Editing Hepatitis (section)

== History ==
=== Early observations ===
Initial accounts of a syndrome that we now think is likely to be hepatitis begin to occur around 3000 B.C.  Clay tablets that served as medical handbooks for the ancient Sumerians described the first observations of jaundice.  The Sumerians believed that the liver was the home of the soul, and attributed the findings of jaundice to the attack of the liver by a devil named [[Akhkhazu|Ahhazu]].<ref>{{cite journal |last1=Trepo |first1=Christian |date=February 2014 |title=A brief history of hepatitis milestones |journal=Liver International |volume=34 |issue=Supplement s1 |pages=29–37 |doi=10.1111/liv.12409|pmid=24373076 |s2cid=41215392 |doi-access=free }}</ref>

Around 400 B.C., [[Hippocrates]] recorded the first documentation of an epidemic jaundice, in particular noting the uniquely fulminant course of a cohort of patients who all died within two weeks.  He wrote, "The bile contained in the liver is full of phlegm and blood, and erupts...After such an eruption, the patient soon raves, becomes angry, talks nonsense and barks like a dog."<ref>{{cite journal |date=July 2012 |title=Viral hepatitis—the silent killer. |journal=Annals of the Academy of Medicine, Singapore |volume=41 |issue=7 |pages=279–80 |pmid=22892603 |last1=Oon |first1=GC|doi=10.47102/annals-acadmedsg.V41N7p279 |s2cid=2757948 |doi-access=free }}</ref>

Given the poor sanitary conditions of war, infectious jaundice played a large role as a major cause of mortality among troops in the Napoleonic Wars, the American Revolutionary War, and both World Wars.<ref>{{cite book |title=Classic papers in viral hepatitis |editor1-last=Lee |editor1-first=Christine A. |editor2-last=Thomas |editor2-first=Howard C. |date=1988 |publisher=Science Press |isbn=978-1-870026-10-9 |location=London, England |others=Foreword by Dame Sheila Sherlock}}</ref> During World War II, estimates of soldiers affected by hepatitis were upwards of 10 million.

During World War II, soldiers received vaccines against diseases such as [[yellow fever]], but these vaccines were stabilized with human serum, presumably contaminated with hepatitis viruses, which often created epidemics of hepatitis.<ref>{{cite journal |date=April 1993 |title=The discovery of the hepatitis viruses. |journal=Gastroenterology |volume=104 |issue=4 |pages=955–63 |pmid=8385046 |last1=Purcell |first1=RH |doi=10.1016/0016-5085(93)90261-a}}</ref> It was suspected these epidemics were due to a separate infectious agent, and not due to the yellow fever virus itself, after noting 89 cases of jaundice in the months after vaccination out of a total 3,100 patients that were vaccinated.  After changing the seed virus strain, no cases of jaundice were observed in the subsequent 8,000 vaccinations.<ref>{{cite journal |date=1946 |title=Homologous Serum Jaundice |journal=Proceedings of the Royal Society of Medicine |volume=39 |issue=10 |pages=649–654 |last1=Bradley |first1=WH|pmc=2181926 |pmid=19993376 |doi=10.1177/003591574603901012 }}</ref>

=== Willowbrook State School experiments ===
A New York University researcher named [[Saul Krugman]] continued this research into the 1950s and 1960s, most infamously with his experiments on mentally disabled children at the [[Willowbrook State School]] in New York, a crowded urban facility where hepatitis infections were highly endemic to the student body.  Krugman injected students with gamma globulin, a type of antibody.  After observing the temporary protection against infection this antibody provided, he then tried injected live hepatitis virus into students.  Krugman also controversially took feces from infected students, blended it into milkshakes, and fed it to newly admitted children.<ref>{{Cite book|title=Intervention and Reflection: Basic Issues in Medical Ethics|last=Munson|first=Ronald|year=1996|pages=273–281}}</ref>

His research was received with much controversy, as people protested the questionable ethics surrounding the chosen target population.  [[Henry K. Beecher|Henry Beecher]] was one of the foremost critics in an article in the ''New England Journal of Medicine'' in 1966, arguing that parents were unaware to the risks of consent and that the research was done to benefit others at the expense of children.<ref>{{Cite journal|last=Beecher|first=Henry|date=1966|title=Ethics and Clinical Research|journal=The New England Journal of Medicine|volume=274|issue=24|pages=1354–1360|doi=10.1056/nejm196606162742405|pmid=5327352|pmc=<!--none-->}}; Reprinted in {{cite journal |pmc=2566401 | pmid=11368058 | volume=79 | issue=4 | title=Ethics and clinical research. 1966 | year=2001 | author=Beecher HK | journal=Bull World Health Organ | pages=367–72}}</ref>  Moreover, he argued that poor families with mentally disabled children often felt pressured to join the research project to gain admission to the school, with all of the educational and support resources that would come along with it.<ref name="ReferenceA">{{cite journal|date=April 1993|title=The discovery of the hepatitis viruses.|journal=Gastroenterology|volume=104|issue=4|pages=955–63|pmid=8385046|last1=Purcell|first1=RH|doi=10.1016/0016-5085(93)90261-a}}</ref> Others in the medical community spoke out in support of Krugman's research in terms of its widespread benefits and understanding of the hepatitis virus, and Willowbrook continues to be a commonly cited example in debates about medical ethics.<ref>{{Cite book|title=The Oxford Textbook of Clinical Research Ethics|last=Emanuel|first=Ezekiel|publisher=Oxford University Press|year=2008|pages=80–85}}</ref>

=== Australia antigen ===
The next insight regarding hepatitis B was a serendipitous one by [[Baruch Samuel Blumberg|Dr. Baruch Blumberg]], a researcher at the NIH who did not set out to research hepatitis, but rather studied lipoprotein genetics.  He travelled across the globe collecting blood samples, investigating the interplay between disease, environment, and genetics with the goal of designing  targeted interventions for at-risk people that could prevent them from getting sick.<ref>{{Cite book|title=Les Prix Nobel|last=Odelberg|first=Wilhelm|year=1976}}</ref>  He noticed an unexpected interaction between the blood of a patient with [[Haemophilia|hemophilia]] that had received multiple transfusions and a protein found in the blood of an indigenous Australian person.<ref>{{Cite journal|last=Alter|first=Harvey J.|date=2014-01-01|title=The road not taken or how I learned to love the liver: A personal perspective on hepatitis history|journal=Hepatology|language=en|volume=59|issue=1|pages=4–12|doi=10.1002/hep.26787|pmid=24123147|issn=1527-3350|doi-access=free}}</ref>  He named the protein the "Australia antigen" and made it the focus of his research.  He found a higher prevalence of the protein in the blood of patients from developing countries, compared to those from developed ones, and noted associations of the antigen with other diseases like leukemia and Down Syndrome.<ref>{{Cite journal|last1=Blumberg BS|last2=Alter HJ|date=1965-02-15|title=A "new" antigen in leukemia sera|journal=JAMA|volume=191|issue=7|pages=541–546|doi=10.1001/jama.1965.03080070025007|issn=0098-7484|pmid=14239025}}</ref>  Eventually, he came to the unifying conclusion that the Australia antigen was associated with viral hepatitis.

In 1970, [[David Dane]] first isolated the hepatitis B [[virion]] at London's Middlesex Hospital, and named the virion the 42-nm "Dane particle".<ref name="ReferenceA"/>  Based on its association with the surface of the hepatitis B virus, the Australia antigen was renamed to "hepatitis B surface antigen" or [[HBsAg]].

Blumberg continued to study the antigen, and eventually developed the first hepatitis B vaccine using plasma rich in HBsAg, for which he received the [[Nobel Prize in Physiology or Medicine|Nobel Prize in Medicine]] in 1976.<ref>{{Cite web|url=https://www.nobelprize.org/prizes/medicine/1976/blumberg/biographical/|title=The Nobel Prize in Physiology or Medicine 1976|website=NobelPrize.org|language=en-US|access-date=2019-10-07}}</ref>