investigators linked higher coffee consumption with lower risk of cirrhosis, liver cancer and liver-related death.

“Previous studies suggested that coffee might benefit the liver, but most were smaller or looked at only one piece of the puzzle,” said hepatologist Hyunseok Kim, MD, MPH, PhD, assistant professor of Medicine at Cedars-Sinai and corresponding author of the study. “We followed hundreds of thousands of people for more than a decade and looked at their health outcomes along with liver MRI scans and blood protein analyses. Together, those findings help explain the biological mechanisms behind coffee’s association with better liver health.”

A Cedars-Sinai study of more than 355,000 adults found that drinking coffee was associated with lower risks of cirrhosis, liver cancer and liver-related death. The investigators analyzed data from 354,957 UK Biobank participants who did not have cirrhosis or liver cancer at the start of the study. Over a median follow-up of 13 years, researchers tracked new diagnoses of cirrhosis, liver cancer and liver-related death through linked health records.

Compared with people who did not drink coffee, those who drank five or more cups of coffee a day had a 32% lower risk of cirrhosis, a 47% lower risk of liver cancer and a 42% lower risk of liver-related death. Participants who drank more coffee also had lower levels of liver fat, liver iron, fibrosis and liver inflammation in MRI scans. And coffee drinkers’ blood tests showed higher levels of proteins tied to healthy liver function and lower levels of proteins linked to scarring and inflammation.

While liver health risk decreased as coffee consumption increased, researchers noted that benefits were seen even at one to two cups per day and appeared strongest around three to four cups per day. They emphasized that while the highest intake group (five or more cups daily) showed benefit, they would not recommend increasing consumption to that level specifically.

Similar protective associations were observed for caffeinated and decaffeinated coffee, suggesting that caffeine itself is unlikely to be the only active component, and that other naturally occurring compounds in coffee may contribute to the benefits. Because the study was observational, investigators noted it does not prove that coffee itself prevents liver disease. And they emphasized that coffee should complement—not replace—established strategies for preventing liver disease.

“Our findings support moderate coffee consumption for people who already enjoy and tolerate it well,” said study senior author Ju Dong Yang, MD, medical director of the Liver Cancer Program at Cedars-Sinai. “However, we would not recommend that someone begin drinking coffee solely for liver protection based on this study alone. Prevention should continue to focus on maintaining a healthy weight, limiting alcohol, exercising regularly, and managing blood sugar, blood pressure and cholesterol.”

Because caffeine isn’t appropriate for everyone, people with uncontrolled high blood pressure, certain heart rhythm disorders, severe anxiety, insomnia or other conditions that require limiting caffeine should consult their healthcare provider before increasing their coffee consumption.

“The next step in our research is to identify the specific compounds in coffee that are responsible for these liver-protective associations,” said study author Shelly Lu, MD, the Women’s Guild Chair in Gastroenterology and director of the Karsh Division of Gastroenterology and Hepatology at Cedars-Sinai. “Our findings point to biological pathways involving inflammation and scarring and highlight molecular targets that future research can explore to better understand how coffee may influence liver health and who stands to benefit the most.”

Additional Cedars-Sinai authors include Yufeng Wang, Abdelrahman M. Attia, Minsun Kwak, Seungwon Burm, Derin Celtik, Daniel Legaspi, Osama Khattab, Naomy Kim, Beza M. Mengistu, Kelsey N. Larios, Walid Ayoub, Alexandar Kuo, Paul Martin, Aarshi Vipani, Yun Wang, Debiao Li and Stephen Pandol.

Other authors include Mohammad Saeid Rezaee-Zavareh, David Sooik Kim and Suthat Liangpunsakul.

Conflicts of Interest: Ju Dong Yang reports the following conflicts of interest: consulting service for AstraZeneca, Eisai, Exact Sciences, and Fujifilm Medical Sciences.

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

Alcohol‐associated liver disease, which is caused by chronic alcohol use, can lead to inflammation and scarring of the liver. In severe cases it can lead to liver failure, with some patients requiring a liver transplant. The condition accounts for nearly half of the liver-disease-related deaths in the U.S., according to the National Institutes of Health.

“We do not have effective therapies for alcohol‐associated liver disease,” said Shelly Lu, MD, the Women's Guild Chair in Gastroenterology and director of the Karsh Division of Gastroenterology and Hepatology. “Abstaining from alcohol can arrest this condition but this is often difficult to achieve. To save lives, we need to target drivers of alcohol-associated liver disease that promote inflammation and scarring. ”

Lu is co-corresponding author of a study, published in Hepatology, which connected a protein called FOXM1 with scarring and inflammation in alcohol‐associated liver disease. Another recent Cedars-Sinai study, published in Science Advances, showed that alcohol caused an enzyme known as SRC to alter the liver’s immune responses.

In Lu’s study, investigators examined alcohol-exposed human liver tissue samples and cells, and those of laboratory mice. They found that the FOXM1 protein controlled a network of genes and proteins that worked together to cause liver scarring and inflammation. FOXM1 is known to be involved in multiple liver diseases, including cancer. When the investigators suppressed the action of FOXM1, liver scarring was reversed.

“We found that FOXM1 is a key regulator of alcohol-associated liver disease progression and represents a promising target for therapeutic intervention,” Lu said.

The Science Advances study demonstrated how alcohol exposure—through the action of the enzyme SRC and the protein called UBC9—triggered inflammation and immune changes in the liver. When investigators used gene editing or enzymes to block SRC activity,  inflammation was reduced.

“The strong effect of enzymes suggests the possibility of therapeutic targets against alcohol‐associated liver disease,” said Maria Lauda Tomasi, PhD, associate professor of Medicine and Biomedical Sciences at Cedars-Sinai and the study’s co-corresponding author.

The findings also highlight UBC9 as a key regulator of the immune response, which could have implications beyond the liver for cancer and other inflammatory diseases, Tomasi said.

“These rigorous studies contribute greatly to our understanding of alcohol‐associated liver disease,” said David E. Cohen, MD, PhD, chair of the Department of Medicine. “The findings could open new pathways for the development of urgently needed treatments.”

Other Cedars-Sinai authors of the Hepatology study include Bing Yang, Liqing Lu, Jiaohong Wang, Lucía Barbier-Torres, Jing Zhang, Jyoti Chhimwal, Sonal Sinha, Brent Beadel, Guo Zhang, Takashi Tsuchiya, Maria Lauda Tomasi and Heping Yang. The other author was Ting Liu.

Funding: This work was supported by NIH grant R01AA026759 (Shelly C. Lu, Heping Yang, and Maria Lauda Tomasi).

Other Cedars-Sinai authors of the Science Advances study include Swati Chandla, Youngyi Lim, Andrea Floris, Michael Mazarei, Xi Yang, Takashi Tsuchiya, Manisha Dagar, Alfonso Darmawan, Monica Justo, Ramachandran Murali, Alexandra Gangi, Nirmala Mavila and Komal Ramani. The other author was Ivan Tomasi.

Funding: This work was supported by the National Institutes of Health, grant 

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

The study, published in the journal Liver Cancer, found that these patients had overall survival rates that were 85% higher than patients who received immunotherapy alone.

“The data we reviewed showed that patients who received follow-up transplants or tumor removal after immunotherapy reduced the size of their tumors lived much longer than patients who just remained on immunotherapy,” said Ju Dong Yang, MD, medical director of the Liver Cancer Program at Cedars-Sinai and senior author of the study.

Liver cancer is rarely detected in the earliest stages, when tumors are small enough that a transplant or removal is possible. In advanced liver cancer, immunotherapy—medications that harness the power of a patient’s immune system—can shrink tumors but not cure the disease.

Previous research, also led by Cedars-Sinai, found that liver transplant or tumor removal is possible after immunotherapy shrinks a tumor to “downstage” the cancer. In this new study investigators wanted to see how well patients treated with these follow-up procedures fared.

They reviewed data on more than 4,300 patients with advanced liver cancer from the National Cancer Database, which contains more than 70% of all newly diagnosed cancer cases in the U.S.

Despite the higher overall survival rates after follow-up procedures, only about 3% of patients on immunotherapy went on to receive transplants or tumor removal. Most of those patients were treated at academic medical centers like Cedars-Sinai, the investigators found.

“Performing liver transplant following immunotherapy isn’t yet common practice,” Yang said. “This is unfortunate, as patients with advanced liver cancer often die without such treatment—even if their cancer is under control—because they also have other liver ailments. A transplant leaves the patient with a healthy liver.”

Yang plans to further make his case for more aggressive treatment for these patients through a new study that will launch in the coming months. Investigators will enroll patients who receive immunotherapy followed by liver transplants and will record their outcomes.

“When our physician-scientists create studies based on patient needs and then apply their findings to patient care, it improves outcomes for everyone we serve and for patients around the world,” said Robert Figlin, MD, interim director of Cedars-Sinai Cancer. “As an academic medical center, that is our mission.”

Additional Cedars-Sinai authors include Gwang Hyeon Choi, Hyun-Seok Kim, Michael Luu, Alexander Kuo, Walid S. Ayoub, Hirsh Trivedi, Yun Wang, Aarshi Vipani, Pin-Jung Chen, Steven A. Miles, Emily A. Kaymen, Andrew Hendifar, Tsuyoshi Todo, Todd V. Brennan, Georgios Voidonikolas, Steven A. Wisel, Justin Steggerda, Cristina Ferrone, Kambiz Kosari and Nicholas Nissen.

Other authors include Neehar D. Parikh and Amit G. Singal.

Funding: Dr. Singal’s research is supported by NCI R01 MD012565 and R01 CA256977. Dr. Yang’s research is supported by NCI K08CA259534.

Conflict of interest: Ju Dong Yang provides consulting service for AstraZeneca, Eisai, Exact Sciences, Exelixis, and Fujifilm Medical Sciences.

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

Hepatology Experts Available

Shelly Lu, MD, the Women's Guild Chair in Gastroenterology and director of the Karsh Division of Gastroenterology and Hepatology, is presenting research related to alcohol-associated liver injury and colorectal-liver metastasis.

Alexander Kuo, MD, professor of Medicine and medical director of Liver Transplantation, is presenting results of a California Liver Network study exploring factors associated with being “too early” for liver transplantation.

Walid Ayoub, MD, professor of Medicine and associate medical director of Liver Transplantation, is available to explain cholestatic and autoimmune liver diseases and related research.

Ju Dong Yang, MD, associate professor of Medicine and director of the Liver Cancer Program, can address questions regarding liver cancer and immunotherapy for hepatocellular carcinoma.

Ekihiro Seki, MD, PhD, professor of Medicine, is moderating a session about therapies for treating alcohol-associated liver disease.

Paul Martin, MD, director of Clinical Hepatology Education and Research, is presenting updated practice guidelines on long-term care of liver transplant recipients.

Maria Lauda Tomasi, PhD, associate professor of Medicine, is available for interviews about alcohol-associated liver disease and related clinical research.

Hyunseok Kim, MD, MPH, PhD, hepatologist and assistant professor of Medicine, is presenting research on the impact of coffee intake on liver health, including coffee’s association with cirrhosis and liver cancer.

Media Contact

To arrange interviews, contact Laura Coverson at 310-562-1112 or Laura.Coverson@cshs.org.

Liver fibrosis can be triggered by many factors, including viruses that cause hepatitis (infection and inflammation in the liver), long-term alcohol use or some metabolic disorders. Because it produces few or no symptoms at first, the condition typically progresses slowly for years, going undetected until it has caused serious organ damage. At that stage, liver transplantation may be the only effective treatment. The ability to undo the scarring would be a major breakthrough for patient care.

In their study, published in the peer-reviewed journal Nature Communications, Cedars-Sinai investigators examined three genes and the proteins that they made. One of them, FOXM1, is known to cause liver cancer, inflammation and fibrosis when it becomes overactive in hepatocytes, a type of liver cell. The two other genes, MAT2A and MAT2B, are required to activate another type of cell, hepatic stellate cells, which plays a key role in liver fibrosis. The study demonstrated that the proteins coded by these three genes interact and that all three are needed to produce liver fibrosis.

“We discovered that these proteins ‘talk’ with each other inside liver cells,” said Shelly Lu, MD, director of the Karsh Division of Gastroenterology and Hepatology at Cedars-Sinai and corresponding author of the study. “They even influence nearby cells through extracellular vesicles—fat molecules filled with genetic fragments, proteins and other biological materials that act as messengers between cells. Working together, that is how these proteins stimulate each other, driving liver inflammation and fibrosis.”

These discoveries raised the possibility that inactivating just one of the three proteins might block liver fibrosis. To test that theory, the team induced liver inflammation and fibrosis in laboratory mice and treated them with a substance known as FDI-6 that blocks the FOXM1 protein. In a series of experiments, they showed that FDI-6 could prevent liver fibrosis from developing, halt further progression and even reverse the condition, resulting in the scarring disappearing.

Although both mice and humans have all three genes, and these genes also are more highly expressed in human liver fibrosis and cirrhosis, the study did not prove that a similar treatment would work in patients with liver fibrosis. Reaching that conclusion would require additional research and testing, Lu said. 

“What we achieved was to unveil the axis of FOXM1, MAT2A and MAT2B as a potential target for developing drugs to treat liver fibrosis,” Lu said. “Our findings suggest that blocking any of these proteins might be useful in treating this condition.”

Peter Chen, MD, professor of Medicine, the Medallion Chair in Molecular Medicine and interim chair of the Cedars-Sinai Department of Medicine, said, “This highly original study significantly advances our understanding of an insidious condition that too often leaves patients and doctors with few treatment options. It is emblematic of Cedars-Sinai’s innovative scientific work.”

Other Cedars-Sinai authors include Bing Yang, Liqing Lu, Ting Xiong, Wei Fan, Jiaohong Wang, Lucía Barbier-Torres, Jyoti Chhimwal, Sonal Sinha, Takashi Tsuchiya, Nirmala Mavila, Maria Lauda Tomasi, DuoYao Cao, Jing Zhang, Hui Peng, Komal Ramani, Jenny Han, Ekihiro Seki and Heping Yang. Additional authors include Jose M. Mato, Ting Liu, Xi Yang and Vladimir V. Kalinichenko.

Funding was provided by the National Institutes of Health grant P01CA233452 to S.C. Lu, H. Yang and E. Seki; Plan Nacional of I + D SAF2017-88041-R to J.M. Mato; and the National Natural Science Foundation of China 82070632 to Liu T.

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The study is published in JAMA Network Open.

“We found that patients in the early stages of steatotic liver disease could consume less than 7.4 grams of alcohol a day without elevating their risk for advanced liver fibrosis which is associated with severe health problems including liver cancer, organ failure and even death,” said Yee Hui Yeo, MD, first author of the study and a clinical fellow in the Karsh Division of Gastroenterology and Hepatology at Cedars-Sinai.

“That amount is equivalent to about 6 ounces of beer, 2.5 ounces of wine and less than 1 ounce of a distilled spirit, like vodka or tequila,” Yeo said.

Steatotic liver disease is the most common chronic liver condition in the U.S., according to the American Liver Foundation, which estimates that 1 in 4 adults have the condition, which is often undiagnosed. Patients are advised to abstain from alcohol consumption, which can further damage the organ. But abstinence can be challenging for many people, even those who are light drinkers and or who have alcohol use disorder, according to the study authors.

“A critical gap in our understanding of steatotic liver disease progression has been the lack of concrete data to define a 'safe' level of alcohol consumption for those patients who can’t quit drinking. Our study addresses this unmet need by providing empirical evidence on the relationship between alcohol intake levels and the progression of early-stage disease,” Yeo said.

In the cohort study, Yeo—working with medical scientists in China—evaluated data from the U.S. National Health and Nutrition Examination Survey III. Investigators reviewed the health surveys from nearly 3,000 people with steatotic liver disease to identify a safe threshold for alcohol consumption.

Yeo emphasizes the findings are not a recommendation that patients with steatotic liver disease continue to drink but are intended to guide their care if abstinence is challenging.

“There has been ambiguity about the extent to which alcohol consumption exacerbates steatotic liver disease. We want to reduce this uncertainty by providing evidence-based information. We favor abstinence as the safest course of action for these patients. But for those who are not able to stop drinking, these findings provide concrete guidelines for making decisions about their health and lifestyle,” Yeo said.

In addition to limiting alcohol consumption, Yeo advises patients with steatotic liver disease improve their diet, get regular physical exercise and manage risk factors, which include hypertension, obesity, diabetes and prediabetes.

“While it is still best to counsel abstinence for patients with this liver disease, the study defines a threshold beyond which alcohol consumption can increase mortality. The results provide new guidance for clinicians and patients,” said Shelly Lu, MD, the Women's Guild Chair in Gastroenterology and director of the Division of Digestive and Liver Diseases at Cedars-Sinai.

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Read more on the Cedars-Sinai Blog: Fatty Liver Disease: Know Your Risk.

“Ours is the first study to show that the liver has protective mechanisms for defending itself against cancer,” said Shelly Lu, MD, director of the Karsh Division of Gastroenterology and Hepatology at Cedars-Sinai and senior author of the study. “We discovered that two proteins in healthy liver cells, working together, curb the action of a third protein that makes the liver a fertile place for cancer to grow.”

Cancer that originates in the liver is one of the leading causes of cancer death. The liver is also a common site for cancer to spread to—most often from colorectal cancer.

“Harnessing the power of the body’s own defense mechanisms represents a promising way forward in the battle against some deadly cancers,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and the PHASE ONE Foundation Distinguished Chair. “This study builds on years of work and is an important step in that direction.”

Two proteins long studied by Lu—prohibitin 1 and methionine adenosyltransferase 1A—are found in healthy liver cells. Previous research by Lu and her team has shown that when either of these proteins is missing in laboratory mice, the mice develop liver cancer, but investigators didn’t yet understand fully why this happens.

“We have been studying these two proteins for several decades,” Lu said. “In this new study, we found that they work together to suppress a particular protein called matrix metalloproteinase-7, which is well known among cancer researchers as one that breaks down the matrix that holds cells together and allows invasion of cancer cells to occur.”

In their latest study, investigators found that prohibitin 1 and methionine adenosyltransferase 1A partner together to shut down expression of cancer-promoting matrix metalloproteinase-7.

“This prevents cancer from taking hold,” Lu said.

Investigators edited the DNA of laboratory mice to knock out expression of the partnering proteins. In some of those mice, investigators also knocked out expression of the cancer-promoting protein. They then studied what happened in a mouse model of colon cancer liver metastasis.

“We found that with either of the partnering protective proteins eliminated, the mice were wildly sensitive to cancer metastasis,” Lu said. “It grows like wildfire. But if you also silence the cancer-promoting protein, that sensitization is gone and the cancer does not grow. This provides strong evidence that it is the cancer-promoting protein that is sensitizing the liver to cancer metastasis, and the combination of the two partnering proteins is keeping its expression down. This is the defense mechanism that no one had yet discovered.”

Investigators will next examine strategies to prevent the partnering protective proteins from being downregulated, so that they suppress the cancer-promoting protein and prevent metastases to the liver, Lu said.

Funding: This study was supported by National Institutes of Health grants P01CA233452 and R01DK123763, Cedars-Sinai Cancer Developmental Funds, Plan Nacional of I+D grant SAF2017-88041-R, and American Heart Association grant 23CDA1052548.

Read more on the Cedars-Sinai Blog: The Liver/Cancer Connection