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Nutrition in chronic liver disease and liver transplantation.

Significant contributions to the field of nutrition and liver disease have been published in the last year. The most relevant includes work on the pathogenic role of energy metabolism disturbances in the development of malnutrition in cirrhosis, as well as data on the relationship between preoperative nutritional deficiencies and the outcome of liver transplantation. However, despite these contributions, large-scale multicentric trials on the therapeutic value of nutritional support and metabolic care in cirrhosis and liver transplantation are still lacking.

Chronic Disease↗

Effects of angiogenic factor overexpression by human and rodent cholangiocytes in polycystic liver diseases.

Liver involvement in autosomal dominant polycystic kidney disease (ADPKD) is characterized by altered remodeling of the embryonic ductal plate (DP) with presence of biliary cysts and aberrant portal vasculature. The genetic defect causing ADPKD has been identified, but mechanisms of liver cyst growth remain uncertain. To investigate the possible role of angiogenic mechanisms, we have studied the immunohistochemical expression of vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2) and their receptors (VEGFR-1, VEGFR-2, Tie-2) in ADPKD, Caroli's disease, normal and fetal livers. In ADPKD and control livers Ang-1 and Ang-2 gene expression was studied by real-time-PCR. Effects of VEGF on cholangiocyte proliferation were studied by PCNA Western Blot in isolated rat cholangiocytes and by MTS assay in cultured cholangiocytes isolated from ADPKD patients and from an ADPKD mouse model (Pkd2(WS25/-)). Cholangiocytes were strongly positive for VEGF, VEGFR-1, VEGFR-2 and Ang-2 in ADPKD and Caroli, and also for Ang-1 and Tie-2 in ADPKD, similar to fetal ductal plate cells. VEGF stimulated proliferation in both normal and ADPKD cholangiocytes, but the effect was particularly evident in the latter. Ang-1 alone had no effect, but was synergic to VEGF. VEGF expression on cholangiocytes positively correlated with microvascular density. In conclusion, consistent with the immature phenotype of the cystic epithelium, expression of VEGF, VEGFRs, Ang-1 and Tie-2 is strongly upregulated in cholangiocytes from polycystic liver diseases. VEGF and Ang-1 have autocrine proliferative effect on cholangiocyte growth and paracrine effect on portal vasculature, thus promoting the growth of the cysts and their vascular supply. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).

Angiogenic Proteins↗

Tyramine oxidase activity in needle biopsy of normal livers and diseased livers.

Tyramine oxidase and UDP-glucuronyl transferase activities were determined in 52 diseased livers obtained by needle biopsy. 14 liver specimens were also subjected to acetyl CoA carboxylase determination. Tyramine oxidase level was elevated in livers with nonalcoholic fatty change or toxic hepatitis, and reduced in livers with fibrosis or chronic alcoholic injury. UDP-glucuronyl transferase activity was reduced in livers with severe parenchymal damage or hyperbilirubinemia. Acetyl CoA carboxylase activity decreased markedly in an active alcoholic cirrhotic liver, and was elevated in alcoholic fatty livers as well as in a liver with acute venous stasis.

Acetyl-CoA Carboxylase↗

Sonographic measurement of the thickness of subcutaneous tissues in nonalcoholic fatty liver disease versus other chronic liver diseases.

PURPOSE: To measure an average subcutaneous tissue thickness in nonalcoholic fatty liver disease (NAFLD) and other liver diseases using bedside sonography and make comparisons of thickness between groups. The study also addressed whether a cut-off subcutaneous tissue thickness exists below which NAFLD is unlikely. METHODS: Sonograph was performed on 113 consecutive patients with chronic liver disease. Diagnosis was derived from serological data combined with liver biopsy in all cases. Distance was measured between the skin and the liver surface and was labeled the subcutaneous tissue thickness. RESULTS: Of the 113 patients, 16 were diagnosed with NAFLD, 56 were diagnosed with chronic hepatitis C, 17 were diagnosed with autoimmune liver disease, and 24 had miscellaneous diagnoses (hepatitis B, hemochromatosis, granulomatous hepatitis, and cryptogenic hepatitis). The subcutaneous tissue thickness was 25.6 mm +/- 5.6 mm in NAFLD versus 19.5 mm +/- 5.2 in the non-NAFLD patients (p < 0.001). The subcutaneous tissue thickness of the HCV group was 20.2 mm +/- 4.8, and although it was not different than all other patients, it was different from the NAFLD patients (p < 0.01). Fifteen out of sixteen of the NAFLD patients had a greater than average subcutaneous tissue thickness (20 mm). CONCLUSIONS: A sonographically measured subcutaneous tissue thickness of less than 20 mm makes the diagnosis of NAFLD unlikely.

Body Mass Index↗

Histological demonstration of copper and copper-associated protein in chronic liver diseases.

Liver copper concentrations in percutaneous biopsy specimens were measured by neutron activation analysis and compared with histological staining for copper by rubeanic acid and rhodanine, and with copper-associated protein stained by orcein. Liver copper concentrations were elevated in 31 of 35 biopsies from patients with primary biliary cirrhosis (PBC), and discrimination between normal and elevated liver copper was correct in 32 of the 35 biopsies by staining with rubeanic acid, and 31 of the 35 by staining with rhodanine. Orcein staining of copper-associated protein was positive in 33 of the 35 biopsies. All 17 biopsy specimens from patients with Wilson's disease had high liver copper concentrations, but only nine had positive staining for copper, and six were orcein positive. Similarly, histological stains gave little indication of the liver copper concentrations in tissue from 16 patients with chronic active hepatitis. Staining of liver sections can be useful in detecting elevation of liver copper in PBC, but not in Wilson's disease, where the absolute concentration must be measured. Excess copper appears to accumulate in the liver in different chemical forms in PBC and Wilson's disease.

Chronic Disease↗

Insights into SEN virus prevalence, transmission, and treatment in community-based persons and patients with liver disease referred to a liver disease unit.

To document the prevalence and routes of transmission of SEN virus (SEN-V) in community-based individuals and patients referred to a liver disease unit, stored serum samples obtained from 160 Canadian Inuit and 140 patients with liver disease were tested for SEN-V DNA by polymerase chain reaction. In the community-based population, SEN-V was present in 57 (36%) of 160 persons. SEN-V-positive individuals tended to be younger and were more often male. Liver enzyme levels and serologic markers for hepatitis A and B viruses were similar in SEN-V-positive and SEN-V-negative individuals. SEN-V was present in 30 (21%) of the 140 patients with liver disease. Age, sex, risk factors for viral acquisition, prevalence of symptoms, and liver biochemical and histological findings were similar in SEN-V-positive and SEN-V-negative patients. These results indicate that SEN-V infection is a common viral infection in both healthy individuals and patients with chronic liver disease, that transmission likely occurs via nonparenteral routes, and that SEN-V infection is not associated with higher rates of or more-severe liver disease in persons with preexisting liver disease.

Adult↗

Physical activity in liver disease and liver function in sportsmen.

Patients with liver disease are often incorrectly restricted in their physical activity. Several studies have shown that physical activity is not detrimental to acute viral hepatitis but it is customary to advise rest in the initial phase of nausea, abdominal pain and fatigue. As soon as these symptoms decline the patient can take part in physical activity. As regards chronic hepatitis and cirrhosis there are divergent views. No restrictions are placed upon patients with chronic active hepatitis in remission. This is also true for the early stage of cirrhosis, while muscle atrophy in more prolonged cases will set a natural limit to the patient's performance. The effect of physical activity on patients with a porto-caval shunt has not been studied. In well trained sportsmen there is no evidence that physical activity within the limits of human performance has an unfavourable effect on liver function.

Adolescent↗

The role of fat-storing cells in Disse space fibrogenesis in alcoholic liver disease.

Liver biopsy samples from 40 chronic alcoholic patients, including 9 with minimal changes of the liver, 6 with mild hepatic fibrosis, 14 with moderate fibrosis, and 11 with severe fibrosis (cirrhosis) were studied by electron microscopy to assess fibrogenesis in the Disse space and the role of fat-storing cells in this process. In the Disse space of normal liver, collagen fibers are few, and while lipid droplets containing fat-storing cells exist, their rough endoplasmic reticulum (RER) is inconspicuous. In the course of progressive hepatic fibrosis, collagen in the Disse space increased. This was significantly associated with gradual development of RER in fat-storing cells, confirmed by morphometric analysis. It is likely, therefore, that the development of RER in the fat-storing cells is a morphological correlative of their activated fibrogenesis and transformation into fibroblasts. To further clarify this, the rate of collagen synthesis was measured by the method of in vitro incorporation of [3H]proline into collagen in 17 liver biopsy samples from alcoholic patients and compared with the degree of morphological changes of RER in fat-storing cells. In liver samples with well-developed RER in fat-storing cells, a significantly higher rate of collagen synthesis was observed. These results suggest that in alcoholic liver injury, fat-storing cells may play an important role in Disse space fibrogenesis.

Adult↗

[Hemostasis in liver diseases].

Liver plays central role in the synthesis and metabolism of the pro- and anticoagulant enzymes of blood coagulation. Acute or chronic liver failure frequently result in different bleeding phenomena. Thrombocytopenia due to hypersplenism and lack of haemopoietic factors seems to be common, but in spite of thrombocytopenia and more or less platelet malfunction thrombocytopenic bleeding is usually less prominent feature. Bleeding esophageal varices, clotting abnormalities with peritonejugular shunts may pose many difficulties in clinical practice. Transjugular intrahepatic shunt (TIPS) has been a major step forward treating refractory esophageal bleeding or ascites, however to keep the stent patent seems to be still unresolved. Along with the bleeding tendency or symptoms concommittant venous thromboembolic events are may not be considered as rare events in cirrhosis. Special problems are also coupled with ascites, which contains an almost full inventory of coagulation proteins, also with the medical and interventional therapy of Budd-Chiari syndrome, and other veno-occlusive conditions with or without transplantation.

Ascites↗

Tissue inhibitor of metalloproteinase-1 in the liver of patients with chronic liver disease.

BACKGROUND/AIMS: Tissue inhibitor of metalloproteinase (TIMP)-1 is an important regulator of matrix metalloproteinase activity. To clarify the changes in TIMP-1 in diseased livers, we measured TIMP-1 concentrations in liver tissue samples from patients with chronic liver disease. The relationship between serum and liver levels of TIMP-1 was also examined in some patients. METHODS: The subjects were 68 patients who underwent liver biopsy. The liver TIMP-1 concentration was measured using an enzyme immunoassay after the extraction of TIMP-1 with 2 M guanidine. RESULTS: As compared with the controls (n=10), the liver TIMP-1 level was increased 2.2-fold in the 24 chronic active hepatitis 2A patients, 2.9-fold in the 10 chronic active hepatitis 2B patients and 4.1-fold in the six liver cirrhosis patients, but no significant increase was observed among the 18 chronic persistent hepatitis patients. The liver TIMP-1 levels were closely correlated with the histological degrees of periportal necrosis, portal inflammation, and liver fibrosis. When the localization of TIMP-1 was examined immunohistochemically, TIMP-1 was stained mainly in hepatocytes, and the intensity was stronger in the livers of chronic active hepatitis and liver cirrhosis patients than in those of the chronic persistent hepatitis patients. The serum TIMP-1 and liver TIMP-1 levels were significantly correlated, indicating that serum TIMP-1 could reflect the change of liver TIMP-1 in patients with chronic liver disease. CONCLUSION: Liver TIMP-1 concentration increases with progression of the liver disease, when the degradation of extracellular matrix proteins is decreased, resulting in the development of liver fibrosis.

Adult↗

Analysis of diffuse parenchymal liver disease by liver scintigrams: differential diagnosis using neuro and fuzzy.

In colloid liver scintigraphy, diagnosis of diffuse parenchymal liver disease such as chronic hepatitis or cirrhosis is evaluated by size and distortion of the liver, distribution of tracer in the liver, size and activities of tracer in the spleen, visualization of the bone marrow and so on. It is not difficult to read a scintigram which shows a typical pattern of normal, chronic hepatitis and cirrhosis; however in some cases it is difficult to distinguish normal or chronic hepatitis and chronic hepatitis or cirrhosis visually. Therefore, we tried to use fuzzy inferences to perform differential diagnosis in chronic hepatitis (CH), severe fibrosis (SF) and liver cirrhosis (LC). First, five features in colloid liver scintigrams were measured or evaluated visually. These features were liver size index (left lobe/right lobe), splenomegaly, the degree of visualization of the bone marrow, liver deformity, and distribution of tracer in the liver. Having fuzziness in these data, certain characteristics of these features were considered to be fuzzy sets and thus could be expressed in membership functions. Fuzzy inference was carried out using these data and fuzzy rules. Using fuzzy inference, differential diagnosis in LC could be performed up to 100%, but those of CH and SF could not be performed sufficiently. Using neural network CH, SF and LC could be diagnosed up to 63%, 80%, and 88%, respectively. But fuzzy inference had the merit to evaluate the degree of disturbance by the center of gravity of the resulting membership function. Therefore by combining neural network and fuzzy inference, CH, SF, and LC could be differentiated to the degree 77%, 80%, and 100%, respectively.

Chronic Disease↗

Ultrasound and liver disease.

The widespread availability of ultrasound has revolutionised the investigation of hepatobiliary disease. Liver ultrasound should be the primary imaging modality in jaundice, suspected diffuse liver disease or focal liver disease and supplemented by other modalities where indicated. The advent of Duplex and Colour Doppler imaging has expanded the utility of ultrasound techniques in relation to the hepatic vasculature. This article presents an overview of the use of ultrasound in liver disease.

Humans↗

Severity of liver disease in liver transplantation recipients with hepatitis C virus infection: relationship to genotype and level of viremia.

Infection with hepatitis C virus (HCV) genotype 1b has been reported to be associated with more severe posttransplantation liver disease than infection with non-1b genotypes. To address this issue, we evaluated the outcome in 124 patients who underwent liver transplantation for chronic HCV infection. The HCV genotype and/or serotype responsible for infection was determined by four different methods. HCV RNA was detected in serum samples by polymerase chain reaction (PCR) amplification, and quantified by branched DNA assay. Disease severity was expressed as a histological score (which included grading of portal inflammation, lobular activity, fibrosis, and cytopathic changes). Median duration of histological follow-up was 25 months (range 1-75 months). Genotype was assignable in 112 (92.5%) patients. Genotypes responsible for infection were as follows: 1a = 32.2%, 1b = 27.3%, 2a = 7.4%, 2b = 8.3%, 3a = 14%, and mixed infection (more than one subtype) = 3.3%. Level of viremia, alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, and total histological score were not significantly different in patients infected with type 1b compared with patients infected with other genotypes. While duration of histological follow-up was greater in patients infected with type lb versus other types (P = .02), by univariate and multivariate analysis neither HCV genotype (lb versus others), level of viremia nor duration of histological follow-up were associated with disease severity. Moreover, there was no significant difference in the actuarial graft survival in patients infected with type lb compared with that of patients infected with non-lb types (82% and 87% at 3 years, respectively). Reanalysis using HCV genotype 1 showed no association with disease severity, graft survival, and patient survival. We conclude that HCV genotype 1 and subtype 1b are not associated with disease severity or graft survival in liver transplantation recipients.

Adult↗

Histologic variation of grade and stage of non-alcoholic fatty liver disease in liver biopsies.

BACKGROUND: Sampling error regarding disease grade and stage has been ascribed to needle liver biopsies in patients with chronic liver disease. Although several studies evaluating sampling error in liver biopsies exist, none have investigated this phenomenon in patients with non-alcoholic fatty liver disease (NAFLD). This study aims to determine the rate and extent of sampling error in liver biopsies obtained from patients undergoing Roux-en-Y gastric bypass (RYGBP) surgery for morbid obesity. METHODS: 10 morbidly obese patients underwent simultaneous liver biopsies from the right and left hepatic lobes during an open examination preceding the RYGBP procedure. The biopsies were subsequently randomly evaluated and then blindly re-evaluated by a liver pathologist. Degrees of inflammatory activity and fibrosis were determined and scored for each sample using a semi-quantitative system with 3 grades and 4 stages. RESULTS: No grading differences were observed, and 3 patients (30%) had a difference of at least 1 stage between the right and left lobes. One patient had a 2-stage difference in paired samples, with significantly different biopsy sizes and number of portal tracts. Blinded histologic re-evaluation did not result in grading or staging scores that differed from the original evaluation. CONCLUSIONS: Liver biopsy samples taken from the right and left hepatic lobes showed similar grades of disease activity, but differed in histopathologic staging in 30% of the NAFLD patients. Obtaining an adequately sized biopsy (>1.0 cm in length with >10 portal tracts) greatly reduces sampling error.

Adult↗

Demonstration of an intracellular copper-binding protein by orcein staining in long-standing cholestatic liver diseases.

Liver biopsies from eight patients with primary biliary cirrhosis, two with chronic active hepatitis of a cholestatic form, three with long-standing alcoholic liver cirrhosis, and one with extrahepatic biliary obstruction were studied. In each case dark brown cytoplasmic material was seen after staining of the tissue sections with Shikata's orcein method. In exactly the same cellular and subcellular locations as the orcein-positive material, and with morphologically equal granules, two different ordinary staining methods for copper (rubeanic acid and Mallory-Parker's haematoxylin) gave positive reactions. The earlier histochemical findings have revealed the protein nature and high sulphydryl content of the orcein-positive material. Its close association with copper in liver sections suggests its copper-binding nature and indicates that a common copper-protein complex accumulates in the cytoplasm of liver cells during longstanding cholestasis in biliary diseases of various pathogenetic origin.

Cholestasis↗

[Significance of the iron and copper content of the liver for the differential diagnosis of chronic liver diseases].

Liver iron and copper concentrations were estimated in 395 patients undergoing hepatological examination. Relations to clinical, morphological and laboratory data were evaluated. Liver iron concentrations were not significantly different in chronic hepatitis of viral, toxic or immunological origin. Liver iron levels exceeding 100 mg/100 g dry liver tissue (normal range up to 300 mg/100 g) were only found in idiopathic hemochromatosis (n = 8), in a patient with prophyria cutanea tarda and in a multiple transfused patient who suffered from aplastic anemia. Liver copper content was significantly increased in primary biliary cirrhosis compared to chronic hepatitis of other origin. Apart from untreated Wilson's disease (n = 3) copper levels higher than 25 mg/100 g dry liver tissue (normal range up to 6 mg/100 g) were measured in chronic active hepatitis B (n = 2), primary biliary cirrhosis (n = 9) and in chronic hepatitis of uncertain origin (n = 3). Therefore excess accumulation of copper in the liver was typical of Wilson's disease but less diagnostic than severely elevated liver iron stores of idiopathic hemochromatosis.

Adolescent↗