Liver Disease in Women: Influence of Gender on Epidemiology, Natural History, and Patient Outcomes

Liver Disease in Women: Influence of Gender on Epidemiology, Natural History, and Patient Outcomes

Jennifer Guy, MD, and Marion Peters, MD

Dr Guy is the medical director of the Liver Cancer Program and gastroenterologist in the Division of Hepatology at the California Pacific Medical Center in San Francisco. Dr Peters is Chief of Hepatology Research and Professor of Medicine at the University of California, San Francisco.

Address correspondence to: Dr Jennifer Guy, California Pacific Medical Center, 2340 Clay Street Third Floor, San Francisco, CA 94115; Tel: 415-600-1020; Fax: 415-600-1200; Email: guyj@sutterhealth.org

Abstract: Women more commonly present with acute liver failure, autoimmune hepatitis, benign liver lesions, primary biliary cirrhosis, and toxin-mediated hepatotoxicity. Women less commonly have malignant liver tumors, primary sclerosing cholangitis and viral hepatitis. There is a decreased rate of decompensated cirrhosis in women with hepatitis C virus, no survival difference in alcohol-related liver disease, and improved survival from hepatocellular carcinoma. In general, men are 2-fold more likely to die from chronic liver disease and cirrhosis than are women. Liver transplant occurs less commonly in women compared with men, with variable disease outcomes based on etiology. In this review we highlight the epidemiology, natural history, treatment outcomes, and pathophysiology of common liver diseases in women. We discuss how gender influences disease incidence, presentation, progression, and outcomes and explore the pathophysiology. Pregnancy related-liver disease is not covered in this review.

The pathophysiology of gender differences in the incidence, natural history, and outcomes of common liver diseases is incompletely understood. Various potential mechanisms include the effect of sex hormones on oxidative and metabolic pathways; differential gene transcription in response to injury in women compared with men; and sex differences in immune regulation. In addition, differences in access to care and treatment and diagnostic considerations may affect gender differences in liver disease.

Alcohol and Toxic Liver Injury

Women are more commonly affected by toxin-mediated liver disease, such as alcohol and drug-induced liver disease, and have an increased prevalence of acute liver failure.^1-3 Women are more susceptible than men to the toxic effects of alcohol on the liver for any given dose of alcohol, despite that men abuse or depend on alcohol more than do women, with a ratio of 2:1 in persons over the age of 26 years. A 12-year prospective study of alcohol use in over 13,000 participants in Denmark showed that the risk of development of alcohol-related liver disease increased in women with consumption of 7 to 13 beverages per week (84–156 g) compared with 14 to 27 beverages per week (168–324 g) for men (Table 1).¹ In persons consuming 28 to 41 beverages per week (336–492 g), the relative risk of alcohol-induced cirrhosis was 7.0 (95% CI, 3.8–12.8) in men vs 17.0 (95% CI, 6.8–40.8) in women. However, alcoholic cirrhosis is less frequently diagnosed in women, as shown by an in a population-based registry of 8482 Danish patients from 1993 to 2005 in which only 33% of patients were women.⁴

Compared with their male counterparts, women with alcoholic liver disease have a more rapid progression to fibrosis that persists even after abstinence from alcohol.^5,6 Dietary factors are known to influence development of alcoholic liver disease. An analysis of 107,000 women from the United Kingdom suggests that the combination of high body mass index (BMI) and high alcohol intake increases the development of chronic liver disease.⁷ Whether there is a survival difference between sexes regarding alcoholic liver disease is less clear. In a prospective study of 490,000 men and women in the United States followed for 9 years, the relative risk of death from cirrhosis or alcoholism was equal in both sexes for those drinking 2 to 3 drinks per day but was increased in men who drank 4 or more drinks per day.⁸

Several factors likely contribute to the severity of alcoholic liver disease in women. Experiments in rats suggest that higher endotoxin levels in females and increased gut permeability to endotoxin likely contribute to more severe liver injury in females.^9,10 Estrogen receptor concentrations within the liver differ between sexes, and estrogen appears to activate liver Kupffer cells.¹¹ This results in increased inflammation and necrosis, which can be counteracted by treating female rats with an anti-estrogen.¹² Alcohol also may induce differential expression of genes in rats leading to increased oxidative stress, inflammation, and injury in female rats.¹³

Women are more likely to present with drug-induced hepatotoxicity and acute liver failure than are men. Prospective data from the Acute Liver Failure Study Group, which included 23 sites from 1998 to 2007, showed that 67% of the 1147 patients were women.² Among 133 cases of drug-induced liver injury assessed, 71% were in women, and women accounted for over 70% of all patients hospitalized with acute liver injury due to acetaminophen and idiosyncratic drug reactions. Further, gender is not a predictor of survival in acute liver failure.³

The female preponderance of drug-induced liver injury may, in part, be related to sex differences in drug bioavailability, metabolism, and excretion, which have been well described in rat and mouse models as well as in humans.¹⁴ There are multiple variations in expression of cytochrome p450 enzymes between persons, which results in varying susceptibility to drugs. Women, for example, are more likely to express CYP3A4, an important mediator of liver oxidative metabolism and a key enzyme in most drug metabolism.¹⁵

Autoimmune Liver Diseases

Women are 10 times more likely to have primary biliary cirrhosis (PBC) compared with men and 4 times as likely to have autoimmune hepatitis.^16,17 The exact mechanism for gender differences in autoimmune liver disease, and in autoimmunity in general, is not known; however, both immunogenetics and sex hormones play a complex and perhaps interactive role. Sex steroids alter the immune system on many levels: they can regulate gene expression through steroid-responsive elements, alter antigen presentation through affects on human leukocyte antigens (HLA) genes, and alter the cytokine environment.^18,19 Additionally, X chromosome monosomy and fetal microchimerism (the presence of fetal cells in maternal circulation) may play a role in pathogenesis of PBC.^20,21 In the case of PBC, epidemiologic studies also have shown different environmental risk factors between sexes, including hair dye use, recurrent urinary tract infections, smoking, and estrogen deficiency, all which may contribute to increased disease in women.^22-24 In patients with PBC, overall survival is similar between the sexes.²⁵ Women with PBC present at a younger age with increased rates of pruritus and appear to have slower rates of fibrosis than men.^6,26 In patients with autoimmune hepatitis, the rates of progression to cirrhosis, treatment failure, and death from liver failure were equivalent in men and women.

Women are less likely to have primary sclerosing cholangitis (PSC). In a study of residents from Olmsted County, Minnesota, the incidence of PSC was 1.25/100,000 person-years (95% CI, 0.70–2.06) in men and 0.54 per 100,000 person-years (95% CI, 0.22–1.12) in women.²⁸ Over 60% of patients with PSC are male. ²⁹ Gender is not an independent risk factor for mortality in PSC although 1 study found cholangiocarcinoma was more common in men.^30-32

Liver Tumors

There are gender differences in the incidence of both benign and malignant liver tumors (Table 2). Whereas the majority of benign liver tumors are more common in women, malignant tumors are more common in men.

Benign liver lesions that predominantly occur in women include cavernous hemangioma, focal nodular hyperplasia (FNH), hepatic adenomas, biliary cystadenomas and solitary hepatic cysts. Hemangioma has the highest prevalence at 1.4%; FNH at 0.4% to 3%; and adenoma at 3 per 100,000.³³   The prevalence of simple hepatic cysts is 0.1% to 2.5%, but imaging recognition increases with age.³⁴ Biliary cystadenoma and adenocarcinomas are rare (1% of cystic liver lesions) and women account for 96% of cystadenomas and 66% of cystadenocarcinomas.³⁵ Simple hepatic adenomas are monoclonal tumors that are defined as HNF1 alpha inactivated adenomas (30%–40%), inflammatory adenomas (35%), and less frequently beta-catenin–activated adenomas (15%–19% of large series).³⁶ The first 2 types of adenomas are more common in women, and men are more predisposed to the beta-catenin–activated adenomas. Beta-catenin–activated adenomas have a higher risk of malignant transformation.³⁷ The data are less convincing regarding whether a gender discrepancy exists in nodular regenerative hyperplasia (NRH).³⁸

Estrogen levels are thought to be associated with benign liver tumors although the potential mechanisms are unclear. The data are inconsistent in determining whether there are increased hormone receptors on benign tumors and whether exogenous estrogens, like oral contraceptive (OCP) pills, stimulate benign tumor growth. The evidence regarding OCP influence on benign liver lesions is most compelling for adenomas, with 80% of woman reporting OCP use.³⁷ Therefore, discontinuation of OCPs is recommended for such patients. For other liver lesions, there is less convincing evidence for the role of OCPs on tumor progression. A small case control study suggested that patients taking OCPs were at increased risk of FNH.³⁹ However, a study of 136 women followed for 9 years did not show an association in size or number of FNH lesions in OCP users.⁴⁰ The overall survey of literature suggests no increased risk of FNH or change in character of FNH on OCPs, and discontinuation is not recommended in these patients. Likewise, there is debate over whether estrogen use increases rates of cavernous hemangiomas. In a study of 94 women followed from 1986 to 2003 (mean follow up of 7 years), there was a trend toward increased incidence of cavernous hemangiomas and hormone therapy but this trend was not statistically significant.⁴¹

In benign liver lesions, an emerging understanding of the molecular pathogenesis of FNH and adenomas suggests that men are predisposed to the subset of adenomas characterized by beta catenin activation, whereas women appear to have a inactivating mutation of a gene involved in estrogen metabolism (CYP1B1), which results in increased risk of the hepatocyte nuclear factor 1-alpha (HNF1A) subtype of adenomas.⁴² Inflammatory adenomas have activation of JAK-STAT signaling, resulting in inflammation. HNF1 is a human tumor suppressor gene, and 1 study found inactivating mutations of HNF1 in 35% to 50% of hepatic adenomas.³⁶ Inactivating mutations of the HNF1 gene were noted in a small minority of cases of well-differentiated hepatocellular carcinomas (HCCs), particularly in cases of HCC that developed in the absence of cirrhosis.

HCC is the most common primary malignant tumor of the liver and affects men 3 to 4 times more frequently than women.⁴³ HCC is the fifth most common malignancy in men and the ninth most common in women.⁴⁴ Data from the Surveillance, Epidemiology, and End Results (SEER) cancer statistics database showed that the annual incidence rate for men was 6.7 per 100,000/yrs compared with 2.0 per 100,000/yrs for women. Interestingly, women typically present with peak incidence 2 decades later: 4.4 per 100,000/yrs at age 65 to 69 years for women, compared with 4.2/1000y at age 45 to 49 years for men. The ratio of male to female cancer cases was similar across all racial and ethnic groups.⁴⁵ The gender difference in HCC incidence persists after adjusting for increased rates of confounding diagnoses, such as viral and alcoholic hepatitis, which are more common in men. A retrospective analysis of a United States cancer database involving over 7000 patients from 1977 to 1996 showed that women and men had the same 1-year survival rate from HCC of 23% (95% CI, 21%–24%) during 1992 to 1996.⁴⁶ An analysis of SEER from 1998 to 2001 showed that 3-year survival was similar in men and women for surgical resection, transplant, and radiofrequency ablation.⁴⁷ Management of liver cancer between sexes does not differ significantly; however, there are differences in surveillance recommendations, such that the American Association for the Study of Liver Diseases guidelines recommend HCC surveillance starting at age 50 years in Asian women compared with age 40 years in Asian men.⁴⁸

The pathophysiology underlying the sex differences in HCC and benign liver lesions continues to be elucidated. There is evidence that HCC is an androgen-sensitive tumor and that sex hormones promote tumor proliferation.^49,50 For example, one study showed that estrogen decreased the secretion of IL-6 from liver Kupffer cells in mice, resulting in less cancer.⁵¹

Nonalcoholic Fatty Liver Disease

There are conflicting data on gender in nonalcoholic fatty liver disease (NAFLD), which represents a spectrum of histologic manifestations, including steatosis, steatohepatitis, and cirrhosis. Some studies found that women were also less commonly affected by NALFD.^52,53 NAFLD is most frequently recognized in men and postmenopausal women who have not received hormone replacement therapy (HRT).⁵⁴ This suggests a role of sex hormones, particularly estrogen, in the pathogenesis of NAFLD.⁵⁵ In a population-based cross-sectional study, Liu and colleagues studied 4338 women aged 20 to 60 years who were enrolled in the Third National Health and Nutrition Examination Survey (NHANES) from 1988 to 1994.⁵⁶ They found that current OCP users showed a 50% lower odds of NAFLD than never users (adjusted odds ratio 0.50; 95 % CI 0.26–0.98) after adjusting for age, race/ethnicity, smoking status, history of diabetes or hypertension, and education. When they adjusted for BMI or waist circumference, the relationship was attenuated. However, of 1266 patients in the US NASH network, 64% were female, and those with NASH were more likely to be female and to have diabetes and metabolic syndrome. These data might be explained by true increased prevalence, older age of participants, or differential interest between men and women in pursuing healthcare and participating in studies.⁵⁷

Viral Hepatitis

Women clear acute hepatitis C virus (HCV) infection at a higher rate than do men.⁵⁸ Of Irish women who were recipients of HCV-contaminated anti-D immune globulin in 1977 to 1978, only 55% were found to be viremic 17 years later.⁵⁸ In addition, progression to severe liver disease was less common than that reported in men.^58,59 In this same cohort, although inflammation was common 20 years after infection, it was minimal (41%) or moderate (52%) in nearly all. Although the biopsy samples from 186 of the 363 women (51%) showed evidence of fibrosis, only 7 (2%) women had probable or definite cirrhosis, and 2 of these 7 reported excessive alcohol consumption. After 3 decades, only 27% showed progression of liver fibrosis and cirrhosis developed in only 4 (2.1%) women.⁶⁰

There is very little information available on the progression of liver disease in women after menopause; a single cross-sectional study of 251 women demonstrated increased progression after menopause in HCV mono-infected women.⁶¹ There are no large studies of the progression of HCV infection through the menopausal transition.

In contrast to the hypothesis that estrogen potentiates fibrosis in alcoholic liver disease, estrogen may have a protective role against fibrosis in viral hepatitis by inhibiting stellate cells, which are responsible for fibrogenesis in the liver.⁶² Animal studies in rats suggest that estradiol decreases fibrosis progression.⁶³ In addition to menopause, comorbid factors have been shown to increase fibrosis progression such as a higher BMI, metabolic syndrome, and steatosis.⁶⁰ In a study of 251 women in which 121 were postmenopausal and 65 were receiving hormone replacement therapy, menopausal women receiving HRT had a lower-stage fibrosis.⁶¹ HCV-infected women have a better response to interferon and ribavirin-based therapies in some studies but not others.^64,65 Early menopause has been reported to decrease response to therapy.⁶⁶ These sex differences are unlikely to be seen with all oral direct-acting antiviral agents.

HBV affects men and women similarly. However male sex is a risk factor for reactivation of HBV infection after seroconversion from hepatitis B e antigen (HBe) positive to negative, cirrhosis, and HCC.⁶⁷

Metabolic Liver Disease

There are limited data on gender differences in Wilson disease. In a cohort study of 627 consecutive patients with Wilson disease in Poland, women were less likely to be affected by the disease overall compared with men (47% vs 53%).⁶⁸ However, compared with men, women were more likely to present with the hepatic form (58% vs 42%) compared with the neuropsychiatric form. There does not appear to be a gender difference in the incidence of genetic hemochromatosis⁶⁹; however, men have higher ferritin and transferrin saturation levels as compared to women, including in those with genetic hemochromatosis and in those without.⁷⁰ The disease phenotype of C282Y hereditary hemochromatosis differs between sexes, with 28% of men showing symptomatic iron overload as compared to 1% of women.⁷¹ In murine models, sex differences exist in the levels of hepcidin expression, an important mediator of iron balance.⁷² Whether this translates to human iron overload requires further exploration.

Cirrhosis and Liver Transplantation

In general, men are 2-fold more likely to die from chronic liver disease and cirrhosis than are women, according to an analysis by the National Center for Health Statistics that was reported in 2005.⁷³ Women represent approximately 30% of liver transplant recipients.⁷⁴ Women appear more likely than men to die on the waiting list in the model for end-stage liver disease (MELD) era versus the pre-MELD era.⁷⁵   In fact, the disparity in transplant rates for women has increased in the MELD era as waiting-list mortality risk has risen, in particular for MELD scores of 15 or greater.⁷⁶ In 1 study, female sex predicted waiting-list mortality in addition to fulminant hepatic failure, primary nonfunction, blood group O patients, Child-Turcotte-Pugh score of 11 or greater, and a MELD score of 20 or greater.⁷⁷ Whether the increased mortality for women is associated with lower creatinine and thus lower MELD scores is unclear. Another study of United Network for Organ Sharing (UNOS) data in the MELD era showed that women have a 19% higher wait-list mortality compared with men. This is, in part, explained by size differences between men and women, as correcting for height in a multivariate analysis explained the mortality difference.⁷⁸ After transplant, Organ Procurement and Transplantation Network/UNOS data confirm that women have better long-term survival after liver transplant than do men.   However older age (>65 years) is associated with worse outcomes and older donors (>60 years) are more likely to be female.⁷⁹

The natural history of liver disease in women varies depending on etiology. Although women have slower progression of fibrosis and decreased incidence of cirrhosis pretransplantation,^59,80 after liver transplantation, women have a higher risk of advanced fibrosis and graft loss in HCV-related disease.^81,82 In the most recent investigation of the role of sex and transplant outcomes in HCV-related disease, women had a 31% increased risk of advanced recurrent disease compared with men in multivariate models.⁸² In patients transplanted for HCV-related disease, women have a 14% increased risk of death at 5 years compared with men.⁸³

Conclusion

Gender differences in incidence, presentation, natural history and outcomes exist for common liver diseases (Table 3). These variations are important for clinicians to recognize, as they influence the likelihood of a given diagnosis for a patient and the potential for progression of the liver disease. This review serves to highlight where gender differences in incidence and natural history are most striking. Therapeutic decisions based on gender are not typically different, but the incidence and natural history of many liver diseases are shaped by gender. Further studies are required to assess the role of sex hormones as well as varying health behaviors and treatment preferences based on gender.

The authors have no conflicts of interest to disclose.

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