injury. A predictable lesion.  Liver. 1983;  3(4) 225-230
  • 46 Torbenson M, Chen Y Y, Brunt E et al.. Glycogenic hepatopathy: an underrecognized hepatic complication of diabetes mellitus.  Am J Surg Pathol. 2006;  30(4) 508-513
  • 47 Iancu T C, Shiloh H, Dembo L. Hepatomegaly following short-term high-dose steroid therapy.  J Pediatr Gastroenterol Nutr. 1986;  5(1) 41-46
  • 48 Goodman Z D. Drug hepatotoxicity.  Clin Liver Dis. 2002;  6(2) 381-397
  • 49 Björnsson E, Kalaitzakis E, Olsson R. The impact of eosinophilia and hepatic necrosis on prognosis in patients with drug-induced liver injury.  Aliment Pharmacol Ther. 2007;  25(12) 1411-1421
  • 50 Benjamin S B, Goodman Z D, Ishak K G, Zimmerman H J, Irey N S. The morphologic spectrum of halothane-induced hepatic injury: analysis of 77 cases.  Hepatology. 1985;  5(6) 1163-1171
  • 51 Donaldson B W, Gopinath R, Wanless I R et al.. The role of transjugular liver biopsy in fulminant liver failure: relation to other prognostic indicators.  Hepatology. 1993;  18(6) 1370-1376
  • 52 Katoonizadeh A, Nevens F, Verslype C, Pirenne J, Roskams T. Liver regeneration in acute severe liver impairment: a clinicopathological correlation study.  Liver Int. 2006;  26(10) 1225-1233
  • 53 Vuppalanchi R, Chalasani N, Saxena R. Restoration of bile ducts in drug-induced vanishing bile duct syndrome due to zonisamide.  Am J Surg Pathol. 2006;  30(12) 1619-1623

David E KleinerM.D. Ph.D. 

Laboratory of Pathology/NCI, Bldg. 10, Room 2B50, MSC 1500, 10 Center Drive

Bethesda, MD 20892

Email: kleinerd@mail.nih.gov