How Do Fatty Liver, Hepatitis and Cirrhosis Connect? — Ground That Hardens as Scars Build Up, and the Stretch Where You Can Still Turn Back

"You Have a Fatty Liver"

The word "fatty liver" is written on your health checkup results. You neither hurt nor feel uncomfortable, yet the doctor brings up your weight and drinking. Another person hears that because someone in their family carries a hepatitis virus, they should also get a blood test.

The questions the two people hold are similar. They are how much of a worry this is, how hepatitis and liver cancer connect, what it means for the liver to harden, and whether what has already formed can be reversed.

This article follows the path where the liver is damaged over a long time and hardens. On the topics of the hepatitis virus and liver cancer, and how common fatty liver is, it is written using data from South Korea. Korea is a country where many people used to live infected with the type B virus that causes hepatitis, and after nationwide vaccinations were given in the 1980s, that proportion dropped from 8% to 3% (PMID 33538133).

This is the final article in this series. In the other installment of this series that covered what the liver does and what liver tests measure, the liver was viewed as a place that first receives and alters blood coming from the gut, and the path by which that liver runs into trouble was handed over to here.

Land Where Scars Pile Up on Wounds

There are many causes that lead to cirrhosis. Obesity and fat accumulated in the liver, heavy alcohol consumption, hepatitis viruses, diseases where the immune system attacks the body itself, diseases where bile pools, and diseases where iron or copper accumulates excessively can all bring on cirrhosis (PMID 34543610). Although the causes differ, the road leading to the end is similar.

Hepatocytes are the main cells that make up the liver and handle most of the work the liver does. When hepatocytes are injured for a long time and inflammation continues, scars fill in the injured spots.

Fibrosis is the process in which scar tissue piles up to patch over long-term damage and inflammation, causing an organ to harden. Fibrosis is commonly graded from stage 0 to stage 4, and stage 4 is cirrhosis (PMID 39983746).

Cirrhosis is a state where fibrosis has spread throughout the entire liver, and the liver's architecture has been replaced by scar tissue and lumps of cells that have regrown between them. Cirrhosis arises after long-standing inflammation (PMID 34543610).

If you compare the liver to land, fibrosis is the process where scars cover each injured spot, hardening the land little by little. Cirrhosis is a state where the hardened spots have connected, making the entire land stiff. In hardened land, waterways are blocked; in the liver, the paths where blood travels are blocked, and pressure rises (PMID 34543610).

In a liver that has progressed to cirrhosis, the risk of liver cancer arising is very high (PMID 33012448).

Although the causes differ, a liver injured for a long time accumulates scars and hardens, and at the end of that path lies the risk of cirrhosis and liver cancer.

A Fat-Accumulating Liver, and a Changed Name

A fatty liver is a state where fat has accumulated excessively inside liver cells. What causes fat to accumulate in the liver is mainly obesity, type 2 diabetes, and alcohol (PMID 39488409).

Fatty liver not related to alcohol was long called nonalcoholic fatty liver disease. This name had two limitations. It defined the disease by "what it is not," and it used language that could carry a stigma (PMID 37364790).

In 2023, through a consensus process led by three major international liver societies, experts and patient advocacy groups from various countries went through multiple surveys and meetings, and 74% of respondents viewed the old name as having flaws worth changing. For the English names, 61% felt "nonalcoholic" and 66% felt "fatty" could be stigmatizing. An independent panel of experts outside that process ultimately recommended the new name and diagnostic criteria (PMID 37364790).

Metabolic dysfunction-associated steatotic liver disease is a condition where fat accumulates in the liver of a person who does not drink heavily, accompanied by at least one metabolic abnormality. There are five conditions counted as metabolic abnormalities. They are an increased waist circumference or obesity, prediabetes or type 2 diabetes, high blood pressure, high triglycerides, and low HDL cholesterol (PMID 41212550).

The new criteria also changed the definition. The old name was defined by confirming that alcohol and other causes were absent, whereas the new name requires at least one metabolic abnormality to be present. The concept of it being a stage where inflammation overlaps on top of fat was kept because it was considered important (PMID 37364790). A 2024 guideline issued by the European Association for the Study of the Liver (EASL) along with the European Association for the Study of Diabetes (EASD) and the European Association for the Study of Obesity (EASO) refers to the old nonalcoholic fatty liver disease by this name (PMID 38851997).

This disease is currently the most common chronic liver disease in the world. It is present in about 30–40% of adults globally, and that proportion varies by continent. It is present in about 60–70% of people with type 2 diabetes and about 70–80% of people with obesity (PMID 41212550). In Korea, an analysis gathering 61 studies based on the old name criteria showed a prevalence of 30.3% (41.1% for men, 20.3% for women), and it increased slightly from 29.0% to 31.0% over a span of about 10 years (PMID 32919911).

The 2023 international consensus process put forward the name metabolic dysfunction-associated steatotic liver disease to change potentially stigmatizing language and a definition previously set by "what it is not," and this disease is present in about 30–40% of adults worldwide.

Most Stay as Fat, Some Move to Scars

Most people with this condition stay at fatty liver, where things do not get much worse (PMID 30398639), and in some, inflammation and liver cell damage overlap on top of the fat.

Metabolic dysfunction-associated steatohepatitis is a condition where, in addition to fat accumulating in the liver, inflammation and liver cell damage occur, which can progress to fibrosis where the liver hardens like a scar. This inflammatory type is present in 10 to 20% of people who have the old name (nonalcoholic fatty liver disease) (PMID 37364164). The inflammatory type progresses to fibrosis faster than the case with fat alone (PMID 33894145).

According to a narrative review, the proportion of people with metabolic dysfunction-associated steatotic liver disease who progress to cirrhosis is 3 to 5%, and that path usually takes over 20 years (PMID 39243773).

The side that stays also moves little by little. In an analysis that gathered 411 adults who underwent two liver biopsies with an interval of over a year, it took an average of 14.3 years for people with only fat and 7.1 years for people with steatohepatitis for their fibrosis to advance by one stage, starting from people who initially had no fibrosis. During the follow-up, 33.6% saw their fibrosis worsen, 43.1% stayed the same, and 22.3% improved. The researchers concluded that fibrosis progresses in both people with only fat and people with steatohepatitis (PMID 24768810).

That fibrosis is the factor that best predicts mortality in this disease is the starting point of a meta-analysis (PMID 28130788). In that analysis, which gathered 1,495 patients from five studies, the liver-related mortality compared to people without fibrosis was 9.57 times higher for stage 2, 16.69 times higher for stage 3, and 42.30 times higher for stage 4, while stage 1 showed a 1.41 times difference that was not distinct. The researchers concluded that the risk of liver-related death grows steeply as the fibrosis stage rises. However, the number of studies was small, making the range of estimation wide, and coexisting diseases or age were not adjusted for (PMID 28130788).

The most common causes of death for people with this condition are heart and blood vessel diseases rather than the liver, followed by several extrahepatic cancers, and liver complications such as cirrhosis and liver cancer (PMID 41212550).

Fatty liver is common and most stays as fat, but some progress to inflammation and fibrosis, and what best tells the future is how far the fibrosis has advanced.

The Same Path That Alcohol Takes

Alcohol is the leading preventable cause of liver disease and related mortality worldwide, and the most common cause of advanced liver disease (PMID 37832648).

Alcohol-related liver disease is an umbrella term for conditions where the liver is damaged by alcohol. It begins with the accumulation of fat, is compounded by inflammation, progresses through fibrosis, and leads in some cases to cirrhosis and its complications (PMID 37832648). It follows the same path as metabolic-associated fatty liver disease.

Among people who continue to drink, a severe form can suddenly appear in some individuals. This is alcoholic hepatitis, where the eyes and skin suddenly turn yellow and the complications of liver disease become apparent (PMID 37832648).

There is still no approved targeted treatment designed to directly stop the progression of this disease. Therefore, stopping drinking is the most effective way to improve prognosis and serves as the primary treatment at every stage (PMID 37832648).

In a meta-analysis of 17 studies examining the relationship between the amount consumed and the risk of cirrhosis, the risk for women was higher than for men even at the same consumption levels, and the impact of alcohol was greater on the risk of death from cirrhosis than on the risk of developing cirrhosis. What each study counted as its endpoint significantly shifted the results (PMID 20636661).

Livers damaged by alcohol follow the same path from fat to inflammation, fibrosis, and cirrhosis, and the most effective treatment available right now is to stop drinking.

The Liver Where Viruses Stay

Worldwide, 254 million people are infected with the hepatitis B virus (PMID 42081318).

Hepatitis B is inflammation of the liver caused by the hepatitis B virus, which spreads through blood or body fluids and multiplies inside liver cells (PMID 42081318, PMID 35632728).

The age at infection largely dictates the outcome. If the virus remains in the body for more than 6 months, it is a chronic infection; when infected as an infant, 90% become chronic, whereas for adolescents and adults with normal immunity, less than 5% become chronic (PMID 42081318).

Globally, the primary cause of chronic infection is transmission from mother to baby. Giving both the vaccine and antibody injections within 12 to 24 hours of birth prevents roughly 94% of infections around the time of birth (PMID 42081318).

Based on a 2021 review, hepatitis B is the leading cause of liver-related deaths in South Korea (PMID 33538133). In data from women aged 20 to 49 visiting a single hospital, the proportion living with the infection dropped by about half over 17 years, from 5.1% to 2.5%, which the researchers suggested points to success in preventing mother-to-infant transmission (PMID 33217571). Chronic hepatitis B is common among middle-aged and older adults (PMID 36263666).

In untreated chronic hepatitis B, the cumulative risk of developing cirrhosis within 5 years is 8 to 15%, and among people with cirrhosis, 3 to 5% develop liver cancer each year (PMID 42081318). Hepatitis B is associated with the risk of liver cancer even in the absence of cirrhosis (PMID 35632728).

Drugs that suppress the virus fall into two classes. These drugs hold down viral multiplication and reduce the risk of liver cancer by about 50% (PMID 42081318).

Functional cure is a state in which surface substances of the hepatitis B virus disappear from the blood and the genetic material of the virus is also no longer detected (PMID 29715359, PMID 40528088). The proportion reaching this state after treatment is low—3 to 7% with one class of drugs and 1 to 12% with the other—meaning most people must continue taking medication indefinitely (PMID 29715359). In a pooled analysis of clinical trials of new treatments in people without cirrhosis, the functional cure rate was also 0.0%, and the researchers concluded that the efficacy of the new treatments remains limited (PMID 40528088).

Hepatitis C is a different story. Hepatitis C is liver inflammation caused when the hepatitis C virus spreads through the blood (PMID 33538133). South Korea's prevalence is estimated at roughly 1%, and there is no vaccine yet (PMID 33538133).

Hepatitis C can now be cleared with a short 8- to 12-week course of treatment using drugs that directly target the virus (PMID 33538133). While these drugs have made high rates of cure expected, accessibility to the medications varies by region, and viral mutations can sometimes arise that make the drugs less effective (PMID 38930417). The remaining homework in South Korea is that both patients and healthcare providers know relatively little about the disease, leaving people who live infected without symptoms (PMID 33538133).

Even after a cure, the risk of liver cancer persists depending on how stiff the liver had become. In an analysis following people whose virus was eliminated by drugs for an average of a little over 2 years, liver cancer developed at a rate of 2.99 per 100 people per year among those with prior cirrhosis, compared to 0.47 per 100 among those without cirrhosis. The risk in people who had cirrhosis tended to decrease as time passed after the cure. The researchers noted that for people without cirrhosis, including stage 3, the risk was lower than the threshold where liver cancer surveillance is cost-effective (PMID 35525392).

Hepatitis B is prevented by vaccines and suppressed by drugs, but a cure is rare, whereas hepatitis C can now be cleared with drugs, yet a risk of liver cancer still remains thereafter in livers that had progressed to cirrhosis.

Two Ways to Measure Stiffness

The old way to measure how stiff a liver is is a biopsy, which involves taking a small piece of liver tissue with a needle and looking at it under a microscope. This test requires putting a needle into the body, has rare but life-threatening complications, and the results can vary depending on the piece taken. There are too many people with fatty liver disease to do this for everyone (PMID 30660725). Therefore, methods measured from outside the body are used.

FIB-4 is a fibrosis score calculated by combining age, two liver enzyme blood tests, and the platelet count (PMID 41212550).

Liver elastography is a test that uses ultrasound from outside the body to measure how stiff the liver is (PMID 29427494). Just as hard ground is firm, a liver with accumulated scars is firm.

Joint guidelines from the European Association for the Study of the Liver (EASL) recommend a stepwise approach of first screening with blood scores like FIB-4, followed by imaging tests like elastography to screen for or confirm advanced fibrosis, and state that advanced fibrosis predicts the future of the liver (PMID 38851997).

In an analysis following 2,518 patients with fatty liver confirmed by biopsy for nearly 5 years, FIB-4 and elastography predicted outcomes such as death, liver cancer, and cirrhosis complications as well as a biopsy did. The researchers concluded that in some cases these tests can replace biopsies (PMID 37290471).

There are also limitations. In an analysis pooling patients who underwent biopsies, using the two tests sequentially reduced the number of people who needed a biopsy, but in one approach, still one in three (33%) required a biopsy for the final judgment (PMID 34001645). These tests are not designed to separate adjacent stages of fibrosis, diagnose steatohepatitis, or track changes over time. Therefore, one review article takes the stance that they should be viewed as complementing rather than replacing biopsies (PMID 32118201). Guidelines determine where to draw the line, and the same number is read within the context of the person's disease and circumstances.

FIB-4 and liver elastography allow us to gauge the degree of stiffness without a biopsy, but a single number cannot precisely separate adjacent stages.

The Two Phases of Liver Cirrhosis

Liver cirrhosis shifts from a phase with almost no symptoms to a phase where symptoms become apparent (PMID 34543610).

Compensated cirrhosis is a phase where the liver has hardened, but complications have not yet appeared, so there are almost no symptoms. The outlook for this phase is very good (PMID 39870944).

The force that divides the two phases comes from the paths blood travels. The portal vein is a blood vessel that sends blood carrying what was absorbed from the stomach and intestines to the liver before the heart. A hardened liver makes it difficult for this blood to pass through.

Portal hypertension is a state where the pressure in the portal vein has risen. It develops as the liver changes into scars and regrown lumps (PMID 34543610), and it is the main force that pushes the condition from the compensated phase to the next phase (PMID 39870944).

The complications that define the next phase are three. Ascites is fluid pooling inside the abdomen, and it appears most commonly among the three (PMID 39870944).

Varices are veins in the esophagus or stomach that have swollen, and if they burst, they become variceal bleeding. One review article covering fatty liver notes that people with cirrhosis should undergo tests to check for liver cancer and esophageal varices (PMID 33894145).

Hepatic encephalopathy is a state where the liver cannot do its job properly, leading to clouded thinking and altered consciousness.

Decompensated cirrhosis is the phase when complications such as ascites, variceal bleeding, and hepatic encephalopathy appear. This phase has a high mortality rate (PMID 39870944). Hospitalizations due to complications are frequent, and the quality of life drops (PMID 34543610). A review considers the first time one of these three complications appears in a person with cirrhosis as the event of transitioning to decompensation (PMID 39870944).

Preventing the transition to decompensation can greatly improve the outlook. Treating the cause stops the progression of the disease and can even reverse cirrhosis, and in compensated cirrhosis where portal pressure has risen past a certain level, a single class of drugs is primarily used to reduce ascites and prevent the transition to decompensation (PMID 39870944).

Liver cirrhosis is divided into compensated, before complications become apparent, and decompensated, when complications appear, and the main force that pushes across between them is portal hypertension.

Watching Liver Cancer

Liver cancer is the fourth most common cancer in Korean men (PMID 36263666).

Hepatocellular carcinoma is cancer that begins in liver cells. People with cirrhosis have a very high risk of developing hepatocellular carcinoma (PMID 33012448). Joint guidelines from the European Association for the Study of the Liver (EASL) and the Latin American Association for the Study of the Liver (ALEH) covering metabolic dysfunction-associated steatotic liver disease recommend liver cancer surveillance for people with cirrhosis (PMID 38851997, PMID 40089151).

According to one review, guidelines from professional societies recommend surveillance every 6 months for people at risk of liver cancer, and its effectiveness is still debated (PMID 30986389). Another review lists combining a liver ultrasound and a blood test every 6 months as the best approach, and notes that this method reduced deaths (PMID 33012448).

There is also a portion that gets missed. Ultrasound alone found 47% of early-stage liver cancers, and adding a blood test found 63% (PMID 29425931).

In an analysis combining 59 studies on liver cancer patients, those found through surveillance had early-stage detection 1.86 times more often, received curative treatments 1.83 times more often, and had a risk of death of 0.67 times. This is a value adjusted for the illusion that survival time appears longer simply because it was found earlier. However, these were studies comparing people who received surveillance with those who did not without randomized trials, and there was substantial variation across studies. Among four studies examining harms, 8.8 to 27.5% of people experienced physical harm due to false alarms or ambiguous results, most of which were mild, and no studies examined financial or emotional burdens. The research team noted that while the value of surveillance is high for patients with cirrhosis, more rigorous studies weighing benefits and harms are needed (PMID 35139400).

If you have cirrhosis, the risk of hepatocellular carcinoma increases, so guidelines recommend surveillance, and while surveillance is associated with early detection and improved survival, a missed portion and false alarms come along with it.

A Reversible Stage

Unlike land, liver scars can sometimes retreat once the cause is gone (PMID 39870944). Joint guidelines from the European Association for the Study of the Liver (EASL) recommend that adults with metabolic dysfunction-associated steatotic liver disease pursue weight loss, dietary changes, exercise, and alcohol abstention, alongside the proper management of co-occurring conditions like diabetes or obesity (PMID 38851997).

Regarding the magnitude of weight loss, a 2017 review notes that losing more than 10% of body weight in people with steatohepatitis can resolve steatohepatitis in nearly all cases and improve fibrosis by at least one stage. The same review notes that weight loss exceeding 5% can also improve fat and inflammation scores in the liver, and that methods to prevent the lost weight from returning are needed as well (PMID 28545937).

Drugs have also begun to emerge. In 2024, a drug to treat metabolic dysfunction-associated steatohepatitis was approved for the first time in the United States (PMID 40050362), and there are now two drugs conditionally approved for adults whose fibrosis has progressed to a moderate degree or worse but has not reached cirrhosis (PMID 41212550). There are still no drugs that can be recommended targeting steatohepatitis at the cirrhosis stage (PMID 38851997).

Fibrosis also retreats on the viral side. Although fibrosis and cirrhosis can reverse after a cure for hepatitis C, it is not yet certain in whom or how quickly this happens (PMID 33529675). In a single-center hospital study of 84 people with advanced fibrosis or cirrhosis, liver stiffness measurements improved toward a reversal of at least one stage in 62% of participants after a cure. The researchers noted that while stiffness measurements may have overestimated the improvement compared to biopsy stages, the improvement was confirmed by directly measured amounts of scar tissue within the tissue samples (PMID 30411079). In hepatitis B, cohort studies have shown an association where long-term suppression of the virus causes fibrosis to regress and lowers the risk of liver cancer (PMID 29715359).

Once cirrhosis progressed to the decompensated stage, it was long considered a point of no return. This view is being shaken as evidence accumulates that the disease can reverse and improve again after the cause is suppressed or removed (PMID 36646527).

Recompensation is a state where, after removing or suppressing the cause in decompensated cirrhosis, complications disappear without preventive medication and liver function improves again. The criteria established by the international consensus on cirrhosis (the Baveno consensus) are threefold: the primary cause must be managed or eliminated; ascites and hepatic encephalopathy must disappear without preventive medication, and there must be no variceal bleeding for 12 months; and liver function must have recovered (PMID 40780235).

Recompensation can occur when the hepatitis C virus is cleared, when the hepatitis B virus (without co-infection with hepatitis D) is continuously suppressed with medication, or when alcohol is abstained from for a long time in alcohol-related cirrhosis. Liver-related cirrhosis from fatty liver can improve with weight loss, but it remains unclear whether true recompensation can be reached (PMID 40780235).

Although removing or suppressing the cause causes fibrosis to regress and allows some people to recover even from decompensated cirrhosis, at the cirrhosis stage there are still no recommended drugs or cases where it is unclear whether recompensation is possible, and the risk of liver cancer also remains.

Starting From a Single Line on a Health Checkup Report

A corporate employee in their 40s is told that a screening ultrasound shows a fatty liver. They rarely drink alcohol, and their blood pressure and triglycerides are slightly high. If fat is seen on ultrasound along with at least one metabolic abnormality and no other causes, it is diagnosed as metabolic dysfunction-associated steatotic liver disease (PMID 41212550). Whether blood pressure and triglycerides fall under those abnormalities must be checked against the criteria.

If this diagnosis is applied, the forks in the road ahead are as follows. The most common path is remaining a fatty liver that does not worsen significantly (PMID 30398639). A portion progresses to inflammation and fibrosis, and according to a narrative review, the proportion of people who progress to cirrhosis is 3–5%, which usually takes over 20 years (PMID 39243773). Even for those who stay put, fibrosis can progress slowly or improve (PMID 24768810). Furthermore, the most common cause of death for people with this disease is heart and blood vessel disease rather than liver disease (PMID 41212550).

Which road you are on is told by fibrosis. Following the order of the guidelines, you first calculate FIB-4, and if necessary, proceed to liver stiffness measurement (PMID 38851997). These tests cannot sharply divide neighboring stages with a single number (PMID 32118201). Which box the result falls into is read by a doctor within the lines set by the guidelines and the individual's circumstances.

Another person has a mother with hepatitis B. Mother-to-baby transmission is the main cause of chronic infection, but giving both the vaccine and an antibody shot right after birth prevents roughly 94% of that infection (PMID 42081318). Which side this person is on is sorted out by a blood test. The blood test distinguishes whether they are currently infected, whether they have immunity, and whether they have ever been infected now or in the past (PMID 42081318).

If infected, medication suppresses the virus and reduces the risk of liver cancer by roughly 50% (PMID 42081318), but people who achieve functional cure are rare, so most continue medication for a long time (PMID 29715359). There are reviews that recommend surveillance every 6 months for people at high risk of liver cancer (PMID 42081318).

The paths of the two people have different causes, but they converge on the same questions. How much scarring has accumulated, and can the cause be removed or suppressed?

Where to Look Next

Whether true recompensation is possible in fatty liver-side cirrhosis (PMID 40780235) and what methods can reliably track fibrosis changes from outside the body during treatment (PMID 37153139) remain open questions.

What liver tests measure is covered in another part of this series, "What Does the Liver Do, and What Do Liver Tests Measure? — The Factory at the Gate, and the Signal That Leaks Through the Wall". Obesity and weight loss drugs can be explored further in "What Are Obesity and GLP-1 Drugs? — A Letter That Lingers, a Weight That Wants to Return", and type 2 diabetes in "What Is Diabetes? — The Letter That Never Comes, the Letter That Isn't Read".

How tests tell us something, such as FIB-4 or liver cancer surveillance, and why the same result is read differently depending on who it comes from, is covered in "What a Test Actually Tells You — An Introduction to Sensitivity, Specificity, and Pretest Probability". The fibrosis stage is a value accepted as a surrogate endpoint in clinical trials of fatty liver rather than cirrhosis (PMID 37290471), and when values measured in place of patient-experienced outcomes are reliable can be seen in "Better Numbers, Better Patients? — An Introduction to Surrogate Endpoints".

This article closes the series. From "How Does Digestion Work? — A Tube Through the Body, and a Wall Only Small Pieces Can Cross" through "What Do the Stomach and Esophagus Do? — A Pouch That Holds Acid, and Its Two Doors", "What Do Gut Microbes Do? — Guests Who Eat the Leftovers, Guests Who Hold the Room", and "What Does the Liver Do, and What Do Liver Tests Measure? — The Factory at the Gate, and the Signal That Leaks Through the Wall" to this piece, five articles have followed the tube through which food passes and the liver that first receives the blood coming from that tube.

Source Papers

• "Epidemiological and Clinical History of Viral Hepatitis in Korea." (2021) — PMID 33538133 — The most important causes of acute and chronic liver disease in Korea are viral hepatitis, with HBV being the number one cause of liver-related deaths, showing an HBsAg positive rate drop from 8% to 3% following nationwide vaccination in the 1980s, an HCV prevalence of about 1% in Korea with no vaccine available, curability within 8 to 12 weeks using DAAs, and the remaining challenge being low awareness.
• "Liver cirrhosis." (2021) — PMID 34543610 — Causes of liver cirrhosis (obesity, NAFLD, heavy alcohol use, hepatitis B/C, autoimmune, cholestasis, excess iron/copper), where healthy parenchyma is replaced by fibrous tissue and regenerative nodules after prolonged inflammation leading to portal hypertension, progressing from asymptomatic (compensated) to symptomatic (decompensated), with decompensated complications causing hospitalization, reduced quality of life, and high mortality.
• "Staging liver fibrosis and cirrhosis using non-invasive tests in people with chronic hepatitis B to inform WHO 2024 guidelines: a systematic review and meta-analysis." (2025) — PMID 39983746 — In the METAVIR staging system, liver cirrhosis corresponds to F4, and non-invasive test cutoff values are reflected in the WHO 2024 guidelines.
• "Surveillance for Hepatocellular Carcinoma." (2020) — PMID 33012448 — Patients with liver cirrhosis are at very high risk for HCC and are candidates for surveillance, with the best approach being AFP plus ultrasound every 6 months (sensitivity about 65%, specificity 90%), improving mortality, and requiring a balance between benefits and harms.
• "Steatotic liver disease." (2024) — PMID 39488409 — Steatotic liver disease is primarily driven by obesity, type 2 diabetes, and alcohol, affecting about 30% of the global population, with only a minority progressing to liver cirrhosis, and inflammation-driven fibrosis acting as the primary predictor of liver-related mortality across the entire spectrum.
• "A multisociety Delphi consensus statement on new fatty liver disease nomenclature." (2023) — PMID 37364790 — Limitations of NAFLD and NASH (exclusionary definitions, potentially stigmatizing terms), led by three pan-national liver associations in a modified Delphi process with 236 participants across 56 countries, 74% agreeing that a name change was necessary, and terms like "nonalcoholic" (61%) and "fatty" (66%) being stigmatizing, leading to the adoption of MASLD with at least one cardiometabolic risk factor, the creation of an undetermined etiology category and MetALD, and the retention of the steatohepatitis concept.
• "EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD)." (2024) — PMID 38851997 — Definition of MASLD (formerly NAFLD), a step-by-step approach of FIB-4 followed by elastography to rule out or confirm advanced fibrosis (predicting liver-related outcomes), recommendations for lifestyle modification and comorbidity management, inability to recommend MASH-targeted drugs at the cirrhosis stage, and HCC surveillance in cirrhosis.
• "Metabolic Dysfunction-Associated Steatotic Liver Disease in Adults: A Review." (2026) — PMID 41212550 — The most common chronic liver disease, affecting 30-40% of adults (varying by continent), 60-70% of individuals with type 2 diabetes, and 70-80% of individuals with obesity, diagnosed by ultrasound evidence of steatosis plus at least 1 of 5 metabolic syndrome criteria, evaluated using FIB-4 (age, AST, ALT, platelets) and controlled attenuation parameter and vibration-controlled transient elastography, with cardiovascular disease as the leading cause of death followed by extrahepatic cancer and liver complications, primary treatment consisting of behavioral modification, and conditional FDA approval of two drugs for MASH with moderate to advanced fibrosis.
• "Nonalcoholic Fatty Liver Disease." (2018) — PMID 30398639 — The vast majority have non-progressive fatty liver, while some develop progressive injury, inflammation, and fibrosis (NASH), with cardiovascular disease being the leading cause of death.
• "Non-alcoholic fatty liver disease: pathophysiological concepts and treatment options." (2023) — PMID 37364164 — Simple steatosis is the most common form, while the progressive form characterized by fibrosis and inflammation (NASH) affects 10 to 20% of patients.
• "Non-alcoholic fatty liver disease." (2021) — PMID 33894145 — NASH has a faster fibrosis progression than simple fatty liver, advanced fibrosis is the core prognostic indicator, and patients with cirrhosis are candidates for HCC and esophageal varices screening.
• "Natural history and progression of metabolic dysfunction-associated steatotic liver disease." (2024) — PMID 39243773 — Only a minority develop inflammation and progressive fibrosis, and progression to cirrhosis occurs in 3 to 5% of patients, usually taking 20 years or more.
• "Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies." (2015) — PMID 24768810 — In 411 patients with repeated biopsies at intervals of 1 year or longer, progressing by one stage from baseline F0 took 14.3 years for NAFL and 7.1 years for NASH, with 33.6% progressing, 43.1% remaining stable, and 22.3% improving, leading to the conclusion that both NAFL and NASH progress in fibrosis.
• "Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis." (2017) — PMID 28130788 — Fibrosis is the most important predictor of mortality in NAFLD, based on 5 cohorts totaling 1,495 individuals, showing liver-related mortality rate ratios compared to F0 of 1.41 for F1 (not significant), 9.57 for F2, 16.69 for F3, and 42.30 for F4, with a limitation of not adjusting for comorbidities and demographics, concluding an exponential increase according to the stage.
• "Alcohol-associated liver disease: Epidemiology and management." (2024) — PMID 37832648 — Alcohol is the global number one preventable cause of liver disease and death and the most frequent cause of advanced liver disease, progressing from steatosis to steatohepatitis, fibrosis, and in some cases cirrhosis, with alcoholic hepatitis presenting as sudden jaundice and decompensation, and lacking approved targeted treatments, making abstinence the most effective way to improve prognosis and the primary treatment at all stages.
• "Hepatitis B: A Review." (2026) — PMID 42081318 — Affecting 254 million people worldwide with 1.1 million deaths annually, transmitted through exposure to blood, semen, and body fluids, with mother-to-child transmission being the primary cause of chronic infection, where vaccine plus immunoglobulin within 12 to 24 hours of birth prevents about 94% of perinatal infections, the birth dose coverage rate was 45% in 2024, the chronicity risk is 90% for infants, 30% for children aged 1 to 5 years, and 5% or less for adolescents and adults, serologic tests distinguish current infection, immunity, and past infection, ALT, FIB-4, and elastography are used to guide treatment decisions, untreated patients have an 8 to 15% cumulative 5-year risk of cirrhosis and a 3 to 5% annual risk of HCC with cirrhosis, antiviral therapy reduces HCC risk by about 50%, and high-risk groups undergo ultrasound and AFP surveillance every 6 months.
• "2022 KLCA-NCC Korea practice guidelines for the management of hepatocellular carcinoma." (2022) — PMID 36263666 — HCC is the fifth most common cancer globally and the fourth most common among Korean men, with Korea having a high prevalence of chronic hepatitis B in middle-aged and older adults.
• "Hepatitis B Virus-Associated Hepatocellular Carcinoma." (2022) — PMID 35632728 — HBV replicates inside hepatocytes, liver cirrhosis is an independent risk factor for HCC, and HBV is associated with HCC risk regardless of the presence of cirrhosis.
• "Chronic Hepatitis B Infection: A Review." (2018) — PMID 29715359 — Antiviral drugs suppress HBV DNA replication and improve inflammation and fibrosis, long-term suppression is associated with fibrosis regression and decreased HCC in cohort studies, and the cure rate (HBsAg loss plus undetectable HBV DNA) is low at 3 to 7% with pegylated interferon and 1 to 12% with nucleos(t)ide analogues, resulting in indefinite treatment for most patients.
• "Functional cure with new antiviral therapy for hepatitis B virus: a systematic review and meta-analysis." (2025) — PMID 40528088 — In 19 clinical trials conducted between 2018 and 2023 involving 1,789 patients without cirrhosis, the functional cure rate was 0.0%, and new treatments had limited efficacy in clearing or reducing HBsAg.
• "Contemporary Insights into Hepatitis C Virus: A Comprehensive Review." (2024) — PMID 38930417 — With approximately 50 million people living with chronic hepatitis C according to WHO criteria in 2024, high cure rates are achievable with DAAs, while regional disparities in accessibility and resistance-associated variants remain challenges.
• "Fibrosis Stage-specific Incidence of Hepatocellular Cancer After Hepatitis C Cure With Direct-acting Antivirals: A Systematic Review and Meta-analysis." (2023) — PMID 35525392 — Following SVR achieved with DAAs, HCC incidence was 2.99 per 100 person-years in 27,711 patients with cirrhosis (mean follow-up 2.1 years), 0.47 in 32,123 patients without cirrhosis, and 0.63 in patients with F3, with the cirrhotic group showing a decreasing trend with longer follow-up, and non-cirrhotic cases (including F3) falling below cost-effective surveillance thresholds.
• "Diagnosis of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis: Non-invasive tests are enough." (2018) — PMID 29427494 — Fibrosis is the primary histological criterion for long-term prognosis, addressing the limitations of biopsy through two approaches: serum markers and ultrasound-based elastography.
• "Noninvasive Assessment of Liver Disease in Patients With Nonalcoholic Fatty Liver Disease." (2019) — PMID 30660725 — Limitations of liver biopsy (invasiveness, rare life-threatening complications, low patient acceptance, sampling variability, cost), making biopsy unrealistic given the scale of the disease prevalence.
• "Performance of non-invasive tests and histology for the prediction of clinical outcomes in patients with non-alcoholic fatty liver disease: an individual participant data meta-analysis." (2023) — PMID 37290471 — Histological fibrosis stage is accepted as a surrogate endpoint in non-cirrhotic NAFLD clinical trials, in 2,518 biopsy-proven NAFLD patients followed for a median of 57 months, FIB-4 and elastography predicted clinical outcomes as well as histological fibrosis, potentially offering an alternative to biopsy in certain cases.
• "Diagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD: an individual patient data meta-analysis." (2022) — PMID 34001645 — In a sequential combination of FIB-4 followed by elastography, biopsy was still required for definitive diagnosis in 33% of cases, and sequential combination reduced the need for biopsy.
• "Limitations of non-invasive tests for assessment of liver fibrosis." (2020) — PMID 32118201 — Variability and accuracy limitations of non-invasive tests, which are not designed to capture the dynamic process of fibrogenesis, distinguish adjacent stages, diagnose NASH, or track longitudinal changes, serving as a complement rather than a replacement for biopsy.
• "Preventing the progression of cirrhosis to decompensation and death." (2025) — PMID 39870944 — Compensation carries a very favorable prognosis while decompensation (ascites, variceal bleeding, hepatic encephalopathy) carries high mortality, portal hypertension is the main driver of this transition, etiological treatment halts progression and can even achieve cirrhosis regression, non-selective beta-blockers primarily reduce ascites to prevent decompensation, and ascites is the most common decompensation event.
• "HCC surveillance improves early detection, curative treatment receipt, and survival in patients with cirrhosis: A meta-analysis." (2022) — PMID 35139400 — In 59 cohort studies involving 145,396 patients, surveillance was associated with early detection (RR 1.86), curative treatment receipt (RR 1.83), and survival (HR 0.67, adjusted for lead time), with high heterogeneity, physical harms ranging from 8.8 to 27.5% (mostly mild), no studies on financial or psychological harms, and the conclusion that while the value of surveillance in cirrhosis is high, rigorous studies on benefits and harms are needed.
• "Updated recommendations for the management of metabolic dysfunction-associated steatotic liver disease (MASLD) by the Latin American working group." (2025) — PMID 40089151 — Complete abstinence from alcohol is recommended in the presence of significant fibrosis, and HCC screening is recommended for all patients with cirrhosis.
• "Surveillance Imaging and Alpha Fetoprotein for Early Detection of Hepatocellular Carcinoma in Patients With Cirrhosis: A Meta-analysis." (2018) — PMID 29425931 — In 32 studies involving 13,367 patients, the sensitivity for early HCC was 47% for ultrasound alone and 63% when combined with AFP.
• "Treatment of NAFLD with diet, physical activity and exercise." (2017) — PMID 28545937 — Weight loss of 10% or more resolved NASH and improved fibrosis by at least one stage in nearly all patients, weight loss exceeding 5% also benefited components of NASH, and strategies to prevent relapse and weight regain are necessary.
• "Metabolic dysfunction-associated steatotic liver disease in adults." (2025) — PMID 40050362 — Adoption of the new nomenclature in 2023, followed by the FDA approval of the first treatment for non-cirrhotic MASH (moderate to advanced fibrosis) in 2024.
• "The Baveno VII concept of cirrhosis recompensation." (2023) — PMID 36646527 — The transition from compensation to decompensation was previously considered irreversible, but this notion is being challenged by evidence of regression and recompensation following the suppression or removal of the underlying cause, and future research is needed on the natural history and modifying factors of recompensation.
• "Recompensation in decompensated cirrhosis." (2025) — PMID 40780235 — Baveno definition (resolution of ascites or hepatic encephalopathy without etiology-controlling or preventive drugs, no variceal bleeding for 12 months, and recovery of liver function), achievable through HCV eradication, HBV suppression (without HDV), and sustained abstinence, while true recompensation remains unclear for MASLD cirrhosis.
• "Recent advances in NAFLD: current areas of contention." (2023) — PMID 37153139 — The utility of non-invasive tests for monitoring treatment response has not been established, and their accuracy in detecting moderate (F2) fibrosis is low.
• "Systematic review on the prevalence of nonalcoholic fatty liver disease in South Korea." (2021) — PMID 32919911 — In 61 studies involving 837,897 individuals, the prevalence of NAFLD in South Korea was 30.3% (41.1% in men, 20.3% in women), rising from 29.0% to 31.0% over about a decade.
• "Hepatitis B surface antigen and antibody positivity among women of childbearing age after three decades of universal vaccination in South Korea." (2021) — PMID 33217571 — In 145,993 women aged 20 to 49 from a single hospital, HBsAg decreased from 5.1% in 2001 to 2.5% in 2018, while anti-HBs increased from 59.9% to 75.8%, leading to the conclusion that vertical transmission prevention has been successful.
• "Alcohol as a risk factor for liver cirrhosis: a systematic review and meta-analysis." (2010) — PMID 20636661 — In 17 studies, there were some signs of a threshold effect, a greater impact on mortality than morbidity, higher risk in women at the same consumption level, and outcome measures identified as the primary source of heterogeneity.
• "Fibrosis Regression After Eradication of Hepatitis C Virus: From Bench to Bedside." (2021) — PMID 33529675 — SVR is achieved almost universally with DAAs, and fibrosis, including that caused by HCV, is reversible, though it remains uncertain in whom and how quickly this occurs.
• "Morphometry Confirms Fibrosis Regression From Sustained Virologic Response to Direct-Acting Antivirals for Hepatitis C." (2018) — PMID 30411079 — In 84 patients with advanced fibrosis or cirrhosis from a single institution, 62% showed improvement in elastography values corresponding to regression of at least one stage following SVR (median 1 year), and while elastography overstates improvement compared to histological staging, this was confirmed by morphometry.
• "Surveillance for Hepatocellular Carcinoma: Current Best Practice and Future Direction." (2019) — PMID 30986389 — Professional society guidelines recommend HCC surveillance every 6 months for high-risk groups, while the efficacy of surveillance remains debated.