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Hepatitis A and Allergic Diseases

A recent hepatitis A outbreak has raised eyebrows in June, 2013[1]:

At least 87 people are now sick in eight states and 36 have been hospitalized with acute hepatitis A infections tied to a contaminated frozen berry and fruit mix sold at Costco and Harris Teeter stores.

In this article, we will examine a different perspective of hepatitis A on human's health: It could be beneficial unless you have the long form of TIM-1 in your gene and Hepatitis A infection have caused you liver failure (see below).

What's Hepatitis A?

Hepatitis A is an acute infectious disease of the liver caused by the hepatitis A virus (HAV)[15].  Hepatitis A is spread when human feces contaminates food or when an infected food handler prepares food without appropriate hand hygiene. The viral liver disease can cause mild to severe illness lasting a few weeks to several months. 

In a research[7], scientists have found that there exists a population at higher risk for HAV-induced liver failure, in contrast to the asymptomatic or mild disease experienced by the majority of patients.   Patients having one or two copies of the long form of TIM1a member of the TIM (T cell, immunoglobulin, and mucin domain) gene family,  was associated with a greater risk of developing severe HAV-induced liver failure, while having the short form was associated with protection against severe hepatitis.

Symptoms of HAV infection can include:
  • Fatigue
  • Nausea
  • Vomiting
  • Abdominal pain
  • Low fever
  • Yellowing of the eyes and skin 
  • Dark urine
    • Bile is removed from blood stream and excreted in urine, giving it a dark amber color
  • Clay-colored feces
But not everyone who contracts hepatitis A shows signs of disease.  There are HAV vaccination available for the public.  However, shots to prevent the illness must be received within two weeks of eating contaminated food in order to prevent illness.

Hepatitis A and Allergic Diseases

The orofecal route (or alternatively the oral–fecal route or fecal-oral route) is a route of transmission of a disease, when pathogens in fecal particles pass from one host and introduced into the oral cavity of another host.  Hepatitis A traveled the orofecal route: Widespread infection meant that stool regularly ended up in food and water. And, hepatitis A infection might simply be a marker for other orofecal infections in general.

An epidemiologist named Paolo Matricardi looked at allergic disease in more than 1600 Italian air force cadets[2]. Those infected with hepatitis A, he found, had half the risk of allergy of those who'd never encountered the virus.

"Indeed, we found that infections transmitted by contaminated food and the orofecal route were inversely related—in a dose-dependent manner—to atopy and respiratory allergies," lead study author Paolo M. Matricardi, MD, recently told RESPIRATORYREVIEWS[3].

The same conclusion was also drawn from the data collected during the Third National Health and Nutritional Examination Survey, or NHANES, in US. The researcher have found that:

For those born before 1920, exposure to the virus conferred no relative advantage.  Everyone born in the early twentieth century, both hepatitis-positive and -negative, had the same odds of allergy—which is to say, less than half the risk of the generation born during the 1960s.  Generally, about 2.7% of those born in the first two decades of the twentieth century developed hay fever, compared with 8.5% of those born in the 1960s. But for those exposed to hepatitis A, the prevalence remained steady at 2% in all decades.

The study also looked at other parasites that are infected via orofecal route:

  • Toxoplasma gondii (a single-celled parasite native to cats)
  • Helicobacter pylori (a corkscrew-shaped bacterium that inhabits the stomach)

Interestingly, scientists have found that: The protective effect for allergies was additive.  Infection with one bug lowered the chances of allergy by nearly one-third.  Infection with two or more lessened the odds by half again.  In all, there was a nearly threefold difference in allergy risk between cadets exposed to more than one of these parasites compared with those exposed none.

By comparison, diseases which were infected via airborne route:

  • Chicken pox
  • Herpes virus
  • Mupmps
  • Rubellla
  • Measles
didn't protect against allergies.  

Figure 1.  The immunopathology of hepatitis A and its relationship to allergic disease.

Hygiene Hypothesis[16]

Later scientists have proposed that allergic disease didn't result from excess exposure to allergens, but from limited exposure to microbes (for example, the ones affect us via orofecal route).  Scientists used the seesaw model of the immune system to explain the phenomenon[7, 10,11].

The immune system had two mutually exclusively responses[4]:
  • Th1
    • Th1 is the host immunity against intracellular bacteria and protozoa.
    • The painful, red swelling around an infected cut or pimple exemplified a Th1 response.
  • Th2
    • Th2 is the host immunity against multicellular heminithes and blood-feeding insects.
    • The itchy red bump of a mosquito bite typified Th2.
    • A misdirected Th2 response—an attack mistakenly directed at birch pollencat hair, or cockroach proteins—typifies allergic disease.  
This  HAV-induced protection against allergic diseases, particularly allergic asthma, has been known for some time. It was first reported that the frequency of multiple sclerosis and type 1 diabetes, two autoimmune diseases, was negatively correlated with anti-HAV seropositivity, used as a marker of poor hygiene[12].

It was thereafter established in a case-control study that patients with anti-HAV antibodies developed reduced frequency of allergic asthma when compared with HAV antibody–negative subjects [13]. Furthermore, it was shown that among anti-HAV antibody carriers, individuals expressing the long form of TIM-1 were protected from allergic asthma [9].

How can one reconcile these observations? An interesting possibility is that the long form of TIM-1 is associated with a “strong” response to HAV, which will contribute first to severity of hepatitis and secondly to protection against allergy (Figure ​1). If this were the case, it would suggest that it is not only the existence of an anti-HAV response that affords protection, but rather its intensity, the underlying molecular mechanisms of which remain to be defined. This explanation would fit with some of the mechanisms proposed to explain the hygiene hypothesis, notably antigenic competition, which suggests that strong anti-infectious immune responses compete with responses against weak antigens such as allergens and autoantigens.

Figure Credit
  • Figure 1 from [7]


  1. 87 now sick with hepatitis A linked to frozen berry mix
  2. Matricardi PM, Rosmini F, Riondino S, et al. Exposure to foodborne and orofecal microbes versus airborne viruses in relation to atopy and allergic rhinitis: epidemiological study. BMJ. 2000;320:412-417.
  4. An Epidemic of Absence — A New of Understanding Allergies and Autoi mune Diseases (excellent book)
  5. Are Dogs More Protective For Children’s Health? (Travel and Health)
  6. Can Parasites Heal the Gut? (Travel and Health)
  7. Genetic control of hepatitis A severity and susceptibility to allergy
  8. McIntire JJ, et al. Identification of Tapr (an airway hyperreactivity regulatory locus) and the linked Tim gene family. Nat Immunol. 2001;2(12):1109–1116. doi: 10.1038/ni739.
    • Their finding provided the first robust molecular explanation for the inverse relationship between HAV infection and the development of allergic hypersensitivity.
  9. McIntire J, et al. Immunology: hepatitis A virus link to atopic disease. Nature. 2003;425(6958):576. doi: 10.1038/425576a.
    • It was shown that individuals expressing the long form of TIM-1 were protected from allergic asthma.
  10. Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med.2002;347(12):911–920. doi: 10.1056/NEJMra020100.
  11. Okada H, Kuhn C, Feillet H, Bach JF. The ‘hygiene hypothesis’ for autoimmune and allergic diseases: an update. Clin Exp Immunol. 2010;160(1):1–9.
  12. Bach JF. Predictive medicine in autoimmune diseases: from the identification of genetic predisposition and environmental influence to precocious immunotherapy. Clin Immunol Immunopathol. 1994;72(2):156–161. doi: 10.1006/clin.1994.1122.
  13. Matricardi PM, Rosmini F, Panetta V, Ferrigno L, Bonini S. Hay fever and asthma in relation to markers of infection in the United States. J Allergy Clin Immunol. 2002;110(3):381–387. doi: 10.1067/mai.2002.126658.
  14. Vaccine Turns Off Autoimmunity in Type 1 Diabetes
    • A "reverse vaccine" was researched at Stanford, that was found to shut down the destructive immune response against insulin-producing beta cells helped preserve pancreatic function in patients with type 1 diabetes.
  15. Risk Factors of Liver Diseases (Travel and Health)
  16. Graham A. W. Rook. Hygiene hypothesis and autoimmune diseases.  Clin Rev Allerg Immu 2012 Feb; 42(1):5-15.
  17. Asthma (Mayo Clinic)
    • Asthma can't be cured, but its symptoms can be controlled.
  18. Justin Sonnenburg on "The Good Gut"
  19. Asthma Associated with Decreased Sepsis-Related Mortality
    • Asthma’s complex immunopathology involves several major mechanisms.  Read this article for more details.