Chronic Hepatitis C

Globally and especially in North America, chronic HCV is a major cause of cirrhosis, hepatocellular carcinoma, and liver-related mortality ( Table 2 ). The natural history of HCV has consistently been shown to be different in women compared with men. Spontaneous clearance of the virus occurs more frequently among women than men. In a recently published collaboration of 9 prospective cohorts of HCV-infected patients, 37% of women with acute HCV infection cleared the virus, whereas only 21% of men did so. Female sex is also a protective factor for the progression of liver fibrosis in premenopausal but not postmenopausal women with HCV, believed to reflect the protective effect of estrogens. In an analysis of 157 women with HCV (61 premenopausal and 96 postmenopausal), postmenopausal women had higher mean fibrosis scores than premenopausal women (1.87 ± 0.16 vs 1.17 ± 0.10; P <.01) and rates of fibrosis progression (119 ± 5 vs 93 ± 12 × 10 ⁻³ METAVIR units/y; P <.05). Moreover, among postmenopausal women, there was less advanced fibrosis in those who had received hormone replacement therapy compared with those who had not (1.79 ± 0.25 vs 1.93 ± 0.20; P <.05) and slower rate of fibrosis progression (99 ± 16 vs 133 ± 6 × 10 ⁻³ METAVIR units/y; P = .02). In addition to the potential fibrosis-modifying effect of sex hormones, other factors contributing to a lower rate of advanced liver disease in women compared with men include the lower frequency of cofactors associated with accelerated disease progression, like alcohol use and human immunodeficiency virus infection. In a study of 376 young Irish women who contracted HCV in 1977 and 1978 from contaminated anti-D immune globulin, only 1.9% had probable or definitive cirrhosis after a follow-up of 17 years. A similar German cohort study of 1980 women who contracted HCV in 1978 to 1979 from contaminated anti-D immune globulin showed that after 25 years, only 9 patients (0.5%) had cirrhosis and 1 hepatocellular carcinoma (HCC) was diagnosed. Comparatively, an analysis of the Electronically Retrieved Cohort of HCV Infected Veterans (92.9% men), in which HCV-positive patients were identified with an initial negative and subsequent positive test result for HCV antibody, showed that after 10 years of follow-up, 18.4% of patients had developed cirrhosis.

To date, there are no sex differences identified in studies of HCV treatment with direct-acting antiviral (DAA) therapy. However, tolerability of ribavirin, a component of some DAA regimens, may be reduced in women due to lower baseline hemoglobin levels. The teratogenicity associated with ribavirin should also be considered in every woman of child-bearing age undergoing HCV therapy.

Chronic Hepatitis B Virus

Chronic HBV is an important disease globally, and in the United States approximately 2.2 million infected persons are chronically infected, mostly among those who are foreign born. Women have a lower rate of progression to cirrhosis and HCC then men. In an analysis of 3582 patients with HBV, followed for a mean of 11 years, male sex was associated with a 2.5 increased risk of progression to cirrhosis. Likewise, the incidence of HBV-related HCC is 3 to 6 times higher in men than in women.

As discussed with HCV, those sex differences may be related to a higher prevalence of cofactors for disease progression, including alcohol use, iron overload, and HCV infection. Additionally, natural history studies suggest a higher frequency of HBV flares in men compared with women. In a longitudinal study of 217 patients with HB envelope Antigen (HBeAg)-negative HBV and alanine aminotransferase (ALT) levels ≤40 IU/mL (with range of HBV DNA levels) followed for a median of almost 6 years, 24% of the men experienced an acute increase in ALT (≥80 IU/mL) compared with only 7% of women. The sex discrepancy persisted even after adjustment for confounders, including age, HBV DNA level, fibrosis stage and presence of precore and basal core promoter variants. Similarly, another study of acute exacerbation of HBV in HBeAg-positive and HBeAg-negative patients, found that men were more likely to develop exacerbations than women. In keeping with those findings, reactivation of HBV following HBeAg seroconversion was found to happen more often in men than in women in a study of 133 patients in Taiwan. This sex difference is not completely understood but it may contribute to the higher prevalence of HBV-related cirrhosis and hepatocellular carcinoma in men.

Treatment recommendations for HBV do not differ for men versus women, other than the upper limits of a normal ALT are 19 U/L for women and 30 U/L for men. Women who have ALT levels greater than 38 U/L (2 times upper of limit of normal) and persistently elevated HBV DNA levels are potential candidates for antiviral therapy. For women with cirrhosis, antiviral therapy is recommended if HBV viremia is present, regardless of ALT level.

Alcoholic Liver Disease

In a recent systematic review on sex differences in alcohol use, women were found to consume less alcohol than men, to drink less frequently, and to be less likely to be hazardous drinkers. Similarly, recent results of the US National Epidemiologic Survey on Alcohol and Related Conditions (which used DSM-5 criteria) reported a higher lifetime prevalence of alcohol use disorders in men (36.0%) compared with women (22.7%). However, women who drink alcohol develop more liver problems than men who drink alcohol. It is recognized that for a comparable amount of alcohol intake, blood ethanol concentrations are higher in women than men. This is likely explained by 2 physiologic differences. First, women express less gastric alcohol dehydrogenase, an enzyme involved in first-pass metabolism of alcohol. Moreover, women have less fat tissue and less total water than men, hence smaller volume of distribution of alcohol. Multiple studies have found that alcohol-related hepatic damage occurs more rapidly in women than in men. The most frequently referenced study, following 13,285 adults prospectively for 12 years, determined that the level of alcohol intake above which the relative risk of liver damage was significantly greater than 1 was 7 to 13 drinks per week for women and 14 to 27 drinks per week for men. Thus, women should be counseled to keep alcohol intake to less than 1 drink per day or 7 per week. If women have another cause for chronic liver disease, such as HCV or HBV, abstinence is recommended.

The cornerstone of treatment of cirrhosis caused by alcohol is abstinence. Women tend to do better after outpatient treatment and achieve more sustained abstinence then men. In a 20-year prospective study of 393 alcoholic patients who had undergone therapy, women achieved higher abstinence rates (47.2% vs 29.0%, P = .005) and had lower mortality (22.4% vs 34.5%, P = .03) than men. There was no sex difference in outcomes among 3 studies looking into the treatment of alcohol dependence with pharmacologic agents (acamprosate and naltrexone).

Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) appears to be less common in women than in men, although population-based studies with accurate measures of NAFLD are lacking. In a study of 328 American patients, 89 (55.3%) of 161 men and 62 (37.1%) of 167 women had evidence of NAFLD on ultrasound. In another study looking into the hepatic triglyceride content of 2287 patients in Texas, using proton magnetic resonance spectroscopy, frequency of hepatic steatosis was 42% in white men and 24% in white women. Black and Hispanic women and men showed approximately the same frequency of hepatic steatosis (45% and 23%, respectively). Among women, advancing age, postmenopausal status, and more features of the metabolic syndrome have been linked with presence of NAFLD.

Whether there are sex differences in the natural history of NAFLD is uncertain. A systematic review of 10 studies evaluating risk factors associated with fibrosis progression in nonalcoholic steatohepatitis (NASH) found that age and hepatic inflammation were predictors of fibrosis, but it did not identify female sex as a significant risk factor. However, in a recent cross-sectional study of 541 patients that examined premenopausal and postmenopausal women and men, greater severity of liver fibrosis was seen in men compared with premenopausal women, but postmenopausal women had comparable degrees of liver fibrosis as men. Adjusted cumulative odds ratio for greater fibrosis severity was 1.4 ( P = .17) for postmenopausal women and 1.6 (95% confidence interval 1.0–2.5, P = .03) for men, compared with premenopausal women. Those findings support the hypothesis that sex hormones influence hepatic fibrosis in NASH, similar to seen in other chronic liver diseases. Along those same lines, hormone replacement therapy has been shown to reduce the serum aminotransferase levels in women with NAFLD. The effect of oral contraceptives on NAFLD progression is unclear. In a study of 4338 menstruating women in NHANES III, oral contraceptive users had 50% lower odds of NAFLD (defined as moderate–severe steatosis on ultrasonography) than nonusers, but this association was no longer significant after adjusting for obesity.

Prognosis

Female sex has been inconsistency associated with mortality in cirrhosis. In a systematic review of 68 studies evaluating prognostic factors associated with mortality and that included sex as an explanatory variable, only 9 studies identified sex as one of the top 5 prognostic factors. In 1 of the larger series of 1155 patients with cirrhosis (404 women and 751 men) followed for 6 years, female sex was associated with a reduced risk of mortality in patients with compensated cirrhosis ( P = .003) but did not influence mortality among decompensated patients. However, other studies have not identified sex as an important factor in predicting mortality in patients with cirrhosis. Heterogeneity in treatable causes of cirrhosis, different times to diagnosis, and/or difference in adherence to cirrhosis management may be potential factors influencing outcomes in women versus men with cirrhosis.

In patients with complications of end-stage liver disease, liver transplantation is the treatment of choice. Women have higher wait-list mortality than men, and this disparity is greater in the model of end-stage liver disease (MELD) era. This is, in part, due to creatinine (a component of MELD) underestimating severity of renal dysfunction in women and also because women are shorter than men and smaller grafts are less available. In general, posttransplant graft and patient survival do not differ by sex, with the notable exception of HCV: women have more severe recurrent disease, with a 23% higher risk of advanced fibrosis than men after a median of 3 years after liver transplantation. Women are also at higher risk of chronic kidney disease posttransplant (5 years posttransplant, odds ratio 2.5, P = .004). The explanation for these sex disparities is unknown.

Portal Hypertension Complications

Rates of portal hypertensive complications are comparable in women and men with cirrhosis. The development and progression of esophageal varices, portal hypertensive gastropathy, ascites, spontaneous bacterial peritonitis, and encephalopathy are not affected by sex. A few notable exceptions are gastric antral vascular ectasia (GAVE) and portopulmonary hypertension. Across all patients (those with and without cirrhosis), GAVE tends to be diagnosed more frequently in women than men, an association thought to reflect the higher prevalence of autoimmune diseases in women. However, among patients with cirrhosis, GAVE does not appear to a sex predilection. Portopulmonary hypertension affects 6% of patients with cirrhosis and some, but not all, studies report a higher rate of this complication among women. In a multicenter case-control study, female sex was associated with a 2.9-fold higher risk of portopulmonary hypertension ( P = .018).

Hepatocellular Cancer Risk

Globally, HCC ranks as the fifth most common cancer diagnosed in men and the ninth most common cancer diagnosed in women. Studies consistently report a lower risk of HCC in women than men. In the United States, results from the Surveillance, Epidemiology, and End Results Program indicate an incidence of liver cancer between 2008 and 2012 of 12.7/ 100,000 persons in males and 4.3/100,000 persons in females, for a risk ratio of 2.95. Worldwide, this ratio varies from 1.3 to 3.6. This difference in incidence is partially explained by the reduced female exposure to HBV and HCV, alcohol, and iron overload. However, the decreased risk of HCC in women persists even after controlling for those confounders. The biological explanation for this residual difference in risk is uncertain, but may in part be related to the protective effect of estrogens. In a multicenter case-control study including only women, the risk of HCC was inversely related to the number of full-term pregnancies at age of menopause. Oophorectomy at age younger than 50 years and absence of hormonal replacement therapy were also risks factors for HCC. Testosterone level also seems to play a role in HCC etiology, as some studies in Taiwan have reported a positive association between the level of circulating testosterone and HCC in men.

In a large Italian study of 1834 patients (482 women and 1352 men), women with HCC were found to be diagnosed at an older age (age of diagnosis >70 years; women 52%, men 32%), had higher alpha-fetoprotein levels (<20 ng/mL; women 31%, men 40%) and were more likely to have smaller unifocal and well-differentiated HCC than men. Women had a significantly longer survival than men after diagnosis (median 29 vs 24 months, P = .0001). However, this survival difference disappeared when only patients undergoing surveillance were considered, which may suggest that women were more compliant with surveillance and, consequently, tumors were detected at an earlier stage, offering more therapeutic opportunities.