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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.
OBJECTIVE: Leptin, an adipocyte-secreted hormone, has emerged as a potential candidate for the link between obesity and the proinflammatory state. Specifically, leptin modulates T-helper (Th) cells toward a Th1 phenotype, with the secretion of proinflammatory cytokines. The aim of this study was to evaluate the Th1/Th2 balance in obese children and its relation with hormonal and metabolic features. STUDY DESIGN: In 50 obese children and 20 control children, we measured the CD4-positive Th cells that secrete interferon (IFN)-gamma or interleukin (IL)-2 (taken as an index of Th1 cells), and IL-4 (taken as an index of Th2 cells) as well as serum glucose, insulin, insulin resistance (IR) index (as homeostasis model assessment model (HOMA)), lipid profile, aminotransferases, leptin and ghrelin. Obese children also underwent dual energy X-ray absorptiometry scan measurements, and liver ultrasound scanning. RESULTS: Geometric mean percentages of IL-2- and IL-4-CD4 secreting cells in obese children were not significantly different from those found in control children. However, the geometric mean percentage of CD4-positive T cells secreting IFN-gamma was significantly higher in the obese than in the control (P < 0.0001, t-test) group. Within the entire group of study children, the percentage of IFN-gamma-positive cells was positively associated with leptin (P = 0.002), insulin (P < 0.00 005), and HOMA-IR values (P < 0.00 005). However, when these associations were restricted to the group of obese subjects, insulin and HOMA-IR values, but not leptin, retained statistical significance. Yet, in the obese group, the percentage of IFN-gamma-positive cells was associated with nonalcoholic steatohepatitis (NASH) (P = 0.001), but not with body mass index-standard deviation score and total body fat mass. CONCLUSIONS: In obese children, a shift to Th1-cytokine profile dominated by the production of IFN-gamma is related to insulin resistance as well as to NASH independently of anthropometric features and other metabolic characteristics. The prevalent Th1 pattern of secreted cytokines may be regarded as a mechanism contributing to inflammation in obesity.
OBJECTIVE: Prevalence of non-alcoholic fatty liver disease (NAFLD) among children is increasing dramatically. It is unclear why some patients develop steatohepatitis (NASH), fibrosis and cirrhosis from steatosis, and others do not. A role for leptin has been claimed. This study aims to evaluate the relationship between leptin, insulin resistance (IR) and NAFLD in children. DESIGN AND METHODS: In 72 biopsy-proven NAFLD children (aged 9-18 years; 51M/21F), fasting leptin and its soluble receptor (sOB-R) were measured; free leptin index (FLI) was calculated as leptin/sOB-R; IR was estimated by homeostasis model assessment (HOMA-IR) and insulin sensitivity index (ISI-comp); glucose tolerance by oral glucose tolerance test (OGTT). Percentage of total body fat (TBF) by dual-energy X-ray absorptiometry (DXA) was available in 65 patients. RESULTS: Prevalence of diabetes, impaired fasting and/or after load glucose tolerance was 11%. HOMA-IR and ISI-comp values were 2.55 +/- 1.39 and 4.4 +/- 2. NASH was diagnosed in 38 and simple steatosis in 25 children; diagnosis was indeterminate in 29 children. Increased fibrosis, mostly of mild severity, was observed in 41 patients. Median NAFLD activity (NAS) score was 3.42 +/- 1.60. According to histology, levels of leptin and FLI increased as steatosis (leptin from 11.9 +/- 6.3 in score 1 to 17.4 +/- 6.9 in score 2 (P = 0.01) and 22.2 +/- 6.8 ng/ml in score 3 (P < 0.001); FLI 2.56 +/- 1.40, 3.57 +/- 0.34, 4.45 +/- 0.64 respectively (P = 0.05)); ballooning (from 13.7 +/- 6.7 in score 1 to 17 +/- 7.5 in score 2 (P = 0.001) and 22.1 +/- 7.1 ng/ml in score 3 (P = 0.01); FLI 2.81 +/- 1.50, 3.40 +/- 1.65, 4.57 +/- 1.67 (P = 0.01 between 0 and 2)); fibrosis (from 14.3 +/- 7 to18.3 +/- 6.9; P = 0.03; FLI 3.03 +/- 1.57 vs 3.92 +/- 077; P < 0.05) and NAS score (score 1-2: 12.9 +/- 6.9; score 3-4: 17 +/- 6.9 (P = 0.01); score 5-7: 22.9 +/- 7.5 ng/ml (P = 0.03); FLI 2.70 +/- 1.53, 3.12 +/- 1.53, 4.58 +/- 1.57 P = 0.01 and P = 0.05 between 1-2 vs 3-4 and 3-4 vs 5-7 respectively) worsened. Higher leptin correlated with more severe steatosis, ballooning and NAS score (r(0) = 0.6, 0.4 and 0.6 respectively; for all P < 0.001); FLI with ballooning (r(0) = 0.4, P < 0.0001), steatosis (r(0) = 0.5, P < 0.0001) and NAS score (r(0) = 0.5, P < 0.0001). CONCLUSIONS: Leptin and liver injury correlated independently of age, BMI and gender in the present study. Nevertheless, any causative role of leptin in NAFLD progression could be established. Thus, studies are needed to define whether the hormone plays a major role in the disease.
We report a 59-year-old woman with type 2 diabetes mellitus (DM) complicated with smoldering myeloma and non-alcoholic steatohepatitis. A diagnosis of smoldering myeloma was made on the basis of elevation of IgA, M-protein (type:IgA-lambda) and histological findings of bone marrow without bone lesion. As to liver dysfunction, anti-HBV, anti-HCV and a series of auto-immune antibody were negative. She had no alcohol drinking habit and histological findings showed pericellular fibrosis without fatty degeneration, suggesting liver cirrhosis due to non-alcoholic steatohepatitis (NASH). To date, there are no reports of cases with DM, NASH and myeloma. Particular attention may be necessary for these complications.
Although steatohepatitis can be induced by an excessive intake of alcohol, it can also arise through various other causes, in which case it is known as non-alcoholic fatty liver disease (NAFLD). NAFLD is classified into two categories:simple fatty liver with a favorable clinical outcome, and non-alcoholic steatohepatitis (NASH), which is intractable and progressive. Recently in Japan, there has been an increase in the number of individuals at risk of lifestyle-related diseases, due to increased insulin resistance and visceral fat obesity. The metabolic syndrome (MS) is associated with several risk factors for atherosclerosis, including diabetes mellitus (DM), hypertension, and hyperlipidemia. Visceral fat obesity is the prime cause of NASH in the liver, and is therefore considered to be one of the phenotypic features of MS. Furthermore, most chronic liver diseases are associated with hepatitis C virus (HCV) infection. Fatty degeneration of hepatocytes is often observed in the liver of HCV-infected individuals, and results from viral suppression of mitochondrial beta-oxidation of fatty acid. The natural outcome of HCV infection is worse in patients with lifestyle-related high insulin resistance and visceral fat obesity. In this review, we describe the recent advances in research on progressive liver diseases that are the result of fat accumulation in the liver, with special reference to MS.
Inoculating of human fecal cysts to suckling Mongolian gerbils, two Giardia lamblia isolates, K1 and K2, were established as axenic cultures. Using this in vitro culture, both isolates were characterized as a "medium-rate grower" upon its growth pattern. These two Giardia isolates were grouped by using two genetic analysis. With genetic analysis of SSU-rDNA sequences, both K1 and K2 were found as members of Hopkins' group 1, despite some nucleotide differences noticed in K2 (5 differences/292 bases). The other genetic study used PCR-RFLP of the tim (triose phosphate isomerase) gene. Both of K1 and K2 were found to belong to Nash's group 2. Our results suggest that Nash's group 2 can not be a separate group, but a part of Hopkins' group 1.
AIM: To explore the relationship between changes of intestinal environment and pathogenesis of non-alcoholic steatohepatitis (NASH). METHODS: Forty-two Sprague-Dawley rats were randomly divided into model group (n = 24), treatment group (n = 12), and control group (n = 6). The rats of model and treatment groups were given high-fat diet, and those of the control group were given normal diet. Furthermore, the rats of treatment group were given lactulose after 8 wk of high-fat diet. Twelve rats of the model group were killed at 8 wk of high-fat diet. At the 16 wk the rats of treatment group, control group, and the rest of the model group were killed. The serum levels of aminotransferase were measured and the histology of livers was observed by H and E staining. RESULTS: The livers of rats presented the pathological features of steatohepatitis with higher serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the model group after 16 wk. Compared to the model group, the serum levels of ALT and AST in treatment group decreased significantly and were close to the normal group, and the hepatic inflammation scores also decreased markedly than those in the model group after 16 wk (5.83+/-2.02 vs 3.63+/-0.64, P<0.05), but were still higher than those in the model group after 8 wk (3.63+/-0.64 vs 1.98+/-0.90, P<0.05). However, the degree of hepatic steatosis had no changes in treatment group compared to the model group after 16 wk. CONCLUSION: Lactulose could ameliorate the hepatic inflammation of rats with steatohepatitis induced by fat-rich diet, but could not completely prevent the development of steatohepatitis. It is suggested that intestinal environmental changes such as intestinal bacteria overgrowth, are one of the important factors in the pathogenesis of NASH.
AIM: To evaluate the prevalence of genetic and acquired prothrombotic risk factors and their association with the extent of fibrosis and fatty infiltration in patients with non-alcoholic fatty liver disease (NAFLD). METHODS: Forty-four patients with chronic hepatitis (28 men and 16 women, with mean age of 45+/-11 and 49+/-12 years, respectively) constituted the patient population of this study. The groups were divided as follows: 15 patients with fatty liver (FL); 15 with non-alcoholic steatohepatitis (NASH); 14 with chronic viral hepatitis (CH) diagnosed by histology and liver technetium scan or ultrasound; and 10 healthy individuals. Thrombophilic, coagulation factors and genetic mutations were diagnosed by standard hemostatic and molecular coagulation assays. RESULTS: Activated protein C (APC) resistance and protein S were the most prevalent thrombotic risk factors (6% and 10% in NAFLD vs 21% and 14% in CH; P<0.01 and P<0.05, respectively). One thrombotic risk factor was identified in 41% of patients (23% mild fibrosis, 18% severe fibrosis) and two thrombotic risk factors in 6% of patients with NAFLD and severe fibrosis. While no differences in APC ratio, lupus anticoagulant, fibrinogen, factor V Leiden, prothrombin, and MTHFR mutation were found. Protein S levels were significantly lower in NASH patients than in patients with FL alone (92+/-19 vs 106+/-2, P<0.01). Protein C levels were markedly higher in patients with NAFLD and mild or severe fibrosis as compared to the patients with CH, respectively (128+/-40 vs 96+/-14, P<0.001 or 129+/-36 vs 88+/-13, P<0.01). CONCLUSION: Up to 46% of patients with NAFLD may have thrombotic risk factors, and the presence of thrombotic risk factors is correlated with the extent of hepatic fibrosis, suggesting a crucial role of the coagulation system in the pathogenesis of hepatic fibrosis.
Adjuvant tamoxifen has become the treatment of choice against estrogen receptor-positive breast cancer. Adverse effects are rarely observed and since symptoms of hepatic steatosis, non-alcoholic steatohepatitis and cirrhosis are usually negligible, such effects are not well characterized despite large cohort studies of adjuvant tamoxifen. This issue remains to be systematically studied. The present study consisted of 136 breast cancer patients treated with or without tamoxifen. Patients had laboratory tests once each month and underwent abdominal computed tomography (CT) annually for 5 years. The extent of hepatic steatosis was assessed by CT as the liver/spleen ratio. While receiving adjuvant tamoxifen, 40 of 105 patients developed hepatic steatosis (liver/spleen ratio <0.9) without obvious changes in body mass index. Twenty-one had a liver spleen ratio of <0.5, whereas none of the 31 patients treated without tamoxifen had a ratio <0.9 or <0.5 (p<0.0001 and p<0.0001, respectively). Hepatic steatosis was recognized in 35 of the 40 patients within the first 2 years of receiving adjuvant tamoxifen and 21 of the 40 had increased transaminase levels. Liver biopsy revealed NASH in 6 of 7 patients among the 21 with a liver/spleen ratio of <0.5. A subset of individuals given adjuvant tamoxifen developed progressive hepatic steatosis without significant changes in the body mass index. We suggest a liver/spleen ratio of <0.5 as a criterion upon which liver biopsy should be recommended since NASH frequently occurred in such patients.
Non-alcoholic fatty liver disease represents a set of liver lesions similar to those induced by alcohol that develop in individuals with no alcohol abuse. When lesions consist of fatty and hydropic degeneration, inflammation, and eventually fibrosis, the condition is designated non-alcoholic steatohepatitis (NASH). The pathogenesis of these lesions is not clearly understood, but they are associated with insulin resistance in most cases. As a result, abdominal fat tissue lipolysis and excessive fatty acid uptake by the liver occur. This, together with a disturbance of triglyceride export as VLDL, results in fatty liver development. Both the inflammatory and hepatocellular degenerative components of NASH are attributed to oxidative stress. Mitochondrial respiratory chain loss of activity plays a critical role in the genesis of latter stress. This may be initiated by an increase in the hepatic TNFalpha, iNOS induction, peroxynitrite formation, tyrosine nitration and inactivation of enzymes making up this chain. Consequences of oxidative stress include: lipid peroxidation in cell membranes, stellate cell activation in the liver, liver fibrosis, chronic inflammation, and apoptosis.
NASH is a frequent liver disease that develops in close association with IR and may progress to cirrhosis. Exclusion of excessive alcohol consumption as well as of other liver diseases and liver histology are required for diagnosis. Progress in the understanding of the pathophysiology of NASH allows interesting therapeutic considerations. It is logical to treat the associated metabolic conditions to influence the disease activity and progression. In view of promising preliminary data, several drugs are currently used in clinical trials.
Non-alcoholic fatty liver disease (NAFLD) is emerging as one of the most common liver disorders claiming the urgent attention of both medical professionals and the public sphere because of the imminent epidemic of advanced liver injury that appendages epidemic of obesity. Recent research reveals simple triglyceride accumulation in hepatocytes (i.e., liver steatosis) frequently becoming complicated by inflammation (i.e., non-alcoholic steatohepatitis, or NASH) that may progress into more advanced stages of the disease including cirrhosis or, eventually, hepatocellular carcinoma. The exact mechanisms of the progression of NAFLD into overt NASH and advanced disease stages are largely unknown. There is urgent need in terms of both intensive research pursuits and effective practical measures to deal with this common threat.
Among 65 patients admitted to the hospital for chronic obstructive lung disease, the following pulmonary tests were systematically performed : spirometric vital capacity and total lung capacity, FEV1, functional residual capacity and total lung capacity measured by body plethysmography, airway resistance and specific conductance, CO diffusion capacity measured by single-breath test, N2 clearance by single breath oxygen dilution, and blood gases. The patients were divided into bronchitics, emphysematous and broncho-emphysematous, according to the clinical and radiological Nash's score, and to another personal score derived from the former. The simple and multiple correlations between the clinico-radiological score and the functional results are low. The clustering analysis groups the 65 patients into four clouds of points, around two principal axes : the volume axis and the overinflation axis. This study indicates that the most suggestive results for emphysema diagnosis are increased FRC and TLC and low Tlco/V'a. The clinical score is not dominant for the clustering of the patients into the dynamic clouds. Beneath the bronchitic, the broncho-emphysematous and the emphysematous groups, the clustering analysis individualizes a fourth group of cases characterized by chronic asthma, and which were not isolated by Nash's score.
Alcoholic and non-alcoholic steatohepatitis (NASH) are often histopathologically indistinguishable. Apart from the clinical and laboratory findings, the patient's history is of key importance for differentiating between alcoholic steatohepatitis with its poor prognosis, and NASH, with its usually bland course. While the latter rarely requires specific treatment, the former, in particular in its severe form, is a therapeutic challenge. In addition to suitable dietary measures, patients with a Maddrey Score > 32, may need corticosteroids. In patients with mild to moderate steatohepatitis, the daily alcohol consumption appears to be decisive for the prognosis. In severe forms of this condition, in contrast, mortality is high, and patients surviving the acute phase often develop cirrhosis, irrespective of their further drinking habits.
Nonalcoholic fatty liver disease (NAFLD) encompasses a broad clinicopathologic spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), which may advance to cirrhosis and end-stage liver disease. Steatosis alone does not appear to be progressive. The prevalence of NAFLD averages 20% and that of NASH, 2% to 3%, making these conditions the most common liver diseases in the United States. NAFLD is associated with insulin resistance, which may be evident clinically with obesity, type 2 diabetes mellitus, and hypertriglyceridemia. The pathogenesis of NAFLD consists of hepatic fat accumulation and oxidative stress with formation of free radicals. The clinical diagnosis is based on the presence of the insulin resistance syndrome and exclusion of alcohol abuse as well as viral, autoimmune, genetic, and drug-induced liver diseases. Liver biopsy is essential for diagnosis but may not be necessary for clinical management. Treatment is aimed at correcting the risk factors for NAFLD and using potentially hepatoprotective agents. Ursodeoxycholic acid and betaine appear particularly promising in early trials.
Nonalcoholic steatotic hepatitis (NASH), the most prevalent form of progressive liver disease in the United States, is considered to be a manifestation of insulin resistance syndrome. There is increasing evidence that steatosis in NASH is a result of the pathology in fat metabolism occurring in obesity and insulin resistance. For steatosis to progress to necroinflammation and fibrosis, however, the theory of mitochondrial oxidative-stress induced cellular damage is receiving wide acceptance. Treatment approaches that address these etiologies are reviewed: betaine, magnesium, and vitamin E.
Non-alcoholic steatohepatitis (NASH) is a chronic liver disease that occurs in patients with no significant alcohol consumption; it is not histologically different from alcoholic hepatitis because it presents macrovesicular steatosis, hepatocellular necrosis, mixed inflammatory infiltrate, and various stages of fibrosis in addition Mallory bodies in some patients. Some authors have even described NASH as a benign disease; however, it is presently considered a potentially serious disease that may evolve into liver cirrhosis and probably, liver cancer. It is more often related to female sex, obesity, and dyslipidemia, although it may be present in other population groups and associated with other factors. Its origin may be multifactorial, including insulin resistance, protein glycation, oxidative stress, and others. The disease may be asymptomatic and found in routine physical exams when the patient shows increased aminotransferases with no other explanation. At present the only specific diagnosis procedure is liver biopsy. The sole available current treatment is body weight control, normalizing glucose and lipid blood levels, as well as the administration of some medication, as illustrated in the subsequent article.
The Nash Equilibrium (put forward by John Nash and celebrated in the film, A Beautiful Mind) mathematically describes multi-player, infinite games. It is a general description of large human transactions, such as health care. Learn how new inputs, new players or new resources can disrupt these transactions.