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.
Gastroenterology . 2001 Sep;121(3):710-23
Polyenylphosphatidylcholine inhibits PDGF-induced proliferation in rat hepatic stellate cells.
Polyenylphosphatidylcholine (PPC), a polyunsaturated phospholipid extract from soy beans, prevents the development of liver cirrhosis in animal models. Its mechanism of action is unknown. Based on the hypothesis that PPC might act by decreasing hepatic stellate cell proliferation, we studied the effect of PPC and its main components, dilinoleoylphosphatidylcholine (DLPC) and palmitoyl-linoleoylphosphatidylcholine (PLPC), on PDGF-induced stellate cell proliferation and intracellular signal transduction. Normal rat hepatic stellate cells in tissue culture were serumstarved, and incubated with 10ng/ml PDGF in the absence or presence of phospholipids. Cell proliferation was measured by 3H-thymidine incorporation. P44MAPK activation was determined by kinase assay, and AP-1 binding by electrophoretic mobility shift assay. PPC (200 ng/ml) significantly inhibited PDGF-induced proliferation (p < 0.05; ANOVA, n = 3) and antagonized PDGF-induced P44MAPK activation and AP-1 binding. This effect was mimicked by DLPC but not by PLPC. Neither DLPC nor PLPC prevented PDGF receptor activation. We conclude that PPC exerts a previously unrecognized effect on mitogen-induced stellate cell proliferation which may be mediated by DLPC. Inhibition of this cascade represents a potential mechanism for the inhibitory effect of PPC on hepatic fibrogenesis.
Biochem Biophys Res Commun . 1998 Jul 9;248(1):174-9
Nonalcoholic steatohepatitis in children.
Nonalcoholic steatohepatitis (NASH) is one entity in a spectrum of chronic liver disease related to obesity, hyperinsulinemia, insulin resistance, and liver cell injury from free fatty acid toxicity or other oxidant stress. The more inclusive term "nonalcoholic fatty liver disease" (NAFLD) is increasingly being used to encompass the entire spectrum, which includes simple hepatic steatosis without inflammation (which may not lead to progressive liver injury), NASH itself, and the resulting cirrhosis (which may be devoid of steatosis). Children get NAFLD, and the incidence of this pediatric liver disease is rising as childhood obesity becomes increasingly prevalent. Although much remains to be learned about pediatric NAFLD, it is already evident that children with NASH risk progressive liver damage, including cirrhosis. Liver biopsy is required for definitive diagnosis, and other causes of fatty liver in childhood must be excluded. Gradual weight loss through increased regular exercise and a low-fat, low-refined carbohydrate diet appears to be effective. Drug treatments are being developed. Pediatric NASH is a serious complication of childhood obesity.
Curr Gastroenterol Rep . 2003 Jun;5(3):253-9
Nonalcoholic fatty liver disease (NAFLD) in children.
Nonalcoholic fatty liver disease (NAFLD) is common in obese children and is a growing problem, given the increase in prevalence of obesity. NAFLD is also associated with diabetes, insulin resistance, hypercholesterolemia, and hypertriglyceridemia. Although mostly benign, some children with NAFLD develop fibrosis and cirrhosis, which necessitates close monitoring. Chronically elevated plasma liver enzyme levels is the most frequent finding. Ultrasound (US) examination allows confirmation of the diagnosis and it is useful for the follow-up. Gradual and sustained weight reduction is a management option that is worth trying initially. Other modalities of management, although interesting, await evidence as well as information on long-term benefits and effects. Sustained increase of transaminases despite weight reduction is a cause for concern and may require a liver biopsy both to assess severity of liver damage and for prognostic purposes.
Curr Opin Pediatr . 2002 Oct;14(5):593-600
Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease.
Nonalcoholic steatohepatitis is a poorly understood and hitherto unnamed liver disease that histologically mimics alcoholic hepatitis and that also may progress to cirrhosis. Described here are findings in 20 patients with nonalcoholic steatohepatitis of unknown cause. The biopsy specimens were characterized by the presence of striking fatty changes with evidence of lobular hepatitis, focal necroses with mixed inflammatory infiltrates, and, in most instances, Mallory bodies; Evidence of fibrosis was found in most specimens, and cirrhosis was diagnosed in biopsy tissue from three patients. The disease was more common in women. Most patients were moderately obese, and many had obesity-associated diseases, such as diabetes mellitus and cholelithiasis. Presence of hepatomegaly and mild abnormalities of liver function were common clinical findings. Currently, we know of no effective therapy.
Mayo Clin Proc . 1980 Jul;55(7):434-8
Motion - all patients with NASH need to have a liver biopsy: arguments against the motion.
Most cases of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are suspected on the basis of the exclusion of viral, autoimmune, metabolic and genetic causes of chronic liver disease in patients with chronic elevation of aminotransferase enzymes. However, the definitive diagnosis of NASH requires liver biopsy. Valuable blood tests include hepatitis B and C serology, iron profile, alpha 1-antitrypsin phenotype, ceruloplasmin, antinuclear antibody and antismooth muscle antibody, and serum protein electrophoresis. If these tests are negative or normal, and if there are no symptoms or signs of chronic liver disease, it is unlikely that a specifically treatable liver disease would be discovered at biopsy. The prevalence of NAFLD in the general population appears to be approximately 20%, and 2% to 3% of people have NASH. There is no proven specific therapy for the spectrum of nonalcoholic liver disease; therefore, the management of the patient with NASH is not likely to be changed after histological assessment. Bleeding, sometimes fatal, and other complications requiring hospitalization can occur, and liver biopsies should not be undertaken without clear clinical indications. The high cost of undertaking histological assessment of all persons with asymptomatic elevations of liver enzymes cannot be justified in view of the risks and limited clinical benefits.
Can J Gastroenterol . 2002 Oct;16(10):722-6
The utility of radiological imaging in nonalcoholic fatty liver disease.
BACKGROUND & AIMS: This prospective study evaluates the role of radiological modalities in establishing the diagnosis of nonalcoholic steatohepatitis (NASH). METHODS: Consecutive patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD) were enrolled (2000-2001). Patients with other liver diseases and significant alcohol consumption (>20 g/day) were excluded. Clinicodemographic data were gathered at the time of liver biopsy. Each biopsy specimen was assessed by a hepatopathologist. Each patient underwent a limited abdominal ultrasonography ( US ), computerized tomography (CT), and magnetic resonance imaging (MRI). Films were interpreted by a radiologist who used a predetermined radiological protocol. Each radiological study was reread by the same radiologist and a second radiologist. RESULTS: Patients with NASH had greater aspartate aminotransferase levels (P = 0.03), greater ferritin levels (P = 0.05), more hepatocyte ballooning (P < 0.0001), and more fibrosis (P = 0.002). None of the radiological features distinguished between NASH and other types of NAFLD. No radiological modality detected the presence of hepatocyte ballooning, Mallory's hyaline, or fibrosis, which are important features in the diagnosis of NASH. The presence of >33% fat on liver biopsy was optimal for detecting steatosis on radiological imaging. CONCLUSIONS: Differences between NASH and nonprogressive NAFLD were not apparent with any radiological modality. Of the pathologic features important for establishing the diagnosis of NASH, only the severity of steatosis was reflected in these radiological modalities. Good intraobserver agreement was evident for each modality (US, CT, and MRI) that was superior to interobserver agreement.
Gastroenterology. 2002 Sep;123(3):745-50
CT and MRI of diffuse liver disease.
CT and MRI contribute important information to the clinical evaluation of diffuse liver disease. In some cases, these modalities can establish a diagnosis that was not ascertained histologically, which is often the case when sampling errors prevent a definitive tissue diagnosis. Characteristic alterations of liver attenuation on CT, signal changes on MRI, and morphological changes appreciated with both modalities can be used to diagnose fatty infiltration, some parenchymal deposition diseases, and cirrhosis. Furthermore, hepatocellular disease can be confirmed in the setting of indeterminate clinical and laboratory findings. Significant overlap in the imaging findings of this wide range of disorders continues to limit specificity; however, at a minimum, these techniques provide a rapid means to a noninvasive evaluation that often guides clinical decisions. Faster scanning techniques available with CT and MRI may provide additional information by assessing contrast dynamics. This review of CT and MRI in diffuse liver disease considers the diagnostic utility and clinical implications of these modalities. Pathological findings relevant to imaging considerations are discussed.
Semin Ultrasound CT MR. 1995 Feb;16(1):16-33
Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values.
A retrospective study was performed to (1) characterize the clinical and histologic features of those with nonalcoholic fatty liver disease (NAFLD) and normal alanine aminotransferase (ALT) values, (2) compare the spectrum of NAFLD associated with normal versus elevated ALT levels, and (3) determine whether there were differences in the clinical or histologic spectrum of NAFLD between those with a low normal versus high normal ALT value. A total of 51 subjects with NAFLD and normal ALT were identified and compared with 50 consecutive subjects with NAFLD and elevated ALT. The major indications for liver biopsy in those with normal ALT were unexplained hepatomegaly (n = 21) and evaluation as a potential donor for living donor liver transplantation (n = 16). The 2 groups were comparable with respect to age, gender distribution, and ethnicity. Approximately 80% of cases in both groups had at least 1 feature of the metabolic syndrome, the major risk factor for NAFLD. The 2 groups were also comparable with respect to the grade of the individual histologic parameters of NAFLD. A total of 12 subjects with normal ALT levels had bridging fibrosis, whereas 6 had cirrhosis. Diabetes was the only factor independently associated with an increased risk of advanced fibrosis (bridging fibrosis or cirrhosis) by multivariate analysis (relative risk: 2.3, P <.01). The mean steatosis (1.6 vs. 2.16, P <.04) and perisinusoidal fibrosis scores (0.35 vs. 0.9, P <.049) were lower in those with low normal (<30 IU/L) ALT versus high normal ALT. However, the prevalence of advanced fibrosis was similar (5 of 15 vs. 13 of 36, respectively). In conclusion, (1) the entire histologic spectrum of NAFLD can be seen in individuals with normal ALT values, (2) the histologic spectrum in these individuals is not significantly different from those with elevated ALT levels, and (3) a low normal ALT value does not guarantee freedom from underlying steatohepatitis with advanced fibrosis.
Hepatology . 2003 Jun;37(6):1286-92