Can perimenopause cause elevated liver function tests (LFTs) in women?

Can Perimenopause Cause Elevated LFTs?

Perimenopause itself does not directly cause elevated liver function tests, but the hormonal transition increases susceptibility to metabolic dysfunction-associated steatotic liver disease (MASLD), which is the actual cause of elevated LFTs in this population. 1

Understanding the Mechanism

The relationship between perimenopause and elevated LFTs is indirect but clinically significant:

• Menopausal status is associated with approximately 2.4-fold higher odds of developing MASLD, which then manifests as elevated liver enzymes 1
• Women aged >50 years have increased odds of advanced fibrosis due to MASLD even after adjustment for other risk factors 1
• The risk of severe fibrosis is elevated even in normal-weight postmenopausal women with MASLD compared to premenopausal women 1

The Estrogen Deficiency Connection

The hormonal changes during perimenopause create a metabolic environment that promotes liver disease:

• Estrogen deficiency increases mitochondrial dysfunction, cellular senescence, declining immune responses, and oxidative stress imbalance, all of which contribute to liver pathology 2
• Duration of estrogen deficiency directly correlates with fibrosis severity - each 5-year increment of estrogen deficiency increases the likelihood of more severe fibrosis 3
• Premature menopause (age <40 years) is associated with a 1.9-fold increased likelihood of having more severe fibrosis in women with NAFLD 3

Clinical Approach to Elevated LFTs in Perimenopausal Women

When evaluating elevated LFTs in this population, follow this systematic approach:

Initial Assessment

• Perform complete blood count, comprehensive metabolic panel, hepatitis B surface antigen, hepatitis C antibody, fasting lipid panel, fasting glucose, and HbA1c 4
• Classify the pattern as hepatocellular (elevated ALT/AST) or cholestatic (elevated alkaline phosphatase) using the R-ratio 4
• Obtain right upper quadrant ultrasound to assess for hepatic steatosis and evaluate the biliary tree 4

Risk Stratification

• Calculate FIB-4 or NAFLD Fibrosis Score to stratify fibrosis risk in patients with metabolic risk factors 4
• FIB-4 <1.3 (or <2.0 if age >65) indicates low risk, while >2.67 (or >3.25 if age >65) indicates high risk of advanced fibrosis 4

Key Metabolic Risk Factors to Assess

The presence of multiple cardiometabolic risk factors exponentially increases liver disease risk:

• Each additional metabolic trait (hypertension, dyslipidemia, obesity, diabetes) leads to stepwise increase in risk of progression to cirrhosis, with type 2 diabetes having the strongest association 1
• Women with both hypertension and dyslipidemia have a 1.8-fold higher risk of progression to cirrhosis or HCC compared to those with no cardiometabolic risk factors 1

Important Clinical Caveats

When to Refer Urgently

Refer immediately to hepatology if: ALT >8× ULN or >5× baseline, evidence of synthetic dysfunction, signs of acute liver failure, FibroScan >16 kPa, or suspected autoimmune hepatitis 4

Medication Review is Critical

• Critically review all medications, over-the-counter drugs, herbal supplements, and biotin-containing products to identify potential hepatotoxic agents 4
• Discontinue hepatotoxic agents immediately if ALT/AST >5× ULN or any elevation with jaundice 4

The Menstrual Irregularity Connection

• Menstrual irregularities are common in advanced liver disease, occurring in >25% of women with chronic liver disease and nearly 75% of premenopausal women awaiting liver transplant 1
• However, altered estrogen metabolism from liver disease causes amenorrhea, not the reverse - perimenopause doesn't directly elevate LFTs 1

Bottom Line for Clinical Practice

The elevated LFTs you observe in perimenopausal women are not from perimenopause per se, but from the metabolic consequences of estrogen deficiency that promote MASLD development and progression. 1, 2, 5 Focus your evaluation on identifying MASLD and its associated metabolic risk factors, as this is the treatable underlying cause requiring lifestyle intervention with weight loss, exercise, and management of cardiometabolic comorbidities. 1