Identification of individuals at risk of hepatocellular carcinoma: screening for clinically significant liver fibrosis in patients with T2DM.

Cancer is a leading cause of premature mortality in patients with type 2 diabetes mellitus (T2DM) [1] and T2DM is strongly associated with site-specific cancers including hepatocellular carcinoma (HCC) [2]. In 2020, 830,200 people died from HCC and the incidence of HCC is expected to increase by 55% in the next 20 years [3]. HCC is now the fastest growing indication for liver transplantation [4] and is predicted to become the third most common cause of cancer death worldwide by 2030 [5]. HCC has a very poor prognosis with a 5-year survival of just ~ 20%; however, if cases are identified at an early-stage, curative treatments are available which include surgical resection, liver transplant, or tumor ablation [6]. A major risk factor for the increasing numbers of HCC is the increasing global prevalence of T2DM [3,5,7]. T2DM is strongly associated with central obesity, insulin resistance (IR), and other features of the metabolic syndrome; and of these linked risk factors, IR in particular is strongly linked with the development of liver steatosis, inflammation, fibrosis, and liver cirrhosis. When insulin resistance is present, in the absence of excess alcohol consumption, it is most likely that NAFLD is responsible for the development of chronic liver disease. Importantly, patients with NAFLD-related cirrhosis have a risk of developing HCC at least similar to [8] that reported for patients with cirrhosis occurring from other etiologies. There is a high prevalence of all chronic liver diseases in people living with T2DM compared to the general population [9]. All stages of NAFLD occur with T2DM [10–13], and we now know that there is a bi-directional causality between NAFLD and T2DM [14,15]. A recent study of 561 patients from the United States showed a high prevalence of liver fibrosis and cirrhosis in patients with T2DM, leading to the authors advocating the need for screening [11]. This study showed that, in patients with T2DM, significant fibrosis was present in 6% and severe fibrosis or cirrhosis in 9% of patients [11]. NAFLD represents a spectrum of liver conditions that begins with hepatic steatosis and progresses to nonalcoholic steatohepatitis (NASH), liver fibrosis, and cirrhosis. Occasionally, hepatic steatosis occurs without changes in easily measured concentrations of liver enzymes such as alanine aminotransferase (ALT) that is commonly measured in primary care. However, it is important to recognize that increases in ALT concentration do not parallel the stages of liver disease and serum concentrations of ALT occurring within the laboratory normal range may occur in NAFLD. Sometimes patients with NAFLD may have ALT concentrations below laboratory upper limits of normal and consequently, people living with T2DM may have undiagnosed NAFLD. With that in mind, the American College of Gastroenterology (ACG) suggests that current upper limits of normal are too high and that there should be sex-specific thresholds for the upper limits of normal. The ACG recommend ALT upper limits of normal of 33 U/L for men and 25 U/L for women, respectively, and that individuals with enzyme catalytic activity concentrations above these upper limits should be further investigated [16]. Despite uncertainty as to what level of ALT should trigger further investigations, concern has also been expressed about the assays used for measurement of ALT concentration [17]. Nevertheless, it seems likely that many laboratories’ current upper limit of normal of 40 U/L is probably too high, and a lower threshold for defining a normal ALT result should be used. Understanding how sex influences NAFLD is important for risk stratification and management of the disease, particularly as there is a disparity between men and women in the prevalence and severity of NAFLD [18]. We know that women with prior gestational diabetes mellitus are more prone to metabolic syndrome [19,20] and have a higher risk of NAFLD compared with women without a history of gestational diabetes mellitus [21,22]. Moreover, the presence of gestational diabetes and NAFLD synergistically increases the risk of developing diabetes [23]. Indeed, NAFLD was initially considered a female disease [24]; however, studies have shown that NAFLD is as common in men as in women [25]. A recent systematic review concluded that women have a lower risk of NAFLD than men [18], but once NAFLD is established the risk of progressing to advanced fibrosis is higher in women [18].