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Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of excess liver triacylglycerol (TAG), inflammation, and liver damage. The goal of the present study was to directly quantify the biological sources of hepatic and plasma lipoprotein TAG in NAFLD. Patients (5 male and 4 female; 44 +/- 10 years of age) scheduled for a medically indicated liver biopsy were infused with and orally fed stable isotopes for 4 days to label and track serum nonesterified fatty acids (NEFAs), dietary fatty acids, and those derived from the de novo lipogenesis (DNL) pathway, present in liver tissue and lipoprotein TAG. Hepatic and lipoprotein TAG fatty acids were analyzed by gas chromatography/mass spectrometry. NAFLD patients were obese, with fasting hypertriglyceridemia and hyperinsulinemia. Of the TAG accounted for in liver, 59.0% +/- 9.9% of TAG arose from NEFAs; 26.1% +/- 6.7%, from DNL; and 14.9% +/- 7.0%, from the diet. The pattern of labeling in VLDL was similar to that in liver, and throughout the 4 days of labeling, the liver demonstrated reciprocal use of adipose and dietary fatty acids. DNL was elevated in the fasting state and demonstrated no diurnal variation. These quantitative metabolic data document that both elevated peripheral fatty acids and DNL contribute to the accumulation of hepatic and lipoprotein fat in NAFLD.

Adult↗

Treatment of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause for elevated liver enzymes in the developed nations. Beyond prevention programs which are of particular interest because of the increasing number of overweight children, treatment should be focussed on the most important risk factors, obesity and insulin resistance. As a consequence of elucidating the pathomechanisms of NAFLD, the number of potential therapeutic options increased. However, many studies investigating the therapeutic effect show shortcomings in at least one of the following points: lack of a serial liver biopsy, short term of treatment and limited number of included patients. The second generation insulin sensitizer pioglitazone and rosiglitazone show the most promising improvements in NAFLD, but weight gain and potential hepatotoxicity calls for attention. In conclusion, a general recommendation for the application of specific drugs cannot be given. Besides controlled clinical trials, weight reduction and physical activity to improve insulin sensitivity in obese patients should be the priority objective.

Alanine Transaminase↗

Serum sialic acid in malignant tumors, bacterial infections, and chronic liver diseases.

The total serum sialic acid concentration was determined in 2,264 persons with various malignant tumors, bacterial infections, rheumatic diseases, and chronic liver diseases, and in a control group. The thiobarbiturate method according to Warren was used. The upper limit (95% percentile) in the control group was 2.23 mumol/ml. Higher values were found in the groups with neoplasms (mean: 3.04 mumol/ml), inflammatory diseases (e.g., pneumonia: 3.02 mumol/ml), and active rheumatoid arthritis (3.05 mumol/ml). In the group with malignant diseases, the sialic acid concentration at the time of diagnosis was highest for bronchial carcinoma (3.29 mumol/ml) and lowest for breast cancer (2.58 mumol/ml). In chronic liver diseases the mean sialic acid level was lower than in a heterogeneous group of noninflammatory and nonneoplastic diseases. The estimation of the serum sialic acid concentration could be useful in the detection of tumor burden and metastases, and in the evaluation of the later course and prognosis of malignant neoplasms if bacterial/inflammatory and active rheumatoid processes can be excluded.

Adolescent↗

Diagnostic value of liver biopsy in alcoholic liver disease.

Because it remains debatable whether all patients with a clinical diagnosis of alcoholic liver disease should have a liver biopsy to help confirm the diagnosis, we evaluated the diagnostic value of liver biopsy in alcoholic liver disease. Studied were 108 consecutive patients who had a percutaneous liver biopsy for the first time. In all cases the patient's clinical diagnosis recorded before biopsy was compared with the histological diagnosis of an experienced histopathologist. Prebiopsy clinical data (reported alcohol intake, signs of chronic liver disease) and laboratory data (liver function tests, mean corpuscular volume, ferritin, hepatitis B serology) were reviewed. We found that a prebiopsy clinical diagnosis of alcoholic liver disease (n = 35) was confirmed by biopsy in all but one case. The prebiopsy diagnosis of alcoholic liver disease was significantly associated with a histological diagnosis of alcoholic liver disease (specificity 98%, sensitivity 79%). Individually, alcohol intake, signs of chronic liver disease, the alanine aminotransferase (ALT), the aspartate aminotransferase to ALT ratio, and the mean corpuscular volume were significantly associated with a histological diagnosis of alcoholic liver disease. When clinical and laboratory parameters were considered jointly using stepwise logistic regression, only reported alcohol intake and mean corpuscular volume were significant. Liver biopsy may not always be necessary for the identification of that broad group of patients with alcoholic liver disease.

Alanine Transaminase↗

Chronic active liver disease with common variable hypogammaglobulinemia.

Progressive liver injury in chronic active liver disease is usually associated with elevation of serum immunoglobulin levels. However, the role of immunoglobulins in the pathogenesis of this disease is still obscure. We report here the case of a 41-year-old man with hypogammaglobulinemia since at least 1964 in whom chronic active liver disease later developed. From 1954 he had had frequent respiratory tract infections, and these continued, along with diarrhea, despite regular gamma-globulin therapy. Studies in 1969 showed absent serum IgA and IgM and an abnormally low level of IgG. In 1974, liver enzyme abnormalities were recorded and a diagnosis of chronic active liver disease was made. A liver biopsy showed cirrhosis with active hepatitis. Lymphocyte function studies revealed that the T cells suppressed B-cell maturation and production of immunoglobulins. He was treated with azathioprine and prednisone, and this therapy has been associated with a decrease in both the elevation in liver enzymes and the frequency of infections. This case suggests that liver cell injury in chronic active liver disease is independent of the elevation of immunoglobulins and that immunosuppressive therapy may be well tolerated by patients with hypogammaglobulinemia.

Adult↗

The choice of inhalation anaesthetic for major abdominal surgery in children with liver disease.

Many children with liver disease undergo major abdominal surgery. Maintenance of anaesthesia is thus an important consideration in this surgical population. Despite a comprehensive and painstaking review of the literature, a sound evidence base, on which a choice of inhalation anaesthetic may be made, is lacking due to limited research in these patients. Differences between the more recent agents such as isoflurane, sevoflurane and desflurane are minor. Sevoflurane is favoured in paediatric practice for gaseous induction, but desflurane or isoflurane are marginally the preferred agents for maintenance of anaesthesia in children with liver disease undergoing major abdominal surgery. However, on the evidence that exists, much of it admittedly in animals and in adults, all three are preferable to halothane in this group of patients. More work is needed in this area before sound conclusions can be drawn and one agent proved to be definitely superior to the others.

Abdomen↗

A practical approach to nutritional support in liver disease.

Nutritional problems are very common in patients with liver disease. The underlying liver disease will cause anorexia, nausea, and a poor appetite. In addition, alcohol acts as "cheap calories" and may be an added problem. Physicians taking care of patients with liver disease often place them on restrictive diets that compound the nutritional problem. Patients must be addressed for both the liver disease and the nutritional problems its treatment may create. One very important fact is that the majority of patients with liver disease will tolerate standard formulas that are much more "cost-effective" for the patients. How to calculate caloric and protein needs and how to select certain formulas are addressed. The results that show nutritional support is beneficial in decreasing mortality and morbidity are reviewed.

Humans↗

Endoscopic stent insertion into the gallbladder for symptomatic gallbladder disease in patients with end-stage liver disease.

BACKGROUND: Endoscopic stent insertion into the gallbladder entails placement of a double-pigtail polyethylene stent between the gallbladder and the duodenum at ERCP. This procedure may be an effective temporary measure in patients with severe comorbid conditions, especially end-stage liver disease, that subsequently allows more definitive therapy, including liver transplantation. METHODS: The records for 29 patients who underwent attempted endoscopic gallbladder stent insertion between May 1999 and May 2004 were reviewed retrospectively. RESULTS: Mean patient age was 47 years; 86% of the patients were listed for liver transplantation, with a mean model for end-stage liver disease score of 15; 72% had Child's class B cirrhosis. Indications for gallbladder stent placement included recurrent biliary colic (69%), acute cholecystitis (17%), acalculous cholecystitis (7%), and gallstone pancreatitis (7%). Of the 29 patients who underwent ERCP, stent placement was successful in 26 (90%). Median follow-up was 9.4 months (range 0.1-40.5 months). Of those who had a stent placed, 6 (22%) subsequently underwent liver transplantation and another 15 (56%) were alive, most awaiting liver transplantation. Only 3 patients had late a complication or recurrence of biliary symptoms after stent placement. CONCLUSIONS: Endoscopic stent placement in the gallbladder is a safe and an effective palliative treatment for patients with symptoms caused by gallbladder disease who are poor surgical candidates.

Adult↗

Effectiveness of orthotopic liver transplantation on the restoration of cholesterol metabolism in patients with end-stage liver disease.

The effects of end-stage liver disease and orthotopic liver transplantation on components that modulate cholesterol esterification in plasma were assessed. In comparison with healthy controls, patients with end-stage liver disease had significantly decreased concentrations of lecithin-cholesterol acyltransferase mass, apolipoprotein A-1, total phospholipids, and both total and esterified cholesterol. Elevated phosphatidylcholine and reduced lysophosphatidylcholine fractions indicated impairment of cholesterol esterification by lecithin-cholesterol acyltransferase. Constituent fatty acids of the patients' phospholipids and cholesterol esters manifested increased saturation and a concomitant reduction of polyunsaturated fatty acids, indicative of impaired hepatic elongation and desaturation of essential fatty acids. By the third month after hepatic replacement, the plasma concentrations of total cholesterol, phospholipids, lecithin-cholesterol acyltransferase, and apolipoprotein A-1 were comparable to those of the healthy subjects. Despite the improvement in cholesterol esterification and the rapid normalization of the enzyme and cofactor involved in this process, the percentage of phosphatidylcholine remained significantly higher and the percentages of lysophosphatidylcholine and esterified cholesterol remained significantly lower than in the healthy subjects at 6 mo. Phospholipid and cholesterol ester fatty acid patterns attained normalcy by the sixth month after transplant. We conclude that hepatic transplantation effectively restores cholesterol and essential fatty acid metabolism in patients with end-stage liver disease.

Adult↗

Value of liver biopsy in the evaluation and management of chronic liver disease in renal transplant recipients.

PURPOSE: Liver disease is a frequent complication in renal transplant recipients. To understand the nature and progression of hepatic disease in these patients, we performed percutaneous biopsies in 77 subjects who had chronic liver dysfunction in the posttransplant period. The purpose of the present investigation is to delineate the morphologic spectrum of chronic liver disease in the renal allograft recipients and to characterize the clinical and histologic progression of each of the different morphologic forms. PATIENTS AND METHODS: Between 1971 and 1990, 915 patients received renal transplants at the Hennepin County Medical Center, Minneapolis, Minnesota. One hundred nineteen (13%) of them had abnormal liver function that persisted for longer than 6 months. Percutaneous liver biopsies were performed in 77 of these patients, but adequate tissue for histologic evaluation was available in only 72. After the biopsy, the clinical and histologic course of each subject was monitored in relation to the baseline hepatic morphology. To assess the predictive value of serum enzymes in diagnosing the histologic lesions, the level of serum enzymes at the time of the biopsy was correlated with the morphologic diagnosis. In addition, several clinical, biochemical, etiologic, and histologic variables were screened for their association with histologic progression to liver cirrhosis. RESULTS: The morphologic diagnosis in the 72 specimens evaluated at baseline was as follows: fat metamorphosis in 8 (11%), chronic persistent hepatitis in 20 (28%), early chronic active hepatitis in 20 (28%), advanced chronic active hepatitis in 15 (21%), and hemosiderosis in 9 (12%). There was no statistical correlation between the serum enzyme levels and the histologic diagnosis. During a mean follow-up of 5.7 +/- 3.9 years, clinical progression to hepatic failure and death occurred in 35% of patients with early chronic active hepatitis, 55% with hemosiderosis, and 60% with advanced chronic active hepatitis. None of the patients with the morphologic diagnosis of fat metamorphosis or chronic persistent hepatitis died as a consequence of hepatic failure. Follow-up liver specimens were obtained in 34 (47%) of the original 72 subjects after a mean interval of 4.5 +/- 4.3 years. Of the 15 patients with the initial diagnosis of early chronic active hepatitis, 9 (60%) showed morphologic transition to advanced chronic active hepatitis, and in 1 of the 5 patients with hemosiderosis (20%), the lesion had resolved after successive phlebotomies. During the follow-up, 60% with early chronic active hepatitis (9 of 14), 66% with hemosiderosis (2 of 3), and 100% with advanced chronic active hepatitis (4 of 4) showed histologic progression to liver cirrhosis. On the contrary, no morphologic alterations were observed in the follow-up specimens of patients with fat metamorphosis or chronic persistent hepatitis. Of the different variables screened for their association with histologic progression, older age at transplant, female sex, and morphologic diagnosis of advanced chronic active hepatitis were found to be significant. CONCLUSION: Histologic diagnosis can be a useful marker in predicting the course of chronic liver disease after renal transplantation. Liver biopsy should be incorporated into the evaluation and management of chronic liver disease in renal transplant recipients.

Adult↗

Atypical ductular proliferation and its inhibition by transforming growth factor beta1 in the 3,5-diethoxycarbonyl-1,4-dihydrocollidine mouse model for chronic alcoholic liver disease.

Many acute and chronic liver diseases are often associated with atypical ductular proliferation (ADP). These ADPs have gained increasing interest since a number of recent observations suggest that ADPs may represent progenies of the putative liver stem cell compartment. In this study, we show that feeding mice with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) results in persistent proliferation of primitive ductules with poorly defined lumens. Similar to oval cell proliferation in other rodent models as well as in various human liver diseases, DDC-induced ADP originated from the portal tract, spread into the hepatic lobule, and was associated closely with appearance of hepatocytes harboring an antigen (A6), which normally is expressed in biliary epithelium. Furthermore, DDC treatment severely inhibited the regenerative capacity of mice after partial hepatectomy. The development of ADP was selectively blocked in DDC-fed TGF-beta1 transgenic mice producing active TGF-beta1 in the liver and no accumulation of new hepatocytes expressing the A6 antigen was observed. Moreover, the transforming growth factor beta1 (TGF-beta1) transgenic mice did not survive beyond 3 weeks from starting the DDC-containing diet. The results suggest that persistent activation of the hepatic stem cell compartment is essential for liver regeneration in the DDC model and that active TGF-beta1 may negatively control activation of stem cells in the liver. These data further emphasize the relevance of the DDC model as an experimental tool for studying chronic liver diseases.

Animals↗

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↗

Current nutrition in liver disease.

Malnutrition is common in severe liver disease. Assessment of malnutrition usually requires a subjective global assessment of the patient with a few additional tests that often include handgrip strength and arm-muscle circumference. The severity of liver disease correlates well with the severity of malnutrition, which has prognostic value. Malnutrition is multifactorial, is difficult to correct, and occurs in liver disease independently of the etiology of hepatic injury. Patients who have severe protein-calorie malnutrition require diets with high calorie and protein intake, even in the presence of hepatic encephalopathy. Some forms of complementary and alternative medicine are frequently used in patients with advanced liver disease, but supporting scientific data is needed. Obesity is detrimental to patients with advanced liver disease and is of greater concern in liver transplant candidates because it increases transplant-related morbidity. Data detailing the effects of aggressive nutritional support before transplantation are scarce, and more studies are needed.

Journal Article↗

The natural history and risk factors for progression of non-alcoholic fatty liver disease and steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is a condition of increasing incidence in western Countries seldom associated to other diseases of high prevalence in general population (i.e. diabetes and obesity). NAFLD ranges from simple fatty liver to steatohepatitis (NASH), which may lead to cryptogenic cirrhosis and in some cases hepatocellular carcinoma (HCC). Natural history of NAFLD in humans is poorly understood and progression of liver disease seems to be due to interaction between hosting (i.e. genetic, gut flora, insulin resistance) and environmental factors (social and eating behaviours) that should be responsible of increased oxidative stress within hepatocytes. Even if we need non-invasive markers able to describe the progression of liver disease, only meaning of liver biopsy is useful to characterize the stigmata of worsening such as inflammation and fibrosis.

Animals↗