’Original article Relationship of hepatic fibrosis, cirrhosis, and mortality with cholecystectomy in patients with hepatitis C virus infection Donald J. Martina,d, Rick Weidemanb, Terri Crookc,e and Geri Browna,d Objectives Studies have suggested that cholecystectomy is a risk factor for nonalcoholic fatty liver disease, but it is not known whether cholecystectomy is a risk factor for the progression of other chronic liver diseases such as hepatitis C virus (HCV) infection. The aim of this study was to assess whether cholecystectomy is associated with an increase in fibrosis, cirrhosis, and cirrhosis-related complications in patients with chronic HCV infection. Methods Among a total of 3989 HCV-positive patients at the VA North Texas Health Care System, we retrospectively reviewed the records of 88 patients who had undergone cholecystectomy between 1998 and 2013, followed up for a median of 4.9 years. We compared the outcomes of these patients with those of two age-matched, race-matched, and sex-matched cohorts: a cohort consisting of 129 HCV-positive patients without gallbladder disease (GBD) and a second cohort consisting of 178 HCVpositive patients with GBD who had not undergone cholecystectomy. Demographics, presence of metabolic syndrome, alcohol use, laboratory data, and clinical progression of liver disease were compared at study entry and 5 years later. Results Controlling for multiple factors associated with increase in liver fibrosis, analyses confirmed that a there was an increase in the proportion of patients who developed cirrhosis [odds ratio (OR) = 3.24, 95% confidence interval (CI) 1.57–6.68, P = 0.001] and ascites (OR = 3.01, 95% CI 1.14–7.97, P = 0.026) as well as in the incidence of death (OR = 6.29, 95% CI 2.13–18.59, P = 0.001) 5 years after cohort entry among HCV-positive patients with cholecystectomy compared with HCV-positive controls. The HCV-positive patient group with previous cholecystectomy showed an increased incidence of cirrhosis (OR = 2.43, 95% CI 1.34–4.41, P = 0.004), hepatocellular carcinoma (OR = 2.85, 95% CI 1.11–7.36, P = 0.030), and death (OR = 3.31, 95% CI 1.50–7.28, P = 0.003) 5 years after cohort entry compared with HCV-positive controls with GBD who had not undergone cholecystectomy. Conclusion Cholecystectomy among HCV-positive patients is associated an increased incidence of fibrosis, cirrhosis, and its complications (ascites, hepatocellular carcinoma, and death) compared with HCV-positive controls and HCV-positive patients with GBD who have not undergone cholecystectomy. Eur J Gastroenterol Hepatol 28:181–186 Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
Introduction
Gallstones, per se, are not a problem until they become symptomatic or complicated. However, symptomatic gallstone disease and its complications remain a major public health problem, and these conditions are some of the most common and costly of all digestive diseases [1]. The Third National Health and Nutrition Examination Survey estimated that 20.5 million individuals in the USA had gallbladder disease (GBD) and that GBD is responsible for several thousand deaths per year [1,2]. In addition, the annual cost of GBD in the USA in 2000 was European Journal of Gastroenterology & Hepatology 2016, 28:181–186 Keywords: cholecystectomy, cirrhosis, hepatitis C a
Division of Gastroenterology and Hepatology, Departments of bPharmacy, Pathology, VA North Texas Healthcare System, dDivision of Digestive and Liver Diseases and eDepartment of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA c
Correspondence to Geri Brown, MD, Division of Gastroenterology and Hepatology, Dallas VA Medical Center, Mail Code 111B1, 4500 South Lancaster Road, Dallas, Texas 75216, USA Tel: + 1 214 857 1603; fax: + 1 214 857 1571; e-mail: [email protected] Received 5 August 2015 Accepted 5 October 2015
approximately $6.5 billion, making it the second most costly digestive disease [3]. Cirrhosis is a well-documented risk factor for the formation of gallstones [4–8]. In addition, the severity of cirrhosis, classified by Child–Pugh class, is one of the strongest predictors of the prevalence and incidence of gallstones in patients with cirrhosis [5]. The prevalence of GBD, including cholecystectomy (CCY), in patients with hepatitis C virus (HCV) infection has been estimated at 12.5% [9]. HCV infection is also an important public health problem in the USA and is a leading cause of chronic liver disease and cirrhosis [3,10]. It is estimated that 3.4–4.4 million people in the USA are infected with HCV, and ∼ 2.7 million people are chronically infected [11–13]. CCY has been associated with nonalcoholic fatty liver disease (NAFLD) in a population-based study, suggesting that CCY may itself represent a risk factor for the development of NAFLD [12]. Both GBD and NAFLD have been associated with an increased mortality from chronic liver disease, cardiovascular disease, and cancer, compared with the general population [14,15]. CCY has been associated with the development of cirrhosis in a population-based study [16]. To our knowledge, the relationship of morbidity or mortality in patients with a prior CCY has not
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DOI: 10.1097/MEG.0000000000000512
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been investigated exclusively in patients with HCV infection. We, therefore, sought to examine the association of GBD in patients with HCV infection in the veterans’ population, with an emphasis on whether CCY was associated with worsening hepatic fibrosis, cirrhosis, and its complications. Methods
Among 3989 HCV-positive patients (identified by HCV antibody positivity and confirmed by PCR testing), we identified 88 patients who had undergone prior CCY (CCY cohort), as determined on the basis of a corresponding International Classification of Diseases-9 code for CCY, imaging consistent with prior CCY, and verification by pathological specimens. We compared outcomes of the CCY cohort with those two cohorts: 178 HCV-positive patients who had GBD, defined by ICD-9 codes for cholelithiasis, choledocholithiasis, acute or chronic cholecystitis, biliary sludge, or choledocholithiasis on imaging, and had not undergone prior CCY (GBD cohort), and 129 HCV-positive patients without GBD or prior CCY (HCV cohort). The three cohorts were agematched, race-matched, and sex-matched for analyses (Fig. 1). The ‘index date’ was the time at CCY for the CCY cohort and the date of diagnosis for the GBD cohort. The HCV cohort was age-matched, race-matched, and sexmatched to the CCY cohort at the time of diagnosis. The cohorts were matched at baseline and the outcomes were assessed over the next 5 years, all of which were within the VA system. The primary outcome was development of cirrhosis and its complications. In addition to the primary outcome, laboratory results were also assessed at baseline and at 5 years, including aspartate aminotransferase level (AST), alanine aminotransferase level (ALT), alkaline phosphatase level, total bilirubin level, international normalized ratio (INR), albumin level, and platelet count. Laboratory data collected also included HCV genotype, total cholesterol level, high-density lipoprotein level, and triglyceride level. The AST/platelet ratio indices (APRIs) and fibrosis-4 (FIB-4) scores were calculated to determine the degree of fibrosis at baseline and 5 years later. To determine liver
fibrosis severity APRI was calculated using the following formula: [AST (IU/l)/upper limit normal/platelet count (×109/l)] × 100 [17]. The FIB-4 count was calculated using the following formula: [age (years) × AST (U/l)]/[platelet count (109/l) × √ALT (U/l)] [18]. The APRIs and FIB-4 scores were analyzed by absolute change and in quartiles, as a means of illustrating the relationship between a binary exposure and continuous outcome. The study was performed at the VA North Texas Health Care System using the medical center’s electronic health record. Records of male and female patients between the ages of 35 and 75 years of all ethnicities and with histories of chronic HCV were reviewed for data collection from 1998 to 2013. The HCV cohort included patients who were nonresponders to HCV therapy. Successfully treated HCV patients with a sustained virological response (SVR) were not included in the HCV cohort as this would decrease fibrosis progression rates. Patients were excluded if they died within 180 days of CCY or if they underwent CCY during liver transplantation. From the patients meeting the inclusion criteria, data on characteristics were collected and included age at the time of HCV and GBD diagnosis, sex, ethnicity, tobacco use history, alcohol use history, and BMI. Alcohol and tobacco use were defined by presence in the problem list at any point in time in the available medical records. Data on medical history included metabolic syndrome and human immunodeficiency virus (HIV) status. Metabolic syndrome was defined by fulfillment of three or more of the following criteria: fasting blood triglyceride level greater than 150 mg/dl, blood high-density lipoprotein level less than 40 mg/dl in men and less than 50 mg/dl in women, blood pressure greater than 135/80 mmHg, and/or fasting blood sugar greater than 100 mg/dl. If available, liver biopsies were assessed and collected, including grade and stage, in all study participants. In addition, data on indication for CCY and pathology from patients who had undergone the procedure were assessed and collected. To understand the etiology and severity surrounding CCY, the chart was reviewed for evidence of acuity, including the following factors: outpatient versus inpatient, clinical laboratory values, surgery within 24 h. Imaging results including
Eligible participants (N = 3989)
Confirmed HCV antibody and PCR
Cholecystectomy cohort (N = 88)
Gallbladder disease cohort (N = 178)
HCV cohort (N = 129; age, race, and sex matched)
Fig. 1. Selection and identification of patient cohorts. HCV, hepatitis C virus.
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Fibrosis, cirrhosis, mortality with cholecystectomy Martin et al.
ultrasound of the abdomen, MRI of the abdomen, and computed tomography of the abdomen were reviewed. In our evaluation, cirrhosis was defined by a liver biopsy showing stage 4 fibrosis, if available, and/or by laboratory values, such as platelet count less than 150 000 and albumin level less than 3.8 g/dl, with imaging showing evidence of cirrhosis (nodular liver, splenomegaly, varices) with or without signs of decompensated liver disease, including hepatic encephalopathy, ascites, and esophageal varices. Data on the presence of hepatocellular carcinoma (HCC) and death from complications of liver disease were also collected. Data for the CCY cohort was collected initially and 5 years later (N = 79) or at time of death (N = 9), whichever event was earlier. All patients had HCV before CCY or GBD diagnosis. Statistical analyses
Continuous parameters were reported as mean ± SD, and discrete parameters were reported as n (%). Data were explored for departures from normality with the Shapiro–Wilk test. Independent sample t-tests and Mann–Whitney U-tests were computed, where appropriate, for continuous data. Pearson’s χ2-tests or Fisher’s exact tests were computed, where appropriate, for categorical data. Multiple logistic regression analyses were carried out on the binary outcomes, with cohort as the predictor and BMI, alcohol use, tobacco use, metabolic syndrome, and HIV as covariates. All analyses were carried out with SPSS 21 for Windows (SPSS Inc., Chicago, Illinois, USA). Results Clinical characteristics
The population’s characteristics (demographics, presence of metabolic syndrome, substance use, APRI, platelet counts, FIB-4 scores) are shown in Table 1. Compared with the CCY cohort, the HCV cohort had a higher BMI (P = 0.027), consumed less alcohol (P = 0.001), and had a lower proportion of patients who developed metabolic syndrome (P < 0.001). No difference in tobacco use or Table 1. Baseline characteristics of the CCY, GBD, and HCV cohorts
Age (average) (years) Men African American White Latino/Native American BMI (kg/m2) Tobacco use Alcohol use Metabolic syndrome Total cholesterol (mg/dl) HDL (mg/dl) Triglyceride (mg/dl) Average APRI at study entry Average FIB-4 at study entry
CCY (N = 88)
HCV (N = 129)
GBD (N = 178)
54.3 91% 33% 62% 2% 28* 64% 52%* 39%* 173 49 199† 1.1 2.9
59.5 95% 40% 58% 1% 30 52% 30% 13% 169 48 168 1.2 2.9
57.3 97% 34% 58% 5% 29 65%* 56%* 36%* 169 46 168 1.1 3.1
APRI, aspartate aminotransferase/platelet ratio indices; CCY, cholecystectomy; FIB-4, fibrosis-4; GBD, gallbladder disease; HCV, hepatitis C virus; HDL, highdensity lipoprotein. *P < 0.05 compared with the HCV cohort. † P < 0.05 compared with the GBD cohort.
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cholesterol levels was observed between the CCY and HCV cohorts. Of note, 14% (n = 12) of the CCY cohort had achieved an SVR after HCV therapy (the majority receiving treatment during 5 years of follow-up). Of the 12 patients who achieved an SVR in the CCY cohort, one died from respiratory failure 5 years after CCY and three had cirrhosis. Of note, 48% of the cholecystectomies were performed for acute cholecystitis, 36% for chronic cholecystitis, 4% for gallstone pancreatitis, and 2% for biliary colic. The patients had similar APRIs and FIB-4 scores at entry, suggesting similar levels of fibrosis. The proportion of patients with decompensated liver disease at study entry was 9% in CCY cohort (N = 8), 10% in GBD cohort (N = 18), and 7% in the HCV cohort (N = 9). The majority (83%) of liver biopsies were performed near study entry. Of note, 40% (n = 35) of the CCY cohort had liver biopsies performed (19% with stage 2, 46% with stage 3, and 9% with stage 4). Compared with the HCV cohort, the GBD group used more tobacco (P = 0.020), consumed more alcohol (P < 0.0001), and had a higher proportion of patients who developed metabolic syndrome (P < 0.0001) and HIV (P = 0.024). Within the GBD cohort, 7% (n = 12) achieved SVR (the majority receiving treatment during 5 years of follow-up). Of these 12, five had cirrhosis, and all survived to the end of the study. Of these five, two hade biopsies (one stage 2 and one stage 3). When controlling for BMI, alcohol use, tobacco use, metabolic syndrome, and HIV, there were trends toward differences between GBD and HCV cohorts, but these results did not meet statistical significance. The patients had similar APRIs and FIB-4 scores at entry, suggesting similar levels of fibrosis. Of note, 67% (n = 92) of the HCV cohort had liver biopsies performed (3% with stage 0, 11% with stage 1, 34% with stage 2, 26% with stage 3, and 26% with stage 4), and 23% (n = 41) of the GBD cohort had liver biopsies performed (7% with stage 0, 17% with stage 1, 29% with stage 2, 32% with stage 3, and 15% with stage 4). Compared with the CCY cohort, the GBD cohort had lower triglyceride levels (P = 0.023). The causes of death in the CCY cohort were examined (N = 20): 30% were due to end-stage liver disease, 25% were due to respiratory failure, 15% were due to infections (vancomycin-resistant Enterococcus spp. bacteremia, Clostridium difficile, and fungemia), and 5% were due to metastatic colon cancer. Among the patients who died, the deaths occurred, on average, 4.9 years after the CCY. Two patients died 10 months after their CCY and 18 died between 2 and 5 years after their CCY. Cholecystectomy and hepatitis C virus cohort comparison
At 5 years, the CCY cohort was found to have a higher incidence of cirrhosis (58% diagnosed by imaging and 42% diagnosed clinically), ascites, hepatic encephalopathy, and deaths compared with the HCV cohort (Table 2). When FIB-4 scores were analyzed in quartiles (< 1.45, 1.45–3.25, > 3.25) for each of the cohorts at 5 years after entry, there were a higher proportion of patients with a FIB-4 score greater than 3.25 in the CCY cohort compared with the HCV cohort in the univariate analysis (P = 0.023). Absolute change in the APRI was
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Table 2. Association between HCV-positive individuals with a history of CCY and GBD and incidence of cirrhosis, hepatic encephalopathy, ascites, HCC, or death at 5 years Clinical endpoint Cirrhosis Hepatic encephalopathy Ascites Hepatocellular carcinoma Death
CCY (%) *†
51 14* 24* 17† 23*†
HCV (%)
GBD (%)
27 5 15 9 5
35 9 15 7 11
CCY, cholecystectomy; GBD, gallbladder disease; HCC, hepatocellular carcinoma; HCV, hepatitis C virus. *P < 0.05 compared with the HCV cohort. † P < 0.05 compared with the GBD cohort.
higher in the CCY compared with the HCV cohort (0.73 vs. 0.36; P = 0.03). When controlling for BMI, alcohol use, tobacco use, metabolic syndrome, and HIV, CCY patients had a higher incidence of cirrhosis [odds ratio (OR) = 3.24, 95% confidence interval (CI) 1.57–6.68, P = 0.001], ascites (OR = 3.01, 95% CI 1.14–7.97, P = 0.026), and death (OR = 6.29, 95% CI 2.13–18.59, P = 0.001) at study end (Table 2). Cholecystectomy and gallbladder disease cohort comparison
At study end, the CCY cohort was found to have increased incidence of fibrosis, cirrhosis (40% diagnosed by imaging and 60% clinically), HCC, and death compared with the GBD cohort. When FIB-4 scores were analyzed in quartiles (< 1.45, 1.45–3.25, > 3.25) for each of the cohorts at 5 years after entry, there were a higher proportion of patients with an FIB-4 score greater 3.25 in the CCY cohort compared with the GBD cohort on univariate analysis (P = 0.019). Absolute change in the APRI was higher in the CCY compared with the GBD cohort (0.73 vs. 0.12, P = 0.023). When APRI was analyzed in quartiles (< 0.5, 0.51–1.50, 1.51–3.0, > 3.01) for each of the cohorts at 5 years after entry, there were a higher proportion of patients with APRIs ranging from 1.51 to 3.0 in the CCY cohort compared with the GBD cohort (OR = 2.11, 95% CI 1.103–4.04, P = 0.024). When controlled for BMI, alcohol use, tobacco use, metabolic syndrome, and HIV, there was a higher incidence of cirrhosis (OR = 2.43, 95% CI 1.34–4.41, P = 0.004), HCC (OR = 2.85, 95% CI 1.11–7.36, P = 0.030), and death (OR = 3.31, 95% CI 1.50–7.28, P = 0.003) in the CCY cohort at study end (Table 2). Discussion
In this retrospective cohort study, we found that, after 5 years, the CCY cohort had an increased incidence of cirrhosis, ascites, hepatic encephalopathy, and death compared with the HCV cohort. In addition, we identified that the group of patients with chronic HCV who underwent CCY had an increased incidence of cirrhosis, hepatocellular carcinoma, and death after 5 years compared with HCV-positive patients with GBD without CCY. Our report is of particular significance as we have demonstrated that the association with cirrhosis, its complications, and death extends to patients with chronic HCV who have undergone CCY. In our study, the CCY
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cohort showed a higher incidence of cirrhosis, ascites, and death compared with the group of HCV-positive patients with GBD who had not undergone CCY. The incidence of cirrhosis, death, and ascites in the CCY cohort may be even higher than reported, as 14% (12/88) of the CCY cohort and 7% (12/178) of the GBD cohort had received HCV therapy that had cleared the virus, which would have favored a reduction in fibrosis over time. Although our findings warrant further epidemiological prospective, clinical, and experimental studies, our report is consistent with the hypothesis that CCY may be a risk factor for fibrosis. A limitation of our study is that it involved a primarily white male veteran population, and future studies should examine whether these findings are reproducible in the general population. Another limitation of our study is the increased proportion of patients with metabolic syndrome in the CCY and GBD cohorts when compared with the HCV cohort, which may contribute to mortality and faster progression of fibrosis. As gallstone disease is mostly asymptomatic, some patients categorized as having no gallstone disease may have had asymptomatic disease. The use of surrogate markers to determine the severity of liver disease has its limitations; a cutoff APRI value of 1.5 has been reported to be specific (93%) and to have a positive predictive value of 82% and a negative predictive value of 63% [19]. Interestingly, the CCY cohort had an initial APRI average of 1.1, with an average change of 0.73 over 5 years, suggesting that this cohort already had fibrosis, which appeared to increase during this period. All of the CCY patients who had stage 3 fibrosis on biopsy progressed to stage 4 fibrosis, suggesting that the median APRI likely correlated with both the initial and the final stage of fibrosis. We also observed that HCV patients who underwent CCY had higher 5-year mortality rates compared with those with HCV alone. Of note, the cause of death in almost half (45%) of the patients was end-stage liver disease and infections, suggesting that their mortality was associated with their liver disease. It is well known that hospitalization of cirrhosis patients with infection is associated with increased length of hospital stay, cost, and mortality [20]. In addition, a prospective, longitudinal study clearly described the chronology and hierarchy of complications from cirrhosis, with HCC being the first clinical decompensation (annual incidence of 3.9%), followed by ascites (annual incidence of 2.9%) [21]. Our findings of an increased proportion of patients developing ascites in the CCY cohort and HCC in the GBD cohort at study end are consistent with the natural history of HCV cirrhosis. Of note, this increase in cirrhosis has been shown in another liver disease process as well, NAFLD. We believe that the higher proportion of patients developing cirrhosis and its major complications may be associated with an increase in the inflammatory process, bile acid metabolism, or the enterohepatic circulation of cholesterol. Earlier studies have shown that CCY has no major adverse effects on bile acid metabolism [22] and does not affect fat absorption [23]. Although bile acid pool size and synthesis remain unchanged, the bile acid pool does circulate faster, increasing the exposure of enterohepatic organs and, eventually, peripheral tissues to a higher flux of bile acids [22,24]. Therefore, in those HCVpositive patients who undergo CCY, bile is continuously
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Fibrosis, cirrhosis, mortality with cholecystectomy Martin et al.
secreted into the small intestine, and the bile acid pool circulates more quickly, exposing the liver to a greater flux of bile acids [22,24–26]. This is potentially significant, given the role bile acids have in the regulation of hepatic lipid and glucose metabolism. Bile acids have a wellestablished role in absorption of dietary lipids and cholesterol homeostasis [27]. We believe that events occurring within the enterohepatic circulation may be relevant to understanding why CCY may induce derangements with downregulation of bile acids through their own synthesis in the liver. Furthermore, we believe that fibroblast growth factor (FGF) 19 may play a role in fibrosis. In patients without a gallbladder, FGF19 may affect hepatic bile through insulin-like effects on hepatic protein and glycogen synthesis, and it may inhibit hepatic fatty acid synthesis. Of note, an increase in the number of patients with cirrhosis after CCY has been shown in NAFLD patients as well. A large, cross-sectional, retrospective study showed that NAFLD was associated with CCY [12]. In another study, CCY was found to be associated with cirrhosis [16]. These findings have not been examined previously exclusively in HCV-positive individuals. Interestingly, in our human study, the CCY cohort had significantly higher triglyceride levels than the GBD cohort. Although the molecular mechanisms are not yet clear, an effect of CCY on triglyceride metabolism has recently been demonstrated in an animal model [25]. In mice, CCY increased serum and hepatic triglyceride levels and led to hepatic very-low-density lipoprotein production [25]. Preliminary studies in humans have shown that serum FGF19 concentration decreases after CCY, which could have an impact on metabolic regulation [27]. Other relevant bile acid-dependent signaling pathways within the enterohepatic circulation are mediated by TGR5, which stimulates gallbladder filling, and TGR5 activation modulates glucose homeostasis in ileal enteroendocrine L cells [26,28]. TGR5 is activated by bile acids in extrahepatic tissues, increasing energy expenditure and preventing dietinduced obesity [29]. Collectively, these data strongly support the fact that the gallbladder is critical in controlling bile acid homeostasis within the enterohepatic circulation, which may be relevant to whole-body metabolic homeostasis, which, in turn, has a myriad of peripheral actions in extrahepatic tissues [30]. Hence, CCY is not inconsequential from a metabolic standpoint. In summary, our observational study suggests that CCY may lead to increased hepatic fibrosis in HCV patients. CCY may be a novel risk factor for liver disease. Future studies should investigate these associations in other cohorts and examine the underlying mechanism.
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There are no conflicts of interest. 25
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Introduction
Gallstones, per se, are not a problem until they become symptomatic or complicated. However, symptomatic gallstone disease and its complications remain a major public health problem, and these conditions are some of the most common and costly of all digestive diseases [1]. The Third National Health and Nutrition Examination Survey estimated that 20.5 million individuals in the USA had gallbladder disease (GBD) and that GBD is responsible for several thousand deaths per year [1,2]. In addition, the annual cost of GBD in the USA in 2000 was European Journal of Gastroenterology & Hepatology 2016, 28:181–186 Keywords: cholecystectomy, cirrhosis, hepatitis C a
Division of Gastroenterology and Hepatology, Departments of bPharmacy, Pathology, VA North Texas Healthcare System, dDivision of Digestive and Liver Diseases and eDepartment of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA c
Correspondence to Geri Brown, MD, Division of Gastroenterology and Hepatology, Dallas VA Medical Center, Mail Code 111B1, 4500 South Lancaster Road, Dallas, Texas 75216, USA Tel: + 1 214 857 1603; fax: + 1 214 857 1571; e-mail: [email protected] Received 5 August 2015 Accepted 5 October 2015
approximately $6.5 billion, making it the second most costly digestive disease [3]. Cirrhosis is a well-documented risk factor for the formation of gallstones [4–8]. In addition, the severity of cirrhosis, classified by Child–Pugh class, is one of the strongest predictors of the prevalence and incidence of gallstones in patients with cirrhosis [5]. The prevalence of GBD, including cholecystectomy (CCY), in patients with hepatitis C virus (HCV) infection has been estimated at 12.5% [9]. HCV infection is also an important public health problem in the USA and is a leading cause of chronic liver disease and cirrhosis [3,10]. It is estimated that 3.4–4.4 million people in the USA are infected with HCV, and ∼ 2.7 million people are chronically infected [11–13]. CCY has been associated with nonalcoholic fatty liver disease (NAFLD) in a population-based study, suggesting that CCY may itself represent a risk factor for the development of NAFLD [12]. Both GBD and NAFLD have been associated with an increased mortality from chronic liver disease, cardiovascular disease, and cancer, compared with the general population [14,15]. CCY has been associated with the development of cirrhosis in a population-based study [16]. To our knowledge, the relationship of morbidity or mortality in patients with a prior CCY has not
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DOI: 10.1097/MEG.0000000000000512
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been investigated exclusively in patients with HCV infection. We, therefore, sought to examine the association of GBD in patients with HCV infection in the veterans’ population, with an emphasis on whether CCY was associated with worsening hepatic fibrosis, cirrhosis, and its complications. Methods
Among 3989 HCV-positive patients (identified by HCV antibody positivity and confirmed by PCR testing), we identified 88 patients who had undergone prior CCY (CCY cohort), as determined on the basis of a corresponding International Classification of Diseases-9 code for CCY, imaging consistent with prior CCY, and verification by pathological specimens. We compared outcomes of the CCY cohort with those two cohorts: 178 HCV-positive patients who had GBD, defined by ICD-9 codes for cholelithiasis, choledocholithiasis, acute or chronic cholecystitis, biliary sludge, or choledocholithiasis on imaging, and had not undergone prior CCY (GBD cohort), and 129 HCV-positive patients without GBD or prior CCY (HCV cohort). The three cohorts were agematched, race-matched, and sex-matched for analyses (Fig. 1). The ‘index date’ was the time at CCY for the CCY cohort and the date of diagnosis for the GBD cohort. The HCV cohort was age-matched, race-matched, and sexmatched to the CCY cohort at the time of diagnosis. The cohorts were matched at baseline and the outcomes were assessed over the next 5 years, all of which were within the VA system. The primary outcome was development of cirrhosis and its complications. In addition to the primary outcome, laboratory results were also assessed at baseline and at 5 years, including aspartate aminotransferase level (AST), alanine aminotransferase level (ALT), alkaline phosphatase level, total bilirubin level, international normalized ratio (INR), albumin level, and platelet count. Laboratory data collected also included HCV genotype, total cholesterol level, high-density lipoprotein level, and triglyceride level. The AST/platelet ratio indices (APRIs) and fibrosis-4 (FIB-4) scores were calculated to determine the degree of fibrosis at baseline and 5 years later. To determine liver
fibrosis severity APRI was calculated using the following formula: [AST (IU/l)/upper limit normal/platelet count (×109/l)] × 100 [17]. The FIB-4 count was calculated using the following formula: [age (years) × AST (U/l)]/[platelet count (109/l) × √ALT (U/l)] [18]. The APRIs and FIB-4 scores were analyzed by absolute change and in quartiles, as a means of illustrating the relationship between a binary exposure and continuous outcome. The study was performed at the VA North Texas Health Care System using the medical center’s electronic health record. Records of male and female patients between the ages of 35 and 75 years of all ethnicities and with histories of chronic HCV were reviewed for data collection from 1998 to 2013. The HCV cohort included patients who were nonresponders to HCV therapy. Successfully treated HCV patients with a sustained virological response (SVR) were not included in the HCV cohort as this would decrease fibrosis progression rates. Patients were excluded if they died within 180 days of CCY or if they underwent CCY during liver transplantation. From the patients meeting the inclusion criteria, data on characteristics were collected and included age at the time of HCV and GBD diagnosis, sex, ethnicity, tobacco use history, alcohol use history, and BMI. Alcohol and tobacco use were defined by presence in the problem list at any point in time in the available medical records. Data on medical history included metabolic syndrome and human immunodeficiency virus (HIV) status. Metabolic syndrome was defined by fulfillment of three or more of the following criteria: fasting blood triglyceride level greater than 150 mg/dl, blood high-density lipoprotein level less than 40 mg/dl in men and less than 50 mg/dl in women, blood pressure greater than 135/80 mmHg, and/or fasting blood sugar greater than 100 mg/dl. If available, liver biopsies were assessed and collected, including grade and stage, in all study participants. In addition, data on indication for CCY and pathology from patients who had undergone the procedure were assessed and collected. To understand the etiology and severity surrounding CCY, the chart was reviewed for evidence of acuity, including the following factors: outpatient versus inpatient, clinical laboratory values, surgery within 24 h. Imaging results including
Eligible participants (N = 3989)
Confirmed HCV antibody and PCR
Cholecystectomy cohort (N = 88)
Gallbladder disease cohort (N = 178)
HCV cohort (N = 129; age, race, and sex matched)
Fig. 1. Selection and identification of patient cohorts. HCV, hepatitis C virus.
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Fibrosis, cirrhosis, mortality with cholecystectomy Martin et al.
ultrasound of the abdomen, MRI of the abdomen, and computed tomography of the abdomen were reviewed. In our evaluation, cirrhosis was defined by a liver biopsy showing stage 4 fibrosis, if available, and/or by laboratory values, such as platelet count less than 150 000 and albumin level less than 3.8 g/dl, with imaging showing evidence of cirrhosis (nodular liver, splenomegaly, varices) with or without signs of decompensated liver disease, including hepatic encephalopathy, ascites, and esophageal varices. Data on the presence of hepatocellular carcinoma (HCC) and death from complications of liver disease were also collected. Data for the CCY cohort was collected initially and 5 years later (N = 79) or at time of death (N = 9), whichever event was earlier. All patients had HCV before CCY or GBD diagnosis. Statistical analyses
Continuous parameters were reported as mean ± SD, and discrete parameters were reported as n (%). Data were explored for departures from normality with the Shapiro–Wilk test. Independent sample t-tests and Mann–Whitney U-tests were computed, where appropriate, for continuous data. Pearson’s χ2-tests or Fisher’s exact tests were computed, where appropriate, for categorical data. Multiple logistic regression analyses were carried out on the binary outcomes, with cohort as the predictor and BMI, alcohol use, tobacco use, metabolic syndrome, and HIV as covariates. All analyses were carried out with SPSS 21 for Windows (SPSS Inc., Chicago, Illinois, USA). Results Clinical characteristics
The population’s characteristics (demographics, presence of metabolic syndrome, substance use, APRI, platelet counts, FIB-4 scores) are shown in Table 1. Compared with the CCY cohort, the HCV cohort had a higher BMI (P = 0.027), consumed less alcohol (P = 0.001), and had a lower proportion of patients who developed metabolic syndrome (P < 0.001). No difference in tobacco use or Table 1. Baseline characteristics of the CCY, GBD, and HCV cohorts
Age (average) (years) Men African American White Latino/Native American BMI (kg/m2) Tobacco use Alcohol use Metabolic syndrome Total cholesterol (mg/dl) HDL (mg/dl) Triglyceride (mg/dl) Average APRI at study entry Average FIB-4 at study entry
CCY (N = 88)
HCV (N = 129)
GBD (N = 178)
54.3 91% 33% 62% 2% 28* 64% 52%* 39%* 173 49 199† 1.1 2.9
59.5 95% 40% 58% 1% 30 52% 30% 13% 169 48 168 1.2 2.9
57.3 97% 34% 58% 5% 29 65%* 56%* 36%* 169 46 168 1.1 3.1
APRI, aspartate aminotransferase/platelet ratio indices; CCY, cholecystectomy; FIB-4, fibrosis-4; GBD, gallbladder disease; HCV, hepatitis C virus; HDL, highdensity lipoprotein. *P < 0.05 compared with the HCV cohort. † P < 0.05 compared with the GBD cohort.
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cholesterol levels was observed between the CCY and HCV cohorts. Of note, 14% (n = 12) of the CCY cohort had achieved an SVR after HCV therapy (the majority receiving treatment during 5 years of follow-up). Of the 12 patients who achieved an SVR in the CCY cohort, one died from respiratory failure 5 years after CCY and three had cirrhosis. Of note, 48% of the cholecystectomies were performed for acute cholecystitis, 36% for chronic cholecystitis, 4% for gallstone pancreatitis, and 2% for biliary colic. The patients had similar APRIs and FIB-4 scores at entry, suggesting similar levels of fibrosis. The proportion of patients with decompensated liver disease at study entry was 9% in CCY cohort (N = 8), 10% in GBD cohort (N = 18), and 7% in the HCV cohort (N = 9). The majority (83%) of liver biopsies were performed near study entry. Of note, 40% (n = 35) of the CCY cohort had liver biopsies performed (19% with stage 2, 46% with stage 3, and 9% with stage 4). Compared with the HCV cohort, the GBD group used more tobacco (P = 0.020), consumed more alcohol (P < 0.0001), and had a higher proportion of patients who developed metabolic syndrome (P < 0.0001) and HIV (P = 0.024). Within the GBD cohort, 7% (n = 12) achieved SVR (the majority receiving treatment during 5 years of follow-up). Of these 12, five had cirrhosis, and all survived to the end of the study. Of these five, two hade biopsies (one stage 2 and one stage 3). When controlling for BMI, alcohol use, tobacco use, metabolic syndrome, and HIV, there were trends toward differences between GBD and HCV cohorts, but these results did not meet statistical significance. The patients had similar APRIs and FIB-4 scores at entry, suggesting similar levels of fibrosis. Of note, 67% (n = 92) of the HCV cohort had liver biopsies performed (3% with stage 0, 11% with stage 1, 34% with stage 2, 26% with stage 3, and 26% with stage 4), and 23% (n = 41) of the GBD cohort had liver biopsies performed (7% with stage 0, 17% with stage 1, 29% with stage 2, 32% with stage 3, and 15% with stage 4). Compared with the CCY cohort, the GBD cohort had lower triglyceride levels (P = 0.023). The causes of death in the CCY cohort were examined (N = 20): 30% were due to end-stage liver disease, 25% were due to respiratory failure, 15% were due to infections (vancomycin-resistant Enterococcus spp. bacteremia, Clostridium difficile, and fungemia), and 5% were due to metastatic colon cancer. Among the patients who died, the deaths occurred, on average, 4.9 years after the CCY. Two patients died 10 months after their CCY and 18 died between 2 and 5 years after their CCY. Cholecystectomy and hepatitis C virus cohort comparison
At 5 years, the CCY cohort was found to have a higher incidence of cirrhosis (58% diagnosed by imaging and 42% diagnosed clinically), ascites, hepatic encephalopathy, and deaths compared with the HCV cohort (Table 2). When FIB-4 scores were analyzed in quartiles (< 1.45, 1.45–3.25, > 3.25) for each of the cohorts at 5 years after entry, there were a higher proportion of patients with a FIB-4 score greater than 3.25 in the CCY cohort compared with the HCV cohort in the univariate analysis (P = 0.023). Absolute change in the APRI was
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Table 2. Association between HCV-positive individuals with a history of CCY and GBD and incidence of cirrhosis, hepatic encephalopathy, ascites, HCC, or death at 5 years Clinical endpoint Cirrhosis Hepatic encephalopathy Ascites Hepatocellular carcinoma Death
CCY (%) *†
51 14* 24* 17† 23*†
HCV (%)
GBD (%)
27 5 15 9 5
35 9 15 7 11
CCY, cholecystectomy; GBD, gallbladder disease; HCC, hepatocellular carcinoma; HCV, hepatitis C virus. *P < 0.05 compared with the HCV cohort. † P < 0.05 compared with the GBD cohort.
higher in the CCY compared with the HCV cohort (0.73 vs. 0.36; P = 0.03). When controlling for BMI, alcohol use, tobacco use, metabolic syndrome, and HIV, CCY patients had a higher incidence of cirrhosis [odds ratio (OR) = 3.24, 95% confidence interval (CI) 1.57–6.68, P = 0.001], ascites (OR = 3.01, 95% CI 1.14–7.97, P = 0.026), and death (OR = 6.29, 95% CI 2.13–18.59, P = 0.001) at study end (Table 2). Cholecystectomy and gallbladder disease cohort comparison
At study end, the CCY cohort was found to have increased incidence of fibrosis, cirrhosis (40% diagnosed by imaging and 60% clinically), HCC, and death compared with the GBD cohort. When FIB-4 scores were analyzed in quartiles (< 1.45, 1.45–3.25, > 3.25) for each of the cohorts at 5 years after entry, there were a higher proportion of patients with an FIB-4 score greater 3.25 in the CCY cohort compared with the GBD cohort on univariate analysis (P = 0.019). Absolute change in the APRI was higher in the CCY compared with the GBD cohort (0.73 vs. 0.12, P = 0.023). When APRI was analyzed in quartiles (< 0.5, 0.51–1.50, 1.51–3.0, > 3.01) for each of the cohorts at 5 years after entry, there were a higher proportion of patients with APRIs ranging from 1.51 to 3.0 in the CCY cohort compared with the GBD cohort (OR = 2.11, 95% CI 1.103–4.04, P = 0.024). When controlled for BMI, alcohol use, tobacco use, metabolic syndrome, and HIV, there was a higher incidence of cirrhosis (OR = 2.43, 95% CI 1.34–4.41, P = 0.004), HCC (OR = 2.85, 95% CI 1.11–7.36, P = 0.030), and death (OR = 3.31, 95% CI 1.50–7.28, P = 0.003) in the CCY cohort at study end (Table 2). Discussion
In this retrospective cohort study, we found that, after 5 years, the CCY cohort had an increased incidence of cirrhosis, ascites, hepatic encephalopathy, and death compared with the HCV cohort. In addition, we identified that the group of patients with chronic HCV who underwent CCY had an increased incidence of cirrhosis, hepatocellular carcinoma, and death after 5 years compared with HCV-positive patients with GBD without CCY. Our report is of particular significance as we have demonstrated that the association with cirrhosis, its complications, and death extends to patients with chronic HCV who have undergone CCY. In our study, the CCY
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cohort showed a higher incidence of cirrhosis, ascites, and death compared with the group of HCV-positive patients with GBD who had not undergone CCY. The incidence of cirrhosis, death, and ascites in the CCY cohort may be even higher than reported, as 14% (12/88) of the CCY cohort and 7% (12/178) of the GBD cohort had received HCV therapy that had cleared the virus, which would have favored a reduction in fibrosis over time. Although our findings warrant further epidemiological prospective, clinical, and experimental studies, our report is consistent with the hypothesis that CCY may be a risk factor for fibrosis. A limitation of our study is that it involved a primarily white male veteran population, and future studies should examine whether these findings are reproducible in the general population. Another limitation of our study is the increased proportion of patients with metabolic syndrome in the CCY and GBD cohorts when compared with the HCV cohort, which may contribute to mortality and faster progression of fibrosis. As gallstone disease is mostly asymptomatic, some patients categorized as having no gallstone disease may have had asymptomatic disease. The use of surrogate markers to determine the severity of liver disease has its limitations; a cutoff APRI value of 1.5 has been reported to be specific (93%) and to have a positive predictive value of 82% and a negative predictive value of 63% [19]. Interestingly, the CCY cohort had an initial APRI average of 1.1, with an average change of 0.73 over 5 years, suggesting that this cohort already had fibrosis, which appeared to increase during this period. All of the CCY patients who had stage 3 fibrosis on biopsy progressed to stage 4 fibrosis, suggesting that the median APRI likely correlated with both the initial and the final stage of fibrosis. We also observed that HCV patients who underwent CCY had higher 5-year mortality rates compared with those with HCV alone. Of note, the cause of death in almost half (45%) of the patients was end-stage liver disease and infections, suggesting that their mortality was associated with their liver disease. It is well known that hospitalization of cirrhosis patients with infection is associated with increased length of hospital stay, cost, and mortality [20]. In addition, a prospective, longitudinal study clearly described the chronology and hierarchy of complications from cirrhosis, with HCC being the first clinical decompensation (annual incidence of 3.9%), followed by ascites (annual incidence of 2.9%) [21]. Our findings of an increased proportion of patients developing ascites in the CCY cohort and HCC in the GBD cohort at study end are consistent with the natural history of HCV cirrhosis. Of note, this increase in cirrhosis has been shown in another liver disease process as well, NAFLD. We believe that the higher proportion of patients developing cirrhosis and its major complications may be associated with an increase in the inflammatory process, bile acid metabolism, or the enterohepatic circulation of cholesterol. Earlier studies have shown that CCY has no major adverse effects on bile acid metabolism [22] and does not affect fat absorption [23]. Although bile acid pool size and synthesis remain unchanged, the bile acid pool does circulate faster, increasing the exposure of enterohepatic organs and, eventually, peripheral tissues to a higher flux of bile acids [22,24]. Therefore, in those HCVpositive patients who undergo CCY, bile is continuously
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Fibrosis, cirrhosis, mortality with cholecystectomy Martin et al.
secreted into the small intestine, and the bile acid pool circulates more quickly, exposing the liver to a greater flux of bile acids [22,24–26]. This is potentially significant, given the role bile acids have in the regulation of hepatic lipid and glucose metabolism. Bile acids have a wellestablished role in absorption of dietary lipids and cholesterol homeostasis [27]. We believe that events occurring within the enterohepatic circulation may be relevant to understanding why CCY may induce derangements with downregulation of bile acids through their own synthesis in the liver. Furthermore, we believe that fibroblast growth factor (FGF) 19 may play a role in fibrosis. In patients without a gallbladder, FGF19 may affect hepatic bile through insulin-like effects on hepatic protein and glycogen synthesis, and it may inhibit hepatic fatty acid synthesis. Of note, an increase in the number of patients with cirrhosis after CCY has been shown in NAFLD patients as well. A large, cross-sectional, retrospective study showed that NAFLD was associated with CCY [12]. In another study, CCY was found to be associated with cirrhosis [16]. These findings have not been examined previously exclusively in HCV-positive individuals. Interestingly, in our human study, the CCY cohort had significantly higher triglyceride levels than the GBD cohort. Although the molecular mechanisms are not yet clear, an effect of CCY on triglyceride metabolism has recently been demonstrated in an animal model [25]. In mice, CCY increased serum and hepatic triglyceride levels and led to hepatic very-low-density lipoprotein production [25]. Preliminary studies in humans have shown that serum FGF19 concentration decreases after CCY, which could have an impact on metabolic regulation [27]. Other relevant bile acid-dependent signaling pathways within the enterohepatic circulation are mediated by TGR5, which stimulates gallbladder filling, and TGR5 activation modulates glucose homeostasis in ileal enteroendocrine L cells [26,28]. TGR5 is activated by bile acids in extrahepatic tissues, increasing energy expenditure and preventing dietinduced obesity [29]. Collectively, these data strongly support the fact that the gallbladder is critical in controlling bile acid homeostasis within the enterohepatic circulation, which may be relevant to whole-body metabolic homeostasis, which, in turn, has a myriad of peripheral actions in extrahepatic tissues [30]. Hence, CCY is not inconsequential from a metabolic standpoint. In summary, our observational study suggests that CCY may lead to increased hepatic fibrosis in HCV patients. CCY may be a novel risk factor for liver disease. Future studies should investigate these associations in other cohorts and examine the underlying mechanism.
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