FDG PET/CT of the non‐malignant liver in an increasingly obese world population

Because of obesity, non‐alcoholic fatty liver disease (NAFLD) is becoming increasingly important. 10% of NAFLD patients develop non‐alcoholic steatohepatitis (NASH), which may progress to cirrhosis and is now the leading indication for liver transplantation in the Western world. Prefibrotic NASH can only be reliably diagnosed by biopsy. However, given its success in other inflammatory diseases, PET/CT with ¹⁸F‐fluorodeoxyglucose (FDG), although non‐specific, may offer a promising approach to diagnosing not only NASH but also other inflammatory liver conditions. In addition, FDG PET has generated pathophysiological information on hepatic glucose metabolism and, diagnostically, used liver for quantification of tumour FDG accumulation (e.g. Deauville scoring). A review of hepatic FDG PET is therefore timely. There are two general approaches to the quantification of hepatic FDG accumulation: firstly, standard uptake value (SUV) and secondly dynamic PET. SUV is a poor index of hepatic metabolic function because most hepatic FDG (~75%) is un‐phosphorylated 60‐min postinjection. Hepatic fat is increased in NAFLD but accumulates negligible FDG. Because fat distribution is heterogeneous, maximum pixel SUV is therefore preferred to mean pixel SUV. Computer modelling of dynamic PET dissects the transport constants governing hepatic FDG kinetics but is challenged by the liver's dual blood supply. Graphical analysis is less informative but more robust and will be the preferred clinical approach to measurement of hepatic FDG phosphorylation. Previous dynamic PET studies have ignored hepatic fat and therefore potentially underestimated glucose accumulation in patients with hepatic steatosis. Future work should use graphical analysis of dynamic PET and correction for hepatic fat.     

Chronic liver disease and arteriosclerosis

The liver is the main metabolic organ of the body and is strongly associated with lifestyle-related diseases in which abnormal metabolism of glucose and lipid are the main manifestations. Recently, the prevalence of nonalcoholic fatty liver disease(NAFLD), including nonalcoholic steatohepatitis (NASH), has been increasing due to a higher rates of obesity. It has been reported that the presence of NAFLD/NASH and associated liver dysfunction are predictors for cardiovascular disease. In addition, attention has been paid to the link between chronic hepatitis C and lifestyle-related diseases such as obesity and insulin resistance. Atherosclerosis is an important risk factor for cardiovascular disease and is associated with lifestyle-related diseases. Thus, chronic liver disease seems to be strongly associated with atherosclerosis. Cardiovascular disease induced by atherosclerosis should be attended to along with liver cirrhosis and hepatocellular carcinoma, and medications for lifestyle-related diseases are needed in patients with chronic liver disease.     

Attenuation of fatty accumulation in hepatocyte by incretin--expectation of novel medicine for treatment of NASH

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) have been recognized as a metabolic disorder characterized by fatty accumulation of the liver without alcohol consumption. The progression of the diseases has been considered to link to metabolic syndrome, consisting of obesity, diabetes mellitus(DM), dyslipidemia and hypertension. Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide(GIP) function as incretin and stimulate glucose-mediated insulin production by pancreatic beta cells. Incretin was also reported to have various kinds of extrapancreatic effects including the regulation of hepatic glucose production, the inhibition of pancreatic exocrine secretion, cardioprotective and cardiotropic effects, the regulation of appetite and satiety, and stimulation of afferent sensory nerves. Therefore, incretins are also expected as therapeutic agents for NFLD and NASH.     

Pediatric nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease related to excessive accumulation of hepatic fat, and represents a spectrum of liver disease ranging from fat accumulation alone (steatosis) to the more significant histologic finding of steatohepatitis. Nonalcoholic steatohepatitis is a progressive liver disease associated with increased risk of liver cirrhosis and cancer. NAFLD is becoming increasingly prevalent in the pediatric population in direct correlation with the emergence of childhood obesity as a significant pediatric health problem. The exact pathophysiology of NAFLD remains unclear, although the interplay of insulin resistance, oxidative stress, and release of proinflammatory cytokines are implicated in the process. The diagnostic workup and treatment for NAFLD and nonalcoholic steatohepatitis remains controversial. This review discusses current concepts regarding the natural history, pathophysiology, and management of pediatric patients with NAFLD.     

Treatment of NASH: nutritional counseling and physical exercise

Nonalcoholic fatty liver disease(NAFLD) is recognized as a cause of potentially progressive liver damage. NAFLD is often associated with metabolic syndrome that comprises central obesity, insulin resistance, and hyperlipidemia. Among these, severer forms with histopathological features of increasing ballooned hepatocytes and fibrosis are defined as nonalcoholic steatohepatitis (NASH). The natural history of NASH is only partly known, the disease is slowly progressive and therapeutic outcomes are difficult to define. Since central obesity and insulin resistance are most likely involved in the pathogenesis, justification of life style including physical exercise and nutritional counseling is essential for the treatment of NASH.     

Nonalcoholic Fatty Liver Disease: Review of Management for Primary Care Providers

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease in the United States and worldwide. The progressive form of NAFLD, nonalcoholic steatohepatitis (NASH), is a leading indication for liver transplant. Comorbidities associated with NAFLD development and NASH include type 2 diabetes, obesity, metabolic syndrome, and dyslipidemia. Extrahepatic morbidity and mortality are considerable as NAFLD is associated with an increased risk of cardiovascular disease and chronic kidney disease. Once NAFLD is diagnosed, the presence of liver fibrosis is the central determinant of hepatic prognosis. Severe liver fibrosis requires aggressive clinical management. No pharmacologic agents have regulatory approval in the United States for the treatment of NAFLD or NASH. Management is centered on efforts to reduce underlying obesity (lifestyle, medications, surgical or endoscopic interventions) and metabolic derangements (prediabetes, type 2 diabetes, hypertension, hyperlipidemia, and others). Current pharmacologic therapy for NAFLD is limited mainly to the use of vitamin E and pioglitazone, although other agents are being investigated in clinical trials. Cardiovascular and metabolic risk factors must also be assessed and managed. Here, NAFLD evaluation, diagnosis, and management are considered in the primary care setting and endocrinology clinics.     

Acute,Withdrawal, and Chronic Alcohol Effects in Man: Event-Related Potential and Quantitative EEG Techniques

The association of metabolic disorders with liver disease is receiving increasing attention in the gastroenterological community. Cohort studies have shown that advanced liver disease may stem from metabolic disorders, via fatty liver, non‐alcoholic steatohepatitis, cryptogenic cirrhosis, and eventually hepatocellular carcinoma. In both obesity and diabetes, deaths from cirrhosis are higher than expected, mainly in subjects with no or moderate alcohol consumption, but high rates of fatty liver disease have been associated with all features of the metabolic syndrome. Also the risk of hepatocellular carcinoma is higher than normal, being dependent on body mass index (BMI) in obesity, and independent of age, BMI, gender and race in diabetes. Finally, metabolic liver disease may interact with hepatitis C virus infection, increasing the risk of steatosis and liver disease progression, as well as reducing the chances of an effective antiviral treatment. There is evidence that treatments aimed at reducing insulin resistance are also effective in improving liver histology. Although cardiovascular disease remains the major cause of increased morbidity and excess mortality in metabolic disorders, the risk of progressive liver disease should no longer be underestimated, being a threat to millions of people at risk in the present epidemics of obesity and diabetes, and therapeutic strategies need to be tested.     

Nonalcoholic steatohepatitis: recent advances from experimental models to clinical management

A condition defined as nonalcoholic fatty liver disease (NAFLD) is frequently found in humans. Deemed as a benign condition until recently, more emphasis is now put on the potential harmful evolution of the inflammatory form, that is, nonalcoholic steatohepatitis (NASH), toward end-stage liver disease. This review highlights the major morphologic and pathophysiological features of NASH. The link between experimental biochemical findings in animal models and clinical and therapeutic approaches in humans is discussed. Once all the other causes of persistent elevation of serum transaminase levels have been excluded, the diagnosis of NASH can be only confirmed by liver histology. Other noninvasive diagnostic tools, however, are being investigated to assess specific subcellular functions and to allow the follow-up of patients at higher risk for major liver dysfunction. A better understanding of various pathogenic aspects of NASH will help in identifying potential therapeutic approaches in these patients.     

Iron homeostasis in the Metabolic Syndrome

The metabolic syndrome (MetS) affects iron homeostasis in a many‐faceted fashion. On the one side, hyperferritinaemia with normal or mildly elevated transferrin saturation is observed in approximately one‐third of patients with non‐alcoholic fatty liver disease (NAFLD) or the MetS. This constellation has been named the ‘dysmetabolic iron overload syndrome (DIOS)’. Current evidence suggests that elevated body iron stores exert a detrimental effect on the clinical course of obesity‐related conditions and that iron removal improves insulin sensitivity and delays the onset of T2DM. On the other side, iron deficiency is a frequent finding in more progressed stages of obesity. The mechanisms underlying the DIOS and obesity‐related iron deficiency appear strikingly similar as elevated hepcidin concentrations, low expression of duodenal ferroportin (FPN) and impaired iron absorption are found in both conditions. This review summarizes the current knowledge about the dysregulation of iron homeostasis in the MetS and particularly in its hepatic manifestation NAFLD.     

Nonalcoholic fatty liver disease as a complication of insulin resistance

Nonalcoholic fatty liver disease (NAFLD) refers to a spectrum of liver damage ranging from simple steatosis to nonalcoholic steatohepatitis, advanced fibrosis, and rarely, progression to cirrhosis. The pathogenesis of NAFLD is thought to be related to insulin resistance and oxidant stress. Truncal obesity, dyslipidema, hypertension, and hyperglycemia are strongly associated with NAFLD; therefore, management of NAFLD entails identification and treatment of metabolic risk factors, improving insulin sensitivity, and increasing antioxidant defenses in the liver. This article briefly summarizes advances in our understanding of the relationship between NAFLD and the insulin resistance (metabolic) syndrome, its prevalence, natural history, and treatment.     

Insulin sensitizers in nonalcoholic fatty liver disease and steatohepatitis: Current status

Nonalcoholic fatty liver disease (NAFLD), first described in 1980, is now recognized as one of the most common causes of elevated liver enzymes and chronic liver disease in Western countries. The incidence of NAFLD in both adults and children is rising, in conjunction with the burgeoning epidemics of obesity and type 2 diabetes mellitus. NAFLD often coexists with other sequelae of the metabolic syndrome: central obesity, type 2 diabetes, hypertension, and hyperlipidemia. NAFLD encompasses a spectrum of pathologic liver diseases ranging from simple hepatic steatosis to a predominant lobular necro-inflammation, with or without centrilobular fibrosis (called nonalcoholic steatohepatitis or NASH). NASH can progress to cirrhosis, decompensated liver disease, and hepatocellular carcinoma. Though the natural history of NASH is still not clearly defined, it has been observed to progress to cirrhosis in 15%–220% of those affected. Insulin resistance is nearly universal in NASH and is thought to play an important role in its pathogenesis leading to dysregulated lipid metabolism. The prevalence of insulin resistance is reported in the general population to be approaching 45%, suggesting that NAFLD and NASH will contin nue to be an important public health concern. To date, NASH has proven to be a difficult disease to treat. Front-line therapy with lifestyle modifications resulting in weight loss through decreased caloric intake and moderate exercise is generally believed to be beneficial in patients with NASH, but is often difficult to maintain long term. Given that insulin resistance plays a dominant role in the pathogenesis, many studies have examined the use of insulin sensitizers: the biguanides (metformin), thiazolidinediones (pioglitazone, troglitazone, and rosiglitazone), glucagon-like peptide-1-receptor agonists, or incretins (exenatide)in NASH. This review will provide an overview of insulin resistance in NAFLD and provide a detailed summary on the clinical data regarding the use of insulin sensitizers in NASH.     

Targeting hepatic kisspeptin receptor ameliorates nonalcoholic fatty liver disease in a mouse model

Nonalcoholic fatty liver disease (NAFLD), the most common liver disease, has become a silent worldwide pandemic. The incidence of NAFLD correlates with the rise in obesity, type 2 diabetes, and metabolic syndrome. A hallmark featureof NAFLD is excessive hepatic fat accumulation or steatosis, due to dysregulated hepatic fat metabolism, which can progress to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Currently, there are no approved pharmacotherapies to treat this disease. Here, we have found that activation of the kisspeptin 1 receptor (KISS1R) signaling pathway has therapeutic effects in NAFLD. Using high-fat diet–fed mice, we demonstrated that a deletion of hepatic Kiss1r exacerbated hepatic steatosis. In contrast, enhanced stimulation of KISS1R protected against steatosis in wild-type C57BL/6J mice and decreased fibrosis using a diet-induced mouse model of NASH. Mechanistically, we found that hepatic KISS1R signaling activates the master energy regulator, AMPK, to thereby decrease lipogenesis and progression to NASH. In patients with NAFLD and in high-fat diet–fed mice, hepatic KISS1/KISS1R expression and plasma kisspeptin levels were elevated, suggesting a compensatory mechanism to reduce triglyceride synthesis. These findings establish KISS1R as a therapeutic target to treat NASH.     

Therapy for Nonalcoholic Fatty Liver Disease: Current Options and Future Directions

PurposeNonalcoholic fatty liver disease (NAFLD) is a highly prevalent chronic liver disease that is driven by the metabolic syndrome. NAFLD encompasses nonalcoholic fatty liver, >5% fat in the liver without inflammation of fibrosis, nonalcoholic steatohepatitis (NASH), fat plus varying degrees of inflammation and fibrosis, and cirrhosis of the liver from NASH. As facets of the metabolic syndrome, particularly diabetes and obesity, become more common worldwide, the incidence of new NAFLD is increasing.MethodsA qualitative systematic review was performed via searches of PubMed and ClinicalTrials.gov for therapeutic interventions for NAFLD.FindingsCurrent therapies rely on metabolic syndrome risk factor control and lifestyle changes to achieve weight loss. Because sustained weight loss is difficult for many patients, there is a critical unmet need for pharmacotherapy to treat NAFLD, especially the progressive form, NASH, to prevent cirrhosis of the liver. New therapies for NAFLD focus on the subset of patients with NASH and some degree of fibrosis. Novel mechanisms of action, including farnesoid X nuclear receptor agonism, C–C motif chemokine receptor 2 and receptor 5 antagonism, stearoyl-CoA desaturase-1, and thyroid hormone receptor β agonism, are currently under investigation as monotherapy. The products also hold potential for use in combination with and without insulin sensitizers and other established drugs in the future.ImplicationsThis review of NASH treatments details the interventions that are currently available as well as those in late-stage clinical trials that may represent the future of NASH therapy.     

Current and Emerging Biomarkers and Imaging Modalities for Nonalcoholic Fatty Liver Disease: Clinical and Research Applications

PurposeNonalcoholic fatty liver disease (NAFLD) is a metabolic disorder that frequently coexists with obesity, metabolic syndrome, and type 2 diabetes. The NAFLD spectrum, ranging from hepatic steatosis to nonalcoholic steatohepatitis, fibrosis, and cirrhosis, can be associated with long-term hepatic (hepatic decompensation and hepatocellular carcinoma) and extrahepatic complications. Diagnosis of NAFLD requires detection of liver steatosis with exclusion of other causes of chronic liver disease. Screening for NAFLD and identification of individuals at risk of end-stage liver disease represent substantial challenges that have yet to be met. NAFLD affects up to 25% of adults, yet only a small proportion will progress beyond steatosis to develop advanced disease (steatohepatitis and fibrosis) associated with increased morbidity and mortality. Identification of this cohort has required the gold standard liver biopsy, which is both invasive and expensive. The use of serum biomarkers and noninvasive imaging techniques is an area of significant clinical relevance. This narrative review outlines current and emerging technologies for the diagnosis of NAFLD, nonalcoholic steatohepatitis, and hepatic fibrosis.MethodsWe reviewed the literature using PubMed and reviewed national and international guidelines and conference proceedings to provide a comprehensive overview of the evidence.FindingsSignificant advances have been made during the past 2 decades that have enhanced noninvasive assessment of NAFLD without the need for liver biopsy. For the detection of steatosis, abdominal ultrasonography remains the first-line investigation, although a controlled attenuation parameter using transient elastography is more sensitive. For detecting fibrosis, noninvasive serum markers of fibrosis and algorithms based on routine biochemistry are available, in addition to transient elastography. These techniques are well validated and have been incorporated into national and international screening guidelines. These approaches have facilitated more judicious use of liver biopsy but are yet to entirely replace it. Although serum biomarkers present a pragmatic and widely available screening approach for NAFLD in large population-based studies, magnetic resonance imaging techniques offer the benefit of achieving high degrees of accuracy in disease grading, tumor staging, and assessing therapeutic response.ImplicationsThis diagnostic clinical and research field is rapidly evolving; increasingly combined applications of biomarkers and transient elastography or imaging of selective (intermediate or high risk) cases are being used for clinical and research purposes. Liver biopsy remains the gold standard investigation, particularly in the context of clinical trials, but noninvasive options are emerging, using multimodality assessment, that are quicker, more tolerable, more widely available and have greater patient acceptability.     

Nonalcoholic Fatty liver disease.

Nonalcoholic fatty liver disease is a condition gaining increasing recognition as a cause of cirrhosis and end-stage liver disease. The condition appears identical to alcoholic liver disease histologically, yet occurs in patients with negligible alcohol intake. Nonalcoholic fatty liver disease covers a spectrum of diseases ranging from simple fatty deposition in the liver to fat and inflammation and finally to fibrosis and cirrhosis. Conditions most frequently found in association with nonalcoholic fatty liver disease include obesity, Type 2 diabetes, and hyperlipidemia. Although the exact etiology of nonalcoholic fatty liver disease is not clear, insulin resistance is thought to play an important factor. Patients typically present with asymptomatic serum aminotransferase elevations of 2-3 times normal. Symptoms may include fatigue and abdominal pain. The clinical course is difficult to predict due to a lack of research in the natural history of the disease. It is known a percentage of patients progress to end-stage liver disease and may require liver transplantation. No medical treatment has been found to be totally effective. Patients who are overweight or obese should be encouraged in gradual weight reduction that has been associated with improvement in liver test abnormalities.     

Blond and blood juice supplementation in high fat diet fed mice: effect on antioxidant status and DDAH/ADMA pathway

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease spread throughout the world. The most frequent causes of death in NAFLD patients are due both to liver and cardiovascular damage. Several pathways, including the dimethylarginine dimethylaminohydrolase (DDAH)/asymmetric dimethylarginine (ADMA) pathway, are involved in the pathogenesis of NAFLD. It has been reported that ADMA plasmatic levels are increased in patients with hepatic dysfunction such as NAFLD. Although many studies demonstrated that some foods are effective in the treatment of NAFLD, few studies have evaluated their effects with respect to the prevention of the disease. It has been reported that sweet orange juice (OJ) consumption may be associated with potential health benefits. However, some varieties of sweet orange are more effective than others. The aim of the present paper was to investigate the effect of blond and blood sweet orange juice in prevention of NAFLD by evaluating its ability to improve liver steatosis in mice with diet-induced obesity, reducing oxidative stress and affecting the DDAH/ADMA pathway. Results obtained in our experimental conditions evidenced that blood orange juice rather than blond orange juice was more effective. Blood orange juice or blond orange juice enriched in anthocyanins may represent a promising dietary option for the prevention of fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease spread throughout the world.     

Lipid balance must be just right to prevent development of severe liver damage

Nonalcoholic fatty liver disease (NAFLD) is a major health concern that often associates with obesity and diabetes. Fatty liver is usually a benign condition, yet a fraction of individuals progress to severe forms of liver damage, including nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Elevated sterol regulatory element–binding protein–driven (SREBP-driven) hepatocyte lipid synthesis is associated with NAFLD in humans and mice. In this issue of the JCI, Kawamura, Matsushita, et al. evaluated the role of SREBP-dependent lipid synthesis in the development of NAFLD, NASH, and HCC in the phosphatase and tensin homolog–knockout (PTEN-knockout) NASH model. Deletion of the gene encoding SREBP cleavage–activating protein (SCAP) from the liver resulted in decreased hepatic lipids, as expected. However, SCAP deletion accelerated progression to more severe liver damage, including NASH and HCC. This study provides a note of caution for those pursuing de novo fat biosynthesis as a therapeutic intervention in human NASH.     

Non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) refers to the accumulation of hepatic steatosis not due to excess alcohol consumption. The prevalence of NAFLD is up to 30% in developed countries and nearly 10% in developing nations, making NAFLD the most common liver condition in the world. The pathogenesis of NAFLD is related to insulin resistance and, thus, it is frequently found in individuals who have central obesity or diabetes. Insulin resistance and excess adiposity are associated with increased lipid influx into the liver and increased de novo hepatic lipogenesis, promoting hepatic triglyceride accumulation. Defects in lipid utilization via mitochondrial oxidation and lipid export may also contribute to hepatic lipid build-up. Adipocytokine alterations, lipotoxicity from saturated fatty acids and fructose have been all been implicated in causing hepatocyte injury in NAFLD through pathways involving oxidative and endoplasmic reticulum stress. Clinically, NAFLD is commonly asymptomatic and frequently detected incidentally by blood liver function tests or imaging performed for other reasons. Subjects with NAFLD have a higher mortality rate than the general population and are at increased risk of developing cardiovascular disease and diabetes in the future. Histologically, NAFLD occurs as a spectrum from mild hepatic steatosis only, to non-alcoholic steatohepatitis (NASH) characterized by hepatocellular injury and inflammation, to cirrhosis. A diagnosis of NASH with associated fibrosis heralds a more significant prognosis as it is more likely to progressive to cirrhosis with complications of hepatic failure and hepatocellular carcinoma. Currently, the diagnosis of NASH requires a liver biopsy, however, serum based markers of hepatocyte apoptosis such as cytokeratin-18 fragments offer promise as accurate non-invasive diagnostic tests. Treatment of NAFLD revolves around addressing concomitant metabolic risk factors and improving insulin resistance through weight loss measures and exercise. Insulin sensitizing agents such as pioglitazone and anti-oxidant agents such as vitamin E show some promise in improving liver histology in patients with NASH, however, the long-term benefit of these medications has not been demonstrated.     

Contribution of adipose tissue and de novo lipogenesis to nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a component of the metabolic syndrome, with a clinical spectrum ranging from simple fatty liver to steatohepatitis, cirrhosis, and hepatocellular carcinoma. The primary event of NAFLD is the accumulation of triacylglycerols (TAGs) in hepatocytes. In this issue of the JCI, Donnelly et al. report on their use of stable isotope methodology to show that fatty acids stored in adipose tissue and fatty acids newly made within the liver through de novo lipogenesis are the major sources of TAGs in the liver and are secreted as lipoproteins in NAFLD.