Close Relation Between Cirrhosis and Gallstones: Cross-sectional and Longitudinal Survey

Background  Increased gallstone prevalence and incidence in cirrhosis have already been reported in different series, including a limited number of patients with cirrhosis.

Objective  To evaluate the frequency of gallstones and related risk factors in a large series of patients with cirrhosis.

Patients and Methods  The cross-sectional study involved 1010 patients with cirrhosis related to alcohol abuse, chronic viral infection, or miscellaneous causes (42%, 48%, and 10%, respectively) in Child class A, B, or C (48%, 36%, and 16%, respectively). In the longitudinal study gallstone development was monitored ultrasonographically in 618 patients free of gallstones at enrollment.

Results  The overall prevalence of gallstone(s) was 29.5% and increased significantly with age without differences according to sex or cause of cirrhosis. Multiple logistic regression analysis showed that only Child classes B and C were significantly related to a higher risk of gallstone (odds ratio, 1.63 for class C vs class A and 1.91 for class B vs class A; P = .001). During a mean ± SD follow-up of 50 months ± 9 months, 141 (22.8%) of 618 patients developed gallstone(s), with an estimated cumulative probability of 6.5%, 18.6%, 28.2%, and 40.9% at 2, 4, 6, and 8 years, respectively. Multivariate analysis showed that Child class (hazard ratio, 2.8 for class C vs class A and 1.8 for class B vs class A; P = .002 and P = .001, respectively) and high–body mass index (hazard ratio, 1.31; P = .04) carried a significantly greater risk of gallstone formation.

Conclusion  Cirrhosis per se represents a major risk factor for gallstones whose prevalence and incidence were far higher than those reported in a general population from the same area.

THE PREVALENCE of gallstones (GSs) in patients with cirrhosis has been investigated in both autopsy series^1-6 and cross-sectional and longitudinal ultrasonographic studies.^7-15 In autopsy studies, mainly of alcoholic subjects with cirrhosis, the frequency of GS varied from 3.6% to 38% with a 1.2- to 3-fold increase compared with the population without cirrhosis.

Real-time ultrasonography is now the imaging technique of choice in evaluating the gallbladder as it is noninvasive, easily repeatable, and currently available in most hospitals. Its sensitivity in the detection of GS is 95%,¹⁶ higher than cholecystography with a lower false-positive rate.¹⁷ Recent epidemiological ultrasonographic studies on patients with cirrhosis of different causes found a prevalence of GS ranging from 22% to 26% and a frequency of previous cholecystectomy for GS of 5.6% to 8.5%,^7-12 the overall frequency of GS being significantly higher than that observed in the general population.^18-24 The frequency of GS in patients with cirrhosis increases with age^9,12 and severity of liver disease.^7-10,12 Unlike findings in the general population, the frequency of GS in male patients with cirrhosis has been reported to be similar to that in female patients with cirrhosis,^7,9 or even higher.¹⁰ Furthermore, preliminary longitudinal ultrasonographic studies^13-15 have shown annual incidences of GS of 2.6% to 5.5% with a significantly higher cumulative probability of GS development than that in the general population.^25,26 Moreover, despite conflicting results concerning risk factors related to GS formation in patients with cirrhosis, the severity of liver disease, expressed by Child class, was the most commonly found independent predictor of GS development in different series.^8,14,15 Based on these considerations we decided to perform a cross-sectional and longitudinal ultrasonographic evaluation of GS frequency in a large series of patients with cirrhosis of different causes, recruited from a well-defined area of northern Italy.

Four different referral hospitals in the industrialized area 100 km around Milan, Italy, were involved in the study, which was approved by the local ethics committee. Data from the different centers were assumed to be homogeneous as the equipment, investigational procedures, and data collection were standardized.

The cross-sectional part of the study was performed on 1010 consecutive patients with cirrhosis recruited from January 1988 to December 1995. There were 645 men (64%) and 365 women (36%) aged 26 to 87 years (mean ± SD age, 60 ± 12 years). The presence of cirrhosis was confirmed by histological liver findings in 721 patients (71%) according to accepted criteria.²⁷ The remaining 289 (29%) had a contraindication to liver biopsy (prolonged prothrombin time and/or low platelet count) or refused the procedure; in these cases diagnosis was based on clinical and biochemical data²⁸ and direct (coarse hepatic echopattern, irregular margins, caudate lobe–right lobe ratio >0.65) and indirect (signs of portal hypertension such as splenomegaly, increased portal diameter, and/or portal collaterals, and/or ascites) ultrasonographic signs.²⁹ Cirrhosis was considered alcohol related in 421 subjects (42%) who reported a daily consumption of more than 100 g for the previous 10 years; and virus related in 480 (48%), of whom 110 were chronic carriers of hepatitis B surface antigen (HBsAg), 266 were positive for antibody to hepatitis C virus (anti-HCV), and 104 had no other cause of chronic liver disease (anti-HCV tests were not performed on the last subgroup who were studied before 1990, and stored serum samples were not available). The other 109 patients had cirrhosis attributable to miscellaneous causes, including genetic hemochromatosis in 81 cases. Characteristics of the study population are given in Table 1. Cholelithiasis was diagnosed in the presence of 1 or more of the following ultrasonographic findings²³: (1) 1 or more echogenic, distally shadowing, possible movable structures within the gallbladder;(2) 1 or more echogenic movable but not shadowing structures within the gallbladder; and (3) echogenic structures with constant shadowing in the region of the gallbladder fossa, with little or no visualization of the gallbladder. After an overnight fast all patients underwent liver ultrasonographic scan performed with a 3.5-MHz transducer (B&K Medical, Gentofte, Denmark; Hitachi EUB-26, Uchi Kanda, Japan). Patients with a history of cholecystectomy for GS after receiving a diagnosis of cirrhosis were also included. All ultrasonographic examinations were performed by 3 of us (M.F, F.F., and L.B.) with specific training and experience in ultrasonography.

Six hundred eighteen patients without GS at enrollment (62% of the whole series) agreed to participate in the longitudinal part of the study and underwent liver ultrasonographic scans at 6-month intervals to investigate GS development. This group consisted of 404 men and 214 women aged 34 to 82 years (mean ± SD age, 60 ± 9 years). Liver cirrhosis was related to alcohol abuse in 278 patients (45%), chronic viral infection in 249 (40%, including 46 chronic carriers of HBsAg and 203 positive for anti-HCV), and miscellaneous causes in the remaining 91 (15%). Severity of cirrhosis was graded according to the time-honored and validated Child-Pugh classification³⁰ that takes into account 5 factors (presence or absence of ascites and hepatic encephalopathy; nutritional status; reduced plasma albumin concentration; prolonged prothrombin time, compared with controls). Each factor has a score that increases from 1 to 3 according to the degree of derangement, with an overall score of 5 to 15; a total score of less than 6 places the patient in class A, a score of 7 to 9 in class B, and a score of 10 to 15 in class C. According to Child-Pugh classification at enrollment 371 patients (60%) were in Child class A, 193 (31%) in class B, and 54 (9%) in class C. The minimum duration of follow-up was 6 months.

Body mass index (BMI), which is a measure of weight in kilograms divided by the square of the height in meters was calculated. The HBsAg was sought by radioimmunoassay (Abbott Laboratories, Chicago, Ill) and anti-HCV by enzyme-linked immunosorbent assay with confirmation by radioimmunoblot assay (Ortho Diagnostic System, Milan) in positive cases.

Fisher exact test was used to evaluate differences in GS prevalence according to the following variables: sex, age group (<40, 40-49, 50-59, 60-69, or ≥70 years), Child class (A, B, or C), and cause of cirrhosis. Multiple logistic regression analysis³¹ was used to identify variables carrying a significant risk for GS.

Kaplan-Meier estimation³¹ was used to calculate the cumulative probability of GS development. Multivariate analysis was carried out using the Cox regression model³² following a backward procedure to identify the best subset of variables with the most important prognostic value for GS development. The following variables were included: sex, age (<40, 40-49, 50-59, 60-69, or >70 years), Child class (A, B, or C), BMI, and cause of cirrhosis. Interaction between sex and the different age groups was also considered.

The level of significance was .05. Statistical analysis was stopped when fewer than 20% of the patients remained under investigation. The Epidemiological Graphics, Estimation, and Testing package analysis module (EGRET; Statistics and Epidemiology Research Corp, Seattle, Wash) was used for data analysis.

The overall prevalence of GS was 298 (29.5%) of 1010 cases, including 237 patients (23.4%) with actual stones seen on ultrasonographic liver scan and 61 (6.1%) who reported a previous cholecystectomy that was confirmed by absence of the gallbladder at ultrasonography. As shown in Table 2, which reports the results of univariate analysis, GS prevalence increased with age from 14% in patients younger than 40 years to 39%, without differences related to sex or cause of cirrhosis. Gallstones were significantly more frequent in patients in both Child classes B (odds ratio, 1.63) and C (odds ratio, 1.91) compared with class A (P = .001). Multiple logistic regression analysis showed that only the severity of liver disease was significantly related to a higher risk of GS (odds ratio, 1.54 for Child class C vs class A and 1.76 for class B vs class A; P = .001).

The mean ± SD duration of follow-up was 50 ± 9 months (range, 6-163 months) and 21 patients were lost to follow-up after 12 to 63 months. During the observation period GS developed in 141 (23.8%) of 618 enrolled patients with cirrhosis, 90 (22.3%) of 404 men and 51 (22.3%) of 214 women, without significant difference between the 2 sexes. No differences in GS development were detected when we considered age, cause of cirrhosis, and the relationship between sex and age. The frequency of newly diagnosed GSs in patients in Child classes B and C was significantly higher than that observed in patients in Child class A (56/193 [29%] and 23/54 [43%] vs 62/371 [16.7%], respectively; P = .001). The cumulative probability of GS development according to observation period was 6.5%, 18.6%, 28.2%, and 40.9% at 2, 4, 6, and 8 years of follow-up, respectively (Table 3). With multivariate analysis the only variables identified as independent predictors of GS development were severity of liver disease at enrollment, with a significantly higher probability of GS formation for patients in Child class C vs class A (hazard ratio, 2.8; P = .001) and Child class B vs class A (hazard ratio, 1.8; P<.002), and high BMI (hazard ratio, 1.31, P = .04).

A recent large nationwide epidemiological study²⁴ aimed at estimating the overall prevalence of GSs (ie, actual GSs or previous cholecystectomy) in Italy involved 29,684 subjects who agreed to participate and were highly representative of the entire population of 46,139 subjects (64.3%). Gallstone disease was diagnosed in a significantly higher proportion of women than men (2603/13,774 [18.8%] vs 1512/15,910 [9.5%]) and the GS frequency rose significantly with age in both sexes. The overall prevalence of GS disease in our patients with cirrhosis of different causes was significantly higher than in the above-mentioned general population (298/1010 [29.8%] vs 4115/29,684 [13.9%]; χ² = 192.8; P = .001), confirming previous findings in comparable but more limited series.^7-12 Our data also confirm that GSs are more prevalent in female patients with cirrhosis. However, the difference was not significant (32% vs 28% in men); moreover, GS prevalence was 3 and 1.5 times higher, respectively, in male and female patients with cirrhosis than in sex-matched controls. This indicates that despite the higher absolute frequency of GS in female patients with cirrhosis observed in this study and in other series,^8,12 the risk of cholelithiasis in male patients with cirrhosis is much higher than in the general population. Another factor that has only little effect on GS prevalence in patients with cirrhosis is age. In fact, unlike findings in the general population, a statistically significant increase in GS prevalence was observed only for the highest age groups (odds ratio, 2.11 for patients aged >70 years and 1.58 for those aged 60-69 years; P<.02 compared with those aged <40 years). Thus, an interesting point emerging from our study is that factors such as sex and age, closely associated with GS in the general population, are far less important in patients with cirrhosis. In these patients the main factor affecting GS prevalence was severity of liver disease as shown by Child class, which was statistically significant also with multivariate analysis. In fact, patients in Child class B or C had a significantly higher prevalence of GSs compared with those in class A. This could merely reflect the duration of underlying chronic liver disease but could also be a consequence of reduced hepatic synthesis and transport of bile salts and nonconjugated bilirubin³³ and of high estrogen levels,³⁴ both frequently reported in end-stage liver disease. A further explanation for the increased prevalence of GSs in advanced liver disease has recently been suggested by ultrasonographic studies³⁵ that demonstrated both reduced gallbladder contraction in response to a meal in patients with cirrhosis and a progressive worsening of gallbladder inertia with progressive liver failure and a possible consequent increase in estrogen levels. Finally, our prevalence study revealed a rate of previous cholecystectomy for symptomatic GSs that was comparable with the rate previously reported in a similar population.^9,10,12

Prospective large series^25,26 focused on general populations in Italy found that the annual rate of GS formation in subjects free of GSs at enrollment was about 0.5%. Of 618 patients with cirrhosis without GSs at entry in this study and followed up for a mean period of about 5 years, 22.8% developed GSs, ie, an estimated annual rate of 5%, with a 10-fold increase in GS incidence compared with that in the general population. The GS incidence was independent of sex and age of patients, whereas, as observed in the cross-sectional part of this study, a 2- to 3-fold increase in GS formation was observed in patients with cirrhosis in Child class B or C ompared with class A. Thus, our findings strongly support the concept that severity of underlying liver disease, in most cases reflecting its duration, represents an independent risk factor for GS formation in patients with cirrhosis. Overall, our results indicate that in patients with cirrhosis the probability of developing GSs is increased per se. In fact, sex and age, which in the general population represent well-known risk factors for GSs, were not significantly related to GS in our patients with cirrhosis. Even though BMI correlated significantly with GS formation, the hazard ratio (1.31) was much lower than that observed in the general population for GS development in patients with a high BMI.

Accepted for publication May 12, 1998.

This study was supported in part by Associazione Amici Gastroenterologia del Padiglione Granelli, Milan, Italy.

Presented as a poster at the Convention of the American Association for the Study of the Liver, Chicago, Ill, November 1997.

Reprints: Dario Conte, MD, Chair of Gastroenterology, IRCCS Maggiore Hospital, Granelli 3°P, Via F. Sforza 35, 20122 Milan, Italy (e-mail: Gastrbia@imiucca.csi.unimi.it).