Download an inverse relationship between autoimmune liver diseases and

Am. J. Trop. Med. Hyg., 76(5), 2007, pp. 972–976
Copyright © 2007 by The American Society of Tropical Medicine and Hygiene
AN INVERSE RELATIONSHIP BETWEEN AUTOIMMUNE LIVER DISEASES AND
STRONGYLOIDES STERCORALIS INFECTION
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 undertaken to describe the prevalence of Strongyloides stercoralis infection
among patients with autoimmune liver diseases, such as primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH),
and primary sclerosing cholangitis (PSC). This study covered 4,117 patients who were admitted to hospitals in Okinawa,
Japan, between 1988 and 2006. During this period, 538 patients had the following chronic liver diseases: PBC, AIH, PSC,
chronic viral hepatitis group, and alcoholic liver disease. The other 3,579 patients who were hospitalized and underwent
parasitologic tests served as controls. The frequency of S. stercoralis infection in the autoimmune liver diseases group
(1.0%) was lower than that found in the control group (7.0%; P ⳱ 0.0063). None of the female patients with PBC born
before 1955 had S. stercoralis infection, which was also statistically significant (P ⳱ 0.045). We hypothesized that
immunomodulation by S. stercoralis infection may lower the incidence of autoimmune liver disease.
nosuppression, many patients chronically infected with S. stercoralis have an asymptomatic infection or mild disease.11
Few epidemiologic studies of parasite infection in patients
with liver diseases have been described.12–14 Hegab and others12 reported a high incidence of opportunistic intestinal protozoa in pediatric patients with chronic liver diseases, but no
S. stercoralis or other helminths were detected. Gaburri and
others13 described a higher prevalence of intestinal parasites
in patients with alcoholic cirrhosis; however, no patients with
autoimmune liver disease were implicated in their study. Until now, no study has focused on the relationship between
chronic helminth infection and autoimmune liver diseases,
such as PBC, AIH, or PSC. We report herein the results of a
case-control study to describe the prevalence of S. stercoralis
infection (also known as strongyloidiasis) among patients
with autoimmune liver diseases, particularly PBC. We subsequently discuss the effect of chronic helminth infections on
autoimmune liver diseases.
INTRODUCTION
Primary biliary cirrhosis (PBC), autoimmune hepatitis
(AIH), and primary sclerosing cholangitis (PSC) are chronic
liver diseases that likely have an autoimmune basis to their
pathogenesis. Although their etiology remains obscure, environmental and genetic factors may play an important role in
the development of these diseases. The majority of surveys
concerning environmental factors and autoimmune liver disease have focused on PBC.1 Some epidemiologic studies have
revealed that environmental factors may be associated with
the onset of PBC in genetically susceptible hosts.2
Helminth infections are highly prevalent in many developing countries, where autoimmune diseases are uncommon.
An inverse epidemiologic relation between helminth infection and autoimmune diseases has been described in some
reports.3,4 Experimental data also showed that parasitic helminths can block autoimmune diseases in mice.5,6 Moreover,
clinical trials have been reported involving the application of
Trichuris suis ova in the treatment of inflammatory bowel
diseases.7 Immunomodulation induced by chronic helminth
infection could be the reason that autoimmune disease was
less prevalent among patients with helminthiasis.8,9
Strongyloides stercoralis is the most common human parasitic helminth. S. stercoralis lives in warm and humid soil, and
its filariform larvae usually infect through the skin of bare
feet. After infection, larvae migrate to the duodenum and
grow into mature females. Rhabditiform larvae hatched from
eggs are ejected from the host; however, some develop into
filariform larvae and reinfect through the large intestine and
the skin around the anus (autoinfection). Therefore, once the
host is infected, this worm is able to complete its life cycle and
proliferate within the host, and the infection can persist for
decades.10 Although hyperinfection occasionally occurs in patients with human T cell lymphotropic virus type 1 or immu-
MATERIALS AND METHODS
Patients. This study involved 4,117 patients who 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 three hospitals are located in Okinawa, Japan. All patients were Japanese and residents of Okinawa. Informed
consent was obtained from all individuals. In all patients, a
detailed history was taken, and a clinical examination was
carried out. All of these patients underwent biochemical
evaluation including liver function tests using standard automated techniques.
Diagnosis of S. stercoralis infection. One fecal sample from
each subject was routinely collected on their admission. Infection of S. stercoralis was diagnosed using the agar plate
culture method.15
Diagnosis of PBC. The diagnosis of PBC was based on the
following criteria: a detectable anti-mitochondrial antibody
(AMA), a persistent increase in biliary enzymes for at least 6
months, and/or compatible or diagnostic liver histology. In
cases of PBC without detectable AMA, criteria were modi-
* Address correspondence to Hajime Aoyama, Control and Prevention of Infectious Diseases, Department of Medicine and Therapeutics, Faculty of Medicine, University of the Ryukyus, 207 Uehara,
Nishihara, Okinawa. E-mail: [email protected]
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STRONGYLOIDES AND AUTOIMMUNE LIVER DISEASES
TABLE 1
Prevalence of S. stercoralis infection
Number of S. stercoralis–positive
patients/number of tested patients (%)
Birth year
Male
Female
Total
1910s and before
32/189 (16.9)
15/123 (12.2)
47/312 (15.1)
1920s
62/489 (12.7)
26/311 (8.4)
88/800 (11.0)
1930s
72/585 (12.3)
22/397 (5.5)
94/982 (9.6)
1940s
28/373 (7.5)
8/289 (2.8)
36/662 (5.4)
1950s
6/340 (1.8)
1/230 (0.4)
7/570 (1.2)
1960s
1/247 (0.4)
0/168 (0.0)
1/415 (0.2)
1970s and after
0/215 (0.0)
0/161 (0.0)
0/376 (0.0)
Total
201/2,438 (8.2)* 72/1,679 (4.3) 273/4,117 (6.6)
* P < 0.001 versus female.
fied as follows: diagnostic histologic findings and a persistent
increase in biliary enzymes.
Diagnosis of AIH. The diagnosis of AIH was based on the
criteria of the International Autoimmune Hepatitis Group.16
Serologic tests for anti-nuclear antibodies, anti-smooth
muscle antibodies, and anti-liver/kidney microsomal antibodies were performed using standard immunofluorescence techniques.
Diagnosis of PSC. The diagnosis of PSC was based on biochemical evaluation, endoscopic retrograde cholangiopancreatography findings, and histology that were compatible with
PSC.
Statistical analysis. Two-tailed Fisher exact test was used to
compare the prevalence of S. stercoralis infection. P < 0.05
was considered significant. The Mann-Whitney U test was
used to compare peripheral eosinophil counts.
RESULTS
Strongyloides stercoralis infection in chronic liver diseases.
The study population was composed of 2,438 men and 1,679
women, with a mean age of 54.8 ± 17.5 (SD) years. During the
study period, 538 patients were found to have the following
chronic liver diseases: PBC (74 cases), AIH (30 cases), PSC (1
case), hepatitis B virus (HBV; 108 cases), hepatitis C virus
(HCV; 255 cases), HBV and HCV (4 cases), and alcoholic
liver disease (66 cases). The other 3,579 patients who were
hospitalized and underwent tests for S. stercoralis during the
same period served as controls.
The total prevalence rate of S. stercoralis infection was
6.6% (273 of 4,117; Table 1). The prevalence rate of S. stercoralis infection in men and women was 8.2% (201 of 2,438)
and 4.3% (72 of 1,679), respectively. The prevalence rate in
men was significantly higher than in women (P < 0.001). The
prevalence rate of S. stercoralis infection was significantly decreased in younger generations, and none of the female patients born after 1955 were infected.
The frequency of S. stercoralis infection in chronic liver
diseases is shown in Table 2. The rate of S. stercoralis infection in the autoimmune liver diseases group (1.0%) was lower
than that found in the control group (7.0%; P ⳱ 0.0046; odds
ratio, 0.127; 95% confidence interval ⳱ 0.018–0.914). Only
one patient with PBC had strongyloidiasis: a 63-year-old man.
None of the patients with AIH or PSC had strongyloidiasis,
although these subgroups were too small for statistical comparison. The frequency of S. stercoralis infection in the
chronic viral hepatitis group (3.8%) was slightly lower than
that in the control group and that in the alcoholic liver disease
group (9.1%) was slightly higher, although these differences
were not statistically significant.
To evaluate the immunologic response, we analyzed peripheral eosinophil counts in patients with autoimmune liver
diseases and in patients with S. stercoralis infection. Peripheral eosinophil counts were measured in 95 of 105 cases of
autoimmune liver diseases and 246 of 273 cases of strongyloidiasis. In patients with S. stercoralis infection, peripheral
eosinophil counts were significantly higher (506.2 ± 504.9
/mm3; reference range, 70–440/mm3) than those in patients
with autoimmune liver diseases (158.4 ± 211.4 /mm3; P <
0.0001; Table 3).
Strongyloides stercoralis infection in patients with PBC.
Clinical characteristics of patients with PBC are shown in
Table 4. In 59 cases, total bilirubin levels were < 2.0 mg/dL,
and these patients were thought to be in the early phase of
PBC. PBC was observed predominantly in middle-aged
women. The difference in prevalence of S. stercoralis between
sexes was also statistically significant (Table 1); therefore,
subgroup analysis of female patients born before 1955 was
performed (Table 5). None of these patients with PBC had
strongyloidiasis, which was statistically significant compared
with sex- and age-matched controls (P ⳱ 0.045).
DISCUSSION
Our results clearly showed that the frequency of S. stercoralis infection among patients with autoimmune liver dis-
TABLE 2
Prevalence of S. stercoralis infection in chronic liver diseases
Etiology
Number of S. stercoralis–positive
patients/number of tested patients (%)
Male
Female
Born
before 1955
Born
after 1955
Autoimmune liver diseases
PBC
AIH
PSC
Chronic viral hepatitis
HBV infection
HCV infection
HBV and HCV infection
Alcoholic liver disease
Control
Total
1/105 (1.0)*
1/74 (1.4)
0/30 (0.0)
0/1 (0.0)
14/367 (3.8)
4/108 (3.7)
10/255 (3.9)
0/4 (0.0)
6/66 (9.1)
252/3,579 (7.0)
273/4,117 (6.6)
7
3
3
1
238
88
147
3
60
2,133
2,438
98
71
27
0
129
19
108
1
6
1,446
1,679
85
62
23
0
249
61
185
3
53
2,758
3,145
20
12
7
1
118
47
70
1
13
821
972
* P ⳱ 0.0046 versus controls.
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AOYAMA AND OTHERS
TABLE 3
Comparison of peripheral eosinophil counts between patients with
autoimmune liver diseases and S. stercoralis–positive patients
TABLE 5
Strongyloides stercoralis infection in female patients born before
1955—primary biliary cirrhosis versus controls
Eosinophils (/mm3)
Patients with autoimmune liver diseases
S. stercoralis–positive patients
158.4 ± 211.4
506.2 ± 504.9*
Values are mean ± SD.
Reference range, 70–440/mm3.
* P < 0.0001 versus patients with autoimmune liver diseases.
TABLE 4
Clinical characteristics of primary biliary cirrhosis patients
Sex
Female
Male
Mean age ± SD (years)
Serum total bilirubin (mg/DL)
< 2.0
2.0–10.0
10.0 >
History of co-morbidities
Sjögren syndrome
CREST syndrome
Autoimmune hepatitis
Hepatocellular carcinoma
* P < 0.0001 versus men.
Tested patients
Prevalence (%)
0
72
60
1,225
0.0*
5.9
PBC patients
Controls
* P ⳱ 0.045 versus controls.
ease, especially PBC, was lower than that in the control
group. To our knowledge, this is the first report to describe an
inverse relationship between autoimmune liver diseases and
chronic helminth infection.
Okinawa is located in the southwestern part of Japan, belonging to the subtropical zone. Okinawa has been recognized
as an area of endemic S. stercoralis infection. In this study, the
prevalence of S. stercoralis among women was found to be
4.3%, and most of the patients positive for S. stercoralis were
older than 40 years of age. In a community-based mass survey
in Okinawa, Asato and Hayashi gave respective reports for
the prevalence of S. stercoralis infection in women of 7.7%
and 14.9%, respectively.17,18 This argues against the possibility of study bias in this study, suggesting that these results may
properly reflect the geoepidemiology of S. stercoralis infection even though this was a hospital-based case-control study.
Correlative studies should be viewed with caution as the
data cannot separate the issues of cause and effect. At least
two hypotheses can be proposed to explain the low prevalence 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 reduce the susceptibility to S.
stercoralis infection. The latter hypothesis would not seem
plausible, 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.14 In this study, most patients with
PBC and other autoimmune liver diseases were in an early
phase in development of the disease. Therefore, their daily
activities, lifestyle, and sanitary environment, which have
most effect on the susceptibility to helminth infection, should
be the same as those in the control group. Thus, we propose
Characteristics
S. stercoralis infection
S. stercoralis–positive
Number of cases
71*
3
55.3 ± 11.7
59
9
6
3
1
2
2
the hypothesis that S. stercoralis infection may reduce the
onset of autoimmune liver disease.
Epidemiologic studies have revealed that regions of the
world with high rates of helminth infections consistently have
a reduced incidence of autoimmune diseases, such as Crohn
disease, insulin-dependent diabetes mellitus, and multiple
sclerosis.19–22 The inverse relationship between helminth infection and autoimmune diseases could be a reflection of the
imbalance of two different types of T-helper cells, namely Th1
and Th2. Th1 and Th2 cells are reciprocally cross-inhibitory;
helminth infections, including strongyloidiasis, are associated
with responses stimulated by Th2-type cytokines such as interleukin (IL)-4, and this impedes the development of Th1
cells that seem to be involved principally in organ-specific
autoaggressive disorders.23–25 In this study, peripheral blood
eosinophilia, which suggest Th2 involvement in the immune
response, were observed in patients with strongyloidiasis but
not in patients with autoimmune liver diseases. As well as the
Th1-Th2 cross-inhibitory process, the anti-inflammatory network seems to play a crucial role in downregulation of autoimmune diseases. Helminths induce CD4+ regulatory T
cells and promote the production of powerful immunomodulatory molecules such as IL-10 and transforming growth factor-␤. The presence of this strong anti-inflammatory regulatory network could help to prevent the development of both
Th1-type and Th2-type immune responses.9,26
PBC is an organ-specific autoimmune disease that is characterized by chronic progressive destruction of small intrahepatic bile ducts, with portal inflammation and fibrosis. Autoreactive T lymphocytes that infiltrate the liver may play a
major role in the bile duct damage that accompanies the disease. Studies analyzing the cytokine mRNA expression have
shown that predominantly Th1 cells are activated in association with damaged bile ducts.27 Although the studies of cytokine profiles in patients with PBC revealed slightly different
patterns according to the tissue examined and stage of the
disease, a number of investigators reported that the expression of interferon-␥ (Th1 cytokine) mRNA in liver tissue was
increased and that interferon-␥ mRNA levels correlated positively with the severity of inflammation and the level of serum
␥-glutamyltransferase.28–30 These results support the idea
that Th1 cells are activated in PBC and play an important role
in its pathogenesis.
However, in view of the eosinophilic reaction observed,
especially in patients with early-stage PBC, the Th1-Th2 dichotomy may not always exist.31 Therefore, it is hypothesized
that concurrent helminth infection induces a Th2-type immune response, which may prevent the Th1-type hepatic inflammation in PBC. Alternatively, because regulatory T cells
suppress the differentiation of Th0 into either Th1 or Th2
cells, these regulatory cells may also be involved in the im-
STRONGYLOIDES AND AUTOIMMUNE LIVER DISEASES
munomodulatory effect of concurrent infection on the course
of PBC.
T cells seem to also play a central role in the immunopathogenesis of AIH. Recent experimental evidence suggests that
immunoregulatory dysfunction characterized by decreased
numbers of CD4+ regulatory T cells may occur in AIH.32
Such observations suggest that a decrease in the number of
regulatory T cells and their ability to expand may lead to
autoimmune liver disease, and CD4+ regulatory T cells induced by chronic helminth infection may therefore impede
the development of AIH.
In conclusion, our results clearly showed an inverse relation
between autoimmune liver disease and S. stercoralis infection.
Immunomodulation induced by chronic S. stercoralis infection may account for this negative relationship. Further study
of the immunomodulation and anti-inflammatory network induced by helminth infection may be highly informative toward the goal of inhibition of the onset and development of
autoimmune liver diseases.
Received August 23, 2006. Accepted for publication February 12,
2007.
Authors’ addresses: Hajime Aoyama, Tetsuo Hirata, Takako Watanabe, Satoru Miyagi, Tatsuji Maeshiro, and Jiro Fujita, Control and
Prevention of Infectious Diseases, Department of Medicine and
Therapeutics, Faculty of Medicine, University of the Ryukyus, 207
Uehara, Nishihara, Okinawa, Japan. Hiroshi Sakugawa and Tomokuni Nakayoshi, Department of Internal Medicine, Heartlife Hospital, 208 Iju, Nakagusuku, Okinawa, Japan. Mariko Kawane, Takayuki Chinen, and Osamu Zaha, Department of Internal Medicine,
Nakagami Hospital, 6-25-5 Chibana, Okinawa city, Okinawa, Japan.
Fukunori Kinjo, Department of Endoscopy, Ryukyu University Hospital, 207 Uehara, Nishihara, Okinawa, Japan.
Reprint requests: Hajime Aoyama, Control and Prevention of Infectious Diseases, Department of Medicine and Therapeutics, Faculty of
Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, Telephone: 81-98-895-1144, Fax: 81-98-895-1414, E-mail:
[email protected].
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