Hepatitis B in the Intellectually Disabled: An Historical Prologue

The purpose of this short commentary on the history of the Hepatitis B virus is to increase understanding of immunity to the virus and to present the fascinating story of how medical scientists approached the problem of detecting an unknown virus.

I-Clinical perspective

Before the history of searching for the virus is recounted, it is important to present a brief description of the state of knowledge of Hepatitis B at the present time. As most readers of this Quarterly realize, Hepatitis B and particularly its “carrier state” (which is usually, but not always, inactive) is common in infected individuals with neurodevelopmental disorders and intellectually disabilities (ND/ID). A carrier state, in the context of the way the statement is usually used, means that the patient has a positive Hepatitis (or Australia) antigen (HbsAG) with no evidence of antibodies (anti-Hbs).

The “inactive” carrier state usually includes a negetive HBeAG,which if present indicates a lack of viral replication in the vast majority of cases. The presence of the core antibody, or HBcAB, of the IgG type may rarely be positive when the Hepatitis B antigen is too low to be detectable in the carrier state. The core antibody of the IgM type in acute Hepatitis B may be positive in the window between a positive Hepatitis antigen (HBsAg) and Hepatitis B antibody (anti-HBsAg) [see Figure 1]. Unlike the carrier state, the Hepatitis B antibody eventually appears, and the antigen does not persist indefinitely [see Figure 1]. The introduction of a positive HBeAG and an elevation in HBV DNA, accompanied by a significant increase in alanine transferase may indicate an active carrier state. It may also indicate Hepatitis B itself depending on the degree of elevation as well as symptoms. Thus, there are three degrees of infection: the inactive carrier state, the active carrier state and accute or chronic hepatitis,depending on the length of elevat of these parameters. All must be followed by periodic serologic and liver function studies and occasionally an HBV DNA level.

Fig. 1: Time Course of Laboratory Findings in Hepatitis B

The reason, of course, that physicians, nurses and ICF/MR staff are concerned with the incidence of Hepatitis B is because there seems to be a higher incidence of carriers in institutions relative to the general population. This is thought to occur largely because of the close contact of the residents and the presence of syndromes like Down syndrome with associated immune deficiencies that make them more likely to become carriers.

In a paper by Vellinga, et al from the Journal of Intellectual Disability Research in 1999, the authors reviewed patients who were HBsAG positive. It varied from a low of 9.7% for patients with Down syndrome and 6.3% for other neurodevelopmental disorders, in one study, to 26.8% for patients with Down syndrome and 1.6% for patients with other neurodevelopmental disorders, in a second. Not only does this point out the magnitude of the problem in the ID population, but it also highlights the increased susceptibility of Down syndrome to hepatitis B. The putative cause of the increased susceptibility among Down syndrome patients is their lack of both cellular and humoral immunity.

II-The History of the Discovery of the Virus

Beginning in 1963, Dr Baruch Blumberg of the National Institutes of Health and the Fox Chase Cancer in Philadelphia became interested in a precipitin (an antibody that reacts with antigens found in the same species) found in the serum of many patients with thalesemia who had received multiple transfusions. Immunological and centrifugal studies, as well as a particular staining pattern (named Sudan black) concluded that the precipitin reacted with a lipoprotein from normal serum. The lipoprotein from normal sera formed a line on the agar gel diffusion plates.

Dr Blumberg became interested in what other proteins reacted with the precipitin found in the serum of patients who had received multiple transfusions, and he was particularly interested in proteins from serum from other cultures and their reaction with the precipitin from the patients who had multiple transfusions (many of these patients had hemophilia). In the process of studying sera (and therefore antigens), he found that one of the serum specimens, which happened to be from an Australian Aborigine, reacted with the serum from two hemophilia patients who had a history of multiple transfusions. The staining of the lines which represented the convergence of the antigen and antibody characteristic of the isoprotein found in normal serum, but instead showed a positive reaction with carmine red stain. Thus, the Australia antigen was born.

More immunodiffusion experiments were performed to be certain that the lipoprotein and the Australia antigen were truly different. The diagrammatic representation below [see Figure 2] demonstrates that they were. To simplify a complex procedure, the lines from the anti-lipoprotein antibody and the lines from the anti-Australian antibody are not of similar thickness or orientation. Furthermore, the line from the precipitin and lipoprotein were stained with Sudan black and the line from the anti-Australian antibody and Australian antigen were stained with carmine red. The lines crossed, demonstrating some similarities between the two antigens.

Figure 2: Diagramatic Representation of Immunodiffusion Studies of the Australian Antigen

An interesting finding that resulted from the above studies was the observation that some leukemia patients were positive for the Australia antigen, and that a virus (along with an abnormal immune reaction) was thought to be the cause in some cases. Blumberg postulated that patients with Down syndrome, who were frequently Au positive and had a tendency to develop myelogenous leukemia (rarely) as well as the Australian antigen (more commonly), were candidates for further investigation of their immune status. These patients were admitted to the Jeannes Hospital Clinical Research Unit in Philadelphia.

One of the patients who had initially been Au negative developed what Dr. Blumberg termed a new “protein” while on the unit. Liver function tests indicated that he had a high SGOT and abnormal prothrombin time, while a liver biopsy showed hepatitis. At this point a second Au antigen was drawn and was found to be positive. This was the kind of epiphany Dr. Blimberg was hoping for. The new hepatitis protein and Australia antigen were one in the same--or to be more precise, two of the three particles of the hepatitis virus on later electron microscopic studies contained the antigen.

This discovery occurred in 1966. In 1967, one of Dr. Blumberg’s technicians developed Au+ hepatitis from working with seropositive sera. In 1969, Dr. John Senior screened all blood that was to be transfused for the Australia antigen at Philadelphia General Hospital. Senior reduced the incidence of post transfusion Hepatitis from 18% to 6% in one year. Dr. Blumberg received the Nobel Prize for his work in 1976.

Meanwhile, another study had been led by Dr. Sol Krugman in 1964 at Willowbrook State School on Staten Island. It had been observed previously that there seemed to be one type of Hepatitis with a relatively short incubation period of 4 to 6 weeks and a second type that was observed after blood transfusions so the incubation period could be determined fairly precisely. This second type had a range of 6 weeks to 6 months and was often called Serum Hepatitis. Hepatitis with both a long and short incubation period had been observed in the South Pacific during War II and in Korea and has been observed in other ICFs/MR similar to Willowbrook.

Figure 3: Ward at Willowbrook School Circa 1955

Dr. Krugman observed that most residents, the majority of whom were children, seemed to develop Hepatitis within 6 to 12 weeks of admission. The institution was over-crowded, and the patients lived and slept in close proximity to each other [see Figure III].

This project was reviewed by the New York University ethics committee, the Armed Forces ethics committee and the New York State Department of Mental Hygiene. The patients who were studied were new admissions for the most part and were admitted after obtaining informed consent from the parents. The note from the Director, which served as “informed” consent, was as follows:

Dear Mrs. ------,

We are studying the possibility of preventing epidemics of hepatitis based on a new principle. Virus is introduced and gamma globulin given later to some so that either no attack or only a mild attack of hepatitis is expected to follow. We should like to give your children this new form of prevention with the hope that it will afford protection. [Gamma globulin had indeed been given to some of the students and prevented or attenuated an attack-author’s comment.]

A permission form is enclosed for your consideration. If you wish to have your child given the benefit of this new prevention, signify by signing the form.

This consent form does not mention that children who were well when they arrived would be given a live virus and that not all the attacks were expected to be mild. Gamma globulin, which had shown some effect in attenuating the disease, would not be given to everyone. Indeed, the tone of the letter was that the institution was providing a service rather than conducting an experiment. Nevertheless, the waiting list was long and placement would be facilitated if the parents agreed to place their child in the new research unit.

The description of the trials along with the results and clinical implications is presented below:

FIRST TRIAL

The first trial was done with a pool of Willowbrook Serum obtained from 27 Willowbrook patients three to seven days before the onset of jaundice. The pool was called WSP-5. The pooled serum was given orally to 11 of 13 patients admitted to the special unit. Two of the children served as controls. All students were isolated from other students at the school. Ten of the 11 fed children developed hepatitis. Nine of the 10 fed students who developed Hepatitis had an incubation period of 30 and 58 days, while one of the students had an incubation period of 165 days. It appeared that most of the students had developed short incubation, infectious Hepatitis, what we now call Hepatitis A.

SECOND TRIAL

This time the decision was made to see if there was more than one infectious agent that might produce Hepatitis with a longer incubation period that had been observed clinically. Indeed, this was the case when the WSP-5 pool was given intramuscularly to ten patients, six of whom developed Hepatitis with a longer incubabation period of 38 to 102 days. The elevation of SGOT also persisted for a longer period--17 to 64 days compared, as compared with 5 to 17 days during the first trial. This seemed to correspond to the second type of virus with a long incubation period (the WSP-5 was not a pure preparation).

What was perhaps more striking was that 4 patients who developed a second attack of Hepatitis had longer incubation periods than they did in the first trial, ranging between 66 to 82 days compared to 31 to 51 days during the first trial. Serum from a patient named Mir who had two attacks was obtained before the onset of jaundice and after recovery from the first attack. Therefore, the serum obtained prior to the first attack (one week before) should contain the virus responsible for the first attack, and serum obtained 6 months after the first attack should contain an antibody conferring immunity to infectious or short incubation Hepatitis. Also, the serum before the second attack should contain the agent responsible for the second attack. The serum obtained before the first attack was termed MS-1, and the serum obtained prior to the second attack was termed MS-2 (six months later the serum obtained from Mir should confer immunity against the agent causing serum or long incubation Hepatitis).

THIRD TRIAL

The next step was to determine whether MS-1 serum caused Hepatitis among newly admitted well children. To determine this, MS-1 serum was given intramuscularly to 8 of these children. Seven developed Hepatitis, most of which were anicteric. The incubation period was relatively short at 30 to 38 days. This was additional evidence that there was an agent out there that caused short incubation, infectious Hepatitis or what we now call Hepatitis A. A transient rise of serum liver function studies (SGOT) was demonstrated for 3 to 19 days.

FOURTH TRIAL

Fourteen newly admitted children were studied during the fourth phase, and nine were given a dose of MS-2 serum or long incubation period Hepatitis. As was observed, seven of nine patients developed Hepatitis with an incubation period of 41 to 69 days, and elevated liver function studies frequently persisted over 100 days. The patients with “serum” hepatitis and a long incubation period were found to be less infectious.

FIFTH TRIAL

The MS-2 virus was fed to six asymptomatic children accompanied by gamma globulin, and although five of the six developed anicteric hepatitis, they remained asymptomatic. The incubation period was between 64 and 209 days. This part of the study demonstrated that while gamma globulin attenuated the symptoms, liver inflammation still persisted for a considerable period of time. It also demonstrated that at least this virus preparation could still cause long incubation viral Hepatitis.

SIXTH TRIAL

Since the fifth trial indicated the MS-2 Hepatitis was contagious by mouth, it was thought important to confirm this finding. The MS-2 virus was given to six patients orally without gamma globulin. Five of the patients developed anicteric, asymptomatic hepatitis with an incubation period between 88 and 108 days. Why contamination of the saliva caused serum or blood-bourn Hepatitis was not explained. Other literature has postulated that open oral lesions might be responsible in such cases.

SEVENTH TRIAL

The presence of homologous immunity was demonstrated by the fact that when the seven of eight subjects who developed Hepatitis after injection with the MS-1 virus were re-challenged with MS-1, no cases of Hepatitis were observed; whereas five of six patients who had MS-1 Hepatitis after MS-1 inoculation developed Hepatitis after inoculation with MS-2, so heterologous immunity was not present.

CONCLUSION AND THOUGHTS

Stated very simply, Dr. Blumberg discovered the cause of “serum hepatitis”, and Dr. Krugman clearly demonstrated that the two viruses (A and B) were different; since that time, Hepatitis C, D, E and G have been identified. We now know that Hepatitis B, C and D can cause liver cancer and cirrhosis (usually in adults) as well a number of other syndromes, and treatment is now available.

In my personal opinion, the problem in the case of the people with ND/ID is the carrier state, particularly when these individuals leave institutions-- How contagious are they and how can we evaluate their degree of contagiousness? Are there problems that need special attention that are not dealt with adequately by universal precautions? How should a staff member who undergoes suspected exposure by needle stick or other means be treated?

When both HBsAg and HBsAb are positive, what does this mean? When an intellectually disabled patient develops elevated liver function studies, what are the major differential diagnoses? Patients with Down syndrome and Williams syndrome have an increased incidence of gall bladder disease and those with Smith-Lemli-Opitz syndrome may develop cholestasis. At times we wonder about how aggressive we should be. For example, how often should we perform a follow-up ultrasound on a patient with Tuberous Sclerosis liver lesions, and when should we consider a biopsy?

Further analysis of these questions will be the topic of discussion at the combined meeting of The American Academy of Developmental Medicine and Dentistry and the Developmental Disabilities Nurses Association at the Foxwoods Resort in Connecticut from June 7 to June 10.

References

1. Blumberg B, Alter H, and Visnich S, A new antigen in leukemia sera. Journal of the American Medical Association, 191:541-546, 1965.

2. Blumberg B. Australia antigen and the biology of Hepatitis B. Nobel Lecture, December 13, 1976 (Available on the internet under Dr Blumberg’s biography)

3. Krugman S, Giles J, Hammond J. Infectious Hepatitis. Journal of the American Medical Association, 200:365-373, 1967.

4. Vellinga A, Van Damme P, and Meheus A, Hepatitis B and C in institutions with intellectual disability. Journal of Intellectual Disability Research. 43:445-451, 1999.

Dr. Ned Rapp has served as an Executive Board Member-at-Large since September 2006 and also works as a consultant in Development Disabilites in Penn Valley, PA.