Can patients with liver failure use testosterone?

Testosterone Use in Patients with Liver Failure

Testosterone therapy may be considered in select men with cirrhosis and documented low testosterone levels, but the risk/benefit profile must be carefully weighed against the increased risks of hepatocellular carcinoma (HCC) and thrombophilia, making it contraindicated in patients with a personal or family history of HCC, other malignancies, or thrombotic disorders. 1

Risk Stratification and Contraindications

The 2021 American Association for the Study of Liver Diseases (AASLD) guidelines explicitly state that testosterone therapy carries increased risk for HCC and thrombophilia in cirrhotic patients 1. The relative contraindications include:

• Personal or family history of HCC 1
• History of prostate cancer 1
• History of thrombophilia or prior thrombotic events 1

The 2019 European Association for the Study of the Liver (EASL) guidelines reinforce this concern, noting that "one concern about restoring testosterone levels in cirrhotic patients is the increased risk of hepatocellular carcinoma" 1. The FDA drug label for testosterone warns of potential hepatic adverse effects and the need to monitor for signs of hepatic dysfunction 2.

When Testosterone May Be Considered

For men with cirrhosis who do NOT have the above contraindications, testosterone replacement may be indicated when:

• Documented hypogonadism with total testosterone <12 nmol/L or free testosterone <230 pmol/L 1
• Presence of sarcopenia or frailty that could benefit from anabolic intervention 1
• Baseline testosterone levels should be checked before initiating therapy 1

The AASLD guidelines note that in one study of 101 male cirrhotic patients with low testosterone, replacement therapy increased muscle mass, decreased fat mass, and improved glucose metabolism 1. A 2016 randomized controlled trial demonstrated that testosterone therapy safely increased appendicular lean mass by 1.69 kg, total lean mass by 4.74 kg, bone mineral density, and hemoglobin while reducing fat mass and HbA1c 3.

Clinical Benefits vs. Mortality Outcomes

Important caveat: While testosterone improves intermediate endpoints (muscle mass, bone density, body composition), no trial has demonstrated improvement in liver-related complications, readmission rates, or mortality 4. The anabolic effects on muscle relate to suppression of muscle cell apoptosis and myostatin production 1.

Low testosterone is independently associated with:

• Increased mortality in cirrhosis 5, 6
• Sarcopenia and reduced lean body mass 6, 4
• Shorter time to hepatic decompensation 4
• Higher MELD scores 4

However, testosterone supplementation has not been shown to reverse these mortality risks despite improving body composition 6, 4.

Specific Monitoring Requirements

If testosterone is prescribed, mandatory monitoring includes:

• Hematocrit levels for polycythemia (a known side effect) 7
• Liver function tests due to potential hepatotoxicity, particularly with oral formulations 7, 2
• Signs of thromboembolism (DVT/PE symptoms) 2
• Serum testosterone concentrations to ensure therapeutic range and prevent abuse 2
• Lipid profile periodically after initiation and dose changes 2

Transdermal testosterone is preferred over oral formulations to avoid hepatotoxic effects 7. The FDA label warns that prolonged use of oral 17-alpha-alkyl androgens has been associated with serious hepatic adverse effects including peliosis hepatis, hepatic neoplasms, cholestatic hepatitis, and jaundice 2.

Special Considerations for Liver Disease

Edema and fluid retention: Testosterone may promote sodium and water retention, which can be particularly problematic in cirrhotic patients with preexisting ascites or portal hypertension 2. Diuretic therapy may be required in addition to drug discontinuation if edema with congestive heart failure develops 2.

Hemochromatosis exception: In males with hemochromatosis and hypogonadism, testosterone supplementation combined with venesection is considered effective and appropriate 1.

Post-Liver Transplant Context

In the post-transplant setting, testosterone deficiency with functional sarcopenia is common (mean testosterone <5% of expected in one series) 8. Short-term testosterone replacement therapy combined with active exercise provided 5-year patient and graft survival of 87.5% in one retrospective study 8, though this represents lower-quality evidence than the pre-transplant data.

Bottom Line Algorithm

1. Screen for absolute contraindications: personal/family history of HCC, other malignancy, thrombophilia 1
2. If contraindications present: Do NOT use testosterone
3. If no contraindications: Check baseline testosterone levels 1
4. If testosterone <12 nmol/L or free testosterone <230 pmol/L: Consider therapy for sarcopenia/frailty 1
5. Use transdermal formulation to minimize hepatotoxicity 7
6. Monitor hematocrit, liver function, and thrombotic symptoms closely 7, 2
7. Recognize that benefits are limited to body composition—no proven mortality benefit 4