Amy Staples
Bio Lab- Thurs 7 pm
AUTOIMMUNE LIVER DISEASES AND STRONGYLOIDES
STERCORALIS INFECTION HAVE AN INVERSE RELATIONSHIP
HAJIME AOYAMA,TETSUO HIRATA, HIROSHI SAKUGAWA, TAKAKO WATANABE,
SATORU MIYAGI, TATSUJI MAESHIRO, TAKAYUKI CHINEN, MARIKO KAWANE,
OSAMU ZAHA, TOMOKUNI NAKAYOSHI, FUKUNORI KINJO, AND JIRO FUJITA
Division of Control and Prevention of Infectious Diseases, Department of Medicine and Therapeutics, Faculty of Medicine, University
of the Ryukyus, Okinawa, Japan; Department of Internal Medicine, Heartlife Hospital, Okinawa, Japan; Department of Internal
Medicine, Nakagami Hospital, Okinawa, Japan; Department of Endoscopy, Ryukyu University Hospital, Okinawa, Japan
ABSTRACT
A case-control study was done to analyze the frequency of Strongyloides stercoralis infection among
patients with autoimmune liver diseases. The study involved 4,117 patients who were admitted to hospitals in
Okinawa, Japan. The study was done between 1988 and 2006. 538 patients were found to have the following
chronic liver diseases: PBC, AIH, PSC, chronic viral hepatitis group, and alcoholic liver disease. The rest
(3,579) of the patients who were hospitalized and underwent tests, served as the control group.
INTRODUCTION
Primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH), and primary sclerosing cholangitis (PSC)
are chronic liver diseases. The cause is unknown, however they are thought to be caused by autoimmune
factors. Environmental and genetic factors may have an impact on their development also.
Helminth (parasitic worm) infections are more common in developing countries, where autoimmune
diseases are not. Strongyloides stercoralis is the most common human parasitic helminth. It is found in the
tropics or subtropics. It is a parasitic worm that enters the host through the skin and migrates to the intestines.
Immunomodulation (modification of the immune response) caused by chronic helminth infection could be the
reason that autoimmune diseases were less common among patients with helminthiasis. This is the first study to
concentrate on the relationship between chronic helminth infection and autoimmune liver diseases.
MATERIALS AND METHODS
The study included 4,117 patients that were admitted to the following hospitals between 1988 and 2006:
the First Department of Internal Medicine, Ryukyu University Hospital, Nakagami Hospital, and Yonabaru
Chuo Hospital. All of these patients had a biochemical evaluation done, including liver function tests.
RESULTS
The study included 2,438 men and 1,679 women. The average age was 54.8 years old. 538 patients had
the following chronic liver diseases: PBC, AIH, PSC, hepatitis B virus, hepatitis C virus, HBV and HCV, and
alcoholic liver disease. The other 3,579 patients were the control group. They were hospitalized and tested for S.
stercoralis.
The rate in women was considerably higher than in men. The rate of S. stercoralis infection was
considerably lower in younger people, and none of the female patients born after 1955 were infected. The rate
of S. stercoralis infection in the autoimmune liver diseases group was lower than that found in the control
group. The recurrence of S. stercoralis infection in the chronic viral hepatitis group was slightly lower than that
in the control group and that in the alcoholic liver disease group was slightly higher (see table below).
Prevealence of S. stercoralis infection in chronic liver diseases
Etiology
Number of S. stercoralis + patients/
Male
Female
number of tested patients
Born before
Born after
1955
1955
Autoimmune Liver Diseases
1/105
7
98
85
20
PBC
1/74
3
71
62
12
AIH
0/30
3
27
23
7
PSC
0/1
1
0
0
1
Chronic Viral Hepatitis
14/367
238
129
249
118
HBV infection
4/108
88
19
61
47
HCV infection
10/255
147
108
185
70
HBV & HCV infection
0/4
3
1
3
1
Alcoholic liver disease
6/66
60
6
53
13
Control group
252/3579
2133
1446
2758
821
TOTAL
273/4,117
2438
1679
3145
972
To evaluate the immunologic response, peripheral eosinophil (a white blood cell that plays a part in the
body's response to parasitic diseases) counts were taken in all of the patients. In patients with S. stercoralis
infection, peripheral eosinophil counts were considerably higher than those in patients with autoimmune liver
diseases.
DISCUSSION
The results showed that the recurrence of S. stercoralis infection among patients with autoimmune liver
disease, was lower than the control group.
Okinawa is considered an area of endemic S. stercoralis infection. In this study, the recurrence of S.
stercoralis among women was 4.3%, and most of the patients with S. stercoralis were 40 years old or older. In a
mass survey done in Okinawa, the results in women were similar to the results in the study. This argues the
possibility of study bias. That suggests that the results may accurately reflect the geoepidemiology of S.
stercoralis infection even though this was a hospital-based case-control study.
There were two hypotheses proposed by the authors to explain the low frequency of S. stercoralis
infection among patients with PBC and other autoimmune liver diseases: 1) S. stercoralis infection decreases
the risk of the onset of autoimmune liver disease or 2) autoimmune liver diseases decrease the susceptibility to
S. stercoralis infection. The second hypothesis would not seem possible, because S. stercolaris infection is
percutaneous; thus, the presence of PBC should not affect the infection by S. stercoralis. In contrast, serious
liver dysfunction increases the risk of strongyloidiasis. In this study, most patients with PBC and other
autoimmune liver diseases were in the early stages of development of their disease. Therefore, their daily lives,
which has the most effect on the susceptibility of the helminth infection, should be the same as those in the
control group, Therefore, the hypothesis, that S. stercoralis infection may decrease the onset of autoimmune
liver disease, was formed. Epidemiologic studies have shown that regions of the world with high rates of
helminth infections also show a lower incidence of autoimmune diseases. The inverse relationship between
helminth infection and autoimmune diseases could be a reflection of the imbalance of two different types of Thelper cells.
In this study, peripheral blood eosinophilia (suggest Th2 involvement in the immune response) was
observed in patients with strongyloidiasis but not in patients with autoimmune liver diseases. The antiinflammatory network seems to play a large role in down regulation of autoimmune diseases. Helminths induce
CD4+ regulatory T cells and increase the production of strong immunomodulatory. With this strong antiinflammatory regulatory network, it could help to prevent the development of both Th1-type and Th2-type
immune responses. Therefore, it was hypothesized that helminth infection gives a Th2-type immune response.
This may prevent the Th1-type hepatic inflammation in PBC. On the other hand, because regulatory T cells
suppress the differentiation of Th0 into either Th1 or Th2 cells, these regulatory cells may also be involved in
the immunomodulatory effect of concurrent infection on the course of PBC.
T cells seem to play a large role in the immunopathogenesis of AIH. There have been experiments that
suggest immunoregulatory dysfunction. This was shown by a decreased numbers of CD4+ regulatory T cells in
AIH. These observations suggest that a lower number of regulatory T cells and their ability to expand, may lead
to autoimmune liver disease. Also, CD4+ regulatory T cells induced by chronic helminth infection may
therefore delay the development of AIH.
The results in the study do show an inverse relation between autoimmune liver disease and S. stercoralis
infection. Immunomodulation brought on by chronic S. stercoralis infection may account for this relationship.