Caffeinated drinks associated with decreased risk of liver scarring

Provided by Baylor School of Medicine

Julia Parsons
713-798-4710 Houston, TX - Apr 14, 2015

Modest daily consumption of caffeinated drinks is associated with less advanced liver scarring in people with hepatitis C, according to a recent study by Baylor College of Medicine researchers that appears online in the journal Clinical Gastroenterology and HepatologyClinical Gastroenterology and Hepatology.

Dr. Hashem El-Serag, chief of gastroenterology and hepatology at Baylor and at the Michael E. DeBakey Veterans Affairs Medical Center and lead author of the study, said the results showed that the risk of liver scarring in hepatitis C patients was decreased when individuals regularly consumed caffeinated coffee, and to a lesser extent tea and soda.

“We found that participants who drank caffeinated coffee daily had the best results,” he said. “This is most likely do to the fact that one coffee drink has more caffeine than tea or sodas.”

He said the researchers saw no benefit to patients who drank decaffeinated coffee, tea and soda.

This cross-sectional study consisted of 910 participants aged 18 to 70 years of age with confirmed hepatitis C who were not receiving antiviral therapy.

“We specifically chose to study hepatitis C patients because they are at an increased risk for hepatic fibrosis (liver scarring), and there is limited data on the effects of coffee or caffeine on the progression of scarring within this patient population,” said El-Serag, also a member of the Dan L. Duncan Cancer Center at Baylor.

Liver scarring can lead to cirrhosis of the liver, liver failure and liver cancer, and may require liver transplantation.

Of the participant study population, 37.6 percent of them had advanced liver scarring while 62.4 percent had milder scarring. Participants with advanced fibrosis were significantly older, more likely to have type 2 diabetes and were more likely to be overweight or obese.

“Most participants reported drinking caffeinated coffee, and about half of those drank one or more cups of coffee per day,” El-Serag said. “Patients with milder liver scarring had a higher average daily intake of caffeinated coffee compared to those with more advanced cases.”

“An estimated 100 milligrams of caffeine from coffee, tea or soda was associated with approximately one-third reduction of advanced scarring, and higher consumption didn’t produce an additional benefit,” he said.

Others who took part in this study include Natalia Khalaf, Donna White, Fasiha Kanwal, David Ramsey, Sahil Mittal, Shahriar Tavakoli-Tabasi and Jill Kuzniarek, all of Baylor.

This research was funded in part by a VA Clinical Research and Development Merit Award (H-22934, PI: El-Serag) and the National Institute of Diabetes Digestive and Kidney Diseases (R03 DK095082, PI:  White).  The efforts of White and El-Serag effort were supported in part by the National Institute of Diabetes Digestive and Kidney Diseases (K24 DK04-107 and K01 DK081736, respectively) and the Houston VA Health Services Research and Development Center of Excellence (HFP90-020).

Source

A Home Run for Hepatitis C Treatment

Medscape Gastroenterology

Digestive Disease Week (DDW) 2014

William F. Balistreri, MD

June 05, 2014

HCV Antivirals: You Can't Tell the Players Without a Program

The rosters change almost daily, and new leaders emerge as the statistics accumulate rapidly. No, I am not referring to Major League Baseball; I am talking about antiviral agents used to treat hepatitis C virus (HCV) infection.

The past year has already seen the approval of new direct-acting agents and a change in recommendations.^[1] And now, data from recent clinical trials have generated further excitement and promise -- that in the year of the 25th anniversary of its discovery, HCV can be cured.

At Digestive Disease Week (DDW) 2014, investigators updated attendees on the pace of progress in the discovery and validation of novel antivirals. The bottom line is that clinicians will soon have the option of using all-oral, interferon-free regimens that are highly effective against all HCV genotypes in all patients -- with "special population" designations no longer needed. There are clearly logistical details that will prove to be unique to each treatment regimen, and perhaps genotype-specific; however, these will be resolved with broader experience.

A Future Without Hepatitis C

But first, let's look at the not-so-distant past. An analysis presented at DDW indicates that overall treatment rates for patients with chronic HCV have been "dismally poor" and that treatment completion of both dual- and triple-therapy regimens -- pegylated interferon (pegIFN) and ribavirin (RBV) with or without a protease inhibitor, telaprevir or boceprevir -- is suboptimal in the real-world clinical setting.^[2]

This comes at a high cost. Hasan and colleagues^[3] reported that the cost of curing HCV genotype 1 with the triple-drug regimen was $125,000-$154,000. This estimate includes the associated costs of utilization of provider services, prescriptions, over-the-counter drug use, laboratory tests, and hospitalizations. These data indicate the need for simpler, safer, less expensive, and more effective options.

In the past month, a series of articles was published in the New England Journal of Medicine describing several new and different regimens. These strategies, based on an improved understanding of the HCV life cycle, have consistently produced rates of sustained viral response (SVR) of more than 90% after brief (8-24 weeks) periods of administration.

Accompanying editorials attest to the impact of these advances in treatment efficacy and safety, while highlighting the challenges presented by these "breakthrough medications." Chung and Baumert^[4] state that "it may now be possible to imagine the global eradication of HCV infection"; however, they cite the need for early diagnosis and cost reduction, especially in low-income countries.

Jayasekera and colleagues^[5] and Hoofnagle and colleagues^[6] project that the use of these new agents will reduce the intensity of follow-up monitoring; the rate of hospitalizations for adverse effects; dependence on specialist care; and resource demands associated with disease progression, including those for liver transplantation and management of end-stage liver disease and liver cancer. However, with drug costs that may exceed $90,000 per course, it remains to be seen how these remarkable advances will extend to the estimated 150 million people with HCV infection living outside the targeted high-income markets for these agents.

Barriers to Care

Access to these medications is limited by case recognition. Recent recommendations for birth-cohort screening for HCV infection among US adults are predicated upon the belief that only a fraction of Americans with the infection has been diagnosed.

On the basis of data generated from a community-wide HCV screening project and a registry of known HCV patients, Kim and colleagues^[7] calculated the proportion of more than 21,000 community residents with undiagnosed HCV infection. The overall prevalence was 2.2%; the age- and sex-specific HCV prevalence was highest (3.3%) in men aged 35-39 years and 45-49 years and lowest (1.0%) in women aged 30-34 years. Most had not been diagnosed.

These data support community-wide programs to institute birth-cohort-based screening as well as appropriate risk-based screening in individuals outside the birth cohort.

Antiviral Agents Soon to be Available

Although the results of multiple recent clinical trials have been reported, we will be unable to discuss all of the agents, studies, combinations, and screening and administration issues. I will therefore highlight a few strategies that have emerged.

Sofosbuvir-Based Regimens

Sofosbuvir (SOF) is a HCV NS5B nucleotide polymerase inhibitor. Several studies have demonstrated high SVR rates in patients with genotypes 1-6 infection treated with SOF combined with RBV with or without pegIFN for 12 or 24 weeks. High efficacy rates were demonstrated across many patient subtypes, including those considered difficult to treat (eg, HIV/HCV coinfection, treatment-experienced patients, and those with cirrhosis).

Many presentations at DDW 2014 described the efficacy and safety of SOF -- often used in combination with ledipasvir (LDV) -- without pegIFN. Subtle differences in response rates and ideal duration of therapy according to genotype were also reported, and these will ultimately be codified in guidelines.

Jacobson and colleagues^[8] reported that the fixed-dose (single tablet) combination of SOF 400 mg/LDV 90 mg administered once daily for 12 weeks was highly effective and well tolerated in treatment-naive patients infected with HCV genotype 1, including those with cirrhosis. The addition of RBV did not enhance the SVR rate.

Kowdley and colleagues^[9] reported that 8-week treatment with the fixed-dose combination regimen of SOF/LDV, with or without RBV, produced SVRs similar to those achieved with a 12-week regimen in noncirrhotic, previously untreated patients infected with HCV genotype 1.

Phase 3 studies^[10] of SOF-based regimens have demonstrated high efficacy of this combination across genotypes, even in patients with multiple traditional negative predictors of diminished efficacy. SVR rates were somewhat lower in patients who had negative predictors; therefore, strategies focusing on addressing these hardest-to-cure populations may be required.

Patients who are considered more difficult to treat owing to advanced liver disease, genotype 3 infection, or previous treatment failure were studied by Gane and colleagues.^[11] They reported that regimens involving SOF/LDV with or without RBV were efficacious in patients with more advanced liver disease and in those with previous treatment failure. In patients infected with the difficult-to-treat HCV genotype 3, the addition of RBV to SOF/LDV enhanced the SVR rate. The regimen was generally safe and well tolerated, with no additional safety issues in patients with decompensated liver disease.

Kwo and colleagues^[12] reported that the SOF/LDV fixed-dose combination tablet can effectively be used to treat a population of treatment-experienced patients with HCV genotype 1 infection. The addition of RBV to the treatment, or extending the treatment from 12 weeks to 24 weeks, did not significantly increase the final SVR12 rates. Adverse events and laboratory abnormalities were more common in recipients of SOF/LDV with RBV and consistent with the safety profile of RBV.

Two additional studies documented successful retreatment.^[13,14] In particular, the study reported by Nyberg and colleagues^[14] included patients infected with HCV genotype 2 and genotype 3 in whom treatment had previously failed. Overall SVR rates were 100% for genotype 2-infected patients and 96% for genotype 3-infected patients after retreatment with SOF regimens for a longer duration.

Safety profile. In all of these clinical trials of SOF-containing regimens, adverse events and laboratory abnormalities were more common with pegIFN- or RBV-containing regimens, and SOF did not contribute to the frequency or severity of these expected events. Gordon and colleagues^[15] also observed low rates of treatment discontinuation and no duration-related side effects.

Sofosbuvir was approved by the US Food and Drug Administration (FDA) in December 2013 for clinical use in the United States. Ledipasvir is not FDA-approved. On the basis of projections from Markov modeling and compared with current treatment regimens, sofosbuvir-based regimens should yield good future health outcomes and less liver disease complications and deaths across all genotypes, levels of treatment experience, severity stage, and coinfection status.^[16]

ABT-Based Regimen

AbbVie's (North Chicago, Illinois) investigational HCV regimen consists of the following fixed-dose combination:

• ABT-450 (an HCV NS3/4A protease inhibitor), 150 mg dosed with ritonavir 100 mg daily (ABT-450/r);

• ABT-267 (a nonnucleoside NS5A inhibitor), 25 mg daily (ombitasvir); and

• ABT-333 (a NS5B RNA polymerase inhibitor), 250 mg twice daily (dasabuvir).

This 3-drug (3D) regimen is administered with or without weight-based RBV. The multitargeted antiviral combination with 3 different mechanisms of action interrupts the HCV replication process, with the goal of optimizing SVR rates across different patient populations.

At DDW 2014, several investigators presented the results of clinical trials of this regimen. Kowdley and colleagues^[17] conducted a double-blind, placebo-controlled study in noncirrhotic, treatment-naive patients with chronic HCV genotype 1 infection. Patients were randomly assigned to receive the coformulated 3D regimen or matching placebo for 12 weeks.

The intention-to-treat SVR12 rate for active drug recipients was 96%; on-treatment failure and post-treatment relapse occurred in 0.2% and 1.5% of patients, respectively. The most common treatment-emergent adverse events were fatigue and headache (approximately 30% each); discontinuation as a result of these events occurred in 0.6% of patients in each arm.

The interferon-free, 12-week 3D regimen was also effective in noncirrhotic, treatment-experienced, genotype 1-infected patients, a group typically associated with the lowest response rates.^[18] The 3D plus RBV regimen led to an SVR12 of 96%.

Andreone and colleagues^[19] also reported that a 12-week regimen of ABT 450/r/ABT-267 and ABT-333 with or without RBV achieved high rates of SVR12 (97% with 3D plus RBV, and 100% with 3D alone) in treatment-experienced patients. The regimen was generally well tolerated, as evidenced by the low rate of treatment discontinuation and serious adverse events.

In a phase 3 study of an all-oral, interferon-free regimen exclusively in HCV genotype 1-infected patients with compensated cirrhosis, treatment with 3D and RBV resulted in high rates (92%-96%) of SVR12 in both the 12- and 24-week treatment arms.^[20]

This highly effective, well-tolerated, 3D HCV regimen is under FDA review.

Other Regimens

Another all-oral, ribavirin-free, interferon-free combination of 3 direct-acting agents -- daclatasvir (an NS5A inhibitor), asunaprevir (an NS3 inhibitor), and BMS-791325 (a nonnucleoside NS5B inhibitor) -- was shown to induce SVR12 in 92% of treatment-naive patients with chronic HCV genotype 1 infection.

Hassanein and colleagues^[21] report that 12 weeks of the all-oral treatment combination achieved SVR12 in all noncirrhotic patients with genotype 4 infection, with no virologic failures. These results extend the potent antiviral activity of this regimen to patients with HCV genotype 4 infection, while maintaining the positive tolerability and safety profile documented previously in patients infected with genotype 1. The investigators state that the rapid attainment of SVR suggests that perhaps an even shorter duration of therapy or elimination of 1 of the agents in the combination may be as efficacious.

This regimen is not FDA approved.

Enhancing the Outcome

It was reported that statin use is associated with SVR in patients with HCV treated with pegIFN and RBV, independent of host metabolic factors.

Sanchez and colleagues^[22] used the Veterans' Affairs Clinical Case Registry to conduct a retrospective cohort study of veterans infected with HCV genotypes 1, 2, and 3 who received treatment between 2002 and 2008. They found that continuous statin use was associated with increased SVR that persisted after adjustment for age, race, sex, body mass index, genotype, diabetes, hypertension, fibrosis, and high-density lipoprotein and low-density lipoprotein cholesterol levels. Although the mechanism responsible for this observation was not defined, it is known that statins have antiproliferative, antiangiogenic, and anti-inflammatory effects on hepatic cells.

Further studies are warranted to explore whether statin use will significantly reduce progression of liver fibrosis in patients with advanced chronic HCV infection treated with the new antiviral regimens.

A Final Note

Coffee drinking has been associated with a reduced risk for progression to cirrhosis and hepatocellular carcinoma. The mechanism is unclear, but caffeine has been proposed to have antifibrotic and antineoplastic effects.

Among HCV-infected veterans, overall coffee intake (but not decaffeinated coffee intake) was inversely associated with advanced fibrosis.^[23] Coffee intake was higher in those with mild fibrosis compared with advanced fibrosis, although none of the comparisons were significant because of the sample sizes. In multivariate analysis adjusting for age, diabetes, alcohol use, obesity, and soda consumption, the inverse association between the number of daily cups of coffee and advanced fibrosis persisted.

So, have a cup of coffee -- it will help us to stay alert as we wade though the continually emerging and voluminous, yet exciting, data on the cure of HCV infection. We eagerly await the next inning.

References

1. American Association for the Study of Liver Diseases; Infectious Diseases Society of America. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org/ Accessed May 25, 2014.

2. Vutien P, Kim Y, Brooks L, Livornese R, Nguyen MH. Low treatment rates and suboptimal treatment completion rates to hepatitis C virus (HCV) therapy: a real-world analysis of a large US cohort. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 648.

3. Hasan SS, Sears DM, Lorden AL. A real world analysis of the cost of current HCV treatment. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 377

4. Chung RT, Baumert TF. Curing chronic hepatitis C -- the arc of a medical triumph. N Engl J Med. 2014;370:1576-1578.

5. Jayasekera CR, Barry M, Roberts LR, Nguyen MH. Treating hepatitis C in lower-income countries. N Engl J Med. 2014;370:1869-1871.

6. Hoofnagle JH, Sherker AH. Therapy for hepatitis C -- the costs of success. N Engl J Med. 2014;370:1552-1553.

7. Kim WR, Wi CI, Larson JJ, Yawn BP, Yao JD, Therneau TM. The tip of an iceberg -- who is known to have hepatitis C? Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract Su1028.

8. Jacobson IM, Marcellin P, Mangia A, et al. All oral fixed-dose combination sofosbuvir/ledipasvir with or without ribavirin for 12 or 24 weeks in treatment-naive genotype 1 HCV-infected patients: the phase 3 ION-1 study. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract Tu2038.

9. Kowdley KV, Gordon SC, Reddy KR, et al. Sofosbuvir/ledipasvir with and without ribavirin for 8 weeks compared to sofosbuvir/ledipasvir for 12 weeks in treatment-naive non-cirrhotic genotype 1 HCV-infected patients: the phase 3 ION-3 study. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 764.

10. Jacobson IM, Christensen C, Conway B, et al. Sofosbuvir-based regimens are associated with high SVR rates across genotypes among patients with multiple negative predictive factors. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 647.

11. Gane E, Hyland RH, Pang P, Symonds WT, McHutchison JG, Stedman CA. Sofosbuvir/ledipasvir fixed dose combination is safe and effective in HCV infected populations including decompensated patients and patients with prior sofosbuvir treatment experience. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 238.

12. Kwo PY, Reddy KR, Pockros PJ, et al. All oral fixed-dose combination sofosbuvir/ledipasvir with or without ribavirin for 12 or 24 weeks in treatment-experienced genotype 1 HCV-infected patients: the phase 3 ION-2 study. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 236.

13. Jacobson IM, Sulkowski M, Hassanein T, et al. Successful retreatment of HCV genotype-1 infected patients who failed prior therapy with peginterferon + ribavirin plus 1 or 2 other direct-acting antiviral agents with sofosbuvir. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 237.

14. Nyberg LM, Lalezari J, Ni L, et al. Successful retreatment with sofosbuvir-containing regimens for HCV genotype 2 or 3 infected patients who failed prior sofosbuvir plus ribavirin therapy. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 239.

15. Gordon SC, Towner W, Aggarval A, et al. Integrated safety analysis of sofosbuvir-based HCV treatment regimens from phase 3 studies. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 650.

16. Saab S, Gordon SC, Park H, Ahmed A, Younossi ZM. A decision analytic Markov model to evaluate the health outcomes of sofosbuvir for previously untreated patients and those without treatment options with chronic hepatitis C virus. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 474.

17. Kowdley KV, Feld JJ, Coakley E, et al. SAPPHIRE I: phase 3 placebo-controlled study of interferon-free, 12-week regimen of ABT-450/r/ABT-267, ABT-333, and ribavirin in 631 treatment-naive adults with hepatitis C virus genotype 1. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 475.

18. acobson IM, Zeuzem S, Baykal T, et al. SAPPHIRE II: phase 3 placebo- controlled study of interferon-free, 12-week regimen of ABT-450/r/ABT-267, ABT-333, and ribavirin in 394 treatment-experienced adults with hepatitis C virus genotype 1. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 235.

19. Andreone P, Colombo M, Enejosa JV, et al. PEARL II: randomized phase 3 trial of interferon-free, 12-week regimen of ABT-450/r/ABT-267, ABT-333 with or without ribavirin in hepatitis C virus genotype 1b-infected, treatment-experienced patients. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 929e.

20. Kowdley K, Poordad F, Trinh R, et al. TURQUOISE-II: SVR12 rates of 92%-96% in 380 hepatitis C virus genotype 1-infected adults with compensated cirrhosis treated with ABT-450/r/ABT-267 and ABT-333 plus ribavirin (3D+RBV). Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract Tu2039.

21. Hassanein T, Everson GT, Sims K, et al. All-oral therapy with daclatasvir in combination with asunaprevir and Bms-791325 for treatment-naive patients with chronic HCV genotype 4 infection. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 763.

22. Sanchez MJ, Augustin S, Balakrishnan M, Lo Re V, Tate JP, Garcia-Tsao G. Statin use is associated with sustained virological response in patients with hepatitis C treated with pegylated interferon and ribavirin, independent of host metabolic factors. Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract Su1050.

23. El-Serag H, Kuzniarek J, Ransey DJ, Tabasi ST, White DL, Kanwal F. Beverage intake and the risk of advanced fibrosis in HCV: coffee, tea, or soda? Program and abstracts of Digestive Disease Week 2014; May 3-6, 2014; Chicago, Illinois. Abstract 775.

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Coffee Is Probably Good For Your Liver

Provided by International Business Times

By Nat Rudarakanchana
on March 21 2014 1:39 PM

Mounting scientific evidence has shown that coffee prevents and mitigates liver disease, even among the thousands of Americans who may not realize they have the disease, according to the Canadian Liver Foundation.

Several studies from the late 1990s to date have shown that coffee helps prevent liver inflammation, which is often related to hepatitis C, cirrhosis and liver cancer. One April 2013 overview study showed that 16 studies, which surveyed more than 500,000 subjects over several years, all demonstrated coffee’s benefits on the liver.

But awareness among the general public about coffee’s benefits for the liver remains “very poor,” Canadian Liver Foundation Chairman Dr. Morris Sherman told IBTimes on Thursday, at a New Orleans coffee conference.

That holds true of the coffee industry itself, which may not know much about the scientific connection, Sherman added.

It’s unclear if caffeine or other ingredients in coffee are responsible for the health benefits, Sherman said at an industry presentation called “Coffee and Liver Health: A Growing Nexus.” One study in Japan showed that green tea failed to help those suffering from liver diseases, Sherman said. Other evidence indicates that tea has little effect on liver diseases.

“Tea doesn’t seem to have any benefit” on the liver, Sherman said.

Still, coffee alone can hardly treat liver disease, and more solid scientific data in coming years is needed to strengthen the evidence of its health benefits. “It is unclear whether any of these benefits [from drinking coffee] are significant enough to 'treat' patients with chronic liver disease,” the 2013 overview study concluded. “In the interim, moderate daily unsweetened coffee ingestion is a reasonable adjunct to therapy.”

Obesity is a leading cause of nonalcoholic fatty liver disease, which many Americans have but don't know it. The disease may affect up to 25 percent of U.S. adults, though the actual figure may be closer to 10 to 15 percent. But if 5 percent of those with a liver disease were aware of it, that would be a significant improvement over the status quo, Sherman said.

Liver diseases don’t cause any symptoms until the liver actually fails, he said.

“The evidence has been slowly building," Sherman said. "These studies are not easy. It’s not easy to find a population large enough, and where someone has had the foresight to ask them about their coffee consumption.”

Coffee’s other health benefits may be dubious, however. The federal Food and Drug Administration (FDA) on Wednesday warned consumers against buying Vitaccino Coffee, which contains harmful substances, despite labelling claiming that the coffee can help drinkers lose weight safely.

Seven coffees that claim to boost weight loss have been found to contain harmful ingredients since 2011, according to the FDA's website.

Mortality rates for liver cancer are rising faster than many other cancers, though the Center for Disease Control and Prevention's data show that liver cancer isn't among the 10 most common cancers in the United States.

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How does coffee prevent liver fibrosis? Biological plausability for recent epidemiological observations - Editorial

Accepted Article - Hepatology Jan 27 2014

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record

Jonathan A. Dranoff1, Jordan J. Feld2, EÅLlise G. Lavoie1, and Michel Fausther1

1Division of Gastroenterology and Hepatology, University of Arkansas for Medical

Sciences; 2Toronto Western Hospital Liver Center

The published epidemiological data demonstrating an inverse relationship between coffee (and potentially other caffeinated beverage) consumption and liver fibrosis and its downstream complications are weighty and rapidly accumulating. Several excellent recent reviews examine this evidence in great detail (1-3), and the overwhelming conclusion is that this inverse relationship is real – coffee drinking reduces liver fibrosis. Among the strongest studies to support this observation are the findings that, after adjustment for confounders, individuals in the highest quintile of caffeine consumption had less than one third the risk of ALT elevation of those in the lowest quintile (odds ratio (OR) 0.31, 95% CI 0.16-0.61) (4) and, perhaps more importantly, advanced liver fibrosis from chronic liver diseases of various etiologies is associated with reduced coffee and total caffeine consumption (5) with one study showing that the odds of having cirrhosis decreased with increasing daily consumption of coffee in a step-wise manner from an OR of 0.47 (95% CI 0.20-1.10) for patients consuming 1 cup of coffee per day to an OR of 0.16 (95% CI 0.05-0.50) for patients consuming 4 cups per day, compared to lifetime abstainers as the reference (OR 1.0) (6). Demonstrating the clinical significance of coffee consumption, Freedman and colleagues found that among patients with advanced fibrosis, those who consumed no coffee had a risk of hepatic decompensation or hepatocellular carcinoma (HCC) of 11.1 per 100 patient-years compared to just 6.3 per 100 patient-years in those consuming ≥ 3 cups of coffee per day, with no beneficial effect seen with tea or other sources of caffeine (7). Coffee consumption has also been shown to be associated with a lower risk of fatty liver disease (8), metabolic syndrome (9), and ultimately hepatocellular carcinoma (10). As a clinician or scientist interested in the pathogenesis of liver fibrosis, one may very well ask whether these findings are of great value.

Biological plausibility is the concept that an observed epidemiological association is “consistent with existing biological and medical knowledge” (11). This concept has long been considered a cornerstone in attempts to move epidemiological associations, even those that have been replicated on multiple occasions, to a high likelihood of causality (e.g., the now overwhelmingly accepted concept that tobacco smoking causes lung disease (12). Here we provide one of potentially several mechanisms by which coffee/caffeine consumption blocks liver fibrosis – that caffeine inhibits adenosinergic signaling in liver myofibroblasts – with strong hopes of providing biological plausibility for the observed epidemiological associations. We acknowledge fully that other potential mechanisms, such as antioxidant and anti-inflammatory properties of coffee constituents, are of possible importance; however, these concepts are not sufficiently developed at the level of observed science.

The beneficial effects of coffee and caffeine extract against liver fibrosis have been demonstrated by several studies using standard rodent models of experimental liver fibrosis induced by intoxication with dimethylnitrosamine (DMN), carbon tetrachloride (CCl4), or thioacetamide (TAA) (13-18). In almost every study, ingestion of coffee blocked toxin-induced liver fibrosis/cirrhosis. Of note, conventional filtered coffee is the form generally used in most of the published studies supporting its protective role. In contrast to the above studies, one report showed that “Turkish style” unfiltered coffee consumption not only lacks any protective effect against CCl4-induced liver fibrosis, but rather aggravates CCl4-induced hepatotoxicity with significant AST and ALT elevation (19). Of note, the mechanism(s) underlying these differences was not studied, so more definitive animal experiments are highly warranted.

One mechanism by which coffee may protect against liver fibrosis is via alterations of liver signaling or inflammation. Transforming growth factor-β (TGF-β) is a major liver regulatory cytokine secreted in large quantities in standard rodent liver fibrosis models (20). TGF-β levels are reduced by coffee and caffeine administration to rats subjected to CCl4-, DMN-, and TAA-induced liver fibrosis (13-18). One of the most significant downstream effects of TGF-β signaling is the activation of hepatic stellate cells (HSC) (21). In normal liver, HSC are vitamin A-rich, lipid-storing cells present in the space of Disse (22-24). In fibrosing liver, HSC undergo myofibroblastic differentiation and markedly upregulate secretion of extracellular matrix proteins, a process commonly known as HSC activation (24). When liver fibrosis models are performed on rodents exposed to coffee, total liver collagen contents are decreased (13-15, 18).

Activated HSC also secrete matrix metalloproteinases (MMPs), whose activity is essential to maintain the balance between tissue repair and scar formation in fibrotic livers (25). Total liver MMP secretion and activity are decreased by coffee consumption (13, 14). Expression of alpha-smooth muscle actin (α-SMA) protein is commonly used as a marker of HSC activation in the fibrotic liver (24). In the presence of coffee and caffeine, α-SMA total liver expression is diminished (13, 16, 18), potentially being indicative of reduced activation of HSCs and disease progression. Altogether, the in vivo studies reviewed here show that the anti-fibrotic properties of coffee/caffeine converge at a point in which HSC activation is diminished, providing biologic plausibility for the human studies cited above.

As noted above, coffee contains myriad chemical substances that could potentially be anti-fibrotic. A number of studies using experimental liver models have specifically addressed this question, by administration of decaffeinated coffee or caffeine solution to animals (13, 16, 19). Non-coffee caffeine was shown to protect liver against fibrosis in both TAA- and CCl4-induced liver fibrosis in rats (16, 19, 26). On the other hand, several studies demonstrate that decaffeinated coffee is also protective, but to a lower extent than caffeinated coffee in experimental animals (13, 19). Taken together, it appears that there are noteworthy holes in the animal liver fibrosis literature; there are simply not enough data to make firm conclusions about the relative importance of coffee caffeine content. At present, while it is premature to assume that the major effect of coffee is mediated by caffeine, the preponderance of evidence would suggest that this is the case.

Caffeine and other xanthines, including theophylline, have several known biological targets. These molecules have been characterized as non-selective antagonists of adenosine receptors (AR), inhibitors of phosphodiesterases, antagonists of the GABAA receptor, and stimulators of intracellular calcium release (27). While each of these effects is relevant to multiple biological processes, this section focuses on the antagonistic effects of caffeine on adenosine receptors, since this biological effect is relevant to the pathogenesis of liver fibrosis/cirrhosis.

Extracellular adenosine acts via four G-protein-coupled receptors (GPCRs), known as A1, A2a, A2b and A3 adenosine receptors to induce downstream effects (for recent review see (28, 29)). The A1AR, A2aAR and A3AR are high-affinity receptors that respond to low concentrations (>10 nM) of extracellular adenosine, while A2bAR is a low affinity receptor (>1 NM) thought to be selectively activated in pathological conditions (30). A1AR and A3AR are coupled to G proteins of the Gi/o type, leading to downregulation of cAMP-dependent signaling pathways. In contrast, A2aAR and A2bAR increase the intracellular concentration of cAMP via Gs coupling. Interestingly, A2bAR can also be coupled with Gq subunit to mobilize intracellular calcium (Ca2+).

Experimental evidence of the antagonist effects of caffeine on adenosine receptors was first reported 40 years ago in the heart (31) and in the brain (32). Caffeine is a nonspecific antagonist of all adenosine receptors. Specific synthetic agonists and antagonists derived from caffeine and other xanthine compounds have been developed for each AR and are now used as research tools in the studies of their functions, as well as potential therapeutic drugs (27). This is relevant, since specific antagonists of the A2aAR inhibit experimental liver fibrosis (26, 33). In contrast, administration of A1AR, A2bAR and A3AR specific antagonists does not significantly impact liver fibrosis progression (26).

Thus, the anti-fibrotic effect of caffeine seems to be modulated by its antagonism of the A2aAR. In addition, mice lacking A2aAR expression are protected against liver fibrosis induced by CCl4 and TAA (26). A potential role of the A1AR in liver fibrosis is more controversial, as A1AR deficient mice are also protected against CCl4-induced liver fibrosis (34), but administration of the A1AR specific antagonist DPCPX has no effect (26).

HSC are well established as primary effector cells during liver fibrosis. Interestingly, human HSC express mRNA for all four adenosine receptors ((35) and Dranoff JA unpublished data), among which A2aAR is the most studied as a regulator of HSC function. Mouse HSC express all but A3AR receptors (35). Thus, HSC represent a highly plausible cellular target mediating the anti-fibrotic effect of coffee/caffeine acting via adenosine receptor antagonism. Indeed, activation of HSC A2aAR by extracellular adenosine markedly upregulates collagen secretion (26, 35, 36). Adenosinergic signaling, via A2aAR activation, redistributes stress fibers and contractile capacity in HSCs (37), likely providing a mechanism for a “stop” signal after cell migration, as evidenced by the observation that A2aAR activation blocks the chemotaxis of HSC in response to platelet derived growth factor (PDGF) (35). Finally, A2aAR activation increased HSC TGFβ secretion (35) and decreased MMP expression (26). Since all of the mechanisms listed can be blocked by caffeine, blockade of pro-fibrotic adenosinergic signaling in HSC is a reasonable explanation for the antifibrotic effects of coffee.

According to the literature presented here, coffee consumption provides protection against liver fibrosis induced by well-established chemical models. The protective mechanism seems to be mediated primarily by the action of caffeine on HSC A2aAR. However, there are holes in the literature that will need to be closed. First, since CCl4 and other pro-fibrotic chemical agents require inflammation to induce fibrosis and cirrhosis, and multiple inflammatory cell types express adenosine receptors (38, 39), the observed effects may be mediated by changes in inflammatory cell function rather than those on HSC function. Second, the animal studies performed have taken only a cursory look at the relative importance of non-caffeine coffee constituents, in part due to methodological limitations. Lastly, animal models of fibrosis are themselves analogues of human fibrosis-to-cirrhosis progression, but they are not identical. Thus, it is very possible that animal models and studies in isolated HSC will prove useful to identify biological mechanisms, but the relevance to human health will be best tested in studies of human patients.

The progression of liver injury to fibrosis to cirrhosis is a slow but deadly process. The number of North American and European patients with chronic liver disease is increasing, primarily due to steady levels of hepatitis C infection but rapidly expanding levels of fatty liver disease (primarily non-alcoholic). Thus, identification of simple measures that can slow fibrosis and prevent cirrhosis in at-risk patients is critical. Since coffee consumption appears to have salutary effects on human health overall, coffee is an attractive lifestyle measure that patients can take.

Are we ready to “write a prescription for coffee”, as asked by Torres and Harrison in a recent commentary article? (1) Most likely, the answer is yes. Our rationale is as follows. First, there is sufficient evidence to provide biological plausibility for coffee as an anti-fibrotic. Second, coffee (for most individuals) is a pleasant addition to the diet, without profound adverse effects and possibly some other health benefits (again for most individuals). Lastly, other anti-fibrotic treatments are simply lacking; they are in the pipeline, but not yet available clinically.

However, we must face caveats as well. The human studies cited suggest that the most potent observed effects of coffee require the equivalent of four or more cups per day. We are not convinced that most individuals would easily tolerate this. Moreover, if we assume that the anti-fibrotic effects of coffee are mediated by caffeine, then should patients also be offered equivalent “doses” of tea, caffeinated soft drinks, or even caffeine pills? The latter two do not seem to be consistent with contemporary health practice, and probably for good reason. Thus, at present, we would suggest that any recommendations be limited to coffee (and for reasons cited above, limited to brewed coffee).

Hopefully, the most important effect gained by the observations reviewed here is not the use of coffee as a drug, but rather the generation of testable hypotheses as to the pathogenesis, prevention, and treatment of liver fibrosis and cirrhosis.

Source NATAP

Coffee Consumption and Chronic Liver Disease: The New Best Prescription?

Medscape Gastroenterology > Viewpoints

David A. Johnson, MD

January 06, 2014

Review Article: Coffee Consumption, the Metabolic Syndrome and Non-alcoholic Fatty Liver Disease

Yesil A, Yilmaz Y
Aliment Pharmacol Ther. 2013;38:1038-1044

Study Summary

Coffee consumption is a part of daily life in most areas of the world. As such, a number of studies have evaluated the chemical composition and related effects that this enjoyable beverage may have on health and disease.

For many years, healthcare providers have advised patients to avoid excessive consumption because of a concern about caffeine dependence. Several recent studies, however, suggest that regular coffee consumption may modulate the risk for fibrosis in chronic liver disease.

Yesil and Yilmaz analyzed the experimental, epidemiologic, and clinical studies and the modulation of the metabolic syndrome and nonalcoholic fatty liver disease (NAFLD). Animal studies showed a reduction in the metabolic syndrome with improvements in glycemic and lipid regulation, as well as reductions in transaminases and proinflammatory cytokine hepatic gene expression. Other studies showed reductions in hepatic fat and collagen proinflammatory tumor necrosis factor, as well as increases in anti-inflammatory interleukins. Epidemiologic and clinical studies demonstrated a significant inverse association between coffee consumption and prevalence of metabolic syndrome, as well as a reduced risk for NAFLD.

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View This Abstract Online

Review article: coffee consumption, the metabolic syndrome and non-alcoholic fatty liver disease.

Aliment Pharmacol Ther.  2013; 38(9):1038-44 (ISSN: 1365-2036)

Yesil A; Yilmaz Y

BACKGROUND: Coffee consumption may modulate the risk of the metabolic syndrome (MetS) and non-alcoholic fatty liver disease (NAFLD).

AIM: To review the experimental, epidemiological and clinical studies investigating the association between coffee consumption and the risk of MetS and NAFLD.

METHODS: A literature search was conducted with the aim of finding original experimental, epidemiological and clinical articles on the association between coffee consumption, MetS and NAFLD. The following databases were used: PubMed, Embase, Scopus and Science Direct. We included articles written in English and published up to July 2013.

RESULTS: Three experimental animal studies investigated the effects of coffee in the MetS, whereas five examined whether experimental coffee intake may modulate the risk of fatty liver infiltration. All of the animal studies showed a protective effect of coffee towards the development of MetS and NAFLD. Moreover, we identified eleven epidemiological and clinical studies that met the inclusion criteria. Of them, six were carried out on the risk of the MetS and five on the risk of NAFLD. Four of the six studies reported an inverse association between coffee consumption and the risk of MetS. The two studies showing negative results were from the same study cohort consisting of young persons with a low prevalence of the MetS. All of the epidemiological and clinical studies on NAFLD reported a protective effect of coffee intake.

CONCLUSIONS: Coffee intake can reduce the risk of NAFLD. Whether this effect may be mediated by certain components of the MetS deserves further investigation.

References

Bhoo-Pathy N, Uiterwaal CS, Dik VK, et al. Intake of coffee, decaffeinated coffee, or tea does not affect risk for pancreatic cancer: results from the European Prospective Investigation into Nutrition and Cancer Study. Clin Gastroenterol Hepatol. 2013;11:1486-1492.

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A coffee a day keeps the doctor away

Scottish study suggests drink helps the liver by postponing development of cirrhosis. Exclusive by Judith Duffy

Sunday 29 December 2013

IT'S almost perfect news for this over-indulgent time of year - for experts have found that drinking coffee is good for your liver.

Research published in the Scottish Medical Journal found a significant link between coffee consumption and the development of liver scarring

Until now, coffee has been best known for pepping you up, giving you the jitters or, erroneously, as a source of instant sobriety. However, a new study carried out by Scottish doctors has found patients with chronic liver disease who developed cirrhosis drank "significantly less" coffee than those who did not develop the condition.

The findings suggest the development of cirrhosis - scarring of the liver caused by long-term, continuous damage - could even be postponed by upping the amount of coffee consumed.

The research, published in the ­ Scottish Medical Journal, analysed coffee consumption among patients attending the liver outpatient department at ­Edinburgh Royal Infirmary.

Study co-author Peter Hayes, ­professor of hepatology at the University of ­Edinburgh, said the findings were another "piece in the jigsaw" that suggested coffee was good for the liver, and that he recommended coffee to patients who were able to drink it.

"Everything seems to point to coffee seeming to help liver to such a degree that I tell all patients who ask 'what can I do to help my liver?' that it's a good idea to lose weight, keep your alcohol intake low or zero and if you like coffee, drink plenty," he said.

But Hayes said it was difficult to carry out a definitive trial that would prove the effect of coffee, as it would involve having to pick people on a random basis and have them drink coffee for a long period of time - even if they did not like it.

But he pointed to other studies that have found beneficial effects from the drink, including a large analysis published in the New England Journal of Medicine last year that found older adults who drank coffee had a lower risk of death overall than others who did not drink coffee.

"The nice thing about it is there is an element of a consistent story that has built up over decades, as opposed to one study that suddenly pops up that suddenly tells you something is bad for you and then there is one tomorrow that tells you it is good for you," he said. "Study after study after study has suggested that coffee seems to be good for the liver."

Hayes cautioned against the idea that drinking enough coffee could make cirrhosis "go away" or that people should suddenly go from having no coffee to drinking 10 cups a day.

"If you are someone that has got an alcoholic liver problem, the right message from the doctors is to say cut back on your alcohol," he said. "When it comes to things like non-alcoholic liver disease related to obesity or diabetes, people often ask if there a special liver diet. The bottom line is, keep the alcohol low and if there is anything that you take by mouth which might be helpful - it is coffee."

Andrew Langford, chief executive of the British Liver Trust, said there was growing evidence from studies that coffee is good for those with liver disease.

But there is still debate over what is in the drink that could have this effect.

He added: "What we don't know yet is whether or not drinking coffee when you haven't got liver disease gives you any sort of protection.

"What we do know from the research which has been done, particularly in Scandinavia, is that for people with liver disease, there is a benefit to drinking coffee."

He added: "What is really important is to find out what it is in coffee that helps the liver. If it is not the caffeine, it would be fantastic if decaffeinated coffee [worked].

"If we could still have coffee without the caffeine, then it is a win-win situation."

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Coffee Reduces Risk for Hepatocellular Carcinoma: An Updated Meta-analysis

Clinical Gastroenterology and Hepatology
Volume 11, Issue 11 , Pages 1413-1421.e1, November 2013

Francesca Bravi, Cristina Bosetti, Alessandra Tavani, Silvano Gallus, Carlo La Vecchia

published online 08 May 2013.

Abstract

Background & Aims

Coffee consumption has been suggested to reduce the risk for hepatocellular carcinoma (HCC). We performed a meta-analysis of epidemiological studies to provide updated information on how coffee drinking affects HCC risk.

Methods

We performed a PubMed/MEDLINE search of the original articles published in English from 1966 through September 2012, on case-control or cohort studies that associated coffee consumption with liver cancer or HCC. We calculated the summary relative risk (RR) for any, low, and high consumption of coffee vs no consumption. The cut-off point for low vs high consumption was set to 3 cups per day in 9 studies and 1 cup per day in 5 studies.

Results

The summary RR for any coffee consumption vs no consumption was 0.60 from 16 studies, comprising a total of 3153 HCC cases (95% confidence interval [CI], 0.50–0.71); the RRs were 0.56 from 8 case-control studies (95% CI, 0.42–0.75) and 0.64 from 8 cohort studies (95% CI, 0.52–0.78). Compared with no coffee consumption, the summary RR was 0.72 (95% CI, 0.61–0.84) for low consumption and 0.44 (95% CI, 0.39–0.50) for high consumption. The summary RR was 0.80 (95% CI, 0.77–0.84) for an increment of 1 cup of coffee per day. The inverse relationship between coffee and HCC risk was consistent regardless of the subjects’ sex, alcohol drinking, or history of hepatitis or liver disease.

Conclusions

From this meta-analysis, the risk of HCC is reduced by 40% for any coffee consumption vs no consumption. The inverse association might partly or largely exist because patients with liver and digestive diseases reduce their coffee intake. However, coffee has been shown to affect liver enzymes and development of cirrhosis, and therefore could protect against liver carcinogenesis.

Keywords: Chemoprevention, Epidemiology, Caffeine, Neoplasm

Abbreviations used in this paper: BMI, body mass index, CI, confidence interval, d, day, HbsAg, hepatitis B surface antigen, HBV,hepatitis B virus, HCC, hepatocellular carcinoma, HCV, hepatitis C virus, OR, odds ratio, RR, relative risk, w, week

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Coffee and Non-Alcoholic Fatty Liver Disease: Brewing evidence for hepatoprotection?

Journal of Gastroenterology and Hepatology

Accepted Articles, Accepted manuscript online: 7 NOV 2013

Article type: Review Article

Received date: 12-Aug-2013 Accepted date: 12-Sep-2013

1 Shaohua Chen *1,2 , Narci C Teoh *2 , Shiv Chitturi 2 , Geoffrey C. Farrell 2

1.Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, No.79, QingChun Road, Hangzhou,310003 P.R.China.

2. Liver Research Group, ANU Medical School at the Canberra Hospital, Level 5 Bldg10, Yamba Drive, Garran, ACT, 2605 Australia.
*Equal first author: Shaohua Chen and Narci C Teoh

Corresponding author: Geoffrey C. Farrell
Address: Liver Research Group, ANU Medical School at the Canberra
Hospital, Level 5 Bldg10, Yamba Drive, Garran, ACT, 2605 Australia.
Email: geoff.farrell@anu.edu.au  
Ph: 61 2 6244 2473  Fx: 61 2 6244 3235

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/jgh.12422

Abstract: Coffee is one of the most popular beverages in the world. Several studies consistently show that coffee drinkers with chronic liver disease have a reduced risk of cirrhosis and a lower incidence of hepatocellular carcinoma (HCC) regardless of primary etiology. With the increasing prevalence of non-alcoholic fatty liver disease (NAFLD) worldwide, there is renewed interest in the effect of coffee intake on NAFLD severity and positive clinical outcomes. This review gives an overview of growing epidemiological and clinical evidence which indicate that coffee consumption reduces severity of NAFLD. The possible mechanisms underlying coffee’s hepatoprotective effects in NAFLD are also discussed. Key words: coffee, nonal

Key words: coffee, nonalcoholic fatty liver disease, hepatocellular carcinoma, fibrotic severity, liver inflammation

Introduction Coffee is a brewed beverage with a distinct aroma and flavor, prepared from the roasted seeds of the coffee plant. It has been part of the human diet since the 15th century. In its various forms (including decaffeinated coffee), coffee is one of the most consumed drinks in the world, partly for its mild mood-enhancing and stimulatory effects on the central nervous system. Caffeine, one of the main constituents of coffee, has been shown to have a wide spectrum of biological activities. The effects of coffee on chronic liver disease, especially in lowering the risk of developing hepatocellular carcinoma (HCC) has recently attracted considerable attention.

The first reported association between caffeine accumulation and liver disease can be attributed to Statland and colleagues in 1976[1]. They found a prolonged caffeine half-time in a case with alcoholic liver disease, reflecting impaired caffeine metabolism in cirrhosis which has subsequently been well documented. During the last 20 years, several investigators have focused more specifically on coffee and its beneficial health effects, especially against liver disease. In 1992, Klatsky and Armstrong reported an inverse relationship between coffee drinking and the risk of cirrhosis in a 10-year follow-up study of a large number of subjects drawn from a North American general population[2]. Their results show that coffee drinkers (at least 3 cups/day), had significantly lower levels of gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), serum alkaline phosphatase (SAP) and bilirubin concentration compared with non-coffee-drinking subjects, or those consuming less than 3 cups daily [3]. Coffee consumption has also been associated with decreased blood GGT levels in humans, and reported to confer possible hepatoprotection against alcoholic liver disease [21, 22].

Coffee consumption may reduce the risk of HCC [4-8]. A consistent inverse relationship between coffee and HCC risk has been found in 3 meta-analyses [9-12]. Further, the relationship between coffee intake and severity of different etiological types of chronic liver disease has been extensively studied. Hepatitis B virus (HBV) infection is the most common cause of HCC worldwide. In those with chronic HBV infection, moderate coffee consumption (drinking coffee ≥4 times/week) reduced the risk of HCC by half (OR=0.54, 95% CI: 0.30 - 0.97) with a significant dose-response effect (χ²=5.41, df=1, p=0.02) [13]. In another hospital-based case-control study, it was found that a high lifetime coffee consumption (≥20,000 cups) was an independent protective factor against HCC in all subjects. However, high levels of coffee consumption did not significantly affect HCC risk in patients with HBV (OR=0.64, 95% CI:0.36-1.14) after adjustment for HBeAg status, serum HBV DNA level and antiviral therapy[14]. In addition, others have reported that caffeine intake did not appear to affect liver stiffness (detected by transient elastography) in patients with chronic HBV [15]. A preliminary conclusion from these observations is that the protective effect of coffee against cirrhosis is not likely to be as significant as the viral determinants of chronic liver disease.

More than 180 million people worldwide are chronically infected with the hepatitis C virus (HCV), and approximately 350,000 people die every year from HCV-related liver disease such as decompensated cirrhosis, and/or HCC. Some case-control studies have shown that coffee consumption can reduce the risk of HCC amongst HCV-infected patients [16, 17]. Costentin et al found that caffeine consumption of >408 mg/day (≥3 cups coffee) was associated with reduced histological activity in patients with chronic HCV infection [18]. Coffee consumption also appeared to slow disease progression. Finally, coffee consumption may improve virologic response to pegylated-interferon and ribavirin antiviral treatment [19] [20] .

The prevalence of NAFLD is escalating rapidly worldwide in association with such metabolic disorders as type 2 diabetes, obesity, hypertension and hyperlipidemia (metabolic syndrome). NAFLD comprises a pathological spectrum characterized by fat accumulation within the liver known as simple steatosis, or “non-NASH NAFLD”, and/or in combination with varying degrees of hepatocellular injury manifest by ballooning, inflammation, liver fibrosis, cirrhosis and HCC. In NAFLD-related cirrhosis, liver histology may no longer show inflammation or even steatosis, and likely represent the largest proportion of cases often referred to as “cryptogenic cirrhosis”. The diagnosis of NAFLD is usually made by abnormal liver tests and hepatic imaging showing features of fatty infiltration (‘bright liver’) in the context of obesity, a family history of diabetes and/or features of metabolic syndrome; as well, other causes of liver disease and significant alcohol intake must be excluded.

Several studies of hepatic lipid metabolism, insulin resistance, mitochondrial dysfunction, oxidative stress as well as genetic predisposition to altered cell metabolism and injury have contributed to current understanding of NAFLD[23]. Lifestyle measures directed at increasing physical activity (which counters insulin resistance) and weight loss remain the cornerstone of management. Notably, the effects of pharmacotherapy are still contentious; most agents studied are either modest in their effects, such as vitamin E, pioglitazone, ezetimibe or pentoxiphyllne, or have no beneficial long term hepatoprotective effects (eg. metformin, ursodeoxycholic acid). In general, moderate energy and simple carbohydrate restriction, reduction of total and saturated fat intake, along with increasing physical activity are beneficial and highly recommended. Interestingly, recent studies have shown that coffee drinking may be protective against NAFLD-related chronic liver disease and possibly, HCC

Sources of information

This systematic review is the first that we are aware of to focus on the epidemiology, magnitude and mechanisms of possible beneficial effects of coffee consumption in patients with NAFLD. Using ‘Liver disease’ and ‘coffee’ as search terms in the PubMed database, 240 articles were returned. The abstracts of all these articles were reviewed, and 12 studies that evaluated relationship between NAFLD and coffee were examined in detail. Specific questions pertaining to this area of research were evaluated, as indicated below. The number of articles published about coffee and liver disease has increased steadily since 2003 (Figure 1).

Relationship between coffee consumption and NAFLD in community studies

Four continuous cycles of the National Health and Nutrition Examination Surveys (NHANES, USA 2001-2008) were used to investigate the effects of dietary behavior in NAFLD patients. Dietary intake was evaluated by questionnaires that included nutrition components. Multivariate analyses were conducted of variables that included demographics, clinical parameters and nutritional components in relation to presence of NAFLD (defined by ultrasonography). Five factors were independently associated with NAFLD: African American race, male gender, obesity, caffeine intake as well as plain water consumption. These findings show a strong association between coffee consumption and protection against the development of NAFLD [24].(See Table 1) The association of caffeine consumption with both the prevalence and severity of NAFLD was further established in another study where a validated questionnaire of caffeine consumption was utilized to determine if there was a relationship between caffeine intake and NAFLD severity as established by histological examination of liver biopsies. In this study, the authors reported an inverse relationship between caffeine consumption and hepatic fibrosis[25] . (See Table 1)

In an Italian study from Europe, 137 NAFLD cases and 108 controls were enrolled, and coffee intake determined by the absolute number of cups of coffee consumed. This was graded as 1 (0 cups of coffee/day), 2 (1-2 cups of coffee/day) and 3 (≥3 cups of coffee/day). Insulin resistance was assessed by homoeostasis model-insulin resistance index (HOMA). When compared with non-coffee drinkers, those who consumed coffee had less severe fatty liver evaluated by ultrasound “bright liver score” (BLS). Further, obesity, insulin resistance, lower HDL cholesterol, older age and arterial hypertension were associated with a greater risk of more severe grades of BLS, while coffee intake was associated with a lower risk of severe BLS. By multiple regression analysis, coffee use was inversely associated with the degree of “bright liver”, while insulin resistance and obesity were directly associated with increased likelihood and severity of BLS on ultrasound[26]. A case-control study from Mexico also found similar protective effects of coffee consumption against NAFLD as assessed by ultrasound [27]. (See Table 1)

Mechanisms by which coffee may reduce severity of NAFLD

Despite firm epidemiological data, the cellular and molecular mechanisms underlying the effects of coffee consumption in patients with NAFLD remain undefined. Antioxidant, anti-inflammatory, antifibrotic and altered energy metabolism have been potentially implicated.

Coffee and oxidative injury

Of interest, there have been several studies which indicate that coffee consumption is inversely related to the incidence of diseases in which reactive oxygen species (ROS) are involved. It is postulated that the antioxidant properties of coffee may account for this phenomenon. Vitaglione et al [28] established a high-fat-diet (HFD)-induced NASH model in male Wistar rats to study the protective mechanisms of coffee, or its component polyphenols or melanoidins against NAFLD. Biomarkers of antioxidant status measured in both serum and liver samples show that HFD-fed rats had significantly higher concentrations of oxidized glutathione (GSSG) than control rats. Coffee, polyphenols, or melanoidins reduced GSSG concentrations in HFD-fed rats supplemented with coffee in their drinking water compared with those given water only. Likewise, serum malondialdehyde concentration was significantly higher in rats in the HFD-water group than in control rats (2.03±0.14 μM vs 1.47±0.12 μM). Coffee consumption (1.50±0.09 μM) or polyphenolss (1.62±0.08 μM) returned these levels to control values. Further, there was a significant increase in antioxidant capacity in rats treated with polyphenols in drinking water compared with controls [0.36±0.02 mM Trolox® equivalent(TE) vs 0.32±0.01 mM TE] [28]

Goya L et al. investigated the potential protective effect of coffee melanoidins, in particular, a water-soluble high-molecular weight fraction, on the redox status of cultured human hepatocellular carcinoma, HepG2 cells. The results show that coffee melanoidins conferred significant protection against oxidative insults [29].

To establish whether coffee consumption protects humans against oxidative DNA-damage, a cross-over intervention study was conducted. In this trial, 38 participants consumed 800 mL coffee (or water in controls) daily over 5 days. DNA-damage was measured in peripheral lymphocytes. The extent of DNA-migration attributable to formation of oxidized purines (also known as formamidopyrimidine glycosylase sensitive sites) was decreased by 12% after coffee intake (p=0.006). These findings suggest that coffee consumption prevents endogenous formation of oxidative DNA-damage in humans. While this observation may be causally related to the beneficial health effects of coffee, biochemical indices of redox status such as malondialdehyde, 3-nitrotyrosine and total antioxidant levels in plasma, glutathione concentrations in blood, intracellular ROS levels and the activities of superoxide dismutase and glutathione peroxidase in lymphocytes, were not markedly altered at the end of the trial[30].

Investigators have observed different levels of oxidative DNA damage and DNA repair in the livers of coffee-fed mice [31]. In one study, lean male mice were fed 0.1% (w/v) instant coffee solution prepared weekly with 60℃ tap water. At 2, 4, and 8 months, there was no difference in the hepatic levels of 8-hydroxydeoxyguanosine (8 Accepted -OH-dG)(a marker of oxidative DNA damage) and 8-OH-dG repair-associated genes, redox system-associated genes and hepatic lipoperoxide levels between the coffee-fed and control groups of mice. These results suggest that instant coffee consumption has little, if any, effect on hepatic oxidative stress in lean mice. Similarly, others report little or no significant difference in catalase (0.2 ± 0.7 vs. 0.3 ± 0.7 nM/min/mL) levels, superoxide dismutase (4.7 ± 2.1 vs. 5.4 ± 3.4U/mL) or thiobarbituric acid-reactive substances (3.9 ± 1.5 vs. 4.0 ± 1.8 µM/mL) between NAFLD and controls. Hence, while coffee intake has a protective effect against severity of NAFLD, the weight of evidence (albeit, currently incomplete) is that coffee’s positive effects are unlikely to be attributable to any differences in antioxidant variables [27].

Coffee and liver Inflammation

Coffee intake has been associated with reduced levels of abnormalities in serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) [32-34] and GGT [35]. Fukushima Y et al [36] conducted a study where mice were fed HFD to induce NAFLD, then treated with or without coffee (1.1% decaffeinated/caffeine-containing instant coffee). Mesenteric fat weight was lower in the HFD+coffee group than those fed a HFD without coffee (p<0.05). Further, serum AST and ALT levels were significantly lower in the HFD+coffee group than in mice fed a HFD only (p < 0.05). Proinflammatory interleukin -1beta(IL-1β) gene expression in murine liver was upregulated in the HFD group and was significantly downregulated by coffee consumption (p<0.01). Expression of monocyte chemoattractant protein-1 (MCP-1) in liver and adipose was also suppressed in the HFD+coffee group. Hence, coffee consumption appears to significantly reduce hepatic pro-inflammatory response.

In a separate study, co-administration of coffee with a HFD in rodents appeared to reduce tumor necrosis factor α (TNF-α), tissue transglutaminase, and transforming growth factor β(TGF-β) expression in the liver, and increased expression of adiponectin receptor and peroxisome proliferator-activated receptor α(PPARα). Coffee also lowered hepatic concentrations of TNF-α, interferon-γ and increased anti-inflammatory cytokines, IL-4 and IL-10.[28]

Coffee and hepatic fibrosis

Few studies have discussed the influence of coffee on liver fibrosis in NAFLD. In a recent European study, 195 morbidly obese patients referred for bariatric surgery were assessed [37]. Liver biopsies showed NASH in 19%, and significant fibrosis in 35%. By logistic regression analysis, regular coffee intake was an independent factor negatively associated with significant fibrosis in a model that included AST, HOMA-IR, presence of the metabolic syndrome, and NASH. Interestingly, the consumption of regular coffee (but not espresso) was associated with an earlier stage of fibrosis and was independently protective against fibrosis [37]. Sucrose, which is composed of glucose and fructose, is often added by espresso consumers to their coffee and may have potentially countered coffee’s positive effects in this study. Fructose consumption has been noted to aggravate the severity of liver fibrosis in North American patients who have NASH [38, 39].

Few studies have addressed the mechanism for the possible anti-fibrotic effects of coffee on liver fibrosis in NAFLD. In NASH-associated fibrosis, the principal cell type responsible for extracellular matrix production is the hepatic stellate cell[40]. The mechanisms of fibrogenesis in the liver are dependent on an interplay of many pro-fibrotic and anti-fibrotic cytokines and growth factors. TGF-β is one such pro-fibrogenic growth factor. In turn TGF-β can activate connective tissue growth factor(CTGF) which is also responsive to insulin and other metabolic factors in NAFLD, and which can also mediate matrix production[41]. Caffeine inhibits CTGF synthesis in hepatocytes and liver non-parenchymal cells, primarily by inducing degradation of Smad2, thereby interrupting TGF-β signaling[42] .

Coffee and hepatic metabolism

The liver plays diverse and crucial roles in lipogenesis, gluconeogenesis and cholesterol metabolism[43]. In a rodent model which develops metabolic syndrome and NAFLD when fed a high-carbohydrate, HFD, supplementation with Colombian coffee extract improved glucose tolerance, decreased hypertension, induced cardiovascular remodeling and attenuated NAFLD severity. Of note, these changes were not associated with weight loss or reduction of serum lipids in the animals [44]. Interestingly, one study reports that some coffee brewing techniques raise serum total and low-density-lipoprotein cholesterol concentrations in humans[45]. The diterpene lipids, cafestol and kahweol (also main constituents of coffee) were considered to be the responsible lipid-altering factors. In contrast, filtered coffee does not appear to affect serum cholesterol and this is thought to be related to the removal of diterpenes by the filtration process (filter paper) [45] .

Adiponectin is an adipokine which governs insulin sensitivity and has potent anti-inflammatory effects. Plasma adiponectin levels are often lower in patients with NAFLD, and correlate inversely with the severity of steatosis and NASH. In a cross-sectional study comprised of 2554 male and 763 female Japanese workers, associations between coffee consumption and adiponectin, leptin, markers for subclinical inflammation, glucose metabolism, lipids and liver enzymes were ascertained. The findings revealed that coffee consumption was associated with higher serum adiponectin and lower serum leptin levels[46].

Coffee is also enriched with polyphenols (coffee polyphenols, CPP). The effects of CPP on diet-induced body fat accumulation was investigated and C57BL/6J mice were fed either a control diet, HFD, or HFD supplemented with 0.5 to 1.0% CPP for 2-15 wk. Supplementation of a HFD with CPP significantly reduced body weight gain, abdominal and liver fat accumulation, as well macrophage infiltration into adipose. Energy expenditure, evaluated by indirect calorimetry, was significantly increased in CPP-fed mice. The hepatic transcript levels of sterol regulatory element-binding protein (SREBP)-1c, acetyl-CoA carboxylase-1 and -2, stearoyl-CoA desaturase-1, and pyruvate dehydrogenase kinase-4 were also significantly reduced in CPP-fed mice compared with controls, reflecting the increased biological activity of adiponectin and leptin. CPP has also been shown to suppress the expression of SREBP-1c in Hepa 1-6 cells, with a concomitant increase in microRNA (miR)-122. Structure-activity relationship studies of nine quinic acid derivatives isolated from CPP in Hepa 1-6 cells also suggest that mono- or di-caffeoyl quinic acids (CQA) may have potent and potentially beneficial effects[47]. Thus, it appears that CPP enhances energy metabolism, reduces lipogenesis by down-regulating SREBP-1c and related signaling pathways, thereby suppressing the accumulation of body fat and newly-synthesized (saturated) fatty acids in the liver[47] .

Conclusions and future perspectives

Taken together, these studies provide reasonable evidence for a protective effect of coffee consumption on NAFLD. The protective effects may be related to a diverse range of mechanisms, including anti-oxidant, anti-inflammatory, anti-fibrotic pathways as well as modulations in energy metabolism (Figure 2). Most studies to date have been exploratory and confined to a limited range of experimental systems, only a small subset of which have utilized clinically relevant experimental models of NASH. It is clear that some components of coffee, other than caffeine may be involved, and specific identification of these compounds require more rigorous study to elucidate the mechanisms underlying coffee’s hepatoprotective effects in patients with NAFLD.

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Figure 1: Number of publications related to coffee intake and liver disease in the past decade

Figure 2: Schematic diagram illustrating the mechanisms underlying coffee’s potential hepatoprotective effects in NAFLD

Key: NASH: non alcoholic steatohepatitis; GSSG: oxidized glutathione; ROS: reactive oxygen species; SREBP-1C: sterol regulatory element-binding protein -1C; IL-1β: interleukin-8; IL-4: interleukin-4; IL-10: interleukin-10; MCP-1: monocyte chemoattractant protein-1; TNF-α: tumor necrosis factor α; IFN-γ: interferon-γ; PPAR-α: peroxisome proliferator-activated receptor α; TGF-β: transforming growth factor β; CTGF: connective tissue growth factor; Smad2: Mothers against decapentaplegic homolog 2, SMAD family member 2

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Coffee consumption affects cancer risk differently for liver vs. pancreatic cancers

11/01.13

By: TARA HAELLE, IMNG Medical News

^{Lynda Banzi/IMNG Medical Media}

According to two recent studies, consuming coffee of any kind may reduce the risk of the most common liver cancer by as much as 50 percent.

Drinking tea or caffeinated or decaf coffee is unlikely to influence a person’s risk for pancreatic cancer, but consuming coffee of any kind may reduce the risk of the most common liver cancer by as much as 50% (depending on amount consumed), according to two recent studies in Clinical Gastroenterology and Hepatology.

In the pancreatic cancer study, Dr. Nirmala Bhoo-Pathy of University Medical Center Utrecht, the Netherlands, and her colleagues reported, "Our results strengthen the conclusion made by the World Cancer Research Fund and the American Institute of Cancer Research that there is little evidence to support a causal relation between coffee and risk of pancreatic cancer (Clin. Gastroenterol. Hepatol. 2013 [doi:10.1016/j.cgh.2013.05.029]).

Meanwhile, a 16-study meta-analysis of coffee intake and risk for hepatocellular carcinoma, which accounts for more than 90% of worldwide liver cancers, revealed a 40% decreased risk (relative risk, 0.60; 95% confidence interval: 0.50-0.71) for any coffee consumption vs. no consumption. Yet Dr. Francesca Bravi of Università degli Studi di Milano and her colleagues reported that their findings could not establish a causal relationship between coffee drinking and hepatocellular carcinoma (Clin. Gastroenterol. Hepatol. 2013 [doi:10.1016/j.cgh.2013.04.039]).

Even such a causal relationship may have limited clinical significance, however, considering that more than 90% of primary liver cancers worldwide can theoretically be prevented through hepatitis B vaccination, control of hepatitis C transmission, and reduction of alcohol consumption, Dr. Bravi’s team wrote.

In the first study, Dr. Bhoo-Pathy’s investigation involved inspection of 865 first incidences of pancreatic cancers reported in a cohort of 477,312 men and women from 10 European countries tracked prospectively over a mean 11.6 years of follow-up. The participants in the EPIC (European Prospective Investigation Into Nutrition and Cancer) cohort completed a dietary questionnaire at baseline in 1992, then calibrated with a 24-hour dietary recall by the final follow-up in 2000.

The 23 participating centers were in Denmark, France, Germany, Greece, Italy, the Netherlands, Norway, Spain, Sweden, and the United Kingdom, and median coffee intake across these ranged from 92 mL/day in Italy to 900 mL/day in Denmark. Among the participants with all information on coffee type intake (n = 269,593), half drank only caffeinated coffee (50%), 4% drank only decaf, a third (34%) drank both, and 12% drank no coffee. Two-thirds (66%) of the total cohort drank tea of any kind (caffeinated, green, or herbal).

Neither total intake of coffee (hazard ratio, 1.03; 95% CI: 0.83-1.27 for high vs. low intake) nor consumption of decaffeinated coffee (HR, 1.12; 95% CI: 0.76-1.63) – reported as cups drunk per day, week, or month and then converted to daily milliliters – showed a significant change in pancreatic cancer risk. Tea consumption of any kind similarly had no impact on risk (HR, 1.22; 95% CI: 0.95-1.56). These risks did not change after accounting for a range of confounders nor when analysis was confined to the 608 (70.3%) cancers that were microscopically confirmed.

Confounders included sex, clinic/center, age at diagnosis, height, weight, physical activity, smoking status, diabetes history, education level, and energy intake, including red meat, processed meat, alcohol, soft drink, tea (for coffee analysis), coffee (for tea analysis), and fruit and vegetable intake.

A comparison of moderately low and low caffeinated coffee intake initially revealed a modest increased risk for moderately low consumption (HR, 1.33; 95% CI: 1.02-1.74) that dropped below statistical significance when only microscopically confirmed pancreatic cancer cases were analyzed. Additionally, no dose-response effect was noted among any of the findings for pancreatic cancer risk.

Yet a dose-response effect was seen in Dr. Bravi’s study investigating coffee consumption and hepatocellular carcinoma risk. Her team’s update of a 2007 meta-analysis included an additional four cohort and two case-control studies, for a total of eight cohort and eight case-control studies from 14 English-language articles included in PubMed/MEDLINE between 1966 and September 2012.

When broken down by study type, the 40% overall risk reduction for any coffee consumption found among 3,153 hepatocellular carcinoma cases split into a 44% reduction in the case-control studies (RR, 0.56; 95% CI: 0.42-0.75) and a 36% reduction in the cohort studies (RR, 0.64; 95% CI: 0.52-0.78).

The dose-response relationship was seen in separate comparisons of low and high coffee consumption with no coffee consumption, using three cups a day as the cutoff in nine papers and one cup a day in five papers. Low coffee consumption reduced hepatocellular carcinoma risk by 28% (RR, 0.72; 95% CI: 0.61-0.84) while high consumption reduced it by 56% (RR, 0.44; 95% CI: 0.77-0.84).

Each additional cup of coffee per day resulted in a 20% risk reduction (RR, 0.80; 95% CI: 0.77-0.84). This split into a 23% risk reduction in the case-control studies (RR, 0.77; 95% CI: 0.71-0.83) and a 17% risk reduction in the cohort studies (RR, 0.83; 95% CI: 0.78-0.88). A temporal analysis of risk reduction for any coffee consumption showed an increase from 20% risk reduction in 2000 (RR, 0.8; 95% CI: 0.50-1.29) to 41% in 2007 (RR, 0.59; 95% CI: 0.48-0.72), which has remained stable at about 40% the past several years.

Accounting for the most [significant] risk factors for liver cancer had little effect on the risk ratios. These factors included hepatitis B and C infections, cirrhosis, and other liver diseases, socioeconomic status, alcohol consumption, and smoking.

Dr. Bravi’s team suggested that the risk reduction effect could be a real, causal effect arising from antioxidants and other minerals in coffee that may inhibit liver carcinogenesis or from the inverse association between coffee and cirrhosis or coffee and diabetes, both conditions known risk factors for liver cancer. Or, the effect could result, at least in part, from reduced consumption of coffee among patients with cirrhosis or other liver disease.

"Thus, a reduction of coffee consumption in unhealthy subjects cannot be ruled out, although the inverse relation between coffee and liver cancer also was present in subjects with no history of hepatitis/liver disease," the researchers wrote. Yet, they also noted the potentially limited utility of coffee risk reduction given the greater impact on reducing liver cancer risk from hepatitis B vaccination, prevention of hepatitis C, and reduction of alcoholic drinking.

The pancreatic cancer study was funded by the European Commission and the International Agency for Research on Cancer, with a long list of additional societies, foundations, and educational institutions supporting the individual national cohorts. The hepatocellular carcinoma study was funded by a grant from the Associazione Italiana per la Ricerca sul Cancro. The authors in both studies reported no disclosures.

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