• artificial sweetener
• chronic liver disease
• coffee
• liver-related events
• sugar

• Humans
• Coffee
• Male
• Female
• Prospective Studies
• Middle Aged
• Liver Diseases/epidemiology
• Liver Diseases/etiology
• Adult
• Chronic Disease
• Longitudinal Studies
• Cohort Studies
• Sweetening Agents/adverse effects
• Sweetening Agents/administration & dosage
• Proportional Hazards Models
• Risk Factors
• Artificially Sweetened Beverages

• NAFLD
• NASH
• inflammation
• pathophysiology
• therapy

• 82073184 The National Natural Science Foundation of China
• 2022-4-4019 The capital health research and development of special
• 2022-PUMCH-A-071 The National High Level Hospital Clinical Research Funding
• 2022-PUMCH-B-024 National High Level Hospital Clinical Research Funding
• 82470700 The National Natural Science Foundation of China
• 2022-PUMCH-C-063 The National High Level Hospital Clinical Research Funding

• Caffeine
• Cirrhosis
• Fibrosis
• Inflammation

• alcohol use disorder
• alcohol-associated cirrhosis
• alcohol-associated hepatitis
• alcohol-associated liver disease
• steatotic liver disease

• American Association for the Study of Liver Diseases
• National Institute on Alcohol Abuse and Alcoholism

• Adenosine
• Adenosine receptor
• Cirrhosis
• Coffee
• Liver
• Myofibroblast

• Humans
• Coffee
• Caffeine/pharmacology
• Liver Cirrhosis
• Adenosine/pharmacology
• Liver
• Receptors, Purinergic P1

We have previously shown that adenosine A1AR antagonists, adenosine A2aAR antagonists, and caffeine have significant inhibitory effects on the activation and proliferation of hepatic stellate cells in alcoholic liver fibrosis. Many recent studies have found that moderate coffee consumption is beneficial for various liver diseases. The main active ingredient of coffee is caffeine, which is a natural non-selective adenosine receptor antagonist. Moreover, numerous preclinical epidemiological studies and clinical trials have examined the association between frequent coffee consumption and the risk of developing different liver diseases. In this review, we summarize and analyze the prophylactic and therapeutic effects of caffeine on various liver diseases, with an emphasis on cellular assays, animal experiments, and clinical trials. To review the prevention and treatment effects of caffeine on different liver diseases, we searched all literature before 19 July 2022, using “caffeine” and “liver disease” as keywords from the PubMed and ScienceDirect databases. We found that moderate coffee consumption has beneficial effects on various liver diseases, possibly by inhibiting adenosine binding to its receptors. Caffeine is a potential drug for the prevention and treatment of various liver diseases.

• National Natural Science Foundation of China

• Chronic liver diseases
• Dietary factors
• NAFLD-to-HCC progression
• Observational studies
• Systematic review

• Antioxidants
• Carcinoma, Hepatocellular/complications
• Carcinoma, Hepatocellular/epidemiology
• Coffee
• Disease Progression
• Humans
• Inflammation/complications
• Liver Cirrhosis/complications
• Liver Cirrhosis/epidemiology
• Liver Neoplasms/complications
• Liver Neoplasms/epidemiology
• Non-alcoholic Fatty Liver Disease/complications
• Risk Factors

The liver is the site of synthesis of the majority of circulating proteins. Besides initial polypeptide synthesis, sophisticated machinery is involved in the further processing of proteins by removing parts of them and/or adding functional groups and small molecules tailoring the final molecule to suit its physiological purpose. Posttranslational modifications (PTMs) design a network of molecules with the common protein ancestor but with slightly or considerably varying activity/localization/purpose. PTMs can change under pathological conditions, giving rise to aberrant or overmodified proteins. Undesired changes in the structure of proteins most often accompany undesired changes in their function, such as reduced activity or the appearance of new effects. Proper protein processing is essential for the reactions in living beings and crucial for the overall quality control. Modifications that occur on proteins synthesized in the liver whose PTMs are cirrhosis-related are oxidation, nitration, glycosylation, acetylation, and ubiquitination. Some of them predominantly affect proteins that remain in liver cells, whereas others predominantly occur on proteins that leave the liver or originate from other tissues and perform their function in the circulation. Altered PTMs of certain proteins are potential candidates as biomarkers of liver-related diseases, including cirrhosis. This review will focus on PTMs on proteins whose structural changes in cirrhosis exert or are suspected to exert the most serious functional consequences.

• Liver cirrhosis
• Post-translational modifications
• Circulation
• Protein function
• Protein structure
• Chronic liver disease

• Acetylation
• Humans
• Liver Cirrhosis
• Peptides/metabolism
• Phosphorylation
• Protein Processing, Post-Translational
• Proteins/metabolism

• Alcohol
• Chronic Hepatitis B
• Coffee
• Hepatitis B Research Network
• Tobacco

• Adolescent
• Adult
• Africa/ethnology
• Aged
• Alanine Transaminase/blood
• Alcohol Drinking/epidemiology
• Asia/ethnology
• Asian People
• Black People
• Canada/epidemiology
• Coffee
• DNA, Viral/blood
• Female
• Hepatitis B e Antigens/blood
• Hepatitis B, Chronic/blood
• Hepatitis B, Chronic/epidemiology
• Humans
• Liver Cirrhosis/blood
• Liver Cirrhosis/epidemiology
• Male
• Middle Aged
• Prevalence
• Severity of Illness Index
• Tobacco Smoking/epidemiology
• United States/epidemiology
• White People
• Young Adult
• Black or African American

• UL1 TR001111 NCATS NIH HHS
• U01 DK082923 NIDDK NIH HHS
• UL1 TR000058 NCATS NIH HHS
• U01 DK082867 NIDDK NIH HHS
• U01 DK082874 NIDDK NIH HHS
• UL1 RR024986 NCRR NIH HHS
• U01 DK082919 NIDDK NIH HHS
• U01 DK082927 NIDDK NIH HHS
• U01 DK082872 NIDDK NIH HHS
• U01 DK082943 NIDDK NIH HHS
• K24 AA022523 NIAAA NIH HHS
• P30 DK050306 NIDDK NIH HHS
• M01 RR000040 NCRR NIH HHS
• U01 DK082871 NIDDK NIH HHS
• U01 DK082944 NIDDK NIH HHS
• U01 DK082864 NIDDK NIH HHS
• U01 DK082843 NIDDK NIH HHS
• U01 DK082863 NIDDK NIH HHS
• UL1 TR000004 NCATS NIH HHS
• U01 DK082866 NIDDK NIH HHS

• liver cirrhosis
• alcohol drinking
• cohort studies
• case-control studies
• systematic review
• meta-analysis

• Alcohol Drinking/adverse effects
• Alcohol Drinking/epidemiology
• Humans
• Incidence
• Liver Cirrhosis/epidemiology
• Liver Cirrhosis/etiology
• Risk Factors
• Sex Factors

• R21 AA023521 NIAAA NIH HHS

• Diet/adverse effects
• Disease Progression
• Energy Intake
• Humans
• Non-alcoholic Fatty Liver Disease/etiology
• Risk Factors

• Beta-blockers
• Cirrhosis
• Diuretics
• Pharmacology
• Proton pump inhibitors
• Rifaximin
• Statins

• Adrenergic beta-Antagonists/therapeutic use
• Animals
• Anti-Bacterial Agents/therapeutic use
• Antibiotic Prophylaxis/methods
• Anticoagulants/therapeutic use
• Antidiuretic Hormone Receptor Antagonists/therapeutic use
• Ascites/drug therapy
• Ascites/etiology
• Ascites/prevention & control
• Chronic Disease/drug therapy
• Disease Models, Animal
• Diuretics/therapeutic use
• Esophageal and Gastric Varices/drug therapy
• Esophageal and Gastric Varices/etiology
• Esophageal and Gastric Varices/prevention & control
• Gastrointestinal Hemorrhage/drug therapy
• Gastrointestinal Hemorrhage/etiology
• Gastrointestinal Hemorrhage/prevention & control
• Hepatic Encephalopathy/drug therapy
• Hepatic Encephalopathy/etiology
• Hepatic Encephalopathy/prevention & control
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
• Hypertension, Portal/drug therapy
• Hypertension, Portal/etiology
• Hypertension, Portal/prevention & control
• Liver Cirrhosis/complications
• Liver Cirrhosis/drug therapy
• Proton Pump Inhibitors/therapeutic use
• Secondary Prevention/methods
• Treatment Outcome

• MR/R000875/1 Medical Research Council

Several types of surgical procedures have shown to elicit an inflammatory stress response, leading to substantial cytokine production and formation of oxygen-based or nitrogen-based free radicals. Chronic liver diseases including cancers are almost always characterized by increased oxidative stress, in which hepatic surgery is likely to potentiate at least in the short term and hereby furthermore impair the hepatic redox state. During liver resection, intermittent inflow occlusion is commonly applied to prevent excessive blood loss but resulting ischemia and reperfusion of the liver have been linked to increased oxidative stress, leading to impairment of cell functions and subsequent cell death. In the field of liver transplantation, ischemia/reperfusion injury has extensively been investigated in the last decades and has recently been in the scientific focus again due to increased use of marginal donor organs and new machine perfusion concepts. Therefore, given the intriguing role of oxidative stress in the pathogenesis of numerous diseases and in the perioperative setting, the interest for a therapeutic antioxidative agent has been present for several years. This review is aimed at giving an introduction to oxidative stress in surgical procedures in general and then examines the role of oxidative stress in liver surgery in particular, discussing both transplantation and resection. Results from studies in the animal and human settings are included. Finally, potential therapeutic agents that might be beneficial in reducing the burden of oxidative stress in hepatic diseases and during surgery are presented. While there is compelling evidence from animal models and a limited number of clinical studies showing that oxidative stress plays a major role in both liver resection and transplantation and several recent studies have suggested a potential for antioxidative treatment in chronic liver disease (e.g., steatosis), the search for effective antioxidants in the field of liver surgery is still ongoing.

• Phenolic compounds
• antimicrobial
• antioxidant
• caffeine
• cigarette smoking
• diterpenes
• liver disease
• mental health
• metabolic syndrome
• modulators
• pregnancy
• risk factors

• coffee
• caffeine
• cirrhosis
• adenosine
• liver fibrosis

• Animals
• Caffeine/pharmacology
• Coffee/metabolism
• Humans
• Liver/drug effects
• Liver/metabolism
• Liver Cirrhosis/epidemiology
• Liver Cirrhosis/prevention & control

• Adult
• Biomarkers/blood
• Cardiovascular Diseases/mortality
• Cause of Death
• Cerebrovascular Disorders/mortality
• Coffee
• Digestive System Diseases/mortality
• Drinking/ethnology
• Europe/epidemiology
• Female
• Humans
• Inflammation/blood
• Liver Function Tests
• Male
• Middle Aged
• Mortality
• Ovarian Neoplasms/mortality
• Proportional Hazards Models
• Prospective Studies
• Risk Factors

• MR/L003120/1 Medical Research Council
• MC_UU_12015/1 Medical Research Council
• MR/N003284/1 Medical Research Council
• G0401527 Medical Research Council
• Z99 CA999999 Intramural NIH HHS
• RG/08/014/24067 British Heart Foundation
• G1000143 Medical Research Council
• 16491 Cancer Research UK
• 14136 Cancer Research UK
• Wellcome Trust
• 001 World Health Organization

• Coffee
• Fatty liver
• Hepatitis
• Hepatocellular carcinoma
• Liver

Growing evidence has shown that coffee consumption is inversely related with the risk of hepatocellular carcinoma. It is suggested that caffeine maintains strong antioxidative activity. With this property, coffee intake may lead to the inhibition of cell proliferation of liver cancer cells; also, some compounds contained in coffee can reduce the genotoxicity of aflatoxin B1 in vitro and lower the damage caused by some carcinogens. A computerized search was performed in PubMed to identify relevant articles published before August 2015. Eleven relevant studies were included with a total of 2,795 cases and 340,749 control subjects. According to the meta-analysis we performed, the pooled odds ratio (OR) from all included studies was 0.49 (95% confidence interval [CI] =0.46–0.52). The subgroup analysis indicated that the pooled ORs for Asian studies and other populations were 0.27 (95% CI =0.23–0.31) and 0.82 (95% CI =0.77–0.87), respectively. The overall pooled OR for high consumption was decreased to 0.21 (95% CI =0.18–0.25) and significance was observed. Among other populations, the pooled OR of subjects with high coffee consumption was 0.65 (95% CI =0.56–0.73) compared to the nondrinker. The corresponding OR of five Asian studies was 0.13 (95% CI =0.09–0.17). The findings from this meta-analysis further confirmed the inverse association between the coffee consumption and hepatocellular carcinoma risk with quantitative evidence. The protective effect can be detected among healthy population and patients with chronic liver diseases, and the consumption can also prevent the development of liver cirrhosis.

• antioxidant
• coffee
• hepatocarcinogenesis
• meta-analysis

• Exercise
• Nonalcoholic fatty liver disease
• Probiotics
• Weight loss

• CGA, chlorogenic acid
• MEC, multiethnic cohort
• MRP, Maillard reaction products
• NAFLD
• NAFLD, nonalcoholic fatty liver disease
• cirrhosis
• coffee
• fibrosis
• hepatocellular carcinoma
• mortality

• NAFLD
• amino acids
• diet
• exercise
• lifestyle
• medicinal plants
• polyphenols
• polyunsaturated fatty acids
• prebiotics
• vitamins

• Cancer
• Epidemiology
• Esophageal
• Gastric

Evidence demonstrating that regular ingestion of coffee has salutary effects on patients with chronic liver disease is accumulating rapidly. Specifically, it appears that coffee ingestion can slow the progression of liver fibrosis, preventing cirrhosis and hepatocellular carcinoma (HCC). This should excite clinicians and scientists alike, since these observations, if true, would create effective, testable hypotheses that should lead to improved understanding on fibrosis pathogenesis and thus may generate novel pharmacologic treatments of patients with chronic liver disease.

This review is designed to examine the relevant clinical and epidemiological data in critical fashion and to examine the putative pharmacological effects of coffee relevant to the pathogenesis of liver fibrosis and cirrhosis. We hope that this will inspire relevant critical analyses, especially among “coffee skeptics”. Of note, one major assumption made by this review is that the bulk of the effects of coffee consumption are mediated by caffeine, rather than by other chemical constituents of coffee. Our rationales for this assumption are threefold: first, caffeine’s effects on adenosinergic signaling provide testable hypotheses; second, although there are  myriad chemical constituents of coffee, they are present in very low concentrations, and perhaps more importantly, vary greatly between coffee products and production methods (it is important to note that we do not dismiss the “botanical” hypothesis here; rather, we do not emphasize it at present due to the limitations of the studies examined); lastly, some (but not all) observational studies have examined both coffee and non-coffee caffeine consumption and found consistent effects, and when examined, no benefit to decaffeinated coffee has been observed. Further, in the interval since we examined this phenomenon last, further evidence has accumulated supporting caffeine as the effector molecule for coffee’s salutary effects.

• adenosine receptor
• cirrhosis
• coffee
• liver fibrosis

• EPIC
• coffee
• hepatocellular carcinoma
• liver cancer
• tea

• Beverages/adverse effects
• Caffeine/adverse effects
• Carcinoma, Hepatocellular/epidemiology
• Carcinoma, Hepatocellular/etiology
• Case-Control Studies
• Coffee/adverse effects
• Europe
• Female
• Humans
• Incidence
• Liver Neoplasms/epidemiology
• Liver Neoplasms/etiology
• Male
• Middle Aged
• Prospective Studies
• Risk
• Risk Assessment
• Risk Factors
• Tea/adverse effects

• MC_UU_12015/1 Medical Research Council
• G0401527 Medical Research Council
• G1000143 Medical Research Council
• 16491 Cancer Research UK
• 14136 Cancer Research UK
• MC_U106179471 Medical Research Council

• Aged
• Biopsy
• Caffeine/administration & dosage
• Cross-Sectional Studies
• Female
• Hepatitis C, Chronic/complications
• Hepatitis C, Chronic/pathology
• Humans
• Liver Cirrhosis/etiology
• Liver Cirrhosis/pathology
• Male
• Middle Aged
• Severity of Illness Index

• coffee
• caffeine
• tea
• alcohol
• cirrhosis

• Alcohol Drinking/mortality
• Asian People/statistics & numerical data
• Beverages
• Carbonated Beverages
• Coffee
• Feeding Behavior
• Female
• Humans
• Liver Cirrhosis/mortality
• Male
• Middle Aged
• Proportional Hazards Models
• Prospective Studies
• Risk Factors
• Singapore/epidemiology
• Tea

• R01 CA080205 NCI NIH HHS
• R01 CA144034 NCI NIH HHS
• R35 CA053890 NCI NIH HHS
• R01 CA80205 NCI NIH HHS

• coffee
• liver disease

The potential role of coffee as a hepatoprotective substance for chronic liver diseases has been widely discussed. Our main aim was to evaluate the effect of coffee intake regarding clinical, biochemical tests and liver biopsy data in treatment naïve patients with chronic hepatitis C. One hundred and thirty-six patients with chronic hepatitis C, diagnosed through liver biopsy, or by means of clinical, ultrasound or endoscopic signs of cirrhosis, were assessed by determination of biochemical tests, metabolic and morphological alterations. Food frequency was scrutinized by using a structured questionnaire. Coffee intake represented more than 90% of the total daily caffeine, and the 75th percentile was 4-Brazilian coffee-cup/day (≥255 mL/day or ≥123 mg caffeine/day). According to caffeine intake, patients were divided into two groups (< or ≥123 mg caffeine/day). Patients with higher ingestion of caffeine had lower serum levels of aspartate aminotransferase (× upper limit of normal) (1.8 ± 1.5 vs 2.3 ± 1.5, p = 0.04), lower frequencies of advanced (F3, F4) fibrosis (23.5% vs 54.5%, p < 0.001) and of histological activity grade (A3, A4) observed in liver biopsies (13.8% vs 36.9%, p < 0.001). By multivariate logistic regression, fibrosis was independently associated with caffeine intake (OR– 0.16; 95%CI – 0.03–0.80; p = 0.026), γ-glutamil transferase serum levels and morphological activity. But only fibrosis was associated with histological activity. In conclusion caffeine consumption greater than 123 mg/day was associated with reduced hepatic fibrosis. In addition, this study supports the assumption that coffee intake has hepatoprotective benefits for Brazilian patients with chronic hepatitis C, even in lower doses than that of American and European population intake.

• Caffeine
• Coffee
• Fibrosis
• Hepatitis C

• Aged
• Alanine Transaminase/blood
• Caffeine/administration & dosage
• Central Nervous System Stimulants/administration & dosage
• Energy Drinks
• Female
• Follow-Up Studies
• Hepatitis C, Chronic/blood
• Humans
• Male
• Middle Aged
• Retrospective Studies

• Caffeine
• Coffee beverages
• Liver fibrosis and carcinogenesis
• Prevention

• BMI
• CI
• Caffeine
• Chemoprevention
• Epidemiology
• HBV
• HCC
• HCV
• HbsAg
• Neoplasm
• OR
• RR
• body mass index
• confidence interval
• d
• day
• hepatitis B surface antigen
• hepatitis B virus
• hepatitis C virus
• hepatocellular carcinoma
• odds ratio
• relative risk
• w
• week

• Alcoholic liver disease
• Practice guidelines

• Alcohol Abstinence/psychology
• Alcohol Drinking
• Alcohol-Related Disorders/diagnosis
• Baclofen/therapeutic use
• Disulfiram/therapeutic use
• Fatty Liver, Alcoholic/physiopathology
• Hepatitis, Alcoholic/physiopathology
• Humans
• Liver Cirrhosis/physiopathology
• Liver Diseases, Alcoholic/epidemiology
• Liver Diseases, Alcoholic/pathology
• Liver Diseases, Alcoholic/prevention & control
• Naltrexone/therapeutic use
• Prevalence
• Prognosis
• Risk Factors
• Severity of Illness Index
• Surveys and Questionnaires

• CTGF
• TGF-β
• antioxidants
• coffee
• liver injury
• thioacetamide