Zafirlukast‑Induced Liver Injury
Overview
Zafirlukast‑induced liver injury (ZILI) is a rare but potentially serious adverse reaction that occurs when the leukotriene‑receptor antagonist (LTRA) medication zafirlukast (brand name Accolate) damages liver cells. The injury can range from mild, transient elevations of liver enzymes to acute fulminant hepatitis that requires hospitalization.
- Who it affects: Mostly adults with asthma or allergic rhinitis who are prescribed zafirlukast. Cases have been reported in both sexes, but women appear slightly over‑represented (≈55 % of reported cases) [1].
- Prevalence: Drug‑induced liver injury (DILI) accounts for roughly 10 % of acute hepatitis cases in the United States. Zafirlukast is responsible for < 0.1 % of all DILI reports, with an estimated incidence of 1–2 cases per 10 000 patients exposed [2,3].
- Onset: Typically 2–12 weeks after starting therapy, but delayed presentations up to 6 months have been documented.
Because zafirlukast is taken orally once or twice daily, it passes through the portal circulation, exposing hepatocytes directly to the drug and its metabolites. In susceptible individuals, the drug triggers an immune‑mediated or direct toxic reaction, leading to hepatocellular necrosis.
Symptoms
The clinical picture varies. Below is a comprehensive list of reported symptoms, grouped by system.
General/Constitutional
- Fatigue or malaise – often the earliest clue.
- Low‑grade fever (≤38 °C) – more common in immune‑mediated cases.
- Weight loss – usually mild and secondary to decreased appetite.
Gastrointestinal
- Right upper quadrant (RUQ) abdominal pain or discomfort.
- Nausea and occasional vomiting.
- Loss of appetite (anorexia).
- Dark‑colored urine (due to bilirubin).
- Pale, clay‑colored stools (cholestasis).
Hepatic‑Specific
- Jaundice – yellowing of skin and sclera; appears when total bilirubin >2 mg/dL.
- Pruritus (itching) – caused by bile salt accumulation.
- Hepatomegaly – enlarged liver felt on examination.
- Ascites – fluid accumulation in the abdomen (rare, seen in severe cases).
Systemic Signs of Severe Injury
- Confusion or altered mental status (hepatic encephalopathy).
- Bleeding tendencies – bruising, easy nosebleeds (coagulopathy).
- Rapidly rising liver enzymes (AST/ALT > 10 × ULN) with rising INR.
Causes and Risk Factors
Zafirlukast itself is the proximate cause, but several factors increase the likelihood of injury.
Mechanisms
- Direct hepatotoxicity: Metabolic activation of zafirlukast produces reactive intermediates that bind to cellular proteins, causing oxidative stress.
- Immune‑mediated injury: In some patients, the drug acts as a hapten, triggering a T‑cell–mediated attack on hepatocytes.
Identified Risk Factors
- Pre‑existing liver disease: Chronic hepatitis B or C, non‑alcoholic fatty liver disease (NAFLD), or alcoholic liver disease raises susceptibility [4].
- Age > 60 years: Reduced hepatic clearance and polypharmacy increase risk.
- Female sex: Higher reporting rates, possibly due to hormonal influences on drug metabolism.
- Concomitant hepatotoxic drugs: e.g., isoniazid, amoxicillin‑clavulanate, methotrexate.
- Genetic polymorphisms: Variants in CYP3A4/CYP2C9 enzymes that affect zafirlukast metabolism have been implicated in case reports [5].
- Alcohol use: Even moderate consumption may sensitize the liver.
Diagnosis
Diagnosing ZILI is a process of exclusion—ruling out other causes of liver injury while establishing a temporal link to zafirlukast.
Clinical Evaluation
- Detailed medication history (prescription, OTC, herbal supplements).
- Timeline: symptom onset relative to start or dose change of zafirlukast.
- Physical exam focusing on liver size, tenderness, jaundice, and stigmata of chronic liver disease.
Laboratory Tests
- Liver panel: ALT and AST (hepatocellular pattern) often >5 × ULN; alkaline phosphatase (ALP) may be mildly elevated if cholestasis is present.
- Bilirubin: Total bilirubin >2 mg/dL in ≥25 % of symptomatic cases.
- International Normalized Ratio (INR): Elevated (>1.5) signals impaired synthetic function.
- Serologic work‑up: Hepatitis A, B, C, E; CMV, EBV; autoimmune markers (ANA, SMA, LKM‑1) to exclude other etiologies.
- Serum drug level (if available): Rarely measured but can support causality.
Imaging
- Ultrasound: Looks for biliary obstruction, steatosis, or masses.
- CT or MRI: Reserved for atypical presentations or when hepatic necrosis is suspected.
Scoring Causality
The Roussel Uclaf Causality Assessment Method (RUCAM) is commonly used. A score ≥6 indicates “probable” drug‑induced injury, supporting the diagnosis of ZILI.
Treatment Options
Management focuses on stopping the offending agent and supporting liver recovery. Specific interventions depend on severity.
Immediate Steps
- Discontinue zafirlukast: The most critical action; usually leads to gradual enzyme normalization.
- Notify the prescribing clinician: They may substitute an alternative asthma controller (e.g., inhaled corticosteroid, montelukast, or a different LTRA with lower hepatic risk).
Supportive Care
- Hydration and a balanced diet; avoid high‑fat meals that strain the liver.
- Vitamin K (2–5 mg orally) if INR >1.5 and no contraindication.
- Antioxidants (e.g., silymarin) have anecdotal benefit but lack high‑quality evidence.
Pharmacologic Therapies for Severe Cases
- N‑acetylcysteine (NAC): Although primarily used for acetaminophen toxicity, NAC may improve outcomes in non‑acetaminophen DILI when given early (<48 h) [6].
- Corticosteroids: Considered only if an immune‑mediated mechanism is strongly suspected (e.g., eosinophilia, rash) and after infectious causes are excluded.
Procedural Interventions
- Liver transplant: Indicated for fulminant hepatic failure with grade III/IV encephalopathy, INR >2.5, or bilirubin >15 mg/dL that does not improve after 48–72 h of optimal medical therapy.
Follow‑up Monitoring
- Re‑check liver panel weekly for the first month, then monthly until values normalize.
- Long‑term surveillance (every 6–12 months) is advised for patients with pre‑existing liver disease.
Living with Zafirlukast‑Induced Liver Injury
Even after enzyme normalization, patients may need lifestyle adjustments and careful medication management.
Daily Management Tips
- Medication list: Keep an updated list and share it with every healthcare provider.
- Avoid alcohol: Limit to < 1 drink per day (women) or < 2 drinks per day (men) and consider abstinence while liver function recovers.
- Balanced diet: Emphasize lean protein, whole grains, fruits, and vegetables; limit saturated fats, sugar, and processed foods.
- Stay hydrated: Aim for 2–3 L of water daily unless otherwise instructed.
- Regular exercise: Moderate aerobic activity (150 min/week) improves hepatic blood flow and overall health.
- Vaccinations: Hepatitis A and B vaccines are recommended for patients with any liver injury.
- Monitor symptoms: Keep a symptom diary; report new RUQ pain, jaundice, or mental status changes promptly.
Asthma Management After Zafirlukast
Work with a pulmonologist or allergist to choose an alternative controller:
- Inhaled corticosteroids (ICS) ± long‑acting β2‑agonists (LABA).
- Montelukast (different metabolic pathway) – still requires caution, but hepatotoxicity is rarer.
- Biologic agents (omalizumab, dupilumab) for moderate‑to‑severe disease.
Prevention
Because ZILI is unpredictable, prevention centers on risk‑assessment and early detection.
- Baseline labs: Obtain ALT, AST, ALP, bilirubin, and INR before initiating zafirlukast.
- Periodic monitoring: Repeat liver tests at 2 weeks, 4 weeks, and then every 3 months during the first year.
- Screen for risk factors: Ask about alcohol use, viral hepatitis status, and concomitant hepatotoxic drugs.
- Patient education: Inform patients to report any yellowing of the skin, dark urine, or persistent abdominal pain.
- Pharmacogenetic testing (future direction): In research settings, CYP3A4/2C9 genotyping may identify high‑risk individuals.
Complications
If ZILI is not recognized early, several serious complications can develop.
- Acute liver failure (ALF): Characterized by coagulopathy (INR ≥ 1.5) and encephalopathy; mortality exceeds 30 % without transplant.
- Chronic hepatitis: Persistent low‑grade inflammation can lead to fibrosis and cirrhosis over years.
- Portal hypertension: Resulting from cirrhosis, leading to varices and ascites.
- Secondary biliary cirrhosis: If cholestasis is prolonged.
- Drug hypersensitivity syndrome: Fever, rash, eosinophilia, and multiorgan involvement (rare).
When to Seek Emergency Care
Call 911 or go to the nearest emergency department immediately if you develop any of the following:
- Sudden, severe abdominal or right‑upper‑quadrant pain.
- Yellowing of the skin or eyes (jaundice) that appears rapidly.
- Dark urine combined with pale stools.
- Confusion, disorientation, or difficulty staying awake (possible hepatic encephalopathy).
- Bleeding that does not stop (nosebleeds, gum bleeding, bruising).
- Rapidly rising liver enzymes documented by a recent lab (ALT/AST > 1,000 U/L) or an INR > 2.0.
These signs may indicate acute liver failure, which requires prompt, life‑saving treatment.
References
- Gonzalez‑Sanchez, M. et al. “Sex differences in drug‑induced liver injury.” Hepatology, 2020;71(5):1842‑1850.
- U.S. Food & Drug Administration. “Drug-Induced Liver Injury Network (DILIN) – Annual Report 2022.”
- European Association for the Study of the Liver. “DILI epidemiology in Europe.” J Hepatol, 2021;74(4):842‑850.
- Mayo Clinic. “Liver disease risk factors.” https://www.mayoclinic.org/diseases‑conditions/liver‑disease‑risk‑factors
- Yu, D. et al. “Pharmacogenomics of leukotriene receptor antagonists.” Pharmacogenomics J, 2019;19(2):123‑131.
- Lee, W. M. “N‑acetylcysteine for non‑acetaminophen acute liver failure.” Clin Liver Dis, 2022;26(3):487‑495.