Fettleberdiagnostik bei Diabetes mellitus Typ 2

Definition of terms

Under the term non-alcoholic fatty liver disease (NAFLD) both simple hepatic fat accumulation and non-alcoholic steatohepatitis (NASH) are combined. NASH is associated with liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC).

Epidemiological importance

In 2020, NAFLD will be the leading cause for liver transplantation in the USA, with rising financial costs for the healthcare system.

Comorbidities, diagnosis, and treatment

Type 2 diabetes (T2D) and metabolic syndrome (MetS) are important risk factors for the development of NAFLD, whereby these three diseases share similar pathophysiologic conditions, e.g., insulin resistance, obesity, and metabolic inflammation. Due to the rising number of patients with T2D and MetS, clinicians should aim to diagnose NAFLD early in this patient population and if necessary start treatment.

Goal

The aim of this work is to give an overview over the topic of NAFLD and diagnostic approaches in patients with T2D.

     

Nichtalkoholische Steatohepatitis und ihre Folgen

Background

The prevalence of nonalcoholic fatty liver disease (NAFLD) continues to increase. An estimated 25?% of the adult population worldwide and more than 50?% of patients with type 2 diabetes or obesity have NAFLD.

Objectives

An overview of the natural history and complications of NAFLD is provided.

Materials and methods

Following an extensive literature research, the current guidelines, expert opinions and studies focusing on NAFLD were analyzed.

Results

The term NAFLD includes the entities nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH), which are defined by histological parameters. Importantly, “benign” NAFL may progress towards more aggressive NASH with the development of liver fibrosis. The grade of fibrosis is the most important predictor for overall and liver-related mortality in NAFLD patients and patients suffering from type 2 diabetes mellitus have a higher risk for progressive fibrosis. Progressive NAFLD can develop into liver cirrhosis with the potential of fatal complications of portal hypertension and liver failure. Notably, hepatocellular carcinoma may also develop in noncirrhotic NAFLD. Furthermore, NAFLD is an independent risk factor for cardiovascular disease and extrahepatic malignancy, which represent the two most frequent causes of death in NAFLD patients. To date, a lifestyle intervention aiming at weight reduction and increased physical activity is the first-line therapy for NAFLD.

Conclusions

NAFLD is one of the most common liver diseases and is associated with relevant hepatic and extrahepatic morbidity and mortality.

     

Diabetestherapie bei nichtalkoholischer Fettlebererkrankung

Background

Nonalcoholic fatty liver disease (NAFLD) is defined by hepatocellular fat accumulation of more than 5?% (fatty liver, NAFL, steatosis) and also comprises steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma. No specific drug treatment for NAFLD in type 2 diabetes mellitus (T2D) is approved.

Methods

In a Medline search, randomized controlled trials on weight- and/or blood glucose-lowering therapies in NAFLD and T2D with the primary endpoints reduction of liver fat content and/or improvement in liver histology were identified.

Results

Lifestyle modification (weight loss of >7?%) and bariatric surgery reduce inflammation and hepatocellular ballooning in NASH. Pioglitazone therapy can improve inflammation and ballooning in prediabetes or T2D within 6 months. This effect remains for at least 3 years. Liraglutide results in reduction of liver fat content and improvement of inflammation and ballooning in NASH, with fewer liraglutide-treated individuals showing an aggravation of fibrosis. Metformin, sulfonylureas and insulin have no clinically relevant effect on liver fat content and liver histology.

Conclusions

Beyond lifestyle modification, the benefit of pioglitazone, liraglutide and bariatric surgery for reduction of liver fat content and NASH must be balanced against the risks and costs. Further specific therapeutic recommendations will require studies on novel drugs and longer-term controlled prospective trials.

     

The Impact of Metabolic Syndrome on the Outcome of NASH: Cirrhosis,Hepatocellular Carcinoma,and Mortality

Purpose of Review

In this review, we examine the interaction between the metabolic syndrome (MS) and non-alcoholic fatty liver disease (NAFLD) and describe the impact of the features of MS on the most worrisome complications of non-alcoholic steatohepatitis (NASH), (cirrhosis, hepatocellular carcinoma) and, ultimately, on liver-related, cardiovascular, and overall mortality.

Recent Findings

Insulin resistance, obesity, and dyslipidemia in a pro-inflammatory environment have a causal role in hepatic fibrogenesis and oncogenesis in NAFLD patients. Natural history, longitudinal studies confirm the conditions linked to MS as independent predictors of overall-, cardiovascular-, and liver-related mortality.

Summary

Dysmetabolic factors stemming from insulin resistance play a key role in liver damage progression. Obesity, type 2 diabetes (T2DM), dyslipidemia, and arterial hypertension are independent predictors of liver fibrosis and cirrhosis; furthermore, obesity and T2DM play a key role in the development of hepatocellular carcinoma both in cirrhotic and non-cirrhotic NASH patients.

     

Association of single nucleotide polymorphism at PNPLA3 with fatty liver,steatohepatitis, and cirrhosis of liver

Background/Purpose

The aim of this study was to determine the association of single nucleotide polymorphism (SNP) in patatin-like phospholipase domain-containing 3 (PNPLA3) at I148 with histological severity of non-alcoholic fatty liver disease (NAFLD).

Methods

Patients were selected for the study if they had histological evidence of NAFLD and clinical evidence of non-alcoholic steatohepatits (NASH) cirrhosis. We included 50 NASH cirrhosis, 99 patients of NAFLD including 36 non-NASH fatty liver (NNFL) along with 63 NASH and 75 healthy controls. PNPLA3 genotyping was done by real-time PCR using a Taqman assay for rs738409.

Results

CC, CG, and GG frequencies were 45 (60.0%)/27 (36.0%)/3 (4.0%) in healthy control, 19 (52.8%)/14 (38.9%)/ 3 (8.3%) in NNFL, 18 (28.6%)/29 (46.0%)/16 (25.4%) in NASH, and 7 (14.6%), 25 (52.1%), 16 (33.3%) in cirrhosis. The frequency of G allele was significantly higher (62.6%) in NAFLD than in healthy control. The GG genotype had 20.25 times odds of NAFLD. The GG genotype had 6.53 times odds of having NASH. HOMA-IR > 1.6 had 3.81 times odds of having NASH. Regression analysis revealed that G allele odds of having cirrhosis was 3.9 times compared to C. The G allele was also significantly associated with steatosis, lobular inflammation, NAFLD activity score, and fibrosis.

Conclusion

PNPLA3 genotype showed an association with NAFLD, NASH, fibrosis, and cirrhosis.

     

Treatment of NASH with Gastric Bypass

Purpose of Review

Nonalcoholic steatohepatitis (NASH) is a spectrum of nonalcoholic fatty liver disease (NAFLD). It is defined as the presence of fatty liver along with inflammation and hepatocyte injury. To date, weight loss achieved via lifestyle intervention remains the mainstay of NASH treatment. However, given the known benefit of weight loss on NASH and the known effect of bariatric surgery on weight loss, several studies have explored the potential role of bariatric surgery on the treatment of NASH.

Recent Findings

This review article summarizes the evidence on the effect of Roux-en-Y gastric bypass (RYGB), a common bariatric surgery, on NASH therapy. Specifically, studies show that RYGB is associated with an improvement of all NASH histologic features at 1 year.

Summary

Compared to adjustable gastric band, RYGB appears to be superior at treating NASH. Randomized controlled trials and long-term studies are underway to better clarify the role of these procedures specifically for NASH therapy.

     

The Stomach as an Endocrine Organ: Expression of Key Modulatory Genes and Their Contribution to Obesity and Non-alcoholic Fatty Liver Disease (NAFLD)

Purpose of Review

Obesity is currently seen in epidemic proportions globally and is one of the largest contributors to the development of NAFLD. The spectrum of NAFLD, particularly the progressive forms of NASH, is likely to become the leading cause of liver disease in the next decade.

Recent Findings

Soluble molecules, encoded by the stomach tissue, have been shown to have pleiotropic effects in both central and peripheral systems involved in energy homeostasis and obesity regulation. As such, the stomach is one of the important players in the complex, multi-system deregulation leading to obesity and NAFLD.

Summary

The understanding of the stomach tissue as an active endocrine organ that contributes to the signaling milieu leading to the development of obesity and NAFLD is crucial.

     

Impact of circulating miR-122 for histological features and hepatocellular carcinoma of nonalcoholic fatty liver disease in Japan

Background and aim

Relationships between circulating microRNA-122 (miR-122) and histological features of nonalcoholic fatty liver disease (NAFLD) are unclear.

Methods

The impact of serum miR-122 levels for histological features and hepatocellular carcinoma (HCC) was investigated in 305 Japanese patients with histological proven NAFLD. Twenty-three patients were with HCC at the time of diagnosis of NAFLD, and four patients developed HCC during the follow-up. The cross-sectional or longitudinal evaluations were performed to investigate the impact for HCC.

Results

Serum miR-122 levels (calibrated relative to the median levels of patients) partly affected severity of steatosis, ballooning, lobular inflammation, and stage. Multivariate analysis identified HCC and/or histological components of NASH as morphological factors that independently influenced serum miR-122 levels at the diagnosis of NAFLD. There was a strong correlation between serum miR-122 levels and AST, ALT levels. In cross-sectional evaluation, serum miR-122 levels of patients without HCC were significantly higher than those with HCC in patients of stage 3 but not stage 4. In longitudinal evaluation of one patient with follow-up time of 25 years, from the diagnosis of NAFLD until HCC, serum miR-122 levels had already tended to decrease before the progression of fibrosis stage.

Conclusions

HCC and/or histological components of NASH affected serum miR-122 levels, independently. In longitudinal evaluation of HCC patients, serum miR-122 levels had already tended to decrease before the progression of fibrosis stage. Further prospective studies are needed to investigate the impact of serum miR-122 for histological features and hepatocarcinogenesis of NAFLD.

     

Surgical Issues in NASH: Bariatric Surgery and Liver Transplantation

Purpose of Review

The rising prevalence of obesity in general and non-alcoholic steatohepatitis (NASH) specifically as an indication for liver transplantation has occurred in parallel with an increase in the consideration and performance of bariatric surgery before and after liver transplantation. We review the impact and relative merits of bariatric surgery before, during, and after liver transplantation.

Recent Findings

The sleeve gastrectomy approach has several practical advantages over other forms of weight loss surgery and has been shown to improve metabolic parameters. Bariatric surgical procedures inevitably affect immunosuppression pharmacokinetics, with the least impact being observed following sleeve gastrectomy. In the non-transplant setting, bariatric surgery has been shown to be an effective therapy for histological features of NASH.

Summary

When compared to lifestyle changes alone, bariatric surgery performed during or after liver transplantation results in sustained weight loss and improved metabolic parameters associated with liver disease, cardiovascular risk, and overall mortality. Further studies are needed to confirm which surgical procedures, timing, and NASH patients will receive most benefit.

     

Update on Pediatric Fatty Liver Disease

Purpose of Review

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the USA, affecting over 7 million children. In this article, we provide an update on pediatric NAFLD by briefly reviewing the recent publications in diagnosis, screening, therapy, and follow-up.

Recent Findings

NAFLD remains a diagnosis of exclusion and liver biopsy is the most accurate test to assess severity of the disease in children. There is a growing collection of studies testing noninvasive tests for hepatic steatosis and fibrosis, several of which have become available in more recent years, such as fibrosis scores, imaging and serum biomarkers. The mainstay of NAFLD treatment remains weight loss through dietary modifications and exercise. There is substantial interest in pharmacological therapies for NAFLD given the frequent failure of lifestyle and behavior modification to resolve the disease. Certain medications of interest target mechanisms involved in the pathogenesis of NAFLD such as insulin resistance, oxidative stress, and dyslipidemia.

Summary

Research within the field of NAFLD has advanced substantially, yet critical gaps remain including lack of accurate noninvasive tests for NAFLD, effective prevention, and treatment.

     

The Role of Radiologic Modalities in Diagnosing Nonalcoholic Steatohepatitis (NASH) and Fibrosis

Purpose of Review

The dramatic increase in nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) fostered the development and evaluation of non-invasive, imaging based methods for diagnosing NAFLD, NASH, and its complications. We herein review different radiologic modalities in diagnosing steatosis, fibrosis, and liver cirrhosis.

Recent Findings

While routine abdominal ultrasound with hyperechogenic liver structure only detects moderate to severe steatosis, controlled attenuation parameter (CAP), magnetic resonance spectroscopy (MRS), and, especially, MRI-proton density fat fraction (MRI-PDFF) are more sensitive to diagnose and quantify steatosis. MRI-PDFF appears suitable to monitor treatment-related changes in liver fat in clinical trials. Liver fibrosis is related to hepatic and extrahepatic morbidity and mortality in NAFLD. Fibrosis and cirrhosis can be suspected by ultrasound-based elastography techniques (vibration-controlled transient elastography, VCTE; acoustic resonance forced impulse imaging, ARFI; shear wave elastography, SWE), which may be used to screen for fibrosis in high-risk patients. MR elastography (MRE) appears advantageous to quantify and stage fibrosis, while angiographic hepatic venous pressure gradient (HVPG) measurement can confirm portal hypertension in cirrhosis. Screening for hepatocellular carcinoma (HCC) in cirrhotic livers is done by ultrasound; suspicious nodules are followed by multiphasic CT/MRI, contrast-enhanced ultrasound (CEUS), or contrast-enhanced MRI.

Summary

Different radiologic modalities exist to screen, diagnose, stage, and monitor steatosis, steatohepatitis, fibrosis, and HCC, thereby complementing liver biopsy and blood biomarkers in the management of patients with NAFLD.

     

The Gut Microbiome as a Target for the Treatment of Type 2 Diabetes

Purpose of Review

The objective of this review is to critically assess the contributing role of the gut microbiota in human obesity and type 2 diabetes (T2D).

Recent Findings

Experiments in animal and human studies have produced growing evidence for the causality of the gut microbiome in developing obesity and T2D. The introduction of high-throughput sequencing technologies has provided novel insight into the interpersonal differences in microbiome composition and function.

Summary

The intestinal microbiota is known to be associated with metabolic syndrome and related comorbidities. Associated diseases including obesity, T2D, and fatty liver disease (NAFLD/NASH) all seem to be linked to altered microbial composition; however, causality has not been proven yet. Elucidating the potential causal and personalized role of the human gut microbiota in obesity and T2D is highly prioritized.

     

Effect of metformin treatment on circulating osteoprotegerin in patients with nonalcoholic fatty liver disease

Purpose/introduction

Growing evidence suggests complex interplay between nonalcoholic fatty liver disease (NAFLD) and bone health. The present study’s aim was to examine the impact of metformin treatment on circulating osteoprotegerin (OPG) in patients with NAFLD, a population in which this relationship has not yet been studied.

Methods

In a randomized, placebo-controlled study, 63 patients with NAFLD were assigned to one of two groups: Group 1 received daily metformin; Group 2 received a placebo. Metabolic parameters, insulin resistance markers and OPG levels were examined at baseline and at the end of the study.

Results

In the placebo group, liver function and OPG levels did not change during the study. Among metformin-treated patients, significant declines in OPG and alkaline phosphatase were observed. CRP and ALT decreased marginally during the 4-month treatment period. While at baseline circulating OPG levels did not differ significantly between the groups, by the end of the study OPG was significantly lower in patients treated with metformin than in the placebo group (p < 0.0001). Delta OPG was significantly greater in the metformin group than the placebo group (p = 0.001). In the general linear model, metformin treatment was the only significant independent predictor of endpoint and delta OPG.

Conclusions

Metformin treatment was associated with a significant decrease in OPG levels in patients with NAFLD. The effect on OPG was associated with exposure to metformin per se.

Clinical trial registration number

NCT01084486.

     

Relationship between obstructive sleep apnea and nonalcoholic fatty liver disease in nonobese adults

Purpose

Obstructive sleep apnea (OSA) is closely related to nonalcoholic fatty liver disease (NAFLD), though the mechanism is not conclusive as obesity is a confounder. The objective of this observational study was to investigate the correlation between these disorders in nonobese subjects.

Methods

We consecutively enrolled nonobese individuals undergoing polysomnography and abdominal ultrasonography and analyzed differences in NAFLD patients grouped by the apnea–hypopnea index (AHI) and in OSA patients according to the presence or absence of NAFLD. Multivariate regression analysis was used to evaluate the independent risks of NAFLD in OSA patients.

Results

A total of 175 participants were included. The 106 ultrasound-diagnosed NAFLD patients were classified into four groups by AHI. There were no significant differences in triglycerides (TG), serum aminotransferase levels of alanine aminotransferase and aspartate aminotransferase, high-sensitivity C-reactive protein, and homeostasis model assessment of insulin resistance (HOMA-IR) with worsening OSA. In both OSA patients with NAFLD and those without NAFLD, body mass index (BMI), the lowest oxygen saturation (LaSO₂), HOMA-IR, and TG were significantly associated. Additionally, BMI, LaSO₂, and TG independently predicted the development of NAFLD after adjustments (odds ratio [OR]?=?1.562, p?=?0.003; OR?=?0.960, p?=?0.03; OR?=?3.410, p?<?0.001, respectively).

Conclusions

In nonobese subjects, OSA itself does not appear to induce significant changes in liver enzymes. With reference to lipid metabolism, weight control and OSA-related hypoxemia are key factors in reducing the risk of NAFLD in OSA patients. Additional large-scale, prospective studies are warranted to investigate the impact of OSA on liver injury in nonobese adults.

     

Identifying Nonalcoholic Fatty Liver Disease Advanced Fibrosis in the Veterans Health Administration

Background

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. Severe NAFLD with advanced fibrosis results in substantial morbidity and mortality. Associated with metabolic syndrome, NAFLD is often initially clinically silent, yet intensive lifestyle intervention with 7% or greater weight loss can improve or resolve NAFLD. Using a Veterans Health Administration (VHA) liver biopsy cohort, we evaluated simple noninvasive fibrosis scoring systems to identify NAFLD with advanced fibrosis (or severe disease) to assist providers.

Methods

In our retrospective study of a national VHA sample of patients with biopsy-proven NAFLD or normal liver (2005–2015), we segregated patients by fibrosis stage (0–4). Non-NAFLD liver disease was excluded. We evaluated the diagnostic accuracy of the NAFLD fibrosis score (NFS), fibrosis-4 calculator (FIB-4), aspartate aminotransferase-to-alanine aminotransferase ratio (AST/ALT ratio), AST-to-platelet ratio index (APRI), and body mass index, AST/ALT ratio, and diabetes (BARD) score by age groups.

Results

We included 329 patients with well-defined liver histology (296 NAFLD and 33 normal controls without fibrosis), in which 92 (28%) had advanced (stage 3–4) fibrosis. Across all age groups, NFS and FIB-4 best predicted advanced fibrosis (NFS with 0.676 threshold: AUROC 0.71–0.76, LR?+?2.30–22.05, OR 6.00–39.58; FIB-4 with 2.67 threshold: AUROC of 0.62–0.80, LR?+?4.70–27.45, OR 16.34–59.65).

Conclusions

While NFS and FIB-4 scores exhibit good diagnostic accuracy, FIB-4 is optimal in identifying NAFLD advanced fibrosis in the VHA. Easily implemented as a point-of-care clinical test, FIB-4 can be useful in directing patients that are most likely to have advanced fibrosis to GI/hepatology consultation and follow-up.

     

Risk factors for non-alcoholic fatty liver disease are common in patients with non-B non-C hepatocellular carcinoma in India

Aim of the study

The aim of the study was to analyze the prevalence of risk factors for non-alcoholic fatty liver disease (NAFLD) in patients with non-B non-C hepatocellular carcinoma (HCC).

Methods

Between June 2012 and November 2014, patients with HCC, negative for hepatitis B surface antigen and hepatitis C virus antibody, were included in this study. All patients were assessed for risk factors for NAFLD such as diabetes mellitus (DM), hypertension, dyslipidemia, metabolic syndrome, and obesity.

Results

Forty-seven patients with non-B non-C HCC (males, 37; age, 60±10 years; mean±SD) were studied. Model for end-stage liver disease score was 11±4. Twenty-five patients were in Child’s class A. History of significant alcohol intake was noted in 11 (23%) patients. Prevalence of risk factors for NAFLD were obesity 24 (51%), DM 22 (47%), metabolic syndrome 21 (45%), hypertension 16 (34%), and dyslipidemia 13 (28%). Forty (85%) patients had at least one risk factor for NAFLD. The mean duration of at least one NAFLD risk factor was 7.5 years, prior to diagnosis of HCC. Thirteen (28%) patients were positive for anti-HBc; however, none of the study patients had detectable HBV DNA in blood.

Conclusions

Eighty-five percent of the patients with non-B non-C HCC had at least one risk factor for NAFLD. None of the study patients had occult hepatitis B infection. NAFLD is emerging as the major etiological contributing factor for non-B non-C HCC in India.

     

EASL–EASD–EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease in severely obese people: do they lead to over-referral?

Aims/hypothesis

We aimed to assess the application of the recent 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) clinical practice guidelines for the management of non-alcoholic fatty liver disease (NAFLD) in severely obese individuals in routine clinical practice.

Methods

We performed a single-centre retrospective observational study of 385 patients referred for severe obesity (BMI ≥ 35 kg/m²) to our Endocrinology, Diabetes and Nutrition department, between 1 November 2014 and 31 December 2015. The recent EASL–EASD–EASO clinical practice guidelines for the management of NAFLD were retrospectively applied to the cohort using, successively, the NAFLD fibrosis score (NFS) and a combination of the NFS and transient elastography (TE) measurement in a subgroup of individuals.

Results

We identified 313 (81.3%) individuals with NAFLD in the cohort. The application of the EASL–EASD–EASO guidelines using NFS would lead to referral to a specialist for up to 289 individuals (75.1%) in the cohort. The combination of NFS and TE measurement reclassified 28 (25%) individuals from the medium/high risk group to low risk and would lead to the referral of 261 (67.7%) individuals to a specialist. These proportions appear to be excessive given the expected prevalence of advanced fibrosis and non-alcoholic steatohepatitis (NASH) of around 10% and 30%, respectively, in the severely obese population.

Conclusions/interpretation

This is the first study to assess the strategy proposed by the EASL–EASD–EASO clinical practice guidelines for the management of NAFLD in severely obese individuals. The retrospective application of the guidelines in a cohort representing the routine clinical practice in our department would lead to an excessive number of specialist referrals and would also lead to an unjustified increase in health costs. Biomarkers and specific strategy for the screening of NASH and advanced fibrosis in morbidly obese individuals are thus crucially needed and would help to improve the actual guidelines.

     

Prevalence of and risk factors for fatty liver in the general population of Northern Italy: the Bagnacavallo Study

Background

The estimation of the burden of disease attributable to fatty liver requires studies performed in the general population.

Methods

The Bagnacavallo Study was performed between October 2005 and March 2009. All the citizens of Bagnacavallo (Ravenna, Italy) aged 30 to 60?years as of January 2005 were eligible. Altered liver enzymes were defined as alanine transaminase >?40?U/l and/or aspartate transaminase >?37?U/l.

Results

Four thousand and thirty-three (58%) out of 6920 eligible citizens agreed to participate and 3933 (98%) had complete data. 393 (10%) of the latter had altered liver enzymes and 3540 had not. After exclusion of subjects with HBV or HCV infection, liver ultrasonography was available for 93% of subjects with altered liber enzymes and 52% of those with normal liver enzymes. The prevalence of fatty liver, non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD) was 0.74 (95%CI 0.70 to 0.79) vs. 0.35 (0.33 to 0.37), 0.46 (0.41 to 0.51) vs. 0.22 (0.21 to 0.24) and 0.28 (0.24 to 0.33) vs. 0.13 (0.11 to 0.14) in citizens with than in those without altered liver enzymes. Ethanol intake was not associated and all the components of the metabolic syndrome (MS) were associated with fatty liver. All potential risk factors were associated with a lower odds of normal liver vs. NAFLD while they were unable to discriminate AFLD from NAFLD.

Conclusions

Fatty liver as a whole was highly prevalent in Bagnacavallo in 2005/9 and was more common among citizens with altered liver enzymes.

     

Pathogenesis of NASH: the Impact of Multiple Pathways

Purpose of review

Advancing our understanding of the mechanisms that underlie NASH pathogenesis.

Recent findings

Recent findings on NASH pathogenesis have expanded our understanding of its complexity including (1) there are multiple parallel hits that lead to NASH; (2) the microbiota play an important role in pathogenesis, with bacterial species recently shown to accurately differentiate between NAFL and NASH patients; (3) the main drivers of liver cell injury are lipotoxicity caused by free fatty acids (FFAs) and their derivatives combined with mitochondrial dysfunction; (4) decreased endoplasmic reticulum (ER) efficiency with increased demand for protein synthesis/folding/repair results in ER stress, protracted unfolded protein response, and apoptosis; (5) upregulated proteins involved in multiple pathways including JNK, CHOP, PERK, BH3-only proteins, and caspases result in mitochondrial dysfunction and apoptosis; and (6) subtypes of NASH in which these pathophysiological pathways vary may require patient subtype identification to choose effective therapy.

Summary

Recent pathogenesis studies may lead to important therapeutic advances, already seen in patients treated with ACC, ASK1 and SCD1 inhibitors, and FXR agonists. Further, advancing our understanding of mechanisms underlying NASH pathogenesis and the complex interplay between them will be crucial for developing effective therapies.