Phenotypes of Patients with Diabetes and NAFLD: History
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Contributor:
Andreea Ciudin
,
Alba Rojano Toimil
,
Jesus Rivera
,
Ramiro Manzano Nunez
,
Juan Bañares
,
David M. Selva
,
Pablo Gabriel-Medina
,
Roser Ferrer Costa
,
Juan M. Pericàs

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in Western countries. Its incidence is expected to keep growing, parallel to the incidence of metabolic syndrome (MetS) and its determinants. Within the MetS spectrum, the bulk of research addresses the relationship between either type 2 diabetes (T2DM) or obesity with NAFLD. However, a growing body of evidence shows that NAFLD is also prevalent in a variety of other forms of diabetes that typically have an earlier onset, such as type 1 diabetes (T1DM), Maturity-onset Diabetes of the Young (MODY) and ketosis-prone diabetes. 

  • type 2 diabetes
  • type 1 diabetes
  • ketone-prone diabetes
  • MODY diabetes
  • NAFLD

1. Type 2 Diabetes and Obesity—The Metabolic Syndrome Paradigm

1.1. Epidemiology

Type 2 diabetes is the most common form of diabetes. It has an estimated prevalence of 26.9 million people of all ages in the US (or 8.2% of the US population) and 536.6 million people worldwide [1][2]. In Spain, the incidence of DM obtained from the di@bet.es study cohort was estimated at 11.6 cases/1000 person-year (OR (95% CI) 11.1–12.1) [3]. T2DM is characterized by hyperglycemia, IR, and relative insulin deficiency [4]. The primary risk factors associated are those related to lifestyle behaviors such as poor physical inactivity and dietary habits, cigarette smoking, and alcohol consumption [5]. Moreover, overweightness and obesity contribute to approximately 89% of cases of T2DM [1].
T2DM has become an epidemic issue in occidental countries. Due to its asymptomatic onset, it is frequently diagnosed at later stages when micro and macrovascular complications are established [6]. Optimization of management of T2DM, screening in primary care, and advances in research have allowed a decrease in the associated complications [7]. In addition, obesity is directly linked to NAFLD due to IR and metabolic syndrome [8][9].
The 2020 Center for Disease Control and Prevention (CDC) report revealed 34.1 million patients diagnosed with diabetes among adults aged 18 years or older in the United States, with type 2 diabetes accounting for 90% to 95% of cases. Among the reported cases, 45.8% of individuals had obesity (body mass index (BMI) of 30.0 to 39.9 kg/m2), and 15.5% presented extreme obesity (BMI of 40.0 kg/m2 or higher) [1].
In global studies, the prevalence of T2DM is estimated at 10.5% [2], which has steadily increased during the last two decades due to changes in nutrition and physical exercise in Western countries. According to current predictions, the incidence of T2DM is expected to rise from 171 million in 2000 to 366 million individuals by 2030 [10]. One of the main drivers of such worrying forecasting is the increased prevalence of childhood obesity, with approximately 35.1% and 26.5% of children being overweight or obese in the US, respectively [11]. Social determinants of health such as gender, race/ethnicity, and socio-economic status expose significant disparities amongst T2DM patients. For example, Black and Hispanic children have higher risk-adjusted obesity odds when compared to Asians or Caucasians [12]. Similar results are described for T2DM, with the highest prevalence among people of Hispanic origin (12.5%) and Blacks (11.7%) [1]. Low socioeconomic status has been found also associated with poorer outcomes [13]. Lifestyle behaviors, e.g., physical inactivity, smoking, or alcohol consumption, are also strong drivers of T2DM, independently of genetic predisposition [5][14].

1.2. Pathophysiology

Type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) have been traditionally linked to one another. The main pathophysiological link between T2DM and NAFLD is IR [15], and hepatic steatosis and fibrosis are also related to the development of IR, which substantially increases the risk of subsequent T2DM [16]. On one hand, hyperglycemia was demonstrated to be a hazard in hepatic steatosis and fibrosis development: several in vitro models demonstrate the role of hyperglycemia in the process, e.g., Robin C et al. in 2017, demonstrated that hyperglycemic cell culturing conditions induced steatosis within a human hepatocyte cell line (HepG2 cells) by the accumulation of intracellular lipids [17]. Experimental models, such as in streptozotocin-induced diabetic models in mice, show that progression in NAFLD is due to hyperglycemia-induced inflammation [18]. An increase in glucose substrate in the hepatocyte promotes the accumulation of free fatty acids in the cell and the stimulation of hepatic lipogenesis by upregulation of the Krebs cycle and an increase in the expression of ChREBPnad liver X receptor alfa. This cascade activates downstream fibrogenic pathways with oxidant stress and inflammasome activation that leads to cell apoptosis by cytokines such as IL-1B, IL-6, or TNF-alfa that finally result in inflammation, hepatocyte injury, and liver fibrosis [19][20][21]. On the other hand, the excess of triglyceride synthesis is another pathophysiological landmark of NAFLD. IR was proven to be responsible for an increase in adiposity in hepatic cells, as demonstrated in studies with the hyperinsulinemic-euglycemic clamp [22] and indirectly measured through the HOMA-IR index [23]. These changes result in a boost of gluconeogenesis cascades, an increase in free fatty acid (FFA) levels, and simultaneously impairment in hepatic glycogen synthesis. These metabolic changes lead to liver fat accumulation, resulting in a preferential shift from carbohydrate to FFA beta-oxidation [24]. FFA accumulation and IR activate several inflammatory pathways related to pro-inflammatory cytokines such as TNFα or IL-6 [25]. Other extrahepatic drivers of liver inflammation include IL-1B, or IL-6 liberated from adipose tissue in obese individuals [26]. These cytokines create a pro-inflammatory environment producing hepatotoxic free oxygen radical species that result in hepatocellular injury and fibrosis [27].
Despite of that, not all patients with NASH exhibit IR. This suggests that other factors may influence the progression to NASH. For example, genetic variants are strongly associated with histologic severity. Petersen et al. demonstrated that specific polymorphisms in the gene encoding for apolipoprotein C3 are markers of hepatic IR and inflammation [28], such as other research related IL-6 polymorphisms [29]. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) is a lipid droplet-associated protein that is increased in obese patients. Higher levels are associated with augmented liver fat content [30]. Finally, hepatic lipid metabolism disruptions, inflammation in adipose tissue, and ectopic sites of fat deposition interfere with normal hepatic function and give way to excess storage of lipid droplets in hepatocytes [31]. In fact, de novo lipogenesis is threefold higher in patients with NAFLD [32]. In addition, hepatocellular FFA accumulation is sustained by impaired synthesis and secretion of very-low-density lipoproteins and excessive importation of FFA from adipose tissue [33]. The activation of these cascades eventually leads to impaired antioxidant capacity with increased oxidative stress and mitochondrial function defects, leading to hepatic fibrosis and IR [27].

1.3. Clinical Manifestations

T2DM and obesity are among the most important risk factors of NASH, liver-related events, hepatocellular carcinoma (HCC), and mortality in patients with NAFLD [34][35][36][37]. The prevalence of NAFLD in T2DM patients is over 50%, and when both T2DM and obesity coexist, the prevalence of NAFLD ranges between 60% and 80% [38][39][40][41]. A global meta-analysis showed that T2DM was present in 22.51% of patients with radiologically defined NAFLD and 43.36% among patients with NASH determined by biopsy. Of note, 56% of the individuals with histologically proven NASH had normal liver enzymes [34][42]. Data recollected from the Edinburgh Type 2 Diabetes Study (ET2DS) registered a prevalence of 42.6% of NAFLD in patients with T2DM. Independent predictors were BMI, duration of diabetes, HbA1c, triglycerides, and metformin use [43]. These studies also showed that some factors play a critical role in the relationship between NAFLD and diabetes. For example, compared to T2DM only, patients with T2DM and NAFLD were more likely to present hypertension, dyslipidemia, and cardiovascular diseases [44] which means that the presence of NAFLD determines a higher risk of poor cardiovascular and metabolic outcomes, a fact that was proven in previous studies. Indeed, a meta-analysis including 16 studies representing more than 34,000 patients demonstrated that NAFLD was associated with a higher cardiovascular risk and conferred a more elevated risk adjusted-odds of cardiovascular events, including myocardial infarction and stroke [45].
Emerging data suggest that up to 20% of patients diagnosed with NASH will develop cirrhosis in the disease course [46]. The fibrosis stage is the main predictor of liver-related illness, liver transplantation, and liver-related mortality [34][42]. Both T2DM and overweight/obesity are predictors of advanced fibrosis and comorbidities in patients with NASH [36][47] with a >10-fold risk of HCC [48]. Remarkably, and contrary to other causes of chronic liver disease, HCC can develop in non-cirrhotic livers in the setting of NAFLD. In addition, patients with obesity have an increased incidence of HCC without cirrhosis compared with non-obese patients [49][50]. Numerous studies linked pro-inflammatory cytokines derived from IR and hyperinsulinemia to activation of carcinogenic pathways [51]. Yet, cardiovascular events such as stroke or myocardial infarction are the leading cause of death in patients with NAFLD [52]. NAFLD also is shown to worsen the prognosis of T2DM, e.g., to worsen glycemic control and microvascular complications such as nephropathy and retinopathy [53][54]. To remark, another factor with a close relationship with metabolic syndrome is the presence of hepatitis virus C infection (HCV). Recent evidence from prospective studies suggests that the treatment of HCV in NAFLD patients with and without fibrosis, would reduce the risk of T2DM by 81% by restoring normal glucose metabolism. The same effect was reported for cardiovascular events such as acute coronary syndrome, myocardial infarction, stroke, or transient ischemic attack, with a decrease between 56 and 75 cases per year for 10,000 HCV patients with long-term remission, independently of other risk factors such as smoking, dyslipidemia, or hypertension [55][56][57].

2. Type 1 Diabetes (T1DM)

Although it appears that the most common liver disease in patients with T1DM is NAFLD [58], the links between both disorders remain largely unelucidated. T1DM is an autoimmune disorder that typically presents in children and younger adults. Until recently, there was not a traditional association between obesity, metabolic syndrome, and T1DM [4], yet with the increasing prevalence of obesity in the general population, a parallel rise has been observed in patients with T1DM and overweight or obesity [59]. Moreover, a pathogenic role of obesity in T1DM was recently described, related to β-cell stress, ectopic adipose tissue, and an increase in autoimmune disorders [60][61][62].

2.1. Epidemiology

A global increase in T1DM incidence has been observed, with a 2–3% increase per year [63][64][65]. The higher incidence is found among children younger than five years, and variations occur according to environmental and behavioral factors such as diet, obesity, vitamin D sufficiency, gut-microbiome changes, or exposure to certain viruses [60][65]. As in the case of T2DM, socioeconomic factors play a paramount role in the differences in the prevalence among genetically similar patients [66]. Although T1DM can also develop in adulthood, the higher incidence of T2DM among adults and the lack of strong diagnostic criteria make such late diagnosis rare and challenging [67].

2.2. Pathophysiology

Although T1DM and T2DM share hyperglycemia as their landmark, various underlying mechanisms primarily differentiate both entities. While an absolute insulin deficiency characterizes T1DM, the natural history of T2DM is marked by IR in peripheral tissues. Yet, T2DM can also lead to insulin deficiency when insulin production is depleted due to exhaustion of pancreatic synthesis [4][68]. As in T2DM, the state of hyperinsulinemia found in T1DM affects glucose and lipid liver metabolism and triggers pro-inflammatory cascades that produce liver fibrosis and cirrhosis [16][20][69][70].
A proposed differential mechanism of liver damage in T1DM relates to the increase in visceral adiposity secondary to frequent snacking in the hypoglycemia context, which increases caloric and fructose intake [71]. Other mechanisms that may explain the development of hepatic complications in patients with T1DM are the relative portal vein insulin deficiency that leads to altered hepatic glycogen storage, absence of inhibition of hepatic gluconeogenesis, and overall metabolic disturbance with a shunt to lipogenic pathways [4][72][73]. The lack of endogenous insulin also alters the dynamic of insulin delivery with more minor variation in the plasma range, ending in downregulation of insulin receptors on hepatic cells due to continuous exposure [74]. This altered pharmacokinetics implies the development of a relative IR with the subsequent hepatic damage [69].
As mentioned above, not all patients with NAFLD are associated with obesity and MetS. This statement acquires relevance in T1DM due to its genetic footprint. Several genetic risk alleles associated with fatty liver disease are described in the literature, including those containing the genes PNPLA3 and transmembrane six superfamily member 2 (TM6SF2) [75]. Other potential genes that are related to T1DM and insulin-dependent T2DM are those that encode sterol regulatory element-binding protein (SREBPs) and carbohydrate-responsive element-binding protein (ChREBP). Alterations in these proteins stimulate lipogenic and glycolytic pathways that contribute to NAFLD [76][77].

2.3. Clinical Manifestations

Despite T1DM being at an increased risk of developing NAFLD, likely higher than T2DM patients (both because of the intensity of metabolic dysfunction and the earlier onset of the disease), a limited number of studies are addressing the prevalence of NAFLD in T1DM. A meta-analysis by Vries et al. reported an overall prevalence of 19.3% in T1DM, which increased to 22% in adults [58]. A recent study showed a NAFLD prevalence of 16–21% in T1DM patients by share wave elastography at liver ultrasound [78].
Evidence on the outcomes of patients with NAFLD and T1DM is also preliminary. In a cohort of 4641 patients with T1DM, Harman et al. found that overall, patients with T1DM were at increased risk of developing liver cirrhosis compared to the general population [79]. Targher et al. demonstrated that NAFLD increases the risk of both microvascular and macrovascular complications in T1DM, i.e., chronic kidney disease (37.8% vs. 9.9% in patients without NAFLD), retinopathy (53.2% vs. 19.8%), coronary artery disease (10.8% vs. 1.1%), cerebrovascular (37.3% vs. 5.5%), and peripheral vascular disease (24.5% vs. 2.5%, p < 0.001 for all comparisons) [45][80]. Further prospective studies are needed to evaluate whether NAFLD is an independent factor for hepatic and cardiometabolic complications that might contribute to the excess mortality in T1DM cohorts [81][82].

3. MODY Diabetes

MODY is a mild, largely asymptomatic form of diabetes that occurs in nonobese children and young adults with a dominant inheritance pattern [83]. This form of diabetes is commonly misdiagnosed as T1DM or T2DM and is often inappropriately managed with insulin, whereas the adequate treatment consists of a sulfonylurea [84][85].

3.1. Epidemiology

MODY represents a clinically heterogeneous form of β-cell dysfunction caused by genetic mutations with an autosomal dominant form of inheritance. Because of the diverse patterns of presentation and the need for costly molecular diagnosis, it is frequently misdiagnosed as other types of diabetes [85][86]. HNF-1α/MODY3 and GCK/MODY 2 are the most common mutations [87][88]. One of the first prevalence studies estimated 35.2 cases per million with a confirmed genetic test in the UK [89]. In a study carried out on Norwegian diabetes registers, MODY accounted for 0.4% of patients [90]. In the US, the estimated prevalence is 2.1 per 100,000 individuals younger than 20 years [91]. In these groups, researchers include a subtype of inherited diabetes associated with lipodystrophies that are associated with severe insulin resistance, premature diabetes, hypertriglyceridemia, and hepatic steatosis due to defects on adipocyte development, differentiation, and apoptosis [92][93]. Although acquired lipodystrophies related with chronic corticosteroids therapy or human immunodeficiency virus (HIV) infection are more common in the general population [94], this group is characterized by a translocation of subcutaneous adipose to ectopic parts of the body, including the liver, which subsequently drives to hepatic inflammation and fibrosis. Therefore, NAFLD has been described in these patients, as confirmed in histologically confirmed cohorts, with a prevalence around 82–90% [95][96][97]. Clinicians must be aware that some of these patients are characterized by low weight and BMI; therefore, recent guidelines recommend the screening of lipodystrophy in lean individuals with a diagnosis of NASH [98]. The severity of NAFLD will depend on the type of lipodystrophy, being more severe in generalized lipodystrophy, but also on specific mutations, such as LMNA mutations [99].

3.2. Pathophysiology

MODY was recognized as a disease in 1964 at the Fifth Congress of the International Diabetes Federation in Toronto, and since then, significant progress has been made in understanding its pathophysiology [100]. In 1974, Tattersall et al. reported a new form of diabetes with an autosomal dominant pattern of inheritance that typically presented in young patients who could discontinue insulin therapy over the course of the disease [101]. Since 1975, various mutated genes were identified and associated with different subtypes of MODY with a wide diversity of clinical features, severity of hyperglycemia, and age onset [102]. GCK (MODY 2) and HNF1A (MODY 3) mutations account for almost 70% of all cases of MODY, followed by HNF4A (MODY 1). HNF1A and HNF4A genes encode the transcription factors hepatocyte nuclear factor-1 alpha and factor-4 alpha [103] and coordinate gene expression of proteins involved in glucose transport and glucose metabolism, and β-cell apoptosis, which lead to an increase in cellular apoptosis and defects in insulin secretion [104]. The Glucokinase gene is responsible for detecting bloodstream glucose by its transformation to glucose-6-phosphate by the glucose transporter 2 (GLUT2). Heterozygous mutations imply less function of this enzyme, and affected β-cells are less sensitive to glucose variations that result in elevated fasting and postprandial blood sugar.

3.3. Clinical Manifestations

Patients diagnosed with the most common forms (MODY 1, 2, and 3) have a similar risk for complications as those with T1DM and T2DM. Therefore, an optimal glycemic control is inversely related to poor micro- and macrovascular outcomes [104]. Patients carrying heterozygous mutations rarely develop micro- or macrovascular complications [105]. Concerning the association of MODY and NAFLD, again, the body of evidence is overall poor. Multisystemic forms that imply alterations in the transcription factor hepatocyte nuclear factor 1β (HNF1B) (MODY 5) with clinical features that include early-onset diabetes mellitus, pancreatic hypoplasia, genital tract, kidney hypoplasia, cognitive impairment, and abnormal liver function might be the subgroup at higher risk of NAFLD. Hepatic dysfunction is presented in 65% of patients, and the classical phenotype is characterized by elevated serum transaminases, steatosis, and periportal fibrosis. Yearly abdominal ultrasonography and biannual laboratory monitoring are proposed for patients with MODY 5 [106][107][108].

4. Ketone-Prone Diabetes (KPD)

In 1987, Winter et al. reported a new form of diabetes called ‘atypical diabetes’ by then [109]. The discovery led to a rise in recognizing this uncommon clinical presentation, with an abrupt onset—typically with ketoacidosis—and transient insulin requirements that usually occurred in African-American or Hispanic patients and were associated with obesity and a strong family history of type 2 diabetes [110][111][112][113]. Some evidence suggests that a primary glucose desensitization acts as a trigger to β-cell exhaustion and dysfunction that lead to acute metabolic failure. Initial aggressive treatment with insulin therapy and antidiabetic drugs such as metformin predict better outcomes and a delay in the recurrence of hyperglycemia [114][115].

4.1. Epidemiology

These patients are often Afro-American and Hispanic, obese, middle-aged men, with a family history of type 2 diabetes. Most prevalence studies on KPD made are US-based, with an estimate of 20% and 50%, respectively, in African American and Hispanic patients with new diagnoses of diabetic ketoacidosis [109][111][116][117]. Obesity is present in 56% of newly diagnosed patients, and more than 80% of patients have a family history of T2DM [118][119]. More recent studies estimated an average incidence of 60% among patients attending emergency rooms due to ketoacidosis [120]. The prevalence of this diabetes seems to be lower in Asian and White Americans, representing less than 10% of cases of diabetic ketoacidosis [121][122]. Patients with KPD present with acute IR, elevated glucose, Hb1Ac, and ketone levels, and unlike T1DM, they do not exhibit β-cell antibodies.

4.2. Pathophysiology

The natural history of KPD has two phases. These individuals initially present an acute form presentation with severe hyperglycemia and ketosis due to a lack of response and stimulus of β-cell insulin secretion [116]. The causes of these acute onsets in patients affected with ketosis-prone diabetes remain unknown. Patients present a diminished insulin and c-peptide response to an oral glucose load in the second phase. In studies with a euglycemic insulin clamp, there was no difference in baseline glucagon levels and glucagon suppression between KPD patients and the normal controls. In short term follow-up, the insulin secretion increased after a few weeks of exogenous insulin treatment, and after months, there was no difference in the beta-cell response and the insulin secretion compared to controls [123]. IR is not systematically found and appears to be associated with ethnicity and geographic variability [124][125].

4.3. Clinical Manifestations

The typical presentation is a new clinical onset with severe hyperglycemia with high ketones or diabetic ketoacidosis, negative GAD, and islet cell autoantibodies. The type and rate of complications are similar to T2DM [105][107][108][126]. Provided that IR characterizes KPD and related metabolic abnormalities, pathogenic liver pathways that contribute to NAFLD are certainly stimulated; yet, there are no specific studies of NAFLD in KPD. It is worth underscoring that African Americans with T2DM are at lower risk for hepatic steatosis than White Americans, which is not explained by ethnic differences in BMI, HOMA-IR, or toxic or drug ingestion [47][118]. In contrast, Hispanics are at higher risk of steatohepatitis, seemingly due to the higher prevalence of obesity and IR [127][128].

This entry is adapted from the peer-reviewed paper 10.3390/jcm11123286

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