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PubMed2004

The histologic spectrum of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) represents a range of histologic lesions in the liver that occur in individuals who do not consume alcohol in quantities that generally are considered to be harmful. The histologic spectrum of NAFLD includes isolated predominantly macrovesicular steatosis alone at one end and steatohepatitis at the other. Nonalcoholic steatohepatitis can progress to cirrhosis and now also is considered to be a precursor of cryptogenic cirrhosis. This article provides an understanding of the histologic features of NAFLD and the potential pitfalls in the histologic assessment of this condition.

Alanine Transaminase↗
PubMed2004

Pharmacologic management of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is an emerging epidemic in Western societies, and therapeutic modalities to treat this condition are needed desperately. Most early treatment studies tended to focus on improvement in the serum aminotransferases. Presently, treatment of NAFLD is aimed at improving the underlying steatosis, necroinflammatory activity, and fibrosis because elevations of the aminotransferases may not accurately reflect these important histologic endpoints. Unfortunately, well-defined treatment options are few,which is largely due to limited experience reported in small, prospective pilot trials. This article focuses on the various therapeutic agents that have been evaluated in the treatment of NAFLD and their efficacy as well as their limitations.

Antihypertensive Agents↗
PubMed2004

Dietary composition and nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a common and potentially serious form of chronic liver disease that occurs in patients who do not abuse alcohol. Present dietary recommendations for all Americans, including those with NAFLD, endorse a low-calorie, low-fat diet. However, little is known about the effect of diet composition on liver histopathology in patients with NAFLD. The aim of this study was to determine whether overall calorie intake and diet composition are associated with the severity of NAFLD histopathology. Seventy-four consecutive morbidly obese patients presenting for bariatric surgery from January 2001 to March 2002 were retrospectively reviewed. In addition to a standard surgical and psychological evaluation, all patients underwent a preoperative dietary evaluation using a standardized 24-hr food recall. Food intake was evaluated for total calories and macronutrients and compared to liver histopathology from biopsies routinely obtained during surgery. Associations with the severity of steatosis and the presence of inflammation or fibrosis were assessed separately using chi-square for categorical variables and ANOVA for continuous variables. Further, we conducted multiple logistic regression analyses for each histological outcome. There were no significant associations between either total caloric intake or protein intake and either steatosis, fibrosis, or inflammation. However, higher CHO intake was associated with significantly higher odds of inflammation, while higher fat intake was associated with significantly lower odds of inflammation. In conclusion, present dietary recommendations may worsen NAFLD histopathology.

Adult↗
PubMedDate not supplied

Mycoplasma gallinarum infection in commercial layers and onset of fatty liver hemorrhagic syndrome.

Fatty liver hemorrhagic syndrome (FLHS) was observed in each of three trials in which commercial layers were utilized to determine the effect of Mycoplasma gallinarum (MGn) on egg and eggshell quality parameters and egg production. In each of three trials, FLHS occurred 31-54 days later in MGn-inoculated hens as compared with the Mycoplasma-clean (control) hens. In trials 1 and 2, no therapeutic intervention was initiated to ameliorate FLHS. In trial 3, therapeutic intervention was instituted and consisted of the addition of 1 pound of choline chloride/ton of feed. Total mortality recorded throughout the duration of each trial and attributable to FLHS was not significantly different between the control and the MGn-inoculated treatment. However, FLHS-associated mortality in each of the three trials was numerically greater for the control treatment.

Animals↗
PubMed2006

Genetic influences in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a metabolic liver disease with widely variable phenotypes extending from simple steatosis, through nonalcoholic steatohepatitis (NASH) to cirrhosis and hepatocellular carcinoma. Inevitably, this reflects the interplay of well-recognized environmental factors and disease associations such as obesity and insulin resistance with host genetic factors, which are polygenic or complex in nature. Most of the observed phenotypic variability will probably be explained by variations in single nucleotide polymorphism frequency, although knowledge of the effect of most polymorphisms on biologic function is currently limited. Several observational studies of kindred with NASH suggest a genetic contribution. Most data characterizing genetic variation in different NAFLD phenotypes is derived from case-control association studies involving putative candidate genes. These candidate genes have been selected largely based upon the "two-hit hypothesis" of the pathogenesis of NAFLD, although other hypothesis-independent approaches can also be informative in gene selection. Thus far, candidate gene association studies have had significant limitations such as small cohort sizes and poor reproducibility. Rapid technologic developments are increasing the capability of detecting genetic variation. Identification of the genetic contribution to NAFLD will inform theories of disease pathogenesis and progression and ultimately improve management.

Fatty Liver↗
PubMed2005

A genomic and proteomic study of the spectrum of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and some of its forms are progressive. This study describes the profiling of hepatic gene expression and serum protein content in patients with different subtypes of NAFLD. Liver biopsy specimens from 98 bariatric surgery patients were classified as normal, steatosis alone, steatosis with nonspecific inflammation, and nonalcoholic steatohepatitis (NASH). Microarray hybridizations were performed in triplicate and the microarray expression levels of a selected group of genes were confirmed using real-time quantitative reverse-transcriptase polymerase chain reaction. Serum protein profiles of the same patients were determined by SELDI-TOF mass spectrometry. Of 98 obese patients, 91 were diagnosed with NAFLD (12 steatosis alone, 52 steatosis with nonspecific inflammation, and 27 NASH), and 7 patients without NAFLD served as obese controls. Each group of NAFLD patients was compared with the obese controls, and 22 genes with more than twofold differences in expression levels were revealed. Proteomics analyses were performed for the same group comparisons and revealed twelve significantly different protein peaks. In conclusion, this genomic/proteomic analysis suggests differential expression of several genes and protein peaks in patients within and across the forms of NAFLD. These findings may help clarify the pathogenesis of NAFLD and identify potential targets for therapeutic intervention.

Adult↗
PubMed2026

Ovarian H3K27ac remodeling is associated with impaired follicular development in laying hens with fatty liver hemorrhagic syndrome.

Fatty liver hemorrhagic syndrome (FLHS) is a metabolic disease of laying hens that reduces egg production and is accompanied by reproductive impairment, but the ovarian regulatory mechanisms that connect nutritional stress to follicular dysfunction remain unclear. This study examined whether active chromatin remodeling in the ovary is associated with FLHS induced by a high-energy, low-protein (HELP) diet. Hy-Line Brown hens were assigned to a basal diet or HELP diet, and ovarian tissue was collected for histone H3 lysine 27 acetylation (H3K27ac) chromatin immunoprecipitation sequencing and RNA sequencing. The HELP diet reduced laying performance and the numbers of small yellow and hierarchical follicles, indicating compromised follicular development. Genome-wide H3K27ac profiling identified 2,111 regions with lower acetylation and 1,707 regions with higher acetylation in FLHS ovaries. Genes linked to differential H3K27ac regions were enriched in pathways related to oocyte meiosis, cell cycle control, FoxO signaling, gonadotropin-releasing hormone signaling, and steroid hormone biosynthesis. RNA sequencing identified 341 differentially expressed genes, with a predominance of downregulated genes. Integration of chromatin and transcriptome data highlighted folliculogenesis-related genes, including FGF1, FGF9, and MMP10, that showed reduced H3K27ac enrichment together with decreased expression. Super-enhancer analysis further identified 131 regions with reduced H3K27ac signal in FLHS ovaries, including regions located near PCNA and RAP1A, two genes involved in cellular proliferation and survival signaling. Motif enrichment of differential H3K27ac regions implicated Fos, SF-1/NR5A1, and GATA-4 as candidate transcriptional regulators. These findings indicate that HELP diet-induced FLHS is associated with broad attenuation of active ovarian regulatory elements and reduced expression of genes required for follicle growth, tissue remodeling, and steroidogenic function. The study provides an ovarian epigenomic framework for understanding reproductive decline in FLHS-affected laying hens.

Fatty liver hemorrhagic syndrome↗
PubMed2005

Design and validation of a histological scoring system for nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis in the absence of a history of significant alcohol use or other known liver disease. Nonalcoholic steatohepatitis (NASH) is the progressive form of NAFLD. The Pathology Committee of the NASH Clinical Research Network designed and validated a histological feature scoring system that addresses the full spectrum of lesions of NAFLD and proposed a NAFLD activity score (NAS) for use in clinical trials. The scoring system comprised 14 histological features, 4 of which were evaluated semi-quantitatively: steatosis (0-3), lobular inflammation (0-2), hepatocellular ballooning (0-2), and fibrosis (0-4). Another nine features were recorded as present or absent. An anonymized study set of 50 cases (32 from adult hepatology services, 18 from pediatric hepatology services) was assembled, coded, and circulated. For the validation study, agreement on scoring and a diagnostic categorization ("NASH," "borderline," or "not NASH") were evaluated by using weighted kappa statistics. Inter-rater agreement on adult cases was: 0.84 for fibrosis, 0.79 for steatosis, 0.56 for injury, and 0.45 for lobular inflammation. Agreement on diagnostic category was 0.61. Using multiple logistic regression, five features were independently associated with the diagnosis of NASH in adult biopsies: steatosis (P = .009), hepatocellular ballooning (P = .0001), lobular inflammation (P = .0001), fibrosis (P = .0001), and the absence of lipogranulomas (P = .001). The proposed NAS is the unweighted sum of steatosis, lobular inflammation, and hepatocellular ballooning scores. In conclusion, we present a strong scoring system and NAS for NAFLD and NASH with reasonable inter-rater reproducibility that should be useful for studies of both adults and children with any degree of NAFLD. NAS of > or =5 correlated with a diagnosis of NASH, and biopsies with scores of less than 3 were diagnosed as "not NASH."

Adult↗
PubMed2005

Histological characteristics and prognosis in patients with fatty liver.

OBJECTIVE: The clinical-pathological spectrum of fatty liver ranges from simple steatosis to end-stage fibrotic liver disease. However, no histological characteristics have been identified that can predict progression from pure steatosis to fibrotic liver disease in non-alcoholic fatty liver disease. The objective of this study was to investigate whether histological characteristics in patients with fatty liver without inflammation could predict mortality or development of cirrhosis. MATERIAL AND METHODS: A total of 417 patients had a liver biopsy performed, which showed fatty liver without inflammation. The population consisted of 170 non-alcoholic and 247 alcoholic fatty liver patients. The study cohort was linked through their unique personal identification number to The National Registry of Patients and the nationwide Registry of Causes of Death. RESULTS: Median follow-up time was 19.9 years in the non-alcoholic group and 12.8 years in the alcoholic group. Overall mortality in the non-alcoholic group was not related to morphological findings in the index liver biopsy. Mortality was significantly (p < 0.05) higher in alcoholic patients with severe steatosis. One non-alcoholic patient (0.6%) developed cirrhosis versus 54 alcoholic patients (22%) during the follow-up period. CONCLUSIONS: In patients with non-alcoholic fatty liver without inflammation, patients at risk for premature death cannot be identified by histological characteristics in the index liver biopsy. Patients with alcoholic fatty liver have a high risk for development of cirrhosis and increased mortality with the severity of steatosis in the index liver biopsy.

Adult↗
PubMedDate not supplied

Liver metastasis rare in colorectal cancer patients with fatty liver.

BACKGROUND/AIMS: As no reports in terms of the relationship between fatty liver and liver metastasis of colorectal cancer clinicopathological analysis of colorectal cancer patients with fatty were found a liver was carried out. PATIENTS AND METHODS: Among 839 patients with single colorectal carcinoma who underwent operations at our department between 1985 and 1994, 121 patients were designated as fatty liver using ultrasonography (FL group). The remaining 718 non-fatty liver patients with colorectal cancer (NFL group) were compared to the FL group regarding clinicopathological aspects. RESULTS: (1) There were only two patients who had liver metastasis in the FL group (1.7%), while the NFL group included 115 patients with liver metastasis (16.0%) (p < 0.01). (2) The five-year survival rate of the FL group was 95.7%, which was significantly higher than that in the NFL group (9.8%) (p < 0.001). (3) In the multivariate analysis, the fatty liver was identified as an independent prognostic factor. CONCLUSIONS: The FL group had a much better prognosis compared to the NFL group. Especially, liver metastasis was extremely rare in the FL group. We believe that these results will lead to the clarification of the liver metastasis mechanism.

Adenocarcinoma↗
PubMed1991

Glutathione S-transferase in alcoholic fatty liver.

Hepatic glutathione (GSH) S-transferase (GST) activity and the tissue distribution of a cationic GST were investigated in biopsy liver samples obtained from patients with alcoholic liver diseases. GST activities in alcoholic fatty liver were significantly high, whereas those in cirrhosis were significantly low compared with normal liver. In fatty liver, immunohistochemically, the staining of the enzyme was strongly positive in hepatocytes around intensive fatty metamorphosis. Then, using experimental chronic alcohol-fed rats, the changes in hepatic GST and GSH peroxidase (GPx) activities and lipid peroxide (LPO) and GSH contents in alcoholic fatty liver were evaluated. Hepatic GST isoenzymes were analyzed and tissue distribution of cationic and neutral GSTs was also investigated. Liver GSH content decreased at two weeks and increased at six weeks. Liver LPO content was elevated at four and six weeks and cytosolic GPx activity was enhanced at four weeks. Cytosolic GST activity was enhanced at six weeks. The cationic and neutral GST isoenzyme pattern was unchanged compared with normal liver. Immunohistochemically, the distribution and intensity of the staining of GSTs were essentially unchanged. There was no evidence of an increase in the GST isoenzyme with selen-independent GPx activity. However, GSTs were strongly stained in the hepatocytes with fatty droplets. Thus, in alcoholic fatty liver, hepatic GST and GPx activities are thought to be enhanced by different mechanisms. The elevated GPx activity may relate to the production of LPO. However, the enhancement of GST activity may result from some other causes which include the enzyme induction.

Alanine Transaminase↗
PubMed2004

Long term prognosis of fatty liver: risk of chronic liver disease and death.

BACKGROUND AND AIMS: Fatty liver is a common histological finding in human liver biopsy specimens. It affects 10-24% of the general population and is believed to be a marker of risk of later chronic liver disease. The present study examined the risk of development of cirrhotic liver disease and the risk of death in a cohort diagnosed with pure fatty liver without inflammation. METHODS: A total of 215 patients who had a liver biopsy performed during the period 1976-1987 were included in the study. The population consisted of 109 non-alcoholic and 106 alcoholic fatty liver patients. Median follow up time was 16.7 (0.2-21.9) years in the non-alcoholic and 9.2 (0.6-23.1) years in the alcoholic group. Systematic data collection was carried out by review of all medical records. All members of the study cohort were linked through their unique personal identification number to the National Registry of Patients and the nationwide Registry of Causes of Death, and all admissions, discharge diagnoses, and causes of death were obtained. RESULTS: In the non-alcoholic fatty liver group, one patient developed cirrhosis during the follow up period compared with 22 patients in the alcoholic group. Survival estimates were significantly (p<0.01) different between the two groups, for men as well as for women, with a higher death rate in the alcoholic fatty liver group. Survival estimates in the non-alcoholic fatty liver group were not different from the Danish population. CONCLUSIONS: This study revealed that patients with type 1 non-alcoholic fatty liver disease have a benign clinical course without excess mortality.

Adult↗
PubMed2000

[The relationship between nonalcoholic fatty liver and insulin resistance with abnormal glucose metabolism].

OBJECTIVE: To explore the correlation of nonalcoholic fatty liver (called "fatty liver" for short) and insulin resistance with abnormal glucose metabolism. METHODS: The subjects were 48 patients with fatty liver, while the controls were 15 normal persons. Oral glucose tolerance test (OGTT) and insulin release test were performed; and the area under curve of serum glucose (AUCSG), area under curve of insulin (AUCIns) and insulin sensitivity index (AUCSG/AUCIns) were calculated. RESULTS: The insulin level in fatty liver group was significantly higher than that in normal control group at 60 min, 120 min and 180 min after glucose intake (P<0.01) with the postpond peak. The blood glucose level in the fatty liver group was significantly higher than that in normal control group at all time intervals except at 180 min after glucose intake (P<0.05). The AUCIns and AUCSG in the patient group were significantly higher than in the control group 209.56 vs 124.22, 24.72 vs 19.96, respectively (P<0.01). The insulin sensitivity index in the patient group was significantly lower than that in the control group (P<0. 05). There is no significant difference in the insulin sensitivity index between different degree of fatty liver (P>0.05). CONCLUSION: It is evident that patients with fatty liver have insulin resistance with abnormal glucose metabolism, which is not related with the extent of fat infiltration in the liver, suggesting that insulin resistance with abnormal glucose metabolism is a very important contributor to the pathogenesis of fatty liver.

Adult↗
PubMed2005

Evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is one of the most frequent causes of abnormal liver dysfunction, and its prevalence has markedly increased; however, the mechanisms involved in the pathogenesis of NAFLD have not been thoroughly investigated in humans. In this study, we evaluated the expression of fatty acid metabolism-related genes in NAFLD. Real-time RT-PCR was performed using liver biopsy samples from 12 NAFLD patients. The target genes studied were: acetyl-CoA carboxylase (ACC) 1, ACC2, and fatty acid synthase (FAS) for the evaluation of de novo fatty acid synthesis; carnitine palmitoyltransferase 1a (CPT1a), long-chain acyl-CoA dehydrogenase (LCAD), and long-chain L-3-hydroxyacyl-coenzyme A dehydrogenase alpha (HADHalpha) for beta-oxidation in the mitochondria; peroxisome proliferator-activated receptor- (PPAR-) alpha and cytochrome P450 2E1 (CYP2E1) for oxidation in peroxisomes and microsomes (endoplasmic reticulum) respectively; and diacylglycerol O-acyltransferase 1 (DGAT1), PPAR-gamma, and hormone sensitive lipase (HSL) for triglyceride synthesis and catalysis. In NAFLD, expression of ACC1 and ACC2, but not FAS was increased, indicating that de novo fatty acid synthesis is enhanced in NAFLD. In contrast, expression of CTP1a, a rate-limiting enzyme, was remarkably decreased, indicating that beta-oxidation in the mitochondria was decreased, although the expression of LCAD and HADHalpha was increased. Expression of PPAR-alpha was increased, whereas that of CYP2E1 was reduced. The expression of DGAT1, PPAR-gamma, and HSL was enhanced. These data suggest that in NAFLD, increased de novo synthesis and decreased beta-oxidation in the mitochondria lead to accumulation of fatty acids in hepatocytes, although the extent of oxidation in peroxisomes and microsomes remains unclear.

Biopsy↗
PubMed2006

Prevalence of undiagnosed diabetes and postchallenge hyperglycaemia in Chinese patients with non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease is prevalent in affluent countries and is strongly associated with metabolic syndrome. AIM: To study the prevalence of undiagnosed diabetes and postchallenge hyperglycaemia in Chinese patients with non-alcoholic fatty liver disease. METHODS: 73 consecutive patients with biopsy-proven non-alcoholic fatty liver disease and no history of diabetes underwent comprehensive metabolic screening. Diagnosis of diabetes and impaired glucose regulation was based on the 2006 American Diabetes Association criteria. RESULTS: The prevalence of undiagnosed diabetes and impaired glucose tolerance in non-alcoholic fatty liver disease patients was 33% and 29%, respectively. Among patients with 2-h plasma glucose above 7.8 mm, 47% had normal fasting glucose (below 5.6 mm). Impaired glucose tolerance was more common in patients with non-alcoholic steatohepatitis than those with simple hepatic steatosis (P = 0.036), and 2-h plasma glucose correlated with fibrosis stage (Spearman coefficient: 0.25, P = 0.046). In a binary logistic regression analysis, high fasting glucose and low high-density lipoprotein cholesterol were independent factors associated with diabetes. Nevertheless, if oral glucose tolerance test was only performed in non-alcoholic fatty liver disease patients with impaired fasting glucose, 20.8% of diabetes cases would be missed. CONCLUSIONS: Isolated postchallenge hyperglycaemia is common among Chinese non-alcoholic fatty liver disease patients without history of diabetes. It is associated with histological severe disease, and cannot be accurately predicted by any fasting glucose cut-off.

Blood Glucose↗
PubMed1996

Disseminated intravascular coagulation and antithrombin III depression in acute fatty liver of pregnancy.

OBJECTIVE: Acute fatty liver of pregnancy has been associated with a syndrome of marked depression of antithrombin III and disseminated intravascular coagulation. We sought to identify the clinical importance of this accelerated coagulation. STUDY DESIGN: The medical records of patients with acute fatty liver of pregnancy identified during the period of 1982 to 1994 were retrospectively reviewed. RESULTS: Twenty-eight patients with acute fatty liver of pregnancy were identified for an incidence of 1:6692 births. Laboratory evidence of persistent disseminated intravascular coagulation was found in all patients tested. Six patients had clinical bleeding, all associated with genital tract injury. Twenty-three of twenty-three patients tested had markedly decreased antithrombin III levels (average 11%, normal range 80% to 100%). Seven patients received antithrombin III transfusions, which was associated with a significant transient rise in the plasma level. Compared with patients not transfused, however, there was a similar clinical outcome. CONCLUSION: Profoundly depressed antithrombin III levels and laboratory evidence of disseminated intravascular coagulation were present in all cases of acute fatty liver of pregnancy but rarely influenced clinical outcome unless there was concomitant genital tract injury. Antithrombin III transfusions increased plasma levels, but no definite clinical benefit was established in this series because of the small number of cases.

Acute Disease↗
PubMed2003

Effects of dietary vegetable oil on Atlantic salmon hepatocyte fatty acid desaturation and liver fatty acid compositions.

Fatty acyl desaturase activities, involved in the conversion of the C18 EFA 18:2n-6 and 18:3n-3 to the highly unsaturated fatty acids (HUFA) 20:4n-6, 20:5n-3, and 22:6n-3, are known to be under nutritional regulation. Specifically, the activity of the desaturation/elongation pathway is depressed when animals, including fish, are fed fish oils rich in n-3 HUFA compared to animals fed vegetable oils rich in C18 EFA. The primary aims of the present study were (i) to establish the relative importance of product inhibition (n-3 HUFA) vs. increased substrate concentration (C18 EFA) and (ii) to determine whether 18:2n-6 and 18:3n-3 differ in their effects on the hepatic fatty acyl desaturation/elongation pathway in Atlantic salmon (Salmo salar). Smolts were fed 10 experimental diets containing blends of two vegetable oils, linseed (LO) and rapeseed oil (RO), and fish oil (FO) in a triangular mixture design for 50 wk. Fish were sampled after 32 and 50 wk, lipid and FA composition of liver determined, fatty acyl desaturation/elongation activity estimated in hepatocytes using [1-14C]18:3n-3 as substrate, and the data subjected to regression analyses. Dietary 18:2n-6 was positively correlated, and n-3 HUFA negatively correlated, with lipid content of liver. Dietary 20:5n-3 and 22:6n-3 were positively correlated with liver FA with a slope greater than unity suggesting relative retention and deposition of these HUFA. In contrast, dietary 18:2n-6 and 18:3n-3 were positively correlated with liver FA with a slope of less than unity suggesting metabolism via beta-oxidation and/or desaturation/elongation. Consistent with this, fatty acyl desaturation/elongation in hepatocytes was significantly increased by feeding diets containing vegetable oils. Dietary 20:5n-3 and 22:6n-3 levels were negatively correlated with hepatocyte fatty acyl desaturation. At 32 wk, 18:2n-6 but not 18:3n-3 was positively correlated with hepatocyte fatty acyl desaturation, whereas the reverse was true at 50 wk. The data indicate that both feedback inhibition through increased n-3 HUFA and decreased C18 fatty acyl substrate concentration are probably important in determining the level of hepatocyte fatty acyl desaturation and that 18:2n-6 and 18:3n-3 may differ in their effects on this pathway.

Animal Feed↗