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Study Finds Diabetes is Associated with HCV & HBV, Triglycerides, Steatosis & More Severe Fibrosis
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"Diabetes mellitus in chronic hepatitis B and C: prevalence and potential association with the extent of liver fibrosis"
Journal of Viral Hepatitis
Volume 13 Page 303 - May 2006
G. V. Papatheodoridis1, N. Chrysanthos1, S. Savvas1, V. Sevastianos1, G. Kafiri2, K. Petraki1 and E. K. Manesis1
1Academic Department of Internal Medicine and 2Department of Pathology, Hippokration General Hospital, Athens, Greece
".....Diabetes was observed significantly less frequently in patients with fibrosis score 0-2 (15/194 or 7.7%) than 3-4 (15/144 or 10.4%) than 5-6 (28/96 or 29.2%) (P < 0.001).... In multivariate analysis, presence of diabetes was independently associated with higher ALT, GGT and triglycerides levels, more severe fibrosis or presence of cirrhosis and presence of hepatic steatosis.....In particular, the prevalence of diabetes in our patients with compensated cirrhosis was approximately 30%, which is in agreement with what has already been reported in similar settings....advanced fibrosis (staging score = 4) was observed relatively more frequently in patients with than without diabetes (10/30 or 33%vs 56/308 or 18%, P = 0.055). In this subgroup, presence of diabetes was found to be associated significantly with older age and higher GGT levels and relatively with higher ALP levels and lower platelet counts.....Our data do not directly support a causative effect of diabetes mellitus on the histological progression of chronic viral hepatitis.....Whether the presence of diabetes mellitus accelerates the worsening of liver fibrosis or whether it follows the development of cirrhosis must be evaluated in properly designed prospective studies.....The hypothesis of a deleterious effect of diabetes on the progression of chronic liver disease is mainly based on the strong link between diabetes and hepatic steatosis or NASH [16,17,19,20]. NASH is a common, well-recognized liver disease that may be associated with development of fibrosis leading eventually to cirrhosis....."
Fig. 1 Prevalence of diabetes mellitus in 434 patients with hepatitis B e antigen-negative chronic hepatitis B (n = 174) or chronic hepatitis C (n = 260) in relation to the extent of liver fibrosis.
Summary. Diabetes mellitus has been reported to have an increased prevalence and to be associated with more severe fibrosis in patients with chronic hepatitis C. We evaluated the prevalence of diabetes mellitus in patients with chronic hepatitis B or C as well as the possible association between presence of diabetes and extent of liver fibrosis. In total, 434 consecutive patients with histologically documented hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (n = 174) or chronic hepatitis C (n = 260) were studied. The relationships of diabetes and epidemiological, somatomorphic, laboratory and histological patient characteristics were evaluated. Liver histological lesions were blindly evaluated according to the Ishak's classification.
Diabetes was present in 58 (13%) patients, without any difference between those with chronic hepatitis B (14%) or C (13%).
Diabetes was observed significantly less frequently in patients with fibrosis score 0-2 (7.7%) than 3-4 (10.4%) than 5-6 (29.2%) (P < 0.001).
The presence of diabetes was independently associated with higher gamma-glutamyl-transpeptidase (GGT) levels and more severe fibrosis or presence of cirrhosis (P < 0.001) as well as with presence of hepatic steatosis and increased serum triglycerides levels (P < 0.02).
In the noncirrhotic patients, diabetes was significantly associated with older age and higher GGT levels, but not with the extent of fibrosis.
In conclusion, diabetes mellitus is observed in more than 10% of patients with either HBeAg-negative chronic hepatitis B or chronic hepatitis C. The presence of diabetes is strongly associated with more severe liver fibrosis, but such an association may be related to the high prevalence of diabetes in patients with cirrhosis.
Table 1 Epidemiological, haematological, biochemical and histological characteristics of 434 patients with hepatitis B e antigen-negative chronic hepatitis B (CHB) or chronic hepatitis C (CHC) in relation to the presence of diabetes mellitus (average age of study patients: 48-59 years)
RESULTS
There were 261 (60%) males and 173 (40%) females, while their mean (SD) age was 50 (14) years. One hundred and seventy-four (40%) patients had HBeAg-negative chronic hepatitis B and 260 (60%) chronic hepatitis C. Patients with chronic hepatitis B compared with those with chronic hepatitis C were older, heavier and more frequently males and they had significantly higher serum cholesterol levels, lower white blood and platelet counts, more severe fibrosis and less hepatic steatosis. Hepatic iron deposits were detected in 22 (5.9%) of 372 patients without difference between chronic hepatitis B and C (12/145 or 8.3%vs 10/227 or 4.4%, P = 0.19).
Diabetes mellitus was present in 58 [13%, 95% confidence interval (CI): 10-16%] of the 434 patients. It was first diagnosed on the liver biopsy day and confirmed later in only two patients, while it had been diagnosed before liver biopsy in the remaining 56 cases. Of the latter 56 diabetic patients, four were treated with diet, 38 were on oral anti-diabetic drugs and 14 were treated with insulin.
The prevalence of diabetes did not differ between patients with chronic hepatitis B (25/174 or 14%) and chronic hepatitis C (33/260 or 13%) (P = 0.72). In a univariate analysis of the total population of 434 patients, the presence of diabetes mellitus was found to be associated with older age (56 ± 11 vs 49 ± 15 years, P < 0.001), higher median AST (75 vs 51 IU/L, P = 0.001), ALP (0.7 vs 0.6 X ULN, P =0.014) and GGT levels (1.2 vs 0.6 X ULN, P < 0.001), higher mean triglycerides levels (123 vs 102 mg/dL, P =0.02) or more frequent presence of increased (>150 mg/dL) triglycerides levels (33%vs 14%, P = 0.001), lower platelet count (165 ± 61 vs 194 ± 72 X 109/L, P = 0.002), more severe fibrosis score (4.1 ± 1.7 vs 3.0 ± 1.5, P = 0.001) and more frequent presence of hepatic steatosis (47/58 or 81%vs 232/376 or 62%, P = 0.004) or more severe grades of steatosis (mild, moderate, severe steatosis: 35%, 28%, 19%vs 38%, 12%, 12%, P = 0.001). In contrast, the presence of diabetes was not associated with patients' sex, weight or body mass index, alcohol abuse or the type of chronic hepatitis (Table 1). Hepatic iron deposits were detected in 5 (11%) of 44 patients with and in 17 (5%) of 328 patients without diabetes (P = 0.20).
Diabetes was significantly more frequent in patients with, than without, advanced fibrosis (38/162 or 23%vs 20/272 or 7%, P < 0.001) or in patients with, than without, cirrhosis (28/96 or 29%vs 30/338 or 9%, P < 0.001). The proportions of patients with diabetes mellitus in relation to the extent of fibrosis are presented in Fig. 1. Diabetes was observed significantly less frequently in patients with fibrosis score 0-2 (15/194 or 7.7%) than 3-4 (15/144 or 10.4%) than 5-6 (28/96 or 29.2%) (P < 0.001).
Associations between the presence of diabetes and patients characteristics, similar to those already described, were also observed when patients with chronic hepatitis B or C were evaluated separately. In particular, in both chronic hepatitis B and C patients, diabetes was associated with older age, higher GGT levels, lower platelet counts, more severe fibrosis or presence of cirrhosis and more severe grades of steatosis (Table 1, Fig. 1). In addition, only in chronic hepatitis B, patients with, compared to those without, diabetes were found to have higher AST levels and higher grading scores (Table 1). The HCV genotype was not associated with the presence of diabetes, which was observed in 18 of 97 (18.6%) patients with genotype 1, zero of seven with genotype 2, five of 58 (8.6%) with genotype 3 and six of 50 (12%) with genotype 4 (P = 0.22).
In multivariate analysis, presence of diabetes was independently associated with higher ALT, GGT and triglycerides levels, more severe fibrosis or presence of cirrhosis and presence of hepatic steatosis. Similarly, in the subgroup of patients with chronic hepatitis B, higher AST, GGT and triglycerides levels, more severe fibrosis or presence of cirrhosis and presence of hepatic steatosis were also variables independently associated with presence of diabetes. In contrast, in the subgroup of patients with chronic hepatitis C, presence of diabetes was associated only with higher GGT and triglycerides levels and more severe fibrosis or presence of cirrhosis, but not with hepatic steatosis (Table 2).
Among the 338 non-cirrhotic patients, the fibrosis score was not significantly higher in diabetic than non-diabetic cases (2.7 ± 1.1 vs 2.4 ± 1.0, P = 0.12), although advanced fibrosis (staging score = 4) was observed relatively more frequently in patients with than without diabetes (10/30 or 33%vs 56/308 or 18%, P = 0.055). In this subgroup, presence of diabetes was found to be associated significantly with older age and higher GGT levels and relatively with higher ALP levels and lower platelet counts (Table 3). Multivariate analysis showed that diabetes was independently associated with older age (OR: 1.03; 95% CI: 1.00-1.06; P = 0.04) and higher GGT levels (OR: 2.02, 95% CI: 1.48-2.76; P < 0.001), but not with the fibrosis score.
DISCUSSION
Diabetes mellitus was present in 13% of our chronic viral hepatitis patients without significant difference between those with chronic hepatitis B or C. This is in contrast to previous reports suggesting that the prevalence of diabetes is higher in patients with HCV than HBV related chronic liver disease [11,13,14,32]. However, data among the several studies cannot be easily compared, as patient populations differed in age and presence or severity of cirrhosis, which are all very important factors associated with the risk of diabetes [11,13-15]. In addition, some of the latter studies evaluated any patient with chronic HBV infection including chronic inactive HBV carriers [11,13], who may represent a population with a different diabetes risk compared with patients with histologically documented chronic hepatitis B, as were those included in our study. It should be also noted that our patients with chronic hepatitis B compared with those with chronic hepatitis C had more frequently factors that may be associated with a higher risk of diabetes, such as older age, heavier weight and more advanced liver disease, as expressed by the lower white blood and platelet count and more severe fibrosis. However, the type of chronic viral hepatitis was not found to be associated with the presence of diabetes in the multivariate analysis after adjustment for several factors. Thus, our data are in agreement with reports suggesting that the prevalence of diabetes mellitus does not differ significantly between patients with chronic hepatitis B or C [15].
More severe fibrosis and particularly presence of cirrhosis as well as higher GGT and increased triglycerides levels were found to be independently associated with presence of diabetes mellitus in our patients with chronic hepatitis B or C. In particular, the prevalence of diabetes in our patients with compensated cirrhosis was approximately 30%, which is in agreement with what has already been reported in similar settings [11,15,33]. The association of diabetes with increased triglycerides is well established, while the increased GGT levels in patients with diabetes mellitus could be reasonably attributed to the more severe hepatic steatosis in these patients, as the presence of diabetes is known to be strongly associated with increased risk for development of nonalcoholic fatty liver disease or NASH [16,17,19,20]. Older age is also a factor that has been frequently shown to be associated with presence of diabetes in patients with or without liver disease [11,13,15]. In our multivariate analysis, however, age was not associated with diabetes in the total patient population probably due to the strong effect of cirrhosis. On the contrary, when only the noncirrhotic patients were evaluated, older age and increased GGT levels were found to be the two factors that were independently associated with presence of diabetes mellitus.
Presence and more severe grades of hepatic steatosis were found to be significantly associated with presence of diabetes in both patients with chronic hepatitis B and C in the univariate analysis. In the multivariate analysis, however, there was an independent association between diabetes and hepatic steatosis only in chronic hepatitis B, but not in chronic hepatitis C patients. Such findings may suggest that hepatic steatosis develops mostly due to diabetes in patients with chronic hepatitis B, while it may develop due to either diabetes or HCV itself in patients with chronic hepatitis C [24,34-36]. This hypothesis is further supported by the significantly more frequent presence of hepatic steatosis in our nondiabetic patients with chronic hepatitis C than B (153/227 or 67%vs 79/149 or 53%, P = 0.007). It should be noted that, in chronic hepatitis C, hepatic steatosis has been independently associated with HCV in patients infected with HCV genotype 3, while it seems to be associated with presence of the metabolic syndrome in those infected with HCV genotype 1 [35]. As it has been shown in other studies including mainly patients with chronic hepatitis C [6,7,34,36-38], the presence and more severe grades of hepatic steatosis were significantly associated with more severe fibrosis in our patients with both chronic hepatitis C and B (data not shown).
The relationship of diabetes mellitus with the severity of liver disease has not been adequately clarified. Although diabetes is present more frequently in patients with cirrhosis or even those with hepatocellular carcinoma [11,15,18,33], it is unclear whether the presence of diabetes precedes and accelerates or whether it follows and results from the progression of chronic liver disease. The hypothesis of a deleterious effect of diabetes on the progression of chronic liver disease is mainly based on the strong link between diabetes and hepatic steatosis or NASH [16,17,19,20]. NASH is a common, well-recognized liver disease that may be associated with development of fibrosis leading eventually to cirrhosis [16,17,20-22]. Although the pathogenesis of NASH remains unclarified, the most favourable hypothesis supports the involvement of increased insulin resistance with subsequent increased fatty acid B-oxidation and hepatic oxidative stress [39,40]. Moreover, hyperglycaemia and hyperinsulinaemia have been suggested to be important factors for the progression of fibrosis in patients with NASH probably through stimulation of connective tissue growth factor expression [41]. Finally, according to recent data, the progression of fibrosis in chronic hepatitis C may be increased in the presence of diabetes mellitus or even insulin resistance [23-26].
Our data do not directly support a causative effect of diabetes mellitus on the histological progression of chronic viral hepatitis. Although a strong association between diabetes and more severe fibrosis was observed in our total patient population, it may be related to the strong link between diabetes and cirrhosis. Such a hypothesis is further supported by the absence of a significant association between diabetes and extent of fibrosis in our noncirrhotic patients. It should be noted, however, that there was a trend for significant difference in the proportion of diabetes in noncirrhotic patients with advanced than nonadvanced fibrosis. Thus, the association of diabetes with the extent of liver fibrosis in noncirrhotic patients with chronic viral hepatitis cannot be definitely excluded. Moreover, the duration of diabetes mellitus might also have an effect on the histological progression of liver disease, which could not be evaluated in our study.
In conclusion, diabetes mellitus is observed in more than 10% of patients with either HBeAg-negative chronic hepatitis B or chronic hepatitis C. The presence of diabetes is strongly associated with more severe liver fibrosis in these patients, but such an association may be related to the high prevalence of diabetes in patients with cirrhosis. Whether the presence of diabetes mellitus accelerates the worsening of liver fibrosis or whether it follows the development of cirrhosis must be evaluated in properly designed prospective studies.
Introduction
Chronic viral hepatitis is a progressive liver disease leading to the development of cirrhosis in about 20-30% of patients [1-5]. Several host or viral factors, such as age, gender, consumption of alcohol, duration of infection, and viral coinfections [1,3,5], have been associated with histological severity and the rate of fibrosis progression. Recently, there is increasing interest for hepatic steatosis, which has been found to be related to the extent of fibrosis in patients with chronic hepatitis C [6,7].
Diabetes mellitus is a common disorder in the general population, but its prevalence is particularly high among cirrhotic patients [8-10]. Data from several studies have suggested that the prevalence of diabetes mellitus is also high among patients with chronic hepatitis C with or without coexisting cirrhosis [11-13]. Moreover, diabetes has been reported to be present more frequently in patients with hepatitis C virus (HCV) than hepatitis B virus (HBV) related chronic liver disease in most but not all studies [11,13-15].
The possible effect of diabetes mellitus on the histological progression of chronic viral hepatitis has been infrequently studied to date. Diabetes is a co-morbid condition of chronic liver disease, mostly nonalcoholic fatty liver disease [16-18], and biochemical evidence of ongoing liver damage, as expressed by increased aminotransferases activity, may be detected in a large proportion of diabetic patients [19,20]. Moreover, progression to cirrhosis has been documented in several patients with diabetes mellitus and nonalcoholic steatohepatitis (NASH) [21,22]. In addition, recent studies have suggested that the presence of diabetes mellitus or even of insulin resistance may be associated with increased fibrosis progression in patients with chronic hepatitis C [23-26].
The aim of the present study was to evaluate the prevalence of diabetes mellitus in patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B and chronic hepatitis C as well as the possible association between the presence of diabetes and the extent of liver fibrosis in these settings.
Patients and methods
Patient population
Four hundred and thirty-four patients with HBeAg-negative chronic hepatitis B or chronic hepatitis C consecutively admitted to our Department between January 1998 and December 2003 in order to undergo a liver biopsy were included in this study. All patients had been followed for at least 6 months at our outpatient Liver clinics before admission for liver biopsy. Patients with malignancy or any type of antiviral or immunosuppressive therapy within the last 6 months as well as those with an inadequate biopsy specimen were excluded. Patients with HBV and HCV coinfection or with detectable antibodies against hepatitis delta virus (anti-HDV) or against human immunodeficiency virus (anti-HIV) were also excluded. No patient had decompensated liver disease (evidence or history of ascites, variceal bleeding, hepatic encephalopathy or jaundice).
All patients with HBeAg-negative chronic hepatitis B had hepatitis B surface antigen (HBsAg) positive and HBeAg negative for at least 12 months, detectable serum HBV DNA, and increased alanine aminotransferase (ALT) activity [greater than upper limit of normal (ULN)] on at least two separate monthly determinations within the last 6 months. All patients with chronic hepatitis C had detectable antibodies to HCV (anti-HCV), detectable serum HCV RNA and increased ALT activity (>ULN) on at least two separate monthly determinations within the last 6 months. There was no patient with persistently normal ALT activity.
Methods
Data about weight, height on the liver biopsy day as well as about average alcohol consumption during the 5 years preceding the liver biopsy were recorded from all patients. Full blood count including platelet count, prothrombin time, liver function tests [ALT, aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl-transpeptidase (GGT)] and serum glucose levels were evaluated on by commercially available assays in all patients on at least two occasions within the last 6 months preceding the liver biopsy as well as on the liver biopsy day. Commercially available enzyme immunoassays were used for the detection of HBsAg, HBeAg and anti-HBe, anti-HCV, anti-HDV and anti-HIV and commercially available polymerase chain reaction assays for the detection of serum HBV DNA and HCV RNA. In patients with chronic hepatitis C, the HCV genotype was also determined by a commercially available assay (InnoLipa; Innogenetics, Gent, Belgium) [27].
Diabetes mellitus was diagnosed in case of known history of diabetes mellitus under anti-diabetic therapy or fasting glucose >126 mg/dL on more than one occasion [28]. Besides the diabetics, no patient was under a specialized diet or parenteral nutrition. Alcohol abuse was defined as average alcohol consumption of more than 40 g/day in male or more than 20 g/day in female patients within the last 5 years.
Liver histology
All 434 liver biopsies had an adequate specimen with length ≥1 cm. Nine additional biopsies were excluded because of an inadequate liver specimen, as it was predefined if no portal tracts were identified or the specimen size itself made it impossible to make a diagnosis. All liver biopsies were evaluated blindly and the histological changes of chronic hepatitis were classified according to the classification proposed by Ishak et al. [29]. The chronic hepatitis grading score (0-18), which represents the necroinflammatory activity, was the sum of piecemeal necrosis score (0-4), confluent necrosis score (0-6), focal lytic necrosis, apoptosis and focal inflammation score (0-4) and portal inflammation score (0-4). The chronic hepatitis staging score (0-6), which is referred as the fibrosis score, was based on the degree and extent of fibrosis, architectural alterations and development of cirrhosis. Advanced staging or severe fibrosis was considered as a staging/fibrosis score ≥4 and cirrhosis as a staging/fibrosis score 5-6. In addition to grading and staging, hepatic steatosis and hepatic iron deposits were also graded. Hepatic steatosis was assessed as the percentage of hepatocytes containing fat droplets and it was graded as 0 or absent (no steatosis), 1 or mild (<33% of hepatocytes affected), 2 or moderate (33%-66% of hepatocytes affected) and 3 or severe (>66% of hepatocytes affected) [30]. Hepatic iron deposits were evaluated by Perls' stain and were graded from 0 to 4 according to Brissot et al. [31] in liver biopsies obtained after 1999.
Statistical analysis
All data were analysed using the statistical package SPSS (version 10.0, SPSS Inc., Chicago, IL, USA). Statistical analysis was performed using t-test or Mann-Whitney test for comparisons of continuous variables between groups and corrected chi-squared method or two-tailed Fisher's exact test for qualitative data, when appropriate. Multivariate analysis was performed using backward logistic regression models. Only variables with a P-value ≦0.10 at univariate analysis were entered in the multivariate analysis models. A two-tailed P-value <0.05 was considered to be statistically significant.
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