What is the recommended treatment for hepatorenal syndrome (HRS) in patients with hepatocellular carcinoma (HCC)?

Treatment of Hepatorenal Syndrome in HCC Patients

Terlipressin plus albumin is the recommended first-line treatment for hepatorenal syndrome in patients with hepatocellular carcinoma, as it significantly improves renal function reversal and may improve short-term survival while serving as a bridge to liver transplantation. 1, 2, 3

Evidence for Terlipressin and Albumin

The combination of terlipressin and albumin represents the most effective pharmacological approach for HRS management in HCC patients:

• Terlipressin (FDA-approved as TERLIVAZ) demonstrated 29.1% verified HRS reversal compared to 15.8% with placebo (p=0.012) in the CONFIRM trial, the largest randomized controlled study of HRS treatment. 1

• The standard dosing regimen is terlipressin 1 mg IV every 6 hours (equivalent to 0.85 mg terlipressin base), with dose escalation to 2 mg every 6 hours on Day 4 if serum creatinine decreases by less than 30% from baseline. 1

• Albumin should be administered at 1 g/kg on day 1 (maximum 100 g), followed by 20-40 g/day thereafter as clinically indicated throughout the treatment course. 1

• Treatment duration is typically up to 14 days, with median treatment duration of 5 days in clinical trials. 1

Mechanism and Clinical Efficacy

Terlipressin works by reversing the fundamental pathophysiology of HRS:

• The vasopressin analog increases mean arterial pressure and systemic vascular resistance while decreasing portal pressure and plasma renin activity, thereby improving renal perfusion. 4, 3

• Terlipressin plus albumin achieves 70.4% recovery of renal function compared to only 28.6% with midodrine/octreotide plus albumin (p=0.01), making it significantly superior to alternative vasoconstrictor regimens. 2

• The combination improves glomerular filtration rate, deactivates the renin-angiotensin-aldosterone system, and increases natriuresis. 4

Patient Selection and Contraindications

Critical eligibility criteria must be assessed before initiating therapy:

• Patients must have cirrhosis with ascites, serum creatinine ≥2.25 mg/dL with rapid progression, and lack of sustained improvement after diuretic withdrawal and albumin challenge (48 hours). 1

• Absolute contraindications include: serum creatinine >7.0 mg/dL at baseline, shock, sepsis, uncontrolled bacterial infection, and concurrent vasopressor use. 1

• The presence of HCC does not contraindicate terlipressin therapy, as the CONFIRM trial included patients with various etiologies of cirrhosis. 1

Treatment Monitoring and Response Assessment

Specific parameters guide treatment continuation and dose adjustment:

• If serum creatinine is at or above baseline value on Day 4, treatment should be discontinued as non-response is established. 1

• HRS reversal is defined as two consecutive serum creatinine values ≤1.5 mg/dL obtained at least 2 hours apart while on treatment by Day 14 or discharge. 1

• Patients must remain alive without renal replacement therapy for at least 10 days after achieving HRS reversal to be considered treatment successes. 1

Role as Bridge to Transplantation

Terlipressin therapy serves a critical bridging function in HCC patients:

• Patients with HRS who achieve renal function improvement with terlipressin and albumin have excellent post-transplantation outcomes similar to patients without HRS. 4

• Liver transplantation remains the only curative treatment for HRS, and terlipressin effectively bridges patients to transplantation by reversing renal dysfunction. 3

• In HCC patients, transplant eligibility depends on tumor burden meeting accepted criteria (typically Milan criteria), with HRS reversal potentially expanding transplant candidacy. 5

Safety Profile and Adverse Effects

Terlipressin demonstrates acceptable tolerability:

• Side effects are generally minimal and usually resolve with dose reduction, making it safe for clinical use. 4

• The drug has no significant drug-drug interactions anticipated based on in vitro studies of CYP enzymes and transporters. 1

• Embryo-fetal toxicity is a concern; female patients of reproductive potential must be counseled about potential fetal harm. 1

Alternative Regimens When Terlipressin Unavailable

In settings where terlipressin is not accessible:

• Midodrine (7.5-12.5 mg orally three times daily) plus octreotide (100-200 μg subcutaneously three times daily) with albumin can be used, though efficacy is significantly lower than terlipressin. 2

• This combination achieved only 28.6% HRS reversal compared to 70.4% with terlipressin, representing a clinically meaningful difference in outcomes. 2

Prognostic Factors

Certain baseline characteristics predict treatment response:

• Lower baseline Model for End-Stage Liver Disease (MELD) scores are associated with better survival and treatment response. 2

• Patients with systemic inflammatory response syndrome (SIRS) showed particularly strong response to terlipressin, with 33.3% HRS reversal versus 6.3% with placebo. 1

• Early mortality rates remain high even in responders without liver transplantation, emphasizing the importance of expedited transplant evaluation. 3

Critical Pitfall to Avoid

The most important clinical pitfall is delaying terlipressin initiation while attempting less effective therapies—early diagnosis and prompt treatment with terlipressin plus albumin maximizes the chance of HRS reversal and survival. 3