# Clopidogrel-Induced Severe Hepatitis: A Case Report and Literature Review

Authors: Hesam Keshmiri; Anuj Behal; Shawn Shroff; Charles Berkelhammer
Journal: Case Reports in Hepatology
 (2016)

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## Abstract

Clopidogrel is a commonly prescribed antiplatelet agent that carries a rare risk of hepatotoxicity. We describe a case of severe clopidogrel-induced hepatitis with liver biopsy assessment. Prompt recognition and withdrawal of the offending agent are imperative to prevent progression and potentially fatal liver injury.


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## Body

## 1. Introduction

Clopidogrel is a commonly used antiplatelet agent, yet only several cases of hepatotoxicity have been described [1–16]. Liver biopsies were not performed in many of these cases. We report a rare case of severe clopidogrel-induced hepatitis with histological assessment.


## 2. Case Description

A 34-year-old male with a history of coronary artery disease and remote coronary artery stent was placed on aspirin plus clopidogrel. His baseline liver biochemistries were normal. He had been on clopidogrel for 2 months 12 years ago without adverse effects but discontinued the medication on his own at that time due to nonadherence. Four and a half months after restarting clopidogrel, he presented with jaundice and fatigue. He denied fever, rash, arthralgias, or abdominal pain. His only other medications were aspirin and metoprolol, which he had been on for many years with normal liver biochemistries.The patient was not on a statin. He denied recent alcohol or herbal medications. Physical examination was significant only for icterus. There was no hepatosplenomegaly, clubbing, rash, asterixis, or other stigmata of chronic liver disease.Initial bilirubin was 5.7 mg/dL (normal 0.2–1.2 mg/dL), ALT 1,393 U/L (normal 7–48 U/L), AST 1,418 U/L (normal 7–48 U/L), alkaline phosphatase 130 U/L (normal 35–115 U/L), INR 1.5, and partial prothrombin time 37 seconds (normal 15–37 seconds). Extensive serologies were negative to hepatitis A, hepatitis B, hepatitis C (including hepatitis C RNA), hepatitis E, IgM to cytomegalovirus and Epstein-Barr virus, anti-nuclear antibody, anti-smooth muscle antibody, anti-mitochondrial antibody, anti-liver kidney microsomal antibody, and ceruloplasmin.Imaging studies were negative, and bile ducts were not dilated, including by ultrasound, computed tomography, and endoscopic retrograde cholangiopancreatography. No gallstones were present on any imaging modality. Liver biopsy revealed severe acute hepatitis with mixed inflammatory portal tract infiltrates including plasma cells, neutrophils and eosinophils, bile ductular reaction, patchy hepatocyte ballooning degeneration, and extensive periportal hepatocyte dropout, without fibrosis (Figure1).Figure 1
Liver biopsy showing severe acute hepatitis with mixed inflammatory portal tract infiltrate (white arrow), patchy hepatocyte ballooning degeneration (black arrow), and extensive periportal hepatocyte dropout (grey arrow).The patient was diagnosed with clopidogrel-induced severe hepatitis. Despite discontinuing clopidogrel, AST increased to 2,107 U/L, ALT to 1,567 U/L, and bilirubin to 37 mg/dL (predominately direct bilirubin). INR had increased to 2.1 despite empiric administration of vitamin K. A brief course of prednisone and ursodiol was initiated, with subsequent normalization of liver biochemistries.


## 3. Discussion

We describe a rare case of severe clopidogrel-induced hepatitis, with histological assessment. Our patient’s drug-induced hepatitis was particularly severe with jaundice (peak bilirubin 37 mg/dL), marked elevation of transaminases (peak ALT of 1,567 U/L), and coagulopathy (INR 2.1). This degree of hepatic injury portends an increased mortality and underscores the importance of early recognition and discontinuation of the offending agent.Clopidogrel-induced hepatitis has been described [1–16]. Table 1 lists reported cases in reverse chronological order. The degree of liver injury has ranged from reversible liver injury and recovery [1–9, 11–16] to acute hepatic failure and death [10]. Onset of liver injury in these cases ranges between 3 and 180 days [1–16]. Rechallenge confirmed clopidogrel-induced hepatitis in some of these cases [2–5]. Our patient’s Naranjo scale and RUCAM (Roussel Uclaf Causality Assessment Method) scores were both 8, indicating probable drug-induced hepatitis [17, 18].Table 1
Clopidogrel-induced hepatitis: reported cases.
Cases
Latency/onset
Peak ALT (U/L)
Peak bilirubin (mg/dL)
Peak alkaline phosphatase (U/L)
Symptoms
Histology
Outcome
Keshmiri et al. 2016 (current)
135 days (4.5 months)
1567
37
130
Jaundice, fatigue
Hepatocellular
Recovery
Kapila et al. 2015 [9]
5 days
716
1.6
160
Nausea, vomiting, fever
No liver biopsy
Recovery
Pisapia et al. 2015 [2]
3 days
1603
24.5
408
Jaundice, arthralgia, papular rash
Mixed hepatocellular and cholestatic
Recovery
Monteiro et al. 2011 [13]
30 days
540
3.5
139
Nausea, vomiting
No liver biopsy
Recovery
Leighton et al. 2011 [11]
1 day
3626
3.3
364
Anorexia, jaundice, epigastric pain
Lymphoplasmacytic portal, interface and lobular hepatitis with no fibrosis
Recovery
Kastalli et al. 2010 [10]
19 days
336
4.7
186
Jaundice, abdominal pain
No liver biopsy
Death
Goyal et al. 2009 [3]
23 days
1011
7.3
1011
Abdominal pain, anorexia, jaundice
No liver biopsy
Recovery
Wiper et al. 2008 [4]
60 days
450
Normal
680
General malaise
No liver biopsy
Recovery
Lo
´pez-Vicente et al. 2007 [12]
30 days
204
1.0
682
Abdominal pain, fever
No liver biopsy
Recovery
Ng et al. 2006 [5]
3 days
536
1.5
247
Fever, chills
No liver biopsy
Recovery
Ho
¨llmu
¨ller et al. 2006 [1]
43 days
1003
20.8
221
Weight loss, anorexia, jaundice, nausea, abdominal pain
Mixed hepatocellular and cholestatic
Recovery
Chau et al. 2005 [7]
37 days
253
6.9
172
Jaundice
No liver biopsy
Recovery
Beltran-Robles et al. 2004 [6]
4 days
318
0.51
100
No symptoms mentioned
No liver biopsy
Recovery
Wolf et al. 2003 [16]
12 days
173
1.3
132
Fever, leukopenia, weakness
No liver biopsy
Recovery
Ramos Ramos et al. 2003 [14]
60 days
710
24.9
118
Jaundice
No liver biopsy
Recovery
Duran-Quintana et al. 2002 [8]
180 days
786
13
474
Icterus, hepatomegaly
No liver biopsy
Recovery
Willens 2000 [15]
21 days
507
3.0
636
Malaise, anorexia, myalgia, icterus
No liver biopsy
RecoveryOur patients liver biopsy revealed severe hepatocellular injury. This adds to the histological findings in clopidogrel-induced hepatitis, as liver biopsy was only performed in 3 of the previously reported cases [1, 2, 11]. Clopidogrel-induced liver injury can be cholestatic, hepatocellular [11], or mixed hepatocellular plus cholestatic [1, 2].The exact mechanism of clopidogrel-induced hepatitis is unclear. The delayed onset of 4.5 months in our case suggests a toxic-metabolic etiology, whereas the inflammatory infiltrate and response to corticosteroids raise the possibility of a superimposed immune mediated mechanism of injury. Clopidogrel is a prodrug which is metabolized to inactive clopidogrel carboxylate (90%) and an active metabolite containing a mercapto group (10%) by cytochrome P450 3A4 and 2C19. In vitro studies suggest that the active metabolite is responsible for the hepatotoxicity and that high cytochrome 3A4 activities coupled with cellular glutathione depletion are potential risk factors [19]. Interestingly, an earlier antiplatelet agent, ticlopidine, has also been reported to cause drug-induced cholestatic hepatitis [20, 21].Clopidogrel-induced hepatitis is a rare but potentially serious adverse effect. A high degree of clinical suspicion is required in patients presenting with abnormal liver biochemistries within a few months after starting clopidogrel. Prompt recognition and discontinuation of the offending agent are necessary, as progressive liver injury and even death can occur.



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*Source: 8068276-2016-06-27.xml*