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Clinical Features, Diagnosis, and Natural History of Drug-Induced Liver Injury

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Clinical Features, Diagnosis, and Natural History of Drug-Induced Liver Injury 134 Clinical Features, Diagnosis, and Natural History of Drug-Induced Liver Injury Paul H. Hayashi, MD, MPH1 Robert J. Fontana, MD2 1 Division of Gastroenterology and Hepatology, University of North Address for correspondence Paul H. Hayashi, MD, MPH, Division of Carolina, Chapel Hill, North Carolina Gastroenterology and Hepatology, University of North Carolina, 2 Division of Gastroenterology, University of Michigan, Burnett-Womack Bldg., Room 8011, Chapel Hill, NC 27599-7584 Ann Arbor, Michigan (e-mail: [email protected]). Semin Liver Dis 2014;34:134–144. Abstract Patients with idiosyncratic drug-induced liver injury (DILI) can pose substantial diagnos- tic, prognostic, and therapeutic challenges to the practicing gastroenterologist. The presentation of DILI may vary from asymptomatic liver enzyme elevation to acute liver failure. Although most DILI resolves following drug discontinuation, up to 20% of patients progress to chronic DILI further challenging the clinicians diagnostic and management skills. Also, some medications can lead to advanced fibrosis, encephalop- Keywords athy, and portal hypertension without significant elevation in liver enzymes during ► hepatotoxicity exposure. Finally, there are no objective tests to definitively diagnose DILI. Although ► diagnostic tools causality assessment instruments are available, none are widely accepted or used in ► prognosis clinical practice. Therefore, the diagnosis of DILI depends on thorough and accurate ► histology history taking, follow-up of the patient’s clinical course and excluding more common ► acute causes of liver injury. In this review, we discuss the variable clinical presentations, ► chronic course, and diagnostic methods used to establish a diagnosis and prognosis in DILI. There are increasing reports of drug-induced liver injury Induced Liver Injury Network (DILIN) registry of over 1,200 (DILI) leading to clinically significant acute and chronic liver consecutive cases, nausea was present in 60% and abdominal – disease in both children and adults.1 4 Drug-induced liver pain in 42% (Robert Fontana, personal communication). The injury remains the leading cause of acute liver failure (ALF) in onset of clinical symptoms can be important in determining Western countries and the most common reason for removal the latency of a possible DILI episode. Liver-specific symptoms of approved medications from the marketplace.5,6 The lack of and signs (e.g., pruritus, jaundice, ascites, and encephalopa- objective diagnostic tests, wide range of clinical presentations thy) are usually only present in patients with more severe and idiosyncratic nature of most cases (i.e., independent of DILI. In the DILIN and Spanish registries, 70% of patients drug dose, duration, route of exposure or identifiable host were jaundiced at presentation and 51% had pruritus. Jaun- factors), makes DILI a significant challenge for the practicing dice in the setting of an acute hepatocellular injury, is gastroenterologist. In the last several years, data acquired associated with a mortality of 10%, often referred to as Hy’s from several ongoing prospective registries of DILI cases have Law after the late Hy Zimmerman.1,2,7,8 Ascites and enceph- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. started to shed more light on the clinical features, diagnosis, alopathy are well-known ominous signs of hepatic failure.9 and clinical course of DILI. Drug-induced liver injury remains the overall leading cause of acute liver failure (ALF) in the U.S. and idiosyncratic DILI is the second leading cause among cases where an etiology is Symptoms and Signs of Drug-Induced Liver fi 10 Injury identi ed. The leading agents causing ALF are antitubercu- losis agents (isoniazid), antiepileptics (phenytoin, valproate), The initial symptoms and signs of DILI are often nonspecific and antibiotics (ketoconazole, nitrofurantoin), followed by (e.g., fatigue, nausea, and abdominal pain). In the U.S. Drug herbal and dietary supplements (HDS).10,11 Issue Theme Drug-Induced Liver Injury; Copyright © 2014 by Thieme Medical DOI http://dx.doi.org/ Guest Editors, Naga Chalasani, MD, and Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0034-1375955. Paul H. Hayashi, MD, MPH New York, NY 10001, USA. ISSN 0272-8087. Tel: +1(212) 584-4662. Clinical Spectrum and Diagnosis of Drug-Induced Liver Injury Hayashi, Fontana 135 Drugs and HDS products may also cause subclinical liver lopathy. Oddly, liver enzyme elevations may be modest in injury.For example, isoniazid therapy for latent TB will cause comparison to other injuries presenting with such severe mild serumalanine aminotransferase (ALT) elevation in up to hepatic dysfunction. Valproate hepatotoxicity can also pres- 20 to30% of treated patients. Many of these will develop ent abruptly with a Reye’s-like syndrome typically in chil- tolerance and experience a decline in ALT levels despite dren. Here again, liver biochemistry abnormalities are often – continued INH use.12 14 The heparin compounds can cause modest and overshadowed by the neurologic complaints of asymptomatic serum ALT elevations as well. A recent study in anorexia, lethargy, cerebral edema, and coma. Lastly, val- healthy volunteers showed that most will have some eleva- proate can cause a hyperammonemic encephalopathy with- tion in serum ALT levels and many had elevations greater than out overt liver injury.30 The reasons for this odd array of 3 to 5 times the upper limit of normal.15 These elevations presentations lie in valproate’s mitochondrial toxicity. Micro- occur with all the heparin compounds even when delivered vesicular steatosis is seen on liver biopsy and carnitine subcutaneously and resolve with continued therapy.16 The depletion is felt to play a role in the pathophysiology. Muta- combination of human immunodeficiency virus (HIV) anti- tions in the gamma polymerase gene that codes for the retrovirals, atazanavir, and ritonavir can also cause self- predominant DNA polymerase in mitochondria may influ- limited unconjugated hyperbilirubinemia in up to 44% of ence patient susceptiblity.31 treated patients that resolves with drug discontinuation.17 Patients with DILI may also rarely present withnoncir- Immunoallergic features may be a prominent feature in rhotic portal hypertension and associated variceal bleeding some DILI patients and at least one immunologic feature was and/or ascites, but preserved hepatic synthetic function. present in 23% of the DILIN patients.2 Certain agents such as Nodular regenerative hyperplasia (NRH) may be present on allopurinol, sulfamethoxazole/trimethoprim, vancomycin, needle biopsy, but other times histology is unrevealing. – and phenytoin18 21 frequently present with prominent im- Several medications including oral contraceptives, antineo- munoallergic features such as rash, fever, serositis, eosino- plastics, and immunosuppressives have been implicated. Due philia, bone marrow suppression, and multiorgan to the indolent development of portal hypertension from involvement (DRESS). In general, rechallenge in such cases stellate cell stimulation and liver regeneration, latency peri- will lead to a more rapid recurrence presumably due to ods can be long. Azathioprine, which has been associated with immunologic memory of T and B cells. Other medications NRH, remains a mainstay treatment for inflammatory bowel such as nitrofurantoin, minocycline, and α-methyldopa may disease and autoimmune hepatitis. Oxaliplatin is commonly cause an immune-mediated injury that is indistinguishable used for stage III colon cancer and has also recently been from sporadic autoimmune hepatitis. Autoimmune markers associated with significant portal hypertension in the ab- (antinuclear and antismooth muscle antibodies) may be sence of overt liver inflammation or synthetic dysfunc- markedly positive and histology may look identical to auto- tion.32,33 Both drugs also have been linked to sinusoidal immune hepatitis. The latencies can be quite long (months to obstructive syndrome. years) and confidently distinguishing DILI from autoimmune Sinusoidal obstructive syndrome (SOD) usually presents hepatitis (AIH) often depends on resolution with medication more abruptly with evidence of portal hypertension and signs discontinuance and lack of need for prolonged immunosup- of hepatic dysfunction, but liver biochemistries may be only pressive therapy.22 Biologics including anti-TNF agents used mildly elevated. Sinusoidal obstructive syndrome is typically to treat inflammatory bowel disease can also lead to severe associated with myeloablative chemotherapy given for he- acute liver injury with autoimmune hepatitis-like features.23 matologic malignancies, but other chemotherapeutic agents given for other diseases have also been implicated.34 Sinusoi- Atypical Clinical Presentations dal obstructive syndrome typically presents with right upper- Drug-induced liver injury can occasionally present with only quadrant pain, weight gain, jaundice, and hepatomegaly of modest or no elevations in liver biochemistries. Chronic use of varying severity. Ascites may or may not be present. Although methotrexate is probably the most well-known example. drug latency is usually short (i.e., 20–30 days), the diagnosis Serum aminotransaminase elevations are typically mild, yet can be difficult to confidently establish because these patients This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. a steatotic liver injury with fibrosis can occur over
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