Non-Alcoholic Fatty Liver Disease, Non-Alcoholic Steatohepatitis and Orthotopic Liver Transplantation

Obesity, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are becoming increasingly common medical problems in the developed world, often in the setting of the metabolic or insulin resistance syndrome (IRS). It is predicted that by the year 2025 > 25 million Americans may have NASH-related liver disease. NASH and NAFLD also affect the donor population. The use of steatotic donor livers for liver transplantation (LT) is associated with an increased risk of primary nonfunction (PNF) in the allograft. There is particular reluctance to use steatotic livers for living donor LT. There is indirect evidence to suggest that patients undergoing LT for cirrhosis resulting from NASH may have poorer outcome, despite careful selection of LT candidates. Indeed it is likely that many potential LT candidates with NASH are excluded from LT due to co-morbid conditions related to IRS. The post-LT patient is at risk of several components of IRS, such as diabetes mellitus, hypertension, hyperlipidaemia and obesity and there is increasing recognition of de novo and recurrent NAFLD and NASH after LT. Thus NAFLD and NASH affect all aspects of LT including donors, patients in evaluation and the LT recipient.     

Predictors of Nonalcoholic Steatohepatitis and Advanced Fibrosis in Morbidly Obese Patients

Background: Nonalcoholic fatty liver disease (NAFLD) is a common form of chronic liver disease in the United States. It is commonly associated with the components of the metabolic syndrome including obesity. From the spectrum of NAFLD, only patients with nonalcoholic steatohepatitis (NASH) have been convincingly shown to have a potential for progression to cirrhosis. We report the prevalence of NAFLD and NASH as well as predictors of NASH and advanced fibrosis in morbidly obese patients. Methods: 212 consecutive patients who underwent bariatric surgery were enrolled in the study. A liver biopsy was performed at the time of the surgery. Causes of chronic liver disease other than NAFLD were excluded by clinical and laboratory evaluation. Results: The prevalence of NAFLD was 93%. Of those with NAFLD, 26% had NASH. 17 patients (9%) had advanced fibrosis (i.e., bridging fibrosis or cirrhosis). Male gender, AST, and type 2 diabetes mellitus were independently associated with NASH. Waistto-hip ratio, AST, and focal hepatocyte necrosis on liver biopsy were independently associated with advanced fibrosis. Interestingly, while AST was associated with NASH and advanced fibrosis, the majority of the patients with either NASH or advanced fibrosis had normal AST. Conclusions: NAFLD and NASH are very common in morbidly obese patients undergoing bariatric surgery. Features associated with the metabolic syndrome and liver cell injury are independently associated with either NASH or advanced fibrosis.     

非酒精性脂肪性肝炎的诊断和治疗进展

非酒精性脂肪肝疾病(nonalcoholic fatty liver disease,NAFLD)以肝细胞中脂肪过多积累为标志,包括非酒精性脂肪肝(nonalcoholic fatty liver,NAFL)和非酒精性脂肪性肝炎(nonalcohol-ic steatohepatitis,NASH),其中NASH可能会...     

Effect of chronic alcohol consumption on the development and progression of non-alcoholic fatty liver disease (NAFLD)

A number of epidemiologic studies show a protective effect of light to moderate daily alcohol consumption on the development of non-alcoholic fatty liver disease (NAFLD). Although these small amounts of ethanol may prevent fatty liver, they may also be a risk factor for other diseases such as breast and colon cancer. Those individuals who have underlying hepatic steatosis or non-alcoholic steatohepatitis (NASH) should not use ethanol chronically since the data available at present do not support a beneficial effect of alcohol in this situation. Especially overweight and obese individuals may be more susceptible towards alcohol even at moderate doses. Animal experiments show a negative effect of ethanol on liver histology in either dietary or genetic NASH models. In addition, patients with NASH reveal a significant increased risk for hepatocellular cancer (HCC) even with social alcohol consumption. Thus, subjects with underlying NASH should abstain from alcohol at any amounts.     

Nonalcoholic Fatty Liver Disease and Psoriasis: What a Dermatologist Needs to Know

Psoriasis is a systemic inflammatory disease associated with a variety of comorbidities. It has been shown that psoriasis patients have an increased incidence of nonalcoholic fatty liver disease over controls. Patients with nonalcoholic fatty liver disease and psoriasis have more severe skin disease and are at higher risk of severe liver fibrosis than patients without psoriasis. The authors will review the diagnosis of nonalcoholic fatty liver disease and also discuss lifestyle changes and treatments for psoriasis that may benefit or worsen nonalcoholic fatty liver disease.Fatty liver disease refers to a condition in which fat accumulates within hepatocytes. Nonalcoholic fatty liver disease (NAFLD) is diagnosed after other causes are eliminated, such as alcoholic fatty liver, autoimmune hepatitis, hepatitis C, primary biliary cirrhosis, and Wilson’s disease.NAFLD is a metabolic disorder that represents a disease spectrum. It ranges from steatosis (isolated fatty liver) without specific liver injury to nonalcoholic steatohepatitis (NASH) in which there is inflammation leading to scarring, fibrosis, and possibly cirrhosis.1NAFLD is a manifestation of abnormal metabolism within the liver resulting in the accumulation of triglycerides within the hepatocytes. Risk factors include male gender, age, obesity, insulin resistance, and metabolic syndrome.2 Proinflammatory adipokines or skin- derived cytokines may lead to insulin resistance and hepatic lipid accumulation.It is not known why some patients develop more serious disease than others. Lifestyle risks that can influence severity include sedentary lifestyle, smoking, and diet. It is also thought that genetic predisposition plays a role. A mutation in the PNPLA3 (phospholipase domain containing protein 3) gene has been shown to confer risk.3 Other factors resulting in more severe disease include excess proinflammatory cytokines/adipokines, mitochondrial dysfunction, and oxidative stress.1 Certainly patients with autoimmune diseases, such as psoriasis, may be prone to more severe inflammation and therefore scarring of the liver. Thus, in NASH, some patients may develop cirrhosis and even more infrequently hepatocellular carcinoma. It has been estimated that NAFLD will be the leading cause of liver transplantation worldwide by 2020.4     

Predictors of Nonalcoholic Steatohepatitis (NASH) in Obese Patients Undergoing Gastric Bypass

Background: Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are conditions gaining increasing recognition in hepatology as a potential cause of cirrhosis and end-stage liver disease. Obesity is one of the main risk factors. The aims of this study were to determine the frequency of NAFLD in obese patients and to identify variables that predict NASH. Methods: A prospective study was conducted of obese patients undergoing gastric bypass over a 20-month period. Assessment included liver function tests and evaluation of insulin resistance with the homeostatic model assessment (HOMA-IR). Liver biopsy was performed in all patients at the time of surgery. Clinical and biochemical variables were analyzed using a multivariate analysis to identify independent predictors of NASH. Results: 127 consecutive patients were included (62% female, 38% male, mean age 40±11 years, mean body mass index 42±6 kg/m²). Arterial hypertension was present in 52 patients (41%) and type 2 diabetes in 18 (14%). NAFLD was confirmed in 80 patients (63%), 47 (37%) had simple steatosis, and 33 (26%) had NASH. Cirrhosis was found in 2 patients corresponding to 1.6% of the total population. On multivariate analysis, AST >31 (IU/L) (OR 3.38, CI 1.17-9.8) and HOMA-IR >5.8 (OR 4.18, CI 1.39-12.49) independently predicted NASH. Conclusions: NAFLD is highly prevalent in morbidly obese patients. A high proportion of these patients exhibit NASH on histological examination. Insulin resistance represents the main predictor of NASH.     

Role of micronutrients in staging of nonalcoholic fatty liver disease:A retrospective cross-sectional study

BACKGROUND Nonalcoholic fatty liver disease(NAFLD) presents high incidence throughout the world and has been progressively increasing in prevalence. This disease has a heterogeneous natural history, including simple steatosis, nonalcoholic steatohepatitis(NASH), and cirrhosis. The factors that determine its evolution to more severe forms of the disease are still poorly understood, and micronutrients with antioxidant potential may be involved in the pathophysiology of the disease.AIM To evaluate the relationship between serum levels of micronutrients and the severity of NAFLD.METHODS A retrospective, observational and cross-sectional study was conducted. This study included all patients undergoing bariatric surgery who experienced liver biopsy during the procedure, and had serum levels of micronutrients(vitamin D,vitamin B12, zinc, iron, and magnesium), which was assessed in a preoperative evaluation conducted at a reference center in southern Brazil.RESULTS A total of 614 patients were analyzed, of which 93% had steatosis, 70.7% had NASH, and 49.3% had some degree of fibrosis. Serum levels of vitamin D were negatively correlated with the severity of steatosis and NASH, and serum levels of vitamin B12 were positively correlated with the severity of steatosis and fibrosis. The other micronutrients showed no association with NAFLD staging.CONCLUSION Serum levels of vitamin D are inversely related to the severity of steatosis and NASH, and serum levels of vitamin B12 are higher in more advanced stages of simple steatosis and liver fibrosis. Serum levels of zinc, iron, and magnesium were not associated with NAFLD severity.     

Nonalcoholic steatohepatitis and insulin resistance in children

Various pathological conditions can cause fatty liver in children. Nonalcoholic steatohepatitis (NASH) in children has been known since 1983. However, NASH diagnosed in childhood does not have a favorable outcome. The pathological characteristics of NASH are significantly different between children and adults. Nonalcoholic fatty liver disease (NAFLD)/NASH is accompanied by insulin resistance, which plays a pivotal role in its pathophysiology in both children and adults. In NASH, a “two-hit” model involving triglyceride accumulation (first hit) and liver damage (second hit) has been accepted. Insulin resistance was found to correlate with changes in fat levels; however, it did not correlate with fibrosis or NAFLD activity score in children. Therefore, insulin resistance may be important in the first hit. Because there is obvious familial clustering in NASH, genetic predisposition as well as environmental factors including diet might be the second hit of NAFLD/NASH.     

Steatohepatitic hepatocellular carcinoma (SH-HCC): a distinctive histological variant of HCC in hepatitis C virus-related cirrhosis with associated NAFLD/NASH

In explant livers with chronic hepatitis C (HCV-C) we have noted a distinctive histologic variant that we have termed steatohepatitic hepatocellular carcinoma (SH-HCC) with features resembling non-neoplastic steatohepatitis, including large droplet steatosis, ballooning of malignant hepatocytes, Mallory-Denk bodies, inflammation, and pericellular fibrosis. This study was undertaken to further describe the characteristics and prevalence of this histologic variant in HCV-C and any possible association with underlying risk factors for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). We selected two 2-year periods (mid-2003 to mid-2005 and 2007 to 2008), from which selected explant livers with HCV-C and HCC were examined to determine the characteristics and frequency of SH-HCC. The underlying cirrhotic liver was also reassessed for steatosis and evidence of steatohepatitis. Clinical records were consulted for concomitant NAFLD and NASH risk factors. The SH-HCC variant was found in a total of 22 of 62 HCC cases (35.5%). Fourteen of the 22 patients with SH-HCC (63.6%) had at least one known risk factor for NAFLD/NASH including diabetes (6 of 22, 27.3%), obesity (6 of 22, 27.3%), hypertension (11 of 22, 50%), and hyperlipidemia (5 of 22, 27.8%). In 14 of the 22 cases (63.6%) of SH-HCC, the non-neoplastic liver showed changes of NAFLD/NASH superimposed on otherwise typical features of HCV-C. In conclusion, in our series of HCV-C explants, approximately one-third of HCCs show a distinctive histological variant termed SH-HCC. Underlying risk factors for NAFLD and for NASH were identified in 63.6% of our cases. Moreover, non-neoplastic tissue in HCV-C explants showed changes of NAFLD/NASH in 63.6% of cases. These results suggest a possible NAFLD/NASH pathway leading to SH-HCC in the setting of HCV-C which requires further investigation in the future.     

Roux-en-Y Gastric Bypass Improves the Nonalcoholic Steatohepatitis (NASH) of Morbid Obesity

Background: Hepatic steatosis and nonalcoholic steatohepatitis (NASH) have been increasingly implicated in the genesis of hepatic fibrosis and cirrhosis. However, no consensus exists about whether weight reduction may reverse this process. Methods: To assess the effect of Roux-en-Y gastric bypass (RYGBP) on the histological evolution of NASH diagnosed in 64 patients by routine liver biopsy ("first" biopsy) performed during surgery, we performed a "second" biopsy after 23.5 ± 8.4 months in 16 patients (14 female, 2 male). Results: From the first to the second biopsy, BMI decreased from 53.4 ± 8.8 kg/m² to 31.1 ± 4.7 kg/m², arterial hypertension decreased from 75% to 43.8%, and type 2 diabetes decreased from 43.8% to zero. On the first biopsy, nonalcoholic fatty liver disease (NAFLD) type 3 was observed in 12 patients (75%) and type 4 in 4 (25%). The second biopsy revealed complete regression of NAFLD in 15 patients (93.7%) and only 1 (6.3%) had NAFLD type 1 (mild steatosis without inflammation). Complete regression of necroinflammatory activity was observed in all patients. Among the 4 patients presenting fibrosis in the first biopsy, complete remission was observed in 1 and improvement in 1. Two continued to show the same degree of fibrosis without evidence of disease activity. No worsening of steatosis, necroinflammatory activity or fibrosis was observed in any of the patients, and none progressed to cirrhosis. Conclusion: RYGBP improves steatosis, necroinflammatory activity and hepatic fibrosis in patients with morbid obesity and NASH.     

Lipid Peroxidation in Bariatric Candidates with Nonalcoholic Fatty Liver Disease (NAFLD) – Preliminary Findings

Background: Pathogenesis of nonalcoholic fatty liver disease (NAFLD) remains incompletely known, and oxidative stress is one of the mechanisms incriminated. The aim of this study was to evaluate the role of liver oxidative stress in NAFLD affecting morbidly obese patients. Methods: 39 consecutive patients with BMI >40 kg/m² submitted to Roux-en-Y gastric bypass were enrolled, and wedge liver biopsy was obtained during operation. Oxidative stress was measured by concentration of hydroperoxides (CEOOH) in liver tissue. Results: Female gender was dominant (89.7%) and median age was 43.6 ± 11.1 years. Histology showed fatty liver in 92.3%, including 43.6% with nonalcoholic steatohepatitis (NASH), 48.7% with isolated steatosis and just 7.7% with normal liver. Liver cirrhosis was present in 11.7% of those with nonalcoholic steatohepatitis. Concentration of CEOOH was increased in the liver of patients with NASH when compared to isolated steatosis and normal liver (0.26± 0.17, 0.20± 0.01 and 0.14± 0.00 nmol/mg protein, respectively) (P <0.01). Liver biochemical variables were normal in 92.3% of all cases, and no difference between NASH and isolated steatosis could be demonstrated. Conclusions: 1) Nonalcoholic steatosis, steatohepatitis and cirrhosis were identified in substantial numbers of morbidly obese patients; 2) Concentration of hydroperoxides was increased in steatohepatitis, consistent with a pathogenetic role for oxidative stress in this condition.     

Nonalcoholic Fatty Liver Disease of Obesity

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are part of the same continuum. They are a major, under-recognized cause of chronic liver disease. Good medical treatment options do not exist to date. The mainstay of treatment is weight loss. Bariatric surgery offers weight loss and improvement of NAFLD and NASH.     

Nonalcoholic Fatty Liver Disease Associated with Obstructive Sleep Apnea: Just a Coincidence?

Background  

Obesity is associated with obstructive sleep apnea (OSA) and nonalcoholic fatty liver disease (NAFLD). It has been shown that OSA could be an independent risk factor for NAFLD. OSA could cause not only insulin resistance but worse NAFLD through nocturnal hypoxemia. This study aimed to evaluate the frequency of OSA and NAFLD in obese patients and the relationship between OSA, insulin resistance, and severity of steatohepatitis (nonalcoholic steatohepatitis (NASH)).     

Hepatocellular Carcinoma Arising from Nonalcoholic Steatohepatitis: Report of Two Cases

Sporadic cases of hepatocellular carcinoma (HCC) originating from nonalcoholic steatohepatitis (NASH) have recently been reported. Thus, we investigated the prevalence of NASH in patients with HCC. A review of the clinical records of 481 patients who underwent liver resection for HCC in our department between January 1991 and December 2003 revealed only two (0.4%) patients with HCC associated with NASH. Both of these patients had noninsulin-dependent diabetes mellitus, and neither had a history of alcohol consumption or blood transfusion. All serologic markers for hepatitis B and C viruses were negative. Histological examination of the noncancerous hepatic tissue revealed NASH with moderate hepatic fibrosis in one patient and cirrhosis in the other. Thus, clinical follow-up and screening for HCC should be done for patients with hepatic fibrosis caused by NASH, even though this form of hepatitis is an uncommon cause of HCC.     

Innate immune signaling and gut-liver interactions in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and covers a disease spectrum ranging from steatosis to inflammation, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The innate immune response in the liver plays an important role during NAFLD progression. In addition, changes in the intestinal microbial balance and bacterial translocation can further affect disease progression. Immune cells in the liver recognize cell damage or pathogen invasion with intracellular or surface-expressed pattern recognition receptors (PRRs), subsequently initiating signaling cascades that trigger the release of factors promoting the inflammatory response during NAFLD progression. Therefore, mechanisms by which cells of the immune system are activated and recruited into the liver and how these cells cause injury and stress are important for understanding the inflammatory response during NAFLD.     

Improved survival outcomes in patients with non‐alcoholic steatohepatitis and alcoholic liver disease following liver transplantation: an analysis of 2002–2012 United Network for Organ Sharing data

There is an increasing trend of patients with hepatocellular carcinoma (HCC) and non‐alcoholic fatty liver disease undergoing liver transplantation in the US. Our study utilized data from the 2002 to 2012 United Network for Organ Sharing registry to evaluate model for end‐stage liver disease era trends in US liver transplantations focused on patients with non‐alcoholic steatohepatitis (NASH), hepatitis C (HCV), alcoholic liver disease (ALD), and HCC. Survival outcomes were stratified by liver disease etiology and compared across time periods using Kaplan–Meier and Cox proportional hazards models. Patients with NASH were more likely to be women, had higher body mass index (BMI), and had higher prevalence of diabetes and cardiac disease. However, overall long‐term survival was significantly higher in patients with NASH and ALD (p < 0.001). Compared to HCV, patients with NASH had significantly higher post‐transplantation survival (HR 0.69, 95% CI 0.63–0.77), and lower risk of graft failure (HR 0.76, 95% CI 0.69–0.83). Despite having higher BMI and higher prevalence of diabetes and cardiac disease, patients with NASH had better post‐liver transplantation survival compared to patients with HCV or HCC. Patients with ALD also had superior survival outcomes. However, these survival differences were limited to patients without HCC that underwent liver transplantation.     

Influence of Liver Biopsy Heterogeneity and Diagnosis of Nonalcoholic Steatohepatitis in Subjects Undergoing Gastric Bypass

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a chronic condition that can progress to cirrhosis and hepatocellular cancer. The most progressive form of NAFLD is nonalcoholic steatohepatitis (NASH). Currently, the only method to diagnose NASH is with a liver biopsy; however. sampling error may limit diagnostic accuracy. We investigated the discordance of paired liver biopsies in individuals undergoing gastric bypass. METHODS: Two liver biopsies, composite size of > or = 25 mm and > or = 8 portal tracts (PTs), were obtained from the left lobe in 31 subjects. Group 1 included specimens at least 15 mm in length with > or = 4 PTs compared to a second biopsy of at least 10 mm and > or = 4 PTs (Group 2). RESULTS: The mean specimen size (number of PTs) for group 1 was 20.4 +/- 4.2 mm (11.7 +/- 5.5 PTs) and group 2 was 16.1 +/- 5.3 mm (8.2 +/- 4.1 PTs). Prevalence of NASH was 26% in Group 1 and 32% in Group 2. Sampling discordance was greatest for portal fibrosis (26%), followed by zone 3 fibrosis (13%) and ballooning degeneration (3%). The negative predictive values from Group 1 liver biopsies for NASH and portal fibrosis were only 83% and 67%, respectively. CONCLUSIONS: The results demonstrate that significant sampling variability exists in class 2 and 3 obese individuals undergoing screening liver biopsies for NAFLD. The degree and histopathological discordance is dependent upon zonal location and types of injury. Nevertheless, a 25-mm biopsy specimen without zone 3 cellular ballooning or fibrosis appears adequate to exclude the diagnosis of NASH.     

Prevalence of NASH/NAFLD in people with obesity who are currently classified as metabolically healthy

BackgroundWhile metabolic health in obesity may confer a protective status, recent studies indicate that nonalcoholic fatty liver disease (NAFLD) or even nonalcoholic steatohepatitis (NASH) may exist in this category of individuals. Although cardiovascular and diabetic risks have been well described, the risk of NAFLD and NASH among this population requires further investigation.ObjectiveOur goal was to compare the prevalence of steatosis, NAFLD, and NASH between individuals with metabolically healthy obesity (MHO) and individuals with metabolically abnormal obesity (MAO) and to identify preoperative risk factors for these conditions in a prospective cohort with morbid obesity scheduled for bariatric surgery.SettingsTertiary referral university hospital in France.MethodsThe prospective cohort included 837 bariatric patients who also had an intraoperative liver biopsy between 2002 and 2015. Obese individuals fulfilling none of the criteria in the strict definition of metabolic syndrome were considered metabolically healthy. Preoperative blood samples and liver pathology examinations were reviewed. Steatosis, NAFLD, and NASH were carefully identified allowing comparison of prevalence and risk factors between the 2 cohorts.ResultsIn total, 149 patients (17.8%) had MHO and the remaining 688 (82.2%) had MAO. The cohort with MHO was significantly younger, had a significantly lower glycosylated hemoglobin, a lower homeostasis model assessment of insulin resistance, and increased C-reactive protein. In individuals with MHO, 44 patients (29.5%) had at least moderate steatosis (>33% macrovesicular steatosis) and 5.4% had NASH. Using logistic regression, waist circumference was positively associated with NASH, whereas body mass index and alanine aminotransferase were significantly associated with severe steatosis (>66%).ConclusionOur study indicates that obese individuals without metabolic syndrome may develop subclinical liver involvement. Therefore, the occurrence of NAFLD and NASH in this population needs further investigation.     

Rapid recurrence of nonalcoholic fatty liver disease after transplantation in a child with hypopituitarism and hepatopulmonary syndrome.

Nonalcoholic fatty liver disease (NAFLD) has been reported in adults with hypothalamic or pituitary dysfunction, and some have progressed to end stage liver disease requiring transplantation. We report a teenager who initially presented with hypoxia due to intrapulmonary shunting, found to have NAFLD and cirrhosis associated with a hypothalamic tumor and panhypopituitarism. The NAFLD recurred very quickly after a successful liver transplant. Hepatopulmonary syndrome may be more common in cirrhosis associated with pituitary dysfunction than in other types of cirrhosis.