HistorID
How Hepatitis Got Its Letters
Before 1947, viral hepatitis had two names: infectious hepatitis and serum hepatitis. Both were misleading. A British physician replaced them with neutral letters — A and B. That decision locked the field into an alphabet it never escaped, and when a third form appeared in 1975, it spent 14 years being called 'non-A, non-B.'
The hepatitis alphabet was not designed. It was improvised. MacCallum chose A and B in 1947 to avoid making assumptions. Alter named 'non-A, non-B' in 1975 because he had no virus to name. When the virus was finally found in 1989, the letter C was waiting. The naming system worked not because it was clever but because it was neutral. It didn't pretend to know things the science hadn't yet figured out.
The hepatitis alphabet sounds inevitable: A, B, C, D, E. But nothing about it was planned. Before 1947, viral hepatitis had exactly two names: infectious hepatitis and serum hepatitis. The first was supposedly spread by food and water. The second was supposedly spread by blood. The distinction was epidemiologically useful but biologically wrong. Both viruses could spread both ways. The names were misleading, and a British physician named F.O. MacCallum decided to fix them. What he did next locked the field into an alphabet it is still using, three-quarters of a century later, for reasons nobody could have predicted.
Historical scene
The problem MacCallum faced in 1947 was practical. During the Second World War, outbreaks of jaundice had swept through soldiers who received vaccines prepared with human serum, and through civilians in crowded camps and hospitals. The old labels \u2014 infectious and serum \u2014 assumed clean distinctions that did not hold. MacCallum argued in The Lancet that both forms could be transmitted by either route. He proposed discarding the old names entirely and replacing them with Hepatitis A and Hepatitis B. The letters carried no assumptions about transmission, no claims about virology. They were just letters. That was the point.
What happened
The letters took hold, and for a while two seemed enough. Then, in 1975, Harvey Alter at the NIH discovered that most cases of post-transfusion hepatitis were caused by neither A nor B. He had found a third disease but he had no virus to name it after. Nobody did. The agent was invisible under electron microscopy, unculturable in the lab, and undetectable by any serologic test. So Alter did the only honest thing possible. He named it by what it was not: non-A, non-B hepatitis. A disease that infected millions of people was officially called a triple negation.
The name was awkward, but it was truthful. Blood banks could only screen for it indirectly, using surrogate markers like ALT levels, starting in the mid-1980s. Before screening began, post-transfusion hepatitis occurred in up to 10 percent of transfusion recipients. For 14 years, non-A, non-B hepatitis was a ghost \u2014 clinically devastating, epidemiologically undeniable, and nameless in any positive sense. Then, in 1989, a team at Chiron Corporation in California, led by Michael Houghton and including Qui-Lim Choo and George Kuo, used a blind immunoscreening approach to clone the virus from infected chimpanzee plasma. They published in Science. The ghost had a genome. The name that had been waiting since 1975 snapped into place: Hepatitis C. Alter, Houghton, and Charles Rice shared the 2020 Nobel Prize for the discovery.
D and E followed naturally. Mario Rizzetto in Turin discovered the delta antigen in 1977 while studying liver biopsies from hepatitis B carriers. At first he thought it was a new HBV antigen. It turned out to be a defective virus that requires HBV to replicate \u2014 Hepatitis D, the only subviral human pathogen. In 1983, the Soviet virologist Mikhail Balayan needed to prove that an unexplained hepatitis outbreak among soldiers in Afghanistan was enterically transmitted. With no animal model, he drank a pooled stool extract from infected soldiers. He developed acute hepatitis 36 days later and detected the virus in his own stool. It became Hepatitis E.
The alphabet also got ghosts. In 1994, researchers proposed Hepatitis F after finding virus-like particles in post-transfusion patients. Subsequent investigations could not confirm its existence, and the letter was vacated. Hepatitis G was found the following year \u2014 a real flavivirus that infects about 2 percent of blood donors \u2014 but exhaustive study showed it causes no disease. It is now classified as human pegivirus, an orphan virus that occupies a letter without an illness. The alphabet had outrun the diseases.
Why it changed infectious diseases
The hepatitis naming system succeeded because it was humble. MacCallum chose letters in 1947 to avoid making assumptions about transmission routes that might later prove wrong. Alter named a ghost in 1975 because he had no alternative but honesty. Both decisions turned out to be more durable than any descriptive name could have been. Descriptive names \u2014 picornavirus hepatitis, flavivirus hepatitis, enteric hepatitis \u2014 would have had to change every time the virology was refined. The letters absorbed new knowledge without breaking. When the molecular biology caught up, the names were waiting.
Why the letters still matter now
The alphabet is now too entrenched to change. Blood banks screen for B and C by letter. Vaccine programs target A and B by letter. Clinicians diagnose and treat by letter. The naming system has become invisible because it works. But behind E is a Soviet virologist who drank infected stool, behind C is 14 years of a disease named by what it wasn't, and behind A and B is a British physician in 1947 who thought that medicine should stop using names that pretended to know more than it did. MacCallum could not have imagined where the alphabet would go. That is exactly why it survived.
References
MacCallum FO. Homologous serum jaundice. Lancet. 1947;250(6480):691-692.
Alter HJ, Purcell RH, Holland PV, Feinstone SM, Morrow AG, Moritsugu Y. Clinical and serological analysis of transfusion-associated hepatitis. Lancet. 1975;2(7940):838-841.
Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science. 1989;244(4902):359-362.
Balayan MS, Andjaparidze AG, Savinskaya SS, et al. Evidence for a virus in non-A, non-B hepatitis transmitted via the fecal-oral route. Intervirology. 1983;20(1):23-31.