SEARCH

SEARCH BY CITATION

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Background  The prevalence of metabolic syndrome and its possible impact on the severity of liver histological lesions have not been studied prospectively in chronic liver diseases.

Aim  To investigate the prevalence of metabolic syndrome in patients with chronic viral hepatitis or non-alcoholic steatohepatitis, and to determine its associations with histological severity.

Methods  We prospectively included 317 patients (hepatitis B e antigen-negative chronic hepatitis B: 95, chronic hepatitis C: 176, non-alcoholic steatohepatitis: 46) with liver biopsy. Metabolic syndrome was defined using the Adult Treatment Panel III criteria. Histological lesions were evaluated according to Ishak’s or Brunt’s classification.

Results  Metabolic syndrome was present in 10.4% of patients being significantly more prevalent in non-alcoholic steatohepatitis than in chronic viral hepatitis (41.3% vs. 5.1%, P < 0.001). In chronic viral hepatitis, cirrhosis (stages 5–6) was independently associated with increasing age, higher aspartate aminotransferase and gamma-glutamyl-transpeptidase levels, severe necroinflammation and metabolic syndrome (P = 0.016). In non-alcoholic steatohepatitis, severe fibrosis (stages 3–4) was independently associated with severe necroinflammation and metabolic syndrome (P = 0.033). Presence of metabolic syndrome was not associated with presence or severity of steatosis both in chronic viral hepatitis and in non-alcoholic steatohepatitis.

Conclusion  Metabolic syndrome is more prevalent in non-alcoholic steatohepatitis than in chronic viral hepatitis; it is associated independently with more severe fibrosis but not with the severity of steatosis, both in chronic viral hepatitis and in non-alcoholic steatohepatitis.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

The prevalence of metabolic syndrome, which is a common metabolic disorder closely related to insulin resistance (IR), is increasing worldwide in parallel with the rising prevalence of obesity.1 Individuals with metabolic syndrome, which is defined by the presence of at least three of five specific factors, namely abdominal obesity, impaired fasting glucose, hypertension and deregulated triglycerides and high-density lipoprotein (HDL) levels, are definitely at high risk for cardiovascular diseases.2, 3 As the characteristics of metabolic syndrome are also high risk factors for hepatic steatosis, it has been hypothesized that non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome.4

Hepatic steatosis and NAFLD are a focus of increasing interest in clinical hepatology.5 In fact, the growing epidemic of obesity has rendered NAFLD as the leading cause of referral to hepatology clinics in most western countries.5 In recent years, it has become evident that hepatic steatosis is not an innocent bystander. A minority of NAFLD patients may develop non-alcoholic steatohepatitis (NASH) having a subsequent increased risk of cirrhosis and even hepatocellular carcinoma (HCC).6 NASH is strongly associated with obesity and presence of IR and type 2 diabetes mellitus,7, 8 while abdominal obesity is a risk factor for NAFLD even in patients with normal body mass index (BMI).5 As the above characteristics are features of the metabolic syndrome, fatty liver is now considered an early indicator of IR.5

Hepatic steatosis often co-exists with other liver diseases including chronic viral hepatitis (CVH).9 It has been mostly studied in patients with chronic hepatitis C (CHC), where its prevalence ranges from 30%to 70%.10, 11 Various studies have shown that both host and viral factors may contribute to the development of steatosis with the relative importance of each varying with HCV genotype. Irrespective of genotype, there is convincing evidence that steatosis correlates with fibrosis progression and negatively affects the response to anti-viral therapy.12 In contrast, little is known about the role of steatosis in chronic hepatitis B (CHB).13 However, given the fibrogenic potential of fat, it may be speculated that fatty liver might be more vulnerable to the progression of inflammation and fibrosis in the presence of liver disease irrespective of aetiology.9

Although the prevalence of NAFLD in patients with metabolic syndrome has been studied, there are few reports on the prevalence and impact of the metabolic syndrome among patients with established liver disease. The aim of this study was to investigate the prevalence of metabolic syndrome in patients with CVH or NASH and to determine its associations with the severity of steatosis and fibrosis.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Patient population

We prospectively studied 317 treatment naive patients with CVH or NASH who consecutively underwent liver biopsy at our Department between August 2004 and March 2007. Patients with NAFLD and histological findings of simple fatty liver, any type of therapy for their liver disease, alcohol abuse, concomitant chronic HBV and HCV infection, antibodies against hepatitis D virus (anti-HDV), antibodies against human immunodeficiency virus (anti-HIV) or evidence of autoimmune liver disease were excluded. Four patients with hepatitis B e antigen (HBeAg)-positive CHB were also excluded. No patient had decompensated liver disease (evidence or history of ascites, variceal bleeding, hepatic encephalopathy or jaundice from hepatic failure) or evidence of HCC. Thus, of the 317 patients, 95 had HBeAg-negative CHB, 176 CHC and 46 NASH. The local ethics committee approved the study protocol and all patients gave informed consent.

Hepatitis B e antigen-negative CHB was diagnosed in patients with positive hepatitis B surface antigen (HBsAg), negative HBeAg and positive to HBeAg antibody (anti-HBe) for at least 6 months, increased alanine aminotransferase (ALT) on at least 2 monthly occasions, detectable serum hepatitis B virus (HBV) DNA and histological lesions compatible with CVH. CHC was diagnosed in patients with positive antibodies against hepatitis C virus (anti-HCV), detectable serum HCV RNA and histological lesions compatible with CVH. NASH was diagnosed in patients with NAFLD and compatible liver histological lesions. The diagnosis of NAFLD was made in patients with increased ALT activity on at least three separate monthly determinations within the last 6 months, absence of any other possible cause of liver injury including alcohol abuse and evidence of hepatic steatosis on liver biopsy.

Epidemiological data were obtained from all patients. Alcohol consumption during the 5 years preceding liver biopsy was taken into account and alcohol abuse was excluded by careful questioning including interrogation of family members, where possible, by at least two individual doctors. Alcohol abuse was considered as a mean daily alcohol consumption of >30 g for males and >20 g for females for CVH and >20 g/day regardless of gender for NAFLD patients. The presence of diabetes mellitus was also recorded with diabetes being diagnosed in cases with known history under antidiabetic treatment and/or fasting glucose >126 mg/dL on more than one occasion. Weight and height were measured and BMI (kg/m2) was calculated on the liver biopsy day. Waist circumference was measured at the midpoint between the lower border of the rib cage and the iliac crest, whereas hip circumference was measured at the widest point between the hip and buttock.

Metabolic syndrome was diagnosed in the presence of three or more criteria out of five defined by the Adult Treatment Panel III, namely: (i) fasting glucose ≥110 mg/dL, (ii) central adiposity, defined as waist circumference >102 cm in men or >88 cm in women, (iii) hypertension, defined as systolic blood pressure ≥135 mmHg, diastolic blood pressure ≥85 mmHg or antihypertensive treatment, (iv) serum triglycerides >150 mg/dL and (v) serum HDL cholesterol <40 mg/dL in men or <50 mg/dL in women.2

Laboratory methods

Blood chemistry values including complete blood count, prothrombin time and levels of serum glucose, cholesterol, HDL and low-density lipoprotein (LDL), triglycerides and liver enzymes [ALT, aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl-transpeptidase (GGT)] were determined by commercially available assays on the liver biopsy day. Serum insulin levels were measured in 52, 70 and 24 randomly chosen patients with CHB, CHC and NASH, respectively. Insulin resistance was determined by the homeostasis model assessment (HOMA) method14 using the following equitation: Insulin resistance (HOMA) = Fasting insulin (μU/mL) × Fasting glucose (mm)/22.5. HOMA has been validated in comparison with euglycaemic/hyperinsulinaemic clamp in both diabetic and nondiabetic patients.15

Commercially available enzyme immunoassays were used for detection of HBsAg, HBeAg, anti-HBe, anti-HCV, anti-HDV and anti-HIV. In patients with CHB, serum HBV-DNA levels were estimated by a commercially available quantitative polymerase chain reaction (PCR) assay (Amplicor HBV Monitor, Roche Molecular Diagnostics Systems, Branchburg, NJ, USA). In patients with CHC, serum HCV-RNA was detected using a commercially available qualitative PCR assay (Amplicor, Roche Molecular Diagnostic Systems) and HCV genotype was determined by a commercially available assay (HCV Genotype Assay, LIPA, Versant, Bayer Healthcare, Tarrytown, NY, USA).

Liver histology

All 317 liver biopsies specimens were of adequate length (≥1 cm, mean length 2.9 ± 1.4 cm). All biopsies from CVH patients were evaluated blindly by a single liver pathologist (GK) according to the classification system proposed by Ishak et al.16 and all biopsies from NAFLD patients were evaluated blindly by another liver pathologist (DGT) according to the classification system proposed by Brunt et al.17 NASH was considered to be present in NAFLD cases with grade ≥2 and/or fibrosis grade ≥1. Advanced staging or severe fibrosis was considered as a staging/fibrosis score ≥4 in CVH and ≥3 in NASH. In both CVH and NASH, hepatic steatosis was assessed as the percentage of hepatocytes containing fat droplets and it was graded as 0 (no steatosis), 1 (mild, <33% of hepatocytes affected), 2 (moderate, 33–66% of hepatocytes affected) and 3 (severe, >66% of hepatocytes affected).

Statistical analysis

All data were analysed using the statistical package spss (version 14.0, SPSS Inc., Chicago, IL, USA). Statistical analysis was performed using t-test, anova, Mann–Whitney U-test or Kruskal–Wallis test for comparisons of continuous variables between or among groups, corrected chi-squared method or two-tailed Fisher’s exact test for comparisons of qualitative data and Spearman’s coefficient for correlations of quantitative data, when appropriate. Multivariate analysis was performed using logistic regression models. Only variables with a P-value of ≤0.10 at univariate analysis were entered in the multivariate analysis models. A two-tailed P-value of <0.05 was considered statistically significant.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

The patients’ baseline characteristics are shown in Table 1. They were mainly middle-aged with equal distribution among genders. NASH patients had significantly more severe steatosis, higher BMI and higher ALP and GGT values compared with CVH patients. Insulin resistance was present in about 40% of patients without significant difference between NASH and CVH.

Table 1.   Baseline characteristics of 317 patients with chronic liver disease [CVH: 271, NASH: 46]
Patient characteristicCHB (n = 95)CHC (n = 176)CVH (n = 271)NASH (n = 46)P-value*
  1. CHB, chronic hepatitis B; CHC, chronic hepatitis C; BMI, body mass index; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, gamma-glutamyl-transpeptidase; HDL, high-density lipoprotein; HOMA-IR, homeostasis model assessment for insulin resistance; N.S., nonsignificant; CVH, chronic viral hepatitis; NASH, non-alcoholic steatohepatitis.

  2. Quantitative variables are expressed as mean ± s.d.

  3. P-values for comparisons between CVH and NASH.

  4. † In 52, 70 and 24 randomly chosen patients with CHB, CHC and NASH, respectively.

Sex, males (%)52 (55)76 (43)128 (47)21 (46)N.S.
Age (years)41.7 ± 13.443.4 ± 12.342.8 ± 12.746.8 ± 14.60.056
BMI (kg/m2)25.9 ± 3.425.2 ± 3.825.4 ± 3.428.7 ± 4.7<0.001
ALT (IU/L)102 ± 12386 ± 7992 ± 9782 ± 60N.S.
AST (IU/L)54 ± 4265 ± 8058 ± 5745 ± 29N.S.
ALP (U/L)94 ± 6677 ± 3683 ± 49108 ± 64<0.001
GGT (U/L)71 ± 17752 ± 5359 ± 111115 ± 128<0.001
Cholesterol (mg/dL)198 ± 42176 ± 41184 ± 43211 ± 450.001
HDL (mg/dL)49 ± 1748 ± 1648 ± 1646 ± 23N.S.
Triglycerides (mg/dL)92 ± 5486 ± 5187 ± 49118 ± 590.002
Fasting insulin† (μU/mL)21.5 ± 33.413.2 ± 8.416.8 ± 2316.3 ± 11.6N.S.
HOMA-IR†5.5 ± 8.73.4 ± 2.54.3 ± 64 ± 2.9N.S.
Insulin resistance, n/N (%)26/52 (50)27/70 (39)53/122 (43)11/24 (46)N.S.
Hypertension, n (%)9 (9)12 (7)21 (8)21 (46)<0.001
Fasting glucose ≥110 mg/dL, n (%)7 (7)9 (5)16 (6)14 (30)<0.001
Necroinflammation6 ± 2.96.1 ± 2.16 ± 2.41.8 ± 0.9
Fibrosis2.7 ± 1.72.4 ± 1.42.5 ± 1.51.9 ± 1.2
Steatosis, n (%)57 (60)117 (66)174 (64)46 (100)<0.001
Severe steatosis, n (%)13 (14)38 (21)51 (19)27 (59)<0.001

The overall prevalence of metabolic syndrome was 10.4% (33 of 317) being significantly higher in NASH than in CVH patients (41.3% vs. 5.1%, P < 0.001). The prevalence of the metabolic syndrome parameters varied substantially ranging from 6% (elevated fasting glucose in CVH) to 61% (decreased HDL in NASH) (Table 2). Decreased HDL levels followed by central obesity were the most prevalent parameters in both CVH and NASH patients. All parameters of the metabolic syndrome were significantly more prevalent in NASH than in CVH patients (Table 2), but there were no differences between CHB and CHC patients.

Table 2.   Positive criteria of metabolic syndrome in 317 patients with CVH or NASH
Patient characteristicCVH (n = 271)NASH (n = 46)P-value
  1. HDL, high-density lipoprotein, M, males, F, females; CVH, chronic viral hepatitis; NASH, non-alcoholic steatohepatitis.

Metabolic syndrome14 (5%)19 (41%)<0.001
Fasting glucose ≥110 mg/dL16 (6%)14 (30%)<0.001
Central obesity64 (23.6%)23 (50%)<0.001
Hypertension21 (8%)21 (46%)<0.001
Triglycerides >150 mg/dL22 (8%)10 (21.7%)0.006
HDL <40/50 mg/dL (M/F) 111 (41%)28 (61%)0.023

Among patients with metabolic syndrome, the prevalence of positive criteria did not significantly differ between NASH and CVH patients (Figure 1). When other characteristics in the patients with metabolic syndrome were examined, NASH patients had significantly more frequently severe steatosis compared with CVH patients (81% vs. 14%, P = 0.001), while age, IR, gender distribution and fibrosis severity did not significantly differ between the two groups (Figure 1). On the other hand, in patients who did not fulfill the criteria of metabolic syndrome, NASH patients had more frequently elevated glucose levels compared with CVH (15.3% vs. 2.7%, P = 0.012) and hypertension (34.6% vs. 5.4%, P < 0.001), while the other metabolic syndrome parameters did not differ significantly between the two groups.

image

Figure 1.  Characteristics of chronic viral hepatitis (CVH) and non-alcoholic steatohepatitis (NASH) patients with metabolic syndrome. Only severe hepatic steatosis was more frequent in NASH than in CVH patients (81% vs. 14%, P = 0.001).

Download figure to PowerPoint

The main characteristics of CVH and NASH patients with and without metabolic syndrome are shown in Table 3. Patients with metabolic syndrome were older in CVH and, as expected, mainly overweight or obese in both CVH and NASH. In particular, BMI of <25, 25–30 and >30 kg/m2 was observed in 14%, 57% and 29% of CVH patients with metabolic syndrome compared to 50%, 40% and 10% of CVH patients without metabolic syndrome (P = 0.004). Similarly, BMI of <25, 25–30 and >30 kg/m2 was observed in 0%, 42% and 58% of NASH patients with metabolic syndrome compared to 27%, 62% and 11% of NASH patients without metabolic syndrome (P < 0.001; Figure 2). In both CVH and NASH, presence of metabolic syndrome was not associated with severe steatosis or significantly higher levels of liver enzymes. Of the established criteria for the diagnosis of metabolic syndrome, only hypertension and decreased HDL in NASH were not found to be significantly associated with presence of metabolic syndrome (Table 3). Presence of IR was significantly associated with metabolic syndrome in NASH (P = 0.002) but not in CVH patients. Fibrosis was significantly more severe in both CVH and NASH patients with than without metabolic syndrome (CVH: 3.4 ± 2.2 vs. 2.5 ± 1.5, P = 0.022; NASH: 2.5 ± 1.3 vs. 1.4 ± 0.9, P = 0.006).

Table 3.   Predictors of metabolic syndrome in CVH or NASH
Patient characteristicCVH Metabolic syndromeP-valueNASH Metabolic syndromeP-value
No (n = 257)Yes (n = 14)No (n = 27)Yes (n = 19)
  1. BMI, body mass index; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, gamma-glutamyl-transpeptidase; HOMA-IR, homeostasis model assessment for insulin resistance; HDL, high-density lipoprotein; M, males; F, females; N.S., nonsignificant; CVH, chronic viral hepatitis; NASH, non-alcoholic steatohepatitis.

  2. Quantitative variables are expressed as mean ± s.d.

Age (years)42.1 ± 12.555.5 ± 8<0.00144 ± 15.149.8 ± 13.3N.S.
Sex, males (%)125 (49)3 (21)0.05615 (55)3 (32)N.S.
BMI (kg/m2)25.3 ± 3.628.6 ± 3.70.00526.7 ± 3.431.4 ± 50.001
ALT (IU/L)93 ± 9970 ± 47N.S.89 ± 6872 ± 47N.S.
AST (IU/L)58 ± 6051 ± 28N.S.44 ± 2646 ± 32N.S.
GGT (U/L)58 ± 11269 ± 104N.S.101 ± 93135 ± 167N.S.
ALP (U/L)81 ± 48100 ± 68N.S.98 ± 53121 ± 76N.S.
Insulin resistance, n (%)48 (42.8)5 (62.5)N.S.3 (20)8 (88.8)0.002
HOMA-IR4.3 ± 6.34.4 ± 1.9N.S.2.6 ± 16.3 ± 3.60.016
Fasting glucose ≥ 110 mg/dL, n (%)7 (2.7)9 (64.2)<0.0014 (15.4)9 (47.3)0.043
Central adiposity, n (%)53 (21)11 (79)<0.0016 (23)17 (89)<0.001
Hypertension, n (%)14 (5.5)7 (50)<0.0019 (34.6)11 (57.8)N.S.
Triglycerides >150 mg/dL, n (%) 18 (7)4 (28.6)0.0181 (3.8)9 (50)0.001
HDL <40/50 mg/dL (M/F), n (%)99 (38)12 (86)0.00114 (54)14 (74)N.S.
Necroinflammation6 ± 2.56 ± 2.2N.S.1.6 ± 0.82.1 ± 0.9N.S.
Fibrosis2.5 ± 1.53.4 ± 2.20.0221.4 ± 0.92.5 ± 1.30.006
Steatosis, n (%)164 (64)12 (86)N.S.17 (100)12 (100)N.S.
Severe steatosis, n (%)49 (19)2 (14)N.S.14 (54)13 (81.3)N.S.
image

Figure 2.  Distribution of body mass index (BMI) in chronic viral hepatitis (CVH) and non-alcoholic steatohepatitis (NASH) patients with and without metabolic syndrome. BMI <25, 25–30 and >30 kg/m2– CVH patients (a) with metabolic syndrome: 14%, 57% and 29%, (b) without metabolic syndrome: 50%, 40% and 10% (P = 0.004); – NASH patients (a) with metabolic syndrome: 0%, 42% and 58%, (b) without metabolic syndrome: 27%, 62% and 11% (P < 0.001).

Download figure to PowerPoint

We finally addressed the predictors of severe fibrosis in CVH and NASH (Table 4). In CVH, fibrosis stages 0–2, 3–4 and 5–6 were observed in 36%, 28% and 36% of those with metabolic syndrome and in 60%, 27% and 13% of those without metabolic syndrome (P = 0.017; Figure 3). In particular, cirrhosis (stages 5–6), which was present in 14% (37 of 271) of CVH patients, was significantly associated with increasing age and BMI, higher levels of liver enzymes, IR, more severe necroinflammation and presence of metabolic syndrome (P = 0.007). When analysis was made separately in CHB and CHC, cirrhosis was associated with presence of metabolic syndrome in CHC patients (50% vs. 2.6%, P = 0.007) but not in CHB patients (11% vs. 5.2%, P = N.S.). When the criteria of metabolic syndrome were independently analysed, severe fibrosis in CVH was significantly associated only with central adiposity (P = 0.021) and had a trend for association with elevated glucose levels (P = 0.06) and hypertriglyceridaemia (P = 0.088). In multivariate analysis, presence of metabolic syndrome was an independent predictor of cirrhosis (Table 5).

Table 4.   Univariate analysis of patients’ characteristics in relation to the severity of fibrosis evaluated by Ishak’s classification16 in CVH and by Brunt’s classification17 in NASH
Patient characteristicCVHP-valueNASHP-value
Fibrosis 0–4 (n = 233)Fibrosis 5–6 (n = 38)Fibrosis 1–2 (n = 35)Fibrosis 3–4 (n = 11)
  1. BMI, body mass index; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, gamma-glutamyl-transpeptidase; HOMA-IR, homeostasis model assessment for insulin resistance; HDL, high-density lipoprotein; M, males; F, females; N.S., nonsignificant; CVH, chronic viral hepatitis; NASH, non-alcoholic steatohepatitis.

  2. Quantitative variables are expressed as mean ± s.d.

Age (years)41.2 ± 1251.8 ± 11.6<0.00143.3 ± 1458.8 ± 8.80.002
Sex, males (%)108 (46)20 (53)N.S.18 (51)3 (27)N.S.
BMI (kg/m2)25.1 ± 3.627.3 ± 3.80.00127.9 ± 3.631.4 ± 7.10.041
ALT (IU/L)76 ± 63183 ± 182<0.00177 ± 5198 ± 88N.S.
AST (IU/L)46 ± 30128 ± 116<0.00139 ± 2066 ± 430.008
GGT (U/L)46 ± 5395 ± 84<0.001117 ± 128105 ± 132N.S.
ALP (U/L)74 ± 37119 ± 68<0.001108 ± 70105 ± 43N.S.
Insulin resistance, n (%)39 (39)14 (66)0.0297 (36.8)4 (80)N.S.
HOMA-IR3.6 ± 3.77.5 ± 11.70.0043 ± 1.37.7 ± 4.40.036
Fasting glucose ≥110 mg/dL, n (%)11 (4.9)5 (13.1)0.068 (22.8)6 (54.5)0.065
Central adiposity, n (%)47 (20)15 (39)0.02116 (46)7 (63.6)N.S.
Hypertension, n (%)17 (7)4 (10.5)N.S.14 (40)7 (63.6)N.S.
Triglycerides >150 mg/dL16 (6.8)6 (15.7)N.S.6 (17.1)4 (21)N.S.
HDL <40/50 mg/dL (M/F), n (%)93 (40)18 (47.3)N.S.18 (51)10 (91)N.S.
Metabolic syndrome, n (%)8 (3.4)6 (15.8)0.00710 (29)9 (81.8)0.001
Necroinflammation5.6 ± 2.18.9 ± 2.7<0.0011.5 ± 0.72.7 ± 0.5<0.001
Severe steatosis, n (%)39 (17)11 (31)0.06519 (54)8 (73)N.S.
image

Figure 3.  Distribution of fibrosis stages in chronic viral hepatitis (CVH) and non-alcoholic steatohepatitis (NASH) patients with and without metabolic syndrome. Fibrosis stages (Ishak’s classification16) 0–2, 3–4 and 5–6 in CVH patients (a) with metabolic syndrome: 36%, 28% and 36%, (b) without metabolic syndrome: 60%, 27% and 13% (P = 0.017). Fibrosis stages (Brunt’s classification17) 1–2 and 3–4 in NASH patients (a) with metabolic syndrome: 53% and 47%, (b) without metabolic syndrome: 96% and 4% (P = 0.001).

Download figure to PowerPoint

Table 5.   Multivariate analysis of factors univariately associated with severe fibrosis in patients with CVH (stages 5–6 by Ishak’s classification16) or NASH (stages 3–4 by Brunt’s classification17)
Patient characteristicCVHNASH
OR (95% CI)P-valueOR (95% CI)P-value
  1. BMI, body mass index; AST, aspartate aminotransferase; GGT, gamma-glutamyl-transpeptidase; OR, odds ratio; CI, confidence interval; N.S., nonsignificant; CVH, chronic viral hepatitis; NASH, non-alcoholic steatohepatitis.

Age1.059 (1.014–1.107)0.011 N.S.
BMI N.S. N.S.
AST1.013 (1.003–1.023)0.014 N.S.
GGT1.008 (1.001–1.015)0.02 
Metabolic syndrome7.635 (1.467–39.729)0.016130.791 (1.470–11634.064)0.033
Necroinflammation1.677 (1.312–2.143)<0.0017.892 (1.290–48.292)0.025

Severe fibrosis (stages 3–4) was detected in 23.9% (11 of 46) of NASH patients being significantly more frequent in those with metabolic syndrome than in those without metabolic syndrome (81.8% vs. 29%, P = 0.001; Figure 3). Severe fibrosis in NASH was also associated with increasing age, BMI, AST levels and HOMA score and with more severe necroinflammation. In multivariate analysis, patients with metabolic syndrome had a 130-fold higher risk for severe fibrosis (P = 0.033; Table 5). When the metabolic syndrome criteria were analysed separately, only elevated glucose levels were relatively associated with severe fibrosis (P = 0.065).

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

The presence and significance of metabolic syndrome, which has been undoubtedly associated with an increased risk for both diabetes and cardiovascular disease,3 have not been adequately studied in patients with chronic liver diseases. The metabolic syndrome was first elaborated in a large Italian study in NAFLD, which is considered as its hepatic manifestation18 and in a recent American study in NASH,19 while its prevalence in relation to chronic HCV infection was retrospectively estimated in a large US survey.20 In the latter study, however, no liver biopsy was performed and thus the impact of metabolic syndrome on the severity of liver disease could not be assessed.

We prospectively determined the prevalence of metabolic syndrome in patients with CVH or NASH who consecutively underwent liver biopsy at our department during a 2-year period. The overall prevalence of metabolic syndrome in our patients was 10.4% depending greatly on the underlying liver disease, as it was only 5.1% in CVH and mounted to 41.3% in NASH. The high prevalence of metabolic syndrome in our patients with NASH is in agreement with other data from the literature reporting prevalence ranging from 34% to even 88% in similar settings.5, 18, 19 The low prevalence of metabolic syndrome among our CVH patients is possibly related to their almost normal body weight and their age being in mid-40s. The prevalence of metabolic syndrome is certainly increasing with higher BMI and older age1 ranging among different age groups from 5% to 43% in a Greek population21, 22 or from 7% to 44% in an adult US population.23 In the greater area of Athens, Greece, the age-standardized prevalence of metabolic syndrome has been found to be approximately 37%.22 It should be noted that patients with CVH have important differences from the general population that might affect their positive criteria of metabolic syndrome. Notably, CHC patients have lower cholesterol levels than matched controls24 as a result of an acquired hypobetalipoproteinemia25 and this effect is more pronounced in patients infected with genotype 3.12 In addition, the prevalence of diabetes mellitus may be increased in patients with CVH, particularly in those with more severe fibrosis.26

The major finding of our study was the independent association of metabolic syndrome with severe fibrosis in both CVH and NASH. Our findings are in line with other studies that have addressed this issue, mostly in NAFLD.18, 19 In CHC, retrospective studies suggested that presence of metabolic syndrome may be associated with histological lesions of NASH,27, 28 but its potential associations with the severity of liver histological lesions were not addressed28 and data on the prevalence and significance of its five criteria were not provided.27 It is of interest that not all criteria of metabolic syndrome were found to be associated with severe fibrosis in our cohort. On the other hand, the presence of metabolic syndrome was more strongly associated with severe fibrosis than any of its criteria alone.

In contrast to the association with fibrosis, the presence of metabolic syndrome was not found to be associated with the severity of necroinflammation or steatosis. This issue was not previously studied in CVH, while a significant association of metabolic syndrome with the severity of necroinflammation but not of steatosis was previously reported in NAFLD patients.18 The absence of association with steatosis severity may be related to the suggestions that hepatic fat accumulation becomes less pronounced in NASH patients with more severe fibrosis.9 On the other hand, the absence of association between metabolic syndrome and the severity of necroinflammation in our study might be because of the exclusion of NAFLD patients with simple fatty liver, who have no or minimal necroinflammation. In addition, a type II error cannot be excluded, as the mean necroinflammation score was 2.1 and 1.6 in our NASH patients with and without metabolic syndrome, respectively.

The main limitation of our study is the relatively small total number of patients with metabolic syndrome, as only 33 of the 317 patients fulfilled the appropriate criteria. Thus, potentially important findings might have been missed due to type II sample errors. Moreover, as only 14 CVH patients had metabolic syndrome, the possibilities of separately analysing CHB and CHC patients were rather limited. The small number of patients with metabolic syndrome has also resulted in rather wide confidence intervals of odds ratio detected in the multivariate analyses (Table 5). It would also be of great interest to know whether the phenotype of metabolic syndrome has a synergistic effect on the severity of liver fibrosis or its effect is just the sum of its different components. To address this important question, evaluation of larger cohorts of patients is required. Adipokines have been recently implicated in the pathogenesis of both metabolic syndrome and liver fibrosis.29 Thus, their determination would have added precious information on their role and sequence of events that lead from metabolic derangement to fibrosis production and progression. Finally, serum insulin levels were not obtained in all patients and this might have resulted in a false estimation of the prevalence of IR, especially in CHC patients, as the HCV virus has been clearly associated with insulin signalling defects.29

In conclusion, the metabolic syndrome is significantly more prevalent in NASH than in CVH, but it is independently associated with more severe fibrosis both in NASH and in CVH. Thus, patients with chronic liver diseases and metabolic syndrome may benefit from therapeutic interventions against both disorders. Therefore, apart from the specific liver disease treatment, patients should be counselled on weight reduction, to have tight glycaemic control and receive antihypertensive or lipid reducing therapy, when appropriate. As a recent study showed that metabolic syndrome in NASH is associated with a diet containing more carbohydrate and less fat,19 a dietary intervention also seems to be reasonable. Finally, according to preliminary evidence, treatment with glitazones appears to be effective in diabetic patients with NASH30 and might be tried in diabetic patients with CVH who do not respond to anti-viral therapy.

Acknowledgement

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Declaration of personal and funding interests: None.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References
  • 1
    Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 2005; 365: 141528.
  • 2
    Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP). Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001; 285: 248697.
  • 3
    Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001; 24: 6839.
  • 4
    Marchesini G, Brizi M, Bianchi G, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 2001; 50: 184450.
  • 5
    Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology 2006; 43: S99112.
  • 6
    Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999; 116: 14139.
  • 7
    Lonardo A, Lombardini S, Ricchi M, Scaglioni F, Loria P. Review article: hepatic steatosis and insulin resistance. Aliment Pharmacol Ther 2005; 22 (Suppl. 2): 6470.
  • 8
    Machado M, Cortez-Pinto H. Non-alcoholic steatohepatitis and metabolic syndrome. Curr Opin Clin Nutr Metab Care 2006; 9: 63742.
  • 9
    Powell EE, Jonsson JR, Clouston AD. Steatosis: co-factor in other liver diseases. Hepatology 2005; 42: 513.
  • 10
    Rubbia-Brandt L, Fabris P, Paganin S, et al. Steatosis affects chronic hepatitis C progression in a genotype specific way. Gut 2004; 53: 40612.
  • 11
    Tsochatzis E, Papatheodoridis GV, Manesis EK, et al. Hepatic steatosis in genotype 4 chronic hepatitis C is mainly because of metabolic factors. Am J Gastroenterol 2007; 102: 63441.
    Direct Link:
  • 12
    Poynard T, Ratziu V, McHutchison J, et al. Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C. Hepatology 2003; 38: 7585.
  • 13
    Tsochatzis E, Papatheodoridis GV, Manesis EK, Chrysanthos N, Kafiri G, Archimandritis AJ. Hepatic steatosis in chronic hepatitis B develops due to host metabolic factors: a comparative approach with genotype 1 chronic hepatitis C. Dig Liver Dis 2007; 39: 93642.
  • 14
    Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 4129.
  • 15
    Ikeda Y, Suehiro T, Nakamura T, Kumon Y, Hashimoto K. Clinical significance of the insulin resistance index as assessed by homeostasis model assessment. Endocr J 2001; 48: 816.
  • 16
    Ishak K, Baptista A, Bianchi L, et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995; 22: 6969.
  • 17
    Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol 1999; 94: 246774.
    Direct Link:
  • 18
    Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003; 37: 91723.
  • 19
    Kang H, Greenson JK, Omo JT, et al. Metabolic syndrome is associated with greater histologic severity, higher carbohydrate, and lower fat diet in patients with NAFLD. Am J Gastroenterol 2006; 101: 224753.
    Direct Link:
  • 20
    Shaheen M, Echeverry D, Oblad MG, Montoya MI, Teklehaimanot S, Akhtar AJ. Hepatitis C, metabolic syndrome, and inflammatory markers: Results from the Third National Health and Nutrition Examination Survey [NHANES III]. Diabetes Res Clin Pract 2007; 75: 3206.
  • 21
    Athyros VG, Bouloukos VI, Pehlivanidis AN, et al. The prevalence of the metabolic syndrome in Greece: the MetS-Greece Multicentre Study. Diabetes Obes Metab 2005; 7: 397405.
  • 22
    Thanopoulou A, Karamanos B, Angelico F, et al. Epidemiological evidence for the non-random clustering of the components of the metabolic syndrome: multicentre study of the Mediterranean Group for the Study of Diabetes. Eur J Clin Nutr 2006; 60: 137683.
  • 23
    Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002; 287: 3569.
  • 24
    Siagris D, Christofidou M, Theocharis GJ, et al. Serum lipid pattern in chronic hepatitis C: histological and virological correlations. J Viral Hepat 2006; 13: 5661.
  • 25
    Serfaty L, Andreani T, Giral P, Carbonell N, Chazouilleres O, Poupon R. Hepatitis C virus induced hypobetalipoproteinemia: a possible mechanism for steatosis in chronic hepatitis C. J Hepatol 2001; 34: 42834.
  • 26
    Papatheodoridis GV, Chrysanthos N, Savvas S, et al. Diabetes mellitus in chronic hepatitis B and C: prevalence and potential association with the extent of liver fibrosis. J Viral Hepat 2006; 13: 30310.
  • 27
    Sanyal AJ, Contos MJ, Sterling RK, et al. Nonalcoholic fatty liver disease in patients with hepatitis C is associated with features of the metabolic syndrome. Am J Gastroenterol 2003; 98: 206471.
    Direct Link:
  • 28
    Solis-Herruzo JA, Perez-Carreras M, Rivas E, et al. Factors associated with the presence of nonalcoholic steatohepatitis in patients with chronic hepatitis C. Am J Gastroenterol 2005; 100: 10918.
    Direct Link:
  • 29
    Tsochatzis E, Papatheodoridis GV, Archimandritis AJ. The evolving role of leptin and adiponectin in chronic liver diseases. Am J Gastroenterol 2006; 101: 262940.
  • 30
    Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006; 355: 2297307.