Hepatitis C Cirrhosis: Gallstones and Liver Disease

Research has shown individuals with liver disease, especially those with cirrhosis have a greater tendency to develop gallstones. However, research for hepatitis C in relation to gallbladder disease is not that abundant or recent. One available 2009 study/abstract was published in the Journal of Viral Hepatitis Volume 16, Issue 12, in December 2009 "Hepatitis C virus infection is a risk factor for gallstone disease: a prospective hospital-based study of patients with chronic viral C hepatitis" with the study concluding; "Our study shows that even HCV patients with chronic hepatitis but not cirrhosis have an increased prevalence of gallstones. Compared with controls, gallstones are present in HCV patients at a younger age and are associated with central obesity and liver steatosis, but not with gallstone heredity, dyslipidaemia, diabetes mellitus or metabolic syndrome. Although we could not establish a temporal relationship, the association between HCV infection and gall stone disease is real and appears to be causally linked, at least in predisposed individuals (obese and with liver steatosis)."
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An older more detailed study was published in the May 2005 issue of Hepatology;" Prevalence of Gallbladder Disease Among Persons With Hepatitis C Virus Infection in the United States", the noted results; "The odds of gallbladder disease increased significantly with the severity of liver disease as assessed via elevated serum bilirubin levels and low levels of serum album and platelets. In conclusion, chronic HCV infection was strongly associated with gallbladder disease among men but not women in the United States, and gallbladder disease was more common in adults with severe liver disease."

Excerpted From The 2005 Study; See Full Data Here
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"GBD-gallbladder disease"
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Men vs Women;

Ultrasonography is a rapid, noninvasive method of imaging the gallbladder, and this technique has contributed greatly to our understanding of the epidemiology of and risk factors for GBD-gallbladder disease.

The risk of GBD increases with age, and the prevalence of GBD in the United Statesis higher in women (16.6%) than in men (7.9%) between the ages of 20 and 74 years.

Population-based studies have revealed a marked variation in the prevalence of GBD among different racial/ethnic groups, and the prevalenceis highest among American Indian and Hispanic women and lowest among non-Hispanic black men.

In addition to age, sex, and race/ethnicity, other potential risk factors for GBD include obesity, rapid weight loss, lower levels of physical activity, pregnancy, increasing number of live births, oral contraceptive use and estrogen replacement therapy, diabetes mellitus, abstinence from alcohol, smoking, low total serum cholesterol levels, low levels of coffee consumption, and genetic factors.

However, some of these variables have not been consistently associated withGBD, and these risk factors may differ considerably among men and women.

Cirrhosis has also been shown to be an important risk factor for the development of GBD. Although cholesterol stones are the most common type of gallstone in the general population, pigment stones are the most prevalent type in patients who have cirrhosis.

Several investigators have noted that the risk of GBD varies according to the cause of cirrhosis. In a prospective study of 165 patients with cirrhosis followed for a mean of 33 months, the incidence of new gallstones was 28.9% in alcoholic cirrhosis but only 1.9% in those with cirrhosis caused by viral hepatitis.

In contrast, Buchner and Sonnenberg found that the prevalence of gallstones was lower in patients with alcoholic cirrhosis (9%) compared with patients with nonalcoholic cirrhosis (14%).

In contrast to the abundance of literature on the association between cirrhosis and GBD, we are unaware of any other population-based studies of the relationship between HCV infection and GBD. In a retrospective review of 1,028 subjects undergoing a periodic health examination at China Medical College Hospital in Taiwan, multivariate analysis identified HCV infection as a risk factor for GBD in women (OR3.6; 95% CI, 1.4-9.7) but not men.

In contrast, a retrospective study by O’Sullivan etal.43 found that the incidence of gallstones in 318 patients infected with HCV was no different than the incidence of gallstones in the general population in Ireland.

In the present study, we found that HCV infection was strongly associated with GBD in men but not women .

The reason for the sex-specific differences in the association between HCV infection and GBD are not known. However, these findings are in agreement with other studies that have shown that cirrhosis is a risk factor for GBD in men but not women.

It is likely that the pathophysiology of and risk factors for gallstone formation differ among men and women. Alternatively, we may have failed to detect a statistically significant association between HCV infection and GBD because of the small proportion of women with chronic HCV infection (1.0%) or because of the fact that women already have a high prevalence of GBD even in the absence of HCV infection.


Cirrhosis and Gallbladder Disease

The mechanisms leading to the development of gallstones in patients with cirrhosis are not well understood. The increased risk of gallstone formation in patients who have cirrhosis, especially those with advanced liver disease, is likely multifactorial; proposed mechanisms include reduced hepatic synthesis and transport of bile salts, impaired gallbladder motility, high estrogen levels, and chronichemolysis secondary to hypersplenism.

Impaired gallbladder motility can result in decreased gallbladder emptying in response to a meal, bile stasis, and increased gallstone formation, and one study proposed that impaired gallbladder motility in patients with cirrhosis who also have gallstones is due to autonomic dysfunction.

Although high estrogen levels have been suggested as a possible mechanism of increased gallstone formation in patients with cirrhosis, did not find any significant differences in plasma levels of sex hormones (estradiol and testosterone) between patients who have cirrhosis with and without gallstones.

Direct infection of the gallbladder by HCV may also play an important role in the development of GBD

In addition to the above-mentioned potential mechanisms of increased gallstone formation in patients with cirrhosis, direct infection of the gallbladder by HCV may also play an important role in the development of GBD. Loriot et al.48 demonstrated that HCV can successfully infect gallbladder epithelial cells. Other investigators have also detected HCV RNA and HCV antigens in gallbladder specimens obtained from HCV-infected patients at the time of autopsy.49

It is possible that HCV infection of the gallbladder may increase the risk of gallstone formation by causing altered gallbladder mucosal function or gallbladder dysmotility, and further investigations to address this interesting hypothesis are needed.

The present investigation found that the relative odds of GBD 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. Several other studies have also demonstrated that the prevalence and incidence of GBD was significantly higher in patients with advanced cirrhosis compared with those with well-compensated liver disease.

In a prospective study of 165 patients with cirrhosis, Fornariet al.10 noted that the cumulative incidence of gallstones at 48 months was 49.3% in patients with Child-Turcotte-Pugh class C cirrhosis, compared with 24.0% in patients with class B and 6.4% in those with class A cirrhosis.

The risk of gallstones becoming symptomatic is higher in patients with cirrhosis due to viral hepatitis than in those with alcoholic cirrhosis.

In addition, patients with cirrhosis are more likely to undergo cholecystectomy for emergent reasons than those who do not have liver disease. These findings—as well as the results of the present study showing a high prevalenceof GBD in persons with advanced liver disease due to chronic HCV infection in the United States—have important implications because cholecystectomy for symptomatic gallstones in patients with advanced liver disease is associated with a high risk of morbidity and mortality.

The main strength of the NHANES III data is that they include a large sample size and allow for the determination of direct estimates of the prevalence of GBD among HCV infected persons in the U.S. population, rather than relying on the prevalence in a highly selected population.

Other strengths of NHANES III include the collection of detailed data on risk factors for GBD, the use of ultrasonography to make the diagnosis of GBD, and the availability of HCV RNA testing to diagnose chronic HCV infection.

However, several limitations should be considered when interpreting our findings. Because of the cross-sectiona ldesign of NHANES III, a temporal relationship between HCV infection and GBD could not be established.

In addition, some risk factors for GBD may have changed from the time when gallstones formed, and data were not available on some potential risk factors such as rapid weight loss. Another potential limitation is that cholesterol and pigment stones were not differentiated in this study; therefore, we cannot be sure that the observed differences between HCV-positive and HCV-negative persons were due to differences in the risk of a particular type of gallstone.

Finally, the use of surrogate markers(serum total bilirubin, albumin, platelet count, and AST/ALT ratio) to determine the severity of liver disease has its limitations, because liver biopsies were not performed.

In conclusion, our study demonstrates that chronic HCV infection is strongly associated with GBD in men but not women in the United States. Among individuals with HCV infection, the prevalence of GBD is highest among those with more severe liver disease.

Further researchis needed to determine the temporal relationship between HCV infection and GBD, as well as to evaluatethe incidence of symptomatic gallstones, the optimal management of GBD, and the outcomes of cholecystectomy among persons with HCV infection. In addition, future studies to determine the impact of antiviral therapy on the incidence and prevalence of GBD among persons with HCV infection in the United States are warranted.
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May 2005 issue of Hepatology;" Prevalence of Gallbladder Disease Among Persons With Hepatitis C Virus Infection in the United States",

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