Nonalcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus: A Bidirectional Relationship

Worldwide, the leading cause of chronic liver disease is represented by nonalcoholic fatty liver disease (NAFLD) which has now become a global epidemic of the 21st century, affecting 1 in 4 adults, and which appears to be associated with the steadily increasing rates of metabolic syndrome and its components (obesity, type 2 diabetes mellitus (T2DM), and dyslipidemia). NAFLD has been reported to be associated with extrahepatic manifestations such as cardiovascular disease, T2DM, chronic kidney disease, extrahepatic malignancies (e.g., colorectal cancer), endocrine diseases (e.g., hypothyroidism, polycystic ovarian syndrome, psoriasis, and osteoporosis), obstructive sleep apnea, and iron overload. The prevalence of NAFLD is very high, affecting 25–30% of the world population and encloses two steps: (1) nonalcoholic fatty liver (NAFL), which includes steatosis only, and (2) nonalcoholic steatohepatitis (NASH) defined by the presence of steatosis and inflammation with hepatocyte ballooning, with or without fibrosis which can progress to liver fibrosis, hepatocellular carcinoma, and liver transplantation. Current data define a more complex relationship between NAFLD and T2DM than was previously believed, underlining a bidirectional and mutual association between the two entities. This review aims to summarize the current literature regarding the incidence of T2DM among patients with NAFLD and also the prevalence of NAFLD in T2DM patients, highlighting the recent key studies. Clinicians should screen, diagnose, and treat T2DM in patients with NAFLD in order to avoid short- and long-term complications.


Introduction
e incidence rate of chronic liver diseases increased through the years with a worrying rise of liver-related morbidity and mortality rates worldwide [1]. One of the major causes of chronic liver diseases is represented by nonalcoholic fatty liver disease (NAFLD) which has now become a global epidemic affecting 1 in 4 adults, with an estimated prevalence between 25% and 30%, and appears to be associated with the steadily increasing rates of metabolic syndrome (MetS) and its components (obesity, type 2 diabetes mellitus (T2DM), and dyslipidemia) [1][2][3]. e mandatory feature of NAFLD is the presence of liver steatosis (LS) in the absence of other causes of chronic liver disease [4]. Although initially NAFLD was considered as the hepatic manifestation of MetS, there is now clear evidence that NAFLD is a key driver in MetS and hepatic involvement is only one component of systemic multiorgan involvement [5,6]. NAFLD encloses two distinct conditions with different histologic features and prognosis: (1) nonalcoholic fatty liver (NAFL), which includes steatosis only, and (2) nonalcoholic steatohepatitis (NASH) characterized by steatosis and inflammation with hepatocyte ballooning, with or without fibrosis, which can progress to liver fibrosis (LF), cirrhosis, hepatocellular carcinoma (HCC), and liver transplantation [7]. e prevalence of NASH among NAFLD patients ranges from 10% to 59% in patients who underwent liver biopsy [1], meaning that millions and millions of people worldwide are at risk of cirrhosis and its complications. Even more alarming is that the continuously increasing rates of MetS and its components parallel the rising prevalence of NASH, with obesity, T2DM, and MetS being the most important risk factors [8,9]. Growing evidence clearly shows that NAFLD is a multiorgan disease, supporting a strong link between NAFLD and cardiovascular diseases (CVDs), T2DM, chronic kidney disease (CKD), extrahepatic malignancies (eg., colorectal cancer), obstructive sleep apnea (OSA), and various endocrinopathies (e.g., thyroid dysfunction, polycystic ovarian syndrome (PCOS), osteoporosis, psoriasis, hypothyroidism, and iron overload) [10,11]. Although the primary site of NAFLD is the liver, the most common causes of mortality are CVDs, followed by extrahepatic malignancies such as colorectal cancer and then liver-related complications (cirrhosis and HCC) [5,6,12]. Considering the high clinical and economic burden of NAFLD, the main point in the management of these patients is an early acknowledgement of both hepatic and extrahepatic manifestations and their subsequent complications [11,13,14]. Current data outline a more complex relationship between NAFLD and T2DM than was previously thought, pointing out a bidirectional and mutual association between the two entities.
us, clinicians should screen, diagnose, and treat T2DM in patients with NAFLD in order to avoid short-and long-term complications. Herein, this review aims to summarize the current literature regarding the incidence of T2DM among patients with NAFLD and also the prevalence of NAFLD in T2DM patients, highlighting recent key studies.

Relation between NAFLD and T2DM
Current data reveal a more complex relationship between NAFLD and T2DM than was previously believed, highlighting a bidirectional and mutual association between the two entities [11,15,16]. Considering that NAFLD and T2DM have similar physiopathological pathways, one can precede and/or promote the other [10,17].

T2DM in Patients with NAFLD. NAFLD is associated
with lipotoxicity which is secondary to the accumulation of triglyceride-derived toxic metabolites in the liver, pancreas, and muscles, which leads to the activation of the inflammation cascade and insulin resistance [18,19]. e hepatic insulin resistance associated with NAFLD is the key driver for the development of T2DM among these patients. e prevalence of T2DM in patients with NAFLD depends on the severity of NAFLD starting from 9.8% in mild NAFLD to 17.8% in moderate to severe NAFLD [20][21][22]. Although NAFLD is considered an independent risk factor for developing T2DM, with a 2-fold incidence increase in these individuals, patients with NASH have an up to threefold higher risk of developing incident T2DM compared with those with simple steatosis [20,23,24].
Despite evidence from several studies which demonstrated that high levels of NAFLD's surrogate markers-gamma-glutamyl transferase and alanine aminotransferase (ALT)-were associated with a high incidence of T2DM, the predictive value of these biologic parameters is limited due to the possibility of normal levels among these patients [25][26][27][28][29]. As for ultrasonography-defined NAFLD (liver steatosis ≥20%) [30,31], recent data showed a twofold to fivefold increased risk of T2DM [32].
Many large-population-based retrospective studies with a follow-up period of 3 to 6.2 years showed an increased incidence risk of T2DM among patients diagnosed with NAFLD (Table 1) [33-37, 42, 43]. Shibata et al. achieved a 4-year follow-up in 3189 patients among whom 1138 had NAFLD at baseline and reported an incidence of 1.8% vs. 8.1% in the non-NAFLD patients compared with those with NAFLD [33]. Similarly, 4 other retrospective studies which included Asian cohorts without T2DM, demonstrated that NAFLD was significantly associated with a high incidence of T2DM during follow-up [34][35][36][37]. In a similar manner, prospective studies which evaluated the prevalence of T2DM among patients with NAFLD have also reported an increased risk associated with baseline NAFLD [38][39][40][41]. Results from an Israeli cohort of 141 nondiabetic participants among which 24.8% had NAFLD, followed up for an average period of 6.08 ± 0.7 years, demonstrated a higher incidence of prediabetes and/or T2DM in patients with NAFLD than in subjects without NAFLD (74.3% vs. 48.1%) [39]. In a recent retrospective study conducted by Liu et al. which included 18,507 nondiabetic subjects, the prevalence of NAFLD was 18.77% with a 5-year T2DM incidence of 2.44%. e authors concluded that patients with baseline NAFLD had a higher risk incidence of T2DM, with an adjusted relative risk of 1.672 [43].

NAFLD in Patients with T2DM.
Once established, T2DM may promote the progression to NASH and become an independent risk factor for chronic liver disease, including cirrhosis and HCC [10]. It has been reported that the presence of NAFLD among patients with T2DM determined a 2.2-fold risk increase in all-cause mortality, compared with those without NAFLD [15]. e estimated prevalence of NAFLD among patients with T2DM is about 75%, which is more than the prevalence in the general population [1].
Evidences from several recent cohort studies highlighted an increased incidence of NAFLD among patients diagnosed with T2DM, with an estimated prevalence ranging between 41.6% and 86% (Table 2) [8,[44][45][46][47][48][49]. For instance, Sporea et al. conducted a prospective study in which 534 patients diagnosed with T2DM were included. Patients with other causes of steatosis were excluded, and LF and steatosis were quantitatively assessed using vibration controlled transient elastography and the controlled attenuation parameter. e authors found an estimated prevalence of NAFLD of 76.1%. Moreover, severe steatosis was detected in 60.3%, while advanced LF had a prevalence of almost 20% [50]. Two other retrospective studies reported a similar prevalence of NAFLD among T2DM patients [45,46].

Management of Patients with NAFLD and T2DM
e reciprocal relationship between T2DM and NAFLD leads to the progression of LF and is secondary to the development of liver-related complications with high morbidity and mortality rates. In order to avoid systemic multicollateral damage, it seems appropriate to screen patients with NAFLD for T2DM, and vice-versa. According to current European Guidelines, screening of T2DM in patients with NAFLD is mandatory, and it consists of random blood glucose or hemoglobin A1C [51]. Furthermore, screening for NAFLD and LF is recommended by the American Diabetes Association in patients diagnosed with T2DM which have elevated liver enzymes (ALT) or LS, while the American Association Society of Liver Disease is not in favour of routine screening in these patients [52,53].
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