Non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH): diagnosis and clinical course

Non-alcoholic fatty liver disease (NAFLD) is a frequent syndrome encompassing fatty liver alone and steatohepatitis (NASH). Often asymptomatic, the suspicion arises because of abnormal aminotransferases or a bright liver on abdominal ultrasound. It should be suspected during evaluation of associated conditions as obesity, diabetes or dyslipidaemia. The diagnostic evaluation must exclude other potential causes of liver disease and may include a liver biopsy, the only method able to confirm features of necroinflammation and fibrosis that define NASH and its prognostic implications. Indeed, the presence of necroinflammation has been associated with a significant risk of progression to cirrhosis and eventually hepatocellular carcinoma. Age >45 years, obesity and diabetes have also been associated with an increased risk of liver fibrosis and progression to cirrhosis. Given the high prevalence of NAFLD, general measures of life-style changes, focusing on exercise, diet, and total alcohol abstinence, should be implemented before a liver biopsy is considered.     

Features, diagnosis, and treatment of nonalcoholic fatty liver disease

As the global incidence of obesity has increased, nonalcoholic fatty liver disease (NAFLD) has become a worldwide health concern. NAFLD occurs in children and adults of all ethnicities and includes isolated fatty liver and nonalcoholic steatohepatitis (NASH). Patients with NASH are at risk for developing cirrhosis, hepatic decompensation, and hepatocellular carcinoma and have increased all-cause mortality. NAFLD is associated with a variety of clinical conditions and is an independent risk factor for hepatocellular carcinoma. The pathogenesis of NAFLD and the specific steps that lead to NASH and advanced fibrosis are not fully understood, although researchers have found that a combination of environmental, genetic, and metabolic factors lead to advanced disease. There have been improvements in noninvasive radiographic methods to diagnose NAFLD, especially for advanced disease. However, liver biopsy is still the standard method of diagnosis for NASH. There are many challenges to treating patients with NASH, and no therapies have been approved by the U.S. Food and Drug Administration; multimodal approaches are being developed and becoming the standard of care. We review pathogenesis and treatment approaches for the West's largest liver-related public health concern.     

Liver fibrosis markers of nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) is one of the major causes of chronic liver injury. NAFLD includes a wide range of clinical conditions from simple steatosis to nonalcoholic steatohepatitis (NASH), advanced fibrosis, and liver cirrhosis. The histological findings of NASH indicate hepatic steatosis and inflammation with characteristic hepatocyte injury (e.g., ballooning degeneration), as is observed in the patients with alcoholic liver disease. NASH is considered to be a potentially health-threatening disease that can progress to cirrhosis. A liver biopsy remains the most reliable diagnostic method to appropriately diagnose NASH, evaluate the severity of liver fibrosis, and determine the prognosis and optimal treatment. However, this invasive technique is associated with several limitations in routine use, and a number of biomarkers have been developed in order to predict the degree of liver fibrosis. In the present article, we review the current status of noninvasive biomarkers available to estimate liver fibrosis in the patients with NASH. We also discuss our recent findings on the use of the glycated albumin-to-glycated hemoglobin ratio, which is a new index that correlates to various chronic liver diseases, including NASH.     

Pediatric nonalcoholic fatty liver disease: overview with emphasis on histology

Nonalcoholic fatty liver disease(NAFLD) is a disease in which excessive fat accumulates in the liver of a patient without a history of alcohol abuse.This disease includes simple steatosis and nonalcoholic steatohepatitis(NASH).NAFLD/NASH is recognized as a hepatic manifestation of metabolic syndrome.In recent years,pediatric NAFLD has increased in line with the increased prevalence of pediatric obesity.The estimated prevalence of pediatric NAFLD is 2.6%-9.6%,and it is associated with sex,age,and ethnicity.W...     

Is there a role of lipid-lowering therapies in the management of fatty liver disease?

Atherogenic dyslipidemia is characterized by increased triglyceride-rich lipoproteins and low high-density lipoprotein cholesterol concentrations. It is highly prevalent in non-alcoholic fatty liver disease (NAFLD) and contributes to the increased cardiovascular risk associated with this condition. Alongside insulin resistance it plays an important pathogenetic role in NAFLD/non-alcoholic steatohepatitis (NASH) development and progression. It has been shown that cholesterol-lowering reduces cardiovascular risk more in NAFLD vs non-NAFLD high-risk individuals. This evidence highlights the importance of effective lipid modulation in NAFLD. In this narrative review the effects of the most commonly used lipid-lowering therapies on liver outcomes alongside their therapeutic implications in NAFLD/NASH are critically discussed. Preclinical and clinical evidence suggests that statins reduce hepatic steatosis, inflammation and fibrosis in patients with NAFLD/NASH. Most data are derived from observational and small prospective clinical studies using changes in liver enzyme activities, steatosis/fibrosis scores, and imaging evidence of steatosis as surrogates. Also, relevant histologic benefits were noted in small biopsy studies. Atorvastatin and rosuvastatin showed greater benefits, whereas data for other statins are scarce and sometimes conflicting. Similar studies to those of statins showed efficacy of ezetimibe against hepatic steatosis. However, no significant anti-inflammatory and anti-fibrotic actions of ezetimibe have been shown. Preclinical studies showed that fibrates through peroxisome proliferator-activated receptor (PPAR)α activation may have a role in NAFLD prevention and management. Nevertheless, no relevant benefits have been noted in human studies. Species-related differences in PPARα expression and its activation responsiveness may help explain this discrepancy. Omega-3 fatty acids reduced hepatic steatosis in numerous heterogeneous studies, but their benefits on hepatic inflammation and fibrosis have not been established. Promising preliminary data for the highly purified eicosapentaenoic acid require further confirmation. Observational studies suggest that proprotein convertase subtilisin/kexin9 inhibitors may also have a role in the management of NAFLD, though this needs to be established by future prospective studies.     

Non‐alcoholic fatty liver disease from pathogenesis to management: an update

Non‐alcoholic fatty liver disease (NAFLD), the most common chronic liver disease in the Western world, is tightly associated with obesity and metabolic syndrome. NAFLD entails an increased cardiometabolic and liver‐related risk, the latter regarding almost exclusively non‐alcoholic steatohepatitis (NASH), the progressive form of NAFLD. Pathogenetic models encompass altered hepatic lipid partitioning and adipokine action, increased oxidative stress, free fatty acid lipotoxicity. On this basis, lifestyle‐, drug‐ or surgically induced weight loss, insulin sensitizers, antioxidants, lipid‐lowering drugs have been evaluated in NAFLD/NASH. Most trials are small, of short duration, nonrandomized, without histological end points, thus limiting assessment of long‐term safety and efficacy of proposed treatments. All NAFLD patients should be evaluated for their metabolic, cardiovascular and liver‐related risk. Liver biopsy remains the gold standard for staging NAFLD, but non‐invasive methods are under intense development. Weight loss through lifestyle intervention is the initial approach, because of established efficacy on NAFLD‐associated cardiometabolic abnormalities, and to emerging benefits on necroinflammation and overall disease activity in NASH. Bariatric surgery warrants further evaluation before it can be routinely considered in morbidly obese NASH. Larger‐ and longer‐duration randomized trials assessing safety and benefits of drugs on patient‐oriented outcomes are needed before pharmacological treatment can be routinely recommended for NASH.     

Dietary approach in the treatment of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD) has been identified as one of the most prevalent chronic liver disease in adults and children populations. NAFLD is usually associated with the metabolic syndrome(MS), which is chiefly related to insulin resistance and its consequences. Insulin resistance has a crucial role in the pathogenesis of hepatic steatosis and potentially nonalcoholic steatohepatitis(NASH). Because of the contemporary epidemics of MS and obesity, the burden of NAFLD is also expected to rise. Unhealthy diets, such as the so-called western diet, are enriched in fructose, trans-fatty acids and saturated fat and seem to be associated with the development of NAFLD. In human studies, certain dietary sugars, particularly fructose, are used as a substrate for lipogenesis leading to hepatic fatty infiltration, inflammation, and possibly fibrosis. Other investigations have shown that fat consumption especially cholesterol and trans/saturated fatty acids are also steatogenic and seem to increase visceral adiposity. The identification of specific dietary components that favor the development of NASH could be important for the management of this disorder. This review focuses on the effects of different dietary approaches to prevent and treat NAFLD emphasizing the macronutrients and energy composition.     

The use of current knowledge and non-invasive testing modalities for predicting at-risk non-alcoholic steatohepatitis and assessing fibrosis

There is ongoing recognition of the burden of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), with fibrosis being the most important histological feature that is associated with progression to cirrhosis and the occurrence of major adverse liver outcomes. Liver biopsy is the gold standard applied to detect NASH and determine the stage of fibrosis, but its use is limited. There is a need for non-invasive testing (NIT) techniques to identify patients considered at-risk NASH (NASH with NAFLD activity score > 4 and ≥ F2 fibrosis). For NAFLD-associated fibrosis, several wet (serological) and dry (imaging) NITs are available and demonstrate a high negative predictive value (NPV) for excluding those with advanced hepatic fibrosis. However, identifying at-risk NASH is more challenging; there is little guidance on how to use available NITs for these purposes, and these NITs are not specifically designed to identify at-risk NASH patients. This review discusses the need for NITs in NAFLD and NASH and provides data to support the use of NITs, focusing on newer methods to non-invasively identify at-risk NASH patients. This review concludes with an algorithm that serves as an example of how NITs can be integrated into care pathways of patients with suspected NAFLD and potential NASH. This algorithm can be used for staging, risk stratification and the effective transition of patients who may benefit from specialty care.     

Abdominal ultrasound for diagnosis of nonalcoholic fatty liver disease (NAFLD)

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease. The progressive subtype of NAFLD or nonalcoholic steatohepatitits (NASH), may progress to cirrhosis and its complications. Unfortunately, accurate noninvasive modalities for diagnosing NASH and monitoring its progression are unavailable, necessitating a liver biopsy. Abdominal ultrasound (US) is widely used for screening asymptomatic patients with an incidental elevation of liver enzymes. However, US cannot detect small amounts of hepatic steatosis and cannot establish the diagnosis of NASH or stage of hepatic fibrosis. In this issue of AJG, a new radiologic scoring system has been reported to have excellent performance in diagnosing NAFLD and visceral obesity. However, the utility of this scoring system in establishing the diagnosis of NASH and hepatic fibrosis, has not been shown. Additionally, validity of this scoring system to other populations (i.e. obese) and in the setting of private practice must be proven. In summary, this study provides some valuable data regarding the utility of radiologic modalities in detecting hepatic steatosis and abdominal fat but still falls short in answering some important diagnostic and prognostic questions in NAFLD. The evolving field of diagnostic imaging for NAFLD holds promise. A combination of serum biomarkers and radiologic modalities may one day provide the best diagnostic approach for patients with NAFLD, and potentially replace the necessity for liver biopsy in most patients.     

Adiponectin, a key adipokine in obesity related liver diseases

Non-alcoholic fatty liver disease (NAFLD) comprising hepatic steatosis,non-alcoholic steatohepatitis (NASH),and progressive liver fibrosis is considered the most common liver disease in western countries.Fatty liver is more prevalent in overweight than normal-weight people and liver fat positively correlates with hepatic insulin resistance.Hepatic steatosis is regarded as a benign stage of NAFLD but may progress to NASH in a subgroup of patients.Besides liver biopsy no diagnostic tools to identify patients ...     

Histopathology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD), a hepatic manifestation of metabolic syndrome, is the most common chronic liver disease, and the prevalence is rapidly increasing worldwide. Nonalcoholic steatohepatitis (NASH), the severe form of NAFLD, can progress to liver cirrhosis and hepatocellular carcinoma (HCC). Although noninvasive clinical scores and image-based diagnosis for NAFLD have improved, histopathological evaluation of biopsy specimens remains the gold standard for diagnosing NAFLD/NASH. Steatosis, lobular inflammation, and hepatocellular ballooning are all necessary components for the diagnosis of NASH; fibrosis is also typically observed. Other histopathological abnormalities commonly observed in NASH include hepatocellular glycogenated nuclei, lipogranulomas, and acidophil bodies. The characteristics of pediatric NAFLD/NASH differ from adult NAFLD/NASH. Specifically, steatosis and portal inflammation are more severe in pediatric NAFLD, while intralobular inflammation and perisinusoidal fibrosis are milder. Although interobserver agreement for evaluating the extent of steatosis and fibrosis is high, agreement is low for intralobular and portal inflammation. A recently reported histological variant of HCC, steatohepatitic HCC (SH-HCC), shows features that resemble non-neoplastic steatohepatitis, and is thought to be strongly associated with underlying NASH. In this report, we review the histopathological features of NAFLD/NASH.     

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

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 typeⅣcollagen 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.     

The clinical aspects of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) has been increasingly recognized as the most common pathological conditions affecting the liver. In concert with the increase in Body Mass Index in developed countries that has occurred during the last decades, more and more individuals referred for evaluation of abnormal liver tests are found to have NAFLD. In most cases, the increase in fat within the liver is not associated with impaired liver structure or function in the long-term. However, liver steatosis should be considered to be a marker of the metabolic syndrome. A minority of patients with NAFLD develop liver cirrhosis but NAFLD is probably the most common underlying cause of cryptogenic cirrhosis. Patients with NAFLD have an increased cardiovascular mortality as well as increase in liver related complications compared with matched controls. The diagnostic evaluation of a patient with suspected NAFLD depends heavily on the setting. In whom and when a liver biopsy is indicated is controversial. An adequate history is of major importance and when alcohol is suspected to be a contributing factor to the liver steatosis, several biochemical and clinical parameters may differentiate alcoholic fatty liver and NAFLD. Unfortunately, no histological gold standard is available for non-alcoholic steatohepatitis (NASH) and there is still a significant diversity among pathologist concerning the minimal requirements for the term NASH. Management of patients with NAFLD should be aimed at fighting the metabolic risk factors such as visceral obesity, hyperglycemia, type II diabetes mellitus (DM) and hypertriglyceridemia. DM has been shown to be a predictor of worsening of fibrosis. Successful lifestyle modification with increased exercise and decreased food intake is able to remove the accumulation of liver fat and can reverse insulin resistance. Unfortunately, there are no well-controlled, randomized trials of weight control as therapy for NAFLD. Some pharmacological pilot trials have been undertaken in NAFLD, but no proved treatment for all patients with NAFLD and/or NASH is available at the current time.     

Current pharmacological therapies for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease(NAFLD)/nonalcoholic steatohepatitis(NASH) is considered to be a hepatic manifestation of metabolic syndrome, and its incidence is rapidly increasing worldwide. It is currently the most common chronic liver disease. NASH can progress to liver cirrhosis and hepatocellular carcinoma, and may result in liver-related death. Currently, the principal treatment for NAFLD/NASH is lifestyle modification by diet and exercise. However, pharmacological therapy is indispensable because obese patients with NAFLD often have difficulty maintaining improved lifestyles. The pathogenesis of NAFLD/NASH has not been completely elucidated. However, insulin resistance, inflammatory cytokines, and oxidative stress are thought to be important in the development and/or progression of the disease. Currently, insulin sensitizers(thiazolidinediones) and antioxidants(vitamin E) seem to be the most promising therapeutic agents for NAFLD/NASH, and lipid-lowering drugs, pentoxifylline, angiotensin receptor blockers, and n-3 polyunsaturated fatty acids also have promise. However, there is a lack of consensus regarding the most effective and appropriate pharmacotherapy for NAFLD/NASH. Animal experiments suggest that herbal medicines and natural products may be promising therapeutic agents for NAFLD/NASH, but their efficacy and safety are yet to be investigated in human studies. In this paper, we review the existing and potential pharmacological therapies for NAFLD/NASH.     

Nonalcoholic Fatty Liver Disease: A Review and Update

The spectrum of nonalcoholic fatty liver disease (NAFLD) ranges from asymptomatic steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Hepatic steatosis occurs when free fatty acids, released in the setting of insulin resistance and the metabolic syndrome, are taken up by the liver. Additional biochemical insults, including oxidative stress, upregulation of inflammatory mediators, and dysregulated apoptosis, can result in inflammation (producing NASH) and fibrosis. Noninvasive methods (e.g., abdominal ultrasonography) are safe ways to support a diagnosis of hepatic steatosis, but advanced liver histopathologic findings including NASH and fibrosis cannot be identified without pursuing liver biopsy. Recent advances in serologic and imaging methods aim to determine severity of inflammation and fibrosis noninvasively. Currently, therapeutic options for NAFLD are limited to medications that reduce risk factors, but the future holds promise for therapies that might slow the progression of this increasingly prevalent disorder.     

Noninvasive Markers of Fibrosis and Inflammation in Nonalcoholic Fatty Liver Disease

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. Nonalcoholic steatohepatitis (NASH) and fibrosis are associated with elevated morbidity and mortality, and a means of differentiating these diseases from simple steatosis (SS) is needed. Liver biopsy in all patients with NAFLD is not feasible, thus necessitating a noninvasive method for discerning the presence of inflammation and fibrosis. Of the various serum markers, cytokeratin-18 seems to best predict NASH, the NAFLD Fibrosis Score is most closely correlated with fibrosis, and transient elastography can be used for diagnosis of cirrhosis, or to exclude cirrhosis, although its utility is limited by obesity.     

Can Nash Be Diagnosed,Graded, and Staged Noninvasively?

Nonalcoholic bland steatosis and nonalcoholic steatohepatitis (NASH) are stages in the spectrum of nonalcoholic fatty liver disease (NAFLD). NASH may progress to end-stage liver disease. Liver biopsy distinguishes between patients with NASH and no NASH and can stage fibrosis. Markers of hepatocyte apoptosis hold promise as noninvasive tests for NASH diagnosis. Several scoring systems that combine routine clinical and laboratory variables and some proprietary panels can assist in predicting fibrosis severity. Noninvasive imaging modalities are reasonably accurate available tools to determine severity of fibrosis in NAFLD, but none of them yet can replace liver biopsy.     

Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis 2020

Nonalcoholic fatty liver disease (NAFLD) has become a serious public health issue not only in Western countries but also in Japan. Within the wide spectrum of NAFLD, nonalcoholic steatohepatitis (NASH) is a progressive form of disease that often develops into liver cirrhosis and increases the risk of hepatocellular carcinoma (HCC). While a definite diagnosis of NASH requires liver biopsy to confirm the presence of hepatocyte ballooning, hepatic fibrosis is the most important prognostic factor in NAFLD. With so many NAFLD patients, it is essential to have an effective screening method for NAFLD with hepatic fibrosis. As HCC with non-viral liver disease has increased markedly in Japan, effective screening and surveillance of HCC are also urgently needed. The most common death etiology in NAFLD patients is cardiovascular disease event. Gastroenterologists must, therefore, pay close attention to CVD when examining NAFLD patients. In the updated guidelines, we propose screening and follow-up methods for hepatic fibrosis, HCC, and CVD in NAFLD patients. Several drug trials are ongoing for NAFLD/NASH therapy, however, there is currently no specific drug therapy for NAFLD/NASH. In addition to vitamin E and thiazolidinedione derivatives, recent trials have focused on sodium glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) analogues, and effective therapies are expected to be developed. These practical guidelines for NAFLD/NASH were established by the Japanese Society of Gastroenterology in conjunction with the Japan Society of Hepatology. Clinical evidence reported internationally between 1983 and October 2018 was collected, and each clinical and background question was evaluated using the Grades of Recommendation Assessment, Development and Evaluation (GRADE) system. This English summary pro- vides the core essentials of these clinical practice guidelines, which include the definition and concept, screening systems for hepatic fibrosis, HCC and CVD, and current therapies for NAFLD/NASH in Japan.     

Serum ferritin is a discriminant marker for both fibrosis and inflammation in histologically proven non‐alcoholic fatty liver disease patients

Introduction: Differentiation between steatosis and non‐alcoholic steatohepatitis (NASH) in non‐alcoholic fatty liver disease (NAFLD) is important as NASH progress to cirrhosis. No specific laboratory/imaging technique exists either to diagnose NASH or to select patients for liver biopsy. Patients and methods: We evaluated serum ferritin and the features of metabolic syndrome with respect to histological inflammation and/or fibrosis in NAFLD patients. The Kleiner scoring system was used to classify NAFLD in consecutive liver biopsies. One hundred and eleven patients: median age 52.6, 64 males, obesity 62, diabetes mellitus (DM) 58, arterial hypertension 26 and hyperlipidaemia 40%. Results: Histologically, 40.7 had fatty liver, 30.6% had borderline NASH, 28.7% had NASH and 11% had cirrhosis. Multivariate regression showed that diabetes, serum ferritin concentrations, body mass index (BMI) and AST were independently associated with NASH: together, the areas under the receiver operating characteristic (AUROC) was 0.91 (95% confidence interval 0.86–0.96); fibrosis was associated with ferritin concentrations and BMI: AUROC 0.87, portal inflammation with ferritin and DM: AUROC 0.82, while lobular inflammation was associated with BMI, DM and ferritin: AUROC 0.85. Conclusion: Serum ferritin concentrations and BMI are strongly associated with fibrosis, portal and lobular inflammation in NAFLD patients. Both ferritin and BMI are potential discriminant markers to select patients for liver biopsy and are associated with inflammation and fibrosis.     

Non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world. It is closely associated with metabolic syndrome. The alarming epidemics of diabetes and obesity have fueled an increasing prevalence of NAFLD, particularly among these high-risk groups. Histologically, NAFLD encompasses a disease spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), which is characterized by hepatocyte injury, inflammation, and variable degrees of fibrosis on liver biopsy. Non-alcoholic steatohepatitis can progress to cirrhosis in a fraction of patients. There is currently little understanding of risk factors for disease progression and the disease pathogenesis has not been fully defined. Liver biopsy remains the gold standard for diagnosis. Weight loss, dietary modification, and the treatment of underlying metabolic syndrome remain the mainstays of therapy once the diagnosis is established. There are no well-established pharmacological agents for treatment of NASH, although this is a subject of ongoing research.