Is It Time to Write a Prescription for Coffee? Coffee and Liver Disease

Gastroenterology

Volume 144, Issue 4 , Pages 670-672, April 2013

Is It Time to Write a Prescription for Coffee? Coffee and Liver Disease

Dawn M. Torres Stephen A. Harrison Division of Gastroenterology, Department of Medicine, Walter Reed National Military Medical Center, Washington, DC Division of Gastroenterology, Department of Medicine, San Antonio Military Medical Center, Fort Sam Houston, Texas published online 22 February 2013.

Obesity, diabetes, the metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD) are on the rise in the United States, with upwards of 40% of the adult population currently meeting criteria for NAFLD. Approximately 10%–20% of patients with NAFLD meet criteria for nonalcoholic steatohepatitis, with a markedly increased risk of developing cirrhosis and/or hepatocellular carcinoma (HCC).1 Therapeutic interventions to mitigate disease on a population level have been limited and lifestyle modification, although effective, is difficult to sustain over time.

Coffee is ubiquitous in our society and has recently been shown to be inversely associated with total and cause-specific mortality.2 Specific to the study of liver disease, coffee has been demonstrated to have beneficial effects on weight gain, development of diabetes, the prevention of hepatic fibrosis in NAFLD, and other chronic liver diseases, including chronic hepatitis C, as well as reduction of HCC (Table 1). One large, retrospective survey of patients who participated in a NAFLD prevalence study found caffeinated coffee intake was associated with a significant reduction in fibrosis among biopsy-proven nonalcoholic steatohepatitis patients.3 Similarly, a meta-analysis with pooled data from 457,922 participants demonstrated an inverse association between coffee and risk of incident diabetes.4 Reduced hepatic fibrosis seems to be specific to caffeinated coffee and does not seem to be shared by other caffeinated beverages.5 There are approximately 1000 substances in coffee, including caffeine, diterphenoic alcohols, potassium, niacin, magnesium, and the anti-oxidants chlorogenic acid (CGA) and tocopherols.6 Diterphenoic alcohols, CGA, and caffeine are the most studied and are the focus of this discussion.

Table 1. Summary of the Major Human Studies Evaluating Coffee Intake and Chronic Liver Disease

First author and year	No. of patients	Diagnoses	Findings
Klatsky 199221	128,934	Californians undergoing physicals	Coffee drinking >4 cups per day had 1/5 the risk of alcoholic cirrhosis as non-coffee drinkers
Ruhl 200522	5994	NHANES III	↑ALT declined with ↑ intake of coffee and caffeine; >2 cups per day vs no coffee; OR 0.56 for ↑ALT
Ruhl 200523	9849	NHANES I: Epidemiologic Follow-up Study	>2 cups coffee daily vs <1 cup/d had <½ risk (OR, 0.43) of chronic liver disease
Bravi 20078	1551	Meta-analysis of case-controlled studies of HCC in Europe/Japan	41% ↓ risk of HCC among coffee vs never coffee drinkers
Larsson 200724	2260 cases 239,146 non-cases	Meta-analysis of 9 studies of HCC	2 cups/d associated with 43% ↓ risk of liver cancer
Freedman 200925	766	HCV patients in the HALT-C trial	RR for disease progression was 1.1 for <1 cup/d; 0.73 for 1–3 cups/d; and 0.47 for >3 cups/d vs no coffee
Modi 20104	177	121 HCV patients	2.25 cups/d associated with ↓ liver fibrosis (OR, 0.33)
Leung WW 201126	234	HBV chronic carriers	Moderate coffee associated with ↓ HCC (OR, 0.54)
Johnson 201127	63,257	Adult, otherwise healthy Chinese	≥3 cups/d associated with ↓ HCC (OR, 0.56)
Costentin 201128	238	HCV treatment-naïve patients	Caffeine >408 mg/d inversely associated with histologic activity (OR, 0.32)
Yamashita 20128	2554 males, 763 females	Healthy Japanese workers	Coffee consumption associated with ↑ adiponectin and ↓ leptin
Matsuura 201229	3284	Healthy Japanese civil servants	≥4 cups/d associated with ↓ metabolic syndrome (OR, 0.79 vs 0.61)
Gutierrez-Grobe 201230	73 subjects + 57 controls	NAFLD and controls	Dose-dependent reduction in consumption of caffeine with increasing severity of steatosis
Freedman 20122	229,119 males; 173,141 females	NIH AARP Diet and Health Study	Coffee consumption inversely associated with total and cause-specific mortality
Molloy 20123	306	NAFLD patients	Caffeinated coffee associated with ↓ hepatic fibrosis in nonalcoholic steatohepatitis patients
Anty 201212	195	Severely obese patients	Regular coffee but not espresso associated with ↓ hepatic fibrosis in severely obese patients

AARP, American Association of Retired Persons; ALT, alanine aminotransferase; HALT, Hepatitis C Antiviral Long-term Treatment against Cirrhosis; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; NAFLD, nonalcoholic fatty liver disease; NHANES, National Health and Nutrition Examination Survey; OR, odds ratio; RR, relative risk.

The exact mechanisms by which coffee exerts its beneficial effects on the liver are still under investigation. The antifibrotic properties of coffee have been demonstrated in Wistar rats, where coffee was shown to protect against liver injury induced by thioacetamide, leading to reduced hepatic necroinflammation and fibrosis.7 Further study has suggested this is mediated by decreased expression of transforming growth factor-β and connective tissue growth factor.8 Another potential mechanism by which coffee exerts hepatoprotective effects was suggested by a Japanese study where coffee consumption was positively associated with adiponectin levels and inversely associated with leptin, high-sensitivity C-reactive protein, and liver enzymes.9

Coffee has also been shown to activate a family of enzymes involved in the hepatic detoxification process including uridine 5'-diphospho-glucuronosyltransferases (UGT), with initial studies demonstrating that the diterpines were responsible for the activation of UGT.10 Kalthoff et al11 further showed UGT activation by coffee to be independent of caffeine content as well as the major diterpines found in coffee, cafestol, and kahweol. In the accompanying editorial to this study, Gressner proposes both coffee and caffeine activate multiple hepatoprotective molecular signaling mechanisms and that a full understanding of the beneficial “blend” of coffee remains to be determined.12

The exact ingredients in coffee responsible for its beneficial effects on the liver are uncertain, although several substances as well as the method of preparation are thought to be of importance. Filtered coffee may provide the most benefit because it is thought to reduce cafestol and kahweol, which can raise serum cholesterol while maintaining CGA and caffeine content. Nonfiltered, boiled coffee includes Turkish coffee and coffee brewed in a French press and has been associated with an increase in low-density lipoprotein cholesterol as well as cardiovascular disease.13 Alternatively, these oily diterpenes may have anticarcinogenic properties as shown in cell culture study,14 possibly via anti-angiogenic processes,15 which may explain the reduced rates of HCC seen in a recent meta-analysis of 6 case-controlled studies.16

The polyphenols are another component of coffee that may explain some of coffee's metabolic benefits. The major polyphenol in coffee is CGA, which has shown potent anti-oxidant activity in vitro and cell culture as well as animal models and human epidemiologic studies.5 A recent study in obese rats fed a high-carbohydrate, high-fat diet demonstrated that filtered Columbian coffee extract with a high concentration of CGA can attenuate the development of glucose intolerance and NAFLD as well as hypertension and cardiovascular remodeling.17 These are compelling data, although they do not confirm that CGAs are the specific beneficial agent and validation in prospective, clinical trials is required.

Caffeine is another potential candidate that may be responsible for the beneficial effects of coffee on hepatic fibrosis. A large survey study with patients from the National Health and Nutrition Examination Surveys (2001–2008) demonstrated that caffeine intake specifically was associated with a lower risk of NAFLD in multivariate analysis (P < .001), although this observational study is limited because coffee intake and caffeine are so highly correlated in most individuals.18 The mechanism of action by which caffeine may have metabolic or hepatic benefits remains an area of investigation: Early data that showed anti-oxidant effects in vitro with high doses of caffeine19 have not been replicated in animal or human models and caffeine does not affect lipid or other metabolic panels. One study of 195 severely obese patients undergoing bariatric surgery evaluation even suggested that caffeine may not provide benefit; patients who consumed regular coffee had lower rates of hepatic fibrosis compared with those who consumed espresso beverages.20 A notable limitation of this study was that extra fructose consumption among those who drink espresso beverages could negate any potential benefit of the caffeine. In addition, espresso is made using high-pressure, boiling water through a column, is not filtered, and has a highly variable concentration of both caffeine and CGA, although generally with more caffeine than regular filtered coffee.

Based on the available data from predominantly observational trials, there seems to be a clinical benefit of coffee consumption for those patients at risk of developing hepatic fibrosis either from NAFLD or viral hepatitis. Rates of liver cancer and the development of metabolic syndrome may also be improved with daily moderate filtered coffee intake. CGA and caffeine are the best candidates for beneficial effects on hepatic fibrosis, and cafestol and kahweol may reduce rates of HCC. It is unclear whether any of these benefits are significant enough to “treat” patients with chronic liver disease and further study is required with standard doses of each of these purported therapies in appropriately powered, multicenter, randomized, controlled trials with both biochemical and hepatic histology as endpoints. In the interim, moderate daily unsweetened coffee ingestion is a reasonable adjunct to therapy for NAFLD patients that often includes lifestyle modification with diet and exercise.

Article Outline

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