There is a wide range in the prevalence of glucose metabolism alterations in cirrhotic patients in various studies. The frequency for overt DM has been reported from 10% to 50% and for IGT up to more than 70% [1
]. Such variations may be mainly due to the criteria employed in the diagnosis of DM. In our study, we employed latest ADA criteria and DM was presented in 21.6% of patients with CLD (53.7% in cirrhosis, 13.7% in chronic hepatitis, and 9.5% in HBV inactive carrier). In Iran the estimated prevalence of overt DM in general population is in the range of about 7.5–10 percent [14
], which is about 2 to 3 times less than what we found in this study, indicating that patients with CLD are a high-risk population for DM. In spite of this fact, we showed that 10 out of 40 (25%) diabetic cases found in this study were unaware of their endocrinal problem before being screened as part of this study. This finding highlights the importance of periodical screening of the patients with CLD especially in advanced stages.
Literature frequently demonstrated the higher prevalence of DM and IGT in cirrhosis than in chronic hepatitis [4
]. However, about the higher DM rate in patients with chronic hepatitis compared with people without liver disease, there is not any widely general agreement. Some studies claimed that DM rate is not appreciably different when compared with general population or individuals without liver disease [11
]. These studies believed that only cirrhosis but not chronic hepatitis were associated with DM [17
]. In our study, multivariate analysis indicates independent association between chronic hepatitis and DM rate, despite the fact that we compared DM occurrence among three groups who all suffered from liver disease. Moreover, our data indicate that the frequency of DM increases significantly with the severity of the liver disease both in cirrhotic cases and in patients with chronic hepatitis. These findings suggest that liver fibrosis but not cirrhosis itself, is the event associated with glucose intolerance. A weak association between glucose intolerance and severity of liver disease in cirrhosis has already been reported by Muller et al [7
], even though they used different criteria to evaluate liver damage severity. Another study applying Child-Pugh's classification showed similar results [11
]. In this context it is worthy to note that although the underlying mechanism of glucose intolerance in cirrhosis has not been fully elucidated, it can be mainly explained by the insulin resistance [9
], in addition to reduced glucose sensitivity in liver cirrhosis [18
]. More interestingly, a recent study suggests that insulin resistance occurs already in the early stages of the chronic hepatitis course [12
], and another study investigating chronic hepatitis patients with normal glucose tolerance revealed a strong relationship between insulin sensitivity and fibrosis score [20
]. In contrast, there is another hypothesis that indicates CLD as a consequence of DM. This theory states that occurrence of insulin resistance initially facilitates lipolysis, and increases free fatty acid deposition in liver, which increases products of lipid peroxidation inducing oxidative stress. This results in cytokine-mediated hepatic inflammatory damage that induces collagen deposition and eventually fibrosis [21
]. Although in this study we could not determine if the onset of DM was before or after of liver disease, our findings show that chronic hepatitis per se has an independent association with DM, and development of DM in chronic hepatitis patients was correlated to the severity of liver fibrosis.
No differences in DM rate were found when we studied patients according to CLD etiological categories both in cirrhosis and in chronic hepatitis group. A positive link between hepatitis C infection and development of DM has been suggested in some studies but not completely characterized. Mason et al surveying a large cohort of patients with viral chronic hepatitis showed a relatively strong association between DM and HCV infection [23
]. They suggested that HCV infection may serve as an additional risk factor for the development of DM beyond that attributable to CLD alone [23
]. In contrast, some studies provided evidence against a potential association between these two disorders [17
]. A more recent study showed that the prevalence of DM among cirrhotic patients with hepatitis C was significantly higher than among those with cirrhosis due to cholestatic liver disease, but this rate difference was not significant when compared with cases with alcohol-induced cirrhosis [10
]. In spite of the fact that they had not enrolled HBV infected cases in their sample population, it suggested that the mechanism of the DM in cirrhotic patients was related more closely to the underlying cause of liver cirrhosis [10
]. Although no single etiological factor was found linked to DM occurrence in our study, we believe that our study was not designed to address this issue considering the fact that we had to exclude patients with NASH as another etiology of CLD because of small number of patients in this group. However, further prospective studies may shed more light on the relationship between DM and the underlying liver disease.
BMI did not differ between diabetic and non-diabetic cases among cirrhotic patients. This finding was expectable as reduction in the muscle mass is well described in liver cirrhosis, which can bias the comparison. On the other hand, among patients with chronic hepatitis BMI did remain as an independent predictive factor of DM. Some studies have indicated that obesity could be a potential risk factor for fibrosis in chronic hepatitis [25
]. Our results suggest that increased BMI also has a role in the pathogenesis of DM in chronic hepatitis independent of liver fibrosis. Furthermore, Muller et al reported that basal free fatty acids and basal free glycerol plasma concentrations were increased in diabetic patients with liver cirrhosis when compared with those without diabetes [7
]. In present study, TG and Chol levels in patients with chronic hepatitis and TG level in cirrhotic patients were higher in diabetic cases compared with non-diabetic ones although not statistically significant (table ). These findings may have therapeutic implications in the management of patients with chronic hepatitis. It appears necessary to greatly encourage overweight patients to make a concerted effort to lose weight in order to both decrease the risk of DM development and to prevent the liver damage.
Although family history of DM is a well-known risk factor for DM, the correlation between DM and both cirrhosis and chronic hepatitis remained significant even when family history of DM was entered through logistic model. This finding, in concordance with similar studies [7
], indicates that liver injury per se is associated with DM and a family history of DM is only an adjunctive factor. However, the possible reporting bias of family history of DM should be carefully considered as it is not unreasonable to think that patients with known DM may be more likely to know or think that they have a family history of DM. When cirrhosis and chronic hepatitis groups were analyzed separately, we observed that patients with a positive family history of DM did not show an increased frequency of DM, particularly in cirrhotic patients. Slightly less than 45% of cirrhotic cases with a negative family history of DM were diabetic. This finding does not support the speculation that cirrhotic patients only with a genetic predisposition for DM are prone to glucose intolerance as the manifestation of their liver disease.
Age is another definite risk factor for type II DM in the normal population [13
], and it was expected also to be associated with DM in CLD. However, the odds ratio for both cirrhosis and chronic hepatitis was higher than that for age, implying a stronger association of the former factors. Although in the part of our study investigating cirrhotic patients, age lost its significance when it was entered in multivariate analysis, the majority of studies demonstrated that IGT and also DM were more frequently seen at advanced age in cirrhotic patients [2
While DM was associated with hypertension in univariate analysis (table ), in multivariate analysis it lost its significance as a predictor of DM (table ). These two variables may both be related to the metabolic syndrome and adjustment for other related variables removes this association. On the other hand, it is currently believed that cardiovascular disease is rare in cirrhosis and studies demonstrate that cirrhotic patients, even in the presence of overt DM, have a low prevalence of vascular disease including hypertension [26
]. Our findings support this hypothesis showing no difference in the rate of hypertension between diabetic and non-diabetic patients.
A few patients have so far been reported to develop DM during interferon therapy [27
], but the evidences are insufficient in this regard as yet. In our study, interferon therapy had no impact on the prevalence of DM, since 15% of subjects with DM and about 39% without had a recorded use of interferon, and the difference was not significant. This is in line with some previous studies clarifying the impact of long-term administration of interferon on glucose metabolism [28