Gene/Protein Disease Symptom Drug Enzyme Compound
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Nonalcoholic steatohepatitis (NASH) is a condition characterized by hepatomegaly, elevated serum aminotransferase levels, and a histologic picture similar to alcoholic hepatitis in the absence of alcohol abuse. Most patients with NASH are obese women, and many have diabetes mellitus, hypercholesterolemia, or hypertriglyceridemia. NASH has also been associated with a number of metabolic conditions, surgical procedures, and drug treatments. Most patients are asymptomatic. The most common sign of NASH is hepatomegaly. Stigmata of chronic liver disease are rare. Laboratory abnormalities include a 2-4-fold elevation of serum aminotransferase levels; other liver function test results are usually normal. Histologically, there is moderate to severe macrovesicular steatosis and lobular hepatitis with necrosis or ballooning degeneration and/or fibrosis. The pathogenesis of NASH is poorly understood, but lipid peroxidation and oxidative stress are the leading culprits. The natural history of NASH is unknown, but NASH seems to be a stable disease in most patients. Treatment of NASH is unproven, but weight reduction is recommended in obese patients. Small pilot studies of several drugs have shown promise, but large randomized clinical trials are awaited. Orthotopic liver transplantation is the treatment of choice for end-stage liver disease secondary to NASH.
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PMID:Nonalcoholic steatohepatitis. 1152 55

To determine the difference between alcoholic hepatitis (AH) and non-alcoholic steatohepatitis (NASH) in Japan, six patients with Ah and four patients with NASH, recently treated at our institute, were clinically and pathologically evaluated. Clinical features of the diseases differed: in NASH patients, mean age was higher, mean body mass index much higher, and the prevalence of diabetes mellitus was higher than in AH patients. The patients with NASH presented with unremarkable symptoms and signs. Abnormalities in liver function tests including prothrombin time and choline esterase were mild in NASH patients, except for the indocyanine green test. They had ALT-dominant hypertransaminasemia. AST, ALT and gamma GTP did not normalize as promptly as in AH patients after admission. However, there was no significant difference in the histological grade of fibrosis, inflammation or hepatocytic metamorphosis between NASH and AH patients. Stellate-form fibrosis was characteristic of AH, whereas pericellular and perivenular types were common in NASH patients. Focal cell necrosis was rather intense, and fatty deposits prominent, in NASH patients. However, it was difficult to histopathologically discriminate between NASH and AH patients. If AH is histologically suspected in non-alcoholic patients, the possibility of NASH should always be considered. Furthermore, even in patients with suspected simple fatty liver, a liver biopsy should be performed, especially in cases with prolonged abnormal liver function findings.
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PMID:Clinical and pathological differences between alcoholic hepatitis and non-alcoholic steatohepatitis. 1268 23

Non alcoholic fatty liver disease (NAFLD) and its more agressive form, non alcoholic steatohepatitis (NASH) are entities that are becoming subject of interest of the medical community in general, especially because of the increased prevalence of diabetes and obesity in the world population. There is solid evidence linking NAFLD with the so called metabolic syndrome or syndrome X, to the point of accepting hepatic steatosis and its spectrum as one more element of the latter, along with diabetes, hipertension, hypertriglyceridemia and obesity. Insulin resistance seems to be the common link between these entities. Clinical evaluation of every patient with abnormal aminotransferase levels should take into account non alcoholic fatty liver and its spectrum, especially if the subject is obese or diabetic. Despite the important developments in the field of imaging, currenty the only way to differentiate NASH from simple NAFLD is by performing a liver biopsy, which should be discussed extensively with the patient. The prognosis of simple NAFLD is generally benign, but if there is fibrosis, ballooning of the hepatocytes, inflammation and Mallory bodies there is risk to progression to cirrhosis. Liver histology in NAFLD is indistinguishable from alcoholic hepatitis, although the clinical course is generally more benign. Despite this long and protracted clinical course, an important number of subjects have complications of cirrhosis including hepatocellular carcinoma, and many patients require a liver transplantation. There is no specific treatment for this condition, although every therapeutic regimen should include a gradual and supervised weight reduction, a balanced diet and exercise, as well as correction of precipitant factors. There is currently no specific pharmacologic treatment for NASH or NAFLD. Current body of evidence and some pilot studies suggest that the future might be concentrated in agents improving insulin resistance. Meanwhile, we should do our best to study the prevalence of NAFLD in our country and, when clinically pertinent, study histologically those patients with high risk of fibrosis.
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PMID:[Non-alcoholic fatty liver]. 1276 15

Nonalcoholic steatohepatitis (NASH) is a condition characterized histologically by macrovesicular steatosis and lobular hepatitis with necrosis or ballooning degeneration and/or fibrosis--a picture resembling alcoholic hepatitis, in the absence of alcohol abuse. Most patients with NASH are asymptomatic, and the disease is detected incidentally. The most common signs of NASH are hepatomegaly and laboratory abnormalities, which include a 2-4-fold elevation of serum aminotransferase levels, while other liver function test results are usually normal. Most patients with NASH are obese, many have diabetes mellitus, hypercholesterolemia, or hypertriglyceridemia. NASH has also been associated with a number of metabolic derrangements, conditions, surgical procedures, and drug treatments. The pathogenesis of NASH is poorly understood, but lipid peroxidation and oxidative stress seem to be the leading culprits. The natural history of NASH is unknown, but it seems to be a stable disease in most patients. Still, the progress to cirrhosis is possible. There is no established treatment for NASH. Treatment is usually directed towards optimizing body weight, and pharmacologic agents are mostly experimentally used. Orthotopic liver transplantation is the treatment of choice for end-stage liver disease secondary to NASH.
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PMID:[Non-alcoholic steatohepatitis]. 1458 65

Nonalcoholic steatohepatitis is an acquired liver disease, usually metabolic characterised by histologic lesions with steatosis, intralobular necrosis and inflammatory infiltrates. Liver biopsy findings are identical to those seen in alcoholic hepatitis. Nonalcoholic steatohepatitis is increasingly reported in industrial countries because of an increase of the prevalence of obesity and diabetes which are the most common risk factors of this disease. The diagnosis of nonalcoholic steatohepatitis is based on a confrontation between clinical and anatomic data and an exclusion of an excessive intake of alcohol and other hepatic disease. Liver biopsy has a prognosis and histologic benefit especially when there is risk factors of fibrosis. This disease is potentially severe with a potential risk for progression to cirrhosis. Progress in pathogenesis is noted but no definite therapy exist. The aim of this review is to indicate current knowledge for the gravity of nonalcoholic steatohepatitis and its consequence and to understand the pathogenesis to prevent cirrhosis.
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PMID:[Non alcoholic steatohepatitis: an emergent and potentially serious pathology]. 1551 46

In 1980, the term non-alcoholic steatohepatitis was coined to describe a new syndrome occurring in patients who usually were obese (often diabetic) females who had a liver biopsy picture consistent with alcoholic hepatitis, but who denied alcohol use. The causes of this syndrome were unknown, and there was no defined therapy. More than two decades later, this clinical syndrome is only somewhat better understood, and still there is no Food and Drug Administration-approved or even generally accepted drug therapy. Patients with primary non-alcoholic steatohepatitis typically have the insulin resistance syndrome (synonymous with the metabolic syndrome, syndrome X, and so forth), which is characterized by obesity, diabetes, hyperlipidemia, hypertension, and, in some instances, other metabolic abnormalities such as polycystic ovary disease. Secondary non-alcoholic steatohepatitis may be caused by drugs such as tamoxifen, certain industrial toxins, rapid weight loss, and so forth. The cause of non-alcoholic steatohepatitis remains elusive, but most investigators agree that a baseline of steatosis requires a second hit capable of inducing inflammation, fibrosis, or necrosis for non-alcoholic steatohepatitis to develop. Our research group has focused its efforts on the interactions of nutritional abnormalities, cytokines, oxidative stress with lipid peroxidation, and mitochondrial dysfunction in the induction of steatohepatitis, both alcoholic and non-alcoholic in origin. Research findings from other laboratories also support the role of increased cytokine activity, oxidative stress, and mitochondrial dysfunction in the pathogenesis of non-alcoholic steatohepatitis. The objectives of this article are to review the (1) definition and clinical features of non-alcoholic steatohepatitis, (2) potential mechanisms of non-alcoholic steatohepatitis, and (3) potential therapeutic interventions in non-alcoholic steatohepatitis.
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PMID:Mechanisms of non-alcoholic steatohepatitis. 1567 Jun 68

The major pathologic manifestations of alcoholic liver injury have been well described, and include three major lesions: steatosis (fatty liver), steatohepatitis (formerly alcoholic hepatitis), and cirrhosis. Recent attention to the problem of nonalcoholic fatty liver disease (NAFLD) in individuals with obesity, diabetes, and other risk factors has shed light on the mechanisms of cellular injury associated with hepatic steatosis and on the potential pathways to steatohepatitis and cirrhosis. Pathologists need to be familiar with the spectrum of changes seen in steatohepatitis, including hepatocyte ballooning, Mallory bodies, mixed inflammatory cell infiltrates, and a distinctive perivenular and pericellular "chicken-wire" fibrosis. These features and other less common histopathologic lesions in the liver are reviewed and illustrated.
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PMID:Morphology of alcoholic liver disease. 1576 28

Clinical and pathological features were reviewed in 76 Japanese patients with non-alcoholic steatohepatitis (NASH). Forty-one were male and 35 were female with the mean age of 49.7 years old (range 15-75 years old, males; 46.3, females; 53.7 years old). Fifty-four percent of patients were preobese with a body mass index (BMI) between 25 and 30, while 16% of the patients were non-obese, and only 30% of the cases were morbidly obese, indicating that Japanese have a greater tendency to develop insulin-resistance and fatty liver disease than Western people. Hyperlipidemia was found in 51%, diabetes mellitus in 38%, and hypertension in 33% of the patients. Abnormally elevated liver function tests were found in one-third to two-thirds of the patients and were characteristically mild with 2- to 3-fold elevation from the normal range in the majority of the cases. Histological features of the liver were similar or identical to those reported in English literature and were characterized by fatty change, perivenular and pericellular fibrosis in zone 3, hepatocyte ballooning and necrosis with occasional Mallory's body formation and polymorphonuclear leukocyte infiltration. Mallory's bodies were found in 39% of patients and were characteristically small and poorly formed compared with those in alcoholic hepatitis. Eosinophilic granular or dirty foggy aggregated, not sufficient to be identified as Mallory's bodies, were a rather characteristic cytoplasmic expression in NASH patients. Portal inflammation and fibrosis were not found in the early stage of NASH, but were found as the disease progresses with formation of C-C and/or P-C bridging fibrosis, and eventually resulting in liver cirrhosis.
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PMID:Clinical and pathological features of non-alcoholic steatohepatitis. 1627 57

Steatohepatitis is pathologically characterized by zone 3-dominant hepatic steatosis with ballooned hepatocytes and Mallory bodies, zone 3 pericellular and perivenular fibrosis with or without bridging fibrosis, and lobular inflammatory cell infiltration. Alcoholic hepatitis is a prototype of this syndrome, but a variety of diseases such as obesity, diabetes mellitus, Wilson disease and hepatitis C could reveal very similar pathological changes in some occasions. Therefore, well defined diseases need to be excluded in the process of differential diagnosis of steatohepatitis. Pathways possibly involved in the development of drug-induced steatohepatitis were categorized into four and outlines of the possible mechanisms involved in the development of this syndrome were proposed in this article.
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PMID:[Drug-induced NASH]. 1676 16

Since the discovery of HFE gene in 1996, considerable progress has been made concerning the iron-metabolism and its major abnormalities. Five types of hereditary hemochromatosis are actually known: type 1 (HFE gene), type 2A (HJV gene), type 2B (HAMP gene), type 3 (TfR2 gene), type 4 (SLC40A1 gene). The HFE C282Y +/+ mutation is responsible for the most frequent type of hemochromatosis in France. Various secondary causes can lead to iron-overload: associated genetic diseases, exogenous iron intake, thalassaemia and refractory anaemia, hepatic siderosis, alcoholic hepatitis, cutaneous porphyria and cirrhosis. The deleterious consequences of iron-overload are due to the interactions of the environmental factors. The role of HFE heterozygote mutations is still discussed. In clinical practice, the interpretation of a serum ferritin increase is a frequent problem that needs a careful evaluation based on the tranferrin saturation measurement. Significant increase of both these factors is in favour of an HFE C282Y +/+ hemochromatosis, after exclusion of a hepatocellular insufficiency or a refractory anaemia. Nevertheless, high ferritin is not always a marker of iron-overload. Thus, there are many disorders increasing the serum ferritin levels without iron overload : cytolysis (hepatic...), inflammatory or infectious syndromes, high alcohol intake, neoplasia... Looking for HFE mutations help to separate type 1 hemochromatosis from other conditions mainly hepatic siderosis (metabolic disorders). The identification of rare types of hemochromatosis (types 2-4) is only required in particular cases. The evaluation of the iron overload is now based on hepatic MRI determination rather than liver biopsy. Repeated phlebotomies remain the essential way to decrease the iron overload in HFE hemochromatosis and to prevent the occurrence of severe and irreversible complications (cirrhosis, arthropathies, cardiac failure, and diabetes). Because of the link established between the amount of iron-overload and the occurrence of complications and the mortality over-risk in HFE C282Y +/+ hemochromatosis, venesections must be started when serum ferritin is higher than 300 microg/l in man and 200 microg/l in woman, whatever the clinical manifestations are and obviously before the symptomatic phase of the disease.
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PMID:[Hereditary and acquired iron overload]. 1737 75


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