Our current study in male veterans who use the VA healthcare system is the first study to evaluate the association of both multiple potential dietary risk factors and physical activity with advanced liver disease in a HCV-infected population in the U.S. We examined and reported risk estimates for a broad number of macronutrients, micronutrients and food-groups, including our novel evaluation of dietary factors of particular interest like the essential mineral copper.
The dietary risk factors we identified as potentially associated with advanced HCV-related liver disease risk varied according to sub-type of hepatic pathology evaluated. For example, although our multivariate analyses suggest lower daily dietary intake of fiber may be associated with strong decreased risk of advanced liver fibrosis, it was not similarly associated with decreased risk of steatosis.
The largest association we observed was the suggestive 7–14 fold reduced risk of advanced fibrosis with lower daily dietary copper intake; both effect sizes were highly significant and followed a dose-response relationship. Some evidence supportive of the biological plausibility of this finding is the well-known increased risk of advanced liver disease in persons with excessive hepatic copper accumulation (e.g., Wilson’s disease, Indian Childhood Cirrhosis).
A single large hospital-based case-control study performed in Italy similarly examined the association between dietary intake and risk of advanced HCV-related liver disease. Some important consistencies in findings include concordance in direction of effect (i.e., risk promoting, no effect, or risk reducing) for 8 of 12 possible individual dietary intake comparisons between studies. Additionally, each study identified several unique dietary factors significantly associated with advanced HCV-related liver disease risk. However, caution most be used when comparing these studies particularly given some key differences in design, including in the underlying target population and the methodology employed to assess dietary intake (i.e., food frequency questionnaire vs. 7-day dietary diary).
Our findings suggesting lower coffee intake may increase risk of advanced fibrosis, steatosis and inflammation are in agreement with other recent research that demonstrated increased coffee and caffeine intake were associated with significantly decreased HCV-related liver disease progression.[29
] If replicated in a larger and therefore more adequately powered study, our results suggest that potentially important hepatoprotective benefits may be obtained with even a comparatively modest, and therefore potentially more widely acceptable, increased intake of coffee.
Our physical activity assessments suggest an increased risk of advanced steatosis with lower weekly MET-minutes per week of customary physical activity, with effects statistically significant for walking and approaching significance for moderate physical activity. The few studies that have evaluated modest exercise interventions in HCV-infected populations indicate that they are well-tolerated and convey benefits in terms of improved liver function and health-related quality of life.[31
] Taken together, our results in conjunction with those from these exercise intervention studies suggest physicians who treat HCV-infected patients may wish to incorporate a specific recommendation on the importance of increased walking.
Our study has multiple strengths. Our utilization of a well-validated food-frequency questionnaire, as opposed to a 3- or 7-day food diary, allowed us to obtain a more stable estimate of daily nutritional intake over a much longer time period while also accounting for any potential effect of seasonal or irregularly eaten foods on disease risk. Isocaloric or energy-adjusted analyses allowed a more valid evaluation of the role individual nutrients may play in disease risk, as did our measurement and adjustment for multiple important confounders for advanced liver disease risk including smoking, alcohol use and BMI. Additionally, our study provides important novel information on estimated effect sizes and variances for multiple potential dietary risk factors within a defined HCV-infected population the U.S., including several that have not been reported on within any other defined HCV-infected population as well. This information is necessary to design adequately powered future nutritional epidemiology studies.
Our study also has several limitations that are important to acknowledge. First, we are unable to make conclusive temporal assessments necessary to infer causality. Although we instructed participants to provide information on their customary diet for the last year if it was indicative of their long-term dietary habits, or else for the year prior to disease diagnosis and any related symptom-onset, we cannot be sure that our single time-point assessment completely accurately reflected actual dietary intake for the salient time period. Also, other than BMI and dietary history, we did not have other measures of nutritional status including a parallel assessment of caloriemetry to determine basal metabolic rate or of nutritional biomarkers. Nutritional biomarkers can be particularly useful for purposes of validating self-reported dietary intake and for augmenting information on dietary intake with potentially metabolically effective intake.[33
] However, they also have important limitations including the limited number of valid and reliable dietary biomarkers, substantial associated costs and interpretative complexity. Additionally, our study included only male veterans who use the VA. Although they represent an important and very large sub-group of HCV cases in the U.S., it is unclear if our findings in this veteran population will generalize to HCV-infected female veterans and mixed gender civilian populations in the U.S. A final limitation was our modest total sample size. We consequently had low study power that limited our ability to: reliably estimate precise confidence intervals, perform traditional statistical criteria-based adjustment for multiple comparisons, or evaluate for potential interaction among multiple dietary factors. Therefore, even our strongest findings of from 7- to 14- fold significantly decreased risk of advanced fibrosis with reduced daily dietary copper intake must be qualified as provisional pending verification in larger prospective studies.
Our study in an HCV-infected male veteran population suggests several components of diet and physical activity may be associated with risk of advanced liver. Additional research examining the role potentially modifiable factors like diet and physical activity may play in risk for advanced liver disease is particularly important in this population as so many HCV-infected individuals are either not treatment candidates, or cannot tolerate or respond to treatment.