new research for liver cirrhosis

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New cell therapy shows progress in treating advanced liver disease

A new type of cell therapy to treat patients with liver scarring, or cirrhosis, shows promise of being the first medical treatment for this common and lethal condition.

Results from a clinical trial of the treatment was presented at the American Association for the Study of Liver Diseases (AASLD) conference (2023) in Boston.

The innovative new approach to treating cirrhosis uses macrophage immune cells – the cells associated with tissue repair – derived from the patient’s own cells. It was tested in a clinical study, called ‘MATCH Phase 2’, involving 50 patients in Scotland with cirrhosis caused by a variety of different factors, such as alcohol, fatty-liver disease and viral hepatitis.

The data shows the treatment - pioneered by Professor Stuart Forbes’ lab at the University of Edinburgh - helped dramatically reduce serious liver-related complications during this one-year study. These complications can lead to hospitalisation and death.

The results indicate the treatment might help delay the need for a liver transplant, which is currently the only treatment option available to patients with advanced liver disease, but is a highly invasive procedure severely limited by organ availability, patient eligibility and complex aftercare.

Professor Forbes who led the trial team said,

We are encouraged by the new results. This trial shows the treatment is well tolerated, and is associated with reducing the clinical complications in patients with end-stage liver disease.

Chronic liver diseases and associated cirrhosis account for approximately one million deaths per year globally, with 4,000 deaths per year in the UK alone.

In MATCH Phase 2, 26 patients received the macrophage treatment, and 24 patients in the control group received standard medical care only. After one year, there were no liver-related clinical events in any of the 26 patients treated with macrophages. In the control group, four patients out of the 24 developed liver-related severe adverse events, and there were three deaths.

Professor Stuart Forbes is a clinical hepatologist, IRR Director, and group leader in the Centre for Regenerative Medicine has spent over a decade researching macrophages, supported by Edinburgh Innovations, the University’s commercialisation service. He and his team, funded by the Medical Research Council, have been investigating ways to understand and enhance the natural regenerative features of macrophage cells to create more effective medicines for liver disease. The MATCH studies have been conducted in partnership with the Scottish National Blood Transusion Servce and the Cell and Gene Therapy Catapult.

Dr Robin Buckle, Chief Science Officer at the Medical Research Council said,

The results of this trial of a novel macrophage cell therapy show great promise and if successfully built upon should provide lasting benefit for patients with chronic liver disease, an area of significant and unmet clinical need. It is exciting to see MRC’s long-term investment in Centre for Regenerative Medicine bearing fruit, and we look forward to the next phase of development.

Co-investigator Professor Jonathan Fallowfield said:

Currently, there is little hope for patients with advanced cirrhosis, apart from a liver transplant and a life on immunosuppressants. Liver-related complications in cirrhosis can be fatal and put huge pressure on health services. We are cautiously optimistic that we can bring hope to patients with this neglected condition.

An initial smaller study led by Professor Forbes in 2019, MATCH Phase 1, showed the treatment was well tolerated, exhibiting none of the side effects commonly observed with immune cell therapy treatments. This was repeated in the MATCH Phase 2 results.

More about the Macrophage Cell Therapy Trials

Liver disease patients could one day benefit from a new cell therapy that has just completed its first clinical trial, published in Nature Medicine.

Researchers who tested the potential treatment in patients with liver cirrhosis – where long term damage produces scarring – found the therapy had no significant adverse effects.

Now the team, led by Professor Stuart Forbes, Director of the Institute for Regeneration and Repair and the MRC Centre for Regenerative Medicine, is to gauge the effectiveness of the treatment – which is based on white blood cells called macrophages, that are key to normal liver repair.

The next stage of the trial will measure whether the therapy helps the liver to reduce scarring and stimulate regeneration.  The results should be known within the next two years.

At present the only successful treatment for end-stage liver cirrhosis – which claims around 14,000 lives in the UK each year (British Liver Trust) – is an organ transplant.  The safety trial is a vital step forward in finding an alternative therapy.

During the trial scientists took cells from the blood of nine patients with the disease and turned them into macrophages, in the Scottish National Blood Transfusion Service’s (SNBTS) cell therapy facility. The new cells were then re-injected into the patient with the hope of repairing the damaged organ from within.

The research, published in the journal Nature Medicine, received funding from the Medical Research Council. The study was conducted in partnership with the SNBTS and the Cell and Gene Therapy Catapult.

Causes of liver cirrhosis include infections such as hepatitis C, obesity, alcohol excess and some genetic and immune conditions.

Professor Stuart Forbes,  who directed the trial, said:

“Liver cirrhosis is a major healthcare issue in the UK and is one of the top five killers.  The results from this first safety trial are encouraging and we can now progress to testing how effective it is in a larger group of people. If this was found to be effective it would offer a new way to tackle this important condition.”

Dr Robin Buckle, Chief Science Officer, Medical Research Council, said:  

“The goal of regenerative medicine is to drive the body to self-repair. This has the potential to provide long-lasting treatments for major and often untreatable health problems, such as liver cirrhosis. “MRC is proud to fund this study which is an important first step in transferring cutting-edge science to the clinic. This will pave the way for testing the effectiveness of this new cell therapy in patients who would otherwise require a liver transplant.”

Pamela Healy, CEO of the British Liver Trust, said:

“Across the UK we are facing a liver disease epidemic. The number of people affected has been rising at an alarming rate and liver disease is now the biggest killer of 35 to 49-year olds. “Chronic liver disease occurs when the liver is damaged irreparably and becomes scarred (cirrhosis).  At this stage, there are very few treatments available. This new innovative approach is an exciting development and could in the future reduce the need for transplantation. More research is needed and the next stage of this work will be to really test the potential benefit for patients.”

More about the Macrophage Cell Therapy Trial

Moroni et al (2019) . Safety profile of autologous macrophage therapy for liver cirrhosis. Nature Medicine, 07 October 2019.

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Press Releases

March 28, 2024

FDA Expands Indication for Gilead's Vemlidy (Tenofovir Alafenamide) to Treat Chronic HBV Infection in Pediatric Patients as Young as Six

– Efficacy and Safety Profile of Once-Daily Vemlidy Demonstrated in Children Six Years of Age (Weighing at Least 25kg) and Older –

FOSTER CITY, Calif.--(BUSINESS WIRE)-- Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the U.S. Food and Drug Administration (FDA) has approved the supplemental new drug application (sNDA) for Vemlidy ® (tenofovir alafenamide) 25 mg tablets as a once-daily treatment for chronic hepatitis B virus (HBV) infection in pediatric patients six years of age and older and weighing at least 25 kg with compensated liver disease.

Vemlidy is a targeted prodrug of tenofovir that was approved by the FDA in 2016 as a once-daily treatment for adults with chronic HBV infection with compensated liver disease. In 2022, the FDA approved Vemlidy for the treatment of chronic HBV infection in pediatric patients 12 years of age and older with compensated liver disease. Vemlidy is recommended as a preferred or first-line treatment for adults with chronic HBV with compensated liver disease by the American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of the Liver (EASL) guidelines.

“Chronic hepatitis B can have a significant and lasting impact on the health of children. If left untreated, hepatitis B can lead to liver cirrhosis and liver cancer,” said Chaun-Hao Lin, MD, Associate Professor of Clinical Pediatrics Krek School of Medicine of USC. “As a clinician, I am well aware of the critical importance of promptly treating this disease to avoid possible complications and liver damage. The clinical trial demonstrated that tenofovir alafenamide may represent an effective treatment option for children as young as six years old affected by this chronic disease.”

Vemlidy’s approval in this pediatric patient population is supported by Week 96 data from a Phase 2 clinical trial (Trial 1092) comparing treatment with Vemlidy 25 mg to placebo among 18 treatment-naïve and treatment-experienced patients aged 6 to less than 12 years weighing at least 25 kg (Cohort 2, Group 1). Participants in the Vemlidy group and in the placebo group who switched to open-label Vemlidy after Week 24 demonstrated progressive increases in the rates of virological suppression through Week 96 overall and within both study cohorts (children and adolescents).

“The expanded indication for Vemlidy for the treatment of children as young as six years old is a testament to the safety, tolerability and efficacy profile of this therapy,” said Frank Duff, MD, Senior Vice President, Virology Therapeutic Area Head, Gilead Sciences. “Effective and tolerable options for children require our best science and a dedicated focus. The work of our Gilead Pediatric Center of Excellence is responsible for coordinating pediatric clinical trials for treatments for cancer, HIV, hepatitis B, and COVID-19 and we will continue our research to help address unmet treatment needs for children.”

Vemlidy has a boxed warning in its product label regarding post-treatment severe acute exacerbation of hepatitis B. See below for important safety information.

U.S. IMPORTANT SAFETY INFORMATION AND INDICATION FOR THE USE OF VEMLIDY

BOXED WARNING: POSTTREATMENT SEVERE ACUTE EXACERBATION OF HEPATITIS B

Discontinuation of anti-hepatitis B therapy, including VEMLIDY, may result in severe acute exacerbations of hepatitis B. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy, including VEMLIDY. If appropriate, resumption of anti-hepatitis B therapy may be warranted.

Warnings and Precautions

• Risk of Development of HIV-1 Resistance in HBV/HIV-1 Coinfected Patients: Due to this risk, VEMLIDY alone should not be used for the treatment of HIV-1 infection. Safety and efficacy of VEMLIDY have not been established in HBV/HIV-1 coinfected patients. HIV antibody testing should be offered to all HBV-infected patients before initiating therapy with VEMLIDY, and if positive, an appropriate antiretroviral combination regimen that is recommended for HBV/HIV-1 coinfected patients should be used.
• New Onset or Worsening Renal Impairment: Postmarketing cases of renal impairment, including acute renal failure, proximal renal tubulopathy (PRT), and Fanconi syndrome, have been reported with TAF-containing products. Patients with impaired renal function and/or taking nephrotoxic agents (including NSAIDs) are at increased risk of renal-related adverse reactions. Discontinue VEMLIDY in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome. Monitor renal function in all patients – See Dosage and Administration.
• Lactic Acidosis and Severe Hepatomegaly with Steatosis: Fatal cases have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate (TDF). Discontinue VEMLIDY if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity develop, including hepatomegaly and steatosis in the absence of marked transaminase elevations.

Adverse Reactions

Most common adverse events in the week 96 pediatric population reported in ≥5% were: nasopharyngitis, headache, COVID-19, pyrexia, diarrhea, upper respiratory tract infection, cough, respiratory tract infection viral, abdominal pain upper. Overall, abdominal pain upper and metabolic nephropathy were the only study drug–related adverse events, which occurred in > 1 participant, reported in 2.3% (2/88 participants) each.

Drug Interactions

• Coadministration of VEMLIDY with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of tenofovir and the risk of adverse reactions.
• Coadministration of VEMLIDY is not recommended with the following: oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, or St. John’s wort. Such coadministration is expected to decrease the concentration of tenofovir alafenamide, reducing the therapeutic effect of VEMLIDY. Drugs that strongly affect P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) activity may lead to changes in VEMLIDY absorption.
• Coadministration of VEMLIDY with carbamazepine, the tenofovir alafenamide dose should be increased to two tablets once daily.

Consult the full prescribing information for VEMLIDY for more information on potentially significant drug interactions, including clinical comments.

Dosage and Administration

• Testing Prior to Initiation: HIV infection.
• Prior to or When Initiating, and During Treatment: On a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus.
• Dosage: 1 tablet taken once daily with food.
• Renal Impairment: Not recommended in patients with end-stage renal disease (ESRD; eCrCl <15 mL/min) who are not receiving chronic hemodialysis; in patients on chronic hemodialysis, on hemodialysis days, administer VEMLIDY after completion of hemodialysis treatment. No data are available to make dose recommendations in pediatric patients with renal impairment.
• Hepatic Impairment: Not recommended in patients with decompensated (Child-Pugh B or C) hepatic impairment.

VEMLIDY is indicated for the treatment of chronic hepatitis B virus infection in adults and pediatric patients six years of age and older and weighing at least 25 kg with compensated liver disease.

About the 1092 Study

Study 1092 is an ongoing Phase 2 clinical trial that randomized 88 treatment-naïve and treatment-experienced patients with chronic hepatitis B infection between the ages of 12 to less than 18 years weighing at least 35 kg to receive either Vemlidy 25 mg (N=47) or placebo (N=23) and 6 to less than 12 years weighing at least 25 kg to receive either Vemlidy 25 mg (N = 12) or placebo (N=6) once daily. The study met its primary endpoint of percentage of patients with HBV DNA levels below 20 IU/mL at 24 weeks of therapy; overall, 19% (11/59) of patients treated with Vemlidy 25 mg achieved HBV DNA < 20 IU/mL at Week 24 compared to 0% (0/23) of patients treated with placebo. The overall percentage of patients with HBV DNA < 20 IU/mL progressively increased in the Vemlidy 25 mg group relative to the Week 24 time point at both Week 48 (37% [22/59 subjects]) and Week 96 (61.0% [36/59 subjects]).

The overall median change from baseline in ALT values for the Vemlidy and placebo-Vemlidy treatment groups, respectively, was -39.5 U/L and -46.5 U/L at Week 96. At 96 weeks, ALT normalization (AASLD criteria) was achieved for 54% of Vemlidy-treated patients and 57% of patients who switched from placebo to Vemlidy. Serum ALT is an enzyme used to monitor liver damage. Importantly, the mean percent changes in bone mineral density from baseline to Week 24 were similar for Vemlidy-treated patients and placebo-treated patients (1.6% (N=48) and 1.9% (N=23) for lumbar spine, and 1.9% (N=50) and 2.0% (N=23) for whole body, respectively). At Week 24, mean changes from baseline BMD Z-scores were 0.01 and -0.07 for the lumbar spine, and -0.04 and -0.04 for whole body, for Vemlidy and placebo groups, respectively.

About Hepatitis B

Hepatitis B (HBV) is a serious disease that attacks the liver and can cause chronic (lifelong) infection, cirrhosis of the liver, liver cancer, and death in up to a third of patients. Hepatitis B is spread through infected blood or body fluids, sexual contact, injection drug use, or perinatally from mother to child. Early symptoms may include loss of appetite, fever, generalized aches and pains, fatigue, itching, urticaria (hives), and joint pain. The disease is often asymptomatic, which may lead to undiagnosed individuals. Later symptoms may include nausea and vomiting, halitosis (bad breath), dark brown urine, jaundice (yellowing of the skin and eyes), and right-sided abdominal pain (especially with external pressure or palpitation).

About Gilead Sciences in Liver Disease

For more than 20 years, Gilead has sought to address some of the biggest challenges in liver disease. The company has transformed the trajectory of multiple liver diseases through a relentless pursuit of innovation and pioneering access programs to bring meaningful therapies to people around the world. More work is required, and Gilead is committed to advancing innovative therapeutics to address the most pressing unmet needs in liver disease and overcoming barriers to better care.

About Gilead Sciences

Gilead Sciences, Inc. is a biopharmaceutical company that has pursued and achieved breakthroughs in medicine for more than three decades with the goal of creating a healthier world for all people. The company is committed to advancing innovative medicines to prevent and treat life-threatening diseases, including HIV, viral hepatitis, COVID-19 and cancer. Gilead operates in more than 35 countries worldwide, with headquarters in Foster City, California.

Forward-Looking Statements

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties, and other factors, including Gilead’s ability to initiate, progress or complete clinical trials or studies within currently anticipated timelines or at all, and the possibility of unfavorable results from ongoing and additional clinical trials or studies, including those involving Vemlidy; the risk that physicians may not see the benefits of prescribing Vemlidy for the treatment of chronic HBV in pediatric patients; and any assumptions underlying any of the foregoing. These risks, uncertainties, and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. The reader is cautioned that any such forward-looking statements are not guarantees of future performance and is cautioned not to place undue reliance on these forward-looking statements. These and other risks are described in detail in Gilead’s Annual Report on Form 10-K for the year ended December 31, 2023, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation and disclaims any intent to update any such forward-looking statement.

U.S. Prescribing Information for Vemlidy, including BOXED WARNINGS , is available at www.gilead.com

Vemlidy, Gilead, and the Gilead logo are registered trademarks of Gilead Sciences, Inc., or its related companies.

For more information about Gilead, please visit the company’s website at www.gilead.com , follow Gilead on Twitter (@GileadSciences), or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

Meaghan Smith, Media [email protected]

Jacquie Ross, Investors [email protected]

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Scientists Identify Potential New Treatment for Liver Disease

By University of California - San Diego August 22, 2023

Scientists found that a drug, Pegozafermin, which mimics the body’s hormone, improved liver fibrosis and inflammation in NASH patients. Currently, there are no FDA-approved treatments for NASH, a common and often silent liver disease.

In a nationwide, multi-center clinical trial, scientists identified a promising new drug medication that improved liver fibrosis in NASH patients by 27%.

Scientists from the University of California San Diego School of Medicine have led an investigation into a promising treatment for individuals with NASH-related fibrosis.

The findings, recently published in The New England Journal of Medicine , indicate that a drug that mimics a hormone in the body improved both liver fibrosis, or scarring of the liver, and liver inflammation in patients with NASH.

Rohit Loomba, MD, the study’s first author and chief of the Division of Gastroenterology and Hepatology at UC San Diego School of Medicine. Credit: UC San Diego Health

“Identifying an effective drug for NASH is extremely promising for patients as currently there are no FDA-approved therapies for this condition,” said Rohit Loomba, MD, the study’s first author and chief of the Division of Gastroenterology and Hepatology at UC San Diego School of Medicine. “NASH can adversely impact the quality of life in patients and can progress to cirrhosis. Its complications can lead to death or liver transplantation.”

“Our findings will further the science of this disease and provide a potential new treatment option to those affected by NASH-related fibrosis.”

The researchers found that the drug, called Pegozafermin, mimicked fibroblast growth factor 21 (FGF21) — a liver-secreted peptide hormone that is naturally produced in the body.

FGF21 controls energy use in the body and lipid metabolism in the liver. It has also been shown in previous studies to lower blood glucose and insulin levels, reducing body weight and liver fat.

“The study’s results show that the new potential treatment not only improves fibrosis but also improves inflammation and liver injury along with significant improvements across multiple non-invasive biomarkers of NASH activity and scarring,” said Loomba, gastroenterologist, and hepatologist at UC San Diego Health.

The 24-week, randomized clinical trial involved 222 participants with NASH assigned to either receive the drug or a placebo.

Of the patients who received the drug at a higher dose, approximately 27% showed an improvement in liver fibrosis, relative to 7% of the patients who received the placebo. The most frequently reported side effect from the drug was gastrointestinal in nature, including nausea.

Currently, there are no medications approved by the U.S. Food and Drug Administration available for the treatment of NASH, which is a type of nonalcoholic fatty liver disease (NAFLD).

According to the National Institutes of Health , approximately 24% of U.S. adults have NAFLD, and about 6% have NASH.

NAFLD and NASH are considered silent diseases with little to no symptoms; however, individuals who are overweight, have type 2 diabetes, or have a family member with NAFLD are at a higher risk of developing the disease. NAFLD — which is an umbrella term for a range of liver conditions affecting people who drink little to no alcohol — can lead to cirrhosis, liver cancer, and liver failure.

Loomba adds next steps for this research will be a larger, multi-center, international trial with a more diverse patient population and a longer treatment period to better assess the safety of the drug.

“If successfully shown to be both safe and effective in a larger Phase 3 trial, this drug could be used to treat millions of patients with NASH, including our patients at UC San Diego Health,” said Loomba.

Reference: “Randomized, Controlled Trial of the FGF21 Analogue Pegozafermin in NASH” by Rohit Loomba, M.D., M.H.Sc., Arun J. Sanyal, M.D., Kris V. Kowdley, M.D., Deepak L. Bhatt, M.D., M.P.H., Naim Alkhouri, M.D., Juan P. Frias, M.D., Pierre Bedossa, M.D., Ph.D., Stephen A. Harrison, M.D., Donald Lazas, M.D., Robert Barish, M.D., Mildred D. Gottwald, Pharm.D., Shibao Feng, Ph.D., Germaine D. Agollah, Ph.D., Cynthia L. Hartsfield, Ph.D., Hank Mansbach, M.D., Maya Margalit, M.D. and Manal F. Abdelmalek, M.D., M.P.H., 24 June 2023, New England Journal of Medicine . DOI: 10.1056/NEJMoa2304286

The study was funded by 89bio, ENLIVEN, and the National Institute of Diabetes and Digestive and Kidney Diseases.

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1 comment on "scientists identify potential new treatment for liver disease".

Please update me of the liver disease drug “Pegozafermin”. I have NASH and liver fibrosis. I am willing to apply on the clinical trials for liver disease.

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Clinical Trials

Displaying 50 studies

This Registry will enroll cirrhotic participants with or without decompensated liver disease who have achieved a sustained virologic response (SVR) after receiving a sofosbuvir (SOF)-based regimen without interferon (IFN) while participating in a Gilead-sponsored hepatitis C virus (HCV) study or commercially at selected sites. Once enrolled, participants will be followed for up to 5 years.

The purpose of this study is to find out how the survival rate of patients with cirrhosis can be improved when admitted to the hospital with complications such as infections.

This is a pilot study to see if hydroxychloroquine (HCQ) if safe and effective to use with patients having cramps due to their cirrhotic liver disease.

The study is a multi-center, prospective, open label, uncontrolled feasibility study enrolling 30 patients with refractory or recurrent ascites and cirrhosis at up to 6 sites. Patients will be enrolled during a 6 month enrollment phase after which data will be collected for 12months with an initial analysis after 3 months. Extended follow-up for safety monitoring purposes will continue for the lifetime of the patient or until the device is explanted.

The puropose of this study is to utilize a discrete-choice experiment (DCE) survey to elicit benefit-risk preferences for interventional treatment attributes in patients with refractory or recurrent ascites due to liver cirrhosis.

The overall objective of the patient preference evaluation is to understand how patients tradeoff the benefits and risks of the alfapump related to the primary endpoints of the current POSEIDON clinical trial in support of future marketing application.

The alfapump system is designed to reduce or eliminate the need for therapeutic paracentesis and to provide relief from symptoms of tense ascites with its attendant effects on patient quality of life (QOL) and nutrition. fits and risks of the alfapump related to the primary endpoints of the current POSEIDON clinical trial in support of future marketing application.

The purpose of this study is to determine whether the ORBERA Intragastric Balloon is a safe and effective means for weight loss and improved metabolic disease in patients with cirrhosis requiring liver transplantation.

The purpose of this study is to confirm the effectiveness and safety of intravenous terlipressin in the treatment of adult patients who have hepatorenal syndrome (HRS) type 1.

The purpose of this study is to define the determinants of cirrhosis progression using clinical and specialized biomarkers over time in North America through a prospective outpatient registry.

The purpose of this study is to evaluate improvements in predictive accuracy for risk of decompensation over time for a composite risk score that includes non-modifiable and modifiable clinical, pathophysiological and behavioral risk factors (i.e., a “test” model) compared to a composite risk score that includes clinical risk factors alone (i.e., a “base” model) in a large, multi-center cohort of patients with cirrhosis.

The purpose of this study is to determine whether ornithine phenylacetate can speed recovery from an acute hepatic encephalopathy episode requiring hospitalization in cirrhotic patients.

early detection of hepatic encephalopathy

The purpose of this study is to assess the effectiveness of a new ultrasound technique for non-invasive evaluation of liver fibrosis.

The purpose of this study is to identify clinical parameters that may help to predict clinical outcomes prior to the evolution of the admitting diagnosis for cirrhosis, a very important clinical observation for the long-term. We are not participating in optional blood collection. 

A Phase 3b, single arm, open-label, multicenter study to evaluate the safety and to demonstrate the non-inferiority of the sustained virologic response 12 weeks post dosing (SVR12) rates of 8 weeks of treatment with the glecaprevir (GLE)/pibrentasvir (PIB) combination regimen to the historical SVR12 rate of 12 weeks of treatment with the GLE/PIB in treatment-naïve adults with chronic HCV GT 1, 2, 4, 5, or 6 infection and compensated cirrhosis.

This is a multicenter, double-blind, randomized, placebo-controlled study to evaluate the safety and efficacy of emricasan in improving event-free survival based on a composite clinical endpoint (where all-cause mortality, new decompensation events, and MELD score progression are events) in subjects with decompensated NASH cirrhosis.

The purpose of this study is to evaluate the safety and effectiveness of OCE-205 at various doses.

OCE-205 is being tested to treat participants who have developed Hepatorenal Syndrome-Acute Kidney Injury as a complication of cirrhosis with ascites.  

This study will evaluate the efficacy, safety, and tolerability of sofosbuvir (SOF)/GS-5816 fixed dose combination (FDC) with and without ribavirin (RBV) for 12 weeks and SOF/GS-5816 FDC for 24 weeks in adults with hepatitis C virus (HCV) infection and Child-Pugh (CPT) class B cirrhosis.

The purpose of this study is to evaluate the diagnostic performance of Endoscopic Ultrasound (EUS) shear wave elastography in the assessment of liver fibrosis compared to magnetic resonance (MR) elastography.

The purpose of this registry is to enroll patients who have cirrhosis with a sustained viral response after receiving a sofosbuvir-based treatment without interferon, either while participating in a Gilead-sponsored hepatitis C virus study or commercially at selected sites. Once enrolled, the patients will be followed for up to 5 years.

Primary sclerosing cholangitis is a chronic inflammation of the bile ducts of unknown cause and eventually results in cirrhosis of the liver. These patients are at increased risk for the development of cancer rising from bile duct tissue. Chromosomal abnormalities of the bile duct tissue, particularly trisomy 7 (i.e. three copies of chromosome 7) can be detected in biopsy samples. Erlotinib (Tarceva) is a human EGFR type 1 tyrosine kinase inhibitor and offers greater survival benefit to EGFR positive patients. This study will assist in determining the safety and tolerability of Tarceva in patients who have primary sclerosing cholangitis.

The primary objective of this program is to provide Daclatasvir (DCV) for 24 weeks to be given in combination with Sofosbuvir (SOF) to post-liver transplant subjects with chronic hepatitis C recurrence and who have a serious or immediately life-threatening condition or experienced an event that has decreased their life expectancy to < 12 months, including advanced fibrosis or fibrosing cholestatic hepatitis.This protocol will be opened at specific clinical sites for the treatment of individual subjects for whom there are no other treatment options and will allow for the collection of safety and efficacy data.

The study plans to follow three groups of cirrhotic patients from the time of hospital dismissal randomly divided into either receiving standard of care, using devices through which they can communicate with the clinical teams and using devices and structured follow-up over thirty days. The study aims to develop these devices so as to learn quickly about issues that patients and their caregivers are facing so that clinicans can intervene to stop unnecessary re-hospitalizations in this population.

The study aims are to evaluate the safety and effectiveness of OCE-205 at various doses. Participants will receive treatment by intravenous infusion and will continue this treatment until participants meet primary endpoint or any discontinuation criteria.  OCE-205 is being tested to treat participants who have developed Hepatorenal Syndrome-Acute Kidney Injury as a complication of cirrhosis with ascites.

This is a phase 3, multicenter, randomized, controlled, parallel-group, and open-label clinical study to evaluate the efficacy of standard medical treatment (SMT) + Albutein 20% administration versus SMT alone in subjects with decompensated cirrhosis and ascites. The study population will consist of subjects being discharged after hospitalization for acute decompensation of liver cirrhosis with ascites (or with prior history of ascites requiring diuretic therapy) with or without acute-on-chronic liver failure (ACLF) at admission or during hospitalization but without ACLF at discharge.

The primary objective of this study is to evaluate whether selonsertib (SEL; GS-4997) can cause fibrosis regression and reduce associated complications in adults with cirrhosis due to NASH.

The purpose of this study is to determine agreement between cardiopulmonary exercise testing and cardiac stress testing (SOC) for the identification of subclinical coronary artery disease in liver transplant candidates, to determine agreement between cardiopulmonary exercise testing and dobutamine stress echocardiogram (SOC) for the identification of cirrhotic cardiomyopathy in liver transplant candidates, and to determine agreement between peak oxygen consumption from cardiopulmonary exercise testing and the liver frailty index or the six-minute walk test (SOC), for the identification of frailty in liver transplant candidates.

The primary purpose of this study is to collect and analze data evaluating the effectiveness of the alfapump to control ascites as determined by the reduction in the need for repeated paracentesis compared to baseline

The primary objective of this study is to evaluate whether obeticholic acid (OCA; INT-747) can lead to histological improvement in fibrosis with no worsening of NASH in adults with compensated cirrhosis due to NASH.

The primary objectives of this study are: - To assess the safety and tolerability of selonsertib (SEL), GS-0976, and GS-9674, administered alone or in combination, in participants with bridging fibrosis or compensated cirrhosis due to Nonalcoholic Steatohepatitis (NASH) - To evaluate changes in liver fibrosis, without worsening of NASH

The purpose of this study is to evaluate the clinical effectiveness of BIV201 continuous infusion in addition to SOC compared to SOC alone in adult patients with refractory ascites secondary to decompensated hepatic cirrhosis.

Primary biliary cirrhosis is a serious, life-threatening, bile acid related liver disease of unknown cause. Without treatment, it frequently progresses to liver fibrosis and eventual cirrhosis requiring liver transplantation or resulting in death. The purpose of this study is to assess the effect of obeticholic acid compared to a placebo, both combined with stable standard care, on the clinical outcomes of patients with primary biliary cirrhosis. 

The purpose of this study is designed to evaluate the effectiveness and safety of intravenous Lucassin® (terlipressin) versus a placebo for the treatment of type 1 hepatorenal syndrome in patients receiving standard of care albumin therapy.

The purpose of this multicenter, double-blind, randomized, placebo-controlled study is to evaluate the safety and efficacy of emricasan in improving event-free survival based on a composite clinical endpoint (where all-cause mortality, new decompensation events, and MELD score progression are events) in subjects with decompensated NASH cirrhosis.

A Study to Evaluate the Safety and Efficacy of Ombitasvir/ABT-450/Ritonavir and Dasabuvir in Adults with Genotype 1b Chronic Hepatitis C Virus (HCV) Infection and Cirrhosis.

The purpose of this study is to develop and validate a brief patient reported outcomes questionaire that is responsive to ascites-related symptoms in liver cirrhosis.

The purpose of this study is to evaluate the usefulness of new markers found in blood that might help to diagnose of liver cancer (HCC) early among people with cirrhosis. We hope that this study will show that these new markers could identify HCC at an earlier stage where better treatment options are available.

The purpose of this study is to validate an NMR-based (Nuclear magnetic resonance) serum metabolite constellation for detection of early Hepatocellular carcinoma (HCC) lesions in liver cirrhosis.

The primary purpose of this study is to is to develop an advanced multiparametric liver magnetic resonance elastography (MRE) imaging technology for early identification of hepatocellular carcinoma (HCC) involvement, differentiation, and risks of microvascular invasion.

This study is to evaluate the safety and efficacy of simtuzumab (GS-6624) in adults with compensated cirrhosis due to Non-Alcoholic Steatohepatitis (NASH). It will consist of 2 phases:

• Randomized Double-Blind Phase
• Open Label Phase (optional)

This study will evaluate whether simtuzumab (formerly referred to as GS-6624) is effective at preventing the histologic progression of liver fibrosis and the clinical progression to cirrhosis in participants with non-alcoholic steatohepatitis (NASH). It will consist of 2 phases: - Randomized Double-Blind Phase - Open Label Phase (optional)

The goals of this study are to establish the role of circulating nucleic acid based biomarkers in early diagnosis, prognosis or treatment response in human diseases. These studies will determine whether alterations in circulating nucleic acids can distinguish between healthy and cancer tissue. 

The purpose of this study is to identify the clinical characteristics, the management and the outcomes of acute kidney injury (AKI) in patients with cirrhosis worldwide. Additionally, to establish the severity of AKI across different regions, to identify precipitants of AKI across different centers, to identify the phenotypes of AKI across different centers, to evaluate differences in the management of AKI across different centers and their impact on clinical outcomes, and to assess outcomes of acute kidney injury (resolution of AKI, in-hospital mortality, 28-day mortality, 90-day mortality).

The purpose of this study is to evaluate the effectiveness of 2 mg/kg and 4 mg/kg lean body mass (LBM) of belapectin (GR-MD-02) compared to placebo in preventing the development of esophageal varices.

The purpose of this study is to define the prevalence and impact of cognitive impairment and their impact on HRQOL in elderly patients with cirrhosis compared to elderly patients without cirrhosis.

The purpose of this study is to assess the effectiveness and safety of rifaximin SSD-40IR for the delay of the first episode of overt hepatic encephalopathy (OHE) decompensation in liver cirrhosis, defined by the presence of medically controlled ascites. Participants who have cirrhosis determined by histopathological evidence, transient elastography or presence of esophageal varices, and who have not previously experienced OHE, spontaneous bacterial peritonitis (SBP), esophageal variceal bleeding (EVB), or acute kidney injury-hepatorenal syndrome (AKI-HRS) will be enrolled in the study. 

The purpose of this study is to establish the Maximum Tolerated Dose (MTD), assess the safety, tolerability, and pharmacokinetics of subcutaneous PHIN-214 in participants with compensated and decompensated cirrhosis. In addition, various exploratory markers of effectiveness will be analyzed. 

A variety of liver insults lead to pathological changes in liver architecture that culminate in cirrhosis. While invasive liver biopsy was required to detect cirrhosis, the development of magnetic resonance elastography (MRE) has revolutionized our ability to detect liver fibrosis through non-invasive means that involve measurement of liver stiffness. However, a number of pathological findings occur in liver in response to various insults that precede cirrhosis and are clinically important to identify such as steatosis associated with NASH, inflammation associated with viral hepatitis, and congestion associated with cardiac hepatopathy. Detection of such entities provides essential diagnostic, prognostic, and treatment information ...

The purose of this study is to assess the effectiveness, safety, and tolerability of LPCN 1148 in men with cirrhosis of the liver and sarcopenia.

We purpose of this study is to evaluate the diagnosis accuracy of the Controlled Attenuation Parameter (CAP) measured by FibroScan® (both with M and XL probes) in all patients who are undergoing liver biopsy for any liver disease.  

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Aspirin shows promise in treating common liver disease.

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Daily low dose aspirin reduced the amount of fat in the liver according to a new study.

Daily, low-dose aspirin may be an effective treatment for a common type of liver disease, according to a new study.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by fat buildup in the liver, affecting its function. Also called non-alcoholic fatty liver disease, it is commonly associated with factors such as type 2 diabetes and obesity, but is not related to alcohol consumption.

Up to a third of Americans have fat build up in the liver and in about 2-5% that fat build up has already caused inflammation and liver cell damage. Although symptoms can take years to develop after the initial fat build-up, with fatty liver disease sometimes being called "silent," they include fatigue, weight loss, weakness, itching and yellowing of the skin or eyes. Permanent, irreversible liver damage called cirrhosis can result and people who are badly affected may develop liver failure where the only suitable treatment is a transplant.

Once fat buildup in the liver has begun to damage the organ, no approved treatments are available to reverse it, but some lifestyle changes such as lowering cholesterol, losing weight and medication to control blood pressure and diabetes may be effective.

Now a new clinical trial led by researchers at Harvard has tested whether low-dose daily aspirin might be an effective treatment for fat build up in the liver.

“Since MASLD is estimated to affect up to a third of U.S. adults, aspirin represents an attractive potential low-cost option to prevent progression to cirrhosis or liver cancer, the most feared complications of MASLD,” said Andrew T. Chan, lead author of the work and a gastroenterologist and professor at Harvard Medical School in Boston, MA.

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The study, published in the Journal of the American Medical Association involved 80 people with MASLD who were split equally into those who received the daily aspirin and those who received a placebo instead. The participants were aged between 18 and 70 years old and did not know whether they were getting the real drug or not. At the beginning of the trial and 6 months after the aspirin, or placebo, the participants had their quantity of liver fat measured. Participants who had received the aspirin had their liver fat reduce by 6.6% on average, whereas those who received the placebo had an increase of 3.6% on average. Other tests of liver function also showed improvement in people who had received the aspirin.

“Multiple noninvasive blood and imaging-based tests for liver fat, inflammation, and fibrosis all showed a similar direction of benefit that favored aspirin treatment,” said Tracey G. Simon, hepatologist and instructor at Harvard Medical School who was lead author of the work. “Together, these data support the potential for aspirin to provide benefits for patients with MASLD," added Simon.

The researchers think aspirin works to reduce liver fat by decreasing inflammation and also affecting fat metabolism. However, they stress that further studies are needed to determine whether the result holds up in a larger number of people and also whether the benefits of aspirin use on liver fat persist long term.

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Clinical trial identifies potential new treatment for liver disease

by University of California - San Diego

Researchers at the University of California San Diego School of Medicine have led a study to examine a potential new treatment option for patients with non-alcoholic steatohepatitis (NASH)-related fibrosis.

The results, published in the June 24, 2023, online edition of The New England Journal of Medicine , found that a drug that mimics a hormone in the body improved both liver fibrosis , or scarring of the liver , and liver inflammation in patients with NASH.

"Identifying an effective drug for NASH is extremely promising for patients as currently there are no FDA-approved therapies for this condition," said Rohit Loomba, MD, the study's first author and chief of the Division of Gastroenterology and Hepatology at UC San Diego School of Medicine. "NASH can adversely impact the quality of life in patients and can progress to cirrhosis . Its complications can lead to death or liver transplantation. Our findings will further the science of this disease and provide a potential new treatment option to those affected by NASH-related fibrosis."

The researchers found that the drug, called pegozafermin, mimicked fibroblast growth factor 21 (FGF21)—a liver-secreted peptide hormone that is naturally produced in the body.

FGF21 controls energy use in the body and lipid metabolism in the liver. It has also been shown in previous studies to lower blood glucose and insulin levels, reducing body weight and liver fat.

"The study's results show that the new potential treatment not only improves fibrosis but also improves inflammation and liver injury along with significant improvements across multiple non-invasive biomarkers of NASH activity and scarring," said Loomba, gastroenterologist and hepatologist at UC San Diego Health.

The 24-week, randomized clinical trial involved 222 participants with NASH assigned to either receive the drug or a placebo. Of the patients who received the drug at a higher dose, approximately 27% showed an improvement in liver fibrosis, relative to 7% of the patients who received the placebo. The most frequent reported side effect from the drug were gastrointestinal in nature, including nausea.

Currently, there are no medications approved by the U.S. Food and Drug Administration available for the treatment of NASH, which is a type of nonalcoholic fatty liver disease (NAFLD).

According to the National Institutes of Health, approximately 24% of U.S. adults have NAFLD, and about 6% have NASH.

NAFLD and NASH are considered silent diseases with few to no symptoms; however, individuals who are overweight, have type 2 diabetes or have a family member with NAFLD are at a higher risk of developing the disease. NAFLD—which is an umbrella term for a range of liver conditions affecting people who drink little to no alcohol—can lead to cirrhosis, liver cancer and liver failure.

Loomba adds next steps for this research will be a larger, multi-center, international trial with a more diverse patient population and longer treatment period to better assess the safety of the drug.

"If successfully shown to be both safe and effective in a larger Phase 3 trial, this drug could be used to treat millions of patients with NASH, including our patients at UC San Diego Health," said Loomba.

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• Cirrhosis: new...

Cirrhosis: new research provides a basis for rational and targeted treatments

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• Peer review
• John P Iredale , professor ( jpi{at}soton.ac.uk ) 1
• Division of Infection, Inflammation and Repair, University of Southampton, Southampton General Hospital, Southampton SO16 6YD
• Accepted 18 June 2003

Liver transplantation and antiviral treatments for hepatitis have improved the outlook for many patients with liver disease. For patients with cirrhosis, new developments herald targeted treatments

Introduction

It is an exciting time to be working in hepatology. The success of liver transplantation and the advances in the radiological and endoscopic management of portal hypertension have improved the longevity and quality of life of patients with liver cirrhosis. Additionally, the development of effective antiviral treatments means that disease can be cured in many patients infected with hepatitis B and hepatitis C. However, these interventions also serve to highlight our current impotence in altering the underlying fibrotic process in many patients with liver disease. This rather depressing perspective may soon change: data from clinical and laboratory based research are showing that cirrhosis may be reversible. By highlighting the attributes required of an effective antifibrotic, a new dynamic model is likely to lead to the development of targeted treatment for liver cirrhosis.

This article is based on knowledge accrued over 13 years of work investigating the mechanisms of fibrosis and aspects of hepatic stellate cell biology and on regular Medline searches of the peer reviewed scientific literature during that time. The field has benefited from the recognition that certain mechanisms are common to hepatic, renal, and pulmonary fibrosis, and I have reviewed models of these processes while preparing this article. My examples highlight how laboratory based studies of the biology of hepatic fibrosis may inform the design of future treatments.

Clinical impact of cirrhosis

Liver fibrosis and its end stage, cirrhosis, represent enormous worldwide healthcare problems. In the United Kingdom, more than two thirds of the 4000 people who died of cirrhosis in 1999 were under 65, and the incidence of cirrhosis related death is increasing. 1 Worldwide, the common causes of liver fibrosis and cirrhosis include hepatitis B and hepatitis C and alcohol. Other causes include immune mediated damage, genetic abnormalities, and non-alcoholic steatohepatitis, which is associated with diabetes and the metabolic syndrome. 2 Changing patterns of alcohol consumption in the West and the increasing rates of obesity and diabetes mean that advances in preventing and treating viral hepatitis may be offset by an increasing burden of fibrosis and cirrhosis related to alcohol and non-alcoholic steatohepatitis. 1 – 3

Summary points

Fibrosis, the liver's wound healing response, is bi-directional and potentially reversible

Antiviral treatments provide increasing evidence for reversibility of fibrosis and cirrhosis

Excess fibrillar (scar) matrix can be degraded even in advanced cirrhosis but is held in check by protease inhibitors termed TIMPs

Antifibrotic treatments are likely to be developed in the next decade, on the basis of a better understanding of the pathogenesis of fibrosis

Hepatic stellate cells have been shown to contribute to portal hypertension by dynamic contractile activity; this could lead to the design of specific agents to reduce portal hypertension

Current treatments for cirrhosis are limited to removing the underlying injurious stimulus (where possible); eradicating viruses using interferon, ribavirin, and lamivudine in viral hepatitis; and liver transplantation. Transplantation is a highly successful treatment for end stage cirrhosis, with a 75% five year survival rate. But limited availability of organs, growing lists of patients needing a transplant, issues of compatibility, and comorbid factors mean that not everyone is eligible for transplantation. As a result, effective antifibrotic treatments are needed urgently.

Inflammation and repair

Liver fibrosis and cirrhosis represent a continuous disease spectrum characterised by an increase in total liver collagen and other matrix proteins which disrupt the architecture of the liver and impair liver function. 4 5 Fibrosis results from sustained wound healing in the liver in response to chronic or iterative injury. The wound healing response is an integral part of the overall process of inflammation and repair: it is dynamic and has the potential to resolve without scarring (fig 1 ).

Liver cirrhosis as wound healing: damage to the normal liver (a) results in inflammation (b) and activation of hepatic stellate cells (brown) to secrete collagen, culminating in the development of fibrosis (c) and ultimately in cirrhosis (d). Withdrawal of the injurious agent may allow remodelling of the fibrillar matrix, leaving an attenuated cirrhosis (e). Spontaneous resolution of fibrosis after removal of injury results in a return to near normal architecture (f). Whether “complete” resolution of cirrhosis can occur is currently unknown

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Pathogenesis of fibrosis

High quality experimental evidence supports the hypothesis that the final common pathway of fibrosis is mediated by the hepatic stellate cells. 4 – 7 Hepatic stellate cells in normal liver store retinoids and reside in the spaces of Disse (fig 2 ). In injured areas of the liver, hepatic stellate cells undergo a remarkable transformation: they resemble myofibroblasts and express contractile proteins. In this “activated” phenotype, hepatic stellate cells proliferate and are known to be the major source of the fibrillar collagens that characterise fibrosis and cirrhosis (fig 2 ). The mechanisms mediating activation of hepatic stellate cells are a major subject of research.

Normal liver (top) and liver injury (bottom). After livery injury, hepatic stellate cells become activated and secrete a collagen rich matrix. Through associated changes in cell-matrix interactions, hepatocytes lose their microvillii and sinusoidal endothelial cells lose their fenestrations. Reproduced with permission 26

In injured areas, soluble factors (cytokines) are released by the incoming inflammatory cells, the damaged and regenerating hepatocytes, and other liver cells that target the hepatic stellate cells, activating them so they become the central mediators of wound healing. 5 Because of the key role of inflammation, removing the causative agent and treating the patient with immunosuppressive drugs are effective interventions for some diseases (box). Greater understanding of the specific cytokine and chemokine messengers that mediate the inflammatory process in liver disease is informing the design of future treatments. This is exemplified by the identification of interleukin-10 as a downregulator of the inflammatory response and tumour necrosis factor α as a pro-inflammatory mediator. 8 9 Studies using interleukin-10 knockout mice have identified this cytokine as a major anti-inflammatory effector in fibrotic liver injury. A pilot study suggested that interleukin-10 may be valuable clinically in the context of hepatitis C virus infection, 10 but definitive evidence of efficacy has yet to be produced in a large scale clinical trial. Antagonising tumour necrosis factor α would also be expected to downregulate hepatic inflammation. Reagents to neutralise tumour necrosis factor α are available for clinical use, and this approach is likely to be investigated further in the clinic. 11

Another approach to chronic liver fibrosis is to block the signals which promote transition of hepatic stellate cells from a quiescent to an activated phenotype and promote collagen secretion. Foremost among the soluble mediators promoting the fibrogenic response from hepatic stellate cells is transforming growth factor β-1 (box). This cytokine also has a role in the development of fibrosis in other organs, including the lung and kidney. 12 13 The activated hepatic stellate cells respond to it by increasing production of collagen and decreasing its breakdown (see below). Models in other internal organs suggest that modifying the secretion or activity of transforming growth factor β-1 can attenuate fibrosis, which indicates that this is a possible antifibrotic target in the liver. 14 Recent studies of experimental liver fibrosis have shown the potential of this approach. 15

Matrix synthesis and turnover in fibrosis and cirrhosis

Activated stellate cells proliferate, with the result that increases in numbers of hepatic stellate cells, in addition to increases in secretion of the fibrillar (or scarring) collagens, result in the deposition of excess fibrotic matrix. Collagen synthesis is therefore clearly a target for therapeutic intervention. 16 Because fibrosis is advanced when most patients present, understanding the processes regulating matrix degradation is likely to be pivotal to the development of effective anti-fibrotic treatments. Effective treatment will require breakdown of the pre-existing matrix.

Stellate cells and other cells involved in the fibrotic process, including macrophages and Kupffer cells, secrete a repertoire of matrix degrading metalloproteinase enzymes (MMPs). 17 These enzymes degrade collagen and other matrix molecules, and their presence in the fibrotic liver highlights the potential dynamic nature of scarring within the liver. Molecular studies of the expression of mRNA for these enzymes (including those with collagenolytic activity) have shown that they are expressed in the liver even in cirrhosis, but their activity is held in check by powerful inhibitors, the tissue inhibitors of metalloproteinases (TIMPs) 1 and 2. 18 The potential for matrix degradation is present, even in advanced cirrhosis—but it is held in check by concurrently secreted TIMPs (fig 3 ). It should be possible to unharness the latent matrix degrading capacity of a fibrotic or cirrhotic liver and to facilitate matrix degradation, resulting in a return to normal or near normal architecture. 19

Tissue inhibitors of metalloproteinases (TIMPs) secreted by activated hepatic stellate cells prevent matrix degradation by inhibiting the enzymatic activity of matrix degrading metalloproteinases (MMPs)

Models of resolution of liver fibrosis

Studies that used pathological specimens and paired biopsies from trials of antiviral treatments in chronic hepatitis have shown that matrix degradation occurs in advanced human cirrhosis. In parallel, rodent models in which spontaneous recovery from liver fibrosis and cirrhosis occurs have allowed the frequent sampling that is needed to identify the critical features of the process. 19 – 21 In recovery, expression of TIMPs 1 and 2 decreases rapidly while matrix degrading metalloproteinases continue to be expressed, resulting in increased collagenase activity and consequent matrix degradation within the liver (see fig 1 ).

Together with these changes, apoptosis of the hepatic stellate cells occurs. Apoptosis, in effect the suicide of a cell, fulfils a function in mammalian tissue, removing unwanted cells when they become too numerous or redundant. During progressive liver injury, when stellate cells are activated in the normal wound healing response, stellate cell apoptosis is forestalled, probably through signals from soluble factors and changes in the matrix. When the injurious stimulus is withdrawn and remodelling of matrix is required, the loss of these survival factors causes the activated stellate cell to default into apoptosis, which facilitates the remodelling process by removing the major cellular source of collagen and TIMPs. Logically, therefore, manipulating matrix degradation or enhancing hepatic stellate cell apoptosis might be expected to reduce fibrosis and promote a return to normal liver architecture. Studies in this area are currently limited to experimental models but show promise that liver fibrosis can be attenuated by manipulating the TIMP-MMP balance or enhancing hepatic stellate cell apoptosis. 22 23

Possible therapeutic interventions in liver fibrosis In progressive or established fibrosis

Inflammation

Removal of injurious agent

Interleukin-10—anti-inflammatory effect

Tumour necrosis factor α inhibitors—anti-inflammatory effect

Antioxidants—suppress fibrotic response to oxidative damage

Stellate cell activation

Interferon gamma (or interferon alfa)—inhibits activation of hepatic stellate cells

Hepatocyte growth factor—inhibits activation of hepatic stellate cells

Peroxisome proliferator-activated receptor ligand—reduces activation of hepatic stellate cells

Perpetuation of stellate cell activation

Transforming growth factor β-1 antagonists—reduce matrix synthesis and enhance matrix degradation

Platelet derived growth factor antagonists—reduce proliferation of hepatic stellate cells

Nitric oxide—inhibits proliferation of hepatic stellate cells

Angiotensin-converting-enzyme inhibitors—inhibit proliferation of hepatic stellate cells

Stellate cell secretion of collagen rich matrix

Angiotensin converting enzyme inhibitors—reduce fibrosis

Polyhydroxylase inhibitors—reduce experimental fibrosis

Interferon gamma—reduces fibrosis

Endothelin receptor antagonists—reduce fibrosis and portal hypertension

To enhance or initiate resolution of fibrosis

Stellate cell apoptosis

Gilotoxin—causes apoptosis of hepatic stellate cells

Nerve growth factor—causes apoptosis of hepatic stellate cells

Degradation of collagen rich matrix

Metalloproteinases—enhance activity of metalloproteinases

Tissue inhibitor of matrix (TIMP) antagonists—enhance activity of metalloproteinases

Transforming growth factor β-1 antagonists—downregulate TIMPs and increases activity of metalloproteinases

Relaxin—downregulates TIMPs and increases activity of metalloproteinases

Stellate cells as mediators of portal hypertension

A major and life threatening consequence of cirrhosis is the development of portal hypertension. Studies of isolated hepatic stellate cells have revolutionised our view of the mechanisms underlying portal hypertension and point to a role for these cells. Activation of hepatic stellate cells is associated with the expression of contractile intracellular proteins such as α smooth muscle actin, and activated cells become sensitive to the potent vasoactive substance endothelin. Endothelin concentrations increase after fibrotic liver injury, promoting contraction of hepatic stellate cells. In parallel, injury results in a reduction in nitric oxide derived from hepatic endothelial cells, which antagonises the effect of endothelin ( fig 4 ). The net result of this imbalance is that stellate cell contraction is stimulated, and the consequent increases in intrahepatic sinusoidal resistance contribute to portal hypertension. The observation that this process is dynamic and might be manipulated has led to the exciting concept that effective endothelin antagonism might reduce portal hypertension in cirrhosis. 24

Endothelin-nitric oxide imbalance results in contraction of hepatic stellate cells, with consequent sinusoidal constriction (indicated by yellow arrows), contributing to portal hypertension

Educational resources

The August 2001 edition of Seminars in Liver Diseases is devoted to the hepatic stellate cell and reviews of hepatic stellate cell biology. Chapters of particular interest are:

Rockey DC. Hepatic blood flow regulation by stellate cells in normal and injured liver. (pp 337-50) Schuppan D, Ruehl M, Somasundaram R, Hahn EG. Matrix as a modulator of hepatic fibrogenesis. (pp 351-72)

Benyon RC. Arthur MJP. Extracellular matrix degradation and the role of hepatic stellate cells. (pp 373-84)

Pinzani M, Marra, F. Cytokine receptors and signalling in hepatic stellate cells. (pp 397-416)

Maher JJ. Interactions between hepatic stellate cells and the immune system. (pp 417-26)

Iredale JP. Hepatic stellate cell behaviour during resolution of liver injury. (pp 427-37)

Design of anti-fibrotic treatments:

Bataller R, Brenner DA. Hepatic stellate cells as a target for the treatment of liver fibrosis. Seminars in Liver Disease 2001;21: 437-51

Murphy F, Arthur M, Iredale J. Developing strategies for liver fibrosis treatment. Expert Opin Investig Drugs 2002;11: 1575-85

Friedman SL. Liver fibrosis—from bench to bedside. J Hepatol 2003;38(suppl): S38-53

For information on the incidence and epidemiology of liver disease, the addresses of patient support groups, and information for patients:

British Liver Trust ( www.britishlivertrust.org.uk ) Children's Liver Disease Foundation ( http://childliverdisease.org )

Serum markers of fibrosis

At present, the clinical assessment of antifibrotic interventions relies on serial liver biopsies. Liver biopsy remains associated with a (small) morbidity and mortality, and even though effective fibrosis scoring systems have been introduced, liver biopsy is prone to sampling error. It may not be an appropriate way of monitoring in a dynamic situation such as a clinical trial of an antifibrotic agent. A further likely development is the identification of a panel of serum fibrosis markers which can be used to predict the stage of fibrosis and monitor disease progression or resolution without recourse to repeated liver biopsies. 25

In future, patients with cirrhosis are likely to be treated simultaneously with a targeted anti-inflammatory agent, an agent to lower portal pressure, and an antifibrotic or fibrolytic agent, and the effectiveness of the treatment may well be monitored by using a panel of serum markers. The development of effective targeted treatments and the tools to monitor their effectiveness non-invasively will change the way we view and treat cirrhosis.

Acknowledgments

I gratefully acknowledge the support of the MRC(UK), the Wellcome Trust, the British Liver Trust, the Children's Liver Disease Foundation, and the Wessex Medical Trust and thank Christothea Constandinou, Catriona J Gunn, and Chris Shepherd for their help in compiling the manuscript.

Competing interests JPI has received research grant funding from Bayer AG.

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• Rosenberg W ,
• Voelker M ,

Research reviews and prospects of gut microbiota in liver cirrhosis: a bibliometric analysis (2001-2023)

Affiliations.

• 1 Department of Infectious Diseases, Hangzhou Ninth People's Hospital, Hangzhou, China.
• 2 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
• 3 Cancer Center, Department of Pulmonary and Critical Care Medicine, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, China.
• PMID: 38550860
• PMCID: PMC10972893
• DOI: 10.3389/fmicb.2024.1342356

Introduction: The gut-liver axis has emerged as a focal point in chronic liver disorders, prompting more research into the role of the gut microbiota in liver cirrhosis. In individuals with liver cirrhosis, changes in the structure and function of the gut microbiota are closely tied to clinical prognosis. However, there is a scarcity of bibliometric evaluations conducted in this particular field.

Methods: This study is aiming to conduct a complete analysis of the knowledge structure and centers pertaining to gut microbiota in liver cirrhosis using bibliometric methods. Publications on gut microbiota and liver cirrhosis from 2001 to 2023 are sourced from the Web of Science Core Collection. For the bibliometric analysis, we employ VOSviewer, CiteSpace, and the R package "bibliometrix".

Results: Our study encompasses a comprehensive collection of 3109 articles originating from 96 countries, with notable contributions from leading nations such as the United States and China. The quantity of publications concerning the gut microbiota of liver cirrhosis rises annually. The University of California San Diego, Virginia Commonwealth University, Zhejiang University are the primary research institutions. World Journal of Gastroenterology publishes the most papers in this field, while hepatology is the most frequently co-cited journal. These publications come from a total of 15,965 authors, and the most prolific authors are Bajaj Jasmohan S., Schnabl Bernd and Gillevet Patrick M., while the most co-cited authors are Bajaj Jasmohan S., Younossi Zobair M., and Reiner Wiest. In addition, "dysbiosis", "gut microbiota", "intestinal barrier", "fecal microbiota transplantation", and "complement-system" are the primary keywords of research trends in recent years.

Discussion: This study offering a comprehensive insight into the research dynamics surrounding gut microbiota in patients with liver cirrhosis. It delineates the current research frontiers and hotspots, serving as a valuable guide for scholars.

Keywords: CiteSpace; VOSviewers; bibliometrics; gut microbiota; liver cirrhosis.

Copyright © 2024 Zhu, Zhou and Pan.

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Surrozen Announces Safety, Pharmacodynamic and Liver Function Data for SZN-043

-Phase 1a trial demonstrated acceptable safety and tolerability with no reported serious adverse events -Phase 1a data demonstrated target engagement, a pharmacodynamic effect and effects on liver function -Initiating Phase 1b proof-of-concept trial in severe alcohol-associated hepatitis - Expect to Present Safety, PD and PK Data for SZN-043 at Upcoming Medical Meeting in 2024

SOUTH SAN FRANCISCO, Calif., April 01, 2024 (GLOBE NEWSWIRE) -- Surrozen , Inc. (“Surrozen” or the “Company”) (Nasdaq: SRZN), a company pioneering targeted therapeutics that selectively activate the Wnt Pathway for tissue repair and regeneration, today provided an update on the Phase 1a clinical trial of SZN-043 in healthy volunteers and patients with cirrhosis.   The Phase 1a study was completed in February 2024. SZN-043 demonstrated acceptable safety and tolerability in all subjects, with evidence of target engagement, Wnt signal activation and effects on liver function.   The observed safety and pharmacodynamic activity were the basis for the Company’s previous announcement that it planned to initiate enrollment in the Phase 1b study in alcohol-associated hepatitis.

The randomized, placebo-controlled Phase 1a trial enrolled a total of 48 subjects, including 40 healthy volunteers and 8 patients with cirrhosis and a history of liver disease. Single or multiple IV doses were administered in doses ranging from 0.5mg/kg to 3 mg/kg. There were no serious adverse events nor infusion reactions observed. In the planned Phase 1b trial dose range (0.5mg/kg to 1.5 mg/kg), adverse events assessed to be drug related were mild to moderate and all resolved during the study. In healthy volunteers a few asymptomatic and transient transaminase elevations (ranging from mild to moderate) were observed which resolved without intervention, and with no clinical sequelae. There were no drug related adverse events reported in patients with cirrhosis at any dose. The pharmacokinetics of SZN-043 were consistent with our expectations and supportive of the planned doses, schedule and route of administration for alcohol-associated hepatitis.

In cirrhotic patients with a history of liver disease, the Phase 1a study also demonstrated dose dependent pharmacodynamic (PD) activity through activation of Wnt signaling as assessed by the methacetin breath test. This test measures activation of the Wnt pathway via the metabolism of a Wnt target gene (CYP1A2) substrate. Target engagement was confirmed via transient increases in alkaline phosphatase (ALP). Increases in ALP are indicative of SZN-043 binding to its targeting receptor ASGR1 and reduction in its capacity to clear ALP, consistent with observations in other ASGR1 binding agents. Cirrhotic patients also showed evidence of liver function effects after treatment with SZN-043 as measured by HepQuant which is a test that measures cholate clearance, a liver specific function that quantifies liver function.

”We are excited to have observed activation of Wnt signaling, target engagement and improvement in markers of liver function during the Phase 1a studies and are pleased to advance SZN-043 into the Phase 1b clinical trial in severe alcohol-associated hepatitis. We look forward to presenting the encouraging Phase 1a data at an upcoming medical conference - the first clinical data for this innovative antibody-based approach to modulating the Wnt pathway,” said Craig Parker, President and Chief Executive Office of Surrozen. “Progress with our platform technologies supports our belief that modulation of the Wnt pathway has the potential to provide important new therapeutic options through targeted tissue regeneration.“

The Company is in the process of initiating the multi-center Phase 1b clinical trial in multiple countries and expects that proof-of-concept data from this trial may be available in the first half of 2025. The study will enroll patients with severe alcohol-associated hepatitis in an open-label trial. The Company plans to evaluate safety, pharmacokinetics, immunogenicity and a number of efficacy endpoints including MELD score, Lille score and survival. The MELD and Lille scores have been shown to correlate with clinical improvement and 90-day survival.

About SZN-043 for Severe Alcohol-Associated Hepatitis SZN-043 is the first development candidate using Surrozen’s SWEETS™ technology. Surrozen is developing SZN-043 for severe liver diseases, initially focusing on alcohol-associated hepatitis. The Company has completed a Phase 1a clinical trial in patients with chronic liver disease and healthy volunteers. SZN-043 demonstrated acceptable safety and tolerability in all subjects, with evidence of target engagement, Wnt signal activation and effects on liver function. The Company is initiating the Phase 1b clinical trial in patients with severe alcohol-associated hepatitis and expects that proof-of-concept data from this trial may be available in the first half of 2025.

About SZN-413 for Retinal Diseases SZN-413 is a bi-specific antibody targeting Fzd4-mediated Wnt signaling designed using Surrozen’s SWAP™ technology. It is currently being developed for the treatment of retinal vascular-associated diseases. Data generated by Surrozen with SZN-413 in preclinical models of retinopathy demonstrated that SZN-413 could potently stimulate Wnt signaling in the eye, induce normal retinal vessel regrowth, suppress pathological vessel growth and reduce vascular leakage. This novel approach could thus potentially allow for regeneration of healthy eye tissue, not only halting retinopathy, but possibly allowing for a full reversal of the patient’s disease.

In the fourth quarter of 2022, Surrozen entered into a strategic partnership with Boehringer Ingelheim for the research and development of SZN-413 for the treatment of retinal diseases. Under the terms of the agreement, Boehringer Ingelheim received an exclusive, worldwide license to develop SZN-413 and other Fzd4-specific Wnt-modulating molecules for all purposes, including as a treatment for retinal diseases, in exchange for an upfront payment to Surrozen of $12.5 million. Surrozen will also be eligible to receive up to $587.0 million in success-based development, regulatory, and commercial milestone payments, in addition to mid-single digit to low-double digit royalties on sales. After an initial period of joint research, Boehringer Ingelheim will assume all development and commercial responsibilities.

About Wnt Signaling Wnt signaling plays key roles in the control of development, homeostasis, and regeneration of many essential organs and tissues, including liver, intestine, lung, kidney, retina, central nervous system, cochlea, bone, and others. Modulation of Wnt signaling pathways has potential for treatment of degenerative diseases and tissue injuries. Surrozen’s platform and proprietary technologies have the potential to overcome the limitations in pursuing the Wnt pathway as a therapeutic strategy.

About Surrozen Surrozen is a clinical stage biotechnology company discovering and developing drug candidates to selectively modulate the Wnt pathway. Surrozen is developing tissue-specific antibodies designed to engage the body’s existing biological repair mechanisms with a current focus on severe liver and eye diseases. For more information, please visit www.surrozen.com .

Forward Looking Statements This press release contains certain forward-looking statements within the meaning of the federal securities laws. Forward-looking statements generally are accompanied by words such as “will,” “plan,” “intend,” “potential,” “expect,” “could,” or the negative of these words and similar expressions that predict or indicate future events or trends or that are not statements of historical matters. These forward-looking statements include, but are not limited to, statements regarding Surrozen’s discovery, research and development activities, in particular its development plans for its product candidates SZN-043, and SZN-413 (including anticipated clinical development plans and timelines, and the availability of data, the potential for such product candidates to be used to treat human disease, as well as the potential benefits of such product candidates), and the Company’s partnership with Boehringer Ingelheim, including the potential for future success-based development, regulatory, and commercial milestone payments, in addition to mid-single digit to low-double digit royalties on sales . These statements are based on various assumptions, whether or not identified in this press release, and on the current expectations of the management of Surrozen and are not predictions of actual performance. These forward-looking statements are provided for illustrative purposes only and are not intended to serve as, and must not be relied on as a guarantee, an assurance, a prediction, or a definitive statement of fact or probability. Actual events and circumstances are difficult or impossible to predict and will differ from assumptions. Many actual events and circumstances are beyond the control of Surrozen. These forward-looking statements are subject to a number of risks and uncertainties, including the initiation, cost, timing, progress and results of research and development activities, preclinical or and clinical trials with respect to SZN-043, SZN-413 and potential future drug candidates; the Company’s ability to fund its preclinical and clinical trials and development efforts, whether with existing funds or through additional fundraising; Surrozen’s ability to identify, develop and commercialize drug candidates; Surrozen’s ability to successfully complete preclinical and clinical studies for SZN-043, SZN-413, or other future product candidates; the effects that arise from volatility in global economic, political, regulatory and market conditions; and all other factors discussed in Surrozen’s Annual Report on Form 10-K for the year ended December 31, 2022 and Surrozen’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2023 under the heading “Risk Factors,” and other documents Surrozen has filed, or will file, with the Securities and Exchange Commission. If any of these risks materialize or our assumptions prove incorrect, actual results could differ materially from the results implied by these forward-looking statements. There may be additional risks that Surrozen presently does not know, or that Surrozen currently believes are immaterial, that could also cause actual results to differ from those contained in the forward-looking statements. In addition, forward-looking statements reflect Surrozen’s expectations, plans, or forecasts of future events and views as of the date of this press release. Surrozen anticipates that subsequent events and developments will cause its assessments to change. However, while Surrozen may elect to update these forward-looking statements at some point in the future, Surrozen specifically disclaims any obligation to do so, except as required by law. These forward-looking statements should not be relied upon as representing Surrozen’s assessments of any date after the date of this press release. Accordingly, undue reliance should not be placed upon the forward-looking statements.

Investor and Media Contact: [email protected]

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StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

StatPearls [Internet].

Hepatic cirrhosis.

Bashar Sharma ; Savio John .

Affiliations

Last Update: October 31, 2022 .

• Continuing Education Activity

Cirrhosis is characterized by fibrosis and nodule formation of the liver secondary to chronic injury, leading to alteration of the normal lobular organization of the liver. Various insults can injure the liver, including viral infections, toxins, hereditary conditions, or autoimmune processes. With each injury, the liver forms scar tissue (fibrosis), initially without losing its function. After a chronic injury, most of the liver tissue becomes fibrotic, leading to loss of function and the development of cirrhosis. This activity reviews the causes, evaluation, and management of hepatic cirrhosis and highlights the interprofessional team's role in the management of patients with this condition.

• Describe the pathophysiology of cirrhosis.
• Identify the etiology of cirrhosis.
• Outline the presentation of a patient with cirrhosis.
• Explain the importance of improving care coordination amongst interprofessional team members to improve outcomes for cirrhotic patients.
• Introduction

Cirrhosis is characterized by fibrosis and nodule formation of the liver, secondary to a chronic injury, which leads to alteration of the normal lobular organization of the liver. Various insults can injure the liver, including viral infections, toxins, hereditary conditions, or autoimmune processes. With each injury, the liver forms scar tissue (fibrosis), initially without losing its function. After a long-standing injury, most of the liver tissue gets fibrosed, leading to loss of function and the development of cirrhosis.

Chronic liver diseases usually progress to cirrhosis. In the developed world, the most common causes of cirrhosis are hepatitis C virus (HCV), alcoholic liver disease, and nonalcoholic steatohepatitis (NASH), while hepatitis B virus (HBV) and HCV are the most common causes in the developing world. [1] Other causes of cirrhosis include autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, hemochromatosis, Wilson disease, alpha-1 antitrypsin deficiency, Budd-Chiari syndrome, drug-induced liver cirrhosis, and chronic right-sided heart failure. Cryptogenic cirrhosis is defined as cirrhosis of unclear etiology.

• Epidemiology

The worldwide prevalence of cirrhosis is unknown; however, it has been estimated to be between 0.15% and 0.27% in the United States. [2] [3]

• Pathophysiology

Multiple cells play a role in liver cirrhosis, including hepatocytes and sinusoidal lining cells such as hepatic stellate cells (HSCs), sinusoidal endothelial cells (SECs), and Kupffer cells (KCs). HSCs form a part of the wall of the liver sinusoids, and their function is to store vitamin A. When these cells are exposed to inflammatory cytokines, they get activated, transform into myofibroblasts, and start depositing collagen, which results in fibrosis. SECs form the endothelial lining and are characterized by the fenestrations they make in the wall that allow the exchange of fluid and nutrients between the sinusoids and the hepatocytes. [4]  Defenestration of the sinusoidal wall can happen secondary to chronic alcohol use and promote perisinusoidal fibrosis. [5]  KCs are satellite macrophages that line the wall of the sinusoids as well. Studies mainly from animal models have shown that they play a role in liver fibrosis by releasing harmful mediators when exposed to injurious agents and acting as antigen-presenting cells for viruses. [6]  Hepatocytes are also involved in cirrhosis's pathogenesis, as damaged hepatocytes release reactive oxygen species and inflammatory mediators that can promote activating HSCs and liver fibrosis. [7]

The major cause of morbidity and mortality in cirrhotic patients is the development of portal hypertension and hyperdynamic circulation. Portal hypertension develops secondary to fibrosis and vasoregulatory changes, both intrahepatically and systematically, leading to collateral circulation formation and hyperdynamic circulation. [8]

Intrahepatically, SECs synthesize both nitric oxide (NO) and endothelin-1 (ET-1), which act on HSCs, causing relaxation or contraction of the sinusoids, respectively, and controlling sinusoidal blood flow. In patients with cirrhosis, there is an increase in ET-1 production, as well as an increase in the sensitivity of its receptors with a decrease in NO production. This leads to increased intrahepatic vasoconstriction and resistance, initiating portal hypertension. Vascular remodeling mediated by the contractile effects of HSCs in the sinusoids augments the increase in vascular resistance. To compensate for this increase in intrahepatic pressure, collateral circulation is formed. [8]

In systemic and splanchnic circulation, the opposite effect happens, with an increase in NO production, leading to systemic and splanchnic vasodilation and decreased systemic vascular resistance. This promotes the activation of the renin-angiotensin-aldosterone system (RAAS), leading to sodium and water retention and resulting in a hyperdynamic circulation. Thus, in cirrhosis with portal hypertension, there is depletion of vasodilators (predominantly NO) intrahepatically but an excess of NO extrahepatically in the splanchnic and systemic circulation, leading to sinusoidal vasoconstriction and splanchnic (systemic) vasodilation. The collaterals also contribute to the hyperdynamic circulation by increasing the venous return to the heart. [8] [9]

• Histopathology

Cirrhosis is classified based on morphology or etiology. 

Morphology Classification

Morphologically, cirrhosis is (1) micronodular, (2) macronodular, or (3) mixed. This classification is not as clinically useful as etiologic classification.

• Micronodular cirrhosis (uniform nodules less than 3 mm in diameter): Cirrhosis due to alcohol, hemochromatosis, hepatic venous outflow obstruction, chronic biliary obstruction, jejunoileal bypass, and Indian childhood cirrhosis.
• Macronodular cirrhosis (i rregular nodules with a variation greater than 3 mm in diameter): Cirrhosis due to hepatitis B and C, alpha-1 antitrypsin deficiency, and primary biliary cholangitis.
• Mixed cirrhosis (when features of both micronodular and macronodular cirrhosis are present): Usually, micronodular cirrhosis progresses into macronodular cirrhosis over time.

Etiology Classification

Based on the cause of cirrhosis which is sub-classified as follows:

• Viral - hepatitis B, C, and D
• Toxins - alcohol, drugs 
• Autoimmune - autoimmune hepatitis
• Cholestatic - primary biliary cholangitis, primary sclerosing cholangitis 
• Vascular - Budd-Chiari syndrome, sinusoidal obstruction syndrome, cardiac cirrhosis
• Metabolic - hemochromatosis, NASH, Wilson disease, alpha-1 antitrypsin deficiency, cryptogenic cirrhosis.  
• History and Physical

Patients with cirrhosis can be asymptomatic or symptomatic, depending on whether their cirrhosis is clinically compensated or decompensated. In compensated cirrhosis, patients are usually asymptomatic, and their disease is detected incidentally by labs, physical exams, or imaging. One of the common findings is mild to moderate elevation in aminotransferases or gamma-glutamyl transpeptidase with possible enlarged liver or spleen on the exam. On the other hand, patients with decompensated cirrhosis usually present with a wide range of signs and symptoms arising from a combination of liver dysfunction and portal hypertension. The diagnosis of ascites, jaundice, hepatic encephalopathy, variceal bleeding, or hepatocellular carcinoma in a patient with cirrhosis signifies the transition from a compensated to a decompensated phase of cirrhosis. Other cirrhosis complications include spontaneous bacterial peritonitis and hepatorenal syndrome, which occur in patients who have ascites.

Multiple Organs Affected

Gastrointestinal

Portal hypertension can cause ascites, hepatosplenomegaly, and prominence of the periumbilical abdominal veins resulting in caput medusa. Esophageal varices are another complication of cirrhosis secondary to increased blood flow in the collateral circulation, with a mortality rate of at least 20% at six weeks after a bleeding episode. [10]  Patients with alcoholic cirrhosis are at increased risk of small bowel bacterial overgrowth and chronic pancreatitis, and patients with chronic liver disease have a higher rate of gallstones formation. [11] [12]

Hematologic

Anemia can occur due to folate deficiency, hemolytic anemia (spur cell anemia in severe alcoholic liver disease), and hypersplenism. There can be pancytopenia due to hypersplenism in portal hypertension, impaired coagulation, disseminated intravascular coagulation, and hemosiderosis in cirrhosis patients due to different causes.

Patients with cirrhosis are prone to develop hepatorenal syndrome secondary to systemic hypotension and renal vasoconstriction, causing the underfilling phenomenon. Splanchnic vasodilation in cirrhosis leads to decreased effective blood flow to the kidneys, which activates the RAAS system, leading to retention of sodium and water and renal vascular constriction. [13]  However, this effect is not enough to overcome the systemic vasodilation caused by cirrhosis, leading to renal hypoperfusion and worsened by renal vasoconstriction with the endpoint of renal failure. [14]

Manifestations of cirrhosis include hepatopulmonary syndrome, portopulmonary hypertension, hepatic hydrothorax, decreased oxygen saturation, ventilation-perfusion mismatch, reduced pulmonary diffusion capacity, and hyperventilation.

Spider nevi (central arterioles surrounded by multiple smaller vessels that look like a spider, hence the name) are seen in cirrhosis patients secondary to hyperestrogenemia. Liver dysfunction leads to a sex hormone imbalance, causing increased estrogen to free testosterone ratio and the formation of spider nevi. [15]  Palmar erythema is another skin finding that is seen in cirrhosis and is also secondary to hyperestrogenemia. Jaundice is a yellowish discoloration of the skin and mucous membranes seen when the serum bilirubin is greater than 3 mg/dL and in decompensated cirrhosis.

Patients with alcoholic liver cirrhosis can develop hypogonadism and gynecomastia. The pathophysiology is multifactorial, mainly due to the hypersensitivity of estrogen and androgen receptors seen in cirrhotic patients. Hypothalamic pituitary dysfunction has also been implicated in the development of these conditions. [16]  Hypogonadism can lead to decreased libido and impotence in males with loss of secondary sexual characteristics and feminization. Women can develop amenorrhea and irregular menstrual bleeding, as well as infertility.

Nail Changes

Clubbing, hypertrophic osteoarthropathy, and the Dupuytren contracture are seen. Other nail changes include azure lunules (Wilson disease), Terry nails, and Muehrcke nails.

Fetor hepaticus (sweet, musty breath smell due to high levels of dimethyl sulfide and ketones in the blood) and asterixis (flapping tremor when the arms are extended and the hands are dorsiflexed) are both features of hepatic encephalopathy that can be seen in cirrhosis. [17] Cirrhosis can lead to hyperdynamic circulation, reduction in lean muscle mass, muscle cramps, and umbilical herniation. 

Physical examination in patients with cirrhosis may reveal stigmata of chronic liver disease (spider telangiectasias, palmar erythema, Dupuytren's contractures, gynecomastia, testicular atrophy), signs of portal hypertension (ascites, splenomegaly, caput medusae, Cruveilhier-Baumgarten murmur- epigastric venous hum), signs of hepatic encephalopathy (confusion, asterixis, and fetor hepaticus), and other features such as jaundice, bilateral parotid enlargement, and scant chest/axillary hair. 

Lab Findings

Aminotransferases are usually mildly to moderately elevated with aspartate aminotransferase (AST) greater than alanine aminotransferase (ALT); however, normal levels do not exclude cirrhosis. [18]  In most forms of chronic hepatitis (except alcoholic hepatitis), the AST/ALT ratio is less than one. As chronic hepatitis progresses to cirrhosis, there is a reversal of this AST/ALT ratio. Alkaline phosphatase (ALP), 5'- nucleotidase, and gamma-glutamyl transferase (GGT) are elevated in cholestatic disorders. Prothrombin time (PT) is elevated due to coagulation factor defects and bilirubin, while albumin is low as it is synthesized by the liver and the liver's functional capacity goes down. Thus serum albumin and PT are true indicators of synthetic hepatic function. Normochromic anemia is seen; however, macrocytic anemia can be seen in alcoholic liver cirrhosis. Leukopenia and thrombocytopenia are also seen secondary to sequestration by the enlarged spleen as well as alcohol suppression effect on the bone marrow. [19]  Immunoglobulins, especially the gamma fraction, are usually elevated due to impaired clearance by the liver. [20]

Specific Labs to Investigate Newly Diagnosed Cirrhosis

Serology and PCR techniques for viral hepatitis and autoimmune antibodies (anti-nuclear antibodies [ANA], anti-smooth muscle antibodies (ASMA), anti-liver-kidney microsomal antibodies type 1 (ALKM-1) and serum IgG immunoglobulins) for autoimmune hepatitis and anti-mitochondrial antibody for primary biliary cholangitis may be ordered. Ferritin and transferrin saturation for hemochromatosis, ceruloplasmin, and urinary copper for Wilson disease, Alpha 1-antitrypsin level, and protease inhibitor phenotype for alpha 1-antitrypsin deficiency, and serum alpha-fetoprotein for hepatocellular carcinoma (HCC) are other useful tests.

Imaging and Liver Biopsy

A number of imaging modalities are used alongside labs to help in the diagnosis of cirrhosis. These include ultrasound, CT, MRI, and transient elastography (fibroscan).

Ultrasonography is a cheap, noninvasive, and available modality for the evaluation of cirrhosis. It can detect nodularity and increased echogenicity of the liver, which are seen in cirrhosis; however, it is nonspecific as these findings can be seen in fatty liver as well. [21]  It can also determine the ratio of the caudate lobe width to right lobe width, which usually increases in cirrhosis. [22]  Moreover, it is a useful screening tool for HCC in cirrhotic patients. Duplex Doppler ultrasonography helps to assess the patency of hepatic, portal, and mesenteric veins.

CT and MRI with contrast can detect HCC and vascular lesions, with MRI being superior to CT. [23]  MRI also can be used to detect the level of iron and fat deposition in the liver for hemochromatosis and steatosis, and biliary obstruction if an MRC (magnetic resonance cholangiography) is obtained. [24] [25]  MRI, however, is expensive and not readily available.

Transient elastography (fibroscan) is a non-invasive method that uses high-velocity ultrasound waves to measure liver stiffness, which correlates with fibrosis. In cirrhosis, a colloid liver spleen scan using technetium-99m sulfur colloid may show increased uptake of colloid in the bone marrow and spleen when compared to the liver. The presence of varices in the esophagus or stomach on esophagogastroduodenoscopy (EGD) suggests portal hypertension.

Liver biopsy is the gold standard for diagnosing cirrhosis as well as assessing the degree of inflammation (grade) and fibrosis (stage) of the disease. Nevertheless, it can miss the diagnosis at times due to sampling errors. [26]  The diagnosis of cirrhosis by biopsy requires the presence of fibrosis and nodules. The nodular pattern can be micronodular, macronodular, or mixed with the micronodular pattern representing an independent risk factor for elevated hepatic venous pressure gradient (HVPG) and more severe disease. [26]

Noninvasive tests using direct and indirect serum markers are used to detect patients with significant fibrosis/cirrhosis from patients with no/mild fibrosis. [27] [28] [29]

• Treatment / Management

Damage to the liver is permanent. Nevertheless, further injury to the liver should be avoided to halt the progression of the disease. General management to prevent chronic liver disease includes avoidance of alcohol, vaccination for HBV and HCV, good nutrition with a balanced diet, weight reduction, and early treatment of precipitating factors like dehydration, hypotension, and infections. This is achieved by routine monitoring of volume status, kidney function, varices development, and progression to HCC.

Specific therapy usually targets the etiology, including antiviral medications in viral hepatitis, steroids, and immunosuppressant agents in autoimmune hepatitis, ursodeoxycholic acid and obeticholic acid in primary biliary cholangitis, copper chelation in Wilson disease, and iron chelation and phlebotomy in hemochromatosis. Weight loss of at least 7% is beneficial in NASH, and alcohol abstinence is crucial in alcoholic cirrhosis. [30]

• Differential Diagnosis
• Acute fatty liver of pregnancy
• Amanita phalloides mushroom poisoning
• Acetaminophen poisoning
• Bacillus cereus toxin
• Fructose intolerance
• Galactosemia
• HELLP(hemolysis, elevated liver enzymes, low platelets) syndrome of pregnancy
• Hemorrhage viruses (Ebola virus, Lassa virus, Marburg virus)
• Idiopathic drug reaction
• Neonatal iron storage diseases
• Tyrosinemia

Predictive models for the prognosis of cirrhosis estimate the ten-year survival in patients with compensated cirrhosis at 47%, but this drops to 16% once a decompensating event occurs. The Child-Turcotte-Pugh (CTP) scoring or classification uses serum albumin, bilirubin, PT, ascites, and hepatic encephalopathy to classify patients with cirrhosis into classes A, B, and C. One- and two-year survival rates for these classes are 100% and 85% (A),  80% and 60% (B), and 45% and 35% (C). The model for end-stage liver disease (MELD) score is another model used to predict the short-term mortality of patients with cirrhosis. It uses serum bilirubin, creatinine, and INR to predict mortality within the next three months. [31]  Based on the MELD score (more recently the MELDNa score), the priority of organ allocation for liver transplantation for patients with cirrhosis is adjudicated in the US. [31]

Liver transplantation is indicated in decompensated cirrhosis that does not respond to medical treatment. The one-year and five-year survival rates after liver transplantation are approximately 85% and 72%, respectively. Recurrence of the underlying liver disease can occur after a transplant. [32]  Long-term side effects of immunosuppressant drugs is another cause of morbidity in transplant patients.

• Complications

Complications accompanying hepatic cirrhosis can include [33] :

• Portal hypertension
• Edema in the abdomen and lower extremities
• Splenomegaly
• Hepatic encephalopathy
• Deterrence and Patient Education

While patient lifestyle changes cannot cure cirrhosis, these behavioral modifications can prevent or at least delay disease progression and provide symptomatic relief. Modifiable lifestyle factors include:

• Eliminating ethanol consumption
• Avoid raw seafood and shellfish
• possible low-sodium diet to reduce water retention
• Vaccinations for pneumonia, influenza, and hepatitis
• Regulate protein intake according to their doctor's directions
• Some doctors will recommend a vitamin and mineral supplement
• Pearls and Other Issues

Hepatocellular Carcinoma

HCC is the most common primary cancer in the liver, and its incidence is increasing. [34]  Cirrhosis secondary to HBV and HCV is the most common risk factor. [34]  Routine monitoring of cirrhotic patients for the development of HCC is recommended, with at least six monthly screenings using abdominal ultrasonography. [2]

• Enhancing Healthcare Team Outcomes

Treatment and prevention of liver cirrhosis are best done by an interprofessional team that includes a hepatologist, gastroenterologist, liver surgeon, pathologist infectious disease specialist, nurse practitioner, primary care provider, and an internist. All healthcare workers should follow patients with liver dysfunction from any cause because it can quickly become irreversible. Liver cirrhosis is associated with many systemic complications that can cause death. A liver transplant is not always an option because of the shortage of donors. 

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Under a magnification of 500X, this photomicrograph of a liver tissue specimen revealed sign of a schistosomiasis infection, included a histopathologic finding known as pipe stem cirrhosis, which occurs when schistosomes infect the liver, known as hepatic (more...)

Cirrhosis, liver. Reticulin stain enhances the fibrous septa dividing the hepatic nodules. 4x. Contributed by Fabiola Farci, MD

Liver cirrhosis, reticulin stain 4x Contributed by Fabiola Farci, MD

Cirrhosis, portal space in fibrous septa. Reticulin stain 4x Contributed by Fabiola Farci, MD

Liver cirrhosis, tricromic stain 4x Contributed by Fabiola Farci, MD

Disclosure: Bashar Sharma declares no relevant financial relationships with ineligible companies.

Disclosure: Savio John declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

• Cite this Page Sharma B, John S. Hepatic Cirrhosis. [Updated 2022 Oct 31]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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• Review Metabolism of N-nitrosodimethylamine, methylation of macromolecules, and development of hepatic fibrosis in rodent models. [J Mol Med (Berl). 2020] Review Metabolism of N-nitrosodimethylamine, methylation of macromolecules, and development of hepatic fibrosis in rodent models. George J, Tsuchishima M, Tsutsumi M. J Mol Med (Berl). 2020 Sep; 98(9):1203-1213. Epub 2020 Jul 14.
• Non-hepatic insults are common acute precipitants in patients with acute on chronic liver failure (ACLF). [Dig Dis Sci. 2010] Non-hepatic insults are common acute precipitants in patients with acute on chronic liver failure (ACLF). Duseja A, Chawla YK, Dhiman RK, Kumar A, Choudhary N, Taneja S. Dig Dis Sci. 2010 Nov; 55(11):3188-92. Epub 2010 Aug 19.
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Aspirin cuts liver fat in trial

10 percent reduction seen in small study of disease that affects up to a third of U.S. adults

Tracy Hampton

MGH Communications

The most common chronic liver disease — metabolic dysfunction–associated steatotic liver disease (MASLD) — is characterized by an increased buildup of fat in the liver due to factors such as obesity and Type 2 diabetes.

Such elevated fat poses serious health risks, but a recent clinical trial published in JAMA and conducted by investigators from Massachusetts General Hospital points to a possible treatment: aspirin.

“Since MASLD is estimated to affect up to a third of U.S. adults, aspirin represents an attractive potential low-cost option to prevent progression to cirrhosis or liver cancer, the most feared complications of MASLD,” said senior author Andrew T. Chan , a gastroenterologist and a professor at Harvard Medical School.

Chan and his colleagues tested aspirin’s potential because the drug reduces inflammation and affects fat metabolism.

In their Phase 2 trial, 80 adults with MASLD were randomized to receive daily low-dose aspirin or placebo for six months. At the end of the study, the average change in liver fat content was minus 6.6 percent with aspirin versus plus 3.6 percent with placebo, showing that low-dose aspirin reduced the average liver fat content by 10.2 percent compared with placebo. The aspirin was found to be safe and well-tolerated, and also improved various markers of liver health.

“Multiple noninvasive blood and imaging-based tests for liver fat, inflammation, and fibrosis all showed a similar direction of benefit that favored aspirin treatment,” said lead author and principal investigator Tracey G. Simon , a hepatologist and an instructor at the Medical School. “Together, these data support the potential for aspirin to provide benefits for patients with MASLD.”

Additional studies are needed to determine whether continued aspirin use can reduce individuals’ risk of long-term health complications associated with MASLD, the researchers said.

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• Published: 26 July 2023

When research on liver fibrosis made the right turn

• Massimo Pinzani   ORCID: orcid.org/0000-0003-1398-1541 1  

Nature Reviews Gastroenterology & Hepatology volume  20 ,  page 632 ( 2023 ) Cite this article

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Liver tissue fibrosis is the common outcome of liver diseases characterized by chronic hepatocellular damage, irrespective of disease aetiology. The process leads to an advanced stage defined as cirrhosis with severe complications due to portal hypertension and progressive hepatocellular failure.

At the end of the 1980s, the cellular origin of excessive extracellular matrix (ECM), typical of liver fibrosis, particularly fibrillar collagens I and III, was still uncertain. Almost dogmatically, hepatocytes were regarded as the main source of collagens in the healthy and diseased liver and directly responsible for developing liver fibrosis and cirrhosis. This belief was based on the common observation that hepatocytes isolated from the liver and maintained in culture produced a substantial amount of fibrillar collagens, exhibiting a delayed acceleration in collagen synthesis after several days in primary culture. This phenomenon was attributed to ‘culture adaptation’, resembling a transition to a more fibrogenic phenotype occurring in vivo in response to chronic damage. Overall, the role of hepatocytes as key drivers of liver fibrogenesis clashed with two main considerations. First, the main effectors of tissue scarring in other organs and systems were always identified in resident or recruited mesenchymal cells (mainly fibroblasts, myofibroblasts and smooth muscle cells) as part of a chronic wound healing process following chronic parenchymal cell injury. Second, it was difficult to conceive how hepatocytes chronically challenged to function and survive in the presence of infectious (particularly hepatitis B and C), toxic (particularly alcohol excess) and autoimmune damage could also be sustaining a major tissue fibrogenic process on their own even considering the possibility of an epithelial-to-mesenchymal transition.

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Original article

Maher, J. J. et al. Collagen measured in primary cultures of normal rat hepatocytes derives from lipocytes within the monolayer. J. Clin. Invest. 82 , 450–459 (1988)

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Milani, S. et al. Cellular localization of type I, III, and IV procollagen gene transcripts in normal and fibrotic human liver. Am. J. Pathol. 137 , 59–70 (1990)

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Massimo Pinzani

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Correspondence to Massimo Pinzani .

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Pinzani, M. When research on liver fibrosis made the right turn. Nat Rev Gastroenterol Hepatol 20 , 632 (2023). https://doi.org/10.1038/s41575-023-00828-6

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Published : 26 July 2023

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DOI : https://doi.org/10.1038/s41575-023-00828-6

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FDA Approves First Treatment for Patients with Liver Scarring Due to Fatty Liver Disease

FDA News Release

Today, the U.S. Food and Drug Administration approved Rezdiffra (resmetirom) for the treatment of adults with noncirrhotic non-alcoholic steatohepatitis (NASH) with moderate to advanced liver scarring (fibrosis), to be used along with diet and exercise. 

“Previously, patients with NASH who also have notable liver scarring did not have a medication that could directly address their liver damage,” said Nikolay Nikolov, M.D., acting director of the Office of Immunology and Inflammation in the FDA’s Center for Drug Evaluation and Research. “Today’s approval of Rezdiffra will, for the first time, provide a treatment option for these patients, in addition to diet and exercise.” 

NASH is a result of the progression of nonalcoholic fatty liver disease where liver inflammation, over time, can lead to liver scarring and liver dysfunction. NASH is often associated with other health problems such as high blood pressure and type 2 diabetes. By at least one estimate, approximately 6-8 million people in the U.S. have NASH with moderate to advanced liver scarring, with that number expected to increase. Rezdiffra is a partial activator of a thyroid hormone receptor; activation of this receptor by Rezdiffra in the liver reduces liver fat accumulation. 

The safety and efficacy of Rezdiffra was evaluated based on an analysis of a surrogate endpoint at month 12 in a 54-month, randomized, double-blind placebo-controlled trial. The surrogate endpoint measured the extent of liver inflammation and scarring. The sponsor is required to conduct a postapproval study to verify and describe Rezdiffra’s clinical benefit, which will be done through completing the same 54-month study, which is still ongoing. To enroll in the trial, patients needed to have a liver biopsy showing inflammation due to NASH with moderate or advanced liver scarring. In the trial, 888 subjects were randomly assigned to receive one of the following: placebo (294 subjects); 80 milligrams of Rezdiffra (298 subjects); or 100 milligrams of Rezdiffra (296 subjects); once daily, in addition to standard care for NASH, which includes counseling for healthy diet and exercise. 

At 12 months, liver biopsies showed that a greater proportion of subjects who were treated with Rezdiffra achieved NASH resolution or an improvement in liver scarring as compared with those who received the placebo. A total of 26% to 27% of subjects who received 80 milligrams of Rezdiffra and 24% to 36% of subjects who received 100 milligrams of Rezdiffra experienced NASH resolution and no worsening of liver scarring, compared to 9% to 13% of those who received placebo and counseling on diet and exercise. The range of responses reflects different pathologists’ readings. In addition, a total of 23% of subjects who received 80 milligrams of Rezdiffra and 24% to 28% of subjects who received 100 milligrams of Rezdiffra experienced an improvement in liver scarring and no worsening of NASH, compared to 13% to 15% of those who received placebo, depending on each pathologist’s readings. Demonstration of these changes in a proportion of patients after just one year of treatment is notable, as the disease typically progresses slowly with a majority of patients taking years or even decades to show progression.

The most common side effects of Rezdiffra included diarrhea and nausea. Rezdiffra comes with certain warnings and precautions, such as drug-induced liver toxicity and gallbladder-related side effects. 

Use of Rezdiffra should be avoided in patients with decompensated cirrhosis. Patients should stop using Rezdiffra if they develop signs or symptoms of worsening liver function while on Rezdiffra treatment. 

Using Rezdiffra at the same time as certain other drugs, in particular statins for lowering cholesterol, may result in potentially significant drug interactions. Health care providers should refer to the full prescribing information  for additional information on these potentially significant drug interactions with Rezdiffra, recommended dosage and administration modifications. 

The FDA approved Rezdiffra under the accelerated approval pathway, which allows for earlier approval of drugs that treat serious conditions and address an unmet medical need, based on a surrogate or intermediate clinical endpoint that is reasonably likely to predict clinical benefit. The required aforementioned 54-month study, which is ongoing, will assess clinical benefit after 54 months of Rezdiffra treatment. 

Rezdiffra received Breakthrough Therapy, Fast Track and Priority Review designations for this indication. 

The FDA granted the approval of Rezdiffra to Madrigal Pharmaceuticals.

Related Information

• NIH: Nonalcoholic Fatty Liver Disease (NAFLD) & NASH

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, radiation-emitting electronic products, and for regulating tobacco products.