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Volume: 22 Issue: 4 April 2024

FULL TEXT

CASE REPORT
Tigecycline-Associated Hepatic Steatosis After Liver Transplant: A Case Report

Tigecycline is a parenteral glycycline antibiotic that is used to treat severe infections caused by susceptible organisms, but it is also associated with hepatotoxicity. We present 2 similar patients with hepatic steatosis possibly associated with early tigecycline after transplant. In the first case, a 61-year-old woman underwent liver transplant for acute severe hepatitis; 6 days posttransplant, because of nonroutine resistant fever, the patient received tigecycline combined with daptomycin. Retransplant was applied to the patient on day 12 posttransplant because of acute liver failure secondary to hepatic vein thrombosis. After retransplant, biochemical levels gradually increased, exceeding the upper limit of normal. In liver biopsy, the patient had macrovesicular steatosis in 70% to 80% of the parenchyma. In the second case, a 53-year-old woman underwent liver transplant for liver cirrhosis. Tigecycline was added to the treatment because of recurrent fever on day 6 after transplant, with treatment also comprising piperacillin-tazo-bactam and meropenem. On day 15 of the patient’s tigecycline treatment, her liver function tests were elevated. In liver biopsy, the patient had 30% to40% macrovesicular steatosis and canalicular cholestasis in the parenchyma, especially in zone 3. Reports of hepatic steatosis associated with early tigecycline after transplant are quite new to the literature.


Key words : Drug-induced hepatosteatosis, Hepatotoxicity, Macrovesicular steatosis, Posttransplant complications

Introduction

Because of immunosuppression used after liver transplant, the risk of hepatic steatosis increases with the frequency of metabolic syndrome. The recurrence can be seen in the long term in patients who have had a transplant due to nonalcoholic steatohepatitis. However, drugs are primarily responsible for hepatic steatosis seen after a short period of time.

Drug-induced fatty liver is related to the dose and duration of medications. Some drugs cause an acute energy crisis by interfering with mitochondrial adenosine triphosphate synthesis, resulting in mi-crovesicular steatosis. However, drugs can cause both micro- and macrovesicular steatosis.1 Tigecycline is a glycycline, a new generation of tetracycline. Tigecycline is a parenteral glycycline antibiotic that is used to treat severe infections caused by susceptible organisms. High intravenous tetracycline doses have been linked to severe direct hepatic injury, including microvesicular steatosis, lactic acidosis, and hepatic failure in autopsied case.2 In contrast, tigecycline therapy is sometimes accompanied by minor amino-transferase elevations but has not been definitely associated with clinically apparent liver injury with jaundice.1

We present 2 cases of severe liver enzyme elevation and biopsy-proven hepatic steatosis associated with tigecycline use after liver transplant. Informed consents were obtained from the patients for publication of this case report.

Case Report

Case 1
A 61-year-old woman received a diagnosis of acute severe hepatitis after she was admitted to the hospital with complaint of fatigue and jaundice. The body mass index (in kilograms divided by height in meters squared) of the patient, who had no disease other than known additional osteoarthritis, was >24.8. The patient had an extended history of oak seed consumption. The patient had no other known hepatobiliary diseases. The patient had liver transplant from a deceased donor on day 10 due to acute liver failure. After the patient developed acute liver failure secondary to hepatic vein thrombosis, she received retransplant on day 12 after first transplant.

During intensive care hospitalization, 6 days after the first transplant, due to nonroutine resistant fever, tigecycline (loading dose 100 mg, followed by 50 mg every 12 h intravenously) combined with daptomycin (1 × 6 mg/kg) and anidulafungin (loading dose 200 mg, followed by 100 mg every 12 h intravenously) was administered. After retransplant, the patient’s liver function started to worsen, with biochemical levels gradually rising and exceeding the upper limit of normal. Of note, the patient had a significant increase in total bilirubin levels (Figure 1). A routine posttransplant computerized tomography (CT) scan of the abdomen showed no masses, gallstones, or biliary dilatation. A color Doppler ultrasonography also showed normal blood flow on hepatic artery, portal vein, and hepatic vein to the transplanted liver. All serological levels of all hepatotropic viruses were negative.

Tigecycline treatment was discontinued on day 10 after retransplant. A hepatobiliary ultrasonography was performed regularly by the same radiologist after liver transplant, and progressive increasing hepatic steatosis was seen. No vascular pathology was detected radiologically, and it was excluded by serological tests for all other reasons.

A liver biopsy was performed on day 13 after the second transplant, due to the presence of grade 3 hepatic steatosis on ultrasonography. The biopsy result showed macrovesicular steatosis (grade 3) in 70% to 80% of the parenchyma. In zone 3, slight ballooning (grade 1) was shown in some areas, with Mallory-Denk body in 1 area (Figure 2A). There was canalicular cholestasis, which was more prominent in zone 3.

The patient’s rapidly developing hepatic steatosis was primarily thought to be drug-related. Scores, calculated from the Roussel-Uclaf Causality Assessment Method (RUCAM), were higher than 9 (highly probable hepatocellular injury of drug-induced liver disease [DILI]). Based on the 2015 Chinese guideline for the management of DILI, we calculated an R value of 16.6 (hepatocellular injury). The patient’s serum lipid levels before transplant were within the normal range (total cholesterol: 121 mg/dL, low-density lipoprotein [LDL]: 78 mg/dL, triglycerides: 129 mg/dL, high-density lipoprotein [HDL]: 46 mg/dL). In addition, liver steatosis in the deceased donor was lower than 5%.

It was thought that the agent causing severe steatosis of the patient was tigecycline in the foreground. After treatment was stopped, the patient’s enzymes regressed and returned to almost normal on day 30 (Figure 3); radiologically, steatosis also showed regression.

Case 2
A 53-year-old woman underwent liver transplant from a living donor (the donor was the patient’s nephew) for liver cirrhosis due to autoimmune hepatitis. Tigecycline was added to the patient’s treatment because of recurrent fever on day 6 after transplant; treatment included piperacillin-tazobactam and meropenem, but piperacillin-tazobactam was discontinued. On day 15 of the patient’s tigecycline treatment, meropenem and tigecycline were discontinued, and enzyme elevation continued for a while after the drug was discontinued. The liver parenchyma was normal by ultrasonography before treatment of tigecycline.

On abdominal ultrasonography imaging, grade 2 steatosis was seen. Radiological and serological tests performed because of enzyme elevation ruled out all etiological causes. On the day 32 posttransplant, a liver biopsy was performed, revealing 30% to 40% macrovesicular steatosis and canalicular cholestasis in the parenchyma, especially in zone 3 (Figure 2B). The patient’s rapidly developing hepatic steatosis was primarily thought to be drug-related. Scores, calculated from the RUCAM, were higher than 9 (highly probable hepatocellular injury of DILI). Based on the Chinese guideline for the management of DILI, we calculated that the R value was 13.2 (hepatocellular injury). Pretransplant values of the recipient showed normal serum lipid values (total cholesterol: 132 mg/dL, LDL: 80 mg/dL, HDL: 36 mg/dL, serum triglyceride: 79 mg/dL). The patient, who had been followed for a long time, showed no evidence of metabolic syndrome. The patient’s donor (32 years of age) had normal pretransplant lipid panel (total cholesterol: 128 mg/dL, LDL: 123 mg/dL, HDL: 51 mg/dL, triglyceride: 89 mg/dL). The donor’s pretransplant ultrasonog-raphy showed no steatosis, and the magnetic resonance image proton density fat fraction had a 4% fat measurement.

At time of biopsy, the recipient’s lipid profile was normal, and the dyslipidemia panel was normal. The patient’s enzyme levels regressed spontaneously and returned to normal on the day 15 after biopsy (day 30 following tigecycline discontinuation), and the steatosis regressed radiologically. About 4 months after discontinuation of tigecycline treatment, liver biopsy was performed because of elevated liver enzymes. Biopsy showed that macrovesicular steatosis was totally resolved.

Discussion

Patients who undergo liver transplant receive piperacillin-tazobactam prophylaxis before transplant in our hospital as per protocol. If no additional clinical pathology develops, antibiotic treatment is discon-tinued within 5 to 7 days.

During transplant, patients are usually given 500 mg of intravenous prednisolone, which is then rapidly reduced (500 mg on day 1, 250 mg on day 2, 40 mg on day 7, 20 mg at the end of month 1) and discontinued within the first 3 to 6 months. This procedure can be changed due to the etiology of liver transplant. Both of the above-mentioned patients received tigecycline treatment in the early posttransplant period because of recurrent fever; however, the patients showed no blood culture-proven infections. Liver function tests peaked approximately 15 to 20 days after the start of tigecycline in both patients. The RUCAM score of both patients was 9, and the R value was calculated consistent with hepatocellular damage. No other cause could be found in the etiology of both patients. The dyslipidemia panel was evaluated as normal. The common agent that was withdrawn from the treatment was tigecycline, and the enzymes returned to normal on day 30 following the discontinuation of the treatment. Other medications related to hepatic steatosis were ruled out. During posttransplant follow-up, total parenteral nutrition was not given.

When steatohepatitis appears to be the direct result of a drug’s liver-damaging side effect, the condition is known as drug-induced fatty liver disease, which is a relatively uncommon condition. It most frequently occurs when the offending medication is taken for an extended period of time. Drug-induced fatty liver disease is thought to account for 2% of cases, proving that it is a relatively uncommon sign of drug toxicity.3

Recent research in mice demonstrated that tetracycline promotes triglyceride esterification and fatty acid transport by increasing the protein expression of the enzymes diacylglycerol acyltran-sferase 2 and fatty acid translocase (or CD36), respectively.4 A severe direct hepatic injury charac-terized by microvesicular steatosis, lactic acidosis, and hepatic failure was linked to high doses of intravenous tetracycline. This syndrome resembled Reyes syndrome and was probably brought on by an injury to the mitochondria. The use of intravenous tetracycline was discontinued as a result. Tigecycline and the other modified tetracyclines, such as omadacycline and eravacycline, have not been associated with this syndrome.1 Tigecycline-asso-ciated DILI presented with cholestatic injury pattern most frequently, which might be explained by its structure derivation from tetracycline, similar to the biochemical properties of tetracycline to some extent. Cases of clinically apparent liver injury with jaundice appear to be rare. A patient with tigecycline-related cholestatic injury in the early period after liver transplant was previously described.5 In our study, both patients received immunosuppressive therapy in accordance with our protocol. It is impossible to say with certainty whether immunosuppressive therapy causes hepatic steatosis.

Tigecycline is reported to cause mild, transient elevations in serum aminotransferase levels in 2% to 5% of recipients, rates similar to those in patients treated with comparable antibiotics. Product labels for tigecycline mention isolated cases of significant hepatic dysfunction cholestasis and jaundice iden-tified from postmarketing experience.6 In a study from China that evaluated 973 patients treated with tigecycline, 45 patients (4.6%) with DILI and 10 patients (1%) with hepatic injuries of DILI were detected (3/10 highly probable).6

Conclusions

Drugs are the most important factors in the early period after liver transplant resulting in moderate to severe hepatic steatosis. In the 2 similar cases with hepatic steatosis in our study, hepatic steatosis was thought to be associated with early tigecycline use after transplant, which is quite new to the literature. More data are needed to define tigecycline-asso-ciated macrovesicular steatosis.


References:

  1. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Tigecycline. National Institute of Diabetes and Digestive and Kidney Diseases; 2012. Updated January 23, 2019. https://www.ncbi.nlm.nih.gov/books/NBK547888
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Volume : 22
Issue : 4
Pages : 318 - 321
DOI : 10.6002/ect.2023.0227


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From the 1Department of Gastroenterology, the 2Department of Gastrointestinal Surgery, the 3Department of Pathology, the 4Department of Infectious Disease and Clinical Microbiology, and the 5Department of Radiology, Ankara City Hospital, Ankara, Turkey
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Dilara Turan Gökçe, Ankara City Hospital, Department of Gastroenterology, 06100, Çankaya, Ankara, Turkey
Phone: +90 543 5484378
E-mail: dilaraturan89@yahoo.com