Dig Liver Dis. 2013 Jun;45(6):499-504.

Effects of coffee consumption in chronic hepatitis C: a randomized controlled trial.

Romilda Cardin1, Marika Piciocchi1, Diego Martines1, Laura Scribano1, Marino Petracco2, Fabio Farinati1.

1 Department of Surgical, Oncological and Gastroenterological Sciences, Section of Gastroenterology, Padua University, Italy

2 Illycaffè SpA, Trieste, Italy

 

ABSTRACT

Coffee is associated with a reduced risk of hepatocellular carcinoma in patients with chronic C hepatitis. This prospective trial was aimed at assessing the mechanisms underlying coffee-related protective effects. Forty patients with virus C-related hepatitis were randomized into two groups: the first consumed 4 cups of coffee/day the first month, while the second remained coffee “abstinent”. At day 30, the two groups were switched over for a second month, with opposite treatments. Before entering the study (time 0), during coffee exposure and abstinence we evaluated: liver function tests, viral load, 8-hydroxydeoxyguanosine (marker of oxidative DNA damage), telomere length, levels of apoptosis and collagen synthesis. At time 0, liver function tests were less altered and viral load significantly higher with consumption of ≥ 3 cups of coffee/day. During coffee intake, 8-hydroxydeoxyguanosine and collagen levels significantly dropped, while telomere length significantly increased. Telomere length and 8-hydroxydeoxyguanosine were inversely correlated. Viral load and apoptosis were significantly higher during coffee intake. Coffee consumption induces a reduction in oxidative DNA damage, correlated with increased telomere length, higher levels of apoptosis and lower collagen synthesis, factors that probably mediate the protection exerted by coffee with respect to progression to cirrhosis and hepatocellular carcinoma.

Copyright © 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd.

PMID: 23238034

 

SUPPLEMENT:

The use of coffee has long been accompanied by a lively debate about its possible risks, in particular on the development of several pathological conditions, and, on the other hand, about its potential beneficial effects in liver damage in particular in the prevention of cirrhosis development and/or of the progression to hepatocellular carcinoma (HCC) [1-2].

Generally speaking, all epidemiological studies confirm the observation of an inverse association between coffee drinking, in terms of consumption/duration, and enzymatic activity (increased levels of aspartate aminotransferase/ alanine aminotransferase -AST/ALT-) and liver cirrhosis, but the mechanisms of this association remain open to discussion [3-4].

Among the mechanisms potentially supporting these effects, it has been reported that the coffee constituents may also protect against reactive oxygen species (ROS) generation and oxidative damage that may lead to development of tissue damage and cancer [5].

Given the possible protective role of coffee, this randomized study was planned to overcome the almost absolute lack of in vivo studies on the effect of coffee exposure in patients with chronic HCV-related hepatitis.

During a 9-months period (September 2009 – June 2010) 40 patients with HCV-related chronic liver disease referring to Gastroenterology Unit of Padua were prospectively recruited and included in the prospective randomized study.

All study participants signed an informed consent form, in agreement with requirements of the Ethical Committee of Padua Hospital, that approved the study.

In this study have been enrolled patients:

 with chronic hepatitis or cirrhosis HCV, with bioptic diagnosis (within the previous 12 months) or clinical in cases of cirrhosis based on:

– an International Normalized Ratio (INR) higher than 1,15;

– White Blood Cell (WBC) lower than 4,40×109/L ;

– platelets (PLTs) below 150×109/L (at least 2/3);

– ultrasound (US) examination showing findings compatible with cirrhosis [coarse liver structure, irregular profiles, dilated portal tract, reduced flow velocity (at least 2/4)];

– anti-HCV and HCV-RNA positivity with AST/ALT at least 1.5x; age range 30-80 years.

 without interferon treatment or treated but non responders or relapsers.

We excluded patients with:

 suspected HCC;

 on interferon treatment;

 severe cardiomiopathy in b-blockers or cardiologic drugs treatment;

 without adequate compliance.

The present study, characterized by a cross-over design, allows the identification of the effects of coffee exposure both as a routinely habit (with the evaluation of the data at T0), and as a programmed exposure/abstinence. The patients included in the study can be compared according to their baseline coffee consumption and serve as the control of themselves when comparing their data at time 1, during coffee exposure and at time 2, during abstinence, whatever came first. The research protocol was aimed at assessing the mechanisms underlying coffee-related protective effect, both as a routine habit and as a programmed, acute, exposure, in particular considering the extent of oxidative DNA damage in relation to liver inflammation, telomere length (TL), fibrosis, apoptosis, angiogenesis and viral load.
Figure-13

Figure 1 gives a schematic overview of the cross-over design of the randomized trial.

 

The patients were investigated for all the markers at the beginning of the study (T0) and then randomized using a computer-generated list in two groups, with either 4 coffee cups/day intake for 1 month or abstinence for the same time period. Obviously, blinding was not possible no wash-out period was prescribed, since T0 sampling was examined in relation to the patients’ routine coffee consumption.

After 30 days, the patients were re-tested, and then exchanged “treatment”: those who were abstinent in the first month were transferred to the coffee arm and vice versa, then, all patients were checked again after the second month.

Each patient was therefore tested three times, at T0, when entering the study, after coffee and following abstinence, each patient being his own control in the two phases. For the sake of simplicity, all data obtained following coffee consumption were compared with the data obtained during abstinence, irrespective of the time sequence of exposure/abstinence.

To reduce the risk of bias the patients were provided with the same type of coffee, same brewing Italian-style coffee machines of the stove-top type (MokaTMBialetti) and instructed to report any deviation from the protocol, not to change their routine alimentary and voluptuary habits and finally to report any consumption of drugs and anti-oxidants. The patients were instructed not to drink any differently prepared coffee and to report any deviation.

The compliance to the study protocol was actually very high and only two patients, considered anyway for the study, slightly deviated. A longer exposure/abstinence might have induced deeper changes but with probably a lower compliance by the patients, mostly used to drinking coffee frequently. The coffee brand was a 100% Coffea arabica product from the shelf.

In our experience, an higher routine consumption of coffee corresponded with significantly lower AST and alkaline phosphatase (ALP) serum levels and with an higher HCV-RNA titer.

The effect of coffee consumption on the two parameters was then controlled during the two test period: during coffee consumption, HCV-RNA levels significantly increased and then dropped during abstinence. On the other hand, lower gamma-glutamyl transpeptidase (GGT) levels was observed during coffee consumption, while AST showed a slight increase.

No clear explanation is available for coffee selectively modifying AST levels after both acute and chronic administration. The respective roles of AST and ALT levels in patients with chronic liver damage are still debatable.

During coffee consumption a clear-cut and significant reduction of DNA oxidative damage was observed that confirmed our working hypothesis, that the protection exerted by coffee with respect to HCC development is mediated by a reduction in oxidative DNA damage, and consequently in DNA mutation.

This reduction was observed in 88% of the investigated patients, well above the target of 40% used to design the sample size. That coffee consumption is associated with lower oxidative DNA damage was recently reported also by Misik [6] in healthy volunteers. We here demonstrated in vivo, in patients with HCV infection, that coffee exposure significantly limits the extent of oxidative DNA damage in circulating leukocytes. The relevance of oxidative damage in carcinogenesis [7] and, in particular in patients with HCV infection [8, 9], is well known.

Oxidative DNA damage, probably in relation to a reduced genomic stability, leads to telomere shortening [10]. One month coffee exposure induced, in this study, a 40% increase in telomere length in 89% of the patients, a finding that strongly confirms coffee effects on oxidative DNA damage and indicates that coffee consumption leads to a stabilization of chromosomal DNA, thus protecting from neoplastic evolution.

The intriguing correlation between coffee exposure and higher HCV-RNA titers was instead confirmed both in chronic and acute coffee exposure. No data have been previously reported on this novel finding that requires some clinical considerations: the increase is almost never higher than one logarithm and is not therefore clinically significant [11] and, in contrast with what happens in HBV-related damage, in HCV infection viral load is not a prognostic factor [12]. Finally HCV-RNA titer does not correlate, in this study, with transaminase levels.

The increase in viral load corresponded to increased serum markers of apoptosis, that together with the higher AST levels, probably indicates one of the followings:

1. Coffee modulates viral load in hepatocytes, inducing an increase replication that in turn causes hepatocytes apoptosis, thus protecting from HCV-related carcinogenesis risk, further potentiating the protective effect of coffee on DNA oxidative damage;

2. Coffee induces hepatocytes apoptosis, thus increasing viral circulating load and AST levels and facilitating the discharge of damaged cells, again potentiating the protective effect on DNA oxidative damage.

Previously published data confirm a role of coffee in cell apoptosis [13,14] but additional mechanisms leading to the modulation of viral replication rate cannot be excluded.

Finally, the above effects of coffee in turn reduce the levels of pro-collagen III in 70% of the patients. PIIIP is a serum marker of fibrosis that indicates a real-time reduction in the deposition of collagen in the liver, that may, at least in part, justify the slower progression to cirrhosis associated with long term coffee consumption, an effect recently confirmed also in non-alcoholic steatohepatitis [15].

This reduced collagen deposition may be due to caffeine activity in antagonizing adenosine receptors, since adenosine and its receptors have been found to promote liver fibrosis [16], or to paraxanthine, a caffeine metabolite, suppressing the expression of the pro-fibrogenic connective tissue growth factor (CTGF) [17].

In summary, this study demonstrates that coffee consumption, in patients with chronic HCV-related hepatitis, reduces oxidative DNA damage, increases apoptosis, leads to telomere elongation and DNA stabilization and finally reduces pro-collagen III deposition. Such a set of factors may well play a major role in reducing the risk of disease progression and of evolution to HCC (Figure 2).
Figure-22 Figure 2: Potential effects of coffee consumption in HCV-related hepatitis patients.

Since a number of studies demonstrated that caffeine can modulate both innate and adaptive immunity [18], and given that, for viral clearance, both immune responses are required, the data obtained prompt additional investigations on the effect of coffee on the human immune-response in patients with HCV-related liver damage.

Secondly, the respective effects of coffee, of the diterpenes kahweol and cafestol, strong antioxidant, and of furan, a coffee volatile aroma, potentially carcinogenic compound, should be tested in established experimental models of liver damage, again in relation to oxidative damage.

 

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