Another Argument for Moderation in All Things

Abstract & Commentary

By Barbara A. Phillips, MD, MSPH, Professor of Medicine, University of Kentucky; Director, Sleep Disorders Center, Samaritan Hospital, Lexington. Dr. Phillips is a consultant for Cephalon, and serves on the speakers bureaus for Resmed and Respironics.

Synopsis: Being overweight or obese increases the risk of cirrhosis. In this study, excess body weight contributed to almost 20% of the cirrhosis-related hospital admissions and deaths, while alcohol contributed to almost 50%.

Source: Liu B, et al; and the Million Women Study Collaborators. Body mass index and risk of liver cirrhosis in middle aged UK women: Prospective study. BMJ 2010;340:c912.

This study is the result of a secondary data analysis from the Million Women Study (www.millionwomenstudy.org). The investigators set out to study the relationship between body mass index (BMI) and liver cirrhosis, and to determine whether alcohol or other factors affect this relationship. The Million Women Study is an ongoing prospective cohort study of 1.3 million women who were recruited through the National Health Service (NHS) in England and Scotland from 1996 to 2001. Participants completed questionnaires at entry to the study and every 3 or 4 years afterward. The questionnaires collected demographic, lifestyle, medical, and sociodemographic details. Once enrolled, study participants were followed through computerized health records by NHS number. During the period of follow-up for this study, both the cause of death and diagnoses on admission to hospital were coded by using ICD-10. Women who reported having had any type of liver disease (including viral hepatitis), cancer, or unknown BMI at recruitment were excluded from analysis.

The investigators estimated the risk of hospital admission with cirrhosis or death from cirrhosis for six categories of BMI (< 22.5 kg/m2, 22.5 to < 25 kg/m2, 25 to < 27.5 kg/m2, 27.5 to < 30 kg/m2, 30 to < 35 kg/m2, and ≥ 35 kg/m2) at recruitment and also, in those with a value > 22.5 kg/m2, for each 5 unit increase. They set the reference group as women with a BMI between 22.5 and 25 kg/m2. They used age as the underlying time variable and adjusted for alcohol intake, socioeconomic status, smoking status and amount smoked, and physical activity. They also examined the effect of adjustment for additional factors, such as use of hormonal therapies, parity, and year of birth.

They also examined the effect of BMI on the risk of subsequent hospital admission with or death from cirrhosis in relation to other factors that have been found to be associated with cirrhosis, including alcohol consumption, smoking, and diabetes. They estimated the proportion of hospital admissions with or deaths from liver cirrhosis in middle-aged women in the U.K. that could be attributed to BMI and to alcohol. They adjusted for age, region, socioeconomic status, smoking, and physical activity.

The final sample included 1,230,662 women. Nearly half (46%) of women in the study were at or below a healthy weight (BMI < 25 kg/m2), 36% were overweight (BMI 25 to < 30 kg/m2), and 18% were obese (BMI ≥ 30 kg/m2). The mean BMI was 27.6 kg/m2, and the mean age at recruitment was 56 years. Of the women included in these analyses, 77% reported drinking some alcohol. Among the drinkers, the mean reported alcohol consumption was about five and a half standard drinks a week. The proportion of women reporting drinking any alcohol and the amount they drank decreased with increasing BMI. The proportion of women who were current smokers and the proportion who reported doing strenuous physical activity more than once a week also decreased with increasing BMI. The proportion of women in the upper socioeconomic group decreased with increasing BMI. As expected, the proportion who reported being treated for diabetes increased with increasing BMI. In other words, the heavier a woman was, the less likely she was to be in the upper socioeconomic group, exercise, smoke cigarettes, or drink alcohol, but the more likely she was to have diabetes.

Over about 6 years of follow-up, 1811 women had their first cirrhosis-related hospital admission or death, and 421 of these women had cirrhosis recorded for the first time at death. The overall incidence of first hospital admission with or death from cirrhosis in this population was 1.2 per 1000 women over 5 years. Compared with the reference group (women with a BMI of 22.5 to < 25 kg/m2), both the women who had a lower BMI and those with a higher BMI had a significantly greater relative risk of cirrhosis. (The authors chose not to do further analysis of the women whose BMI was < 22.5 kg/m2 because they could not exclude the possibility that previous illness may have contributed to weight loss, and there were not very many women in this category). Among women who had a BMI of ≥ 22.5 kg/m2, the estimated increase in the risk of cirrhosis was 28% for each 5 unit increase in BMI. Routine adjustment for socioeconomic status, alcohol consumption, smoking, and physical activity, in addition to age and recruitment region, did not alter the pattern of risks substantially.

The authors were also interested in learning if other factors, particularly alcohol consumption, interacted with body weight in affecting cirrhosis risk. They compared the effect of BMI on the relative risk of cirrhosis in categories of alcohol consumption, smoking, and diabetes. They found that the trend in the relative risk with increasing BMI did not differ significantly between drinkers with increasingly larger consumptions of alcohol. However, although the relative risk per unit increase in BMI did not vary by alcohol intake, the absolute risk did. In women drinking < 70 g alcohol per week (mean intake 0.4 drinks/day), the incidence of liver cirrhosis was 0.8/1000 over 5 years for those with BMI between 22.5 and 25 kg/m2 and increased to 1.0/1000 in women with BMI of ≥ 30 kg/m2. For women drinking ≥ 150 g per week (mean intake, 2.5 drinks per day) the risks of cirrhoses were 2.7/100 and 5.0/1000 for those of healthy weight and those who were obese, respectively.

The relative risk of cirrhosis with increasing BMI did not vary between women who had diabetes and those who did not, but it was increased in women who were current smokers; smokers had relative risks of cirrhosis almost three times those of never-smokers.

Commentary

Alcohol consumption is a well-known cause of liver cirrhosis, but recent increases in the prevalence of cirrhosis are unlikely to be driven by increased alcohol consumption alone. Obesity has been implicated as a contributing cause of cirrhosis.1 These authors have strengthened the evidence that obesity and overweight cause liver cirrhosis, and have quantified the risk in middle-aged women. In a companion paper in the same issue of the British Medical Journal, Hart et al described a similar relationship in a large population of British men, and noted that "raised BMI and alcohol consumption are both related to liver disease, with evidence of a supra-additive interaction between the two."2

The likely mechanism is increased fat deposition within the hepatocytes and the development of fatty liver (hepatic steatosis) that occurs with obesity. This can lead to inflammation (non-alcoholic steatohepatitis) and subsequent liver fibrosis and cirrhosis.3 People with a high alcohol intake and diabetes also have fatty livers, and hepatic steatosis in the presence of diabetes may increase the likelihood of progression to cirrhosis.4 In addition to the association of alcohol, obesity, and diabetes with cirrhosis, the authors of this study found that the relative risks associated with increasing body mass were increased by smoking, but did not speculate on the mechanism.

Although the risk for cirrhosis posed by obesity appears to be less than half that posed by heavy alcohol consumption, it is clearly a substantial risk. And heaven forbid that you also smoke.

References

1. Williams JG, et al. Gastroenterology services in the UK: The burden of disease, and the organisation and delivery of services for gastrointestinal and liver disorders: A review of the evidence. Gut 2007;56 (suppl 1):1-113S.

2. Hart CL, et al. Effect of body mass index and alcohol consumption on liver disease: Analysis of data from two prospective cohort studies. BMJ 2010;340:c1240.

3. Farrell GC, Larter CZ. Nonalcoholic fatty liver dis- ease: From steatosis to cirrhosis. Hepatology 2006; 43:99-112S.

4. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002;346:1221-1231.