Diabetes and NASH
People with Type 2 diabetes mellitus (T2DM) are at greater risk of NAFLD and NASH than the general population, therefore monitoring and assessment in this population is important. People with T2DM and NASH also have worse outcomes than people without diabetes with NASH, highlighting the need for proactive management strategies.
Type 2 diabetes mellitus (T2DM) is closely associated with nonalcoholic fatty liver disease (NAFLD), with each disease contributing to the risk, severity and prognosis of the other. Therefore, it is important to closely monitor people with T2DM for possible NAFLD and NASH and perform the appropriate investigations to identify advanced disease.1
Figure 1.0 T2DM and NAFLD are closely associated1
Prevalence of NAFLD in the context of T2DM
People with T2DM should be tested for NAFLD as it is more common in those with T2DM than without.
- One large Italian study reported the prevalence of NAFLD in patients with T2DM to be 70%.2
- A small UK-based study found the prevalence of NAFLD to be 43% in people with T2DM.3
- In a recent meta-analysis, the pooled prevalence across an international set of studies was approximately 60%.4 In comparison, the global prevalence of NAFLD in the general population is 25%.5
There are limited estimates for NASH prevalence in people with T2DM in real-world settings. However, in the studies available in this population, prevalence of NASH in people with T2DM has been shown to vary significantly, from 22% to 87%.6–8 Another study showed that the prevalence of NASH in people with T2DM who require insulin therapy was greater than in those not receiving insulin.9
An increased prevalence of T2DM has also been found in people with NAFLD, compared with the general population; one meta-analysis reported an overall T2DM prevalence rate of 23% globally in people with NAFLD.5 In those with NASH, the prevalence was shown to be much higher at 44%.5
Insulin resistance (IR) is thought to be, in part, responsible for the link between NAFLD and T2DM; IR is strongly associated with NAFLD, even in lean patients with normal glucose tolerance.10 Further information on the prevalence of NAFLD and NASH can be found in the Burden of NAFLD and NASH section.
Figure 2.0 Prevalence of NASH with and without T2DM4–8
The burden of NAFLD and NASH in diabetes
NAFLD already represents a high social and economic burden, but increasing obesity and T2DM rates are predicted to push this even further in the coming years.11 The number of NASH cases is projected to increase by 63% by 2030, based on 2015 figures.11 These increases have been shown to correlate with corresponding increases in T2DM and obesity, as well as ageing populations, which are thought to be in part responsible for this trend.11,12
NASH with T2DM: potential for poorer outcomes
In a UK study, people with T2DM were approximately 2–3 times more likely to be admitted to hospital for NASH than those without.13 Between 2004 and 2015, NASH-related hospital admissions decreased by 3% in patients without T2DM and increased by 1% in patients with T2DM.13 A number of potential reasons may explain this effect: increasing rates of diabetes; improved risk factor management, which has led to a decrease in hospitalisations in those without diabetes; and increased survival in people with T2DM, resulting in more age-related hospitalisations.13
People with T2DM receiving a liver transplant as a result of advanced fibrosis due to NASH have worse outcomes compared with people with NASH without T2DM.14 Post-transplant, those with T2DM were shown to have longer hospital stays, higher peri-transplant mortality, greater re-admission rates, and shorter survival.14 Further information on the social and economic burden of NAFLD and NASH can be found in the Burden of NAFLD and NASH section.
Hepatic and non-hepatic complications of diabetes and NASH
NASH can lead to a number of serious hepatic and non-hepatic complications, which are often compounded in patients who also have T2DM. Hepatic complications of NASH include fibrosis, cirrhosis and hepatocellular carcinoma (HCC), and non-hepatic complications can include cardiovascular disease (CVD) and chronic kidney disease (CKD).15–20
Fibrosis and other hepatic complications
Hepatic fibrosis is defined as the thickening and scarring of connective tissue due to hepatic injury. T2DM has been associated with a greater severity of fibrosis in people with NAFLD, compared with those without T2DM.15,16 One study reported that approximately 54% of NAFLD patients with T2DM have advanced fibrosis (≥F3); when T2DM and obesity coexist in people older than 45 years, the proportion of people with advanced fibrosis rises to two-thirds.16
Despite an increase in fibrosis risk, current awareness of, and adherence to, guidelines for diagnosing and managing advanced fibrosis in people with T2DM is lacking.21 More information on the stages of fibrosis can be found in the Burden of NAFLD and NASH section.
Increased risk of cirrhosis and HCC
Patients with NAFLD and T2DM are at greater risk of cirrhosis than those without.17 In a US-based study analysing long-term pathology and mortality, cirrhosis occurred in more than twice as many people with T2DM than those without.17 When adjusting for age, body mass index (BMI) and cirrhosis, people with T2DM were also at >3 times greater risk of overall mortality and >22 times greater risk of mortality related to liver disease.17
T2DM increases the risk of HCC; in a study of mostly men, the risk of HCC was doubled in people with T2DM vs those without.18
Retinopathy and CKD are both common microvascular complications of T2DM.19,22,23 People with T2DM and NAFLD have higher prevalence rates of non-proliferative retinopathy, laser-treated/proliferative retinopathy and CKD than those with T2DM alone.22 NAFLD has also been shown to lead to higher prevalence rates of microalbuminuria and a greater albumin-to-creatinine ratio in people with either prediabetes or T2DM.19 Microalbuminuria is an early marker of glomerular injury and is associated with greater risk of nephropathy.23
The leading cause of death in people with NAFLD is CVD, and people with T2DM are at even greater risk.24,20 T2DM was shown to be a significant predictor of cardiac-cause specific mortality in people with NAFLD, after adjusting for strong confounders of cardiac-related death (HR: 1.83; 95% CI: 1.35–2.47).24
Assessment and diagnosis
Assessment for NAFLD in people with T2DM
Due to poorer outcomes in this population, people with T2DM should be assessed for NAFLD and potential advanced fibrosis due to NASH. Noninvasive tests should be considered by primary care providers and diabetes specialists who are responsible for managing people with T2DM.25
Fibrosis is the most important prognostic marker in NAFLD and can be measured with a number of noninvasive tests with an acceptable level of diagnostic accuracy.25 These include the following:
- The Fibrosis–4 (FIB-4) index, which uses age, platelet count, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels to assess fibrosis/cirrhosis26
- The NAFLD Fibrosis Score (NFS), which uses routine clinical and laboratory data, including hyperglycaemia, albumin, age, BMI, platelet count, and AST/ALT ratio, to assess the presence of advanced fibrosis in NAFLD27
- Transient elastography (fibroscan)25
The FIB-4 and NFS calculators and guidance for interpreting results can be found here.
Transaminase levels should not be used in isolation to diagnose NAFLD
Transaminase levels are only elevated in a minority of NAFLD patients with T2DM – less than 20% of people with histologically- or ultrasound-diagnosed NAFLD.6,28 In addition, transaminase levels are often normal in people with NASH and are not reliable predictive markers.28 Therefore, further investigation for NAFLD should be performed in people with T2DM, regardless of liver enzyme levels. More information on the assessment of people suspected to have NAFLD can be found in the Identifying people with NAFLD section.
Referral and management
A large proportion of patients with advanced fibrosis also have T2DM and should be under the care of a liver specialist. Noninvasive tests conducted in primary care can help identify individuals who should be referred to a liver clinic for further investigation. Although serum transaminase levels should not be used in isolation, an increase in ALT or AST levels in people with T2DM and confirmed steatosis warrants referral to a liver specialist.25
Figure 3.0 Identifying and referring patients with suspected NASH29
Given the role of IR in the pathogenesis of both NAFLD and T2DM, restoring insulin sensitivity is a major treatment target.25 The most effective way to achieve this is lifestyle modifications such as diet and exercise.25 Even modest reductions in weight can improve steatosis; ≥5% weight loss improves steatosis, and ≥9% weight loss significantly improves steatosis, inflammation and ballooning.30
Currently, there are no approved pharmacological treatments for NAFLD/NASH.25 A number of insulin-sensitising drugs, approved for T2DM, have been investigated in NASH patients. However, evidence for their effectiveness and safety is lacking, and their use is not approved in NAFLD/NASH patients.25,31–34
NAFLD and NASH
Introductions to pages in the NAFLD and NASH section of the site.
The Burden of NAFLD and NASH
An overview of the burden of NAFLD and NASH, with definitions and information on fibrosis, epidemiology, societal impact and natural history.
Identifying people with NAFLD
Identifying people at risk of NAFLD and information on screening tests for NAFLD in primary care.
Referral and diagnosis
Information on diagnostic tests including liver biopsy, Fibroscan® and noninvasive testing and outcomes.
Management of NAFLD and NASH
In the absence of approved pharmocotherapies, this content explores guideline recommendations, lifestyle interventions and surgical interventions for people with NAFLD and NASH.
Obesity and NASH
Assessment and diagnosis, referral and management in relation to people with obesity and the prevalence of advanced fibrosis due to NASH.
- Radaelli MG, et al. NAFLD/NASH in patients with type 2 diabetes and related treatment options. J Endocrinol Invest 2018;41:509–21.
- Targher G, et al. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care 2007;30:1212–8.
- Williamson RM, et al. Prevalence of and risk factors for hepatic steatosis and nonalcoholic fatty liver disease in people with type 2 diabetes: The Edinburgh type 2 diabetes study. Diabetes Care 2011;34:1139–44.
- Dai W, et al. Prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus. Medicine 2017;96:e8179.
- Younossi ZM, et al. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016;64:73–84.
- Gupte P, et al. Non-alcoholic steatohepatitis in type 2 diabetes mellitus. J Gastroenterol Hepatol 2004;19:854–8.
- Williams CD, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterol 2011;140:124–31.
- Prashanth M, et al. Prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus. J Assoc Physicians India 2009;57:205–10.
- Wanless IR and Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: An autopsy study with analysis of risk factors. Hepatology 1990;12:1106–10.
- Marchesini G, et al. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med 1999;107:450–5.
- Estes C, et al. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology 2018;67:123–33.
- Younossi ZM, et al. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol 2011;9:524–530.e1.
- Carruthers JE, et al. Nation-wide trends in non-alcoholic steatohepatitis (NASH) in patients with and without diabetes between 2004–05 and 2014–15 in England. Diabetes Res Clin Pract 2017;132:102–7.
- Hoehn RS, et al. Effect of pretransplant diabetes on short-term outcomes after liver transplantation: a national cohort study. Liver Int 2015;35:1902–9.
- Hossain N, et al. Independent predictors of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2009;7:1224–9.e2.
- Angulo P, et al. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999;30:1356–62.
- Younossi ZM, et al. Nonalcoholic fatty liver disease in patients with type 2 diabetes. Clin Gastroenterol Hepatol 2004;2:262–5.
- El-Serag HB, et al. Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 2004;126:460–8.
- Hwang ST, et al. Impact of non-alcoholic fatty liver disease on microalbuminuria in patients with prediabetes and diabetes. Intern Med J 2010;40:437–42.
- Söderberg C, et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology 2010;51:595–602.
- Serfaty L. Management of patients with non-alcoholic steatohepatitis (NASH) in real life. Liver Int 2018;38:52–55.
- Targher G, et al. Non-alcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and proliferative/laser-treated retinopathy in type 2 diabetic patients. Diabetologia 2008;51:444–50.
- Adler AI, et al. Development and progression of nephropathy in type 2 diabetes: The United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int 2003;63:225–32.
- Golabi P, et al. Components of metabolic syndrome increase the risk of mortality in nonalcoholic fatty liver disease (NAFLD). Medicine 2018;97:e0214.
- European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL–EASD–EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016;64:1388–402.
- Sterling RK, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology 2006;43:1317–25.
- Angulo P, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 2007;45:846–54.
- Leite NC, et al. Histopathological stages of nonalcoholic fatty liver disease in type 2 diabetes: prevalences and correlated factors. Liver Int 2011;31:700–6.
- Castera et al. Noninvasive assessment of liver disease in patients with nonalcoholic fatty liver disease. Gastroenterol. 2019 [Epub ahead of print].
- Harrison SA, et al. Orlistat for overweight subjects with nonalcoholic steatohepatitis: a randomized, prospective trial. Hepatology 2009;49:80–6.
- Haukeland JW, et al. Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial. Scand J Gastroenterol 2009;44:853–60.
- Shields WW, et al. The effect of metformin and standard therapy versus standard therapy alone in nondiabetic patients with insulin resistance and nonalcoholic steatohepatitis (NASH): A Pilot Trial. Therap Adv Gastroenterol 2009;2:157–63.
- Boettcher E, et al. Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2012;35:66–75.
- Lago RM, et al. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet 2007;370:1129–36.
LID/IHQ/18-12//1048d(1) Date of preparation August 2019