Although a higher prevalence of raised liver enzymes and altered echotexture on ultrasound have been reported in patients with type 1 diabetes mellitus (T1DM), the histological spectrum and natural history of chronic liver disease (CLD) in T1DM is unknown. We investigated the prevalence and outcome of histologically proven CLD in a longitudinal cohort of patients with T1DM. We identified patients who have had liver biopsy from a computerized database (DIAMOND; Hicom Technology, Brookwood, UK) containing longitudinal data for over 95% of type 1 diabetes patients from an overall catchment population of 700,000 people. Gender-matched patients with oral hypoglycemic-treated (T2OH) and insulin-treated type 2 diabetes (T2IN) who had liver biopsy formed two comparative cohorts. We collated clinical and histological data, as well as long-term outcomes of all three groups, and compared T1DM cirrhosis incidence to UK general population data. Of 4,644 patients with T1DM, 57 (1.2%) underwent liver biopsy. Of these, 53.1% of patients had steatosis, 20.4% had nonalcoholic steatohepatitis, and 73.5% had fibrosis on index liver biopsy. Cirrhosis was diagnosed in 14 patients (24.6%) during follow-up. T1DM with age under 55 years had an odds ratio of 1.875 (95% confidence interval: 0.936-3.757) for cirrhosis incidence, compared to the general population. Longitudinal liver-related outcomes were similar comparing the T1DM cohort and respective type 2 diabetes cohorts—when adjusted for important confounders, diabetic cohort type did not predict altered risk of incident cirrhosis or portal hypertension. Conclusion: Type 1 diabetes is associated with a previously unrecognized burden of CLD and its complications. (Hepatology 2014;60:158–168)
Type 2 diabetes and nonalcoholic fatty liver disease (NAFLD) are intimately related, with insulin resistance (IR) and subsequent hyperinsulinaemia being critical steps for their pathogenesis. Type 2 diabetes is a well-recognized risk factor for the development and progression of NAFLD. The estimated prevalence of type 2 diabetes in Western populations has continued to rise in recent decades[2, 3] and is approximately 4.5% in the UK4; this increases to 18%-45% in patients with NAFLD. Confirming this association, the prevalence of NAFLD rises from an estimated 34% in the general population to up to 70% in patients with type 2 diabetes. Patients with type 2 diabetes show an increased prevalence of nonalcoholic steatohepatitis[8, 9] (NASH; the progressive subtype of NAFLD), advanced liver fibrosis and cirrhosis,[10-12] hepatocellular carcinoma (HCC),[12, 13] as well as liver-related mortality.[14-16]
In contrast, type 1 diabetes has not been regarded as a significant risk factor for chronic liver disease (CLD). Small case series have reported on the presence of hepatic glycogenosis, a benign, readily reversible condition resulting from persistent hyperglycemia in patients with type 1 diabetes.[17, 18] However, recent studies demonstrated an increased prevalence of elevated alanine aminotransferase (ALT) levels in patients with type 1 diabetes,[19, 20] one that was higher than expected in the general population and comparable with patients with type 2 diabetes. Using ultrasonographic features, 44% of a group of patients with type 1 diabetes were considered to have NAFLD.
However, neither ALT elevation nor ultrasound (US) features are specific for the diagnosis of CLD. We have investigated the prevalence and outcome of histologically proven CLD in a longitudinal cohort of patients with type 1 diabetes.
The prevalence of elevated liver enzymes has been reported to be higher in association with type 1 diabetes than in the general population19,20; NAFLD, as determined by US of the liver has also been considered very common in these patients.[21, 26] In a longitudinal cohort of patients with type 1 diabetes, we have demonstrated a substantial burden of biopsy-proven CLD; 86% of biopsied patients had histological evidence of CLD, including the presence of fibrosis in 74%, and nearly 25% of patients developed cirrhosis during longitudinal follow-up from diabetes diagnosis. In addition, we have found that in those under the age of 55 years, type 1 diabetes tended to be associated with a 1.875-fold increased incidence of liver cirrhosis, when compared to the general population. During follow-up, liver-related adverse outcomes were similar in type 1 diabetes, compared to those with type 2 diabetes, on either treatment modality (oral hypoglycemic agents or insulin), after adjusting for, in particular, the younger age of diabetes diagnosis in the type 1 diabetes cohort.
Previous histological analysis of patients with type 1 diabetes and liver disease have been limited to small case series of patients with hepatic glycogenosis,[17, 18, 27, 28] a benign and reversible condition characterized by acute hepatomegaly, abdominal pain, and gross hyperlipidemia exacerbated by poorly controlled insulin deficiency. In only two instances was coexistent NAFLD or fibrosis histologically reported. Subsequently, Targher et al.'s evaluations of patients with type 1 diabetes demonstrated a 44.4%-54.9% prevalence of US-based diagnosis of NAFLD in their secondary care clinics.[21, 29] US has both a relatively poor sensitivity and specificity in diagnosing NAFLD in type 1 diabetes; it has limited ability to detect fatty infiltration when this affects less than one third of hepatocytes, and it is not able to distinguish steatosis from glycogenosis. We have demonstrated that 53.1% of patients with type 1 diabetes who had undergone liver biopsy had histological evidence of steatosis and 20.4% met the histological criteria for NASH—not statistically different from matched patients with type 2 diabetes requiring insulin therapy. The comparative histological findings and longitudinal outcomes, compared to type 2 diabetic patients, and a trend toward a 1.875-fold increased incidence of liver cirrhosis, when compared to the general population, suggests that the presence of type 1 diabetes may be an important cofactor for progressive CLD.
It is important to note that only biopsy-proven patients with cirrhosis were identified by our database search; cirrhosis incidence and prevalence in our type 1 diabetic population may therefore be an underestimate, missing patients diagnosed on clinical grounds alone, or by radiological or other noninvasive biomarker methods. Nonetheless, we have found that type 1 diabetes tended to be associated with a near 1.9-fold increase of cirrhosis incidence, compared to the general UK population, when those under 55 years are considered. However, we excluded 3 T1DM patients who had incident cirrhosis before the age of 25 years to allow direct age-standardized comparison to the GPRD UK population data, which included those 25 years of age or older. Regardless of the statistical significance, the effect size with the sufficient follow-up period in our studied T1DM cohort (a median age of only 43.7 years) emphasizes that cirrhosis incidence in this cohort is clinically important.
Type 1 diabetes is primarily an insulin-deficient state. Therefore, its association with NAFLD, NASH, and fibrogenesis is counterintuitive; hence, the underlying mechanisms are poorly understood. However, multiple studies utilising the hyperinsulinemic-euglycemic clamp test have demonstrated both whole-body and hepatic IR[32, 33] in patients with type 1 diabetes, although it is worth noting that glycemic control of patients included in these initial studies was poor. Interestingly, Bergman et al. confirmed hepatic and skeletal muscle IR in 25 patients with type 1 diabetes with adequate glycemic control (mean hemoglobin A1c: 7.7%) and similar metabolic characteristics to healthy controls. This suggests that IR in type 1 diabetes may be one of the mechanisms underlying steatosis and hepatic fibrosis. In the current study, though NAFLD prevalence in biopsied patients with type 1 diabetes was high, only 1 patient with NAFLD developed cirrhosis. Despite insulin therapy, transient, prolonged hyperglycemia in patients with type 1 diabetes is not uncommon and is a feasible cofactor for fibrosis both in the presence and absence of NAFLD. Glucose, in particular, is a major source of acetyl-coenzyme A for TG production. Glucose can also act through carbohydrate response element-binding protein, which regulates both glycolytic and lipogenic enzymes in hepatocytes, hence,playing a central role in coupling these two pathways.[35, 36] Additionally, hyperglycemia stimulates the transcription of connective tissue growth factor (CTGF), which appears to be responsible, in part, for development of hepatic fibrosis, and CTGF blockade inhibits hepatic stellate cell activation in rat models of hepatic fibrosis.[38, 39] Mechanisms underlying the development of steatosis, hepatic fibrosis both in the presence and absence of steatosis, and their subsequent progression need further evaluation.
The current study has some limitations. First, this was a retrospective analysis, and the findings should be interpreted accordingly. However, both the DIAMOND baseline characteristic and longitudinal patient data, as well as histological data, were collected prospectively as part of standard care. As previously described, longitudinal data were present for 95% of all the patients with type 1 diabetes in the region. Therefore, we are confident that we have correctly identified the vast majority of biopsy-proven cirrhosis in the regional type 1 diabetes population. Second, the diagnosis of type 1 diabetes was based on clinical criteria, made by specialist diabetologists in secondary care, and pancreatic autoimmunity was not consistently demonstrated in all cases. Whereas we clarified, to our best knowledge, that the individual patients making up the type 1 diabetes cohort had been correctly classified, it is possible that bidirectional misclassification with type 2 diabetes and early insulin requirement may have occurred at the time of initial diabetes diagnosis. It is worth noting that the T1DM and T2IN cohorts in this study had vastly different demographic and metabolic characteristics to each other, as one would expect with differing contributions of insulin deficiency and resistance, and therefore we are confident that any disease misclassification is likely to be small. Last, there is likely to be a selection bias, particularly with type 2 diabetics included in the study; only an estimated 25% of all patients with type 2 diabetes undergo review in secondary care and hence included in the DIAMOND database. Patients with type 2 diabetes requiring secondary care intervention, particularly those in the T2OH cohort, are likely to be those with multiple comorbidities or difficult-to-control hyperglycemia. These patients are likely to have a greater prevalence of both significant liver disease and adverse longitudinal outcomes, compared to the region's entire type 2 diabetic population. Although we did not directly compare the type 2 diabetes cohorts together, this is likely to explain the evident increased severity of histologically proven CLD in T2OH versus T2IN patients, which is in contrast to previous large observational studies.
In conclusion, we found that type 1 diabetes is associated with a substantial burden of CLD and its complications, with a 1.875-fold increased cirrhosis incidence, although this was not statistically significant, compared to the general population, in selected age groups. Further investigations should focus on the risk factors associated with CLD in patients with type 1 diabetes and intervention that detect these early and prevent liver disease progression in these patients.