It seems like a truism, but establishing the cause of hepatitis of unknown origin is not easy. The investigation has nothing to envy to those of Sherlock Holmes or, in any case, those of his famous healthcare alter ego, Dr. House.
As the weeks go by, the hypotheses are expanded and new ones are opened. time is short: the World Health Organization has already warned that it is a “very urgent” public health problem and to which they are prioritizing.
The United Kingdom Health Security Agency has indicated, in its latest report, that findings continue to suggest adenovirus infection but other causes continue to be exploredsuch as another infection or an environmental cause.
They have even added the possibility of increased susceptibility due to reduced exposure to adenoviruses during the pandemic or if there has been a change in the virus genome that has led to the appearance of liver damage.
Spain is working under the coordination of the United Kingdom and the European Center for Disease Control (ECDC) to establish the guidelines to follow in determining cases and how to act to find out their origin.
“Establishing a causal relationship is complicated, especially since adenoviruses, like SARS-CoV-2, are very common,” he says. Raphael ToledoProfessor of Parasitology at the University of Valencia.
“You have a cohort [un grupo representativo de la población] cases of hepatitis and you see a certain prevalence of adenoviruses, but if you take a cohort of children who have not suffered from hepatitis, the prevalence is probably very similar“.
Added to all this is a circumstance that further complicates the situation: unknown hepatitis – that is, its origin has not been clearly clarified – are frequent in the population, not only in children.
In fact, in Spain the number is very similar to that given in other years. It has been the alert issued by the United Kingdom, which is experiencing a significant increase, which has moved other countries to check their own data and identify those cases that may be related to the British.
“In Spain we only have a slight increase between 0 and 4 years”, observes Toledo. Although the initial British alert considered those under 11 years of age, it has been extended to 16 (as probable cases) and there are even cases identified with 19 years of age. In total, there would be more than 200 cases worldwide.
Hepatitis of unknown cause
The protocol of ECDC to report possible cases of hepatitis of unknown origin consists of 28 pages specifying from the age, symptoms and previous conditions that the minor may have to their vaccination status against Covid (including which vaccine was administered and when) or laboratory tests for transaminases, bilirubin, adenoviruses (in stool, respiratory samples, or blood tests), and numerous others for different viruses.
In other words, not all hepatitis whose origin is unknown is valid. In Spain, the average number of hospitalizations for hepatitis of unknown origin in children between 2016 and 2020 was 116.4 per year, 38.8 in four months. Health has already ruled out some of those that it had included at first.
“There may be around 10% of cases of hepatitis [de todas las edades] of which the cause is never identified”, explains Raul Andradeprofessor of Medicine at the University of Malaga and director of the Digestive Clinical Management Unit at the Virgen de la Victoria University Hospital, in the same city.
“It also occurs in acute liver failure, in some countries around 30% is of unknown cause, probably viruses or toxic, like some herbs that are sold in herbalists“, he points out.
The discovery of new hepatitis viruses has been a not too distant phenomenon. The A and B viruses are the best known and most distant in time: the B virus was discovered in the 1960s by Baruch Blumberg when he verified that many patients had received blood transfusions. For this discovery he won the Nobel Prize in 1976.
However, there was a part of patients with chronic inflammation of the liver who had received transfusions and in whom the B virus was not detected. In 1989, the C virus was discovered, which led Harvey J. Alter, Michael Houghton and Charles M. Rice the Nobel Prize in Medicine and Physiology in 2020. A few years earlier the hepatitis E virus had been discovered.
There are also viruses that cause hepatitis in the context of a systemic viral infection, such as the Epstein-Barr virus, which causes mononucleosis, but whose symptoms “do not occur exclusively in the liver, and the information available on these cases does not speak of symptoms other than liver symptoms”.
Therefore, the doctor is waiting for the publication of a scientific article where there is a complete description of the situation. “The first thing is to think of an infectious cause, which is the most frequent in hepatitis“, he points out, and recalls the importance of the epidemiological context: if there are outbreaks in nearby environments “we must think of an infectious cause, especially in fecal-organ transmission (as in hepatitis A), it may be a virus that we have not been able to identify.
Rafael Toledo assesses the possibility of a new virus, although he sees it as complicated because “they leave certain characteristic signs of a pathology, infiltrates, cirrhosis and curious things that have been detected.”
Combination of factors
In the United Kingdom, which has a powerful health surveillance system, the increase in hepatitis of unknown origin has gone hand in hand with an increase in adenovirus infections (which generally cause respiratory disease). In fact, type 41 has been singled out as the main suspect. But of course: “If it were caused by the adenovirus, 100% of the cases should be positive for adenovirus and it turns out not.” Only 75% of the 53 samples analyzed so far tested positive.
“It will be necessary to carry out analysis of the presence-absence of infections, of the livers through biopsy or of those that have been transplanted and, above all, the epidemiological parameters are going to have a lot of value”, points out the professor of Parasitology.
“The important thing is not to identify the cause but to discern if it falls within that baseline casuistry [de hepatitis no filiadas] Or is it something extraordinary? Why does it occur in children between the ages of 1 and 9, and why now?”
Toledo is inclined to think that some environmental factor may have to be added to the equation to clarify the matter. “It’s probably a combination of factors.” He also acknowledges the possibility, pointed out by the United Kingdom Health Security Agency, that there is an immune debt against adenoviruses caused by their absence during these two years of pandemic. They are all hypotheses that must be discarded until there is only one left.
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This is how the origin of childhood hepatitis that worries the WHO is being investigated in record time