Non-alcoholic steatohepatitis. Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc, ; A wider view on diagnostic criteria of nonalcoholic steatohepatitis reply. Gastroenterology, ;

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Non-alcoholic steatohepatitis: physiopathological, clinical and therapeutic implications. Rev Esp Enferm Dig ; Correspondencia : F. Servicio de Medicina Digestiva. Hospital Universitario La Fe. Campanar, Non-alcoholic steatohepatitis NASH must be considered as a part of a broader-spectrum condition -non-alcoholic fatty liver disease NAFLD - that ranges from hepatic steatosis, as its initial form, to NASH, which can progress to liver cirrhosis at the other end of the spectrum.

It is usually classified as cryptogenic because of loss of specific characteristics. Histologically, NASH is similar to alcoholic hepatitis and is characterized by macrovesicular steatosis, necroinflammation, hepatocyte ballooning degeneration, and fibrosis.

NASH is a chronic disease that is very frequently detected in patients with impaired liver function. However, it may also appear in lean males and females with no associated pathology, and in relation to a variety of situations such as diversion surgery, medication, etc.

Powell et al. Since it was first described by Ludwig in 2 , the epidemiological impact and the number of recent publications on this condition have increased. Information is scarce on the natural history of this disease, which can progress to the following consecutive stages in some patients: fatty liver, steatohepatitis, steatohepatitis with fibrosis, and cirrhosis.

Matteoni et al. Other studies 4, have corroborated the possible progression of this condition in a significant percentage of patients Fig.

Similarly, many patients with cryptogenic cirrhosis may develop NASH with a loss of the peculiar histological characteristics of this condition 14, These cryptogenic cirrhosis may even recur in the form of NASH following transplantation Many factors can contribute to NASH-related mortality, including the complications of obesity and diabetes. Causes of liver disease-related mortality include liver failure, cirrhosis complications hemorrhage due to varices or ascites , and hepatocarcinoma, although the precise incidence of each of these complications is unknown Histological improvement can also occur, especially in those with minimal fibrosis.

Following weight loss, a drop in inflammation and Mallory bodies may be detected -including perisinusoidal fibrosis- particularly if weight is gradually lost and diet is associated with physical exercise 20, In many cases liver failure manifests during rapid weight loss, regardless of the method used, especially in patients with morbid obesity undergoing weight-loss surgery 22, Insulin resistance plays a fundamental role in type-2 diabetes mellitus, as well as in obesity, and is the most predisposing and reproducible factor in NASH 24 Table I.

Up to one third of patients have diabetes or fasting hyperglycemia at the time of diagnosis with NASH 12, The most frequent association is type-2 diabetes, although difficult-to-control insulin-dependent diabetes may also be present Diabetes is an important independent predictor of severe hepatic fibrosis in NASH Autopsy studies have revealed that type-2 diabetes is associated with NASH, with a 2. An autopsy study found the prevalence of NASH to be 6-fold greater among obese versus lean individuals Obesity also correlates with the severity of fibrosis in NASH, regardless of the diabetes status or age Distribution of body fat may be important; a significant correlation has been found between grade of steatosis and waist-to-hip ratio 33 , indicating the importance of visceral fat as a predictor of steatosis Lean males rarely present with significant hepatic fibrosis; Ratziu et al.

A relevant role has been ascribed to hypertriglyceridemia in the pathogenesis of NASH, since a correction of this lipid anomaly has been associated with improved liver function tests NASH has been associated with rapid weight loss following surgery for obesity, extensive intestinal resection, and severe fasting Older age and female sex are considered independent factors associated with liver fibrosis in NASH 17, Jejunoileal bypass, gastroplasty, gastric bypass and other surgical techniques leading to rapid weight loss, as well as feeding disorders such as anorexia or bulimia, celiac disease, jejunal diverticulosis, other causes of bacterial overgrowth, total parenteral nutrition, abetalipoproteinemia, partial lipodystrophy, Weber-Christian disease, toxic oil syndrome, etc.

Cardiovascular drugs such as amiodarone, perhexiline maleate, and more rarely calcium channel blockers such as nifedipine and diltiazem, high-dose glucocorticoids, synthetic estrogens, tamoxifen, chloroquine, etc. Amiodarone, perhexiline maleate, diethylaminoetoxyhexestrol and tamoxifen cross the mitochondrial external membrane without difficulty because of their lipophilic properties, and are "pushed' into the mitochondria from the intermembranous space by the high electrochemical potential at the internal membrane, thus reaching high intramitochondrial levels.

Beta-oxidation causing steatosis is thus inhibited, and electron transfer throughout the respiratory chain is blocked, which leads to a transfer of electrons to oxygen, thereby forming superoxide radical anions and generating oxygen free radicals. Insulin resistance appears to be a key pathogenic and reproducible factor in NASH 30,39, It is defined as a reduced capacity of insulin to perform its biological functions in typical target tissues such as musculoskeletal, liver or fat tissues.

This concept falls within the so-called metabolic syndrome or syndrome X in which several clinical diseases are associated, including obesity, hyperlipemia, arterial hypertension, and diabetes mellitus, and which carries a higher risk for cardiovascular disease. Hyperinsulinemia basically results from compensatory hypersecretion by beta-cells and not, as previously believed, from reduced insulin breakdown as a result of liver disease, although this mechanism may also have an influence in cirrhotics.

Insulin-stimulated intracellular glucose transport is preferably controlled by a translocation of the GLUT4 carrier from an intracellular vesicular membrane to the plasma membrane, which occurs after the binding of insulin to its cell receptor.

GLUT4 expression is altered in different forms of insulin resistance; e. A hypothesis has recently been put forward that fat cells may play a central role in the development of insulin resistance, as well as of NASH. Fat cells appear to be an important endocrine organ that may trigger an inflammatory process in relation to NASH development. It can secrete potentially toxic substances such as tumor necrosis factor TNF , leptin, resistin, and fatty acids whose concentration levels correlate with insulin resistance, and therefore they should be relevant in the development of type-2 diabetes.

Furthermore, it has been observed that visceral fat and not total body fat is a predictive factor of liver steatosis, hyperinsulinemia, reduced hepatic extraction of glucose, and insulin resistance.

For a better understanding of the emerging hypotheses on NASH, it may be appropriate to review the normal metabolism of fatty acids. During digestion, dietary triglycerides are converted by enterocytes into chylomicrons, which then migrate via the lymphatics and are subsequently hydrolyzed into fatty acids by lipoprotein lipase at the capillary endothelium of adipose and liver tissues. Free fatty acids thus produced are highly miscible with cell membranes, so that they immediately go to fat cells where they are converted into resterified triglycerides, or to the muscle as energy supply, or enter the liver.

During fasting, fatty acids supplied to the liver result from a hydrolysis of triglycerides stored within the adipose tissue. Thus, under normal conditions hydrolysis is stimulated by catecholamines, glucagon, and growth hormone, and is inhibited by insulin.

In the liver, fatty acids undergo mitochondrial beta-oxidation, a step of triglyceride synthesis or phospholipid and cholesterol ester formation. However, in situations of insulin resistance, as is the case with most patients with NASH, increased blood levels affect the adipocyte and liver cells in a different way. In the adipocyte it favors lipolysis with the consequent release of more fatty acids to the liver; in the hepatocyte it stimulates fatty acid synthesis and inhibits mitochondrial beta-oxidation of fatty acids Furthermore, high levels of insulin can inhibit apolipoprotein B, a component of VLDL, synthesis, which makes it difficult for triglycerides to be transported out of the liver.

The greater afflux of fatty acids to the liver, together with the potential alterations of its metabolization within the liver including greater triglyceride synthesis, reduced triglyceride elimination, and reduced beta-oxidation of fatty acids , results in hepatic steatosis; these mechanisms are considered a "first impact' in the development of NASH.

However, steatosis is not always quiescent, since high intrahepatic concentrations of free fatty acids and their saturation of mitochondrial beta-oxidation make them susceptible to a "second impact', where additional factors influencing oxidative stress and lipid peroxidation are involved; this leads to a high afflux of electrons to the mitochondrial respiratory chain, and an increased production of oxygen free radicals OFR , which are responsible for the hepatic lesions of NASH Fig.

Patients with NASH have been shown to present ultrastructural mitochondrial lesions 40,45 , reduced activity of mitochondrial complexes 46 , and deficient mitochondrial ATP formation 47 , which are also involved in OFR formation. OFR determine the production of various cytokines in different types of cells hepatocytes, adipocytes, and Kupffer cells. This factor is normally found synthesized and maintained in an inactive form within the cell cytoplasm, bound to the IKK protein.

In turn, each one of these cytokines may be involved in the pathogenesis of hepatic lesions. It should be pointed out that the products derived from lipid peroxidation, melandialdehyde MDA and 4-hydroxynonenal HNE 48 , appear to be involved in the pathogenesis of NASH-related hepatic lesions.

Both cause direct toxicity and can trigger immune reactions when they covalently bind to proteins Fig. HNE also has a chemotactic activity on neutrophils Fig. Most patients with primary iron overload unrelated to hemochromatosis have insulin resistance , which may improve with phlebotomy 55, Insulin resistance causes a greater expression of transferrin receptors on the cell surface, and increases the exocytosis of pre-existing intracellular receptors in association with high concentrations of serum ferritin 12,51,53 and increased liver iron in some patients Elevated ferritin does not necessarily mean increased liver iron, but is due to NASH as an acute phase reactant.

Ferrous iron is a potent generator of hydroxyl radicals and can contribute to OFR accumulation, cell injury, and cell death; when stellate cells are activated, it can stimulate fibrogenesis. It has yet to be determined whether moderate iron overload in NASH participates in the pathogenesis of this disease, or is related to associated metabolic anomalies, or is due to unidentified environmental or genetic factors.

For example, heterozygous mutation of the HFE gene, frequently detected in these patients, might increase iron deposition in the liver It has been suggested that leptin may be classified as a cytokine as it does not only regulate food intake and energy consumption, but also modulates immune and inflammatory responses Furthermore, its production by stellate cells may play an important role in hepatic fibrosis It can contribute to the progression of steatosis to NASH and finally to cirrhosis, given its profibrogenic and modulating activity on the hepatic inflammatory response On the other hand, it has been observed that the administration of leptin to congenitally leptin-deficient mice with generalized lipodystrophy induces a reduction in body fat and a marked reduction of insulin resistance Endotoxin and endotoxin-mediated cytokine release plays an important role in the pathogenesis of alcoholic hepatitis.

Endotoxin can also contribute to the development of NASH in some cases, as in those arising from intestinal diversion surgery. Experimentally, in genetically obese rats there is a significantly increased production of endogenous ethanol, an enhanced sensitivity to endotoxin, and an alteration of Kuppfer cells, all of which favor the development of NASH.

Furthermore, it has been observed that the production of endogenous ethanol decreases after treatment with oral neomycin; therefore one could hypothesize on whether the small amount of ethanol detected in some patients as produced by the intestinal flora could be involved in the pathogenesis of this disease Proliferating peroxisome activated receptors PPAR are expressed in tissues with important oxidative phosphorilation, and regulate lipids through the peroxisomal, microsomal, and mitochondrial pathways.

Some mutations of the encoding gene for these nuclear receptors have been identified in patients with NASH, and might be involved in its pathogenesis The possible role of different drugs in the pathogenesis of this disease is discussed in a previous section.

Although most cases of NASH are detected in the fifth and sixth decades of life, it should be emphasized that the prevalence of this disease is increasing in children 67,68 ; it can therefore present at any age. It is interesting to remember that many cases of cryptogenic cirrhosis could be the end stage of NASH and present with the multiple complications of advanced cirrhosis.

Several studies 73,74 suggest that hepatocarcinoma could be a complication of this disease. According to this study, metabolic anomalies might facilitate the progression of NASH to hepatocarcinoma In patients with cryptogenic cirrhosis, the incidence of hepatocarcinoma was found to be higher than in cirrhotic patients with a well-defined viral or alcoholic etiology 76 , and therefore hepatocarcinoma could be a late complication of NASH.

However, more recent studies have shown an association of diabetes with hepatocarcinoma only in the presence of hepatitis C virus, hepatitis B virus, or alcoholic cirrhosis 77 , which suggests that diabetes may only be a marker of advanced liver disease with a greater likelihood of progression to hepatocarcinoma. The most frequent anomaly in liver function tests in this disease is a fold increase in transaminases 10, 17,71 , occasionally a fold increase 17 , although they normally remain within normal values.

Bilirubin and albumin usually remain within their normal ranges 7,69,70, George et al. Moirand et al. Younossi et al. Fargion et al. Mendler et al. Chitturi et al. Other diseases of the liver can be associated with NAFLD, and the latter can influence the prognosis of conditions such as hepatitis C virus-related cirrhosis or HFE-hemochromatosis; therefore, tests positive for the C virus or hemochromatosis do not exclude the diagnosis of NAFLD.


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Non-alcoholic steatohepatitis: physiopathological, clinical and therapeutic implications. Rev Esp Enferm Dig ; Correspondencia : F. Servicio de Medicina Digestiva.

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