Arianna Mazzotti

The Role of Medications for the Management of Patients with NAFLD

The article is intended to provide an overview of the strengths and limits of controlled trials of pharmacologic treatment of nonalcoholic fatty liver disease. No drug has so far been approved, although validated on histologic outcomes. Several new drugs are under scrutiny, acting with different mechanisms along the chain of events from fatty liver to fibrosis, cirrhosis, and hepatocellular carcinoma. The article investigates which drug, if any, should be preferred for a tailored intervention in individual patients, according to age, comorbidities, and disease severity, and if treatment should be continued lifelong, to prevent disease progression and long-term occurrence of cirrhosis.

NAFLD incidence and remission: Only a matter of weight gain and weight loss?

The prevalence of non-alcoholic fatty liver disease (NAFLD) in the community is probably rising, driven by the epidemics of obesity and diabetes. A provocative study on obesity prevalence in the U.S. suggested that, given the trend observed between 1970 and 2004, all American adults would become overweight or obese by 2048, with differences between genders and ethnic ancestry [1]. Similar data exist for the prevalence of type 2 diabetes, which is now well above a 10% prevalence rate in several countries, with an estimated total of 382 million cases throughout the world and a prospective rise to 592 million cases in the next 25 years [2]. From the early description of NAFLD, we know that the disease is intimately connected with obesity, diabetes and the metabolic syndrome, therefore it is not surprising that NAFLD is among the top three causes of liver transplantation. Considering the rapid advances in antiviral therapy, it is expected to become the most common indication in the near future. A correct identification of incident cases may help to determine additional risk factors and program therapeutic interventions. Only a few studies have been available so far on fatty liver or NAFLD incidence (Table 1). The usual method to diagnose NAFLD has been ultrasonography, sometimes coupled with raised liver enzymes [3–10]. We all know that this method is crude, imprecise, highly insensitive and operator-dependent and cannot provide quantitative data. Overall, data are remarkably different in relation to study population, age, gender and comorbidities (in particular, to the presence/absence of obesity and the method of ascertainment). In the present issue of the Journal, Wong et al. present their analysis of NAFLD incidence based on paired proton-magnetic resonance spectroscopy (MRS) in a community-based Hong-Kong cohort, where also the parameters of metabolic syndrome were recorded [11]. In 565 cases without evidence of NAFLD at baseline (intrahepatic triglyceride (IHTG) content 5%) was set at 3.4% per year, after exclusion of two cases with excessive alcohol intake, with 20% of new cases in the range of moderate-severe steatosis and only one patient with liver stiffness indicative of advanced fibrosis. The presence of metabolic syndrome at baseline was the strongest predictor of incident steatosis, which was also associated with incident obesity, incident metabolic syndrome, and no remission of impaired glucose tolerance.

Which treatment for type 2 diabetes associated with non-alcoholic fatty liver disease?

Type 2 diabetes (T2DM) and nonalcoholic fatty liver disease (NAFLD) are highly prevalent in the community, and share common pathogenic mechanisms. There is also evidence that T2DM may be favored by hepatic fat accumulation; in turn the presence of T2DM is a risk factor for liver disease progression. The treatment of T2DM has considerably changed in the past few years; new drug classes, promoting glucose-lowering through mechanisms different from classical insulin-sensitizing or insulin-secreting action, have been added to continuing lifestyle intervention. Metformin and pioglitazone may be safely used in the presence of liver fat, whereas sulfonylureas and insulin itself have been associated with NAFLD progression and adverse outcome. Drugs acting on the incretin axis and on Na-glucose co-transport at renal tubular level offer new hopes for a tailored treatment able to reduce the burden of hepatic triglyceride accumulation and liver disease progression.

Pathophysiology of Nonalcoholic Fatty Liver Disease: Lifestyle-Gut-Gene Interaction.

Background: The accumulation of fat droplets in the hepatic parenchyma is driven by several factors, synergistically acting to increase triglyceride flow to the liver (diet and metabolic factors, endotoxemia from gut microbiota, genetic factors). Key Messages: In the presence of unhealthy lifestyles and behavioral factors, leading to enlarged adipose tissue and insulin resistance (IR), both lipolysis and de novo lipogenesis are expected to increase the risk of hepatic lipid depots, in association with high calorie (either high-fat or high-carbohydrate) diets. The gut microbiota may also be involved via obesity, IR and hepatic inflammation generated by gut-derived toxic factors. Finally, several data also support a primary role of genetic factors. A few gene polymorphisms have also been associated with the risk of nonalcoholic fatty liver disease development and nonalcoholic steatohepatitis progression to more fibrosis and advanced liver disease. In a few cases (e.g., patatin-like phospholipase domain-containing 3/adiponutrin), steatosis carries a high risk of both liver disease and cardiovascular morbidity/mortality; in other cases (e.g., transmembrane 6 superfamily 2 human gene), dissociation has been observed between the increased risk of liver disease versus cardiovascular disease. Conclusions: A variable interplay between the genetic background and the metabolic milieu is the likely physiopathologic mechanism involved in individual cases, which must be considered for implementing effective treatment strategies.

An internet-based approach for lifestyle changes in patients with NAFLD: Two-year effects on weight loss and surrogate markers

BACKGROUND & AIMS Interventions aimed at lifestyle changes are pivotal for the treatment of non-alcoholic fatty liver disease (NAFLD), and web-based programs might help remove barriers in both patients and therapists. METHODS In the period 2010-15, 716 consecutive NAFLD cases (mean age, 52; type 2 diabetes, 33%) were treated in our Department with structured programs. The usual protocol included motivational interviewing and a group-based intervention (GBI), chaired by physicians, dietitians and psychologists (five weekly meetings, n = 438). Individuals who could not attend GBI entered a web-based intervention (WBI, n = 278) derived from GBI, with interactive games, learning tests, motivational tests, and mail contacts with the center. The primary outcome was weight loss ≥10%; secondary outcomes were alanine aminotransferase within normal limits, changes in lifestyle, weight, alanine aminotransferase, and surrogate markers of steatosis and fibrosis. RESULTS GBI and WBI cohorts had similar body mass index (mean, 33 kg/m2), with more males (67% vs. 45%), younger age, higher education, and more physical activity in the WBI group. The two-year attrition rate was higher in the WBI group. Healthy lifestyle changes were observed in both groups and body mass index decreased by almost two points;the 10% weight target was reached in 20% of WBI cases vs. 15% in GBI (not significant). In logistic regression analysis, after adjustment for confounders and attrition rates, WBI was not associated with a reduction of patients reaching short- and long-term 10% weight targets. Liver enzymes decreased in both groups, and normalized more frequently in WBI. Fatty liver index was reduced, whereas fibrosis remained stable (NAFLD fibrosis score) or similarly decreased (Fib-4). CONCLUSION WBI is not less effective than common lifestyle programs, as measured by significant clinical outcomes associated with improved histological outcomes in NAFLD. eHealth programs may effectively contribute to NAFLD control. LAY SUMMARY In patients with non-alcoholic fatty liver disease, participation in structured lifestyle programs may be jeopardized by job and time constraints. A web-based intervention may be better suited for young, busy patients, and for those living far from liver units. The study shows that, following a structured motivational approach, a web-based, interactive intervention coupled with six-month face-to-face meetings is not inferior to a standard group-based intervention with respect to weight loss, adherence to healthy diet and habitual physical activity, normalization of liver enzymes, and stable surrogate markers of fibrosis.

Pharmacotherapy of type 2 diabetes in patients with chronic liver disease: focus on nonalcoholic fatty liver disease

ABSTRACT Introduction: Pharmacotherapy used to treat type 2 diabetes mellitus (T2DM) is facing a paradigm shift in clinical practice with recent cardiovascular (CV) outcome trials having a substantial impact on drug prescription with treatment having a more tailored approach. In patients with T2DM, the issue of chronic liver disease is multifaceted. However, a clinical evidence is emerging on the beneficial effect of antidiabetic medications on nonalcoholic fatty liver disease (NAFLD). Areas covered: The authors provide a synopsis on the current and upcoming pharmacotherapy for NAFLD, including the challenges with their development, focusing on drugs for T2DM. Clinical data on the potential benefits and safety issues are assessed with the aim of proposing an individualized algorithm for patient management. Both MEDLINE and ClinicalTrials.Gov are used to derive the relevant information. Expert opinion: Considering the pivotal role of insulin resistance in NAFLD, insulin sensitizers should be the treatment of choice. Accordingly, pioglitazone is the only drug with a significant effect on liver fibrosis, the driver of disease progression and long-term outcome. Among new glucose-lowering drugs, glucagon-like-peptide 1 receptor agonists or sodium-glucose cotransporter type 2 inhibitors have shown positive effects in phase II studies and are qualifying as potential candidates for NAFLD treatment in diabetes.

Trend over time in hepatic fibrosis score in a cohort of type 2 diabetes patients.

AIMS The prevalence and progression of hepatic fibrosis and its correlated factors in type 2 diabetes (T2DM) are poorly known. We aimed to define the percentage of T2DM patients who progress to fibrosis and the factors associated with disease progression. METHODS Data from the electronic health records of 1527 patients with diagnosed T2DM and nonalcoholic fatty liver disease (NAFLD), as diagnosed by the Fatty Liver Index, were extracted from the AMD Annals database, which collects data from the Italian network of diabetes clinics. For the main analysis, we evaluated variables associated with Fibrosis 4 [FIB-4] score at baseline and at 3-year follow-up to determine their role in predicting FIB-4 at 3 years and the risk of hepatic fibrosis in T2DM. RESULTS High-risk of advanced fibrosis was detected in 13.1% of patients at baseline and in 18.1% at 3 years, LDL cholesterol, and body-mass index, correlated negatively with baseline FIB-4 scores, whereas gamma glutamil transerasi correlated positively . The FIB-4 score at 3 years was associated with lower values of baseline renal function, LDL, and BMI; however, the baseline FIB-4 score was the strongest predictor for the FIB-4 score at 3 years. CONCLUSIONS The prevalence of and progression to hepatic fibrosis within 3 years in patients with T2DM is not negligible. Patients with a higher likelihood of liver scarring differ from those with hepatic steatosis. Differently from NAFLD, the FIB-4 score is inversely correlated with insulin resistance and appears to increase independent of classic metabolic factors.

Insulin resistance: mechanism and implications for carcinogenesis and hepatocellular carcinoma in NASH

IntroductionThe effects of insulin resistance in human diseases are of paramount importance. Since the original proposal by the WHO indicating insulin resistance as the common substrate of the metabolic syndrome, large data are now available on its significance in cardiovascular diseases, nonalcoholic fatty liver disease and cancer risk.Materials and methodsWe reviewed the evidence linking hyperinsulinemia to insulin resistance and ultimately to increased cancer risk. Insulin resistance, by reducing substrate flux along the PI3-K pathway, is followed by compensatory hyperinsulinemia, considered a potential stimulus for cancerogenesis along the MAP-K pathway. Adaptive mechanisms of fat storage, promoted by insulin resistance, chronically maintained in an obesiogenic environment, may lead to oxidative stress and inflammation and modify the immune responses, further increasing the carcinogenic potential. The increased cancer risk associated with obesity, type 2 diabetes and nonalcoholic fatty liver may thus be fueled by hyperinsulinemia. Insulin secretagogs and insulin treatment, by raising circulating insulin levels, further increase cancer risk, whereas insulin sensitizers are associated with decreased cancer risk (all sites) and specifically decrease hepatocellular carcinoma. Likewise, drugs related to the incretin system, which are weight neutral or even reduce whole-body and hepatic fat, improve insulin sensitivity and potentially reduce the cancer risk.ConclusionNew diabetes treatments might thus help decrease the future burden of diabetes-associated cancer and particularly of hepatocellular carcinoma.