Hepatitis Discovery Saga

Nancy Abdel Fattah Ahmed

Mini Review

Hepatitis Discovery Saga

Nancy Abdel Fattah Ahmed*

Professor of Internal Medicine, (Hepatology and Gastroenterology), Faculty of Medicine, Mansoura University, Egypt

Corresponding Author

Received Date:May 01, 2025; Published Date:June 10, 2025

Abstract

As often with scientific ventures, this hepatitis discovery saga now evolving towards full blessed achievements was a blend of genius thinking, team work, rivalry and serendipity.

Introduction

The liver , considered the centre of life, was examined by well trained “religious experts”. Those experts knew the anatomy of the liver of the sheep. Interesting is the legend of Prometheus, the Titan, who stole the fire from the Gods, to give it to the humans. Prometheus, in eternal punishment, was chained to a rock in a mountain, where his liver was eaten daily by an eagle, to be regenerated night time. This legend supports, that it was known in the antiquity that the liver could regenerate [1]. The first description was found in Sumeria (3rd millennium B.C.) with the first description of jaundice on clay tablets that were the first handbook of medicine. The etiological agent was a devil Ahhazu who attacked the liver, which in those days was the home of the soul. (Hippocrates 460 to 375 B.C.) described the first clinical features of epidemic jaundice including a fulminant course in patients who died within 11 days. The recommended treatment was a diet of honey and water The word icterus was first found in the Hippocratic Corpus [2]. The cause of jaundice was not understood and up till the outbreak of the second world war many clinicians accepted Virchow’s theory that a mucous plug at the mouth of the common bile duct caused “catarrhal jaundice”. The large number of hepatitis cases acted as a major stimulus to understanding hepatitis [3]. Epidemic jaundice was reported by the Greeks and Romans but poorly described and probably confused with malaria and leptospirosis etc. During the middle ages, jaundice was well recognized and blamed on a divine malediction. Patients were considered ‘impure’ and were therefore to be ‘avoided’ and isolated. This was best formulated by Pope Zackary who clearly recommended isolation as the best approach in dealing with an epidemic of jaundice.

Indeed in the 18th century, many epidemics were reported during military campaigns and in particular at the Siege of Saint- Jean-d’Acre in 1799 and Paris in 1870. The American Civil War (1861–1865) was also plagued by 52 000 cases of hepatitis. In World War 2, the estimated death toll from hepatitis was 16 million cases. The US Army identified 150 000 cases whereas 4 million were ‘the census data’ in the German military and civil population Finally, in 1942, there was a major outbreak of hepatitis in the US Navy when 56 000 patients were infected following administration of the yellow fever vaccine contaminated with normal human plasma. Mac Callum made the first historical distinction between two forms of hepatitis in 1947, The ultimate experimental confirmation of the two distinct forms of viral hepatitis was provided by Saul Krugman between 1964 and 1967 at the Willowbrook School (for mentally retarded children) in New York State. All the residents in this institution developed hepatitis often with successive episodes. After careful authorization from the institution and the parents he performed two well- controlled inoculations which generated distinct plasma incubation pools called MS1 and MS2 which were infectious and could transmit either hepatitis A with a short incubation period (30 to 45 days/MS1) or long incubation hepatitis (60–90 days/MS2) [2].

Subsections

The discovery of hepatitis B:

In 1963, Baruch Blumberg, a geneticist working at the National Institute of Health (NIH)on the polymorphism of lipoproteins, observed an unusual reaction between the serum of a poly-transfused haemophiliac and that of an Australian aborigine in an immunodiffusion gel. He thought that he had identified a new lipoprotein. However, the red staining of this reaction was different. The new antigen was called the Australia antigen (Au). In 1967, the serendipity of a lab technician who got jaundice and follow-up studies prompted Blumberg to suggest that the Au antigen was linked to viral hepatitis In 1968, Alfred Prince at the New York Blood Center used the immuno-electrophoretic technique and described a serum antigen that was specifically associated with post transfusion hepatitis that he called the serum hepatitis antigen (SH antigen). The Au antigen and the SH antigen were soon found to be identical and electron microscopic density gradient experiments of Au SH positive serum demonstrated virus like particles. In 1968, Alfred Prince at the New York Blood Center used the immuno-electrophoretic technique and described a serum antigen that was specifically associated with post transfusion hepatitis that he called the serum hepatitis antigen (SH antigen). The Au antigen and the SH antigen were soon found to be identical and electron microscopic density gradient experiments of Au SH positive serum demonstrated virus like particles. In 1970, David Dane identified the famous eponym 42 nm particle, hallmark of the HB virion, and progress was exponential thereafter. Several determinants of the Au antigen were identified and the two major subtypes AY and AD were reported, suggesting the diversity of HBV. Based on the studies by Okochi in Japan, the correlation between the Au/SH antigen in blood donors and post-transfusion hepatitis was established in 1972. The new antigen was renamed the HBs antigen and its detection became mandatory, but fortunately, most of the blood centres had been screening since the 1970s.

The discovery of hepatitis D:

Italian Mario Rizetto in Torino identified a new nuclear antigen distinct from the HBc antigen in 1977 by liver immunostaining. The surprising discordance between strong nuclear staining and an absence of the characteristic ultra-structural core antigen particle in the liver was a first hint. Since this antigen was distinct from the HBc and HBe antigens, it was called the Delta antigen. Although it was always restricted to HBV carriers, this marker was associated with specific clinical forms of the disease Thanks to elegant transmission studies in chimpanzees performed at the NIH in a collaboration between John Gerin and Robert Purcell, the new agent was identified as a defective virus requiring the helper function of HBV for its replication. Although it affects 25 million people worldwide hepatitis D is a neglected disease. At the same time, because of massive immigration and uncontrolled parenteral injection in the developing countries, interest has been renewed in this disease.

The discovery of hepatitis A:

In 1979, Fritz Deinhardt in Chicago successfully transmitted documented clinical and histological short incubation hepatitis to marmosets. The absence of the HBs antigen in cases of short incubation hepatitis helped to identify the agent of epidemic hepatitis, which was characterized as a highly contagious orofecal infection. In 1977, Stephen Finestone at the NIH identified a new agent in stool specimens from acute hepatitis A outbreaks. Soon after the identification of HAV on electron microscopy, specific serology for HAV antigen in stools and HAV antibody in serum (IgM and IgG) was developed. The virus was then grown in tissue cultures and a vaccine was rapidly developed.

The discovery of hepatitis C:

In 1974, soon after the identification of HAV, the Purcell and Finestone groups at the NIH and Prince at the New York Blood Center independently noted that most cases of post-transfusion hepatitis were HBs negative and therefore were neither HAV nor HBV infections. These cases of post-transfusion hepatitis were because of unidentified agents. They were called non-A non-B hepatitis since they could be related to several agents and there was optimism at the time could that they would soon be identified. As we will see, this was not the case at all Investigators were frustrated for many years. In fact, it almost 15 years passed between the identification of the non-A non-B post-transfusion hepatitis entity and the etiologic agent. HCV was finally identified thanks to the close collaboration between the private scientific teams at Chiron Corp. (Emeryville – California) led by Michael Houghton and the team led by Daniel Bradley at the Center for Disease Control (CDC) in Atlanta Georgia. In fact, this discovery introduced a new dimension in viral research: the molecular virology revolution, resulting in the identification of numerous viruses including certain orphan viruses such as hepatitis G virus and the transfusion transmitted virus (TTV). Daniel Bradley at the CDC and Harvey Halter at the NIH, identified high titer plasma infectious inoculums for non-A non-B hepatitis. Thanks to an original direct molecular approach, nucleic acid extracted from plasma was cloned in an expression vector, which generated a library of clones allowing the Chiron team to identify the first epitope, characteristic of the HCV envelope in 1989 HCV and its nucleic acid structure were rapidly identified. HCV is a single strand positive RNA of 9,6 kb. A new paradigm for the identifica tion of infections was born since this was the first time in history that a pathogenic agent was identified with a straightforward molecular biology approach without tissue culture, serology or immune-electron microscopy. Finally, the assembly model and the envelope protein display of HCV was found to be similar to the tick borne encephalitis (TBE) flavirirus and the International Taxonomy Committee classified HCV in the new genus of hepaci viruses in the flaviride family.

The discovery of hepatitis E:

A unique massive water borne epidemic attracted major attention in December, 1955 when 29 300 residents of a New Delhi suburb developed acute hepatitis. Epidemiologically it was surprising to have so many patients who were not immunized against HAV in a developing country, thus, it had to be a distinct agent . Other small outbreaks were studied by Mohamed Sultan Khuroo in Cashmere The same year, the Russian virologist Mikhail Balayan of the Poliomyelitis Institute in Moscow, reported his self-inoculation prompted by an outbreak in Tashkent. After ingesting stool extracts Balayan developed acute hepatitis and used his own feces to look for the virus by immune-electronmicroscopy. He observed 27–32 virus like particles, Daniel Bradley and his team soon successfully transmitted the virus to Marmosets, chimpanzees and then cynomolgus macaques. Then, using the same approach as for HCV, the CDC team successfully identified an antigen characteristic of the hepatitis E virus: a non-enveloped virus with isocahedric symmetry and 27–34 nm in diameter. The genome is a positive single stranded RNA of 7,2 kb. After being initially classified in a separate genus of the caliciviridae, the taxonomic virology committee reclassified it into the Hepeviridae family genus Hepevirus as its sole member.

HEV is the only hepatitis virus with animal reservoirs, mainly pigs. HEV should now be considered a zoonosis as confirmed by phylogenic studies that have traced uncooked pork and deer meat to human outbreaks [2].

Discussion and Conclusion

Hepatitis viruses have been major plagues of mankind. Epidemics of hepatitis A crippled troops and assailed towns over the ages until the 19th century. Giant epidemics of HEV occurred and mysterious mortality of women in late pregnancy persisted in developing countries until recently. Successful HAV and now HEV vaccine will soon eliminate such tragedies. Two billion people are infected with HBV and 350 million are chronic carriers of the virus. New immunotherapy approach combined with antiviral drugs must be developed to extend the benefit of treatment to millions of infected people living in resource limited countries of Asia and Africa. The progress in HCV therapy has been dramatic and successful eradication of the virus by antiviral treatment progressed from 6% with interferon alone in 1986 to more than 80% in 2013 with triple combination therapies. This unprecedented therapeutic victory benefiting hundred millions of people matches the triumphs over small pox, polio and tuberculosis [2].