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Coffee and Tea Consumption are Associated with a Lower Incidence of Chronic Liver Disease in the United States
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Coffee and Tea and Chronic Liver Disease
".....The principal finding of this large, national, population-based prospective study was that higher coffee and tea consumption reduced the risk of chronic liver disease, and this effect was limited to persons who were at increased risk of liver injury. For the U.S. population, this finding supports and significantly extends a previous finding of another study, in which coffee and caffeine intake was associated with a lower prevalence of elevated ALT activity. As in the previous study, higher consumption was associated with about half the risk of liver injury as lower consumption......"
James E. Everhart, M.D., M.P.H.
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health
Department of Health and Human Services
2 Democracy Plaza, Room 655
6707 Democracy Boulevard MSC 5450
Bethesda, MD 20892-5450
This work was supported by a contract from the National Institute of Diabetes and Digestive and Kidney Diseases (#N01-DK-1-2478). The authors thank Ms. Danita Holt for computer programming assistance.
ABSTRACT
Background & Aims. Coffee drinking has been suggested to protect against liver injury, but it is uncertain whether this is of clinical significance. We examined the relationship of coffee and tea consumption with the incidence of hospitalization or death from chronic liver disease (CLD).
Methods. Participants in the population-based first National Health and Nutrition Examination Survey, 1971-75, were asked about coffee and tea consumption, which was categorized as <1 cup (mean 0.2 cups), 1 to 2 cups, and > 2 cups per day (mean 4.0 cups). A second analysis included persons who in 1982-84 were asked more detailed questions on coffee and tea drinking. Participants were followed through 1992-93 for hospital or death certificate diagnosis of CLD or cirrhosis (ICD-9-CM 571). Hazard rate ratios for CLD according to coffee and tea intake were calculated using Cox proportional hazards analysis.
Results.
- 9,849 persons were followed for a median of 19.0 years (range 0.02-22.1) with a cumulative incidence of CLD of 1.4%.
- In multivariate analysis, participants who drank > 2 cups per day had less than half the rate of CLD as those who drank < 1 cup per day (hazard ratio = 0.43, 95% confidence interval = 0.24-0.78).
- Protection by coffee and tea was limited to persons at higher risk for liver diseases from heavier alcohol intake, overweight, diabetes, or high iron saturation.
- Among 9,650 participants who provided detailed drink information in 1982-84, intake of regular ground coffee and of caffeine was associated with lower incidence of CLD.
- in multivariate analysis, higher risk participants who consumed more than 2 cups per day of coffee and tea had only 40 percent of the risk of those drinking less than 2 cups per day.
Conclusions. Coffee and tea drinking decreases the risk of clinically significant CLD.
BACKGROUND
Consumption of coffee or caffeine or both may reduce liver injury, as suggested by
studies of liver enzymes. Greater coffee, and especially caffeine, intake was associated with a lower prevalence of abnormal alanine aminotransferase (ALT) activity in the United States population.1 Studies in Europe and Japan also found inverse relationships of coffee with seru levels of _-glutamyltransferase2-12 and aminotransferases4, 8, 13, 14
Fewer studies have investigated the relationship of coffee and caffeine consumption with chronic liver disease and hepatic cirrhosis. In a large prospective study of Kaiser Permanente Medical Care Program members in California, coffee but not tea drinking was independently associated with a lower incidence of alcoholic, but not nonalcoholic cirrhosis hospitalization or death.15 Three Italian hospital-based case-control studies found inverse relationships of coffee consumption with alcoholic16 or unspecified cirrhosis.17, 18 Most recently, a large Norwegian population-based prospective study found a lower risk of both alcoholic and all cirrhosis mortality among coffee drinkers.19 In addition, hepatocellular carcinoma, for which cirrhosis is the primary risk factor, has been associated with lower coffee intake in some studies,20-23 though not in all.24, 25
To our knowledge, no studies have prospectively investigated the relationship of coffee or tea consumption with chronic liver disease in the general U.S. population. Therefore, we examined the relationship of coffee and tea drinking with incident chronic liver disease in the first National Health and Nutrition Examination Survey Epidemiologic Followup Study, a large U.S. national, population-based study. Consistent findings based on beverage consumption at two time points about 10 years apart established more conclusive evidence of a protective effect.
METHODS
First National Health and Nutrition Examination Survey (NHANES I)
Conducted between 1971 and 1975, NHANES I included interview, examination, and laboratory data collected from a national probability sample of the civilian, noninstitutionalized population.26, 27 At the NHANES I interview, participants were asked about coffee or tea consumption, which was categorized as 0 to <1, 1 to 2, and >2 cups per day for this analysis. Participants were also asked about frequency and quantity of beer, wine, or liquor consumption and alcohol use (drinks per day) was summarized as none, <1, 1 to 2, or >2. Doctor-diagnosed diabetes mellitus was determined by interview. Body mass index (BMI) [weight in kg/(height in m)2] and subscapular and triceps skinfolds were measured at examination. Serum iron and total iron binding capacity were measured from blood samples by a modification of the automated Technicon AAII-25 Method32 and transferrin saturation (%) was calculated. Demographic
variables were age (years; 25-39, 40-59, 60+), sex, ethnicity (white, black, other), and education (less than high school graduate, high school graduate).
NHANES I Epidemiologic Followup Study (NHEFS)
The NHEFS was a longitudinal study of 14,407 NHANES I participants aged 25-74 years conducted in four waves: 1982-84, 1986, 1987, and 1992-93.28-31 Follow-up included measured weight in 1982-84 and interviews and collection of hospital and nursing home records and death certificates at each wave. Excluded from the current analysis were 546 survey participants who could not be traced; 1,138 who at baseline reported ever having yellow jaundice, had hepatomegaly or splenomegaly on abdominal examination, or had a serum albumin level <3.0 gm/dL; and 2,874 with missing data on coffee and tea consumption. Remaining for analysis were 9,849 persons with a median follow-up time of 19.0 years (range, 0.02-22.1 years). Records were obtained for overnight medical facility stays occurring since the participant's NHANES I examination. Hospital discharge and nursing home admission diagnoses were recoded by trained medical coders using the Ninth Revision of the International Classification of Diseases with Clinical Modification (ICD-9-CM).33 We defined chronic liver disease as a facility stay with an ICD-9-CM diagnosis of a 3-, 4-, or 5-digit code for which the first three digits were 571, chronic liver disease and cirrhosis. Of 94 first facility stays with a chronic liver disease diagnosis, 97 percent were hospitalizations and 3 percent were nursing home admissions. An additional 14 participants died with chronic liver disease listed as underlying cause of death without a prior facility stay diagnosis. The date of diagnosis was considered to be the admission date of the first facility stay with a chronic liver disease diagnosis or date of death.
RESULTS
The baseline characteristics of the 9,849 participants who were followed for chronic liver disease are shown in Table 1 according to coffee and tea consumption. Coffee and tea intake ranged from zero to 16 cups per day with a median of two cups per day. Mean consumption by category was 0.2 for less than 1 cup per day, 1.5 for 1 to 2 cups per day, and 4.0 for greater than 2 cups per day. Of the persons who reported less than 1 cup per day, 35 percent drank no coffee or tea at all.
Higher coffee and tea consumption was associated with middle-age, male sex, white race, greater education, lower BMI, and less central fat as determined by subscapular-to-triceps skinfold ratio.
Moderate alcohol consumption (1 to 2 drinks per day) was associated with greater coffee and tea drinking, but higher consumption was not.
The overall risk of hospitalization or death with chronic liver disease was 1.4 percent at 20 years. Unadjusted cumulative incidence of chronic liver disease over the 20 years of followup according to coffee and tea consumption was 1.8 percent for less than 1 cup per day, 1.6 percent for 1 to 2 cups per day, and 1.1 percent for greater than 2 cups per day.
A lower incidence of chronic liver disease was associated with higher consumption of coffee and tea, with a significant test for trend (p=0.002). Other factors associated with increased risk of chronic liver disease were age greater than 40 years, male sex, less than a high school education, one or more alcoholic drinks per day, elevated transferrin saturation, a subscapular-totriceps skinfold ratio in the upper two tertiles, and diabetes.
Blacks and overweight and obese persons (BMI ≥25 kg/m2) had non-significantly higher rates of chronic liver disease.
In multivariate analysis, greater coffee and tea consumption remained associated with decreased risk of chronic liver disease, such that persons who drank more than 2 cups of coffee or tea per day had less than half the risk of those consuming less than 1 cup per day.
There was a positive trend test of decreasing chronic liver disease with increasing coffee and tea intake (p=0.003). The association of coffee and tea drinking with chronic liver disease was further examined among participants at low risk for liver injury and those at higher risk based on the factors in Table 2 that were associated with a higher incidence of chronic liver disease: >2 alcoholic drinks per day, transferrin saturation >50%, diagnosed diabetes, BMI ≥30 kg/m2, subscapular-to-triceps skinfold ratio in the highest third.
Persons in the higher risk subgroup had 2.7 times the risk of chronic liver disease (95% confidence interval (CI)=1.6-4.5) compared with those in the low risk group, independent of demographics and education. The cumulative incidence of chronic liver disease differed by coffee consumption among persons at higher risk for liver injury, but not among those at low risk. These findings were substantiated in multivariate analysis, in which higher risk participants who consumed more than 2 cups per day of coffee and tea had only 40 percent of the risk of those drinking less than 2 cups per day.
A non-statistically significant trend for interaction of coffee and tea consumption with risk group for chronic liver disease was found in unadjusted (p=0.12) and multivariate-adjusted analysis (p=0.11).
To limit a theoretical effect of occult liver disease on coffee and tea consumption, we performed an analysis that excluded participants who died or had a chronic liver disease diagnosis within five years of baseline. This restriction had little effect on the results.
Relative to consumption of less than 1 cup per day, the multivariate-adjusted hazard ratio was 0.90 (95% CI=0.50-1.6) for 1 to 2 cups per day and 0.42 (95% CI=0.21-0.86) for more than 2 cups per day (p-value for trend = 0.008). Because of the small number of coffee and tea abstainers (5.0%), we used an intake of less than 1 cup per day as the reference group.
If non-coffee and tea drinkers were used instead as the comparison group, a similar but less precise inverse relationship was found. The multivariate-adjusted hazard ratio was 0.95 (95% CI=0.39-2.3) for more than 0, but less than 1 cup per day, 0.76 (95% CI=0.36-1.6) for 1 to 2 cups per day, and 0.42 (95% CI=0.18- 0.95) for more than 2 cups per day (p-value for trend = 0.005). An additional analysis was performed in the entire population utilizing sample weights and design effects. The results were similar to those of the unweighted analysis. The multivariate-adjusted hazard ratio for 1 to 2 cups of coffee or tea per day compared with less than 1 cup per day, was 0.82 (95% CI=0.42-1.6) and for more than 2 cups of coffee or tea per day was 0.43 (95% CI=0.19-0.95) (p-value for trend = 0.013).
The consistency of coffee and tea drinking over time was investigated by comparing intake at NHANES I and 10 years later at the 1982-84 follow-up examination when more detailed information on beverage consumption was obtained. In general, participants were more likely to have increased than decreased their coffee and tea consumption, but those drinking more than 2 cups at the initial examination were more likely to be the highest consumers at follow-up. Among those who drank more than 2 cups of coffee or tea a day at the NHANES I examination, 64 percent reported drinking greater than 2 cups of coffee per day in 1982-1984, with a larger proportion reporting regular coffee consumption (45%) rather than decaffeinated consumption (16%). Tea consumption of more than 2 cups per day was reported by a small proportion (11%).
Subsequent to the 1982-84 examination, greater total coffee and tea drinking was associated with a lower risk of chronic liver disease to a similar degree as was found during the entire NHANES follow-up. For total coffee consumption and total tea consumption the hazard ratios were about the same, but statistically significant only for total coffee consumption. Similar effects were seen with regular coffee and with regular tea. Chronic liver disease was unrelated to intake of decaffeinated coffee, instant coffee, or cola.
Greater intake of total caffeine from coffee, tea, cola, and chocolate was associated with a lower risk of chronic liver disease (p-value for trend=0.023). Finally, we compared the incidence of chronic liver disease among participants who reported consuming more than 2 cups per day at both time points (n=2,477) with those who reported drinking less than 1 cup per day at both time points (n=456). Relative to the low consumers at both time points, the high consumers had a hazard rate ratio of chronic liver disease of 0.20 (95% CI=0.05-0.84) in multivariate analysis.
DISCUSSION
The principal finding of this large, national, population-based prospective study was that higher coffee and tea consumption reduced the risk of chronic liver disease, and this effect was limited to persons who were at increased risk of liver injury. For the U.S. population, this finding supports and significantly extends a previous finding of another study, in which coffee and caffeine intake was associated with a lower prevalence of elevated ALT activity.1 As in the previous study, higher consumption was associated with about half the risk of liver injury as lower consumption. Two advantages of the current study were its prospective design and use of significant liver disease as the outcome. First, with a prospective evaluation, it is unlikely that the presence of chronic liver disease caused the participants to stop drinking coffee and tea because of gastrointestinal symptoms or impaired caffeine metabolism.15, 39, 40 Persons with evidence of liver disease at baseline were excluded and similar effects were seen when participants who died or had a chronic liver disease diagnosis within the first five years of follow-up were excluded. Second, the use of clinically significant outcomes of hospitalization and death meant that disease and not just a laboratory finding was being studied.
The major weaknesses of the current study arose from vagueness of information on beverage consumption and liver disease outcomes. The principal analysis was based on quite limited information on coffee and tea drinking in the NHANES I survey. We partly compensated for this problem by using the more in depth information on beverage intake that was gathered in the detailed dietary questionnaire used in the first wave of follow-up. That survey showed that most persons who drank two or more cups of tea or coffee per day continued to do so and that coffee, particularly regular coffee, was the beverage of choice. Furthermore, the consumption of ground regular coffee at the 1982-84 follow-up was associated with a lower risk of chronic liver disease, although the smaller number of cases did not permit a very precise estimate of the reduction in risk. Regular tea decreased the risk by a similar magnitude as regular coffee, though the relationship was not statistically significant, and there was no effect with decaffeinated coffee or cola. The protective relationship with caffeine intake was similar to that with total coffee and tea, suggesting that caffeine may be at least partially responsible for the effects of coffee on the liver.
We were unable to ascribe the etiology of the chronic liver disease due to lack of
precision in ICD-9-CM coding of liver disease and its application in the clinical setting. What today are known as the two most common causes of chronic liver disease, non-alcoholic fatty liver disease and hepatitis C infection, were not recognized through most of the years of the study. This is a problem inherent to population-based studies that span decades. Nevertheless, it would be clinically relevant to know if the protective effects found in the current study apply to all chronic liver diseases or just to one or two major causes. Furthermore, relying on facility stay and death certificate diagnoses may have underestimated the incidence of chronic liver disease.
An additional limitation is the lack of baseline data on hepatitis B and C status. Consequently, we were unable to adjust for any effect of viral hepatitis on the relationship of coffee drinking and chronic liver disease. However, there is no reason to expect that viral hepatitis status would be related to coffee intake among persons free of liver disease at baseline. In fact, among participants in the third National Health and Nutrition Examination Survey, in which data on both coffee drinking and viral serologies were obtained, there was no difference in coffee consumption based on viral hepatitis status (data not shown).
This is one of several prospective studies that have indicated a protective effect of coffee consumption on chronic liver disease and liver cancer. In a large study of Kaiser Permanente Medical Care Program members in California, the risk of alcoholic liver cirrhosis was decreased to one fifth among persons who drank four or more cups compared with non-drinkers.15 Similarly, among a Norwegian population, cirrhosis mortality was only 60 percent as common with an increase of two cups of coffee.19 Recently, in two Japanese populations, hepatocellular carcinoma risk was reduced among coffee drinkers.21, 22 Despite this consistent protective effect of coffee on the liver, a mechanism is not yet known, nor have there been clinical trials. Furthermore, it is uncertain what component or combination of components might be protective. Various coffee constituents, including caffeine, cafestol and kahweol (nontriglyceride lipid components of coffee oils), and antioxidants from coffee beans extracts, have been found to have a favorable effect on the liver in experimental studies,41-44 but the evidence is not conclusive for any of these components. Because caffeine is the best known constituent and is present in high and measurable concentration in coffee, it is the most reasonable compound to investigate.
Recent epidemiological evidence suggests that coffee drinking lowers the risk of type 2 diabetes.45 A potential mechanism could be an effect of caffeine or some other coffee component on insulin resistance. A protective effect of coffee and tea drinking on the liver could, likewise, be partially mediated through an influence on insulin sensitivity. It is possible, but unlikely that coffee and caffeine could be surrogates for another factor or factors that protect against liver disease. Over the time period of this study, coffee was not generally considered to be part of a healthy diet or life-style. In fact, one well-publicized report suggested (perhaps erroneously) that coffee was a risk factor for pancreatic cancer.46 Furthermore, the large and relatively consistent body of evidence in favor of coffee has been collected over more than 30 years and has spanned diverse cultures.1-23 It seems unlikely that unknown behavioral factors would have carried a consistent association with coffee over such extensive time and distance. Nevertheless, confirmation that coffee or caffeine is effective in preventing chronic liver disease will require much further clinical investigation.
The consistent finding of a protective effect of coffee in areas of the world with markedly different causes of liver disease suggests that protection may be through a modulating effect on factors that promote or worsen liver disease. Support for this concept in the current study comes from the finding that the effect of coffee and tea was observed only among those participants who were at high risk of liver disease. Identifying the pathways through which coffee and caffeine act might lead to a better understanding of chronic liver disease and to more specific pharmacological interventions.
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