Drug-Induced Liver Disease
Abnormal Liver Enzymes: To Steroid Or Not To Steroid?

Abnormal liver enzymes: To steroid or not to steroid?

June 27, 2021

Nneka Ufere

Case

A 57-year-old woman presents with an acute history of fevers to 101°F, RUQ abdominal pain, fatigue, arthralgias, and elevated liver enzymes. Her symptoms first started two weeks prior to presentation. She does not drink alcohol or use illicit drugs. She has not had any recent travel. She does not take NSAIDs or Tylenol. Her labs on admission are WBC 6.5, Hct 42, Plts 222, ALT 348, AST 225, ALP 185, Tbili 4.5, INR 1.1. A Tylenol level is undetectable. Hepatitis A, B, and C testing are negative. COVID-19 testing and tickborne panel are negative. A doppler ultrasound of the liver is normal. Additional lab testing revealed a positive antinuclear antibody, an elevated anti-smooth muscle antibody at a titer of 1:320 and an elevated IgG at 2052.

What is the next best step in evaluation and/or management?

Start prednisone Start prednisone + azathioprine Check hepatitis E serologies Medication review Liver biopsy

Correct Answer:

Medication review

What is Drug-induced AIH-like liver injury and how does it present?

Drug-induced liver injury can be associated with autoimmune-like features and may account for 9-12% of cases with classical features of AIH
Key clinical features in drug-induced AIH-like liver injury include right upper quadrant pain, hypersensitivity manifestations including fever, rash, arthralgias, eosinophilia and positive autoantibodies (antibodies to nuclear antigen [ANA], smooth muscle [SMA] and soluble liver antigen [SLA])

Back to the case

In the clinical case above, our patient acutely presented with a hepatocellular pattern of liver injury with associated immunoallergic features of fever and arthralgias.

Viral hepatitis testing was negative and imaging was normal. She was found to have positive autoantibodies and elevated immunoglobulin G levels, findings that are consistent with AIH.

However, with drug-induced AIH-like liver injury making up approximately 10% of AIH cases, a thorough medication review is the appropriate next step in evaluation.

How is a diagnosis of drug-induced liver injury made?

Obtaining an accurate clinical history is key. In addition, the American College of Gastroenterology set forth a helpful diagnostic algorithm to evaluate for suspected idiosyncratic drug-induced liver injury (Figure 1).

Figure 1- An algorithm to evaluate for suspected idiosyncratic drug-induced liver injury

Taken from: Chalasani, N., et al., ACG Clinical Guideline: Diagnosis and Management of Idiosyncratic Drug-Induced Liver Injury. Am J Gastroenterol, 2021. 116(5): p. 878-898.

Back to the case

A thorough medication history was obtained from the patient to assess medications, herbals and dietary supplements she was currently prescribed. She confirmed that she was currently taking no medications, herbals, or supplements. On further questioning about her medication exposure over the past year, she shared that she had a history of recurrent UTIs and was prescribed nitrofurantoin 3 months prior to presentation.

Drug-induced AIH-like liver injury – Medication history

Nitrofurantoin, minocycline, hydralazine, methyldopa and infliximab are the most common drugs shown to have a definite association with drug-induced AIH-like liver injury
The latency period from drug exposure to disease onset in drug-induced AIH-like liver injury can be as short as 1 week to as long as over 12 months, though it is rare to see the presence of autoantibodies prior to 2 months after drug exposure
Other drugs associated with liver injuries resembling AIH are shown in Table 1.

Table 1: Drugs Associated with Liver Injuries Resembling AIH

Taken from: Mack, C., et al., Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and Guidelines from the American Association for the Study of Liver Diseases. Hepatology, 2020. 72(2): p. 671-722.

Back to the case

Given her severe icteric hepatitis, a liver biopsy was pursued. Her liver biopsy showed evidence of marked necroinflammatory activity with numerous plasma cells (Figure 2). There was no evidence of advanced fibrosis or cirrhosis.

Figure 2: Drug-induced autoimmune hepatitis

Taken from: Ramachandran, R., and Sakar, S., Histological patterns in drug-induced liver injury. Journal of Clinical Pathology, 2009. 62: p. 481-492.

Drug-induced AIH-like liver injury – Liver biopsy

Liver biopsy is warranted if there is diagnostic uncertainty, if labs indicate severe injury, or if glucocorticoid therapy is being considered
Liver biopsies in drug-induced AIH-like liver injury usually show features that are typical of autoimmune hepatitis such as interface hepatitis and lymphoplasmocytic infiltrates
The absence of advanced fibrosis or cirrhosis on biopsy may help to differentiate drug-induced AIH-like liver injury from classical AIH
The 2019 AASLD Practice Guideline: Diagnosis and Management of Autoimmune Hepatitis in Adults and Children highlights features of drug-induced AIH-like liver injury vs. AIH (Table 2)

Table 2: Features of drug-induced AIH-like injury and AIH

Drug-induced AIH like liver injury -- Treatment

The mainstay of therapy for drug-induced AIH-like liver injury is withdrawal of the culprit drug with close monitoring until complete and sustained resolution of clinical and laboratory findings
Corticosteroid therapy is appropriate if there is no evidence of recovery within weeks of stopping the medication, if labs continue to worsen, or if there is any evidence of hepatic failure such as prolongation of PT-INR, progressive jaundice, or new hepatic encephalopathy or ascites
The outcome of drug-induced AIH-like liver injury is excellent and many patients respond to corticosteroid therapy
Patients with suspected drug-induced AIH-like liver injury should be closely monitored for at least 6 months after corticosteroids have been withdrawn to confirm full recovery and absence of relapse, which would suggest underlying spontaneous AIH. The presumptive drug culprit should be avoided to avoid triggering relapse. (Figure 3)

Figure 3: Suggested treatment algorithm for autoimmune hepatitis vs. drug-induced autoimmune-like liver injury

Taken from: EASL Clinical Practice Guidelines: Autoimmune hepatitis. J Hepatol, 2015. 63(4): p. 971-1004.

Back to the case

She was started on a prednisone taper with normalization of her liver enzymes after several weeks of therapy. She was monitored closely for 6 months after her steroid taper and her liver enzymes remained normal. Her allergy list was updated in her medical record to document her adverse reaction to nitrofurantoin.

Take Home Points:

Between 9-12% of cases with classical features of AIH may be due to drug-induced AIH-like liver injury – make sure to take a thorough medication history for AIH cases!
Common culprits for drug-induced AIH-like liver injury include nitrofurantoin, minocycline, hydralazine, methyldopa and infliximab
The latency period between drug exposure and drug-induced AIH-like liver injury can be as short as 1 week to as long as over 12 months
Diagnostic features that favor drug-induced AIH-like liver injury over AIH include the following: recent drug exposure; presence of features of hypersensitivity (fever, rash, eosinophilia); absence of advanced fibrosis or cirrhosis on biopsy.
The mainstay of therapy is withdrawal of the culprit drug with close monitoring until complete and sustained clinical resolution

Drug-Induced Liver Disease Autoimmune Hepatitis

Written By:

Nneka Ufere

Abnormal liver enzymes: To steroid or not to steroid?

Case

Correct Answer:

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Take Home Points:

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