What is the role of steroids, such as prednisolone, in the management of liver failure?

Role of Steroids in Liver Failure

Severe Alcoholic Hepatitis: Clear Benefit

Prednisolone 40 mg daily for 28 days is the standard first-line treatment for severe alcoholic hepatitis (defined as mDF ≥32, MELD >21, or GAHS ≥9) and improves short-term survival. 1, 2

Indications for Steroid Treatment

• Patients with severe alcoholic hepatitis meeting any of the following criteria should receive prednisolone: mDF score ≥32, MELD score >21, GAHS ≥9, or presence of hepatic encephalopathy 1, 2
• Pooled data from multiple trials demonstrate 28-day survival of 84.6% with steroids versus 65.1% with placebo (P = 0.001), representing a 30% relative risk reduction 2
• The number needed to treat is 5, meaning five patients must be treated to prevent one death 2

Absolute Contraindications to Steroids

Do not use steroids in patients with:

• Active infection or sepsis (obtain cultures and chest radiograph before starting treatment) 1, 2
• Active gastrointestinal bleeding 1, 2
• Acute renal failure 1, 2
• Acute pancreatitis 1, 2

Treatment Algorithm for Alcoholic Hepatitis

Step 1: Assessment (Days 1-6)

• Calculate mDF, MELD, and GAHS scores 1
• Screen for infections with cultures (blood, urine, sputum) and chest radiograph 2
• Obtain abdominal ultrasound with Doppler to exclude other causes 2
• Allow sufficient time (average 6 days) to identify contraindications before starting steroids 2

Step 2: Initiate Treatment (Day 7)

• Start prednisolone 40 mg daily orally for patients without contraindications 1, 2
• Consider adding N-acetylcysteine (same dosing as for acetaminophen overdose) to reduce early complications, though this requires further validation 2

Step 3: Assess Response (Day 7 of Treatment)

• Calculate Lille score at day 7 to predict treatment response 1, 2
• Complete responders (Lille ≤0.16): 91.1% 28-day survival 1
• Partial responders (Lille 0.16-0.56): 79.4% 28-day survival 1
• Null responders (Lille ≥0.56): 53.3% 28-day survival 1

Step 4: Continue or Discontinue

• If Lille score <0.56 (responder): complete full 28-day course, then taper over 2 weeks 1, 2
• If Lille score ≥0.56 (non-responder): discontinue steroids as continued treatment provides no benefit and increases infection risk 2

Important Caveats

• Patients with very high disease severity (mDF >90 or MELD >30) have extremely poor prognosis and require careful assessment for occult infection before steroid initiation 2
• One study suggested patients with mDF >54 may have higher mortality with steroids than without, though this requires confirmation 2
• The presence of infection does not preclude steroid use if appropriately treated with antibiotics; response to steroids (Lille score) remains the key predictor of survival even with concurrent infection 2
• Patients with resolved gastrointestinal bleeding can receive steroids starting approximately 5 days after bleeding cessation 2

Acute Liver Failure: No Benefit or Harm

Corticosteroids should NOT be used in acute liver failure, including drug-induced, indeterminate, or even autoimmune causes presenting as fulminant hepatic failure. 2, 3

Evidence Against Steroid Use in ALF

• A large retrospective analysis of 361 ALF patients (autoimmune, drug-induced, and indeterminate causes) found no improvement in overall survival (61% vs 66%, P = 0.41) or spontaneous survival with steroid use 3
• Steroids were associated with significantly lower survival in patients with highest MELD scores (>40): 30% survival with steroids versus 57% without (P = 0.03) 3
• Corticosteroids should not be used to control elevated intracranial pressure in acute liver failure 2

Exception: Autoimmune Hepatitis

• While chronic autoimmune hepatitis responds well to steroids, fulminant presentations have poor outcomes with steroid therapy in systematic studies 3
• Individual case reports describe survival with steroids in fulminant autoimmune hepatitis, but this is not supported by larger cohort data 4
• If autoimmune hepatitis is strongly suspected in ALF, steroids may be considered only after excluding infection and in consultation with transplant centers, recognizing the lack of strong evidence 4

Autoimmune Hepatitis (Chronic): Standard Treatment

Prednisolone is the cornerstone of treatment for chronic autoimmune hepatitis, but this represents a different clinical entity than acute liver failure. 5

• Liver biopsy should be performed before initiating steroids to confirm diagnosis 5
• Treatment should not be initiated until infection is excluded and diagnosis is established 5

Special Populations and Pharmacokinetic Considerations

• Patients with hypoalbuminemia have decreased protein binding of prednisolone, leading to higher free drug levels and increased risk of side effects 6
• Prednisolone clearance is impaired in liver disease, resulting in higher drug exposure 6, 7
• Elderly patients have reduced metabolic clearance and higher prednisolone concentrations, though they appear less sensitive to cortisol suppression 7
• Dosage reduction should be considered in patients with severe hypoalbuminemia 6

Mechanistic Insights and Warnings

• Prednisolone prevents T/NKT cell-mediated hepatitis but paradoxically exacerbates hepatotoxin-induced liver injury by inhibiting macrophage and neutrophil phagocytic functions critical for liver regeneration 8
• This explains why steroids help immune-mediated alcoholic hepatitis but worsen outcomes in drug-induced or toxin-mediated ALF 8
• Rare cases of corticosteroid-induced acute liver failure have been reported, though this is exceedingly uncommon 9

COVID-19 Considerations

• In patients with autoimmune liver disease or post-transplant on chronic steroids who develop COVID-19, maintain sufficient steroid dosing to avoid adrenal insufficiency or disease flare 2
• Consider minimizing high-dose steroids in COVID-19 patients, but do not discontinue abruptly 2