Prednisolone: role in amoxicillin–clavulanate-induced cholestatic liver injury

Background

Hepatotoxicity is one of the most common side effects of antibiotics. Antimicrobials, including amoxicillin clavulanate, are implicated in approximately 45% of drug-induced liver injury (DILI) cases identified.1 According to recent data from LiverTox, hepatotoxicity occurs in approximately 1 in 2500 patients treated with amoxicillin–clavulanate.1 The typical onset of amoxicillin–clavulanate-induced liver injury is usually within a few days to as long as 8 weeks from the start of therapy and commonly occurs following completion of treatment.2 Currently, there is no effective initial treatment for DILI apart from withdrawal of the causative medication and there are limited studies on the potential benefit of corticosteroids. Our case report showed a significant improvement in the patient’s liver function after commencement of prednisolone for the management of severe cholestatic liver injury induced by amoxicillin–clavulanate.

Case presentation

A 68-year-old Caucasian woman was admitted with symptoms of a urinary tract infection (UTI) and received a 5-day course of amoxicillin–clavunalate. Baseline liver function tests (LFTs) were elevated due to a history of chronic liver disease secondary to long-term alcohol use. Eleven days following completion of antibiotic therapy, a slight elevation of alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) was noted; however, the patient was asymptomatic. Repeat LFTs 1 week later showed a further derangement of LFTs as follows: ALP 855 IU/L (50—135 IU/L); alanine aminotransferase (ALT) 351 IU/L (7–40 IU/L); GGT 757 IU/L (9–48 IU/L); total bilirubin 44.4 umol/L (4–19 umol/L) and serum albumin 19.8 g/L (35–55 g/L).

The patient reported fatigue and decreased appetite; however, denied pruritus, steatorrhea or dark urine. Physical examination revealed scleral icterus, jaundice, bilateral pitting lower limb oedema, abdominal distension, mild epigastric and right hypochondrium tenderness on deep palpation.

Her previous medical history was significant for stage IV nonsmall cell lung carcinoma for which she underwent multiple courses of chemotherapy in 2018. A recent Positron Emission Tomography (PET) scan performed in February 2019 had shown recurrent lung carcinoma resulting in an upper lobectomy. Other notable medical history included chronic hypoalbuminemia, atrial fibrillation, type 2 diabetes mellitus, recurrent UTI and chronic pancreatitis. A benign mucinous cyst adenoma was diagnosed in 2012 for which she underwent Whipple’s procedure with removal of the pancreatic head, gall bladder, duodenum and parts of the bile duct. She was an ex-smoker with a 20-year pack history and had a history of previous heavy alcohol use before 2018. No relevant family history was noted.

On day 28, LFTs worsened further: ALP 989 IU/L, GGT 1116 IU/L, ALT 136 IU/L, total bilirubin 52.6 umol/L and serum albumin of 19.8 g/L. The pattern of liver injury was identified by calculating the R factor (patient’s ALT/upper limit of normal ALT)/(patient’s ALP/upper limit of normal ALP). In this case, she had a value of 0.14, which indicated cholestatic liver injury. (R>5 hepatocellular injury, R<2 cholestatic injury and R 2–5 mixed liver injury).3 As other potential diagnoses were ruled out by investigation, the conclusion of DILI secondary to amoxicillin-clavulanate was reached.

Investigations

A series of diagnostic tests were carried out to identify the aetiology of deranged LFTs. Abdominal ultrasound revealed severe hepatic steatosis and moderate subphrenic ascites bilaterally without intrahepatic or extrahepatic biliary ductal dilation or splenomegaly. CT of thorax, abdomen and pelvis (CT-TAP) was performed to investigate possible liver metastasis on the background of her history of lung carcinoma. It showed new focal sigmoid circumferential thickening, descending and transverse colitis; however, there were no interval lung changes or liver lesions noted in comparison to a previous CT-TAP performed in April 2020.

Viral hepatitis screen including hepatitis B, hepatitis C, hepatitis E, cytomegalovirus and Epstein-Barr virus was negative. An autoimmune liver screen including antinuclear antibody, antimitochondrial antibody, antismooth muscle antibody, antiliver–kidney microsomal antibodies and antineutrophil cytoplasm antibody) was negative. Alpha-1 antitrypsin and alpha-fetoprotein were normal. Faecal calprotectin was mildly elevated at 90 µg/g (normal range 0–40 µg/g); however, rectosigmoidoscopy and biopsy showed no inflammation or evidence of metaplasia or dysplasia. Stool alpha-1-antitrypsin was normal. Immunoglobulin levels were all normal with the exception of IgA, which was 6.21 g/L (normal range 0.7–4 g/L). Cerulosplasmin was mildly reduced at 0.13 g/L (normal range 0.16–0.45 g/L).

Differential diagnosis

Several diagnoses were considered based on her presentation and medical history. These included alcoholic hepatitis, liver metastases, viral hepatitis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cholangitis, alpha-1 antitrypsin deficiency, choledocholithiasis and DILI secondary to amoxicillin–clavulanate. CT-TAP results and negative viral hepatitis screen excluded liver metastasis and viral hepatitis, respectively. Primary sclerosing cholangitis was considered due to evidence of descending and transverse colitis on CT, however, liver autoantibodies were normal, hence reducing the likelihood. Absence of ductal dilation on abdominal ultrasound excluded choledocholithiasis. We also considered cholangiocarcinoma as a differential diagnosis as several case reports had highlighted a correlation between lung adenocarcinoma and primary cholangiocarcinoma.4 She was not keen for further investigations with liver biopsy, MRI or magnetic resonance cholangiopancreatography (MRCP), therefore, these avenues were not explored. Additionally, as her LFTs improved following commencement of a trial of corticosteroids, the possibility of cholangiocarcinoma was deemed unlikely.

After excluding other potential causes of liver injury, the diagnosis of DILI was made. This was based on the fact that amoxicillin–clavulanate is well known for its hepatotoxicity and typically causes a cholestatic pattern of liver injury.2 Second, the timeline of onset of amoxicillin–clavulanate liver injury is typically within a few days to 8 weeks (average of 3 weeks) following initiation of treatment with the antibiotic and frequently occurs following completion of the antibiotic course.2 This is consistent with the onset of LFT deterioration seen in our patient’s case.

Treatment

The patient was asymptomatic in the first 2 weeks following completion of amoxicillin–clavulanate. Her LFTs continued to worsen despite reduction of potentially hepatotoxic medications on her prescription. Lactulose was commenced to prevent hepatic encephalopathy. By day 28, there was a moderate improvement in ALT, however, ALP and GGT levels remained significantly high at 989 IU/L and 1116 IU/L, respectively. A trial of corticosteroids was introduced with an initial dose of 30 mg of prednisolone per day from day 30. By day 32, the first improvement LFTs was noted as follows: ALP 775 IU/L, GGT 1003 IU/L, ALT 74 IU/L and total bilirubin 28. The dose of prednisolone was slowly tapered to 20 mg/day on day 45 and 15 mg/day on day 52. LFTs continued to improve and by day 52, LFTs were as follows: ALP 172, ALT 25, GGT 287, total bilirubin 11.5.

Outcome and follow-up

The patient’s LFTs continued to show significant improvement following the introduction of prednisolone. On day 33, prednisolone was held, which resulted in a rebound worsening of LFTs. Prednisolone was restarted and the baseline LFTs were attained by day 52. Her appetite, fatigue and jaundice also improved significantly. Figure 1 demonstrates LFT trend throughout admission. The patient was maintained on 10 mg of prednisolone per day and her LFTs remained at baseline. Her blood sugar level was also tightly monitored by our diabetes nurse specialist due to her history of type 2 diabetes mellitus. She was discharged on 10 mg of prednisolone/day for 2 weeks and planned for an outpatient review within 2 weeks. Unfortunately, shortly after discharge, the patient developed a UTI and passed away from complications of urinary sepsis.

Figure 1

Patient’s liver function test (LFTs) results. ALP, alkaline phosphate; ALT, alanine aminotransferase; GGT, gamma-glutamyl transferase. Hold/reduce hepatotoxic medication on day 19. Prednisolone was started on day 30. Prednisolone was on hold on day 33. Prednisolone was restarted on day 36.