Obesity and overweight in relation to liver disease mortality in men: 38 year follow-up of the original Whitehall study

Abstract

Obesity has been implicated in the aetiology of liver disease. However, to date, evidence is largely drawn from cross-sectional studies, where interpretation is hampered by reverse causality, and from studies on clinical populations that have limited generalisability. In this prospective cohort study, data on body mass index (BMI) and covariates were collected at baseline on 18 863 male government employees (aged 40–69 years). Respondents were then followed up for a maximum of 38 years of age. Mortality surveillance gave rise to 13 129 deaths, 122 of which were due to liver disease (57 cancers; 65 non-cancers). In age-adjusted analyses, BMI was positively related to total liver disease mortality (hazards ratio per 1 s.d. increase in BMI; 95% confidence interval (CI): 1.36; 1.14, 1.62) in a graded fashion across the weight categories (P-value for trend: 0.01). The magnitude of this association was somewhat stronger for non-cancer liver disease deaths (1.47; 1.16, 1.86) than for cancer liver disease deaths (1.25; 0.96, 1.62). Excluding deaths in the first 10 years of follow-up somewhat strengthened the BMI—non-cancer liver disease association. Adjustment for socioeconomic position, other candidate confounders and mediating factors led to the modest attenuation of these associations. Further investigation in prospective cohort studies with more detailed data on liver disease, for instance using biochemical tests of liver function or hepatic ultrasonography, is warranted.

Introduction

There has been a marked increase in rates of chronic liver disease mortality and morbidity in western societies since the early 1980s.1, 2, 3 In particular, fatty liver disease is becoming common, with some estimates suggesting that almost one-third of US adults are affected.4 Despite its increasing prevalence, the aetiology of liver disease is not well understood. Heavy alcohol consumption is regarded as a major risk factor, however, given that only a small fraction of people with liver disease have a history of heavy drinking,5 it clearly does not fully explain variation in the disorder. This has prompted exploration into other causes. With increases in rates of liver disease paralleling well-documented secular rises in the prevalence of obesity,6, 7 adiposity has been implicated as a risk factor.

There is some evidence from cross-sectional studies that obesity is positively related to the severity of fibrosis or cirrhosis in liver disease patients.8, 9, 10, 11, 12 In the few general population-based surveys conducted, the prevalence of liver disease, particularly hepatic steatosis (fatty liver disease), also appears to be higher in heavier people.13, 14 However, as has been highlighted,15 interpretation of these findings is complicated by the issue of reverse causality. Thus, while it may be that obesity is indeed a risk factor for liver disease, it is equally plausible that liver disease may lead to weight reduction (through, for instance, the loss of muscle mass), thereby resulting in an underestimation of the importance of obesity as a risk factor, or weight gain (through, for instance, peripheral oedema), thereby leading to an overestimation of its role. Furthermore, with few exceptions,13, 14 these studies are based on clinical samples without normal weight comparison groups. Hence, it is less clear what influence, if any, obesity may have on liver disease in population-based studies of individuals who are initially free of the condition. Prospective cohort studies are best placed to examine this question, and in the only such study of which we are aware, obesity was related to an elevated risk of cirrhosis-related death/hospitalization.15

We contribute to the scant literature on the role of obesity in aetiology of liver disease by using extended follow-up of a large cohort of UK men who participated in a baseline medical examination and were then followed up to 38 years for mortality experience.

Methods

In the Whitehall study, data were collected on 19 019 male government employees aged from 40 to 69 years, when examined between 1967 and 1970, representing a 77% response.16 This involved the completion of a study questionnaire and participation in a medical examination, both of which have been described in detail elsewhere.16 In brief, the questionnaire included enquiries regarding civil service employment grade (an indicator of socioeconomic position), smoking habits, intermittent claudication, angina, chronic bronchitis, marital status, physical activity, unexplained weight loss in the preceding year and prescribed drug use. Ischaemia, fasting plasma cholesterol and blood pressure were all determined using standard protocols.16 After an overnight fast, capillary blood was drawn 2 h after consumption of a glucose preparation equivalent to 50 g of anhydrous dextrose. Blood sugar concentration was estimated using the ferricyanide reduction micromethod on an autoanalyser (Technicon method N-9a). Height and weight were measured by a research nurse, and body mass index (BMI) computed (weight (kg)/height2 (m2)) and categorized:17 normal weight (18.5–<25.0 kg/m2), overweight (25.0–<30 kg/m2) and obesity (30.0 kg/m2). Given that underweight people may be so categorized because of comorbidity, we excluded these 232 men from all analyses.

A total of 18 863 men (99.2% of participants in baseline survey) were traced using the National Health Service Central Registry. The present analyses are based on 18 401 men with complete data on discrete variables (662 men with missing cholesterol and five with missing systolic blood pressure continuous data had values imputed). Liver disease deaths were ascertained from death certificates. These were coded as: 70, 155–156, 570–573 (all ICD 9), and B15-B19, C22-C24 and K70-K77 (all ICD10), with subdivisions for cancer and non-cancers.

In preliminary analyses, we used plots created by fitting restricted cubic splines18 to allow us to inspect and formally test the ‘shape’ of the relationship between BMI and liver disease mortality. Both the plots for liver disease versus BMI, and the tests for non-linearity (all P-values >0.25), indicated that the relationship was well described using a single linear BMI term. The proportional hazards assumption was tested by fitting interaction terms between the exposure and the logarithm of the follow-up period. With no strong evidence for violation, we summarized the relationship between obesity and liver disease deaths using Cox's proportional hazards regression model to produce hazard ratios and accompanying confidence intervals (CIs). In these analyses, starting time was age at date of entry into the cohort. Men were censored at the time of death, emigration, or 30 September 2005; whichever came first. Using current age during follow-up as the time scale enabled us to have a flexible model and high resolution for the age adjustments.

Results

Thirty-eight years follow-up gave rise to 13 129 deaths, 122 of which were ascribed to liver disease (57 cancers; 65 non-cancers). In age-adjusted analyses, there was evidence of a stepwise increase in mortality from all liver disease across the weight categories (Table 1) relative to the normal weight group, the greatest risk was apparent in obese men, with an intermediate elevation in mortality rate in the overweight group (P for trend: 0.01). Adjustment for employment grade and other possible confounding variables led to the modest attenuation of this positive relation, but the relationship remained (P for trend: 0.04). In multiply adjusted analyses, a one standard deviation increase in BMI was associated with a 30% increase in the risk of mortality from all liver disease (hazards ratio; 95% CI: 1.30; 1.09, 1.55).

Table 1 Hazard ratios (95% confidence intervals) for obesity and overweight in relation to liver disease mortality in men in the original whitehall study (18 401)

When the analyses were stratified by cause of liver disease death, the pattern of association between BMI and non-cancer liver death was similar to that evident for all liver disease mortality. Thus, in the fully adjusted model, a one standard deviation increment in BMI was associated with a 40% increase in the risk of mortality from all non-cancer liver disease (1.40; 1.11, 1.77) and, again, there was evidence of a stepwise relation (P for trend: 0.05). Death rates from liver cancer were elevated in the obese men, although the CI included unity (2.37; 0.95, 5.90), but not in those who were overweight (0.93; 0.53, 1.64). The number of cases in some of these analyses was low as reflected in the wide CIs. Anticipating that subclinical liver disease at study induction could lead to weight loss and result in an underestimation of the effect of obesity and overweight, we dropped men who had died (N=1879) or who were otherwise censored (N=124) during the first 10 years of follow-up, and repeated our analyses. As anticipated, the positive gradient was somewhat strengthened for both all liver disease and non-cancer liver disease.

Discussion

In this study, excess weight was positively related to death from liver disease with a graded association being particularly apparent for non-cancer liver disease. Our finding of a positive relation between obesity and non-cancer liver disease mortality accords with those from other population-based studies in which cirrhosis-related deaths (in prospective analyses)15 or fatty liver disease (in cross sectional analyses)13, 14 were the outcomes of interest. The elevated risk of liver cancer mortality in obese men apparent herein also supports the findings of a recent meta-analysis of 10 published studies.19

That adjustment for covariates, such as blood pressure and blood glucose, attenuated the strength of this relationship suggests that these metabolic factors may lie on the causal pathway linking obesity with fatal liver disease. Men with diabetes or impaired glucose tolerance (combined) experienced higher rates of liver cancer mortality (2.18; 1.02, 4.68) in multiply adjusted analyses (Table 1 available upon request) in comparison to other men, but there was no apparent association for non-liver cancer deaths (0.82; 0.29, 2.29). This suggests that diabetes/impaired glucose tolerance may have a mediating role in the influence of obesity on the former but not the latter mortality endpoint. However, numbers were low in these analyses owing to the very low prevalence of diabetes/impaired glucose tolerance in the 1960s in these men. With substantial fat deposits within hepatocytes apparent in 29% of obese persons versus 7% in the non-obese at autopsy,20 a further plausible mechanism linking adiposity with liver disease mortality is that obesity precipitates hepatic steatosis (fatty liver), which in turn leads to steatohepatitis.

We did not have data on alcohol consumption in the full Whitehall cohort with which to test the suggestion that the apparent relation between obesity and non-cancer liver disease is confounded by this behaviour. However, alcohol consumption was quantified in a subgroup (N=1669) of study participants and was found to be unrelated to BMI (Spearman rank correlation=0.024, P-value=0.32),21 so breaking any confounding structure and rendering this a highly unlikely explanation for any of the reported BMI–liver disease associations.

In conclusion, the positive relation between obesity and mortality due to liver disease mortality warrants further investigation in prospective cohort studies with more detailed data on adiposity and liver disease, for instance using biochemical tests of liver function or hepatic ultrasonography.

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Acknowledgements

The original screening of the Whitehall study was funded by the Department of Health and Social Security and the Tobacco Research Council. David Batty is a Wellcome Trust Fellow; Michael Marmot is a UK Medical Research Council Research Professor. Martin Shipley is supported by the British Heart Foundation and Mika Kivimaki by the Academy of Finland.Rachel Huxley and David Batty generated the idea for the present manuscript, and jointly wrote a first draft around analyses conducted by Martin Shipley. The remaining authors commented extensively on drafts of this paper.

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Correspondence to G D Batty.

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Batty, G., Shipley, M., Kivimaki, M. et al. Obesity and overweight in relation to liver disease mortality in men: 38 year follow-up of the original Whitehall study. Int J Obes 32, 1741–1744 (2008). https://doi.org/10.1038/ijo.2008.162

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Keywords

  • overweight
  • liver disease
  • liver cancer
  • cohort

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