Liver Disease Of Various Etiologies Research Articles

The role of bright liver echo pattern on ultrasound B-mode examination in the diagnosis of liver steatosis

Aim The observation of bright liver echo pattern on ultrasound is commonly considered a sign of hepatic steatosis. However, the interference of liver fibrosis on sensitivity and specificity of bright liver echo pattern has caused many to question its effectiveness as a diagnostic tool. The objective of this study was to evaluate the sensitivity, specificity and predictive values of bright liver echo pattern for liver steatosis. Patients and methods We studied 235 consecutive patients suspected of having liver disease of various aetiologies. Median age was 52 years (range, 17–72 years), and there was a male/female ratio of 1:18. All patients underwent ultrasound examination before liver biopsy and was performed by two operators. The presence or absence of bright liver echo pattern and posterior attenuation or areas with different patterns of fat infiltration were noted. Histologic evaluation was performed and graded by Ishak score. Steatosis was categorised as absent, 0–2%, 3–29% to 30–49% or >50%. Results Interobserver concordance was high. Bright liver echo pattern was found in 67% of patients with steatosis of any degree and 89% of patients with steatosis of ≥30%. Only three patients without steatosis, who had a low Ishak score, demonstrated bright liver echo pattern on ultrasonography. The sensitivity, specificity, positive predictive value and negative predictive value of bright liver echo pattern for steatosis were 64%, 97%, 96.0% and 65%, respectively. Among the subgroup of patients who had steatosis of ≥30%, the sensitivity, specificity, positive predictive value and negative predictive value of bright liver echo pattern were 91%, 93%, 89% and 94%, respectively. The sensitivity, specificity, positive predictive value and negative predictive value of posterior attenuation and/or skip areas associated with bright liver echo pattern for steatosis were 89.7%, 100%, 100% and 92.3%, respectively. Univariate analysis showed bright liver echo pattern to be associated only with steatosis and not with fibrosis. Conclusion We concluded that the presence of bright liver echo pattern is a sign of liver steatosis and that liver fibrosis does not interfere with ultrasound measurements. Posterior attenuation and/or skip areas are closely related to steatosis of ≥30%.

Is Silymarin Hepatoprotective in Alcoholic Liver Disease?

Silymarin is the main active complex extracted from the milk thistle (Silybum marianum L.), an annual plant that has been used by herbalists since antiquity. Pharmacologic evidence from numerous studies in the last few decades supports potential therapeutic benefits of milk thistle and silymarin in liver necroinflammation and fibrogenesis given its free-radical scavenging, antioxidant, anti-inflammatory, immunomodulatory, iron chelating, and membrane stabilizing properties as well as its purported ability to selectively stimulate hepatocyte proliferation. Current knowledge of the role of oxidative stress in the pathogenesis of alcohol liver disease (ALD), suggests that silymarin’s pharmacological properties may have potential therapeutic value in ALD. Since the 1960s, milk thistle products have been prescribed by physicians in Europe for ALD as well as other liver-related conditions. Several European manufacturers have developed pharmaceutical grade milk thistle products standardized to a higher content of silymarin (70%–80%) than in non-standardized herbal preparations (≈5%), mainly because of silymarin’s poor oral bioavailability. As part of pharmaceutical development, several clinical studies have been conducted in Europe to assess the efficacy of oral milk thistle products in liver diseases of diverse etiology. Recently, a systematic review sponsored by the Agency for Healthcare Research and Quality (AHRQ) selectively analyzed 16 prospective randomized placebo-controlled European trials in terms of the efficacy and safety of milk thistle products in alcohol, viral or toxin-related liver diseases. Six of the selected trials evaluated ALD using various doses of Legalon, a milk thistle product standardized to 80% silymarin manufactured in by Madhaus AG (Cologne, Germany). The reviewers found these trials difficult to interpret due to unclear and variable definitions of disease chronicity and severity. Some of the studies included liver diseases of various etiologies. None of the studies stratified patients by presence or absence of ongoing alcohol consumption or chronic hepatitis C infection as potential confounders. All 6 studies on silymarin and ALD found at least 1 biochemical parameter of liver function or liver histology that improved significantly with silymarin compared with placebo. The parameters that were significant varied from study to study. Importantly, 1 of the 6 studies showed significant improvement in overall survival among cirrhotic patients treated with silymarin, a second study showed a non-statistical trend toward improved survival and yet another study showed no improvement in overall survival in silymarin compared with placebo. No relationship was found between duration of therapy and improvement in liver function, although 3 of the reports did not clearly describe the duration of therapy. The previous data on silymarin in ALD along with current evidence on the potential benefit of antioxidant therapies in ALD, justify a more systematic assessment of silymarin in ALD. Furthermore, an evidence-based approach to the evaluation of the safety and efficacy is crucial because at least 1 multicenter survey has shown that milk thistle is the most frequently used supplement in patients with liver disease. In 2001, milk thistle products ranked 12th in the list of supplements sold in the US surpassing 7 million dollars.

Ultrasound Detection of Abdominal Lymph Nodes in Chronic Liver Diseases. A Retrospective Analysis

AIM: To retrospectively evaluate the prevalence of lymph nodes of the hepato-duodenal ligament in a group of patients with chronic liver disease of various aetiologies and to investigate what clinical, aetiological and laboratory data may lead to their appearance. MATERIALS AND METHODS: One thousand and three patients (554 men, 449 women) were studied, including 557 with chronic hepatitis and 446 with liver cirrhosis. The presence of lymph nodes near the trunk of the portal vein, hepatic artery, celiac axis, superior mesenteric vein and pancreas head was investigated using ultrasound. RESULTS: Lymph nodes were detected in 394 out of the 1003 study patients (39.3%); their number ranged from one to four, with a diameter ranging between 0.8 and 4 cm. The highest prevalence was in the subgroup of patients with primary biliary cirrhosis (87.5%), followed by patients with hepatitis C virus (HCV; 42%), patients with HCV and hepatitis B virus (HBV; 41.3%), autoimmune hepatitis (40%), and HBV alone (21.2%). In the alcoholic and idiopathic subgroups prevalence was 9.5%, while in the non-alcoholic steatohepatitis and haemochromatosis subgroups it was 0%. HCV RNA was present in 97 out of 103 lymph node-positive patients and in 141 out of 168 lymph node-negative HCV-negative patients ( p<0.003). Lymphadenopathy frequency increased as the liver disease worsened ( χ 2 MH=74.3; p<0.0001). CONCLUSION: Despite the limitations of a retrospective study, our data indicate a high prevalence of lymphadenopathy in liver disease patients; ultrasound evidence of lymph nodes of the hepato-duodenal ligament in a given liver disease may most likely suggest a HCV or an autoimmune aetiology and a more severe histological picture.

Infection with an unenveloped DNA virus (TTV) in patients with acute or chronic liver disease of unknown etiology and in those positive for hepatitis C virus RNA

Abstract Background/Aims: An unenveloped single-stranded DNA virus (TTV) has been reported in association with elevated transaminase levels in patients with posttransfusion hepatitis and in those with acute or chronic liver disease of unknown etiology. To further evaluate the association of TTV with liver disease, TTV DNA was searched for in patients with acute or chronic liver disease of various etiologies. Methods: TTV DNA was determined by polymerase chain reaction with hemi-nested primers in 64 patients with acute or chronic liver disease of unknown etiology and in 100 with acute or chronic liver disease positive for antibody to hepatitis C virus (HCV) as well as HCV RNA. Results: TTV DNA was detected in two of the seven (29%) patients with acute hepatitis of unknown etiology, but in none of the four patients with acute HCV-associated hepatitis. It was detected in 27 of the 57 (47%) patients with chronic liver disease of unknown etiology at a frequency significantly higher ( p Conclusions: Based on the obtained results, TTV has a role in the development of acute and chronic liver disease of unknown etiology.

Serum hyaluronan as a marker of liver fibrosis in asymptomatic chronic viral hepatitis B

Increased concentrations of serum hyaluronan, a polysaccharide widely distributed in the extracellular space, have been demonstrated in liver disease of various aetiologies and proposed as a useful marker of liver fibrosis. The aim of the present study was to evaluate the association of serum hyaluronan with the extent of hepatic fibrosis in asymptomatic cases of chronic hepatitis B viral infection. The study was conducted in a consecutive sample of 111 asymptomatic chronic carriers of hepatitis B surface antigen. Liver function tests, alcohol consumption and cigarette smoking were determined and, for 84 subjects, liver biopsy was performed and degrees of inflammation and fibrosis were scored. Hyaluronan was measured using a radiometric assay. Mean serum hyaluronan increased with increasing fibrosis score (from 22.2 +/- 4.8 to 50.6 +/- 12.7 microg/l, p = 0.058) or pathological severity (from 18.8 +/- 5.9 to 50.6 +/- 12.5 microg/l, p = 0.048), even after adjusting for the effect of age. No such correlation was found with portal inflammation. The study showed that, in asymptomatic chronic carriers of hepatitis B, serum hyaluronan concentration correlates with hepatic fibrosis, a known marker of disease prognosis. This finding supports the hypothesis that hyaluronan might be of use in assessing and monitoring time trends in liver disease, substituting for repeated biopsies.

Tissue inhibitors of metalloproteinases, hepatic stellate cells and liver fibrosis.

Hepatic stellate cells (HSC) play a central role in the pathogenesis of liver fibrosis. Following liver injury, these cells proliferate and are activated to a profibrogenic myofibroblastic phenotype. In addition to increased matrix protein synthesis, there is evidence to indicate that these cells are able to regulate matrix degradation. In the early phases of their cellular activation, HSC release matrix metalloproteinases with the ability to degrade the normal liver matrix. When HSC are fully activated, there is a net down-regulation of matrix degradation mediated by increased synthesis and extracellular release of tissue inhibitors of metalloproteinase (TIMP)-1 and -2. These studies in cell culture have been complemented by in vivo studies of hepatic TIMP-1 and TIMP-2 gene expression. In advanced human liver disease of various aetiologies, there is increased TIMP-1-mRNA and protein and increased TIMP-2-mRNA in fibrotic liver compared with control liver. Temporal studies of progressive rat liver fibrosis caused by bile duct ligation or by carbon tetrachloride, indicate an important role for increased TIMP-1 and TIMP-2 expression in pathogenesis. Moreover, in a rat model of reversible liver fibrosis, matrix remodelling and resolution of liver fibrosis is closely associated, temporally, with a marked decrease in TIMP-1 and TIMP-2 expression. These combined cell culture and in vivo findings have led us to investigate the mechanisms of regulation of TIMP-1 gene expression in hepatic stellate cells. Our recent data indicate that transcriptional regulation of TIMP-1 gene expression in HSC is mediated via a mechanism which differs considerably from that previously identified in skin fibroblasts. We conclude that increased TIMP-1 and TIMP-2 expression by HSC plays an important role in the pathogenesis of liver fibrosis. This may represent an important therapeutic target in the design of anti-fibrotic strategies for chronic liver disease.

Transforming growth factor-beta1 in plasma and liver of children with liver disease.

Although several liver diseases of childhood, particularly biliary atresia (BA) and cystic fibrosis (CF) liver disease (CFLD) are characterized by hepatic fibrosis, the pathogenesis of this process is incompletely understood. The cytokine transforming growth factor-beta1 (TGF-beta1) has been implicated in hepatic fibrosis in experimental animals, in which both the hepatic expression and plasma concentration of this cytokine are increased. The objective of our study was to determine whether there are similar alterations of TGF-beta1 in patients with hepatic fibrosis secondary to either BA and/or CFLD. The study design was as follows. In study 1, plasma TGF-beta1 was assessed by ELISA in 9 children with BA undergoing liver transplantation, 11 patients with CFLD, and appropriate control subjects. In study 2, hepatic expression of TGF-beta1 protein (assessed immunohistochemically) and hepatic fibrosis were scored semiquantitatively, on a 1-3 scale, by blinded investigators, in archival liver biopsy specimens from 10 children with BA, 10 with CFLD, and from 10 older children with normal hepatic histology, as well as in 4 patients with liver diseases of various etiologies. Simultaneous plasma and liver TGF-beta1 studies were performed in 8 patients with liver disease. Results were as follows. Plasma TGF-beta1 values were inversely correlated with age in healthy subjects (r=-0.54, p < 0.0001). The plasma TGF-beta1 protein of children with BA was decreased (13+/-2 ng/mL) compared with values for healthy children (42+/-6 ng/mL, n=10, p < 0.005). Similarly, the plasma TGF-beta1 concentration in patients with CFLD was also decreased compared with values for children with CF and normal serum liver profiles (n=14) (2+/-1 ng/mL versus 12+/-1, p < 0.05). However, the plasma TGF-beta1 concentration was increased in two patients with other types of liver disease. The hepatic expression of TGF-beta1 was increased in the presence of hepatic fibrosis in all types of liver diseases studied. Forty-six percent of patients had both marked hepatic fibrosis and marked TGF-beta1 labeling; 86% of samples without fibrosis showed no TGF-beta1 labeling, p=0.007. In conclusion, these studies have established the association of hepatic TGF-beta1 protein and hepatic fibrosis in several common liver diseases of childhood. Our data also suggest that, in children, plasma TGF-beta1 does not appear to be a useful marker of hepatic expression of this cytokine.

Growth factor and procollagen type I gene expression in human liver disease

Background/Aims : Growth factors have been implicated in the pathogenesis of liver fibrosis, a major determinant of the clinical course of chronic liver disease. The aim of this study was to study the relationship of growth factor expression to inflammation and fibrosis in a variety of human liver diseases. Methods : We studied by in situ hybridization the expression of transforming growth factor (TGF) β1, platelet-derived growth factor (PDGF) A and PDGF-B, and procollagen type I (pro-I) messenger RNAs (mRNAs) in liver diseases of various etiologies. Results : Pro-I mRNA was expressed by mesenchymal cells at sites of inflammation and scarring, where TGF-β1 immunoreactivity was often found, and by perisinusoidal cells. TGF-β1 and PDGF-A mRNAs were expressed mainly by mononuclear cells and proliferating ductular cells. TGF-β1 mRNA was also expressed by perisinusoidal cells. PDGF-A gene expression was more common than that of PDGF-B. Pro-I and TGF-β1 expression correlated with both ductular proliferation and tissue inflammation, whereas PDGF-A and PDGF-B only correlated with ductular proliferation. Conclusions : Our data suggest that TGF-β1 and PDGF are involved in human liver inflammation and fibrosis. The expression of growth factor mRNAs in proliferating ductular cells may indicate a role for these cells in liver fibrogenesis and may help explain the pathophysiology of conditions such as biliary atresia progressing to fibrosis despite the absence of marked inflammation.

Increased serum iron and iron saturation without liver iron accumulation distinguish chronic hepatitis C from other chronic liver diseases

One hundred twenty-three patients with chronic liver diseases of various etiologies were evaluated for their iron status. The patients were divided into four distinct groups: chronic hepatitis C (63), chronic hepatitis B (14), B + C (3) and nonviral chronic liver diseases (43). In 107 patients (87%) the chronic liver disease was confirmed by biopsy. Mean serum iron (+/- SD) levels in the above four groups were: 166 +/- 62, 103 +/- 52, 142 +/- 48, and 115 micrograms/dl; iron-binding capacity was 346 +/- 80, 325 +/- 72, 297 +/- 27, and 374 +/- 75 micrograms/dl, and iron saturation 50 +/- 18, 32 +/- 16, 48 +/- 16, and 28 +/- 10%, respectively. Serum ferritin, increased in all four groups, was highest in HCV; however, no evidence of hepatic iron accumulation could be found in any of the patients. There were no significant differences in liver function parameters measured in the four groups. We conclude that serum iron, iron saturation, and ferritin are increased in patients with hepatitis C in comparison to hepatitis B or other nonviral, nonhemochromatotic liver diseases. The increased iron status in hepatitis C patients is not manifested by increased liver iron. Awareness of these distinct features of chronic hepatitis C is essential in the diagnosis and treatment of chronic liver diseases.

Value of urinary copper excretion after penicillamine challenge in the diagnosis of Wilson's disease

To investigate the diagnostic value of 24-hr urinary copper excretion testing after penicillamine challenge in the diagnosis of Wilson's disease, 75 consecutive children referred for a variety of liver problems and in whom parameters of copper metabolism had been investigated were analyzed retrospectively. Seventeen had Wilson's disease, 22 had autoimmune chronic active hepatitis, 6 had primary sclerosing cholangitis, 12 had chronic liver disease of various etiologies, 4 had cryptogenic acute liver failure, 6 had acute hepatitic illnesses and 8 had a variety of disorders featuring normal liver histological appearance. Serum ceruloplasmin and total copper levels were significantly lower in Wilson's disease patients compared with all other groups, but three children with Wilson's disease had normal ceruloplasmin levels and seven had normal total copper levels. No significant difference was found for free serum copper levels and liver copper content between Wilson's disease patients and the other groups. Baseline 24-hr urinary copper excretion was significantly higher in Wilson's disease patients compared with that of the other patients, but six children with Wilson's disease had levels just above the upper limit of normal, overlapping with values obtained in three children with liver failure, two with acute hepatitis, two with autoimmune chronic active hepatitis and three with primary sclerosing cholangitis. The 24-hr urinary copper excretion after penicillamine challenge proved the most accurate single diagnostic test; levels more than 25 mumol/24 hr were present in 15 of 17 patients with Wilson's disease, but in only 1 child with liver failure of the 58 with other disorders.(ABSTRACT TRUNCATED AT 250 WORDS)

Logistic-regression model for assessing portal hypertension by measuring hyaluronic acid (hyaluronan) and laminin in serum

We earlier observed a positive correlation between portal venous pressure (PVP) and the concentration of laminin in serum. Here we investigated whether the diagnostic efficacy could be improved by considering additional analytes and application of multivariate statistical analysis. In 102 patients with fibrotic liver disease of various etiologies we measured PVP as the gradient of the wedged and free hepatic venous pressures and determined the concentrations of hyaluronic acid and laminin in serum. Regression coefficients established by logistic regression in this group were subsequently used to predict portal hypertension (PVP greater than mmHg) in an independent group of 45 patients. By comparison with the known PVP, we obtained a sensitivity of 0.83 (confidence interval: 0.63-0.93) and a specificity of 0.82 (0.61-0.93) for diagnosis of portal hypertension by means of the concentrations of hyaluronic acid and laminin in serum. Application of the model is suggested as a tool for pre-screening and monitoring patients to be subjected to assessment of portal hypertension.

Platelet-associated IgG in hepatitis and cirrhosis.

Increasing evidence is accumulating which indicates that immunological abnormalities contribute to the development of liver disease and its signs and symptoms. Platelet-associated IgG (PAIgG) levels were quantified in 42 patients with biopsy-proven liver disease of various etiologies to determine the relationship of thrombocytopenia to immunologic abnormalities in these disorders. Five of six nonthrombocytopenic patients with acute viral hepatitis B had elevated PAIgG. Six of ten patients with chronic active hepatitis had elevated PAIgG and thrombocytopenia. In contrast, only one of six patients with chronic persistent hepatitis had elevated PAIgG. Nine of ten patients with alcoholic hepatitis had elevated PAIgG; seven of the nine were thrombocytopenic. Seven of ten alcoholic patients with cirrhosis had elevated PAIgG; six of seven were thrombocytopenic. Thus the increase in PAIgG may be present without thrombocytopenia in acute liver injury, while patients with chronic persistent hepatitis do not usually exhibit this abnormality. Severe chronic active liver disease is accompanied by thrombocytopenia and an increase in PAIgG levels.