Sudden elevation of liver enzymes in a 64-year-old patient: a case report
© Wiedmann et al; licensee BioMed Central Ltd. 2009
Received: 7 November 2009
Accepted: 18 November 2009
Published: 18 November 2009
Eradication of Helicobacter pylori usually consists of a 7-day course of triple therapy including metronidazole or amoxicillin plus clarithromycin plus a proton pump inhibitor. We report about a rare adverse event of Hp eradication in a patient with moderate chronic and moderate active pangastritis. Shortly after the end of treatment cholestatic hepatitis occurred which was most likely related to clarithromycin, perhaps enhanced by amoxicillin. Since liver dysfunction was self-limited, no further treatment was required. In summary, clinicians should be aware about the presented rare adverse event of Helicobacter pylori eradication treatment for a close monitoring of those patients and rapid management of acute liver failure.
According to the current DGVS (German Association of Gastroenterologists) S3-guidelines eradication of Helicobacter pylori (Hp) is indicated in patients with gastric or duodenal ulcer and gastric marginal zone B-cell lymphoma of MALT-type (mucosa-associated lymphoid tissue). It is facultative in patients with dyspepsia (following upper GI endoscopy), chronic asymptomatic Hp-associated gastritis, Mënëtrier's disease, idiopathic thrombocytopenic purpura, and lymphocytic gastritis . A 7-day course of triple therapy is recommended including metronidazole or amoxicillin plus clarithromycin plus a proton pump inhibitor (PPI). Common adverse events of clarithromycin are nausea, vomiting, abdominal tenderness, diarrhea, (very) rare adverse events are crampy abdominal pain, pseudomembranous colitis, acute pancreatitis, elvated liver enzymes, interstitial nephritis, hypersensitivity reaction, "Torsades de pointes" tachycardia, tinnitus, hearing loss, dizziness, confusion, anxiety, sleeplessness, nightmares, hallucinations, psychosis, headache, hypoglycemia, leukopenia, and thrombocytoenia (according to patient information leaflet). Amoxicillin my induce diarrhea, gastritis, stomatitis, nausea, vomiting, glossitis, darkening of the tongue, enterocolitis, pseudomembranous colitis, hypersensitivity reaction, mild elevation of ASAT, anemia, thrombocytopenia, eosinophilia, and agranulocytosis (according to patient information leaflet).
We report the case of a 64-year-old patient who presented with unclear elevation of liver enzymes. Alcohol-induced liver injury, viral hepatitis, auto-immune hepatitis, Wilson's disease, hemochromatosis, and α1-antitrypsin deficiency were unlikely according to the laboratory and histology results. Cholecysto-/choledocholithiasis could also be excluded due to normal MRCP results and normal alkaline phosphatase value. Liver biopsy was suspicious for drug- or toxin-induced liver injury. Regarding the patient's drug history it was remarkable that liver enzymes started to raise shortly after completion of Hp eradication. Since pantoprazole was not very likely the culprid, clarithromycin and amoxicillin were the drugs in suspicion. It has been known for many years that several antibiotics can cause severe hepatic injury . In the case of the penicillins, the combination amoxicillin-clavulanate and the penicillinase-resistant penicillins oxacillin, (di-)cloxacillin, and flucloxacillin can cause (mainly cholestatic) hepatitis. Cephalosporins have little hepatotoxicity; ceftriaxone can cause drug-induced gallstones. The potential of erythromycin and several other macrolides to cause (usually cholestatic) hepatitis is well established. Tetracyclines can cause a syndrome mimicking acute fatty liver of pregnancy, but this complication has virtually disappeared. Quinolones seem to be able to cause cholestasis. Sulfamethoxazole/trimethoprim can cause severe hepatotoxicity, especially in patients with acquired immunodeficiency syndrome (AIDS). Finally, nitrofurantoin can cause acute cholestatic and hepatocellular reactions as well as chronic hepatitis mimicking chronic auto-immune hepatitis . There are three reports indicating that intrahepatic cholestasis , acute liver injury and even liver failure [4, 5] may be caused by amoxicillin alone. Possible drug interactions include induction of anti-coagulation effects of coumarins, inhibition of effects of contraceptives, and increase of hypersensitivity reactions in combination with allopurinol (according to patient information leaflet). Regarding clarithromycin, cholestatic liver disease [6–8] and fulminant liver failure  have been described even more often in the literature [10, 11]. Patients with cholestatic liver disease present usually with minimal elevations of ALAT and ASAT but significant elevations of alkaline phosphatase and/or GGT. It appears that these subjects have dose-related toxicity, not a hypersensitivity reaction . This phenomenon has already been described in several preclinical animal models prior to the marketing authorisation of the drug . Since clarithromycin is primarily metabolized in the liver the patient information leaflet warns about administration of this drug in patients with advanced liver dysfunction. In patients with mild liver dysfunction, frequent monitoring of ASAT, ALAT, GGT, alkaline phosphatase, and bilirubin is recommended. Since clarithromycin inhibits liver enzyme CYP3A, clinicians have to be aware that plasma levels of drugs that are metabolized by this enzyme may increase. Typical drugs are antiarrythmics, carbamazepine, colchicine, digoxine, HMG-CoA reductase inhibitors, oral anticoagulants, sildenafile, tadalafile, vardenafile, theophylline, tolterodine, triazolo-benzodiazepines, and zidovudine. In addition, there are drugs like pimozide, astemizole, terfenadine, and ergotamine/dihydroergotamine that are contraindicated in combination with clarithromycin due to increased toxicity based on other mechanisms. Moreover, drugs like fluconazole and ritonavire can increase plasma level of clarithromycin, thus potentiating its side effects. However, in our case, we could not detect any typical drug interactions. We presume that clarithromycin was the main culprid for the increase in liver enzymes due to the empirical probability, although an additional adverse event of amoxicillin can not be excluded. The short course of sultamicillin administration seems to be irrelevant since liver enzyme increased prior to onset of treatment. Interestingly, the pattern of elevated liver enzymes was very unusual in this case, thus significant elevation of ALAT instead of GGT/alkaline phosphatase was the major finding. There is no good explanation for this finding. However, we speculate that preexisting fatty liver disease, respectively nonalcoholic steatohepatitis (NASH) may be a prediposition for antibiotic-induced liver injury. Steatohepatitis is characterized microscopically by hepatic fat accumulation (steatosis), mixed lobular inflammation, ballooning degeneration of hepatocytes (sometimes with identifiable Mallory bodies), glycogenated hepatocyte nuclei, and pericellular fibrosis. These are features that could also be found in the liver histology of our patient, although the "chicken wire" pattern of the pericellular fibrosis, which affects portal areas only secondarily in later stages, was not present.
In summary, clinicians should be aware about the presented rare adverse event of Hp eradication treatment. In patients with pre-existing liver disease like steatohepatitis, a close look at concomitantly prescribed drugs and monitoring of ASAT, ALAT, GGT, alkaline phosphatase, and bilirubin prior and after Hp eradication is recommended. Although only moderate liver injury was detected in our case, physicians should be prepared for rapid management of acute liver failure. In addition, alternative drug combinations, such as amoxicillin + metronidazole + PPI, metronidazole + doxycycline + bismuth subcitrate + PPI, or rifabutine + levofloxacine + PPI, should be discussed for Hp eradication in these patients.
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
We thank the patient for allowing us to report this case.
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