https://www.journal-of-hepatology.eu/article/S0168-8278(14)00933-7/pdf

NAFLD: A multisystem disease

Gut microbiota dysbiosis has been repeatedly observed in obesity and type 2 diabetes mellitus, two metabolic diseases strongly intertwined with non-alcoholic fatty liver disease (NAFLD). Animal studies have demonstrated a potential causal role of gut microbiota in NAFLD. Human studies have started to describe microbiota alterations in NAFLD and have found a few consistent microbiome signatures discriminating healthy individuals from those with NAFLD, non-alcoholic steatohepatitis or cirrhosis. However, patients with NAFLD often present with obesity and/or insulin resistance and type 2 diabetes mellitus, and these metabolic confounding factors for dysbiosis have not always been considered. Patients with different NAFLD severity stages often present with heterogeneous lesions and variable demographic characteristics (including age, sex and ethnicity), which are known to affect the gut microbiome and have been overlooked in most studies. Finally, multiple gut microbiome sequencing tools and NAFLD diagnostic methods have been used across studies that could account for discrepant microbiome signatures. This Review provides a broad insight into microbiome signatures for human NAFLD and explores issues with disentangling these signatures from underlying metabolic disorders. More advanced metagenomics and multi-omics studies using system biology approaches are needed to improve microbiome biomarkers.

/pdf/gut-microbiota-and-human-nafld-disentangling-microbial-2b62qctp4x.pdf

Gut microbiota and human NAFLD: disentangling microbial signatures from metabolic disorders

https://www.gastrojournal.org/article/S0016-5085(14)00981-0/pdf

Pathological features of fatty liver disease.

Sarcopenia is associated with significant liver fibrosis independently of obesity and insulin resistance in nonalcoholic fatty liver disease: Nationwide surveys (KNHANES 2008-2011)

The prevalence of non-alcoholic fatty liver disease (NAFLD) has been increasing rapidly. It is nowadays recognized as the most frequent liver disease, affecting a quarter of global population and regularly coexisting with metabolic disorders such as type 2 diabetes, hypertension, obesity, and cardiovascular disease. In a more simplistic view, NAFLD could be defined as an increase in liver fat content, in the absence of secondary cause of steatosis. In fact, the clinical onset of the disease is a much more complex process, closely related to insulin resistance, limited expandability and dysfunctionality of adipose tissue. A fatty liver is a main driver for a new recognized liver-pancreatic α-cell axis and increased glucagon, contributing to diabetes pathophysiology. This review will focus on the clinical and pathophysiological connections between NAFLD, insulin resistance and type 2 diabetes. We reviewed non-invasive methods and several scoring systems for estimative of steatosis and fibrosis, proposing a multistep process for NAFLD evaluation. We will also discuss treatment options with a more comprehensive view, focusing on the current available therapies for obesity and/or type 2 diabetes that impact each stage of NAFLD. The proper understanding of NAFLD spectrum—as a continuum from obesity to metabolic syndrome and diabetes—may contribute to the early identification and for establishment of targeted treatment.

/pdf/nafld-as-a-continuum-from-obesity-to-metabolic-syndrome-and-3oq68ehohi.pdf

NAFLD as a continuum: from obesity to metabolic syndrome and diabetes

It is estimated that 30% of the adult population in Japan is affected by nonalcoholic fatty liver disease (NAFLD). Fatty changes of the liver are generally diagnosed using imaging methods such as abdominal ultrasonography (US) and computed tomography (CT), but the sensitivity of these imaging techniques is low in cases of mild steatosis. Alanine aminotransferase levels may be normal in some of these patients, warranting the necessity to establish a set of parameters useful for detecting NAFLD, and the more severe form of the disease, nonalcoholic steatohepatitis (NASH). Although liver biopsy is currently the gold standard for diagnosing progressive NASH, it has many drawbacks, such as sampling error, cost, and risk of complications. Furthermore, it is not realistic to perform liver biopsies on all NAFLD patients. Diagnosis of NASH using various biomarkers, scoring systems and imaging methods, such as elastography, has recently been attempted. The NAFIC score, calculated from the levels of ferritin, fasting insulin, and type IV collagen 7S, is useful for the diagnosis of NASH, while the NAFLD fibrosis score and the FIB-4 index are useful for excluding NASH in cases of advanced fibrosis. This article reviews the limitations and merits of liver biopsy and noninvasive diagnostic tests in the diagnosis of NAFLD/NASH.

Limitations of liver biopsy and non-invasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.

The prevalence of obesity or metabolic syndrome is increasing worldwide (“Globally metabodemic”). Approximately 25% of adult general population is suffering from nonalcoholic fatty liver disease (NAFLD) which has become serious health problem. Hepatic fibrosis is the most significant determinant of all cause and liver -related mortality in NAFLD. Noninvasive test (NIT) should be urgently required to evaluate hepatic fibrosis in NAFLD. Fibrosis-4 (FIB-4) index is the 1st triaging tool for excluding advanced fibrosis because of its accuracy, simplicity, and cheapness especially for general physicians or endocrinologists, although FIB-4 index has several drawbacks. Accumulating evidence has suggested that vibration controlled transient elastography (VCTE) and the enhanced liver fibrosis (ELF) test may become useful as the 2nd step after triaging by FIB-4 index. The leading cause of mortality in NAFLD is cardiovascular disease (CVD), extrahepatic malignancy, and liver-related diseases. NAFLD often complicates chronic kidney disease (CKD), resulting in increased simultaneous liver kidney transplantation (SLKT). FIB-4 index could be a predictor of not only liver-related mortality and incident hepatocullar carcinoma (HCC) but also prevalent and incident CKD, CVD, and extrahepatic malignancy. Although NITs as milestones for evaluating treatment efficacy have never been established, FIB- 4 index is expected to reflect histological hepatic fibrosis after treatment in several longitudinal studies. We here review the role of FIB-4 index as 1st step NIT in management of NAFLD.

https://www.preprints.org/manuscript/202008.0417/v1/download

FIB-4 First in Diagnostic Algorithm of MAFLD at the Era of “Global Metabodemic “

The prognosis of chronic liver disease depends on the progression of liver fibrosis. Liver biopsy is recommended as the gold standard method for determining fibrosis stage, prognosis and therapeutic indications in patients with chronic liver disease. However, liver biopsy is an invasive procedure associated with a risk of potentially serious complications. Approximately 1–3% of patients require hospitalization for complications, and a quarter of them report pain after percutaneous liver biopsy. The diagnostic accuracy of liver biopsy for assessing liver fibrosis is influenced by the quality of the biopsy samples. In addition, there are several absolute or relative contraindications to liver biopsy, including severe coagulopathy. A safe and non-invasive alternative to liver biopsy is therefore needed for assessing liver fibrosis in daily clinical practice.

/pdf/acoustic-radiation-force-impulse-elastography-a-non-invasive-i5arqc0sso.pdf

Acoustic Radiation Force Impulse Elastography: A Non-Invasive Alternative to Liver Biopsy

The invention relates to a medicament for preventing and/or treating fatty liver which comprises as an active ingredient cilostazol or a pharmaceutically acceptable salt thereof

Carbostyril derivatives including cilostazol for treating fatty liver

© Digestive Medicine Research. All rights reserved. Dig Med Res 2020 | http://dx.doi.org/10.21037/dmr-20-15 Nonalcoholic fatty liver disease (NAFLD) has become one of the most frequent causes of chronic liver disease in the past 2 decades. Almost 25% of the adult population presently suffers from NAFLD worldwide (1,2). Especially, patients with nonalcoholic steatohepatitis (NASH), which is a more severe type of NAFLD, can progress to liver cirrhosis over time and associated with a high risk of hepatic failure and hepatocellular carcinoma (HCC). As mentioned previously, NALFD/NASH is rapidly becoming the foremost cause of liver-related morbidity (e.g., end-stage liver disease, HCC, and liver transplantation) as well as cardiovascular disease (1,3). Improvement of lifestyle, such as low-calorie diet and exercise (aerobic and resistance), are currently the firstline therapy for NAFLD/NASH, but can be difficult to succeed and continue good condition, emphasizing the urgent issue for pharmacotherapy. Nevertheless, no established pharmacological therapies and no Federal Drug Administration (FDA)-approved drugs or European Medicines Agency (EMA)-approved drugs are available for the treatment of NASH despite numerous clinical trials to date. Ursodeoxycholic acid (UDCA), a secondary bile acid, has historically been one of the most generalpurpose therapies for chronic hepatitis, however it has no histological benefit over a placebo in NAFLD/NASH patients (4). Therefore, UDCA is not recommended as a therapeutic medication for NAFLD/NASH (5). In recent years, several innovative medicines have been developed in the drug pipeline for the treatment of NAFLD/NASH. Among them, obeticholic acid, a selective farnesoid X receptor (FXR) agonist, have entered phase 3 trials for NASH treatment and are thought to have potential for the treatment of NASH (6). To overcome this background and these limitations, the medical need for an effective pharmacological treatment for NAFLD/NASH must be met. In their report on this issue, Traussnigg et al. showed a dose-dependent reduction in serum ALT in patients treated with norursodeoxycholic acid (norUDCA), a synthetic side chain-shortened C23 homologue of UDCA (7), versus a placebo in a phase 2, multicenter, double-blind, clinical trial (8). Although it is also well known that the serum ALT values may not always be well-correlated with the severity of liver disease (9), they also demonstrated a decrease in the hepatic fat fraction as measured using MRI or MRS in a group of receiving 1,500 mg of norUDCA, even if the number of patients in whom MRI/MRS was performed was too small to allow a definitive conclusion. NorUDCA is known not to activate FXR, but was reported to be relatively resistant to conjugation reaction with glycine or taurine, compared with UDCA. Furthermore, norUDCA goes through cholehepatic shunting, causing ductular targeting, bicarbonate-rich hypercholeresis, and cholangiocyte protection (10). NAFLD with Advanced fibrosis is associated with an increased all-cause mortality and liver-related mortality (11,12), and several trials evaluating anti-fibrotic agents Editorial Commentary

Atsushi Nakajima

Papers

Limitations of liver biopsy and non-invasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.

FIB-4 First in Diagnostic Algorithm of MAFLD at the Era of “Global Metabodemic “

Acoustic Radiation Force Impulse Elastography: A Non-Invasive Alternative to Liver Biopsy

Carbostyril derivatives including cilostazol for treating fatty liver

Norursodeoxycholic acid as a candidate pharmacological therapy for nonalcoholic fatty liver disease