.jpg)
HEPATITIS C–A RISK FACTOR FOR GALLSTONE DISEASE
Good afternoon folks, its a lovely Sunday here in Michigan, a perfect day for a walk around the neighborhood. Did you all have a great Halloween? Our little people sure did, despite a few snowflakes.
Welcome back to another edition of
weekend reading. Today's subject is gallbladder disease and
HCV.
ORIGINAL ARTICLE
HEPATITIS C–A RISK FACTOR FOR GALLSTONE DISEASE
Syed Inamullah Shah, Sajida Shah*, Abdul Hannan
Department of Surgery, Fauji Foundation Hospital, *Department of Radiology, Combined Military Hospital, Rawalpindi
Download PDF
BACKGROUND: There is increasing evidence that chronic liver disease is one of the risk factors for gallstone disease. A few published studies have documented the link between Hepatitis C Virus (HCV) related chronic liver disease and increased incidence of gallstones but these studies did not exclude subjects with other risk factors like cirrhosis. This study aimed to establish an association between HCV infection and gallstones by excluding subjects with all other risk factors for gallstones.
METHODS: This cross sectional study was carried out at four hospitals of Rawalpindi, Pakistan, over a period of 18 months. It included all cases referred for ultrasound scan of abdomen. A total of 2000 cases, were included in the study by consecutive, non-probability sampling. Anti-HCV antibody test was carried out in all subjects by ELISA and sonography was done to determine presence or absence of gallstones.
RESULTS:Patients suffering from HCV had a significantly high percentage of gallstones as compared to seronegative subjects (p = 0.001). In seropositive group, more males had gallstones (p = < 0.001) and prevalence of gallstones was significantly high in younger population with age at or below 40 years (p = < 0.001).
CONCLUSION: Risk of gallstone disease is increased in patients suffering from HCV infection. This association is more pronounced in males.
INTRODUCTION
HCV is globally distributed and it is estimated that up to 170 million people (3% of the world’s population) are infected worldwide.1 In Pakistan, about 4.7% of the population is HCV positive. This ranks as the second highest percentage after Egypt (15.5%).
In recent years more and more males have been diagnosed with symptomatic gallstones and their complications including choledocholithiasis, gallstone pancreatitis and cholangitis. A significant proportion of these patients have been observed to be seropositive for HCV.
Association of gallstones with chronic liver disease is documented in medical literature1,3,4 but no such study has been carried out in Pakistan or the subcontinent despite the fact that HCV is endemic in this region. Risk factors described for gallstones include hyperlipidemia5 , obesity6,7, high serum levels of female sex hormones8 , sickle cell disease, and thalassaemia9 among others. Cirrhosis of liver is a known risk factor for gallstones10,11 but very little is known about gallstone disease in individuals with HCV infection without cirrhosis. 1,4 None of the studies previously conducted have investigated HCV infection as a solitary risk factor for gallstones.
Some findings of these studies have a significant bearing on the health economy. It has been found that HCV positive subjects develop gallstone disease at a younger age3 and are more likely to have gallstones in bile ducts (0.4%) as compared to normal population (0.1%). 12 It was also found that males with HCV infection were more likely to need surgery for gallstone disease compared to women.5 Keeping in view that HCV infection is endemic in Pakistan, the demographics of the affected population and the burden on the hospitals for gallstone related complications would lead to a significant financial burden. A common observation was made in our institution that there was a clear difference in gall stones occurrence in patients with and without HCV infection. Our hypothesis was that HCV infection is a risk factor for gallstone disease.
The objective of this study was to compare the frequency of gallstones in patients who have hepatitis C virus infection, with seronegative subjects.
MATERIAL AND METHODS
This cross-sectional study was carried out from November, 2011 to April, 2013 at the Fauji Foundation
Hospital and the Combined Military Hospital at Rawalpindi. Patients from Military Hospital and AlIhsan Hospital were also included. In order to maintain
the same standard in sonography, all the scans were
performed by the same radiologist.
The study included
all cases referred for ultrasound scan of abdomen. Patients in this study were sampled by consecutive nonprobability sampling technique. Data was collected
using a structured pro forma. Anti-HCV antibody was
tested by ELISA on all subjects. An equal number of
patients with and without HCV infection were chosen
and presence of any gallstones was observed in both
groups. Ultrasound scan of abdomen was done on all
subjects and special note was made of gallstones in the
gallbladder or the bile ducts and presence or absence of
cirrhosis.
Patients diagnosed as suffering from hepatitis
C were included in Group-1 while those without
Hepatitis C were included in Group-2. Patients of either
gender, between and including the ages of 18 years and 70 years, were included. An equal number of HCV
positives and HCV negative patients were included
without taking into account their gender. Patients who
were excluded from study were those with: deranged
LFTs due to any cause other than hepatitis C; deranged
lipid profile; BMI in obese range; acute or fulminant
hepatitis and/or cirrhosis; pregnancy; sickle cell disease;
malignancy; thalassemia; and history of abdominal
surgery or birth control measures. Anti-HCV antibody
detected positive by ELISA at least three months before
the ultrasound examination was considered as suffering
from HCV infection.
Gallstones were considered
present if they were detected on ultrasound. Data was analyzed by SPSS-18. Chi-square test was used to determine the association of HCV infection with gallstones by comparing the frequency of gallstones in the two groups. p-value of <0.05 was considered significant. Odds Ratios with 95% confidence intervals (CI) were also calculated.
RESULTS
A total of 2000 patients were included in the study, 1000 subjects were HCV negative and while the other 1000 subjects were HCV positive. Of the total 2000 participants in the study, 1066 (53.3%) individuals were males while 934 (46.7%) were females. The age of subjects ranged between 19 and 66 years with a mean of 41.66±10.11 years. As far the age groups are concerned, 63.2% of the HCV positive subjects aged 40 years or below, while 60.4% of HCV negative group were above 40 years of age. Males and females with Hepatitis C antibodies were 575 (57.5%) and 425 (42.5%) respectively.
Overall presence of gallstones in both
groups was a total of 514 subjects (25.7%). In HCV
negative males, gallstones were found in only 0.9%
as compared to 13.9% in females. Frequency of
gallstones in both groups and their comparison is
shown in
Table-1.
Gender distribution of gallstones in both
groups is detailed in
Table-2 whereas
Figure-1 shows
age distribution. The odds ratio for exposure of HCV
and effect of gall stones with 95% confidence
interval was 3.39 (95% CI 3.1 to 4.8). The results are
statistically significant with a risk range given in the
CI for those exposed compared to non-exposed.
Distribution of gall stones in either gender showed
that frequency of gallstones is high in HCV positive
males (p=.001) but decreases in HCV positive
females.
FIGURE 1
Quantity of stones in gallbladder was
labeled as single, multiple or no stones. Cross tabulation of number of stones with study group
revealed a significant association between multiple
gallstones and HCV infection (p=<.001) as shown in
Table-3
Presence of gallstones in the common bile duct
was evaluated between the two groups. There were
more cases of CBD gallstones in HCV positive group
(2.5%) as compared to HCV negative group (0.9%).
The difference is statistically significant (p=<0.001).
DISCUSSION
Cholelithiasis has been traditionally associated with
middle aged females. Gall stones are of various types
but the commonly found calculi are cholesterol stones.
Risk factors described for cholesterol stones, in addition
to those described above, include rapid weight loss13,14 female sex hormones8,15,16, multiparity and diabetes
mellitus.
Cirrhosis has long been known to be a risk
factor for gallstones.10,11,18 Stroffolini et al, reported in
2007 that gallstone prevalence was significantly higher
in patients with HCV-related cirrhosis than in those with
HBV-related or alcoholic cirrhosis.18 Formation of
gallstones in cirrhosis is due to many factors such as
reduced secretion of bile acids, reduced gallbladder
motility19 and reduced synthesis of cholesterol. Although high estrogen levels have been suggested as a
possible mechanism of increased gallstone formation in
cirrhotic patients, Li et al did not find any significant
differences in plasma levels of sex hormones between
cirrhotic with and without gallstones.20
In contrast to the abundance of literature on
cirrhosis and its association with gallstones, very little is
known about gallbladder disease in individuals with
HCV infection in the absence of cirrhosis.
There are
only three published studies on this subject so far.1,3,4
Probably the first study to establish the link between
HCV infection and gallstone disease was carried out in
2000 at Taiwan. In this study by Chang et al3
, the
prevalence of gallstones in HCV positive subjects was
found to be significantly higher (11.7%) than the control
subjects (6%). Bini et al4
examined the data of more
than 13000 subjects who participated in a United States
national survey for health and nutrition, in 2005, and
discovered that 12.5% of those with HCV infection had
gallstone disease, most of whom were males. They also
discovered that the relative odds of gallstone disease
among persons with HCV infection increased with the
severity of liver disease as assessed by serum total
bilirubin levels, serum albumin levels, and platelet
counts. This was construed as demonstrating a direct
link between liver disease and gallstone formation. A
2009 Romanian study by Acalovschi et al1
, reported
19% incidence of gallstones in HCV positive patients.
In our study, we found that a total of 37.4% of
HCV positive individuals had gallstones as compared to
14% in HCV negative group.
The significant difference
between the two groups (p=.001) clearly establishes an
association between HCV infection and gallstone
disease, keeping in view the fact that we excluded
subjects with all other known risk factors for gallstone
disease. As compared to previous studies, the
prevalence in this study is higher in both groups. It may
be argued that this extraordinarily high prevalence in
our results is due to the peculiar sampling technique, but
the study of Acalovschi et al used a similar technique
with comparable sample size and revealed lower overall prevalence.
Therefore, results of our study may partly reflect an actual rise in the incidence of gallstone disease in Pakistani population.
Bini et al found that HCV infection was a
strong risk factor for gallstone disease in men but not in women. 4
The reason for this difference is not cited
except for the likelihood that the pathophysiology of and
risk factors for gallstone formation differ among men
and women. This study corroborates this observation as
our results that show that 28.2% of HCV positive males
had gallstone disease whereas prevalence in HCV
positive females was only 8.5%. This difference
becomes more significant because only 0.1% HCV
negative males in our study had gallstone disease
whereas 19.2% HCV negative females had the disease.
This means that HCV infection may actually be
protective to women against gallstone disease. In
contrast, males revealed a strong association (p=.001)
between HCV infection and gallstones.
Our results revealed that younger males are
more prone to acquire gallstones if they are HCV
positive. This age association is statistically significant
in males (p=<.001). These results are in conformity with
those of Acalovschi et al and Chang et al.
1,3 Younger
age group was also found to have a predilection for
acquiring multiple gallstones.
There is also a significant association
(p=<.001) between HCV infection and development of
multiple, as opposed to single gallstones. HCV infection
appears to make the patients more prone to suffer from
choledocholithiasis.
Various reasons have been postulated for HCV
infection causing gallstones. Sluggish function of the
liver in synthesizing bile acids has been cited.
21 Direct
infection of the gallbladder by HCV22 and gallbladder
hypomotility19 has been demonstrated. This direct effect
is more probable because an infection by Hepatitis B
virus does not increase the risk of gallstone disease4
despite having a similar effect on liver function. Some
studies have even suggested a protective effect of
hepatitis B in developing gallstones.
23 This direct effect
seems to spare the gallbladders in females.
The findings of this study significantly bear on
the health economy. As established, males less than 40
years are more prone to develop gallstones if they are
HCV positive. These stones are usually multiple with
more likelihood of causing obstructive jaundice. These
patients are more likely to need surgery for gall stone
disease4
and morbidity may be high because of
compromised liver function. In economic terms, the
breadwinner of the family is disabled, workplace gets
affected and hospitals have to allocate more resources
for HCV positive patients undergoing surgery.
The strength of our study is in the fact that this
is the first attempt to describe association of gallstones
with HCV not only in Pakistan but in the entire South
Asian region. Secondly, we have been scrupulous in the
selection of subjects by excluding those HCV positive
individuals who had any other risk factor of gallstone
disease. The limitation of this study is that the study
sample is not representative of the general population. Subjects were selected from patients coming for
treatment to four large hospitals of Rawalpindi.
CONCLUSION
There is a strong association between HCV infection
and gallstones. HCV infection is definitely a risk factor
for gallstone disease particularly in young males. By
invalidating young subjects and rendering them as
potential candidates for surgery, this association has a
profound effect on health economy. There is a
predilection for HCV positive patients to acquire
multiple gallstones. Further studies are needed to
evaluate the precise cause for this association.
REFERENCES
.jpg)
