There are an overwhelming number of studies that conclude that coffee drinking reduces liver fibrosis (please see the bibliography). These studies avoid the mistakes of mid-century research into coffee: They adjust for confounding factors, like cigarette smoking and lifestyle issues.

Chronic damage causes liver fibrosis; as a result, the liver's capacity to regenerate falters, and the extracellular matrix (ECM) takes the place of hepatocytes. Fibrosis disorganizes the architecture of the liver anatomically and functionally, which is a characteristic of most types of chronic liver diseases. Under normal conditions of wound healing, tissues are replaced without cellular overgrowth, but injury to the liver from inflammation, physical disturbances or injury can lead to excessive connective tissue formation. Repair happens in a sequence that produces an inflammatory response with numerous actions involving neutrophils, macrophages, lymphocytes, and leukocytes, the last one producing cytokines that trigger the proliferation of capillary production, fibroblasts and smooth muscle cells.

If the damage to the liver is worse and the inflammatory response lasts longer, the tissue reconstruction process (fibrotic process) can include too much extracellular matrix (ECM), which forms scar tissue and fibrosis. Fibrous overgrowth is thought to be caused by fibrotic cytokines and hepatic stellate cells (HSCs). Coffee has been shown to stop these effects by working on different parts of the above-mentioned pathological processes (Ramos-Tovar & Muriel 2019). The main injuries to the liver that produce hepatic fibrosis include chronic hepatitis C or B infections, alcohol abuse, cholestasis, and nonalcoholic steatohepatitis.

Coffee exerts protective effects against liver fibrosis through antioxidant action and the suppression of fibrogenic cytokines (that trigger ECM growth). There are many antioxidants and liver-protecting substances in coffee. Because they are found in large amounts in coffee, chlorogenic acids and other polyphenols have been suggested as important compounds (Ashihara et al. 2019, Farah 2012, Farah et al. 2006). These findings indicated that other components besides caffeine are involved in the hepatoprotective effects of coffee against liver fibrosis (Shin et al. 2010).

Researchers have found that advanced liver fibrosis from chronic liver diseases (CLDs) of various etiologies is associated with low coffee and total caffeine consumption. To show how important coffee consumption is in the real world, Freedman et al. discovered that among people with advanced fibrosis, those who did not drink any coffee had an 11.1 per 100 patient-years risk of hepatic decompensation or hepatocellular carcinoma (HCC), but only 6.3 per 100 patient-years for those who drank at least three cups of coffee every day. Tea or other caffeine-containing drinks had no positive effect (Freedman et al. 2009).

Researchers have found that coffee can slow the progression of liver fibrosis in people who already have liver disease (Shin et al. 2010, Modi et al. 2010, Shi et al. 2009). It has also been linked to less hepatic fibrosis in people who have liver diseases like hepatitis C (Molloy et al. 2012). The strongest proof came from a meta-analysis done in 2015 that looked at 4 cross-sectional studies and 2 case-control studies with more than 20,000 patients. It found that regular coffee drinking greatly lowers the incidence and severity of hepatic fibrosis in people with liver disease (Shen et al. 2015). Caffeine itself was not significantly associated with the results, but regular coffee (naturally caffeinated) intake was significantly associated with reduced hepatic fibrosis. In some cases, depending on the degree, hepatic fibrosis could be reversed, and the liver could return to a normal structure. Coffee caffeine is associated with a significant reduction in the risk of fibrosis among patients with nonalcoholic fatty liver disease (Shen et al. 2015).

The progression of liver injury from fibrosis to cirrhosis is a slow and terminal process. Fatty liver disease and hepatitis-C have caused an increase in the numbers of patients with fibrosis and cirrhosis over the past decade, and a simple, cost-effective mechanism to slow down the process seems to be readily available: Coffee. Even better: good-quality, organic, clean, mycotoxin-free coffee. Aflatoxins in particular are hepatocarcinogenic in humans, especially in conjunction with chronic hepatitis B virus infection (Wild& Gong 2010), so consuming coffee that is free of toxins is also critical to a healthy liver.

Nonalcoholic fatty liver disease (NAFLD) has been a term used for decades, but in 2019 an international consensus panel presented new terminology to better reflect its causes: Metabolic associated fatty liver disease [MAFLD]. We will use the two interchangeably for this review because the vast body of literature refers to it as NAFLD.

MAFLD is a condition characterized by a buildup of fat in the liver. It is the most common liver disease globally, with estimates that close to a billion people have a degree of the disease. “NAFLD is associated with many metabolic comorbidities, including obesity, type II diabetes, dyslipidemia, and metabolic syndrome. Its potential to develop into more severe liver conditions, such as nonalcoholic steatohepatitis, advanced fibrosis, cirrhosis and hepatocellular carcinoma, can lead to a state in which liver transplantation is the only treatment option available” (Chalasani 2012).

Because MAFLD is so common, scientists looked at the epidemiological and clinical evidence from the last 20 years that showed coffee might protect the liver by having anti-inflammatory, antioxidative, and antifibrotic effects. A 2013 study conducted a systematic review of the epidemiology, magnitude, and mechanisms of possible beneficial effects of coffee consumption in patients with NAFLD using 12 detailed prior 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. Taking into account diet, nutrition, demographics, and other factors, findings showed a strong association between coffee consumption and protection against the development of NAFLD (Birerdinc 2012).
• In an Italian study, 137 NAFLD cases and 108 controls participated, and the total number of cups consumed served as the measure of coffee intake. When compared with non-coffee drinkers, those who consumed coffee had a less severe fatty liver evaluated by an ultrasound “bright liver score.”. Bright Liver Score (BLS) is the observation of a bright liver echo pattern on ultrasound; it is considered a sign of hepatic steatosis and provides accurate and reliable detection of moderate-severe fatty liver.
• Researchers used a questionnaire to look at liver biopsies and found a strong negative correlation between caffeine use and hepatic fibrosis. They also found a link between caffeine use and both the frequency and severity of MAFLD (Molloy 2012).

More recently, coffee has been associated with a significant reduction in the risk of fibrosis among non-alcoholic steatohepatitis (NASH) patients (Kopzhassaruly 2020). NASH is the most severe form of metabolic-associated fatty liver disease and is closely related to obesity, pre-diabetes, and diabetes. As with other studies, they showed dose-related results—that those who drank 2-4 cups per day showed a significant difference from those who drank 1 cup per day.

In 2020, Alessio Calabrò et. al. conducted a literature review on coffee and MAFLD/NAFLD, and they summed up the beneficial effects of coffee consumption reported in dozens of papers, highlighting seven key studies since 2014. These studies showed that coffee consumption in patients with NAFLD can be protective against liver steatosis, progression of fibrosis and liver damage, primarily through antioxidant activity and coffee caffeine intake, which improve insulin resistance and reduce the production of inflammatory and fibrogenic cytokines. Although the researchers found some controversy due to a lack of information on types of coffee, dosages, etc., they concluded that 2-3 cups of coffee a day in patients with MAFLD should be encouraged.

Cirrhosis is a late-stage liver disease in which healthy liver tissue is replaced with scar tissue and the liver is permanently damaged. Scar tissue keeps your liver from working properly. Many types of liver diseases and conditions injure healthy liver cells, causing cell death and inflammation (my.clevelandclinic.org). Cirrhosis always develops because of another liver problem or disease: alcohol abuse, nonalcoholic (or metabolic-associated) fatty liver disease, hepatitis B, hepatitis C, certain autoimmune diseases, and other causes. Cirrhosis isn't curable, but it's treatable. Doctors have two main goals in treating this disease: to stop the damage to your liver and prevent complications.

For several decades, researchers have been making connections between liver health and coffee consumption. Data collected from 1978–1985 supported the hypothesis that there were ingredients in coffee that protect the liver against cirrhosis, especially alcoholic cirrhosis. A 10-year study of 128,934 patients hospitalized with cirrhosis carried out by Klatsky et. al. (1992) showed coffee intake was associated with a lower prevalence of cirrhosis. In addition, coffee consumption seemed to help prevent death from cirrhosis.

Ten years later, in a study of more than 700 individuals, a relationship was observed between how much coffee was consumed per day and the risk of liver cirrhosis. The odds ratio[1] for liver cirrhosis decreased for each cup of coffee:

• From 1.0 for those who did not drink coffee to 0.47 for those who consumed 1 cup of coffee daily,
• 0.23 for consumers of 2 cups,
• 0.21 for 3 cups, and
• 0.16 for 4 cups

Was it just the caffeine in coffee that caused this? The team studied other beverages that had caffeine and compared those with the risk of liver cirrhosis, and they found that caffeine alone was not significantly associated with lower cirrhosis risk. These findings support the hypothesis that coffee, but not other beverages containing caffeine, may inhibit the onset of alcoholic and nonalcoholic liver cirrhosis—and there must be something else in the coffee (Corrao 2001).

The following year, in a study of 101 cirrhosis patients (with more than 1500 control subjects), the risk among coffee drinkers showed a significant reduction in cirrhosis (the odds ratio was 0.54) compared with individuals who never drank coffee. Similar to the previous study, for those drinking more than 3 cups per day, there was a significant trend for lower cirrhosis risk with an odds ratio of 0.29. Repeating assumptions from the previous study, the consumption of other caffeine-containing beverages did not reduce the occurrence of cirrhosis. The researchers followed up a few years later and continued to find evidence for the beneficial role of coffee consumption in reducing the risk of death from liver cirrhosis. The mortality rate of people who drank 3 or more cups of coffee was lower than that of those who drank 2 cups of coffee or less (Tverdal 2003).

The correlation was also valid for alcoholic cirrhosis as well as cirrhosis from other causes, which was different from the study from the 1990s. There also seemed to be a threshold for how much coffee was effective; there was no further decline in mortality when the intake was more than three to four cups of coffee. The meta-analysis done by Kennedy et al. in 2016 concluded that an increase in daily coffee consumption of two cups is associated with a near halving of the risk of cirrhosis.

A number of research studies have examined the role of coffee in preventing liver cirrhosis, with consistently positive and sometimes quite dramatic results. A 2002 study also published in the Annals of Epidemiology concluded that there is a 71% lower risk for those drinking more than three cups per day (Gallus 2002). Drinking three or more cups of coffee daily lowers the risk by up to 53% of liver disease progression for patients with chronic hepatitis C. Black tea or green tea, however, had no effect on liver disease (Freedman 2009).

Hepatocellular carcinoma (HCC) is a type of liver cancer that frequently stems from cirrhosis of the liver or hepatitis infection. It is becoming more common in developing countries and is often fatal. For decades, scientists have studied the relationship between coffee consumption and the preventive effect against liver cancer. In the 1990s, animal experiments showed chlorogenic acids in coffee had inhibitory effects against chemical carcinogenesis in liver tissue (Tanaka 1990).

Researchers found that subjects with a history of liver disease had a significant inverse relationship between coffee consumption and liver cancer. They concluded that coffee may prevent liver cancer more effectively among subjects with liver disease than among those without liver disease, but at the same time, their conclusion stated, “…coffee consumption is significantly associated with a decreased incidence of liver cancer.” (Shimazu 2005).

This was followed by several epidemiologic studies:

A large-scale study followed 90,000 Japanese subjects over ten years in the Journal of the National Cancer Institute in 2005 and concluded that coffee drinkers have half the risk of developing liver cancer as non-coffee drinkers. This effect was recorded for those who drank just one to two cups daily, with an increasing effect at three to four cups. Unfortunately, because decaffeinated coffee is rarely consumed in Japan, they could not make a distinction between caffeinated and decaffeinated coffee and could not determine if caffeine was partly responsible for the decreased risk of HCC (Inoue 2005). In a similar study in Italy, where coffee is widely consumed, men and women who drink coffee may be reducing their risk of liver cancer, but tea and decaf did not appear to share regular coffee's protective effects. Abstainers of coffee drinking resulted in a doubled risk for HCC with respect to moderate drinkers (<14 cups/week) (Montella 2007).

In another 2007 meta-analysis of published studies on HCC, quantitative information on coffee consumption from thousands of cases and controlled studies from Europe and Japan (approximately 240,000 thousand people, among them 2,260 diagnosed with HCC) had similar conclusions: They observed a 41% reduction in the risk of HCC among coffee drinkers compared with never-drinkers. Regardless of study design, geography and other biases, men and women who regularly drink coffee have a significantly reduced risk of developing liver cancer and other liver diseases, suggesting a continuum of the favorable effect of coffee on liver function (Bravi 2007).

That same year, another review of studies that represented hundreds of thousands of cases observed an inverse relation between coffee consumption and the risk of liver cancer, and in six studies, the association was statistically significant. Overall, an increase in the consumption of 2 cups of coffee per day was associated with a 43% reduced risk of liver cancer, and the odds dropped by 23% with each cup (Larsson 2007).

Additional large studies were done and showed similar results: High coffee consumption was significantly associated with a lower risk of HCC in subjects, but the predominant role of viral replication in chronic hepatitis B patients reduced that risk. They said that more research was needed to prove how certain coffee ingredients protect against certain diseases and how coffee might interact with viruses that cause HCC in people with chronic liver disease (Jang 2014).

The relationship between coffee intake and decreased risk of HCC appears to be consistent for several etiological types of chronic liver disease, including HCC. Lifetime coffee consumption is shown to be an independent protective factor against HCC.

In 2020, Bhurwal et. al. did a meta-analysis to evaluate the association of coffee with HCC or liver cancer development along with the amount of coffee needed to prevent HCC or liver cancer. They reviewed dozens of articles from 1996–2019 that associated coffee with liver cancer, narrowing them down to 20 studies for data. Their systematic review showed that drinking coffee provides benefits with a reduction in the risk of HCC, or liver cancer and that higher doses of coffee have higher benefits in terms of risk reduction.

Chlorogenic acids (CGA), a rich group of plant polyphenols consumed by humans, are the components primarily responsible for the functional properties of coffee. CGA are esters formed between quinic acid and some trans-cinnamic acids (caffeic, ferulic, and p-coumaric), and coffee has a high concentration of them, which is why coffee is considered one of the most important contributors to antioxidant intake in many countries since people drink it often multiple times daily. Some of the original CGAs degrade into CGA lactones (CGL) or quinides during the roasting process, up to the point where heat degradation occurs (Farah et al. 2005).

Part of the lactone is converted into caffeoylquinic acid after contact with the alkaline pH of human digestive fluids. So, it is likely that a lot of the lactones that are consumed in the beer change back into their original chlorogenic acid forms during digestion, which indirectly raises the total amount of chlorogenic acid that is taken in (Farah 2012).

CGA has been shown to have the following impacts and actions: antioxidant activity, anti-inflammatory, antibacterial, anti-mutagenic, possible anti-opioid activity, hypoglycemic, and others. The polyphenols in black coffee (without milk products) are readily bioavailable, which is not the case with all foods (Duarte & Farah 2011). There is an abundance of literature on coffee CGAs and their antioxidant activity, especially on coffee’s positive impact on liver health.

One of the medical benefits of caffeoylquinic and dicaffeoylquinic acids is that they can fight viruses like adenovirus and herpes (Chiang et al. 2002). They can also protect the liver in a model of liver damage (Basnet et al. 1996). CGA has shown anti-hepatitis B virus potency as well (Wang et al. 2009).

Approximately 80%–100% of chlorogenic acids are extracted in coffee brewing, yielding approximately 35–100 mg of chlorogenic acids per 100-mL cup of arabica coffee in free form and soluble fiber (Díaz-Rubio & Saura-Calixto 2007). Although maintaining coffee brews at a high temperature (like on a hot plate) reduces chlorogenic acid and lactone concentrations, they are still present in relatively high amounts in medium-roasted coffees compared with most food sources (Clifford 2000). Non-coffee drinkers usually take in less than 100 milligrams of chlorogenic acids per day, whereas modest and heavy coffee drinkers ingest 0.1–2 grams (Farah 2012).

It was found that chlorogenic acid lactones could bring rats' blood sugar levels back to normal. Later, these effects were seen with chlorogenic acids themselves (Farah 2012).

Diterpenes are active compounds found in plants, fungi, bacteria, and animals in both terrestrial and marine environments. Diterpenes have shown medicinal biological activities, and some diterpenes are produced at a commercial scale to be used as medicines, food additives, in the synthesis of fragrances, or in agriculture (de Sousa 2018).

Cafestol and kahweol (C&K) are specific to coffee and contribute to its bitterness. These chemicals, C&K, are bioactive, and their derivatives, which are mostly salts or esters of saturated fatty acids (mostly) and unsaturated fatty acids, make up about 20% of the lipid fraction of coffee. Cafestol makes up about 0.2% to 0.6% of coffee weight (Farah 2012).

Diterpenes have been shown to have the following impacts and actions: Antioxidant, hypoglycemic, hypolipidemic, antimicrobial, antiviral, and cafestol effects from high habitual coffee consumption are associated with a reduced risk of developing type 2 diabetes (Mellbye et al. 2015). Additionally, diterpenes have been associated with anticarcinogenic and hepatoprotective properties in vitro and as agents for cancer chemopreventive blocking (Cavin et al. 2002).

In human liver epithelial cell lines, C&K treatment decreased the binding of aflatoxin B1 to DNA. This was linked to the enzyme GST-mu, which is known to remove aflatoxin B1. It was also discovered that C&K blocks one of the human enzymes that activates aflatoxin B1. This helps explain some of C&K's anticancer effects (Cavin et al. 2002).

The brewing method has a direct impact on the dosage of diterpenes per cup: Paper filters trap most of the diterpenes, whereas the metal filters of the French press, espresso, Turkish and Scandinavian coffee maximize diterpenes. You can see the oils floating on the surface of your coffee if you reflect the light off of it the right way. C&K may increase blood cholesterol levels, which is something that some people may need to avoid. If this is the case, choosing to brew the coffee with a paper filter using a pourover or drip method will virtually eliminate the diterpenes while allowing the caffeine and chlorogenic acids to still be bioavailable.

Melanoidins are what make coffee (and other foods) turn brown when roasted, baked or toasted. They are formed during the Maillard reaction, when sugars and amino acids combine at high temperatures and low water activity. They may be considered bioactive compounds (Bekedam et. al. 2008). The amount of melanoidin formation is directly related to the amount of antioxidant formation. The longer we roast, the more intermediate- and high-molecular-weight melanoidins are made (Moreira et al. 2019). They are shown to have the following impacts and actions: antioxidant activity, metal-chelating, antibacterial and prebiotic functionality.

Several studies have shown that melanoidins extracted from coffee possess antioxidant activity. (Tagliazucchi, 2010). They inhibit lipid peroxidation. Increasing evidence shows that oxidized lipids, advanced lipid oxidation end products, and lipid peroxidation play a major role in developing most oxidative stress-related diseases. Lipid peroxidation occurs in all human neurodegenerative diseases, such as Alzheimer’s disease, Parkinson's disease, and even atherosclerosis (Tagliazucchi, 2010).

Coffee melanoidins do not seem to be absorbed in humans, but they can function as an antioxidant dietary fiber with an overall antioxidant capacity via embedded low molecular compounds. Melanoidins can act like a ‘sponge’ for free radicals in the gut (Garsetti, 2000; Folmer, 2017). This improves the reduced or oxidized glutathione balance in the colon. Glutathione is an antioxidant produced in our cells. Oddly, the antioxidative structures formed in coffee melanoidins are similar to vitamin E. These appear to activate their scavenging properties gradually (Bekedam, 2008).

In the same way, coffee melanoidins are able to chelate transition metal ions; that is, they are able to bind Zn2+, Cu2+, and Fe2+ (Takenaka, 2005; Morales, 2005). Metal-chelating ability is key to inhibiting lipid peroxidation, among other benefits.

The soluble fiber role of melanoidins enhances their immune-stimulating properties and contributes significantly to reducing the risk of colon cancer. More colon motility (the need to go to the bathroom) and better microbiota balance may help lower inflammation in the colon and speed up the removal of carcinogens (Vitaglione, 2012; Moreira, 2015; Fogliano, 2011). Melanoidins can also stimulate beneficial microbiota growth in the gut, acting as prebiotics (Sales et al, 2020).

Coffee melanoidins may promote the growth of a beneficial colon microbiota, affecting inflammatory pathways in the colon and the liver (Folmer, 2017). Model melanoidin solutions (Moreira et al. 2019) show that melanoidins can change the bacteria that live in the colon, even though they are changed in the human gut.

Coffee melanoidins seem to have a protective effect on liver steatosis in obese rats (Vitaglione, 2012), which suggests that the melanoidins in coffee may have an influence on liver fat and functionality. Glutathione may be involved.

It is undeniable that many people drink coffee because of the effect of caffeine on their wakefulness. However, in the case of liver health, the interaction of coffee’s many beneficial compounds appears to work in tandem with coffee’s caffeine. Scientists have shown caffeine produced in the laboratory does not have the same effect as natural coffee with caffeine. Caffeine metabolites have shown antioxidant activity in vitro (by measuring the average plasma iron-reducing capacity). This shows that whole coffee is better at protecting cells from damage than decaffeinated coffee (Moura-Nunes et al. 2009).

Caffeine is an alkaloid found in the leaves, seeds, and fruits of coffee, tea, cocoa, cola, and guarana plants. Within 10 minutes of drinking coffee, the stomach and first part of the intestine absorb the caffeine, and it reaches the maximum concentration in the bloodstream within about an hour. Caffeine has been shown to be anti-inflammatory, and caffeine metabolites have shown antioxidant activity (Farah 2018).

The liver metabolizes the caffeine into paraxanthine, theobromine, and theophylline, which contribute to enhancing its effects. In humans, caffeine and theophylline block adenosine receptors. Adrenosine interacts with certain cell receptors, mainly by slowing down neural activity and making you sleepy, but it also does many other things in the body (Nehlig et al. 1992). Caffeine’s catabolic products, theobromine and xanthine, exhibit antioxidant properties (Azam et al. 2003).

Fibrosis, cirrhosis, HCC, MAFLD and alcoholic liver disease are all connected to oxidative stress, which is an imbalance between the production and accumulation of oxygen reactive species (ROS) in cells and the antioxidant system that detoxifies these reactive products. The liver metabolizes substances to maintain homeostasis in the organism, but this process produces free radicals, including ROS, which in turn produces more oxidative stress. Antioxidants are molecules that help delay or prevent oxidation, fighting free radicals and keeping us healthy. Caffeine is an effective inhibitor of all three ROS species (Scalbert & Williamson 2000).

In some parts of the body, caffeine changes the amount of cyclic adenosine monophosphate (cAMP) inside cells. cAMP controls the functions of immune cells, is an important part of metabolism, and helps pancreatic beta cells release insulin. Upregulation of cAMP inhibits the activation of inflammatory effector cells, such as T cells. In T cells, cAMP downregulates various cellular functions, including cytokine production and cytotoxicity (Sitkovsky et al. 1988).

The anti-inflammatory properties of caffeine are also due to its function as a phosphodiesterase (PDE) inhibitor (Horrigan et al. 2006). Phosphodiesterase inhibitors encourage blood vessel dilation and smooth muscle relaxation and are used to treat people with pulmonary hypertension or lung issues, sometimes even reversing some of the damage to the heart and lungs.

Several studies using common rodent models have shown the beneficial effects of coffee and caffeine extracts against liver fibrosis. In almost every study, coffee blocked toxin-induced liver fibrosis and cirrhosis. In one key study using rats, the scientists induced liver disease in the animals and then tested regular coffee, decaffeinated coffee and a water-caffeine solution. Regular coffee produced the most impactful positive results, showing that it was not just the caffeine that benefits the liver. “A reduction in hepatic TGF-β1 expression in the group receiving decaffeinated coffee indicates that caffeine may not be the solely hepatoprotective compound in coffee beverages” (Furtado 2012).

Numerous studies indicate that damage to the genetic material plays a crucial role in a variety of human diseases, in particular in the etiology of cancer. Chronic consumption (8 weeks) of a pure arabica dark-roast coffee blend significantly reduced spontaneous DNA strand breaks in the blood cells of healthy volunteers, pointing to a DNA protective effect (Pahlke et al 2019) and (Schipp et al. 2018).

Caffeine and Telomeres: Telomeres play a vital role in preserving the information in our genome. Telomeres are DNA-protein structures found at both ends of each chromosome that protect the genome from degradation, unnecessary recombination, repair, and interchromosomal fusion. Caffeine promotes the expression of telomerase reverse transcriptase (TERT), extending the telomere length and preventing cellular deterioration and loss of division and growth capacity (Tao et al. 2021).

Caffeine has also been shown to improve microscopic structural changes of the thymus, spleen and liver due to aging, which helps to clarify different ways coffee benefits health with regard to longevity (Tao et al. 2021).

Caffeine and Adenosine: There is evidence that caffeine may protect by blocking adenosine, which is a powerful internal regulator of inflammation and tissue repair (Chakraborti et al. 2003). There are four subtypes of extracellular adenosine: A1, A2A, A2B, and A3 (Fredholm et al. 2001). Activation of adenosine A2A receptors promotes tissue repair, wound healing, and matrix production (Montesinos et al. 1997 & 2002), reduces inflammation and prevents acute inflammatory injury in the liver [Ohta & Sitkovsky 2001]. In other cell types, adenosine A2A receptors stimulate collagen production via mitogen-activated protein (Revan et al. 1996).

At high doses, caffeine inhibits cAMP, yet a low dose of caffeine regulates cAMP levels through antagonism of the A2A receptor. In short, the lower doses of caffeine were proinflammatory, which would be difficult to deduce from the observational and epidemiological studies (Ohta & Sitkovsky 2001). This is one reason that scientists believe it is the caffeine in conjunction with other compounds in coffee (chlorogenic acid, caffeic acid, ferulic acid, etc.), diterpenes (cafestol, kahweol), and trigonelline, which may exert liver protective effects (Farah et. al. 2019).