clinical presentation of viral hepatitis

Overview of Acute Viral Hepatitis

Symptoms and Signs |
Diagnosis |
Treatment |
Prevention |
Key Points |

Acute viral hepatitis is diffuse liver inflammation caused by specific hepatotropic viruses that have diverse modes of transmission and epidemiologies. A nonspecific viral prodrome is followed by anorexia, nausea, and often fever or right upper quadrant pain. Jaundice often develops, typically as other symptoms begin to resolve. Most cases resolve spontaneously, but some progress to chronic hepatitis. Occasionally, acute viral hepatitis progresses to acute liver failure (indicating fulminant hepatitis). Diagnosis is by liver function tests and serologic tests to identify the virus. Good hygiene and universal precautions can prevent acute viral hepatitis. Depending on the specific virus, preexposure and postexposure prophylaxis may be possible using vaccines or serum globulins. Treatment is usually supportive.

(See also Causes of Hepatitis and Neonatal Hepatitis B Virus Infection .)

Acute viral hepatitis is a common, worldwide disease that has different causes; each type shares clinical, biochemical, and morphologic features. The term acute viral hepatitis often refers to infection of the liver by one of the hepatitis viruses. Other viruses (eg, Epstein-Barr virus , yellow fever virus , cytomegalovirus ) can also cause acute viral hepatitis but less commonly.

Etiology of Acute Viral Hepatitis

At least 5 specific viruses appear to be responsible (see table Characteristics of Hepatitis Viruses ) for acute viral hepatitis:

Hepatitis A (HAV)

Hepatitis B (HBV)

Hepatitis C (HCV)

Hepatitis D (HDV)

Hepatitis E (HEV)

Other unidentified viruses probably also cause acute viral hepatitis.

Symptoms and Signs of Acute Viral Hepatitis

Some manifestations of acute hepatitis are virus-specific (see discussions of individual hepatitis viruses), but in general, acute infection tends to develop in predictable phases:

Incubation period: The virus multiplies and spreads without causing symptoms (see table Characteristics of Hepatitis Viruses ).

Prodromal (pre-icteric) phase: Nonspecific symptoms occur; they include profound anorexia, malaise, nausea and vomiting, a newly developed distaste for cigarettes (in smokers), and often fever or right upper quadrant abdominal pain. Urticaria and arthralgias occasionally occur, especially in HBV infection.

Icteric phase: After 3 to 10 days, the urine darkens, followed by jaundice . Systemic symptoms often regress, and patients feel better despite worsening jaundice. The liver is usually enlarged and tender, but the edge of the liver remains soft and smooth. Mild splenomegaly occurs in 15 to 20% of patients. Jaundice usually peaks within 1 to 2 weeks.

Recovery phase: During this 2- to 4-week period, jaundice fades.

Appetite usually returns after the first week of symptoms. Acute viral hepatitis usually resolves spontaneously 4 to 8 weeks after symptom onset.

Anicteric hepatitis (hepatitis without jaundice) occurs more often than icteric hepatitis in patients with HCV infection and in children with HAV infection. It typically manifests as a minor flu-like illness.

Recrudescent hepatitis occurs in a few patients and is characterized by recurrent manifestations during the recovery phase.

Manifestations of cholestasis may develop during the icteric phase (called cholestatic hepatitis) but usually resolve. When they persist, they cause prolonged jaundice, elevated alkaline phosphatase, and pruritus, despite general regression of inflammation.

Diagnosis of Acute Viral Hepatitis

Liver tests (aspartate aminotransferase [AST] and alanine aminotransferase [ALT] elevated out of proportion to alkaline phosphatase, usually with hyperbilirubinemia)

Viral serologic testing

Prothrombin/international normalized ratio (PT/INR) measurement

Initial diagnosis of acute hepatitis

Acute hepatitis must first be differentiated from other disorders that cause similar symptoms. In the prodromal phase, hepatitis mimics various nonspecific viral illnesses and is difficult to diagnose. Anicteric patients suspected of having hepatitis based on risk factors are tested initially with liver tests, including aminotransferases, bilirubin, and alkaline phosphatase. Acute hepatitis often manifests in the icteric phase and so should be differentiated from other disorders causing jaundice (see figure Simplified diagnostic approach to possible acute viral hepatitis ).

Acute hepatitis can usually be differentiated from other causes of jaundice by

Its marked elevations of AST and ALT: Typically ≥ 400 IU/L (6.68 microkat/L)

ALT is typically higher than AST, but absolute levels correlate poorly with clinical severity. Values increase early in the prodromal phase, peak before jaundice is maximal, and fall slowly during the recovery phase. Urinary bilirubin usually precedes jaundice. Hyperbilirubinemia in acute hepatitis varies in severity, and fractionation has no clinical value. Alkaline phosphatase is usually only moderately elevated; marked elevation suggests extrahepatic cholestasis and prompts imaging tests (eg, ultrasonography).

Liver biopsy is usually not needed unless the diagnosis is uncertain.

If laboratory results suggest acute hepatitis, particularly if ALT and AST are > 1000 IU/L (16.7 microkat/L), PT/INR is measured to assess liver function.

Manifestations of portosystemic encephalopathy combined with bleeding diathesis or prolongation of INR suggest acute liver failure , indicating fulminant hepatitis .

If acute hepatitis is suspected, efforts are next directed toward identifying its cause. A history of exposure may provide the only clue of drug-induced or toxic hepatitis. The history should also elicit risk factors for viral hepatitis.

Prodromal sore throat and diffuse adenopathy suggest infectious mononucleosis rather than viral hepatitis.

Simplified diagnostic approach to possible acute viral hepatitis

In patients with findings suggesting acute viral hepatitis, the following studies are done to screen for hepatitis viruses A, B, and C:

IgM antibody to HAV (IgM anti-HAV)

Hepatitis B surface antigen (HBsAg)

IgM antibody to hepatitis B core (IgM anti-HBc)

Antibody to HCV (anti-HCV)

Hepatitis C RNA (HCV-RNA) polymerase chain reaction

If any are positive, further serologic testing may be necessary to differentiate acute from past or chronic infection (see tables Hepatitis A Serology , Hepatitis B Serology , and Hepatitis C Serology ).

If serologically confirmed HBV infection is severe, anti-HDV is measured.

If the patient has recently traveled to an endemic area or is immunosuppressed, IgM antibody to HEV (IgM anti-HEV) should be measured if the test is available.

Biopsy is usually unnecessary but, if done, usually reveals similar histopathology regardless of the specific virus:

Patchy cell dropout

Acidophilic hepatocellular necrosis

Mononuclear inflammatory infiltrate

Histologic evidence of regeneration

Preservation of the reticulin framework

HBV infection can occasionally be diagnosed based on the presence of ground-glass hepatocytes (caused by HBsAg-packed cytoplasm) and using special immunologic stains for the viral components. However, these findings are unusual in acute HBV infection and are much more common in chronic HBV infection.

Treatment of Acute Viral Hepatitis

Supportive care

Treatment of acute hepatitis C, partly to prevent transmission to others

No treatments attenuate acute viral hepatitis. Alcohol should be avoided because it can increase liver damage. Restrictions on diet or activity, including commonly prescribed bed rest, have no scientific basis.

Patients with acute HCV infection should be treated with antiviral therapy upon initial diagnosis without awaiting spontaneous resolution in order to prevent transmission to others. Owing to the high efficacy and safety, the same regimens that are recommended for chronic HCV infection are recommended for acute infection ( 1 ).

Viral hepatitis should be reported to the local or state health department.

Treatment reference

1. American Association for the Study of Liver Diseases (AASLD) and Infection Diseases Society of America (IDSA) : HCV Guidance: Recommendations for testing, managing, and treating hepatitis C. Management of acute HCV infection. Accessed July 6, 2022.

Prevention of Acute Viral Hepatitis

Because treatments have limited efficacy, prevention of viral hepatitis is very important.

General measures

Good personal hygiene helps prevent transmission, particularly fecal-oral transmission, as occurs with HAV and HEV.

Blood and other body fluids (eg, saliva, semen) of patients with acute HBV and HCV infection and stool of patients with HAV infection are considered infectious. Barrier protection is recommended, but isolation of patients does little to prevent spread of HAV and is of no value in HBV or HCV infection.

Posttransfusion infection is minimized by avoiding unnecessary transfusions and by screening all donors for hepatitis B and C. Screening has decreased the incidence of posttransfusion hepatitis B and hepatitis C, which are now extremely rare in the US.

Immunoprophylaxis

Immunoprophylaxis can involve active immunization using vaccines and passive immunization.

Vaccines for hepatitis A and hepatitis B are available in the US.

Routine vaccination for hepatitis A and B is recommended in the US for all children and for adults at high risk (see Adult Immunization Schedule ).

A vaccine for hepatitis E is not available in the US but is available in China.

No product exists for immunoprophylaxis of HCV or HDV. However, prevention of HBV infection prevents HDV infection. The propensity of HCV for changing its genome hampers vaccine development.

Transmission is the fecal-oral route for hepatitis A and parenterally or via blood for hepatitis B and C.

Hepatitis B and C, unlike hepatitis A, predispose to chronic hepatitis and liver cancer.

Patients with acute viral hepatitis may be anicteric or even asymptomatic.

Do viral serologic testing (IgM anti-HAV, HBsAg, anti-HCV) if clinical findings are consistent with acute viral hepatitis and AST and ALT are elevated out of proportion to alkaline phosphatase.

Treat patients supportively. Treat acute hepatitis C to prevent transmission.

Routine vaccination for hepatitis A and B is recommended in the US for all children and for adults at high risk.

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Editorial article, editorial: viral hepatitis: pathophysiology, prevention, and control.

1 Molecular and Cellular Biochemistry, Indiana University, Bloomington, IN, United States
2 Vaccine and Infectious Disease Research Center, Translational Health Science and Technology Institute (THSTI), Faridabad, India
3 University School of Biotechnology, Guru Gobind Singh Indraprastha University, New Delhi, India

Editorial on the Research Topic Viral Hepatitis: Pathophysiology, Prevention, and Control

Viral hepatitis, characterized by liver inflammation and damage, is among the leading human global health threats ( World Health Organization, 2012 ). Billions of people worldwide have been infected with hepatitis viruses. Millions worldwide are living with viral hepatitis and over 1.4 million deaths occur annually as a result of liver cirrhosis and cancer ( World Health Organization, 2016 ). Notably, many infected individuals are unaware of their infection and can transmit the virus to others.

The majority of viral hepatitis, alphabetically referred to as Types A, B, C, D, and E, are caused by five different viruses. In addition, human adenoviruses are also known to cause hepatitis in immunocompromised individuals. These viruses are from distinct taxonomic grouping, have different infectivity, replication strategies, reservoirs, and pathogenesis. In turn, the course of the disease, epidemiology, prevention and treatment could differ.

The enveloped hepatitis B virus (HBV) and hepatitis C virus (HCV) cause both acute and chronic liver disease. Together HBV and HCV account for ~ 90% of the fatalities. HCV, a member of the Flaviviridae family of positive-strand RNA virus, infects through exposures to virus-containing blood or body fluids that contain blood. HBV is a member of the Hepadnaviridae family with a reverse-transcribed partially double-stranded genome. It infects through puncture of the skin or mucosal contact with infectious blood or body fluids. Hepatitis D virus (HDV) contains a circular single-stranded negative-sense RNA genome and it co-infects people along with hepatitis B or infect people who are already chronically infected by HBV. The envelope of HDV contains the HBV envelope proteins and it uses the same cellular receptor for entry as HBV ( Yan et al., 2012 ). HDV and HBV co-infection can speed up liver disease progression.

Hepatitis A virus (HAV) and hepatitis E virus (HEV) from feces are nonenveloped viruses. Interestingly, HEV from blood contain membrane from exosomes and are classified as quasi-enveloped ( Nagashima et al., 2017 ). Both viruses spread through close contact with an infected individual or through ingestion of virus-contaminated food or drink. HAV and HEV belong to the family of Picronaviridae and Hepeviridae , respectively, and both possess single-stranded positive-sense RNA genomes ( Aggarwal, 2013 ; Lemon et al., 2017 ). It is important to note that HEV also infects a number of animals that serve as reservoirs and ingestion of undercooked meats can lead to transmission ( Doceul et al., 2016 ). HAV and HEV typically lead to self-limiting diseases, although the illness could last for a few months. In a small percentage of people, especially immunocompromised individuals, specific genotypes of HEV can cause chronic infection ( Hoofnagle et al., 2012 ). Severe acute infections can also lead to a small percentage of fatalities, and fatalities could be higher in pregnant women ( Khuroo and Kamili, 2003 ).

Significant progress to prevent infection by hepatitis viruses has been made. Highly effective and safe prophylactic vaccines are available for hepatitis A and B. For hepatitis B, vaccination of newborns weighing over 2 kg is recommended ( Schillie et al., 2018 ). Proper vaccination will also produce essentially life-long immunity ( Loader et al., 2019 ). Preventing HBV infection will also protect against HDV infection. For chronically infected hepatitis B patients, the vaccine will not cure the infection, but family members and associates who receive the vaccine can be protected from infection. A recombinant vaccine against HEV is available in China ( Zhu et al., 2010 ). A vaccine is not available for hepatitis C. Prevention of infection should focus on improved education, hygiene, improving infrastructure, and healthcare practices.

It is important to have therapies for viral hepatitis. Thus far, therapy development have primarily focused on hepatitis B and C. HBV can now be controlled with direct-acting antivirals (DAAs), although the virus cannot be effectively eliminated. Additional therapies with multiple modalities that can achieve functional cures, the sustained loss of the HBV surface antigen, are actively pursued by the biotech and pharma industry ( Lok et al., 2017 ; Tang et al., 2017 ). Treatment for hepatitis C has shifted from the use of immunomodulators and the general viral inhibitor ribavirin to molecules that target the viral replication proteins ( Scheel and Rice, 2013 ). Several combinations of DAAs can effectively elimination pan-genotypic HCV with very low rate of viral relapse ( Zoratti et al ). The general recommendation for individuals infected with HAV is to rest and avoid stressors that can exacerbate symptoms. As discussed above, there is more urgent need to treat HEV infection. Currently, recombinant interferon and ribavirin are available, but effective DAAs remain to be identified ( Netzler et al ).

This Research Topic contains both reviews and original articles that deal with a range of topics on viral hepatitis. Despite the significant advances made in Hepatitis B research, HBV continues to be a serious threat to public health worldwide. In their review, Steinmann et al. put hepatitis B into a historical context and the lessons on proper formulation of vaccines. The authors emphasized on the high heat tolerance of HBV and suggested the importance of proper washing and disinfection to minimize HBV contamination and overall safety. The entry of HBV into host cells is not completely understood and is an area that requires more attention. Though sodium-taurocholate cotransporting polypeptide (NTCP) was shown to be a functional receptor for HBV, other molecules are reported to aid in HBV infection. To better understand HBV infectivity, Hu et al. documented that E-cadherin, an adhesion molecule that is abundant in epithelial tissue, can interact with the HBV receptor to affect its localization in cells and thus impact HBV entry. Interestingly, E-cadherin binds only to the glycosylated form of NTCP, which is important for it to act as the HBV receptor, and thus preferentially regulates the membrane localization of glycosylated NTCP.

Three articles dealt with viral pathogenesis. Liu et al. used transcriptome analysis to demonstrate that the HCV Core protein expressed from a chimeric virus can induce interleukin-32 expression. Use of specific inhibitors in their study pointed to the involvement of PI3K/AKT pathway in IL32 induction. Authors suggested that the HCV core protein dependent IL32 expression leads to the elevated inflammation associated with severe hepatitis. One of the peculiar disease manifestations of HEV is its involvement in neurological disorders. Not much is known about how HEV induces neurological complications. Tian et al. showed that HEV could cause mitochondrial-associated apoptosis in cultured human brain cells and in the brains of HEV-infected gerbils. This further induced the production of high amounts of pro-inflammatory cytokines possibly explaining the observed extrahepatic injuries associated with HEV infection. In the review by Sehgal et al. , the link between gut microbiota and the severity of viral hepatitis was examined. The authors focused on the role of bacterial pathogen-associated molecular patterns in activating innate immune receptors resulting in the NFκB signaling in hepatitis B and C dependent hepatitis. Fecal microbiota transplant could be an alternative method of treatment and management for viral hepatitis.

Four articles deal with therapeutic development and possible therapeutic molecules. Khan et al. reviewed the diverse HCV replicons that were instrumental to the development of HCV drugs and threw light on drug resistance. The replicons for all the major HCV genotypes, including subgenomic and full-length replicons, and their importance in HCV drug discovery are discussed. For HEV, a promising drug target is the protease. HEV encoded protease was suggested to be a papain-like cysteine protease as well as chymotrypsin like protease. In their work, Saraswat et al. showed that the HEV protease was able to process the ORF1 polyprotein. Furthermore, the authors used biochemical assays and in silico modeling to show that the HEV protease is indeed a papain-like cysteine protease. Also in this Research Topic, the modulation of polyamine synthesis as a possible antiviral strategy was investigated. Polyamines are known to play a role in the replication of many RNA and DNA viruses. Mao et al. showed that polyamines help in HBV replication and an inhibitor of polyamine synthesis can inhibit HBV by increasing the proteasome-mediated degradation of the Core protein. Finally, in this Research Topic, Wang et al. focused on another virus whose infection can cause hepatitis, the human adenovirus. They developed a mouse monoclonal antibody against one of the major capsid proteins of human adenovirus (HAdV-7) and showed that this antibody has a potent neutralizing activity.

The original articles and reviews presented in this Research Topic showcase the work of diverse group of researchers from different parts of the world on viral hepatitis. The knowledge provided will contribute to the development of interference strategies and treatment for viral hepatitis.

C. Cheng Kao

Milan Surjit

C. T. Ranjith-Kumar

Author Contributions

CK, MS and CR-K were the topic editors of this Research Topic and co-wrote the editorial. All the authors contributed to the article and approved the submitted version.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Aggarwal, R. (2013). Hepatitis E: Epidemiology and Natural History. J. Clin. Exp. Hepatol. 3, 125. doi: 10.1016/j.jceh.2013.05.010

PubMed Abstract | CrossRef Full Text | Google Scholar

Doceul, V., Bagdassarian, E., Demange, A., Pavio, N. (2016). Zoonatic Hepatitis E Virus: Classification, Animal Reservoirs and Transmission Routes. Viruses 8 (10), 270. doi: 10.3390/v8100270

CrossRef Full Text | Google Scholar

Hoofnagle, J. H., Nelson, K. E., Purcells, R. H. (2012). Hepatitis E. N. Engl. J. Med. 367, 1244. doi: 10.1056/NEJMra1204512

Khuroo, M. S., Kamili, S. (2003). Aetiology, Clinical Course and Outcome of Sporadic Acute Viral Hepatitis in Pregnancy. J. Viral Hepat. 10, 61. doi: 10.1046/j.1365-2893.2003.00398.x

Lemon, S. M., Ott, J., Damme, V., Shouval, D. (2017). Type A Hepatitis: A Summary and Update on the Molecular Virology, Epidemiology, Pathogenesis and Prevention. J. Hepat. 68, 167. doi: 10.1016/j.jhep.2017.08.034

Loader, M., Moravek, R., Witowshi, S., Driscoll, L. M. (2019). A Clinical Review of Viral Hepatitis. J. Am. Acad. Physic. Assit. 32, 15. doi: 10.1097/01.JAA.0000586300.88300.84

Lok, A. S., Zoulim, F., Dusheiko, G., Gheny, M. (2017). Hepatitis B Cure: From Discovery to Regulatory Approval. J. Hepatol. 67, 847. doi: 10.1016/j.jhep.2017.05.008

Nagashima, S., Takahashi, M., Kobayashi, T., Nishiyam, T. T., Nishiyama, T., et al. (2017). Characterization of the Quasi-Enveloped Hepatitis E Virus Particles Released by the Cellular Exosomal Pathway. J. Virol. 22, e00822–e00817. doi: 10.1128/JVI.00822-17

Netzler, N. E., Tuipulotu, D. E., Vasudevan, S. G., Mackenzie, JM, White, P. A. (2019). Antiviral Candidates for Treating Hepatitis E Virus Infection. Antimicrob. Agents Chemotherap. 63, e00003–e00019. doi: 10.1128/AAC.00003-19

Scheel, T. K., Rice, C. M. (2013). Understanding the Hepatitis C Virus Life Cycle Paves the Way for Highly Effective Therapies. Nat. Med. 19, 837. doi: 10.1038/nm.3248

Schillie, S., Vellozzi, C., Reingold, A., Harris, A., Haber, P., et al. (2018). Prevention of Hepatitis B Virus Infection in the United States: Recommendations of the Advisory Committee on Immunization and Practices. Morbidity Mortality Wkly. Rep. 67, 1. doi: 10.15585/mmwr.rr6701a1

Tang, L., Zhao, Q., Wu, S., Cheng, J., Guo, J.-T. (2017). The Current Status and Future Directions for Hepatitis B Antiviral Drug Discovery. Expert Opin. Drug Disc. 12, 5. doi: 10.1080/17460441.2017.1255195

World Health Organization (2012). Prevention and Control of Viral Hepatitis Infection: Framework for Global Action . World Health Organization. Available at: https://apps.who.int/iris/handle/10665/130012 .

Google Scholar

World Health Organization (2016). Combating Hepatitis B and C to Reach Elimination by 2030. Advocacy Brief . World Health Organization. Available at: https://apps.who.int/iris/handle/10665/206453 .

Yan, H., Zhong, G., Xu, G., He, W., Jing, Z., et al. (2012). Sodium Cholate Co-Transporting Polypeptide Is a Functional Receptor for Human Hepatitis B and D Virus. eLife 1, e00049. doi: 10.7554/eLife.00049

Zhu, F.-C., Zhang, J., Zhang, X.-F., Zhou, C., Want, Z.-Z., et al. (2010). Efficacy and Safety of a Recombinant Hepatitis E Vaccine in Healthy Adults: A Large-Scale, Randomized, Double-Blind Placebo-Controlled, Phase 3 Trial. Lancet 376, 895. doi: 10.1016/S0140-6736(10)61030-6

Zoratti, M. J., Siddiqua, A., Morassut, R. E., Zeraatkar, D., Chou, R., van Holten, J., et al. Pangenotypic Direct Acting Antivirals for the Treatment of Hepatitis C Virus Infection: A Systematic Literature Review. EClin. Med. 18, 100237. doi: 10.1016/j.eclinm.2019.12.007

Keywords: viral hepatitis, HAV, HBV, HCV, HDV, HEV

Citation: Kao C, Surjit M and Ranjith-Kumar CT (2021) Editorial: Viral Hepatitis: Pathophysiology, Prevention, and Control. Front. Cell. Infect. Microbiol. 11:633580. doi: 10.3389/fcimb.2021.633580

Received: 25 November 2020; Accepted: 09 July 2021; Published: 26 August 2021.

Edited and reviewed by:

Copyright © 2021 Kao, Surjit and Ranjith-Kumar. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Cheng Kao, [email protected] ; Milan Surjit, [email protected] ; C. T. Ranjith-Kumar, [email protected]

This article is part of the Research Topic

Viral Hepatitis: Pathophysiology, Prevention, and Control

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Roingeard, P., & Hourioux, C. (2007). Hepatitis C virus core protein, lipid droplets and steatosis. Journal of Viral Hepatitis, 15 (3), 157-164. doi:10.1111/j.1365-2893.2007.00953.x

Normal Physiology

The liver is the largest solid organ in the human body. Under healthy conditions the liver plays a large role in digestion. It creates bile to help with fat emulsion and absorption in the intestines and filters the blood as it comes from the digestive tract. Once inside the liver the nutrients are then synthesized before they are distributed throughout the body. The liver is also responsible for creation of proteins called albumins that help maintain the plasma intravascular colloid osmotic pressure. Lastly the liver helps create clotting factors, maintain blood glucose levels, metabolize drugs, and store vitamins and minerals.

Pathophysiology of Hepatitis C Virus

Hepatitis C Virus (HCV) disrupts this system and causes permanent, irreversible harm to the liver. While some individuals exposed to HCV are able to clear the virus from their system about 85% will develop a chronic infection. Early on the symptoms are generally mild or absent, children especially are asymptomatic. However, as the virus advances and starts to cause harm to the liver many manifestations of liver disease begin to appear. This is due to the process known as cirrhosis, or scarring of the liver, which is an irreversible change to the tissues of the liver resulting in a loss of function of the cells involved. This loss of function manifests in symptoms such as jaundice, fatigue and malaise, nausea and anorexia, portal hypertension, and many other liver failure symptoms. Cryoglobulinemia vasculitis and lymphoproliferative disorders may also be present due to the progression of the liver disease process. HCV is diagnosed via blood work with detection of anti-HCV IGG. Persistent infections, with acute symptoms, and elevated aminotransferase levels may also accompany a clinical presentation. There is currently no vaccine for HCV, this is due to viral mutations and genetic diversity between genotypes, post treatment reinfection is also likely.

Progression of disease to cirrhosis is the most common cause of hepatocellular carcinoma in the United States and of liver transplant worldwide (McCance & Huether, 2019).

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Chapter 25: Hepatitis, Viral

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Introduction, hepatitis a.

HEPATITIS B
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Viral hepatitis refers to the clinically important hepatotropic viruses responsible for hepatitis A (HAV), hepatitis B (HBV), delta hepatitis, hepatitis C (HCV), and hepatitis E.

HAV infection usually produces a self-limited disease and acute viral infection, with a low fatality rate, and confers lifelong immunity. Outbreaks occur each year in the United States.

HAV infection primarily occurs through transmission by the fecal-oral route, person-to-person, or by ingestion of contaminated food or water. HAV’s prevalence is linked to resource-limited regions and specifically to those with poor sanitary conditions and overcrowding. Rates of HAV infection are increased among international travelers, persons who inject drugs, persons unhoused, and men who have sex with men.

The disease exhibits three phases: (1) incubation (averaging 28 days, range 15–50 days), (2) acute hepatitis (generally lasting 2 months), and (3) convalescence. Acute hepatitis is marked by an abrupt onset of nonspecific symptoms; some very mild. Some patients may experience symptoms for up to 9 months. Nearly all individuals have a clinical resolution within 6 months of the infection, and a majority have resolution within 2 months. HAV does not lead to chronic infections.

The clinical presentation of HAV infection is given in Table 25-1 . There are no specific symptoms unique to HAV. Children younger than 6 years of age are typically asymptomatic.

The diagnosis of acute HAV is made through the IgM anti-HAV which is detectable 5 to 10 days prior to symptomatic HAV infections in the majority of patients. Clinical criteria consist of acute onset of fatigue, abdominal pain, loss of appetite, intermittent nausea and vomiting, jaundice or elevated serum aminotransferase levels, and serologic testing for immunoglobulin (Ig) M anti-HAV.

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Clinical presentation of acute viral hepatitis

Affiliation.

1 Academic Department of Medicine, Royal Free Hospital School of Medicine, London, UK.
PMID: 2116216
DOI: 10.1093/oxfordjournals.bmb.a072414

Acute viral hepatitis may be asymptomatic, symptomatic but anicteric, or a classical icteric hepatitis; rarely it is very severe and may be fatal. Different types of illness may be caused by the various hepatitis viruses. This does not help precise diagnosis, which is based on serological tests. This paper describes hepatitis seen with the A, B, C, D and E viruses, and also some of the unusual complications which have been recognized. Serological tests allow precise diagnosis of acute hepatitis A and B, and should be used more widely, because viral hepatitis is often diagnosed when jaundice is caused by other conditions. They also allow diagnosis when viral hepatitis has an atypical presentation, and is thus not considered as the cause of the liver disease. Negative tests suggest the need for further investigation.

Publication types

Acute Disease
Hepatitis A*
Hepatitis B*
Hepatitis C*
Hepatitis D*
Hepatitis, Viral, Human*

Correspondence
Open access
Published: 03 May 2017

Late presentation of chronic viral hepatitis for medical care: a consensus definition

Stefan Mauss 1 , 2 ,
Stanislas Pol 2 , 9 ,
Maria Buti 2 , 3 ,
Erika Duffell 4 ,
Charles Gore 5 ,
Jeffrey V. Lazarus 6 ,
Hilje Logtenberg-van der Grient 7 ,
Jens Lundgren 6 ,
Antons Mozalevskis 6 , 8 ,
Dorthe Raben 6 , 10 ,
Eberhard Schatz 11 ,
Stefan Wiktor 12 &
Jürgen K. Rockstroh 10 , 13

on behalf of the European consensus working group on late presentation for Viral Hepatitis Care

BMC Medicine volume 15 , Article number: 92 ( 2017 ) Cite this article

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Introduction

We present two consensus definitions of advanced and late stage liver disease being used as epidemiological tools. These definitions can be applied to assess the morbidity caused by liver diseases in different health care systems. We focus is on hepatitis B and C virus infections, because effective and well tolerated treatments for both of these infections have greatly improved our ability to successfully treat and prevent advanced and late stage disease, especially if diagnosed early. A consensus definition of late presentation with viral hepatitis is important to create a homogenous, easy-to-use reference for public health authorities in Europe and elsewhere to better assess the clinical situation on a population basis.

A working group including viral hepatitis experts from the European Association for the Study of the Liver, experts from the HIV in Europe Initiative, and relevant stakeholders including patient advocacy groups, health policy-makers, international health organisations and surveillance experts, met in 2014 and 2015 to develop a draft consensus definition of late presentation with viral hepatitis for medical care. This was refined through subsequent consultations among the group.

Two definitions were agreed upon. Presentation with advanced liver disease caused by chronic viral hepatitis for medical care is defined as a patient with chronic hepatitis B and C and significant fibrosis (≥ F3 assessed by either APRI score > 1.5, FIB-4 > 3.25, Fibrotest > 0.59 or alternatively transient elastography (FibroScan) > 9.5 kPa or liver biopsy ≥ METAVIR stage F3) with no previous antiviral treatment. Late stage liver disease caused by chronic viral hepatitis is clinically defined by the presence of decompensated cirrhosis (at least one symptom of the following: jaundice, hepatic encephalopathy, clinically detectable ascites, variceal bleeding) and/or hepatocellular carcinoma.

These consensus definitions will help to improve epidemiological understanding of viral hepatitis and possibly other liver diseases, as well as testing policies and strategies.

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Over 13 million adults are living with hepatitis B, and 15 million with hepatitis C, in the World Health Organization (WHO) European Region [ 1 , 2 , 3 , 4 ]. The prevalence of chronic hepatitis B virus (HBV) infection (commonly defined as the persistence of hepatitis B surface antigen for six months or more) and chronic hepatitis C virus (HCV) infection (as determined by the persistence of hepatitis C nucleic acid or HCV core antigen for more than six or 12 Footnote 1 months) ranges from 0.1% to 6% across Europe, with major differences between countries and population subgroups [ 2 , 3 , 4 ]. Chronic HBV and HCV infections may remain clinically silent for decades, and symptoms do occur at a late stage. Diagnosis in the absence of widespread screening programmes may therefore be based on signs of late stage liver disease such as hepatic decompensation, variceal bleeding or hepatocellular carcinoma.

Many people with chronic HBV and/or HCV infection are go undiagnosed [ 5 ]. Of those already diagnosed, many are not necessarily linked to parts of the healthcare system that are able to provide comprehensive care (e.g. to accurately classify the extent of liver disease and provide treatment when indicated) [ 6 ]. Consequently, a large (but undetermined) proportion of the chronically infected population enters comprehensive care only after developing liver disease-related clinical symptoms.

Effective and well tolerated treatments for both HBV and HCV infection have greatly improved our ability treat patients successfully, especially if they are diagnosed early [ 7 , 8 , 9 , 10 ]. In asymptomatic individuals, treatment is indicated for those at increased risk of symptomatic chronic liver disease, and those at risk of transmitting the infection. All patients with symptomatic disease should be treated. For many, treatment can prevent further progression of liver disease to liver cirrhosis, and can even revert existing liver fibrosis [ 7 , 8 ].

In most European countries, it remains unknown as to what extent testing policies and strategies succeed in identifying the undiagnosed population during the course of their disease. The extent to which diagnosed patients are linked to and retained in sections of the healthcare system that are able to provide comprehensive care is also unknown.

To fully exploit the strategic use of treatment and to optimise its benefit, infected persons in need of treatment must enter comprehensive care before their liver disease progresses to considerable liver damage. Patients with advanced liver fibrosis may be considered as “late presenters”. Of these, a subgroup of individuals with “late stage liver disease”, such as decompensated liver cirrhosis, portal hypertension or hepatocellular carcinoma, can be further defined as a subgroup where there is indisputable evidence that earlier initiation of treatment would have provided significant benefit. These definitions will help quantify the proportion of cases missing timely diagnosis and treatment.

Method/process of developing a consensus definition of late presentation with viral hepatitis

In 2014, a group of viral hepatitis experts within the European Association for the Study of the Liver (EASL) and the HIV in Europe Initiative [ 11 ] formed a working group to develop a consensus definition of late presentation with viral hepatitis. Key stakeholders were invited to participate, including patient advocacy groups, health policy-makers, international health organisations, surveillance experts and medical experts. The consensus-building process involved all of the important constituencies in Europe involved in both treatment and surveillance of hepatitis. A series of teleconferences took place in 2014, in parallel with the organisation of the first HepHIV Conference in Barcelona in October 2014, where the first draft of the definition for late presentation was presented and discussed [ 12 ]. Following the conference, key stakeholders were consulted on the proposed consensus definitions in a public hearing phase. The definitions were finally endorsed by the EASL governing board in September 2015.

Two definitions relating to late presentation were agreed upon (Table 1 ).

The term “late presentation for care” should be used to refer to HBV or HCV-infected people who enter care when substantial liver fibrosis is already present (i.e. they present with advanced liver disease). This implies that the time of HBV or HCV diagnosis is considered late, as “late presenters” have not been diagnosed earlier. In contrast, the term “presentation with late stage liver disease” should be reserved for the subgroup of these late presenters who are additionally at greater imminent risk of severe complications of liver disease or death. The term “presentation for care” means attendance at a healthcare facility that is able to monitor progression of chronic hepatitis B and C and associated liver disease and initiate appropriate medical care, including treatment.

These consensus definitions may be considered for inclusion within countries’ routine viral hepatitis surveillance systems. Investigations performed on the basis of a common definition will enable epidemiological data to be compared between countries and trends to be monitored over time.

For this purpose the definition of “presentation with advanced liver disease in patients with chronic hepatitis B and C” includes several different technical procedures to estimate the degree of liver fibrosis to improve its practicality, which all have different sensitivities and specificities [ 13 , 14 ]. In particular, the inclusion of APRI and FIB-4 should enable this definition to be used on a broad scale, and also in low-income countries. However, since the accuracy of APRI in assessing fibrosis in HBV infection has been challenged [ 15 ], APRI should only be used in chronic hepatitis B in the absence of other tools including FIB-4. Using a uniform cut-off for the recommended tests for chronic hepatitis B and C may lead to a loss in accuracy [ 15 , 16 , 17 ], but is in line with current WHO recommendations [ 9 , 10 ]. In addition, using the same cut-offs for chronic hepatitis B and C increases the practicality of this definition as a population-based tool.

The second definition of “presentation with late stage liver disease in patients with chronic hepatitis B and C” is based on clinical symptoms alone, with no need for sophisticated technology. This enables its use in any health care system. In some patients, particularly those with chronic hepatitis B, hepatocellular carcinoma may occur without cirrhosis, but usually after prolonged periods of chronic infection [ 18 ].

The two key indicators to be derived from using the two definitions of late presentation of patients for medical care with chronic hepatitis B and C within a population of new referrals are: 1) the proportion of referrals that fulfil either of these definitions, and 2) the incidence of presenters with late stage liver disease in the population.

If the definitions are implemented in surveillance structures, the data on which these definitions are based must be readily available from routine care in centres that are specialised to diagnose and treat liver diseases. To achieve this, these centres must adequately capture data on liver fibrosis stage and presence of hepatocellular carcinoma or decompensated cirrhosis.

It is important that viral hepatitis surveillance systems capture the public health consequences of these infections by focusing on the proportion of patients referred to a specialised medical site who present late and/or with advanced liver disease. In the past, this was demonstrated by the introduction of a comparable definition of late presentation with HIV. The broad acceptance of this definition (defined as individuals newly presenting for HIV care with a CD4 count below 350 cells/μl, or with an AIDS-defining event) has allowed the percentages of late presenters in various countries and regions to be compared, and also allows changes in the numbers of late presenters to be monitored after implementing improved testing strategies [ 19 , 20 ].

Using this definition has been particularly instrumental in identifying risk factors for late presentation, and therefore has had an impact on new testing strategies. Indeed, a recent Swiss cohort analysis showed that patients outside established HIV risk groups are most likely to be late presenters. Provider-initiated testing must therefore be improved to reach these groups, which include heterosexual men and women, and older patients [ 21 ].

The late presenter definition has also been used to characterize a specific group of HIV patients with prolonged low CD4-positive cell counts, who behave very differently to other HIV-infected patient groups. More recently, a study on non-infectious comorbidities revealed that these were also far more prevalent in late presenters [ 22 ]. In summary, the definition of late presentation has been instrumental in better understanding clinical presentation, course and epidemiology of HIV in various regions of the world.

The two definitions presented here for liver disease in patients with chronic hepatitis B and C can be used for different purposes. Firstly, they will unify methods of monitoring and evaluating the effectiveness of testing and referral services. For example, if a large percentage of patients are “late presenters”, it implies that intervention testing needs improvement to ensure earlier diagnosis. As such, the definitions can be used to monitor the effect of interventions that aim to reduce the number of late presenters. Secondly, their use will enable future studies across Europe to determine the size of the population at risk, and to identify vulnerable groups and risk factors for late presentation. They will also increase understanding of the social and medical barriers that limit access to healthcare in different European countries, and may initiate studies on access to treatment for late presenters across the region. It would therefore be beneficial if all national health agencies, institutions and researchers could implement these consensus definitions when reporting surveillance or research data on late presentation of chronic hepatitis B or C.

These consensus definitions of late presentation for viral hepatitis provide a useful tool for public health authorities in Europe and elsewhere, to gain a better understanding of epidemics. They will help to improve the quality of available epidemiological information on viral hepatitis and the prevention and control responses to the viral hepatitis epidemic.

Case definitions for hepatitis B and C vary across European countries. Countries in the European Union (EU) and European Economic Area (EEA) are requested to follow EU 2012 case definitions for reporting at the European level. 2012/506/EC – Commission Implementing Decision of 8 August 2012 amending Decision 2002/253/EC laying down case definitions for reporting communicable diseases to the Community network under Decision No 2119/98/EC of the European Parliament and of the Council.

Abbreviations

European Association for the Study of the Liver

Hepatitis B Virus

Hepatitis C Virus

Hepatitis D Virus

World Health Organization

World Health Organization Regional Office for Europe. Hepatitis C in the WHO European region. Fact sheet July 2015 [Internet]. World Health Organization; 2015. http://www.euro.who.int/__data/assets/pdf_file/0010/283357/fact-sheet-en-hep-c.pdf?ua=1 . Accessed [03 Apr 2017].

Hope VD, Eramova I, Capurro D, Donoghoe MC. Prevalence and estimation of hepatitis B and C infections in the WHO European region: a review of data focusing on the countries outside the European Union and the European Free Trade Association. Epidemiol Infect. 2014;142(2):270–86.

Article CAS PubMed Google Scholar

European Centre for Disease Prevention and Control (ECDC). Hepatitis B surveillance in Europe 2013. Stockholm: ECDC; 2015. http://ecdc.europa.eu/en/publications/publications/hepatitis-b-surveillance-in-europe-2013.pdf . Accessed [03 Apr 2017].

European Centre for Disease Prevention and Control. Hepatitis C surveillance in Europe 2013. Stockholm: ECDC; 2015. http://www.euro.who.int/__data/assets/pdf_file/0010/283357/fact-sheet-en-hep-c.pdf?ua=1 . Accessed [03 Apr 2017].

Hatzakis A, Wait S, Bruix J, Buti M, Carballo M, Cavaleri M, et al. The state of hepatitis B and C in Europe: report from the Hepatitis B and C Summit Conference. J Viral Hepat. 2011;18 Suppl 1:1–16.

Article PubMed Google Scholar

Blachier M, Leleu H, Peck-Radosavljevic M, Valla DC, Roudot-Thoraval F. The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol. 2013;58(3):593–608.

American Association for the Study of Liver Diseases (AASLD)/Infectious Diseases Society of America (IDSA). When and in whom to initiae HCV therapy. In: HCV guidance: recommendations for testing, managing, and treating hepatitis C. AASLD/IDSA; 2015. http://www.hcvguidelines.org/full-report/when-and-whom-initiate-hcv-therapy . Accessed 4 Jan 2016.

European Association for the Study of the Liver (EASL). EASL recommendations on treatment of hepatitis C. J Hepatol. 2015;63(1):199–236.

Article Google Scholar

World Health Organization. Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection. Geneva: World Health Organization; 2015.

Google Scholar

World Health Organization. Guidelines for the screening, care and treatment of persons with hepatitis C infection. Geneva: World Health Organization; 2014.

HIV in Europe Initiative. http://www.hiveurope.eu . Accessed [03 Apr 2017].

Buti M, Pol S, Walker M, on behalf of the working group. A consensus definition of late presentation of viral hepatitis for medical care. Barcelona, Spain: HepHIV Conference; 2014.

Castera L. Noninvasive methods to assess liver disease in patients with hepatitis B or C. Gastroenterology. 2012;142(6):1293–302.

Degos F, Perez P, Roche B, Mahmoudi A, Asselineau J, Voitot H, et al. Diagnostic accuracy of FibroScan and comparison to liver fibrosis biomarkers in chronic viral hepatitis: a multicenter prospective study (the FIBROSTIC study). J Hepatol. 2010;53:1013–102.

Kim WR, Berg T, Asselah T, Flisiak R, Fung S, Gordon SC, et al. Evaluation of APRI and FIB-4 scoring systems for non-invasive assessment of hepatic fibrosis in chronic hepatitis B patients. J Hepatol. 2016;64:773–80.

Teshale E, Lu M, Rupp LB, Holmberg SD, Moorman AC, Spradling P, et al. APRI and FIB-4 are good predictors of the stage of liver fibrosis in chronic hepatitis B: the Chronic Hepatitis Cohort Study (CHeCS). J Viral Hepat. 2014;21:917–20.

Zhu MY, Zou X, Li Q, Yu DM, Yang ZT, Huang D, et al. A novel noninvasive algorithm for the assessment of liver fibrosis in patients with chronic hepatitis B virus infection. J Viral Hepat. 2017; doi: 10.1111/jvh.12682 .

Chen CF, Lee WC, Yang HI, Chang HC, Jen CL, Iloeje UH, et al. Changes in serum levels of HBV DNA and alanine aminotransferase determine risk for hepatocellular carcinoma. Gastroenterology. 2011;141(4):1240–8.

Late presenters working group in COHERE in EuroCoord, Mocroft A, Lundgren J, Antinori A, Monforte Ad, Brännström J, et al. Late presentation for HIV care across Europe: update from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) study, 2010 to 2013. Euro Surveill. 2015;20(47). http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=21315 .

Mocroft A, Lundgren JD, Sabin ML, Monforte A, Brockmeyer N, Casabona J, et al. Risk factors and outcomes for late presentation for HIV-positive persons in Europe: results from the Collaboration of Observational HIV Epidemiological Research Europe Study (COHERE). PLoS Med. 2013;10(9):e1001510.

Article PubMed PubMed Central Google Scholar

Darling KE, Hachfeld A, Cavassini M, Kirk O, Furrer H, Wandeler G. Late presentation to HIV care despite good access to health services: current epidemiological trends and how to do better. Swiss Med Wkly. 2016;146:w14348.

PubMed Google Scholar

Guaraldi G, Zona S, Menozzi M, Brothers TD, Carli F, Stentarelli C, et al. Late presentation increases risk and costs of non-infectious comorbidities in people with HIV: an Italian cost impact study. AIDS Res Ther. 2017;14(1):8.

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Acknowledgements

European Consensus Working Group on Late Presentation for Viral Hepatitis Care: Stanislas Pol, European Association for the Study of the Liver (EASL), Paris; Maria Buti, EASL, Barcelona; Stefan Mauss, EASL, Düsseldorf; Erika Duffell, European Centre for Disease Prevention and Control (ECDC); Stefan Wiktor, Team Lead, Global Hepatitis Programme, World Health Organization (WHO), Geneva; Antons Mozalevskis, WHO Regional Office for Europe, Copenhagen; Irene Veldhuijzen, Public Health Service Rotterdam, the HEPscreen project, Hilje Logtenberg-van der Grient, European Liver Patients Association (ELPA); Nikos Dedes, European AIDS Treatment Group (EATG); Charles Gore, Hepatitis C Trust, World Hepatitis Alliance; Eberhard Schatz, Foundation De Regenboog Groep (FRG) representing Correlation Network, Hepatitis C Initiative; José Gatell, University of Barcelona, European AIDS Clinical Society (EACS); Jeffrey V Lazarus, Copenhagen HIV Programme (CHIP), Rigshospitalet, University of Copenhagen; Jens Lundgren, CHIP, Rigshospitalet, University of Copenhagen, EACS; Dorthe Raben, CHIP, Rigshospitalet, University of Copenhagen; Jürgen Rockstroh, University of Bonn, EACS, Chair of HIV in Europe; Brian West, European AIDS Treatment Group (EATG), Co-chair of HIV in Europe; Jordi Casabona, Centre d'Estudis Epidemiològics sobre les Infeccions de Transmissió Sexual i Sida de Catalunya (CEISCATT), Barcelona; Nikos Dedes, EATG, Greece.

The HIV in Europe initiative has received unrestricted funding from Gilead Sciences, Merck, Tibotec, Pfizer, Schering-Plough, Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, and ViiV Healthcare. The operational procedures within the initiative include the following, to maintain the autonomy of the initiative: the Steering Committee is the governing body on which sponsors have no representation; data, records, reports, intellectual property rights and know-how generated as result of the initiative shall be deemed vested in and the property of the Steering Committee, represented by AIDS Fonds Netherlands and CHIP Department of Infectious Diseases, Rigshospitalet. CHIP has received funding from the European Union for the OptTEST project, within the framework of the Second Health Programme (2008–2013), and the Danish National Research Foundation (grant number DNRF126). The funders had no role in the study design, analysis, decision to publish, or preparation of the manuscript.

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SM, JL, JR made substantial contributions to the conception and design; SM, MB, JL, SP, DR, and JR performed analysis and interpretation; SM, JL, ED, DR, and JR drafted the article; SM, MB, ED, HL, AM, JL, JL, SP, DR, CG, ES, SW, and JR critically revised the manuscript for important intellectual content. All authors read and approved the final manuscript.

Competing interests

SM has received honoraria for speaking and advisory boards from AbbVie, Bristol-Myers Squibb (BMS), Gilead, Janssen, Merck Sharp and Dohme (MSD), and ViiV Healthcare; SP has received honoraria for speaking and advisory boards from AbbVie, BMS, Gilead, Janssen, and MSD; MB has received honoraria for speaking and advisory boards from AbbVie, Gilead, Janssen, and Merck; JKR has received honoraria for speaking and advisory boards from Abbott, Abbvie, Gilead, Hexal, Janssen, Merck and ViiV; JVL has received speaker fees and/or research grants from AbbVie, Gilead Sciences, and MSD; ES has received grants/research support from AbbVie, and Gilead. All other authors declare that they have no competing interests.

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Mauss, S., Pol, S., Buti, M. et al. Late presentation of chronic viral hepatitis for medical care: a consensus definition. BMC Med 15 , 92 (2017). https://doi.org/10.1186/s12916-017-0856-y

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MAFLD: an optimal framework for understanding liver cancer phenotypes

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Hepatocellular carcinoma has a substantial global mortality burden which is rising despite advancements in tackling the traditional viral risk factors. Metabolic (dysfunction) associated fatty liver disease (MAFLD) is the most prevalent liver disease, increasing in parallel with the epidemics of obesity, diabetes and systemic metabolic dysregulation. MAFLD is a major factor behind this sustained rise in HCC incidence, both as a single disease entity and often via synergistic interactions with other liver diseases. Mechanisms behind MAFLD-related HCC are complex but is crucially underpinned by systemic metabolic dysregulation with variable contributions from interacting disease modifiers related to environment, genetics, dysbiosis and immune dysregulation. MAFLD-related HCC has a distinct clinical presentation, most notably its common occurrence in non-cirrhotic liver disease. This is just one of several major challenges to effective surveillance programmes. The response of MAFLD-related HCC to immune-checkpoint therapy is currently controversial, and is further complicated by the high prevalence of MAFLD in individuals with HCC from viral aetiologies. In this review, we highlight the current data on epidemiology, clinical characteristics, outcomes and screening controversies. In addition, concepts that have arisen because of the MAFLD paradigm such as HCC in MAFLD/NAFLD non-overlapping groups, dual aetiology tumours and MAFLD sub-phenotypes is reviewed.

Evidence-based clinical practice guidelines for Liver Cirrhosis 2020

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Biomarkers of liver diseases

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Introduction

Hepatocellular carcinoma (HCC) is a major global public health challenge. Already the third leading cause of cancer-related mortality, deaths attributable to HCC are predicted to grow at a rate exceeding that of all other commonly encountered cancers, from 800,000 in 2020 to 1.3 million by 2040 [ 1 ]. Global efforts to tackle the traditional risk factors such as hepatitis B virus (HBV) and hepatitis C virus (HCV) have been counteracted by a rise in fatty liver disease driven by epidemics of obesity, type 2 diabetes mellitus (T2DM) and metabolic dysfunction. Metabolic (dysfunction) associated fatty liver disease (MAFLD) is now a substantial contributor to the global HCC burden [ 2 ], either as the primary aetiology of liver disease or in combination with other aetiologies such as hepatitis B and hepatitis C virus (HBV and HCV) infection, and alcohol-related liver disease (ARLD).

In response to the global disease burden of fatty liver disease, an international panel of experts undertook a revision of the nomenclature and diagnostic criteria to align better with the current understanding of the disease as the hepatic manifestation of systemic metabolic dysregulation. Thus, in 2019, the previous term non-alcoholic fatty liver disease (NAFLD) was proposed to be replaced by MAFLD [ 3 ]. HCC categorisation using terminology such as “non-viral” or “non-B non-C” is also replaced by MAFLD [ 4 ]. Importantly, exclusion of alcohol, viruses, or other causes of steatosis is no longer required for diagnosis, rather the diagnosis can be made “positively” in the presence of steatosis with evidence of metabolic dysfunction, defined by the presence of one of the following three criteria: (1) overweight/obesity (2) T2DM, or (3) evidence of metabolic dysregulation. The latter is defined by the presence of at least two metabolic risk abnormalities listed in Fig. 1 [ 5 , 6 ]. These criteria give rise to distinct but overlapping clinical sub-phenotypes, namely overweight/obese MAFLD, MAFLD with T2DM and MAFLD in individuals of normal weight.

MAFLD diagnostic algorithm (adapted with permission)

The aim of this review is to provide an update on MAFLD-associated HCC, including epidemiology, mechanisms, challenges in screening, clinical characteristics and outcomes. In addition, concepts that have arisen from MAFLD such as HCC in MAFLD/NAFLD non-overlapping groups, dual aetiology cancers and MAFLD sub-phenotypes will be reviewed.

MAFLD, NAFLD, non-overlapping groups

Although there is considerable overlap between NAFLD and MAFLD disease definitions, the terms are not interchangeable, in that there are non-negligible proportions of individuals who have NAFLD but not MAFLD and vice versa (Fig. 2 ) . A meta-analysis comprising 9,808,677 patients estimated 79.9% of patients with fatty liver disease met both disease definitions, 4.0% had NAFLD-only and 15.1% had MAFLD-only [ 7 ]. Patients with MAFLD-only are characterised by the presence of steatosis and metabolic dysfunction, with a secondary cause of steatosis which excludes them from a NAFLD diagnosis (such as viral hepatitis, excessive alcohol consumption or medications). The same meta-analysis reported that these patients have the highest prevalence of fibrosis (as measured by elastography or FIB-4 > 2.67) of 10.2% (vs 4.9% in the overlap group, 3.2% in patients without steatosis, and 2.2% in NAFLD only group), as well as higher ALT and AST compared to NAFLD. As the MAFLD concept is still in its infancy, the HCC incidence of this group has not yet been well defined, however, MAFLD-only have one (or multiple) superimposed liver diseases with a propensity for more severe liver damage. Thus, it is essential that all liver diseases be identified so that they can be managed accordingly.

NAFLD/MAFLD overlap

In contrast, patients with NAFLD-only are characterised by hepatic steatosis with normal body weight, absence of T2DM and < 2 markers of metabolic dysfunction. Whether these patients have an increased risk of HCC is not established, however, it should be noted that many studies have shown this subgroup of patients to have the lowest rates of advanced fibrosis and equivalent all-cause mortality risk to patients with no steatosis [ 8 , 9 , 10 ]. One Taiwanese insurance registry study did report an increased HCC risk in a cohort of patients with “NAFLD without metabolic syndrome” (albeit not synonymous to NAFLD without MAFLD) relative to individuals without steatosis, however, this cohort may have included a significant portion of patients who did in fact have MAFLD due to the different disease definition used. That study also confirmed a strong link between the extent of metabolic dysregulation and HCC risk with T2DM being the most significant individual risk factor [ 11 ]. Another retrospective study of 1286 patients who underwent liver biopsy at an Italian centre reported that HCC did occur in a NAFLD-only cohort in the absence of metabolic dysfunction (defined using the MAFLD definition, albeit without waist circumference or CRP data), but who had genetic predisposition with high-risk alleles of PNPLA3 and TM6SF2. The authors concluding that MAFLD may miss genetically predisposed individuals who do not have metabolic dysfunction [ 12 ]. However, conflicting with this are several studies that suggest metabolic dysfunction is a prerequisite for adverse liver outcomes in genetically predisposed individuals. A large study from UK biobank participants reported that while genetic variants amplify HCC risk in patients with metabolic dysfunction, no significant increase in HCC risk in metabolically healthy patients was reported [ 13 ]. A Chinese study also reported that in patients with PNPLA3/TM6SF2 variants, metabolic dysfunction was a prerequisite for the development of steatosis [ 14 ]. Another study similarly found low rates of hepatic steatosis in PNPLA3 p.I148M variants in individuals of normal bodyweight. Together, these results suggest genetic variants might act more as an amplifier or disease modifier than a disease driver [ 15 ]. Further research on HCC risk in individuals with NAFLD without MAFLD is warranted, especially amongst those with a genetic predisposition.

MAFLD HCC epidemiology

The obesity epidemic has been well documented, fuelled by a global behavioural trend towards increased caloric intake, poor diet quality, a reduction in energy expenditure and an ageing population [ 16 ]. The result has been a six-fold increase in the global prevalence of obesity since 1975 [ 17 ], and has led to MAFLD becoming the most prevalent chronic liver disease [ 18 ]. A recent meta-analysis estimated the overall prevalence of MAFLD to be 38.77% [ 19 ]. Globally, overweight / obesity (BMI ≥ 25 kg/m 2 ) prevalence is predicted to rise from 2.6 billion to over 4 billion people by 2035, constituting more than 50% of the global population. Obesity (BMI ≥ 30 kg/m 2 ) prevalence will rise from 14 to 24% over the same period [ 20 ]. Given the prevalence of MAFLD among overweight/obese adults is 50.7% [ 21 , 22 ], the MAFLD epidemic shows no signs of abating.

Multiple studies have evaluated the risk of HCC development in NAFLD cohorts, with yearly HCC incidence between 0.9 and 2.6% in western cohorts amongst individuals with cirrhosis [ 2 , 23 , 24 ]. Approximately 38% of HCC in patients with NAFLD occurs in individuals without cirrhosis [ 25 ], however, annual incidence rates are substantially lower with rates of 0.1 to 1.3 per 1,000 patient years reported [ 26 , 27 ]. MAFLD tends to be associated with worse markers of liver damage and fibrosis as well as more metabolic comorbidity compared to NAFLD [ 28 , 29 ], all factors associated with elevated HCC risk in non-cirrhotic MAFLD [ 30 ]. Despite this, no studies have directly compared HCC incidence between the different definitions.

MALFD-related HCC is increasing as a proportion of total HCC. An Italian study using the large ITA.LI.CA registry reported that patients with MAFLD as a single disease aetiology had increased as a proportion of total HCC from 3.6% in 2002/2003 to 28.9% in 2018/2019. The proportion of HCV-related HCC decreased over this time (64.4% to 45.8%) as did HBV (15.7% to 10.6%) and alcohol (14.5% to 12.4%). MALFD was modelled to overtake HCV as the single greatest cause of HCC in 4–6 years. Remarkably, in 10–12 years, the investigators predicted that virtually all HCC in Italy would be either MAFLD, or “mixed MAFLD”[ 31 ]. Another Swiss study utilised Geneva Cancer Registry data and reported that the proportion of HCC attributable to MAFLD increased from 21% between 1990 and 1994 to 68% from 2010 to 2014, while NAFLD/MAFLD as a single aetiology increase from 2 to 12% in men and from 0 to 29% in women over the same period [ 32 ]. Similarly in Japan, MAFLD as a single disease aetiology increased five-fold from 1.5% pre-2008 to 7.2% post-2014 [ 33 ].

While MAFLD is traditionally thought of as a Western disease, this not the case. The prevalence of MAFLD in Asia and Middle East and North Africa (MENA) region has been increasing since the 1990s in line with rising rates of obesity and metabolic syndrome. In fact, Asian and MENA countries have experienced a steep rise in liver-related deaths attributable to MAFLD in recent decades, and these regions now account for a larger proportion of deaths than European and American populations [ 34 , 35 ]. HBV and HCV remain the predominant risk factors for HCC in Asia, but with improving vaccination and treatment programs, between 2006 and 2019, there has been a decline in the incidence rate for HCC owing to HBV (4.08 to 3.81 per 100,000) and HCV (2.65 to 2.17 per 100,000), while HCC owing to MAFLD increased (0.48 to 0.50 per 100,000) over the same period [ 36 ]. MALFD is likely to continue to offset the gains made by the reducing incidence of viral HCC in the future.

A distinct subgroup of MAFLD which has generated increasing interest and challenges our understanding of MAFLD pathogenesis is so called “lean-MAFLD”, that is individuals who develop MAFLD within a normal BMI category (BMI 18.5–24.9 kg/m 2 among those of European descent, or 18.5–22.9 kg/m 2 in Asian populations). A meta-analysis of 93 studies reported a prevalence of lean MAFLD in the global MAFLD population of 19.2%, constituting 5.1% of the general population [ 37 ]. Interestingly, several studies have reported worse long-term liver outcomes in lean—as compared to obese-MAFLD including more severe fibrosis, higher rates of progression to severe liver disease and transplantation [ 38 , 39 , 40 ]. Regarding HCC risk, few studies have compared HCC incidence between lean-MAFLD and obese-MAFLD, however, the available data would suggest the rates are similar [ 41 , 42 ]. Of note, the ITA.LI.CA registry study reported 32.26% of patients with MAFLD HCC had the lean-MAFLD phenotype, while a strikingly high proportion (52.81%) of patients with HCC from another aetiology met the definition of lean-MAFLD.

Combined aetiology HCC

There is accumulating evidence of synergistic effects on hepatocarcinogenesis between MAFLD and other aetiologies of liver disease such as HBV, HCV and ARLD. Hence, the paradigm of attributing HCC to a single aetiology likely underestimates the true impact of MAFLD on HCC development. Several studies have quantified the size of this combined MAFLD aetiology subgroup and suggests that it is substantial (Fig. 3 ). The ITA.LI.CA registry estimated mixed-MAFLD tumours to constitute 48.4% of new HCC diagnoses in 2018–2019, of which HCV was the most common cofactor (67%). The proportion of mixed MAFLD HCC had remained fairly stable since 2002–2003, likely reflective of a simultaneous increasing prevalence of MAFLD offset by decreasing prevalence of viral aetiologies [ 31 ]. Similarly, the Geneva Cancer Registry study estimated the size of this combined MAFLD aetiology group to be 41% with HCV and ARLD being the most common cofactors [ 32 ].

Old paradigm of attributing HCC to a single aetiology. In reality, there is substantial overlap between MAFLD-HCC with other liver diseases, yet little is known about the distinct mechanisms, outcomes and response to treatments in these “dual-aetiology” tumours. Adapted from [ 4 ]

Although the prevalence of MAFLD in HCV infection has not been well defined, evidence does suggest that amongst patients with HCV, both steatosis and metabolic dysfunction are highly prevalent, underdiagnosed and likely play a significant role in the divergent outcomes post-SVR on progressive liver dysfunction and HCC risk. For example, NHANES III data suggests patients with HCV are disproportionately affected by metabolic dysfunction with 69.6% of individuals with HCV having at least 1 major metabolic comorbidity, including 18.9% having T2DM and 20.9% having obesity [ 43 ]. In a cohort of 2611 Italian patients with advanced liver fibrosis or cirrhosis post-SVR, 58% of were reported to have metabolic dysfunction as defined using MAFLD criteria. Furthermore, metabolic dysfunction portended an increased risk of de-novo HCC (HR 1.97 95% CI 1.27–3.04), whereas steatosis visible on ultrasound did not predict HCC [ 44 ]. A Chinese study reported that steatosis (HR 2.4) and T2DM (HR 4.2) were both highly associated with HCC development post-SVR in a cohort of 1336 patients followed up post-SVR from either pegylated-interferon plus ribavirin or direct-acting antiviral (DAAs) therapy [ 45 ]. Another study found T2DM was independently associated with HCC development in 1000 patients post-SVR by 2.4 fold [ 46 ]. A study on 29,887 DAA treated US Veterans who achieved SVR reported that T2DM was independently associated with HCC, as well as cirrhosis and all-cause mortality (HR 1.32, 1.31, 1.25, respectively) [ 47 ]. MAFLD, therefore, may have a role in HCC risk stratification post-SVR, particularly amongst patients with F3 fibrosis in whom the need for surveillance is controversial. A recent meta-analysis estimated the pooled incidence of HCC development post-SVR amongst patients with cirrhosis and F3 fibrosis to be 2.1 and 0.5 per 100 patient years, respectively [ 48 ]. Application of MAFLD criteria has been proposed as one strategy which may be useful to inform surveillance strategies [ 49 ], however, studies to assess HCC incidence rates post-SVR in MAFLD vs non-MAFLD cohorts, both in cirrhosis and F3 fibrosis are waiting to be done.

The relationship between HBV infection and MAFLD is complex and incompletely understood. Lower prevalence of hepatic steatosis amongst HBV surface antigen (HBsAg)-positive patients compared to HBsAg-negative patients has been reported [ 50 ]. However, unsurprisingly given its high global prevalence in the general population, hepatic steatosis remains common in patients with HBV; a recent meta-analysis reported a prevalence of 34.93% [ 51 ]. In addition, the proportion of patients with HBV with superimposed MAFLD is increasing. One study from the Netherlands reported that patients with HBV referred to their centre after 2010 tended to have less active HBV-related disease including less e-antigen positivity, less indication for antiviral therapy and less severe fibrosis (OR 0.32, 0.30, 0.18, respectively) compared to patients referred prior to 2000. However, improvement in these metrics related to HBV was offset by higher prevalence of metabolic syndrome, steatosis and MAFLD (OR 2.77, 1.56, 1.35, respectively) (this does raise the question of whether the primary cause of liver disease and reason for referral for a subset of these “HBV cohorts” is in fact MAFLD) [ 52 ]. These findings are consistent with multiple other reports showing a temporal trend of worsening metabolic comorbidity and steatosis amongst HBV-infected individuals [ 53 , 54 , 55 ]. Interestingly, steatosis itself has been reported to be inversely associated with HBV viraemia and intrahepatic HBsAg expression [ 56 , 57 ], however, despite this, MAFLD (with its associated metabolic dysfunction as opposed to simple steatosis) does appear to be associated with liver-related events including HCC amongst patients with HBV, highlighting the prognostic relevance of metabolic dysfunction. One study which used MAFLD criteria to stratify patients with HBV found that in a cohort of 1076 patients with HBV who underwent liver biopsy, the presence of MAFLD was associated with reduced event-free survival (using a composite endpoint of HCC, liver decompensation, liver transplantation, and all-cause mortality), while fatty liver disease without metabolic dysfunction (NAFLD-only), was not associated with adverse outcomes [ 58 ].

Regarding HCC risk specifically, simultaneous HBV and MAFLD appears to be common amongst HBV patients with HCC ( Table 1 ) . One large Taiwanese study reporting that amongst a cohort of 800 patients diagnosed with early-stage HBV HCC between 2009 and 2018, 45.6% had concurrent MAFLD [ 59 ], while MAFLD prevalence in a Chinese cohort of 453 patients with HBV-related HCC was 57% [ 60 ]. A large Korean insurance registry study in HBsAg-positive individuals reported that the co-presence of MAFLD significantly increased the risk of HCC development with an adjusted hazard ratio of 1.37 [ 61 ]. MAFLD with T2DM was noted to have the highest risk for HCC development, however, all MAFLD sub-phenotypes had increased risk. Similarly, a Chinese study found metabolic syndrome to be independently associated with a twofold increased HCC risk amongst 6,545 prospectively enrolled individuals with HBV after adjusting for age, gender, cigarette smoking, alcohol consumption, liver cirrhosis, and elevated aspartate aminotransferase levels [ 62 ]. Some studies have reported poorer prognosis in patients with concurrent HBV MAFLD HCC, including increased HCC recurrence and all-cause mortality following surgical resection, as well as higher risk of death and progression [ 60 , 63 ].

There is a paucity of epidemiological and outcomes data on combined ARLD and MAFLD-related HCC, however, alcohol is known to have a synergistic effect with T2DM and obesity on the progression of liver fibrosis and development of HCC [ 64 ]. A prospective population-based study of 23,712 Taiwanese residents found that alcohol use (defined as use of any quantity greater than 4 days per week for 1 year) and obesity (BMI > 30 kg/m2) were significantly and synergistically associated with HCC (HR 7.19) [ 65 ]. A French study reported that in a cohort of 478 biopsy proven patients with cirrhosis from ARLD, overweight (BMI > 25 kg/m2) or obesity (BMI > 30 kg/m2) and T2DM were both independent predictors of HCC development (HR 2.0, 2.8, 1.4, respectively) [ 66 ]. Obesity was also an independent predictor of HCC development in patients with cirrhosis due to ARLD in an analysis of the United Network for Organ Sharing database (aHR 3.2) [ 67 ]. Several studies have reported an extremely high prevalence of MAFLD amongst individuals with ARLD-related HCC. In the ITA.LI.CA cohort, 80% of 1391 ARLD-related HCC cases between 2006 and 2020 were reported to have MAFLD [ 68 ], while a Belgian cohort of 142 ARLD-related HCC individuals who underwent transplant between 1990 and 2020 similarly had a MAFLD prevalence of 79.5% [ 69 ]. Taken together, these results suggest that MAFLD is not only very common, but also has synergistic effects with ARLD for the development of HCC, although further studies to quantify the strength of this relationship as well as outcomes are still needed.

Epidemiological research assessing alcohol consumption is challenging, with studies often plagued by methodological issues including failure to account for the pattern and type of alcohol consumption, changing habits over time, issues with under reporting, and incomplete adjustment for confounders. An Austrian study found that amongst 114 patients from outpatient liver clinics with presumed fatty liver disease, 29.8% were found to have evidence of moderate to excessive alcohol consumption on hair ethylglucuronide testing [ 70 ]. Furthermore, those with biopsy confirmed metabolic steatohepatitis (MeSH) are known to have altered gut microflora with an increased abundance of alcohol producing bacteria, with blood-ethanol concentrations that are higher than healthy controls or obese patients without liver disease [ 71 ]. These studies highlight that even in “bona fide MAFLD” cohorts, disentangling the effects of MAFLD and alcohol has significant challenges. In contrast, one study found that 68.7% of patients undergoing transplant for ARLD had concomitant MAFLD [ 69 ], while patients who have undergone liver transplant for ARLD-related cirrhosis have the highest rates of de-novo steatosis (37% vs 26%), even in the setting of alcohol abstinence, suggesting other factors such as metabolic dysfunction predispose many of these patients to liver disease in the first place [ 72 , 73 ]. Dichotomising liver disease or HCC aetiology into ARLD or MAFLD based off an arbitrary alcohol consumption cut-off of 20 g/day for women and 30 g/day ignores the continuum on which these two interacting disorders exist. Hopefully, the concept of MAFLD which is not mutually exclusive to ARLD will lead to wider recognition that many patients have multiple liver disease which each require appropriate diagnosis and management, while paving the way for further research in this area.

MAFLD HCC mechanisms

Excess weight, insulin resistance, lipotoxicity, oxidative stress.

The pathway from metabolic dysfunction to HCC is complex and multifactorial ( Fig. 4 ) . Excess weight and ensuing insulin resistance is crucially linked to the development of hepatic steatosis via several mechanisms including increased release of non-esterified fatty acids (NEFA) from adipocytes and their delivery to hepatocytes, as well as increased de-novo lipogenesis (DNL) from carbohydrates in the liver. Upregulated DNL is a crucial feature of MAFLD and HCC development, with ubiquitin-specific protease 22 (USP22) recently identified as a key regulator of DNL in MAFLD HCC, with high USP22 expression associated with poor prognosis and overall survival [ 80 ]. Accumulation of toxic lipid species can cause injury and cell death in hepatocytes and non-parenchymal liver cells via generation of reactive oxygen species (ROS), oxidative stress, endoplasmic reticulum stress and inflammasome activation. Oxidative stress-induced DNA damage can predispose to carcinogenesis [ 81 ]. Increasing mutational burden in genes regulating lipid processing and storage FOXO1, CIDEB and GPAM develop due to the selective pressure on hepatocytes induced by lipotoxicity. These mutations may protect hepatocytes from lipotoxicity but also predispose to malignancy [ 82 ]. The oxidative environment generated in MAFLD can also lead to oxidation and inactivation of protein tyrosine phosphatases (PTPs), leading to increased STAT-1 and STAT-3 signalling. Interestingly STAT-1 signalling appears to mediate steatohepatitis and fibrosis but not carcinogenesis, while STAT-3 signalling increases carcinogenesis in the absence of liver damage, in keeping with the clinical observation that HCC and fibrosis can occur as independent events [ 83 ]. Insulin resistance induces compensatory hyperinsulinaemia which increases production of insulin-like growth factor 1 (IGF-1). This further promotes cellular proliferation and inhibits apoptosis [ 84 ]. Numerous hepatokines and adipokines are also implicated in hepatocarcinogeneisis [ 85 ]. Leptin is an important adipokine which decreases appetite and increases energy expenditure via its actions on the hypothalamus. Leptin is increased in obesity, MAFLD and HCC and acts as a mitogen which stimulates cellular proliferation and is associated with carcinogenesis in obesity [ 86 , 87 ].

MAFLD-HCC mechanisms schematic. Systemic metabolic dysregulation crucially underpins MAFLD. Many interacting disease modifiers influence the phenotypic manifestations and progression to cirrhosis and/or HCC

Immune microenvironment

The immune microenvironment of MAFLD appears to be distinct compared to other chronic liver diseases, creative a permissive setting for the development of HCC. For example, dysregulated lipid metabolism causes accumulation of free fatty acids (in particular linoleic acid) leading to selective CD4 + loss. CD4 + cells are important in inhibiting HCC initiation and mediating tumour regression [ 88 , 89 ]. T H 17 cells also infiltrate the liver in response to hepatic DNA damage, triggering neutrophil recruitment via IL-17A, leading to subsequent fatty acid accumulation, steatohepatitis and HCC [ 90 ]. Liver resident macrophages (Kupffer cells) are another important regulator of inflammatory and fibrotic signalling cascades in MAFLD which may predispose to HCC [ 91 ]. Studies have recently highlighted the role for aberrant T cell activation in MAFLD and HCC. One study reported on an abundance of liver-resident CD8 + T cells in MAFLD mice with markers of exhaustion and effector functions. These cells were triggered to become “auto-aggressive” by IL-15-induced downregulation of the transcription factor FOXO1 followed by metabolic stimuli exposure including acetate [ 92 ]. Another study reported the presence CD8 + PD1 + T cells in MeSH with features of exhaustion, lacking in immune surveillance functions and with tissue damaging functions. Expansion of this population with immunotherapy led to increasing liver cancer incidence, highlighting their potential role in MAFLD HCC pathogenesis [ 93 ].

A confounder in all such studies is that patients are typically considered to have MAFLD-related or viral (or other) hepatitis-related HCC. This ignores the role and impact of concomitant MAFLD in patients with liver disease from another aetiology. Hence, we suggest that future studies on the immune microenvironment should focus on HCC development in MAFLD, in those with MAFLD and another liver disease and those with another liver disease but without concomitant MAFLD (Fig. 3 ). The mechanisms for HCC development, the outcomes, and response to therapy are likely very different among these groups. Such mechanistic insights are especially important in the era of immunotherapy in order to leverage the most effective therapies for patients.

Complex interactions between genes and the environment shape MAFLD phenotype and progression including towards HCC. The importance of genetics is illustrated by mono and dizygotic twin studies estimating that 61% of liver fat content is genetically determined [ 94 ]. A number of single nucleotide polymorphisms (SNPs) associated with abnormal hepatocyte lipid metabolism are linked to hepatic steatosis and increase HCC risk [ 95 ]. One of the most notable is the rs738409 SNP in PNPLA3 that changes residue 148 of patatin-like phospholipase 3 (PNPLA3) from isoleucine to methionine (G allele), which causes impaired degradation of lipid droplets in hepatocytes. PNPLA3 rs738409 C > G is associated with increased risk of HCC in MAFLD with an approximate doubling of HCC risk for each copy of the minor (G) allele [ 96 ]. TM6SF2 SNP rs58542926 is associated with upregulation of cholesterol and fatty acid biosynthesis pathways and increases HCC risk relative to those without fatty liver without the variant (OR 1.92) [ 97 , 98 ]. MBOAT7 rs641738 is also associated with increased intrahepatic triglyceride content and is independently associated with HCC (OR 2.10) [ 99 ]. A loss of function variant of GCKR rs1260326 (encoding glucokinase regulator) increases de novo lipogenesis and increases HCC relative to MeSH without the variant (OR 1.84) [ 100 ]. Combining all this data, a polygenic risk score (PRS) has been proposed as a tool to stratify MAFLD individuals at risk for HCC to improve surveillance yield [ 101 ].

The gut microbiome is an important regulator of digestion and multiple metabolic processes, and influences the susceptibility to many liver diseases from steatosis to steatohepatitis, fibrosis and HCC. Dysbiosis is known to occur in MAFLD, with distinct but overlapping microbial signatures at the level of phylum, family and genera reported amongst MAFLD patients with simple steatosis, steatohepatitis and advanced fibrosis [ 102 , 103 ]. Dysbiosis contributes to hepatic steatosis by increasing short-chain fatty acid (SCFA) generation which serves as a substrate for hepatic de-novo lipogenesis, as well as increasing absorption of monosaccharides across the intestine.

MAFLD is also characterised by increased intestinal permeability due to alterations in tight junctions which may lead to increased hepatic exposure to pro-inflammatory and oncogenic microbes and microbial products [ 104 , 105 , 106 ]. Increased translocation of microbial-associated molecular patterns (MAMPs) and danger-associated molecular patterns (DAMPs) can activate toll like receptors (TLRs) on Kupffer cells, hepatocytes and stellate cells, triggering inflammatory and fibrotic signalling cascades and predisposing to carcinogenesis [ 107 ].

The gut microbiome also has important immunomodulatory effects which can predispose to HCC. A recent study reported enrichment in SCFA producing bacteria in MAFLD-HCC patients which resulted in immunomodulation towards immunosuppression characterised by increased peripheral T reg cells and reduced CD8 + T cells [ 108 ]. Bile acids are another important metabolite linking the microbiome to HCC development. Bile acids are regulators of lipid and glucose handling and modulate inflammation in MAFLD. Since the gut microbiome converts primary bile acids to secondary bile acids, it has a profound impact on bile acid signalling via suppression of farnesoid X receptor (FXR) signalling. This predisposes to liver damage [ 109 ], as well as increasing the levels of the secondary bile acid deoxycholic acid (DCA) (a gut bacterial metabolite known to cause DNA damage) [ 110 ].

Chemoprevention

Addressing well-established lifestyle-related modifiable risk factors remain a key tool in HCC prevention in individuals with MAFLD. These include improving dietary patterns (including a hypocaloric and Mediterranean diet), increasing physical activity, measures to achieve weight loss and avoidance of other carcinogens including smoking and alcohol [ 111 ]. Indeed, mounting evidence implicates even moderate quantities of alcohol as a cofactor for HCC development in MAFLD [ 112 ]. A number of other pharmacotherapies have garnered interest as chemopreventative agents, including coffee, metformin, aspirin, statins and several novel T2DM therapies [ 113 ] ( Table 2 ) . Chemoprevention is yet another unmet need and a number of these therapies show promise, however, in the absence of prospective efficacy data, coffee is the only chemopreventative therapy to be explicitly endorsed by any of the major society guidelines[ 114 ], highlighting the need for dedicated prospective studies.

MAFLD HCC clinical presentation

MAFLD-related HCC appears to exhibit a distinct phenotype in terms of both patient and tumour characteristics. A recent meta-analysis which included 61 studies on MAFLD-HCC reported that these patients were older (mean difference 5·62 years), with a higher mean BMI (mean difference 2·99 kg/m 2 ), and more likely to have metabolic complications including diabetes (OR 4·31), hypertension (OR 2·84), dyslipidaemia (OR 3·43) and cardiovascular disease (OR 2·23) compared to HCC due to other aetiologies [ 142 ]. In addition, MAFLD HCC tumours tend to be larger (mean difference 0·67 cm), are more likely to be uninodular (OR 1·36) and occur on a background of non-cirrhotic liver disease (38.5% vs 21.7% for HBV, 6.4% for HCV and 9.1% for ARLD). Importantly, only 32.8% of patients with MAFLD HCC were undergoing surveillance compared to 55.7% of patients with other aetiologies, reflecting the fact that a significant proportion patients would not have had indications for routine surveillance based on current recommendations.

Several studies have examined the clinical characteristics of patients with HCC with MAFLD, utilising the newer disease definition and including the non-overlap group (MAFLD without NAFLD). An analysis of the large Italian ITA.LI.CA HCC registry classified tumours into either single aetiology MAFLD (S-MAFLD), mixed-aetiology MAFLD (M-MAFLD) or non-MAFLD, and found that S-MAFLD tumours were larger, more frequently associated with extrahepatic metastases, but less frequent clinically relevant portal hypertension or MELD score > 10 and with lower AFP compared with non-MAFLD tumours. Interestingly the M-MAFLD group, appeared to have a distinct clinical phenotype. Compared to non-MAFLD tumours, M-MAFLD tended to occur on less advanced cirrhosis by MELD score > 10 or significant portal hypertension, as well as being older, having poorer performance status (ECOG > 0) and lower AFP. However, this subgroup was also distinct from S-MAFLD tumours due to being more likely to have cirrhosis, with smaller tumours and higher AFP level [ 31 ]. Another study from Switzerland compared the non-overlapping MAFLD group (i.e., MAFLD without NAFLD) to NAFLD HCC, and found MAFLD HCC tended to occur in settings of more severe liver dysfunction, more severe portal hypertension and were less likely to receive curative therapy [ 32 ].

Overall survival

Overall mortality for MAFLD HCC was reported by the ITA.LI.CA HCC registry study and reported a significantly longer median survival in patients with single aetiology MAFLD HCC (28.1 months) compared to non-MAFLD HCC (23.8 months) after adjusting for baseline differences between subgroups and lead time bias, as well as a lower competing risk of death related to HCC progression compared to non-MAFLD. This was partially offset by a significantly higher risk of death by other causes in single aetiology MAFLD. The authors postulated that these results hint towards a less biologically aggressive phenotype of MAFLD HCC, particularly because MAFLD HCC tend to be more advanced at time of diagnosis [ 31 ]. MAFLD HCC patients were also more likely to be treated by resection, but less likely to receive liver transplant.

Other studies assessing overall survival in MAFLD HCC have documented conflicting results, including a retrospective cohort study of 1119 HCC patients in Germany which reported a shorter median overall survival for MAFLD HCC compared to non-MAFLD (11.28 vs 15.5 months). Higher BMI was associated with longer survival in all HCC groups. There was a trend towards more advanced HCC at diagnosis in the MAFLD group (trend towards larger tumour size, more multifocal disease and distant metastases), thus differences in surveillance and lead time bias may explain some of these results [ 143 ]. Of note, a recent meta-analysis reported no difference in overall survival between MAFLD and non-MAFLD HCC, however, MAFLD HCC was associated with improved disease-free survival including amongst those who received curative therapy. When the analysis was limited only to patients with cirrhosis, however, MAFLD HCC was associated with worse overall survival. MAFLD HCC was associated with a similar overall likelihood of receiving curative therapy, with a higher likelihood of resection but a lower likelihood of receiving transplant. There was substantial heterogeneity between studies [ 142 ]. Another study found no difference in overall survival between cirrhotic MAFLD HCC and non-cirrhotic MAFLD HCC as cirrhotic patients were more likely to have their tumours detected on surveillance imaging and therefore were found at an earlier stage, thereby offsetting the detrimental effect of their more advanced liver dysfunction and thus highlighting the importance of effective surveillance on outcomes [ 144 ].

Outcomes post-curative therapy

Outcomes post-MAFLD-HCC resection were recently evaluated in a large Italian cohort who underwent HCC resection. Consistent with other studies, MAFLD HCC tended to occur in older patients with more metabolic comorbidity, with larger tumours and lower rates of cirrhosis. MALFD HCC was found to have the lowest overall survival compared to HCV, HBV and ARLD post resection, and was an independent prognostic factor on multivariable survival analysis. Recurrence free survival was similar. The short-term (90 day) post-operative mortality rate was nearly double that of other aetiologies at 5.9% despite similar rates of major complications and post-hepatectomy liver failure (PHLF) [ 75 ]. In contrast, a recent meta-analysis reported a superior overall and disease free survival of MAFLD HCC resections compared to other aetiologies [ 145 ], suggesting longer term outcomes may in fact be favourable in well-selected patients despite the short-term perioperative cardiometabolic risk.

Amongst patients who receive a liver transplant for HCC, MAFLD is an increasingly common cause of underlying liver disease, increasing from 1.3% in 2002–2004 to 8.3% from 2014–2016 in a European registry study [ 146 ]. There were no significant differences in post liver transplant survival outcomes or graft survival outcomes between MAFLD and non-MAFLD recipients reported, either for recipients with or without HCC [ 146 ] although recurrence of MAFLD is known to be common post-transplant [ 147 ]. A United Network for Organ Sharing (UNOS) database did report superior overall survival in patients transplanted for MAFLD, however, in the sub-population who received transplant for HCC, there was no difference in overall survival by liver disease aetiology [ 148 ]. Post-transplant tumour recurrence between MAFLD and non-MAFLD also appears similar, although a longer time to recurrence (22.6 vs 13.3 months) has been reported in MAFLD [ 149 ].

Outcomes post-systemic therapy

The treatment landscape for advanced HCC has changed dramatically and there is growing interest in the influence of liver disease aetiology on the efficacy of systemic therapy. Sorafenib was the first multikinase inhibitor (MKI) approved for first line treatment of advanced HCC in 2008 following the SHARP trial showed an improvement in median survival and time to progression [ 150 ], followed by the REFLECT trial which showed non-inferiority of the MKI lenvatinib in 2018 [ 151 ]. Immunotherapy subsequently emerged as first line therapy in advanced-stage HCC following the IMbrave150 trial which showed superior overall and progression free survival with anti-programmed cell death-ligand 1 (PD-L1) atezolizumab in combination with anti-vascular endothelial growth factor (VEGF) bevacizumb compared to sorafenib [ 152 ]. More recently, the HIMALAYA trial demonstrated the efficacy of a dual immunotherapy approach with combination anti-cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) tremelimumab plus durvalumab (anti-PD-L1) with superior overall survival compared to sorafenib [ 153 ], establishing a new first line option. Another phase III study, COSMIC-312, compared atezolizumab in combination with the MKI cabozantinib to sorafenib and found an improvement in progression free survival but no overall survival benefit over sorafenib [ 154 ]. Interestingly, the results from these recent trials did suggest a differing efficacy of immunotherapy depending on the aetiology of liver disease. COSMIC-312 reported that overall survival appearing longer in the immunotherapy arm in patients with HBV (HR 0.53 95% CI 0.33–0.87) but not with non-viral aetiology (HR 1.18 95% CI 0.78–1.79). Likewise IMbrave150 reported a beneficial effect of immunotherapy in patients with HBV (HR 0.51 95% CI 0.32–0.81) and HCV (HR 0.43 95% CI 0.22–0.87) but not in non-viral HCC (0.91 95% CI 0.52–1.60).

Pfister et al. proposed a mechanism for this observation, by reporting an increased population of hepatic CD8 + PD1 + T cells in MeSH with features of exhaustion, lacking in immune surveillance functions and with tissue damaging functions. In pre-clinical models, prophylactic treatment with anti-PD-1 therapy expanded this CD8 + PD1 + population and led to an increase in HCC, while anti-PD-1 treatment in MeSH-HCC pre-clinical models also expanded this population in tumours but without tumour regression.

The investigators performed a meta-analysis of three large phase III RCTs which reported overall survival data for immunotherapy for advanced HCC (IMbrave150, KEYNOTE-240 and CheckMate-459) and reported superior survival of immunotherapy compared to the control arm overall (HR 0.77, 95% CI 0.63–0.94), and in subgroups with HBV-related HCC ( n = 574, P = 0.0008) and HCV-related HCC ( n = 345, P = 0.04), but not in patients with non-viral HCC ( n = 737, P = 0.39) [ 93 ]. A subsequent meta-analysis of five RCTs (IMbrave150, COSMIC-312, CheckMate 459, KEYNOTE-240 and HIMALAYA) also concluded that viral HCC responds better to immunotherapy compared to non-viral aetiology ( P * = 0.0469) [ 95 ].

Real world data from a recent retrospective analysis of prospectively collected data from Italy, Japan, Republic of Korea and UK likewise reported that lenvatinib was associated with superior overall survival (aHR 0.65 95% CI 0.44–0.95) and progression free survival (aHR 0.67 95% CI 0.51–0.86) compared to atezolizumab and bevacizumab in advanced HCC, which was driven by superior overall survival in patients with MAFLD (HR 0.46 0.26–0.84) and MeSH (HR 0.55 95% CI 0.38–0.82) [ 155 ]. The results were consistent following a propensity matched analysis. Similarly, an international study from Japan and Italy reported that in a cohort of 320 patients with advanced HCC treated with lenvatinib, MAFLD aetiology was associated with significantly longer overall survival (median 21.1 vs 15.1 months). It is difficult to conclude whether this was due to a differential response to lenvatinib or to other between-group differences such as treatment duration, liver function or comorbidities [ 156 ]. Caution is necessary when drawing conclusions from retrospective analyses. Furthermore, it should be emphasised that the RCTs tend to report data from a “non-viral HCC” subgroup which includes both MAFLD, ARLD and potentially other rarer liver diseases. Also of note, the HIMALAYA trial did report improved overall survival in the immunotherapy arm for non-viral HCC (HR 0.74 95% CI 0.57–0.95) [ 153 ]. Currently, none of the major society guidelines recommend any significant differences in the management of MAFLD vs non-MAFLD HCC [ 114 , 157 , 158 ], however, these results highlight the need for well-designed prospective studies to determine the clinical impact of underlying aetiology on responsiveness to treatment. Indeed, in the era of precision medicine, other biomarkers as predictors of disease response beyond liver disease aetiology are lacking and desperately needed.

MAFLD HCC screening

Surveillance is recommended in patients at high risk of HCC due to the differential prognosis based on HCC stage at time of diagnosis. A 2022 meta-analysis of 59 studies reported that screening was associated with earlier stage detection (RR 1.86, 95% CI 1.73–1.98) and improved overall survival (HR 0.64, 95% CI 0.59–0.69) in patients with cirrhosis [ 159 ]. Screening is generally considered to be cost effective in those with an estimated yearly incidence of 1–1.5% [ 114 ], albeit this is context and country cost dependent. Thus, despite there being no studies specifically examining screening in cirrhotic MAFLD populations, it is widely recommended that these patients undergo screening given a reported HCC incidence of 0.9 – 2.6% [ 2 , 23 , 24 , 114 , 157 , 158 ].

It is well recognised that a significant proportion of HCC in patients with MAFLD occurs in the absence of cirrhosis, estimated to be 38% in a 2018 meta-analysis [ 25 ]. This is a function of the high global prevalence of non-cirrhotic MAFLD. There is a substantially reduced annual HCC risk amongst non-cirrhotic individuals and routine screening in this population is not recommended [ 160 ]. There is also limited data regarding the benefit of screening of patients with F3 fibrosis. Of note, a Veterans Health Administration cohort study found an annual HCC incidence of > 1% in individuals with a FIB-4 score > 2.67, irrespective of a known cirrhosis diagnosis, suggesting this to be a population that may benefit from screening [ 26 ]. There is a need therefore for validated risk stratification models to identify non-cirrhotic patients with MAFLD who will benefit from screening, given that current screening algorithms will continue to result in a high proportion of MAFLD HCC detected outside of routine surveillance.

Society guidelines currently recommend 6 monthly transabdominal ultrasound surveillance with or without serum AFP measurement as a surveillance strategy [ 114 , 157 , 158 ]. However, the inherent limitations of ultrasound in terms of its sensitivity and operator dependency are amplified in patients with MAFLD. A meta-analysis of 32 studies reported a sensitivity of ultrasound of only 47% for early-stage HCC [ 161 ]. Furthermore, a retrospective cohort study on 941 patients undergoing regular surveillance for HCC found that 20.3% of ultrasound examinations were inadequate to exclude HCC, with body mass index category (OR 1.67) and MAFLD aetiology (OR 2.87) both independent predictors of an inadequate examination [ 162 ]. Computed tomography (CT) imaging as an alternative is limited primarily by increased cost, risk of contrast-related complications and requirement for repeated exposures to ionising radiation. Magnetic resonance imaging (MRI) with liver specific contrast has similarly been shown to have improved sensitivity for very early-stage HCC compared to ultrasound (84.8% vs 27.3%) with a lower false positive rate in patients with advanced cirrhosis at high risk of HCC [ 163 ]. However, this strategy may not be cost effective or feasible in most resource limited settings. The use of abbreviated non-contrast MRI (NC-MRI) protocols may be advantageous over conventional MRI protocols in terms of time and cost, with a typical scan time of 15–20 min compared to 40–45 min for conventional MRI protocol. A meta-analysis reported a pooled sensitivity of 77.1% for lesions < 2 cm with NC-MRI which compares favourably to 47% reported by a previous meta-analysis of US [ 161 , 164 ], thus NC-MRI as a surveillance tool appears promising.

Use of serological biomarker panels are another surveillance strategy to overcome the current limitations, of which GALAD (combining gender, age, AFP, AFP-L3%, and DCP) is perhaps the most mature in terms of validation. A case–control study of 125 patients in Germany with HCC due to MeSH showed that GALAD had a sensitivity of 68% and specificity of 95% with AUC of 0.91 for detecting HCC within Milan criteria [ 165 ]. However, these results require further validation. Liquid biopsy techniques, often focussing on DNA methylation panels arising from circulating tumour cells have also been studied and show promising results [ 166 ], likewise identification of circulating lipid metabolite signatures to identify MAFLD HCC may be another promising strategy [ 167 ]. Improved surveillance methods are a major unmet need to improve the dismal proportion (32%) of MAFLD HCC detected on surveillance [ 142 ].

The obesity epidemic has resulted in the HCC landscape evolving from one in which HCC is concentrated amongst high-risk populations with easily identifiable risk factors, to one of increasing prevalence amongst “low risk” populations. MAFLD HCC presents unique challenges in terms of identifying at risk populations, surveillance, as well as management of HCC, their underlying liver disease and comorbidities. Furthermore, the increasing prevalence of MAFLD amongst patients with other liver diseases necessitates a more holistic approach to identifying and managing multiple concurrent interacting liver diseases. Hopefully, the MAFLD framework will facilitate this paradigm shift moving forward.

Rumgay H, Arnold M, Ferlay J, et al. Global burden of primary liver cancer in 2020 and predictions to 2040. J Hepatol. 2022;77:1598–606.

Article PubMed PubMed Central Google Scholar

Huang DQ, El-Serag HB, Loomba R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2021;18:223–38.

Article PubMed Google Scholar

Eslam M, Sanyal AJ, George J, et al. MAFLD: A Consensus-Driven Proposed Nomenclature for Metabolic Associated Fatty Liver Disease. Gastroenterology. 2020;158:1999-2014.e1.

Article CAS PubMed Google Scholar

Kawaguchi T, Tsutsumi T, Nakano D, et al. MAFLD enhances clinical practice for liver disease in the Asia-Pacific region. Clin Mol Hepatol. 2022;28:150–63.

Gofton C, Upendran Y, Zheng M-H, et al. MAFLD: How is it different from NAFLD? Clin Mol Hepatol. 2023;29:S17–31.

Eslam M, Newsome PN, Sarin SK, et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J Hepatol. 2020;73:202–9.

Ayada I, Van Kleef LA, Alferink LJM, et al. Systematically comparing epidemiological and clinical features of MAFLD and NAFLD by meta-analysis: focusing on the non-overlap groups. Liver Int. 2022;42:277–87.

Huang Q, Zou X, Wen X, et al. NAFLD or MAFLD: Which Has Closer Association With All-Cause and Cause-Specific Mortality?-Results From NHANES III. Front Med (Lausanne). 2021;8:693507.

Kim D, Konyn P, Sandhu KK, et al. Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United States. J Hepatol. 2021;75:1284–91.

Nguyen VH, Le MH, Cheung RC, et al. Differential Clinical Characteristics and Mortality Outcomes in Persons With NAFLD and/or MAFLD. Clin Gastroenterol Hepatol. 2021;19:2172-81.e6.

Chen Y-G, Yang C-W, Chung C-H, et al. The association between metabolic risk factors, nonalcoholic fatty liver disease, and the incidence of liver cancer: a nationwide population-based cohort study. Hep Intl. 2022;16:807–16.

Article Google Scholar

Meroni M, Longo M, Paolini E, et al. MAFLD definition underestimates the risk to develop HCC in genetically predisposed patients. J Intern Med. 2022;291:374–6.

Liu Z, Suo C, Shi O, et al. The health impact of MAFLD, a novel disease cluster of NAFLD, is amplified by the integrated effect of fatty liver disease-related genetic variants. Clin Gastroenterol Hepatol. 2022;20:e855–75.

Xia M, Zeng H, Wang S, et al. Insights into contribution of genetic variants towards the susceptibility of MAFLD revealed by the NMR-based lipoprotein profiling. J Hepatol. 2021;74:974–7.

Stender S, Kozlitina J, Nordestgaard BG, et al. Adiposity amplifies the genetic risk of fatty liver disease conferred by multiple loci. Nat Genet. 2017;49:842–7.

Article CAS PubMed PubMed Central Google Scholar

Xie X, Guo B, Xiao X, et al. Healthy dietary patterns and metabolic dysfunction-associated fatty liver disease in less-developed ethnic minority regions: a large cross-sectional study. BMC Public Health. 2022;22:118.

Abarca-Gómez L, Abdeen ZA, Hamid ZA, et al. Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128·9 million children, adolescents, and adults. The Lancet. 2017;390:2627–42.

Asrani SK, Devarbhavi H, Eaton J, et al. Burden of liver diseases in the world. J Hepatol. 2019;70:151–71.

Chan KE, Koh TJL, Tang ASP, et al. Global Prevalence and Clinical Characteristics of Metabolic-associated Fatty Liver Disease: A Meta-Analysis and Systematic Review of 10 739 607 Individuals. J Clin Endocrinol Metab. 2022;107:2691–700.

World Obesity Federation. World Obesity Atlas 2023.

Liu J, Ayada I, Zhang X, et al. Estimating global prevalence of metabolic dysfunction-associated fatty liver disease in overweight or obese adults. Clin Gastroenterol Hepatol. 2022;20:e573–82.

Lin S, Huang J, Wang M, et al. Comparison of MAFLD and NAFLD diagnostic criteria in real world. Liver Int. 2020;40:2082–9.

Ascha MS, Hanouneh IA, Lopez R, et al. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology. 2010;51:1972–8.

Sanyal AJ, Banas C, Sargeant C, et al. Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C. Hepatology. 2006;43:682–9.

Stine JG, Wentworth BJ, Zimmet A, et al. Systematic review with meta-analysis: risk of hepatocellular carcinoma in non-alcoholic steatohepatitis without cirrhosis compared to other liver diseases. Aliment Pharmacol Ther. 2018;48:696–703.

Kanwal F, Kramer JR, Mapakshi S, et al. Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease. Gastroenterology. 2018;155:1828-37.e2.

Alexander M, Loomis AK, van der Lei J, et al. Risks and clinical predictors of cirrhosis and hepatocellular carcinoma diagnoses in adults with diagnosed NAFLD: real-world study of 18 million patients in four European cohorts. BMC Med. 2019;17:95.

van Kleef LA, Ayada I, Alferink LJM, et al. Metabolic dysfunction-associated fatty liver disease improves detection of high liver stiffness: The Rotterdam Study. Hepatology. 2022;75:419–29.

Yamamura S, Eslam M, Kawaguchi T, et al. MAFLD identifies patients with significant hepatic fibrosis better than NAFLD. Liver Int. 2020;40:3018–30.

Piscaglia F, Svegliati-Baroni G, Barchetti A, et al. Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: A multicenter prospective study. Hepatology. 2016;63:827–38.

Vitale A, Svegliati-Baroni G, Ortolani A, et al. Epidemiological trends and trajectories of MAFLD-associated hepatocellular carcinoma 2002-2033: the ITA.LI.CA database. Gut. 2023;72:141–52.

Myers S, Neyroud-Caspar I, Spahr L, et al. NAFLD and MAFLD as emerging causes of HCC: A populational study. JHEP Rep. 2021;3:100231.

Enomoto H, Ueno Y, Hiasa Y, et al. The transition in the etiologies of hepatocellular carcinoma-complicated liver cirrhosis in a nationwide survey of Japan. J Gastroenterol. 2021;56:158–67.

Golabi P, Paik JM, AlQahtani S, et al. Burden of non-alcoholic fatty liver disease in Asia, the Middle East and North Africa: data from global burden of disease 2009–2019. J Hepatol. 2021;75:795–809.

Tran NH. Shifting epidemiology of hepatocellular carcinoma in far eastern and southeast Asian patients: explanations and implications. Curr Oncol Rep. 2022;24:187–93.

Zhang CH, Cheng Y, Zhang S, et al. Changing epidemiology of hepatocellular carcinoma in Asia. Liver Int. 2022;42:2029–41.

Ye Q, Zou B, Yeo YH, et al. Global prevalence, incidence, and outcomes of non-obese or lean non-alcoholic fatty liver disease: a systematic review and meta-analysis. The Lancet Gastroenterology & Hepatology. 2020;5:739–52.

Cruz ACD, Bugianesi E, George J, et al. 379 characteristics and long-term prognosis of lean patients with nonalcoholic fatty liver disease. Gastroenterology. 2014;5:S-909.

Hagström H, Nasr P, Ekstedt M, et al. Risk for development of severe liver disease in lean patients with nonalcoholic fatty liver disease: A long-term follow-up study. Hepatol Commun. 2018;2:48–57.

Nabi O, Lapidus N, Boursier J, et al. Lean individuals with NAFLD have more severe liver disease and poorer clinical outcomes (NASH-CO Study). Hepatology. 2023. https://doi.org/10.1097/HEP.0000000000000329 .

Almomani A, Kumar P, Onwuzo S, et al. Epidemiology and prevalence of lean nonalcoholic fatty liver disease and associated cirrhosis, hepatocellular carcinoma, and cardiovascular outcomes in the United States: a population-based study and review of literature. J Gastroenterol Hepatol. 2023;38:269–73.

Younes R, Govaere O, Petta S, et al. Caucasian lean subjects with non-alcoholic fatty liver disease share long-term prognosis of non-lean: time for reappraisal of BMI-driven approach? Gut. 2022;71:382–90.

Lazo M, Nwankwo C, Daya NR, et al. Confluence of epidemics of Hepatitis C, Diabetes, Obesity, and Chronic Kidney disease in the United States population. Clin Gastroenterol Hepatol. 2017;15:1957-64.e7.

Pelusi S, Bianco C, Colombo M, et al. Metabolic dysfunction outperforms ultrasonographic steatosis to stratify hepatocellular carcinoma risk in patients with advanced hepatitis C cured with direct-acting antivirals. Liver Int. 2023.

Ji D, Chen G-f, Niu X-X, et al. Non-alcoholic fatty liver disease is a risk factor for occurrence of hepatocellular carcinoma after sustained virologic response in chronic hepatitis C patients: A prospective four-years follow-up study. Metabolism Open. 2021;10:100090.

van der Meer AJ, Feld JJ, Hofer H, et al. Risk of cirrhosis-related complications in patients with advanced fibrosis following hepatitis C virus eradication. J Hepatol. 2017;66:485–93.

Benhammou JN, Moon AM, Pisegna JR, et al. Nonalcoholic fatty liver disease risk factors affect liver-related outcomes after direct-acting antiviral treatment for hepatitis C. Dig Dis Sci. 2021;66:2394–406.

Lockart I, Yeo MGH, Hajarizadeh B, et al. HCC incidence after hepatitis C cure among patients with advanced fibrosis or cirrhosis: a meta-analysis. Hepatology. 2022;76:139–54.

Fouad Y, Lazarus JV, Negro F, et al. MAFLD considerations as a part of the global hepatitis C elimination effort: an international perspective. Aliment Pharmacol Ther. 2021;53:1080–9.

Joo EJ, Chang Y, Yeom JS, et al. Hepatitis B virus infection and decreased risk of nonalcoholic fatty liver disease: A cohort study. Hepatology. 2017;65:828–35.

Jiang D, Chen C, Liu X, et al. Concurrence and impact of hepatic steatosis on chronic hepatitis B patients: a systematic review and meta-analysis. Annal Transl Med. 2021;9:1718.

van der Spek DPC, Katwaroe WK, van Kleef LA, et al. Time-trends in disease characteristics and comorbidities in patients with chronic hepatitis B in the period 1980–2020. Eur J Intern Med. 2023;107:86–92.

Tseng CH, Hsu YC, Ho HJ, et al. Increasing age and nonliver comorbidities in patients with chronic hepatitis B in Taiwan: a nationwide population-based analysis. Dig Dis. 2021;39:266–74.

Liu A, Le A, Zhang J, et al. Increasing co-morbidities in chronic hepatitis B patients: experience in primary care and referral practices during 2000–2015. Clin Transl Gastroenterol. 2018;9:e141.

Oh H, Jun DW, Lee IH, et al. Increasing comorbidities in a South Korea insured population-based cohort of patients with chronic hepatitis B. Aliment Pharmacol Ther. 2020;52:371–81.

Wang M-M, Wang G-S, Shen F, et al. Hepatic steatosis is highly prevalent in hepatitis B patients and negatively associated with virological factors. Dig Dis Sci. 2014;59:2571–9.

Hui RWH, Seto WK, Cheung KS, et al. Inverse relationship between hepatic steatosis and hepatitis B viremia: results of a large case-control study. J Viral Hepatitis. 2018;25:97–104.

Article CAS Google Scholar

Van Kleef LA, Choi HSJ, Brouwer WP, et al. Metabolic dysfunction-associated fatty liver disease increases risk of adverse outcomes in patients with chronic hepatitis B. JHEP Reports. 2021;3:100350.

Lin YP, Wang PM, Chuang CH, et al. Metabolic risks are increasing in Non-B Non-C Early-Stage hepatocellular carcinoma: a 10-year follow-up study. Front Oncol. 2022;12:816472.

Xue J, Wang QX, Xiao HM, et al. Impact of metabolic dysfunction associated fatty liver disease on the prognosis of patients with hepatitis b virus-related hepatocellular carcinoma based on propensity score matching analysis. Cancer Manag Res. 2022;14:2193–202.

Yun B, Ahn SH, Oh J, et al. Effect of metabolic dysfunction-associated fatty liver disease on liver cancer risk in a population with chronic hepatitis B virus infection: a nationwide study. Hepatol Res. 2022;52:975–84.

Tan Y, Zhang X, Zhang W, et al. The influence of metabolic syndrome on the risk of hepatocellular carcinoma in patients with chronic hepatitis B infection in Mainland China. Cancer Epidemiol Biomarkers Prev. 2019;28:2038–46.

Yun B, Ahn SH, Oh J, et al. Prognostic Impact of MAFLD Following Surgical Resection of Hepatitis B Virus-Related Hepatocellular Carcinoma: A Nationwide Cohort Study. Cancers (Basel). 2022;14.

Huang DQ, Mathurin P, Cortez-Pinto H, et al. Global epidemiology of alcohol-associated cirrhosis and HCC: trends, projections and risk factors. Nat Rev Gastroenterol Hepatol. 2023;20:37–49.

Loomba R, Yang HI, Su J, et al. Synergism between obesity and alcohol in increasing the risk of hepatocellular carcinoma: a prospective cohort study. Am J Epidemiol. 2013;177:333–42.

N’Kontchou G, Paries J, Htar MTT, et al. Risk Factors for Hepatocellular Carcinoma in Patients With Alcoholic or Viral C Cirrhosis. Clin Gastroenterol Hepatol. 2006;4:1062–8.

Nair S, Mason A, Eason J, et al. Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis? Hepatology. 2002;36:150–5.

Reggidori N, Bucci L, Santi V, et al. Lack of substantial improvements in the landscape of alcohol-related hepatocellular carcinoma in the last 15 years: The need to improve cancer prevention and surveillance. Dig Liver Dis. 2023;55:S16–7.

Vanlerberghe BTK, van Malenstein H, Sainz-Bariga M, et al. Utility and prognostic value of diagnosing MAFLD in patients undergoing liver transplantation for alcohol-related liver disease. Clin Transpl. 2023.

Staufer K, Huber-Schönauer U, Strebinger G, et al. Ethyl glucuronide in hair detects a high rate of harmful alcohol consumption in presumed non-alcoholic fatty liver disease. J Hepatol. 2022;77:918–30.

Zhu L, Baker SS, Gill C, et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: A connection between endogenous alcohol and NASH. Hepatology. 2013;57:601–9.

Åberg F, Färkkilä M. Drinking and obesity: alcoholic liver disease/nonalcoholic fatty liver disease interactions. Semin Liver Dis. 2020;40:154–62.

Losurdo G, Castellaneta A, Rendina M, et al. Systematic review with meta-analysis: de novo non-alcoholic fatty liver disease in liver-transplanted patients. Aliment Pharmacol Ther. 2018;47:704–14.

Lin Y-P, Lin S-H, Wang C-C, et al. Impact of MAFLD on HBV-related stage 0/A hepatocellular carcinoma after curative resection. J Personal Med. 2021;11:684.

Conci S, Cipriani F, Donadon M, et al. Hepatectomy for Metabolic Associated Fatty Liver Disease (MAFLD) related HCC: propensity case-matched analysis with viral- and alcohol-related HCC. Eur J Surg Oncol. 2022;48:103–12.

Kim MN, Han K, Yoo J, et al. Metabolic dysfunction-associated fatty liver disease subgroups and risk of hepatocellular carcinoma and mortality in patients with chronic viral hepatitis. Hep Intl. 2022;16(Supplement 1):S60.

Google Scholar

Xue J, Wang Q-X, Xiao H-M, et al. Impact of metabolic dysfunction associated fatty liver disease on the prognosis of patients with hepatitis B virus-related hepatocellular carcinoma based on propensity score matching analysis. Cancer Manage Res. 2022;14:2193–202.

Ning Z, Guo X, Liu X, et al. USP22 regulates lipidome accumulation by stabilizing PPARγ in hepatocellular carcinoma. Nat Commun. 2022;13:2187.

Daugherity EK, Balmus G, Al Saei A, et al. The DNA damage checkpoint protein ATM promotes hepatocellular apoptosis and fibrosis in a mouse model of non-alcoholic fatty liver disease. Cell Cycle. 2012;11:1918–28.

Ng SWK, Rouhani FJ, Brunner SF, et al. Convergent somatic mutations in metabolism genes in chronic liver disease. Nature. 2021;598:473–8.

Grohmann M, Wiede F, Dodd GT, et al. Obesity Drives STAT-1-Dependent NASH and STAT-3-Dependent HCC. Cell. 2018;175:1289-306.e20.

Font-Burgada J, Sun B, Karin M. Obesity and cancer: the oil that feeds the flame. Cell Metab. 2016;23:48–62.

Kucukoglu O, Sowa JP, Mazzolini GD, et al. Hepatokines and adipokines in NASH-related hepatocellular carcinoma. J Hepatol. 2021;74:442–57.

Sharma D, Wang J, Fu PP, et al. Adiponectin antagonizes the oncogenic actions of leptin in hepatocellular carcinogenesis. Hepatology. 2010;52:1713–22.

Garofalo C, Surmacz E. Leptin and cancer. J Cell Physiol. 2006;207:12–22.

Ma C, Kesarwala AH, Eggert T, et al. NAFLD causes selective CD4+ T lymphocyte loss and promotes hepatocarcinogenesis. Nature. 2016;531:253–7.

Rakhra K, Bachireddy P, Zabuawala T, et al. CD4+ T Cells contribute to the remodeling of the microenvironment required for sustained tumor regression upon oncogene inactivation. Cancer Cell. 2010;18:485–98.

Gomes AL, Teijeiro A, Buren S, et al. Metabolic inflammation-associated IL-17A causes non-alcoholic steatohepatitis and hepatocellular carcinoma. Cancer Cell. 2016;30:161–75.

Govaere O, Petersen SK, Martinez-Lopez N, et al. Macrophage scavenger receptor 1 mediates lipid-induced inflammation in non-alcoholic fatty liver disease. J Hepatol. 2022;76:1001–12.

Dudek M, Pfister D, Donakonda S, et al. Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH. Nature. 2021;592:444–9.

Pfister D, Núñez NG, Pinyol R, et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature. 2021;592:450–6.

Makkonen J, Pietiläinen KH, Rissanen A, et al. Genetic factors contribute to variation in serum alanine aminotransferase activity independent of obesity and alcohol: a study in monozygotic and dizygotic twins. J Hepatol. 2009;50:1035–42.

Llovet JM, Willoughby CE, Singal AG, et al. Nonalcoholic steatohepatitis-related hepatocellular carcinoma: pathogenesis and treatment. Nat Rev Gastroenterol Hepatol. 2023.

Liu YL, Patman GL, Leathart JBS, et al. Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma. J Hepatol. 2014;61:75–81.

Liu Y-L, Reeves HL, Burt AD, et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nat Commun. 2014;5:4309.

Prill S, Caddeo A, Baselli G, et al. The TM6SF2 E167K genetic variant induces lipid biosynthesis and reduces apolipoprotein B secretion in human hepatic 3D spheroids. Sci Rep. 2019;9:11585.

Donati B, Dongiovanni P, Romeo S, et al. MBOAT7 rs641738 variant and hepatocellular carcinoma in non-cirrhotic individuals. Sci Rep. 2017;7:4492.

Kawaguchi T, Shima T, Mizuno M, et al. Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers. PLoS ONE. 2018;13:e0185490.

Bianco C, Jamialahmadi O, Pelusi S, et al. Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores. J Hepatol. 2021;74:775–82.

Jadhav K, Cohen TS. Can you trust your gut? Implicating a disrupted intestinal microbiome in the progression of NAFLD/NASH. Front Endocrinol. 2020;11:592157.

Aron-Wisnewsky J, Vigliotti C, Witjes J, et al. Gut microbiota and human NAFLD: disentangling microbial signatures from metabolic disorders. Nat Rev Gastroenterol Hepatol. 2020;17:279–97.

Rainer F, Horvath A, Sandahl TD, et al. Soluble CD163 and soluble mannose receptor predict survival and decompensation in patients with liver cirrhosis, and correlate with gut permeability and bacterial translocation. Aliment Pharmacol Ther. 2018;47:657–64.

Lin R-S, Lee F-Y, Lee S-D, et al. Endotoxemia in patients with chronic liver diseases: relationship to severity of liver diseases, presence of esophaegeal varices, and hyperdynamic circulation. J Hepatol. 1995;22:165–72.

Luther J, Garber JJ, Khalili H, et al. Hepatic injury in nonalcoholic steatohepatitis contributes to altered intestinal permeability. Cell Mol Gastroenterol Hepatol. 2015;1(222–32):e2.

Parthasarathy G, Revelo X, Malhi H. Pathogenesis of Nonalcoholic Steatohepatitis: An Overview. Hepatology Communications. 2020;4:478–92.

Behary J, Amorim N, Jiang XT, et al. Gut microbiota impact on the peripheral immune response in non-alcoholic fatty liver disease related hepatocellular carcinoma. Nat Commun. 2021;12:187.

Jiao N, Baker SS, Chapa-Rodriguez A, et al. Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD. Gut. 2018;67:1881–91.

Yoshimoto S, Loo TM, Atarashi K, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature. 2013;499:97–101.

Lange NF, Radu P, Dufour JF. Prevention of NAFLD-associated HCC: role of lifestyle and chemoprevention. J Hepatol. 2021;75:1217–27.

Petroni ML, Brodosi L, Marchignoli F, et al. Moderate alcohol intake in Non-Alcoholic fatty liver disease: to drink or not to drink? Nutrients. 2019;11:3048.

Plaz Torres MC, Jaffe A, Perry R, et al. Diabetes medications and risk of HCC. Hepatology. 2022;76:1880–97.

Galle PR, Forner A, Llovet JM, et al. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol. 2018;69:182–236.

Ono M, Fujita K, Kobayashi K, et al. Influence of diabetes mellitus and effectiveness of metformin on hepatocellular carcinoma. Hepatol Res. 2023;53(7):579–94.

Ma S, Zheng Y, Xiao Y, et al. Meta-analysis of studies using metformin as a reducer for liver cancer risk in diabetic patients. Medicine. 2017;96:e6888.

Simon TG, Duberg A-S, Aleman S, et al. Association of Aspirin with Hepatocellular Carcinoma and Liver-Related Mortality. N Engl J Med. 2020;382:1018–28.

Memel ZN, Arvind A, Moninuola O, et al. Aspirin use is associated with a reduced incidence of hepatocellular carcinoma: a systematic review and meta-analysis. Hepatol Commun. 2021;5:133–43.

Goh MJ, Sinn DH. Statin and aspirin for chemoprevention of hepatocellular carcinoma: Time to use or wait further? Clin Mol Hepatol. 2022;28:380–95.

Bosch J, Gracia-Sancho J, Abraldes JG. Cirrhosis as new indication for statins. Gut. 2020;69:953–62.

Simon TG, Duberg A-S, Aleman S, et al. Lipophilic statins and risk for hepatocellular carcinoma and death in patients with chronic viral hepatitis: results from a nationwide swedish population. Ann Intern Med. 2019;171:318–27.

Nakano D, Kawaguchi T, Iwamoto H, et al. Effects of canagliflozin on growth and metabolic reprograming in hepatocellular carcinoma cells: Multi-omics analysis of metabolomics and absolute quantification proteomics (iMPAQT). PLoS ONE. 2020;15:e0232283.

Jojima T, Wakamatsu S, Kase M, et al. The SGLT2 inhibitor canagliflozin prevents carcinogenesis in a mouse model of diabetes and non-alcoholic steatohepatitis-related hepatocarcinogenesis: association with SGLT2 expression in hepatocellular carcinoma. Int J Mol Sci. 2019;20:5237.

Kaji K, Nishimura N, Seki K, et al. Sodium glucose cotransporter 2 inhibitor canagliflozin attenuates liver cancer cell growth and angiogenic activity by inhibiting glucose uptake. Int J Cancer. 2018;142:1712–22.

Barone M, Viggiani MT, Losurdo G, et al. Systematic review: Renin-angiotensin system inhibitors in chemoprevention of hepatocellular carcinoma. World J Gastroenterol. 2019;25:2524–38.

Zhang X, Wong GL, Yip TC, et al. Angiotensin-converting enzyme inhibitors prevent liver-related events in nonalcoholic fatty liver disease. Hepatology. 2022;76:469–82.

Yoshiji H, Noguchi R, Toyohara M, et al. Combination of vitamin K2 and angiotensin-converting enzyme inhibitor ameliorates cumulative recurrence of hepatocellular carcinoma. J Hepatol. 2009;51:315–21.

Yoshiji H. Combination of branched-chain amino acids and angiotensin-converting enzyme inhibitor suppresses the cumulative recurrence of hepatocellular carcinoma: A randomized control trial. Oncol Rep. 2011;26(6):1547–53.

CAS PubMed Google Scholar

Bravi F, Tavani A, Bosetti C, et al. Coffee and the risk of hepatocellular carcinoma and chronic liver disease. Eur J Cancer Prev. 2017;26:368–77.

Salomone F, Godos J, Zelber-Sagi S. Natural antioxidants for non-alcoholic fatty liver disease: molecular targets and clinical perspectives. Liver Int. 2016;36:5–20.

Arvind A, Memel ZN, Philpotts LL, et al. Thiazolidinediones, alpha-glucosidase inhibitors, meglitinides, sulfonylureas, and hepatocellular carcinoma risk: A meta-analysis. Metabolism. 2021;120:154780.

Galli A, Crabb DW, Ceni E, et al. Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro. Gastroenterology. 2002;122:1924–40.

Yang Y, Zhao L-H, Huang B, et al. Pioglitazone, a PPARγ agonist, inhibits growth and invasion of human hepatocellular carcinoma via blockade of the rage signaling. Mol Carcinog. 2015;54:1584–95.

Hsu W-H, Sue S-P, Liang H-L, et al. Dipeptidyl peptidase 4 inhibitors decrease the risk of hepatocellular carcinoma in patients with chronic hepatitis C infection and type 2 diabetes mellitus: a nationwide study in Taiwan. Front Public Health. 2021;9: 711723.

Kawakubo M, Tanaka M, Ochi K, et al. Dipeptidyl peptidase-4 inhibition prevents nonalcoholic steatohepatitis-associated liver fibrosis and tumor development in mice independently of its anti-diabetic effects. Sci Rep. 2020;10:983.

Kawaguchi T, Nakano D, Koga H, et al. Effects of a DPP4 Inhibitor on Progression of NASH-related HCC and the p62/ Keap1/Nrf2-Pentose Phosphate Pathway in a Mouse Model. Liver Cancer. 2019;8:359–72.

Nishina S, Yamauchi A, Kawaguchi T, et al. Dipeptidyl peptidase 4 inhibitors reduce hepatocellular carcinoma by activating lymphocyte chemotaxis in mice. Cell Mol Gastroenterol Hepatol. 2019;7:115–34.

Simon TG, Patorno E, Schneeweiss S. Glucagon-like peptide-1 receptor agonists and hepatic decompensation events in patients with cirrhosis and diabetes. Clin Gastroenterol Hepatol. 2022;20:1382-93.e19.

Kojima M, Takahashi H, Kuwashiro T, et al. Glucagon-like peptide-1 receptor agonist prevented the progression of hepatocellular carcinoma in a mouse model of nonalcoholic steatohepatitis. Int J Mol Sci. 2020;21:5722.

Zhou M, Mok MTS, Sun H, et al. The anti-diabetic drug exenatide, a glucagon-like peptide-1 receptor agonist, counteracts hepatocarcinogenesis through cAMP–PKA–EGFR–STAT3 axis. Oncogene. 2017;36:4135–49.

Li Q, Xue A, Li Z, et al. Liraglutide promotes apoptosis of HepG2 cells by activating JNK signaling pathway. Eur Rev Med Pharmacol Sci. 2019;23:3520–6.

Tan DJH, Ng CH, Lin SY, et al. Clinical characteristics, surveillance, treatment allocation, and outcomes of non-alcoholic fatty liver disease-related hepatocellular carcinoma: a systematic review and meta-analysis. Lancet Oncol. 2022;23:521–30.

Weinmann A, Alt Y, Koch S, et al. Treatment and survival of non-alcoholic steatohepatitis associated hepatocellular carcinoma. BMC Cancer. 2015;15:210.

Chen VL, Yeh ML, Yang JD, et al. Effects of cirrhosis and diagnosis scenario in metabolic-associated fatty liver disease-related hepatocellular carcinoma. Hepatol Commun. 2021;5:122–32.

Molinari M, Kaltenmeier C, Samra P-B, et al. Hepatic resection for hepatocellular carcinoma in nonalcoholic fatty liver disease: A systematic review and meta-analysis of 7226 patients. Annals of Surgery Open. 2021;2:e065.

Haldar D, Kern B, Hodson J, et al. Outcomes of liver transplantation for non-alcoholic steatohepatitis: A European Liver Transplant Registry study. J Hepatol. 2019;71:313–22.

Han MAT, Olivo R, Choi CJ, et al. De novo and recurrence of metabolic dysfunction-associated fatty liver disease after liver transplantation. World J Hepatol. 2021;13:1991–2004.

Wong RJ, Chou C, Bonham CA, et al. Improved survival outcomes in patients with non-alcoholic steatohepatitis and alcoholic liver disease following liver transplantation: an analysis of 2002–2012 United Network for Organ Sharing data. Clin Transplant. 2014;28:713–21.

Sadler EM, Mehta N, Bhat M, et al. Liver transplantation for NASH-related hepatocellular carcinoma versus non-NASH etiologies of hepatocellular carcinoma. Transplantation. 2018;102:640–7.

Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.

Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. The Lancet. 2018;391:1163–73.

Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020;382:1894–905.

Abou-Alfa GK, Lau G, Kudo M, et al. Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma. NEJM Evidence. 2022;1.

Kelley RK, Rimassa L, Cheng A-L, et al. Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23:995–1008.

Rimini M, Rimassa L, Ueshima K, et al. Atezolizumab plus bevacizumab versus lenvatinib or sorafenib in non-viral unresectable hepatocellular carcinoma: an international propensity score matching analysis. ESMO Open. 2022;7:100591.

Shimose S, Hiraoka A, Casadei-Gardini A, et al. The beneficial impact of metabolic dysfunction-associated fatty liver disease on lenvatinib treatment in patients with non-viral hepatocellular carcinoma. Hepatol Res. 2023;53:104–15.

Heimbach JK, Kulik LM, Finn RS, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018;67:358–80.

Omata M, Cheng A-L, Kokudo N, et al. Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hep Intl. 2017;11:317–70.

Singal AG, Zhang E, Narasimman M, et al. HCC surveillance improves early detection, curative treatment receipt, and survival in patients with cirrhosis: a meta-analysis. J Hepatol. 2022;77:128–39.

Natarajan Y, Kramer JR, Yu X, et al. Risk of cirrhosis and hepatocellular cancer in patients With NAFLD and normal liver enzymes. Hepatology. 2020;72:1242–52.

Tzartzeva K, Obi J, Rich NE, et al. Surveillance imaging and alpha fetoprotein for early detection of hepatocellular carcinoma in patients with cirrhosis: a meta-analysis. Gastroenterology. 2018;154:1706-18.e1.

Simmons O, Fetzer DT, Yokoo T, et al. Predictors of adequate ultrasound quality for hepatocellular carcinoma surveillance in patients with cirrhosis. Aliment Pharmacol Ther. 2017;45:169–77.

Kim SY, An J, Lim Y-S, et al. MRI with liver-specific contrast for surveillance of patients with cirrhosis at high risk of hepatocellular carcinoma. JAMA Oncol. 2017;3:456.

Chan MV, Huo YR, Trieu N, et al. Noncontrast MRI for hepatocellular carcinoma detection: a systematic review and meta-analysis – a potential surveillance tool? Clin Gastroenterol Hepatol. 2022;20:44-56.e2.

Best J, Bechmann LP, Sowa JP, et al. GALAD score detects early hepatocellular carcinoma in an international cohort of patients with nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2020;18:728-35.e4.

Chalasani NP, Porter K, Bhattacharya A, et al. Validation of a novel multitarget blood test shows high sensitivity to detect early stage hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2022;20:173-82.e7.

Lu H, George J, Eslam M, et al. Discriminatory changes in circulating metabolites as a predictor of hepatocellular cancer in patients with metabolic (Dysfunction) associated fatty liver disease. Liver Cancer. 2023;12:1–13.

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Crane, H., Gofton, C., Sharma, A. et al. MAFLD: an optimal framework for understanding liver cancer phenotypes. J Gastroenterol 58 , 947–964 (2023). https://doi.org/10.1007/s00535-023-02021-7

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Cold Spring Harb Perspect Med
v.8(9); 2018 Sep

Natural History, Clinical Manifestations, and Pathogenesis of Hepatitis A

Eui-cheol shin.

1 Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea

Sook-Hyang Jeong

2 Department of Internal Medicine, Seoul National University Bundang Hospital, College of Medicine, Seoul National University, Seongnam, Gyeonggido 13620, Republic of Korea

Hepatitis A virus (HAV) is transmitted by the fecal–oral route and is a major cause of acute viral hepatitis. The clinical manifestations of HAV infection range from asymptomatic infection to acute liver failure (ALF), but do not include progression to chronic hepatitis. Risk factors for severe acute hepatitis A are older age (>40 years) and preexisting liver disease. Some patients may show atypical clinical features such as relapsing hepatitis, prolonged cholestasis, or extrahepatic manifestations. Almost all hepatitis A patients spontaneously recover with supportive care. However, in the case of ALF (<1%), intensive care and urgent decision on liver transplantation are required. Liver injury during hepatitis A is not directly caused by HAV but is known to be caused by immune-mediated mechanisms. In this review, the natural history and clinical manifestations of hepatitis A are described. In addition, mechanisms of immunopathogenesis in hepatitis A are discussed.

Hepatitis A virus (HAV) is transmitted by the fecal–oral route and is a major cause of acute viral hepatitis, which can lead to acute liver failure (ALF) and mortality in severe cases. The number of global hepatitis A cases was ∼1.4 million with 27,731 deaths in 2010 ( Havelaar et al. 2015 ). HAV infection often causes symptomatic hepatitis in adults, whereas it tends to result in an asymptomatic subclinical infection in children. Following socioeconomic development and public health improvement, the global incidence of HAV infection has been decreasing. However, an increasing number of individuals are infected at older ages, leading to more severe clinical manifestations and greater disease burden ( Murphy et al. 2016 ). The clinical manifestations of HAV infection range from asymptomatic infection to ALF, and some patients show atypical features such as relapsing hepatitis or prolonged cholestatic hepatitis, as well as extrahepatic manifestations. In this review, we consider pitfalls in the diagnosis of hepatitis A, therapeutic considerations including predictors for urgent liver transplantation, and mechanisms of pathogenesis.

NATURAL HISTORY OF HEPATITIS A

HAV is highly stable in ambient temperatures and can withstand low pH, drying, and detergents. HAV inactivation requires heating foods (>85°C) for 1 min or disinfecting surfaces with a 1:100 dilution of sodium hypochlorite (household bleach) for 1 min ( Nainan et al. 2006 ). After ingestion of HAV through the fecal–oral route, HAV survives the acidic stomach environment and is ultimately delivered to the liver. Whether it first replicates at a primary site within the gastrointestinal tract is uncertain. HAV replicates in hepatocytes and is then secreted into bile and thus back into the gastrointestinal tract. It is finally excreted via feces or transferred to the liver through an enterohepatic cycle until virus neutralization ( Cuthbert 2001 ).

Following an incubation period of 15–50 days (mean, 30 days) after HAV infection, patients develop symptoms of acute hepatitis with elevated levels of serum aspartate/alanine aminotransferases (AST/ALTs) ( Fig. 1 ). Before symptoms, there are waves of viremia and copious amounts of fecal viral shedding. Feces are the primary source of HAV transmission because of their high viral load. In comparison, serum HAV concentrations are two or three log 10 units lower than in the feces ( Martin and Lemon 2006 ). Therefore, risk of transmission is highest during the prodromal phase before symptoms or biochemical manifestations. The virus is also shed in the saliva at even lower concentrations ( Amado Leon et al. 2015 ). Concordant with clinical hepatitis, anti-HAV immunoglobulin M (Ig)M and subsequently anti-HAV IgG appear in the serum and saliva, accompanied by a marked reduction of fecal virus shedding and viremia ( Fig. 1 ). Although anti-HAV IgM is detectable for up to 6 months, anti-HAV IgG persists, conferring lifelong immunity ( Normann et al. 2004 ).

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A typical course of hepatitis A. After a 3- to 5-week incubation period following hepatitis A virus (HAV) infection, patients develop symptoms of hepatitis with elevation of serum alanine aminotransferase (ALT) levels. Fecal virus shedding and viremia are present and peak during the incubation period. Anti-HAV antibodies appear in serum first as immunoglobulin (Ig)M and subsequently as IgG. Virus-specific T-cell responses coincide with the elevation of serum ALT levels.

CLINICAL MANIFESTATIONS OF HEPATITIS A

Clinical signs and symptoms of acute hepatitis a.

The clinical manifestations of HAV infection range from asymptomatic infection to ALF, but it does not progress to chronic hepatitis. Development of symptomatic hepatitis is associated with patient age. Relatively few children under 6 years of age (<30%) manifest hepatitis symptoms, whereas the majority of adults (>70%) develop symptoms that persist for 2–8 weeks ( Fig. 2 ) ( Armstrong and Bell 2002 ). The onset of hepatitis A is often abrupt with fever (18%–75%), malaise (52%–91%), nausea or vomiting (26%–87%), abdominal discomfort (37%–65%), and then dark urine (28%–94%) and jaundice. Less commonly, pruritus, diarrhea, arthralgia, or skin rash develop. When the patient seeks medical advice, the fever has usually disappeared. On physical examination, hepatomegaly (78%) and jaundice (40%–80%) are frequently detected ( Koff 1992 ; Khan et al. 2012 ).

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The clinical outcomes of hepatitis A virus (HAV) infection. Clinical manifestations of HAV infection depend on the age of patients. Most adult patients develop symptomatic hepatitis, whereas most young children do not. Common hepatitis symptoms are fever, malaise, nausea or vomiting, abdominal discomfort, and dark urine and jaundice. Reported extrahepatic complications include acute kidney injury, acalculous cholecystitis, pancreatitis, pleural or pericardial effusion, hemolysis, hemophagocytosis, pure red-cell aplasia, acute reactive arthritis, skin rash, and neurological manifestations such as mononeuritis, Guillain–Barré syndrome, and transverse myelitis.

Laboratory Findings and Diagnosis

Laboratory results show elevated levels of total bilirubin (mean peak level of 7–13 mg/dL), alkaline phosphatase (mean peak level of 319–335 IU/L), and ALT (mean peak level of 1952-3628 IU/L). Sometimes, very high levels of ALT (∼10,000 IU/L) are observed, but this is not a poor prognostic indicator ( Tong et al. 1995 ; Jung et al. 2010b ). Prolonged prothrombin time ([PT] <40%) and high bilirubin levels in the absence of hemolysis indicate severe hepatitis with a potential risk for ALF. Radiological findings of hepatitis A include hepatomegaly, gallbladder wall thickening more than 3 mm (80%) with arterial heterogeneity, periportal tracking, and perihepatic lymph node enlargement (>7 mm in diameter) ( Fig. 3 ) ( Park et al. 2013 ). Gallbladder wall thickening is associated with high bilirubin levels and may be an independent factor of severe hepatitis, which is defined as PT ≤ 40% or bilirubin ≥10 mg/dL ( Suk et al. 2009 ).

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Radiological findings of hepatitis A. ( A ) Transabdominal ultrasonography shows diffuse wall thickening of the gallbladder (arrows) measuring ∼10 mm. ( B ) Transverse computed tomography (CT) scan depicts low attenuating halo around the right portal vein indicating periportal tracking (arrowheads). Perihepatic lymph node enlargement is also noted (arrow).

Because symptoms or biochemical laboratory findings are nonspecific for HAV infection, serological confirmation is essential for diagnosis. Detection of serum anti-HAV IgM via commercially available assays is the primary diagnostic method in clinical settings. However, 6%–11% of symptomatic patients do not show a detectable anti-HAV IgM at clinical onset, especially during the early symptomatic phase ( Jung et al. 2010b ; Lee et al. 2013 ). Therefore, repeated examination of anti-HAV IgM 2 to 5 days after the first examination should be performed if there is clinical suspicion. Seroconversion to anti-HAV IgM positivity on the second examination leads to the correct hepatitis A diagnosis. Rarely (8%–20%), anti-HAV IgM can be transiently detected in persons who have recently received an HAV vaccine ( Nainan et al. 2006 ). Previous HAV infection is diagnosed by a positive serum anti-HAV test in the absence of IgM anti-HAV. Although saliva anti-HAV IgM testing can be used as a screening test in the setting of outbreak investigations, its sensitivity is lower than serum testing ( Amado Leon et al. 2015 ).

Complications of Acute Hepatitis A

HAV infection is self-limited and does not progress to chronic hepatitis. However, 10%–20% of patients develop relapsing hepatitis or prolonged cholestasis lasting for more than 6 months ( Fig. 2 ). Relapsing hepatitis develops in up to 12% of patients after initial hepatitis resolution but is mostly a milder form of hepatitis compared with the initial one. Viremia and fecal viral shedding reappear with relapsing hepatitis ( Glikson et al. 1992 ). A study using a chimpanzee model suggested that relapsing hepatitis might be associated with rapid contraction of or failure to maintain virus-specific CD4 + T-cell responses ( Zhou et al. 2012 ).

Prolonged cholestasis (total bilirubin level >5 mg/dL lasting for >4 weeks) is observed in 5%–7% of patients and presents with pruritus and fatigue. It is related to preexisting chronic hepatitis B, prolonged PT, and high total bilirubin at initial examination ( Jung et al. 2010b ). Although these patients show severe cholestasis with total bilirubin levels of up to 40 mg/dL, patients are generally in good condition with nearly normal levels of AST/ALT and PT and finally recover.

Acute Liver Failure in the Setting of HAV Infection

Hepatitis A severity is related to age at infection and preexisting liver diseases. ALF, which develops in 0.015%–0.5% of hepatitis A patients, has the highest rates in older adults (>40–50 years of age) and patients with underlying chronic liver diseases with limited hepatic functional reserve ( Chen et al. 2016 ; Murphy et al. 2016 ). In a prospective, multicenter study in South Korea of 595 adult hepatitis A cases (mean age of 31 years), 99.5% of patients spontaneously recovered, 0.5% developed ALF, and 0.2% experienced ALF-related mortality ( Jung et al. 2010b ). The 1988 Shanghai hepatitis A epidemic, which affected >300,000 people mostly in their 20s to 40s, showed a similar case fatality rate (0.015%). In that study, the case fatality rate of hepatitis A with underlying chronic hepatitis B (0.05%) was 5.6 times higher than in those without hepatitis B virus infection (0.009%) ( Keeffe 1995 ; Cooksley 2000 ).

The effect of HAV viral load on the ALF risk is controversial. One study reported that lower serum HAV viral load was associated with a higher risk of ALF ( Rezende et al. 2003 ). However, more recent studies have shown that a higher viral load is related to ALF ( Lee et al. 2015 ). Variable blood sampling times and the fluctuating nature of viremia during the acute phase may be related to this discrepancy. Likewise, although nucleotide sequence variation in the 5′ nontranslated segment of the HAV genome has been associated with severe acute hepatitis A, this has not been confirmed ( Fujiwara et al. 2002 ; Kanda et al. 2010 ; Ajmera et al. 2011 ). A human genetic polymorphism, 157insMTTTVP, in the gene encoding T-cell immunoglobulin and mucin domain-1 (TIM1)/HAVCR1 was associated with ALF in Argentinean patients ( Kim et al. 2011 ). TIM1 is a phosphatidylserine receptor that facilitates cellular entry of many enveloped viruses. Recent studies show that it does not play an essential role in HAV entry, but TIM1 does enhance uptake of quasi-enveloped “eHAV” virions ( Das et al. 2017 ).

HAV-related ALF outcomes from a U.S. study ( n = 29) and a South Korean study ( n = 35) similarly showed that 55%–57% of patients spontaneously recovered, 31–38% underwent liver transplantation, and 6%–14% died without transplantation ( Fig. 2 ). A prognostic model incorporating serum ALT <2600 IU/L, creatinine >2.0 mg/dL, intubation, and pressor use was proposed for predicting transplantation or death ( Taylor et al. 2006 ). An independent factor for spontaneous survival was degree of hepatic encephalopathy in the Korean study ( Kim et al. 2008 ).

Extrahepatic Manifestations

Reported extrahepatic manifestations include acute kidney injury, acalculous cholecystitis, pancreatitis, pleural or pericardial effusion, hemolysis, hemophagocytosis, pure red-cell aplasia, acute reactive arthritis, skin rash, and neurological manifestations such as mononeuritis, Guillain–Barré syndrome, and transverse myelitis ( Jeong and Lee 2010 ). Acute kidney injury (AKI), defined by serum creatinine level >2.0 mg/dL or at least a 1.5-fold increase from baseline serum creatinine level, develops in 1.5%–7.6% of hepatitis A patients ( Jung et al. 2010b ; Choi et al. 2011 ). Prerenal azotemia, interstitial nephritis, and acute tubular necrosis predominantly contribute to AKI in hepatitis A along with intravascular hemolysis, direct hepatotoxicity of hyperbilirubinemia, or immune complex-associated glomerulopathy. It is associated with older age (>40 years), male sex, diabetes, high alcohol intake, leukocytosis, elevated C reactive protein (CRP) level, higher bilirubin level, higher AST/ALT level, or low albumin level. In nonfulminant hepatitis A, 10%–50% of AKI cases require renal replacement therapy ( Jung et al. 2010a ). Rare cases of autoimmune hepatitis following hepatitis A have been reported. However, prior HAV infection has been associated with a lower probability of having hay fever and asthma ( Matricardi et al. 2002 ).

Hepatitis A during pregnancy is generally benign. However, preterm uterine contraction is commonly associated with HAV infection, especially during the second and third trimester. This may be associated with proinflammatory cytokines or hyperbilirubinemia. In Israel, 13 pregnant cases showed a high rate (9/13, 69%) of gestational complications such as premature contraction, placental separation, premature rupture of membranes, and vaginal bleeding ( Elinav et al. 2006 ). In 12 South Korean pregnancy cases, there were two preterm labors, one premature rupture of membranes, and one fetal ascites and intraabdominal calcification, which spontaneously resolved ( Cho et al. 2013 ). Fetal meconium peritonitis may be related to intrauterine HAV infection, which in two reported cases led to neonatal small bowel perforation ( Leikin et al. 1996 ; McDuffie and Bader 1999 ). However, fetal outcome is generally benign and mother-to-child transmission is very rare. Although HAV RNA may be detected in breast milk, breastfeeding is not contraindicated.

There is no specific antiviral therapy for hepatitis A. Supportive care such as adequate hydration and symptomatic control of fever or vomiting with antipyretics or antiemetics is generally performed. Extrahepatic complications must be monitored, and renal function support via hemodialysis may be required. In the case of prolonged cholestasis, a few studies have reported response to corticosteroid therapy. However, corticosteroid treatment should be used with caution, considering the prolonged presence of HAV RNA (up to 12 months) in the liver ( Lanford et al. 2011 ) and potentially harmful effects of corticosteroids on the immune control of HAV. Administration of ursodeoxycholic acid or cholestyramine may be considered for pruritus control ( Jeong and Lee 2010 ). Furthermore, hepatitis A-associated ALF may rapidly progress within a week. Thus, intensive, multidisciplinary care and recognition of poor prognostic factors are needed to facilitate urgent decision-making situations regarding liver transplantation.

PATHOGENESIS

Viral replication in the host.

According to a recent study, a quasi-enveloped form of HAV (eHAV) is detected in the serum and plasma of infected hosts, whereas a non-enveloped, naked form of HAV is shed through feces ( Fig. 4 ) ( Feng et al. 2013 ). eHAV is released from hepatocytes and subsequently loses its lipid envelope following exposure to high concentrations of bile salts in the biliary canaliculus ( Walker et al. 2015 ; Hirai-Yuki et al. 2016b ). HAV can take advantage of the specific characteristics of eHAV and nonenveloped HAV for immune evasion and efficient viral transmission, respectively. Within infected hosts, the quasi-envelope of eHAV cloaks the capsid, sequestering it from neutralizing antibodies that target capsid proteins ( Feng et al. 2013 ). Non-enveloped, naked HAV is very stable and is shed in feces via the intestinal tract while preserving its infectivity. Moreover, in the environment, nonenveloped, naked HAV is highly transmissible to other hosts because of its high physicochemical stability ( Walker et al. 2015 ).

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Two different forms of infectious hepatitis A virus (HAV) virions. Quasi-enveloped HAV (eHAV) is detected in serum and plasma of the infected host, whereas nonenveloped, naked HAV is shed in feces. New replicated progeny virus is released from hepatocytes in the quasi-enveloped form and subsequently loses its lipid envelope following exposure to bile salts in the biliary canaliculus. The viral capsid within the quasi-enveloped eHAV virion is protected from neutralizing antibodies. Nonenveloped, naked HAV is highly stable. It is shed in feces via the intestinal tract and maintains infectivity in the environment. LSECs, Liver sinusoidal endothelial cells.

During acute hepatitis A, peaks of fecal shedding of the virus and viremia are followed by hepatocellular injury, which is manifested by elevation of liver enzymes in the serum such as ALT ( Fig. 1 ) ( Shin et al. 2016a ). After the first increase in serum ALT levels, viral shedding in feces usually continues for ∼2 to 3 weeks, although sensitive reverse transcription polymerase chain reaction methods may detect it for longer periods ( Martin and Lemon 2006 ). Clinical relapse with fecal viral shedding can occur following the resolution of hepatitis A ( Sjogren et al. 1987 ), and prolonged viremia has also been reported in some adult patients with hepatitis A ( Normann et al. 2004 ). A chimpanzee study reported the persistence of hepatitis C virus (HCV) RNA in the liver for months after cessation of fecal virus excretion ( Lanford et al. 2011 ). Meanwhile, protracted forms of HAV infection were strongly associated with a specific HLA-DR allele, HLA-DRB1*1301 ( Fainboim et al. 2001 ).

Extrahepatic sites of HAV replication have been suggested. In fact, HAV antigens can be detected in not only hepatocytes but also in the spleen, lymph nodes, and kidneys of infected nonhuman primates ( Mathiesen et al. 1978 ). HAV antigens have also been detected in small intestine crypt cells in owl monkeys ( Aotus trivirgatus ) orally inoculated with HAV ( Asher et al. 1995 ); this has not been confirmed in humans. In addition, HAV has been detected in the tonsils and saliva shortly after viremia ( Cohen et al. 1989 ) although the viral titer in saliva is very low.

Liver Injury

As described above, acute HAV infection often causes severe liver injury in adults, whereas it tends to result in a subclinical, asymptomatic infection in children ( Shin et al. 2016a ). ALF develops in extreme cases. In the liver with hepatitis A, hepatocyte degeneration and infiltration by mononuclear inflammatory cells are observed. Activation of Kupffer cells and disruption of bile canaliculi may also be observed.

The mechanism for liver injury during hepatitis A has not yet been clearly elucidated. Moreover, the reason why adults tend to experience symptomatic liver injury after HAV infection is poorly understood. However, it is known that the liver injury is not caused by direct cytopathic effect of HAV ( Siegl and Weitz 1993 ). This is indirectly supported by the fact that viral replication and fecal excretion both peak before serum ALT level elevation. Moreover, HAV-infected cells do not show cytopathic effects, and their metabolism is not impacted when infected by HAV in vitro ( Gauss-Muller and Deinhardt 1984 ), further indicating that hepatitis A liver injury is not caused by virus-induced cytopathology. Instead, liver injury in hepatitis A is caused by immune-mediated mechanisms involving both innate and adaptive immune responses to the virus ( Shin et al. 2016a ). Indeed, patient studies indicate possible roles for T cells, cytokines, and chemokines in liver injury during hepatitis A, as described below.

MECHANISMS OF IMMUNOPATHOGENESIS

During hepatitis A, the appearance of T cells in the liver temporally coincides with an increase in serum ALT levels ( Fig. 1 ), suggesting an important role for T cells in liver injury ( Shin et al. 2016a ). At the same time, viral titers in feces and serum start to decrease. Virus-specific CD8 + T cells may contribute to both viral control and liver injury in HAV-infected hosts. Early studies reported that peripheral blood lymphocytes or liver-derived CD8 + T-cell clones from hepatitis A patients exert cytotoxicity against HAV-infected cells ( Kurane et al. 1985 ; Vallbracht et al. 1986 , 1989 ) and produce IFN-γ ( Kurane et al. 1985 ; Maier et al. 1988 ; Fleischer et al. 1990 ), which can amplify inflammation at the infection site. Following on these early reports, other studies suggest a role for HAV-specific CD8 + T cells in the induction of liver injury in hepatitis A. A recent study described CD8 + T-cell responses targeting multiple epitopes of HAV and observed an activated phenotype of HAV-specific CD8 + T cells in the blood of patients with acute HAV infection ( Schulte et al. 2011 ). On the contrary, a chimpanzee study showed that HAV-specific CD8 + T cells were undetectable in the blood during acute HAV infection or were nonfunctional if detected ( Zhou et al. 2012 ). Instead, HAV-specific CD4 + T cells were detected and polyfunctional. In summary, how T cells contribute to liver injury in hepatitis A has yet to be fully elucidated, including antigen specificity, subsets, activating signals, and effector molecules, all of which need to be further clarified.

A role for natural killer T (NKT) cells was suggested in relation to the 157insMTTTVP polymorphism described above in the gene encoding TIM-1/HAVCR1 ( Kim et al. 2011 ). TIM1 was previously considered to be an essential cellular receptor for HAV, but is now known to contribute only to the cellular entry of quasi-enveloped virions ( Das et al. 2017 ). Severe HAV-induced liver injury was associated with the six amino acid insertion in TIM-1 ( Kim et al. 2011 ). Moreover, NKT cells expressing the long form of TIM-1 exerted stronger cytolytic activity against HAV-infected cells than those expressing the short form ( Kim et al. 2011 ).

Antibodies and Immune Complexes

Early clinical studies showed immune complex deposition in the liver and reduced levels of serum complement in hepatitis A patients ( Inman et al. 1986 ; Margolis et al. 1988 ). These immune complexes contained IgM and IgG antibodies, HAV capsid proteins, and C3 complement cleavage products ( Margolis et al. 1988 ). However, it is not clear whether immune complexes and complement activation contribute to liver inflammation and injury during hepatitis A.

A recent study with peripheral blood from hepatitis A patients showed that a substantial number of antibody-secreting cells (ASCs) have specificities to antigens unrelated to HAV, a bone marrow plasma cell–like phenotype, and dominantly secrete IgM during acute HAV infection ( Hong et al. 2013 ). These data suggest that preexisting plasma cells are mobilized and released into the circulation and contribute to antigen-nonspecific IgM secretion during acute HAV infection. However, the role of the antigen-nonspecific IgM response in the immunopathogenesis of HAV infection has not yet been clarified.

Cytokines and Chemokines

Diverse cytokines and chemokines play a role in immune-mediated host injury by their effector and immunomodulatory functions. In hepatitis A patients, serum levels of several cytokines and chemokines are increased compared with healthy controls, including interleukin (IL)-6, IL-8, IL-18, IL-22, CXC-chemokine ligand (CXCL)9, and CXCL10, although the cells that produce them have not been identified ( Shin et al. 2016b ). In addition, serum levels of granzyme B and soluble Fas ligand, which are molecules involved in T-cell cytotoxicity, are also increased in hepatitis A patients. Among them, serum levels of Fas ligand and IL-18 significantly correlate with serum ALT levels and total bilirubin levels, respectively, in hepatitis A patients ( Shin et al. 2016b ), suggesting that different immune mechanisms may contribute to hepatocellular injury and cholestatic injury during hepatitis A. Moreover, serum levels of CXCL9 and CXCL10 significantly correlate with serum ALT levels ( Shin et al. 2016b ). CXCL9 and CXCL10 are chemokines that recruit effector T cells to peripheral inflammatory sites by binding to CXCR3, which is typically expressed by effector helper 1 CD4 + T cells and cytotoxic CD8 + T cells. Amplification of liver injury by antigen-nonspecific mononuclear cells, which are recruited to the liver by CXCL9 and CXCL10, is well known, although studied in a murine model of hepatitis B ( Iannacone et al. 2007 ).

Very recently, a unique mechanism for CXCL10 production in HAV-infected cells was elucidated. HAV RNA is sensed by pathogen-associated molecular pattern receptors such as MDA5 in the cytosol or TLR3 in the endosome ( Fig. 5 ). However, downstream signals are interrupted by HAV proteins. An intermediate product of HAV polyprotein processing, 3ABC, cleaves MAVS ( Yang et al. 2007 ), and another precursor, 3CD, cleaves TRIF ( Qu et al. 2011 ). In addition, the HAV 3C pro protease cleaves NEMO ( Wang et al. 2014 ). Although HAV blocks signals downstream from MDA5 and TLR3 by such mechanisms, type III interferon (IFN)-λs and CXCL10 are produced by HAV-infected cells, particularly at an early stage of HAV infection ( Sung et al. 2017 ). CXCL10 is produced in HAV-infected cells in a MAVS and IRF3-dependent manner ( Fig. 5 ) ( Sung et al. 2017 ). However, secreted type I or III IFNs are not required for CXCL10 production. This finding corresponds to the fact that CXCL10 expression is increased in the liver and blood of HAV-infected chimpanzees, whereas IFN responses are minimally induced in the infected liver ( Lanford et al. 2011 ). This mechanism may be pivotal for liver inflammation during HAV infection, as it induces the production of CXCL10 even without IFNs. Similar findings have been reported in a murine model of hepatitis A (see below) ( Hirai-Yuki et al. 2016a ).

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Mechanism of CXC-chemokine ligand (CXCL)10 expression in Hepatitis A virus (HAV)-infected hepatocytes. HAV RNA is sensed by MDA5 in the cytosol or TLR3 in the endosome. However, downstream signaling is interrupted by HAV proteins as described in the text. Nonetheless, interferon λ (IFN-λ) and CXCL10 are produced from HAV-infected cells, particularly at an early stage of HAV infection. CXCL10 is produced in HAV-infected cells in a MAVS- and IRF3-dependent but IFN-independent manner. CXCL10 can contribute to liver inflammation and hepatocyte injury by recruiting CXCR3 + immune cells to the HAV-infected liver.

Regulatory T Cells

In immune-mediated host injury, regulatory T (Treg) cells can modulate effector T-cell activity. Treg cells have been shown to play a role in liver injury regulation during acute HAV infections. The number of circulating CD4 + CD25 + Foxp3 + Treg cells is diminished by Fas-mediated apoptosis during hepatitis A ( Choi et al. 2015 ). In addition, the suppressive function of Treg cells can be directly inhibited by the binding of HAV particles to TIM-1 expressed by Treg cells ( Manangeeswaran et al. 2012 ). Furthermore, the number of Treg cells in the blood and the suppressive activity of the total Treg cell population are inversely correlated with serum ALT levels ( Choi et al. 2015 ). These data indicate that decreased CD4 + CD25 + Foxp3 + Treg cell population activity is associated with severe liver injury during hepatitis A. However, the frequency of circulating Treg cells does not correlate with the frequency of HAV-specific, IFN-γ-producing CD8 + T cells in the blood ( Choi et al. 2015 ). Further studies are required to identify the effector cells mainly targeted by the suppressive activity of Treg cells during hepatitis A and to clarify how reduced Treg cell population frequencies and activities are related to liver injury.

A Murine Model of HAV Infection

As described above, the mechanisms responsible for immune-mediated liver injury have not yet been clearly elucidated. This is in part attributed to the absence of a small animal model for HAV infection and hepatitis A. Recently, a murine model of HAV infection with human hepatitis A features was described ( Hirai-Yuki et al. 2016a ). In this study, mice lacking the type I IFN receptor or both type I and II IFN receptors were inoculated intravenously with HAV, resulting in the development of features typifying human hepatitis A, including fecal virus shedding, viremia, increased serum ALT levels, necrosis or apoptosis of hepatocytes, and infiltration of the liver by inflammatory cells, including macrophages, natural killer cells, and CD4 + and CD8 + T cells ( Hirai-Yuki et al. 2016a ). Further analyses with this model revealed that hepatocellular apoptosis and hepatic inflammation occurs by a MAVS and IRF3/7-dependent, but IFN-independent mechanism ( Hirai-Yuki et al. 2016a ). In this model, multiple cytokines and chemokines were expressed in the liver by the same mechanism ( Hirai-Yuki et al. 2016a ), corresponding with the recent finding in human cells described above ( Sung et al. 2017 ). This study revealed the critical role of MAVS signaling in liver injury induced by HAV infection using a unique murine model. However, it remains to be confirmed whether this model exactly recapitulates the mechanisms of pathogenesis of hepatitis A in humans.

CONCLUDING REMARKS

In regions with inadequate levels of sanitation, HAV is readily propagated among children and often results in a self-limited, asymptomatic, and subclinical infection, which induces neutralizing antibodies that confer lifelong protective immunity. Thus, improvements in sanitation increase the size of the HAV-naïve adult population susceptible to HAV infection. In this situation, increasing numbers of individuals can be infected at older ages, leading to more severe clinical manifestations and greater disease burden. Currently, inactivated HAV vaccines that elicit neutralizing antibodies are available, and vaccination will largely reduce the incidence of HAV infection and symptomatic hepatitis.

Although liver injury in hepatitis A is known to be caused by immune-mediated events, the exact pathogenesis mechanisms have not yet been clarified. Immune-mediated mechanisms of liver injury are common to the pathogenesis of hepatitis A, hepatitis B, and hepatitis C ( Shin et al. 2016a ). Elucidating the immunopathogenesis of hepatitis A will not only lead to better clinical management of hepatitis A patients, but could also facilitate the development of novel therapeutic approaches reducing liver injury in patients with hepatitis B or C.

ACKNOWLEDGMENTS

We are grateful to Dr. Yoon Jin Lee in the Department of Radiology in Seoul National University Bundang Hospital for selecting and describing the radiological images of our patients. We also thank Prof. Su-Hyung Park (Graduate School of Medical Science and Engineering, KAIST) and Dr. Hyung-Don Kim (Graduate School of Medical Science and Engineering, KAIST) for critical reading of the manuscript. This work is supported by the National Research Foundation Grant NRF-2014R1A2A1A10053662, and the Korea Advanced Institute of Science and Technology Future Systems Healthcare Project, which is funded by the Ministry of Science, ICT, and Future Planning of Korea.

Editors: Stanley M. Lemon and Christopher Walker

Additional Perspectives on Enteric Hepatitis Viruses available at www.perspectivesinmedicine.org

Ajmera V, Xia G, Vaughan G, Forbi JC, Ganova-Raeva LM, Khudyakov Y, Opio CK, Taylor R, Restrepo R, Munoz S, et al. 2011. What factors determine the severity of hepatitis A-related acute liver failure? J Viral Hepat 18 : e167–e174. [ PMC free article ] [ PubMed ] [ Google Scholar ]
Amado Leon LA, de Almeida AJ, de Paula VS, Tourinho RS, Villela DA, Gaspar AM, Lewis-Ximenez LL, Pinto MA. 2015. Longitudinal study of hepatitis A infection by saliva sampling: The kinetics of HAV markers in saliva revealed the application of saliva tests for hepatitis A study . PLoS ONE 10 : e0145454. [ PMC free article ] [ PubMed ] [ Google Scholar ]
Armstrong GL, Bell BP. 2002. Hepatitis A virus infections in the United States: Model-based estimates and implications for childhood immunization . Pediatrics 109 : 839–845. [ PubMed ] [ Google Scholar ]
Asher LV, Binn LN, Mensing TL, Marchwicki RH, Vassell RA, Young GD. 1995. Pathogenesis of hepatitis A in orally inoculated owl monkeys ( Aotus trivirgatus ) . J Med Virol 47 : 260–268. [ PubMed ] [ Google Scholar ]
Chen CM, Chen SC, Yang HY, Yang ST, Wang CM. 2016. Hospitalization and mortality due to hepatitis A in Taiwan: A 15-year nationwide cohort study . J Viral Hepat 23 : 940–945. [ PubMed ] [ Google Scholar ]
Cho GJ, Kim YB, Kim SM, Hong HR, Kim JH, Seol HJ, Hong SC, Oh MJ, Kim HJ. 2013. Hepatitis A virus infection during pregnancy in Korea: Hepatitis A infection on pregnant women . Obstet Gynecol Sci 56 : 368–374. [ PMC free article ] [ PubMed ] [ Google Scholar ]
Choi HK, Song YG, Han SH, Ku NS, Jeong SJ, Baek JH, Kim H, Kim SB, Kim CO, Kim JM, et al. 2011. Clinical features and outcomes of acute kidney injury among patients with acute hepatitis A . J Clin Virol 52 : 192–197. [ PubMed ] [ Google Scholar ]
Choi YS, Lee J, Lee HW, Chang DY, Sung PS, Jung MK, Park JY, Kim JK, Lee JI, Park H, et al. 2015. Liver injury in acute hepatitis A is associated with decreased frequency of regulatory T cells caused by Fas-mediated apoptosis . Gut 64 : 1303–1313. [ PubMed ] [ Google Scholar ]
Cohen JI, Feinstone S, Purcell RH. 1989. Hepatitis A virus infection in a chimpanzee: Duration of viremia and detection of virus in saliva and throat swabs . J Infect Dis 160 : 887–890. [ PubMed ] [ Google Scholar ]
Cooksley WG. 2000. What did we learn from the Shanghai hepatitis A epidemic? J Viral Hepat 7 : 1–3. [ PubMed ] [ Google Scholar ]
Cuthbert JA. 2001. Hepatitis A: Old and new . Clin Microbiol Rev 14 : 38–58. [ PMC free article ] [ PubMed ] [ Google Scholar ]
Das A, Hirai-Yuki A, González-López O, Rhein B, Moller-Tank S, Brouillette R, Hensley L, Misumi I, Lovell W, Cullen JM, et al. 2017. TIM1 (HAVCR1) is not essential for cellular entry of either quasi-enveloped or naked hepatitis A virions . mBio 8 : e00969–00917. [ PMC free article ] [ PubMed ] [ Google Scholar ]
Elinav E, Ben-Dov IZ, Shapira Y, Daudi N, Adler R, Shouval D, Ackerman Z. 2006. Acute hepatitis A infection in pregnancy is associated with high rates of gestational complications and preterm labor . Gastroenterology 130 : 1129–1134. [ PubMed ] [ Google Scholar ]
Fainboim L, Canero Velasco MC, Marcos CY, Ciocca M, Roy A, Theiler G, Capucchio M, Nuncifora S, Sala L, Zelazko M. 2001. Protracted, but not acute, hepatitis A virus infection is strongly associated with HLA-DRB*1301, a marker for pediatric autoimmune hepatitis . Hepatology 33 : 1512–1517. [ PubMed ] [ Google Scholar ]
Feng Z, Hensley L, McKnight KL, Hu F, Madden V, Ping L, Jeong SH, Walker C, Lanford RE, Lemon SM. 2013. A pathogenic picornavirus acquires an envelope by hijacking cellular membranes . Nature 496 : 367–371. [ PMC free article ] [ PubMed ] [ Google Scholar ]
Fleischer B, Fleischer S, Maier K, Wiedmann KH, Sacher M, Thaler H, Vallbracht A. 1990. Clonal analysis of infiltrating T lymphocytes in liver tissue in viral hepatitis A . Immunology 69 : 14–19. [ PMC free article ] [ PubMed ] [ Google Scholar ]
Fujiwara K, Yokosuka O, Ehata T, Saisho H, Saotome N, Suzuki K, Okita K, Kiyosawa K, Omata M. 2002. Association between severity of type A hepatitis and nucleotide variations in the 5′ non-translated region of hepatitis A virus RNA: Strains from fulminant hepatitis have fewer nucleotide substitutions . Gut 51 : 82–88. [ PMC free article ] [ PubMed ] [ Google Scholar ]
Gauss-Muller V, Deinhardt F. 1984. Effect of hepatitis A virus infection on cell metabolism in vitro . Proc Soc Exp Biol Med 175 : 10–15. [ PubMed ] [ Google Scholar ]
Glikson M, Galun E, Oren R, Tur-Kaspa R, Shouval D. 1992. Relapsing hepatitis A. Review of 14 cases and literature survey . Medicine 71 : 14–23. [ PubMed ] [ Google Scholar ]
Havelaar AH, Kirk MD, Torgerson PR, Gibb HJ, Hald T, Lake RJ, Praet N, Bellinger DC, de Silva NR, Gargouri N, et al. 2015. World Health Organization global estimates and regional comparisons of the burden of foodborne disease in 2010 . PLoS Med 12 : e1001923. [ PMC free article ] [ PubMed ] [ Google Scholar ]
Hirai-Yuki A, Hensley L, McGivern DR, Gonzalez-Lopez O, Das A, Feng H, Sun L, Wilson JE, Hu F, Feng Z, et al. 2016a. MAVS-dependent host species range and pathogenicity of human hepatitis A virus . Science 353 : 1541–1545. [ PMC free article ] [ PubMed ] [ Google Scholar ]
Hirai-Yuki A, Hensley L, Whitmire JK, Lemon SM. 2016b. Biliary secretion of quasi-enveloped human hepatitis A virus . mBio 7 : e01998–01916. [ PMC free article ] [ PubMed ] [ Google Scholar ]
Hong S, Lee HW, Chang DY, You S, Kim J, Park JY, Ahn SH, Yong D, Han KH, Yoo OJ, et al. 2013. Antibody-secreting cells with a phenotype of Ki-67 low , CD138 high , CD31 high , and CD38 high secrete nonspecific IgM during primary hepatitis A virus infection . J Immunol 191 : 127–134. [ PubMed ] [ Google Scholar ]
Iannacone M, Sitia G, Ruggeri ZM, Guidotti LG. 2007. HBV pathogenesis in animal models: Recent advances on the role of platelets . J Hepatol 46 : 719–726. [ PMC free article ] [ PubMed ] [ Google Scholar ]
Inman RD, Hodge M, Johnston ME, Wright J, Heathcote J. 1986. Arthritis, vasculitis, and cryoglobulinemia associated with relapsing hepatitis A virus infection . Ann Intern Med 105 : 700–703. [ PubMed ] [ Google Scholar ]
Jeong SH, Lee HS. 2010. Hepatitis A: Clinical manifestations and management . Intervirology 53 : 15–19. [ PubMed ] [ Google Scholar ]
Jung YJ, Kim W, Jeong JB, Kim BG, Lee KL, Oh KH, Yoon JH, Lee HS, Kim YJ. 2010a. Clinical features of acute renal failure associated with hepatitis A virus infection . J Viral Hepat 17 : 611–617. [ PubMed ] [ Google Scholar ]
Jung YM, Park SJ, Kim JS, Jang JH, Lee SH, Kim JW, Park YM, Hwang SG, Rim KS, Kang SK, et al. 2010b. Atypical manifestations of hepatitis A infection: A prospective, multicenter study in Korea . J Med Virol 82 : 1318–1326. [ PubMed ] [ Google Scholar ]
Kanda T, Jeong SH, Imazeki F, Fujiwara K, Yokosuka O. 2010. Analysis of 5′ nontranslated region of hepatitis A viral RNA genotype I from South Korea: Comparison with disease severities . PLoS ONE 5 : e15139. [ PMC free article ] [ PubMed ] [ Google Scholar ]
Keeffe EB. 1995. Is hepatitis A more severe in patients with chronic hepatitis B and other chronic liver diseases? Am J Gastroenterol 90 : 201–205. [ PubMed ] [ Google Scholar ]
Khan KM, Kumar NC, Gruessner RW. 2012. The liver and parenteral nutrition . In Zakim and Boyer’s hepatology: A textbook of liver disease , 6th ed. (ed. Boyer TD, Manns MP, Sanyal AJ), pp. 986–995. W.B. Saunders, Philadelphia. [ Google Scholar ]
Kim JM, Lee YS, Lee JH, Kim W, Lim KS. 2008. Clinical outcomes and predictive factors of spontaneous survival in patients with fulminant hepatitis A . Korean J Hepatol 14 : 474–482. [ PubMed ] [ Google Scholar ]
Kim HY, Eyheramonho MB, Pichavant M, Gonzalez Cambaceres C, Matangkasombut P, Cervio G, Kuperman S, Moreiro R, Konduru K, Manangeeswaran M, et al. 2011. A polymorphism in TIM1 is associated with susceptibility to severe hepatitis A virus infection in humans . J Clin Invest 121 : 1111–1118. [ PMC free article ] [ PubMed ] [ Google Scholar ]
Koff RS. 1992. Clinical manifestations and diagnosis of hepatitis A virus infection . Vaccine 10 : S15–S17. [ PubMed ] [ Google Scholar ]
Kurane I, Binn LN, Bancroft WH, Ennis FA. 1985. Human lymphocyte responses to hepatitis A virus-infected cells: Interferon production and lysis of infected cells . J Immunol 135 : 2140–2144. [ PubMed ] [ Google Scholar ]
Lanford RE, Feng Z, Chavez D, Guerra B, Brasky KM, Zhou Y, Yamane D, Perelson AS, Walker CM, Lemon SM. 2011. Acute hepatitis A virus infection is associated with a limited type I interferon response and persistence of intrahepatic viral RNA . Proc Natl Acad Sci 108 : 11223–11228. [ PMC free article ] [ PubMed ] [ Google Scholar ]
Lee HK, Kim KA, Lee JS, Kim NH, Bae WK, Song TJ. 2013. Window period of anti-hepatitis A virus immunoglobulin M antibodies in diagnosing acute hepatitis A . Eur J Gastroenterol Hepatol 25 : 665–668. [ PubMed ] [ Google Scholar ]
Lee HW, Chang DY, Moon HJ, Chang HY, Shin EC, Lee JS, Kim KA, Kim HJ. 2015. Clinical factors and viral load influencing severity of acute hepatitis A . PLoS ONE 10 : e0130728. [ PMC free article ] [ PubMed ] [ Google Scholar ]
Leikin E, Lysikiewicz A, Garry D, Tejani N. 1996. Intrauterine transmission of hepatitis A virus . Obstet Gynecol 88 : 690–691. [ PubMed ] [ Google Scholar ]
Maier K, Gabriel P, Koscielniak E, Stierhof YD, Wiedmann KH, Flehmig B, Vallbracht A. 1988. Human γ interferon production by cytotoxic T lymphocytes sensitized during hepatitis A virus infection . J Virol 62 : 3756–3763. [ PMC free article ] [ PubMed ] [ Google Scholar ]
Manangeeswaran M, Jacques J, Tami C, Konduru K, Amharref N, Perrella O, Casasnovas JM, Umetsu DT, Dekruyff RH, Freeman GJ, et al. 2012. Binding of hepatitis A virus to its cellular receptor 1 inhibits T-regulatory cell functions in humans . Gastroenterology 142 : 1516–1525.e1513. [ PMC free article ] [ PubMed ] [ Google Scholar ]
Margolis HS, Nainan OV, Krawczynski K, Bradley DW, Ebert JW, Spelbring J, Fields HA, Maynard JE. 1988. Appearance of immune complexes during experimental hepatitis A infection in chimpanzees . J Med Virol 26 : 315–326. [ PubMed ] [ Google Scholar ]
Martin A, Lemon SM. 2006. Hepatitis A virus: From discovery to vaccines . Hepatology 43 : S164–S172. [ PubMed ] [ Google Scholar ]
Mathiesen LR, Drucker J, Lorenz D, Wagner JA, Gerety RJ, Purcell RH. 1978. Localization of hepatitis A antigen in marmoset organs during acute infection with hepatitis A virus . J Infect Dis 138 : 369–377. [ PubMed ] [ Google Scholar ]
Matricardi PM, Rosmini F, Panetta V, Ferrigno L, Bonini S. 2002. Hay fever and asthma in relation to markers of infection in the United States . J Allergy Clin Immunol 110 : 381–387. [ PubMed ] [ Google Scholar ]
McDuffie RS Jr, Bader T. 1999. Fetal meconium peritonitis after maternal hepatitis A . Am J Obstet Gynecol 180 : 1031–1032. [ PubMed ] [ Google Scholar ]
Murphy TV, Denniston MM, Hill HA, McDonald M, Klevens MR, Elam-Evans LD, Nelson NP, Iskander J, Ward JD. 2016. Progress toward eliminating hepatitis A disease in the United States . MMWR Suppl 65 : 29–41. [ PubMed ] [ Google Scholar ]
Nainan OV, Xia G, Vaughan G, Margolis HS. 2006. Diagnosis of hepatitis A virus infection: A molecular approach . Clin Microbiol Rev 19 : 63–79. [ PMC free article ] [ PubMed ] [ Google Scholar ]
Normann A, Jung C, Vallbracht A, Flehmig B. 2004. Time course of hepatitis A viremia and viral load in the blood of human hepatitis A patients . J Med Virol 72 : 10–16. [ PubMed ] [ Google Scholar ]
Park SJ, Kim JD, Seo YS, Park BJ, Kim MJ, Um SH, Kim CH, Yim HJ, Baik SK, Jung JY, et al. 2013. Computed tomography findings for predicting severe acute hepatitis with prolonged cholestasis . World J Gastroenterol 19 : 2543–2549. [ PMC free article ] [ PubMed ] [ Google Scholar ]
Qu L, Feng Z, Yamane D, Liang Y, Lanford RE, Li K, Lemon SM. 2011. Disruption of TLR3 signaling due to cleavage of TRIF by the hepatitis A virus protease-polymerase processing intermediate, 3CD . PLoS Pathog 7 : e1002169. [ PMC free article ] [ PubMed ] [ Google Scholar ]
Rezende G, Roque-Afonso AM, Samuel D, Gigou M, Nicand E, Ferre V, Dussaix E, Bismuth H, Feray C. 2003. Viral and clinical factors associated with the fulminant course of hepatitis A infection . Hepatology 38 : 613–618. [ PubMed ] [ Google Scholar ]
Schulte I, Hitziger T, Giugliano S, Timm J, Gold H, Heinemann FM, Khudyakov Y, Strasser M, Konig C, Castermans E, et al. 2011. Characterization of CD8 + T-cell response in acute and resolved hepatitis A virus infection . J Hepatol 54 : 201–208. [ PubMed ] [ Google Scholar ]
Shin EC, Sung PS, Park SH. 2016a. Immune responses and immunopathology in acute and chronic viral hepatitis . Nat Rev Immunol 16 : 509–523. [ PubMed ] [ Google Scholar ]
Shin SY, Jeong SH, Sung PS, Lee J, Kim HJ, Lee HW, Shin EC. 2016b. Comparative analysis of liver injury-associated cytokines in acute hepatitis A and B . Yonsei Med J 57 : 652–657. [ PMC free article ] [ PubMed ] [ Google Scholar ]
Siegl G, Weitz M. 1993. Pathogenesis of hepatitis A: Persistent viral infection as basis of an acute disease? Microb Pathog 14 : 1–8. [ PubMed ] [ Google Scholar ]
Sjogren MH, Tanno H, Fay O, Sileoni S, Cohen BD, Burke DS, Feighny RJ. 1987. Hepatitis A virus in stool during clinical relapse . Ann Intern Med 106 : 221–226. [ PubMed ] [ Google Scholar ]
Suk KT, Kim CH, Baik SK, Kim MY, Park DH, Kim KH, Kim JW, Kim HS, Kwon SO, Lee DK, et al. 2009. Gallbladder wall thickening in patients with acute hepatitis . J Clin Ultrasound 37 : 144–148. [ PubMed ] [ Google Scholar ]
Sung PS, Hong SH, Lee J, Park SH, Yoon SK, Chung WJ, Shin EC. 2017. CXCL10 is produced in hepatitis A virus-infected cells in an IRF3-dependent but IFN-independent manner . Sci Rep 7 : 6387. [ PMC free article ] [ PubMed ] [ Google Scholar ]
Taylor RM, Davern T, Munoz S, Han SH, McGuire B, Larson AM, Hynan L, Lee WM, Fontana RJ. 2006. Fulminant hepatitis A virus infection in the United States: Incidence, prognosis, and outcomes . Hepatology 44 : 1589–1597. [ PMC free article ] [ PubMed ] [ Google Scholar ]
Tong MJ, el-Farra NS, Grew MI. 1995. Clinical manifestations of hepatitis A: Recent experience in a community teaching hospital . J Infect Dis 171 : S15–S18. [ PubMed ] [ Google Scholar ]
Vallbracht A, Gabriel P, Maier K, Hartmann F, Steinhardt HJ, Muller C, Wolf A, Manncke KH, Flehmig B. 1986. Cell-mediated cytotoxicity in hepatitis A virus infection . Hepatology 6 : 1308–1314. [ PubMed ] [ Google Scholar ]
Vallbracht A, Maier K, Stierhof YD, Wiedmann KH, Flehmig B, Fleischer B. 1989. Liver-derived cytotoxic T cells in hepatitis A virus infection . J Infect Dis 160 : 209–217. [ PubMed ] [ Google Scholar ]
Walker CM, Feng Z, Lemon SM. 2015. Reassessing immune control of hepatitis A virus . Curr Opin Virol 11 : 7–13. [ PMC free article ] [ PubMed ] [ Google Scholar ]
Wang D, Fang L, Wei D, Zhang H, Luo R, Chen H, Li K, Xiao S. 2014. Hepatitis A virus 3C protease cleaves NEMO to impair induction of β interferon . J Virol 88 : 10252–10258. [ PMC free article ] [ PubMed ] [ Google Scholar ]
Yang Y, Liang Y, Qu L, Chen Z, Yi M, Li K, Lemon SM. 2007. Disruption of innate immunity due to mitochondrial targeting of a picornaviral protease precursor . Proc Natl Acad Sci 104 : 7253–7258. [ PMC free article ] [ PubMed ] [ Google Scholar ]
Zhou Y, Callendret B, Xu D, Brasky KM, Feng Z, Hensley LL, Guedj J, Perelson AS, Lemon SM, Lanford RE, et al. 2012. Dominance of the CD4 + T helper cell response during acute resolving hepatitis A virus infection . J Exp Med 209 : 1481–1492. [ PMC free article ] [ PubMed ] [ Google Scholar ]

IMAGES

Viral hepatitis: Clinical: Video, Anatomy & Definition
The ABCDE of Viral Hepatitis
Hepatitis
Hepatitis
The ABC's of Hepatitis: know and fight the viral disease
Viral Hepatitis Facts

VIDEO

Clinical Case Presentation in Urdu/Hindi. / Acute Viral Hepatitis / Hepatitis A / Hepatitis E
case presentation on hepatitis B
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Acute Hepatitis

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Viral Hepatitis Clinical Presentation
The incubation period of hepatitis A virus (HAV) is 2-7 weeks (average, 28 days). Clinical symptoms then develop, often with a presentation similar to that of gastroenteritis or a viral respiratory infection. The most common signs and symptoms include fatigue, nausea, vomiting, fever, hepatomegaly, jaundice, dark urine, anorexia, and rash.
Hepatitis
Viral Hepatitis Clinical presentation of viral hepatitis can be different in every individual depending on the type of virus causing the infection. Patients can be entirely asymptomatic or only mildly symptomatic at presentation. A small number of patients can present with rapid onset of fulminant hepatic failure.
What is Viral Hepatitis?
Hepatitis means inflammation of the liver. The liver is a vital organ that processes nutrients, filters the blood, and fights infections. When the liver is inflamed or damaged, its function can be affected. Heavy alcohol use, toxins, some medications, and certain medical conditions can cause hepatitis. However, hepatitis is often caused by a virus.
Acute Hepatitis
Acute hepatitis is a term used to describe a wide variety of conditions characterized by acute inflammation of the hepatic parenchyma or injury to hepatocytes resulting in elevated liver function indices. In general, hepatitis is classified as acute or chronic based on the duration of the inflammation and insult to the hepatic parenchyma. If the period of inflammation or hepatocellular injury ...
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Patients with acute viral hepatitis may be anicteric or even asymptomatic. Do viral serologic testing (IgM anti-HAV, HBsAg, anti-HCV) if clinical findings are consistent with acute viral hepatitis and AST and ALT are elevated out of proportion to alkaline phosphatase. Treat patients supportively. Treat acute hepatitis C to prevent transmission.
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Viral hepatitis, characterized by liver inflammation and damage, is amongst the leading human global health threats (22). Billions of people worldwide have been infected with hepatitis viruses. Millions worldwide are living with viral hepatitis and over 1.4 million deaths occur annually as a result of liver cirrhosis and cancer (23). Notably, many infected individuals are unaware of their ...
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Clinical studies have shown that chronic hepatitis D is the most severe and progressive form of viral hepatitis in humans. 2 The infection is ubiquitous, yet 40 years after it was identified, the ...
Laboratory Diagnosis and Monitoring of Viral Hepatitis
Symptoms of hepatitis are not specific to a single hepatitis virus, and thus clinical presentation does not distinguish between different viral etiologies. Hepatitis virus infection may be mild or asymptomatic. In symptomatic cases, acute hepatitis is associated with flu-like illness, fever, fatigue, loss of appetite, abdominal pain, nausea ...
Hepatitis, Viral
Viral hepatitis refers to the clinically important hepatotropic viruses responsible for hepatitis A (HAV), hepatitis B (HBV), delta hepatitis, hepatitis C (HCV), and hepatitis E. ... The clinical presentation of HAV infection is given in Table 25-1. There are no specific symptoms unique to HAV. Children younger than 6 years of age are typically ...
PDF Late presentation of chronic viral hepatitis for medical care: a
A consensus definition of late presentation with viral hepatitis is important to create a homogenous, easy-to-use reference for public health authorities in Europe and elsewhere to better assess the clinical situation on a population basis. Methods: A working group including viral hepatitis experts from the European Association for the Study of the
Hepatitis A virus infection in adults: Epidemiology, clinical
Schiff ER. Atypical clinical manifestations of hepatitis A. Vaccine 1992; 10 Suppl 1:S18. Ilan Y, Hillman M, Oren R, et al. Vasculitis and cryoglobulinemia associated with persisting cholestatic hepatitis A virus infection. Am J Gastroenterol 1990; 85:586. Lavine J, Bull F, Millward-Sadler G. Acute viral hepatitis.
Clinical presentation of acute viral hepatitis
Clinical presentation of acute viral hepatitis. 1990 Apr;46 (2):533-47. doi: 10.1093/oxfordjournals.bmb.a072414. Academic Department of Medicine, Royal Free Hospital School of Medicine, London, UK. Acute viral hepatitis may be asymptomatic, symptomatic but anicteric, or a classical icteric hepatitis; rarely it is very severe and may be fatal.
Hepatitis
Clinical Trials. Find a Clinical Trial. Become a Healthy Volunteer. Participant's Guide to Clinical Trials. Participant Testimonials. HIV and Emerging Infectious Diseases. ... Liver tissue specimen extracted from a viral hepatitis patient. Credit. CDC. More Hepatitis Research at NIAID
Late presentation of chronic viral hepatitis for medical care: a
In 2014, a group of viral hepatitis experts within the European Association for the Study of the Liver (EASL) and the HIV in Europe Initiative [] formed a working group to develop a consensus definition of late presentation with viral hepatitis.Key stakeholders were invited to participate, including patient advocacy groups, health policy-makers, international health organisations, surveillance ...
Viral Hepatitis B: Clinical and Epidemiological Characteristics
Clinical presentation varies from asymptomatic infection in two-thirds of patients to icteric hepatitis and, rarely, fulminant liver failure. A serum-sickness-like illness, characterized by fever, arthralgias, and rash, may occur in the prodromal period, followed by constitutional symptoms, anorexia, nausea, jaundice, and right upper quadrant ...
To eliminate viral hepatitis, a silent killer, it must be tracked
Before the Covid-19 pandemic, viral hepatitis killed more people in the United States than all 60 other reportable infectious diseases combined, including HIV, pneumonia, and tuberculosis. Which ...
PDF Prevention Treatment of Hepatitis and Chronic Liver Disease
Pre-Lecture 1 - Viral Hepatitis -A summary for discovery and natural history of HCV 60 min Pre-Lecture 2 - End Stage Liver Disease: An overview of Treatment, Managing Complications chronic liver disease, cirrhosis, and the transplant process - 45 min 7:30 am Registration and View Exhibits 8:00 am Opening Comments and Pre-Test 8:20 am
MAFLD: an optimal framework for understanding liver cancer ...
Hepatocellular carcinoma has a substantial global mortality burden which is rising despite advancements in tackling the traditional viral risk factors. Metabolic (dysfunction) associated fatty liver disease (MAFLD) is the most prevalent liver disease, increasing in parallel with the epidemics of obesity, diabetes and systemic metabolic dysregulation. MAFLD is a major factor behind this ...
Viral hepatitis: Past, present, and future
Core Tip: Viral hepatitis encompasses a wide array of clinical diseases—from asymptomatic and self-limited to chronic liver disease to acute liver failure.Extensive historical research has resulted in vaccines to prevent Hepatitis A, B, and E and highly efficacious antivirals for Hepatitis B and C, and these therapeutic breakthroughs are transforming the fields of hepatology, transplant ...
Excision BioTherapeutics Announces Oral Presentation of HSV ...
SAN FRANCISCO, April 16, 2024 (GLOBE NEWSWIRE) -- Excision BioTherapeutics Inc. ("Excision", the "Company"), a clinical-stage biotechnology company developing CRISPR-based therapies to cure serious latent viral infectious diseases, today announced that it will make an oral presentation on April 24, 2024, at CRISPRMED24, the first CRISPR Medicine Conference, which is being held from ...
Natural History, Clinical Manifestations, and Pathogenesis of Hepatitis
Hepatitis A virus (HAV) is transmitted by the fecal-oral route and is a major cause of acute viral hepatitis. The clinical manifestations of HAV infection range from asymptomatic infection to acute liver failure (ALF), but do not include progression to chronic hepatitis. Risk factors for severe acute hepatitis A are older age (>40 years) and ...
PDF www.cquin.icap.columbia.edu HTN/HIV facility and community models of
clinical screening ART CLINIC Clinician's (ART Drs, Nurses & CHEWs) assessment and diagnosis of NCDs and OIs as per National HTN/DM protocol; Adherence counselling and treatment monitoring ART CLINICIAN Multi-disease clinical screening and assessment ART TRIAGE Lab test for TB, COVID 19 and LAB other OIs PLHIVs with signs of TB and Other OIs

Overview of Acute Viral Hepatitis

Etiology of Acute Viral Hepatitis

Symptoms and Signs of Acute Viral Hepatitis

Diagnosis of Acute Viral Hepatitis

Initial diagnosis of acute hepatitis

Simplified diagnostic approach to possible acute viral hepatitis

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Pathophysiology and Clinical Presentation – Correct Diagnoses

Roingeard, P., & Hourioux, C. (2007). Hepatitis C virus core protein, lipid droplets and steatosis. Journal of Viral Hepatitis, 15 (3), 157-164. doi:10.1111/j.1365-2893.2007.00953.x

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Natural History, Clinical Manifestations, and Pathogenesis of Hepatitis A

Sook-Hyang Jeong

NATURAL HISTORY OF HEPATITIS A

CLINICAL MANIFESTATIONS OF HEPATITIS A

Laboratory Findings and Diagnosis

Complications of Acute Hepatitis A

Acute Liver Failure in the Setting of HAV Infection

Extrahepatic Manifestations

PATHOGENESIS