Aggressive gastric carcinoma producing alpha-fetoprotein: a case report and review of the literature.

A 65-year-old man presented to our hospital with abdominal pain, dyspepsia and anorexia. Laboratory tests showed an altered liver function and abdomen ultrasonography revealed multiple liver nodules, suspected to be metastatic lesions. Serous tumor markers were elevated and a very high level of alpha-fetoprotein was found. Computer tomography confirmed the hepatic lesions and disclosed a thickening of the lesser curvature of the gastric wall. A subsequent endoscopy showed an ulcer on the lesser curvature. Biopsies taken from the gastric ulcer and the liver nodule revealed an adenocarcinoma, both of gastric origin. Shortly after the diagnosis, the patient's condition worsened and he died only 15 days later. This case report illustrates how alpha-fetoprotein-producing gastric adenocarcinomas have a high incidence of venous and lymphatic invasion and a rapid hepatic spread with a very poor prognosis.

Transient elastography for the assessment of liver fibrosis in patients with chronic viral hepatitis: the missing tool?

The fibrogenic evolution of chronic viral hepatitis B and C towards cirrhosis represents a key issue in clinical Hepatology whose monitoring still relies on liver biopsy and consequent histopathological staging. In the last decade, non-invasive methodologies have been proposed to predict the presence of fibrosis in chronic liver disease. Most of these methods are based on algorithms, including biochemical parameters, which have demonstrated an acceptable diagnostic accuracy towards the two extremities of the fibrogenetic process. The introduction of transient elastography has represented a further advancement in clinical Hepatology and it seems that the combination of different non-invasive methodologies will provide an improvement in the clinical management of disease progression in viral chronic hepatitis. Studies, conducted especially in chronic viral hepatitis C, suggest that transient elastography is a useful technique for the detection of severe fibrosis-cirrhosis and for the exclusion of significant fibrosis (>or=F2), that could be employed as "diagnostic discriminator" for establishing clinical priorities and reducing the number of liver biopsies. This review article will focus on the clinical utility of this novel methodology for the assessment of liver fibrosis in chronic viral hepatitis and will highlight potential further advantages.

Liver failure complicating segmental hepatic ischaemia induced by a PTFE-coated TIPS stent.

The use of polytetrafluoroethylene (PTFE)-covered prostheses improves trans-jugular intrahepatic porto-systemic shunt (TIPS) patency and decreases the incidence of clinical relapses and re-interventions. Therefore, the improvement provided by covered stents might expand the currently accepted recommendations for TIPS use. Stent-related occlusion of the hepatic vein with consequent ischaemia of the corresponding liver parenchyma emerges as a novel complication reported in at least 5% of patients implanted with coated stents. However, this complication was reported to be mild, without signs or symptoms of liver failure, and self-limiting. We report a case of segmental liver ischaemia following PTFE-covered stent placement resulting in a marked impairment in liver function in a patient with hepatitis C virus cirrhosis implanted because of refractory oesophageal bleeding, thus expanding the severity range of this new procedural complication. Moreover, we discuss the possible involvement of additional pathogenetic mechanisms other than out-flow obstruction in the onset of coated-stent induced congestive liver ischaemia.

Non invasive diagnosis of portal hypertension in cirrhotic patients.

The measure of disease progression in chronic liver disease represents a key challenge in any of the different stages of evolution. Indeed, a correct and reliable measure of the stage of the disease has relevant implications for assessing the effectiveness of the current therapeutic regimens and for predicting the occurrence of complication. Accordingly, a current major effort is directed at evaluating methodologies characterized by no or low invasiveness to be employed as clinical discriminators in patients populations potentially requiring invasive assessment. This appears particularly relevant in patients with compensated cirrhosis, where the only reference standard is the measurement of portal pressure by hepatic venous pressure gradient (HVPG). In this particular context, transient elastography (TE) appears to be promising and needs to be further investigated, possibly in combination with other non-invasive methodologies such as serum markers algorithms and/or imaging techniques. On the other hand, the application of non-invasive methods for monitoring the response to vasoactive treatment for the reduction of portal pressure and the prevention of related complications seems at the moment not realistic.

Reliability of transient elastography for the diagnosis of advanced fibrosis in chronic hepatitis C.

BACKGROUND: Transient elastography (TE) has received increasing attention as a means to evaluate disease progression in patients with chronic liver disease. AIM: To assess the value of TE for predicting the stage of fibrosis. METHODS: Liver biopsy and TE were performed in 150 consecutive patients with chronic hepatitis C-related hepatitis (92 men and 58 women, age 50.6 (SD 12.5) years on the same day. Necro-inflammatory activity and the degree of steatosis at biopsy were also evaluated. RESULTS: The areas under the curve for the prediction of significant fibrosis (> or = F2), advanced fibrosis (> or = F3) or cirrhosis were 0.91, 0.99 and 0.98, respectively. Calculation of multilevel likelihood ratios showed that values of TE < 6 or > or = 12, < 9 or > or = 12, and < 12 or > or = 18, clearly indicated the absence or presence of significant fibrosis, advanced fibrosis, and cirrhosis, respectively. Intermediate values could not be reliably associated with the absence or presence of the target condition. The presence of inflammation significantly affected TE measurements in patients who did not have cirrhosis (p<0.0001), even after adjusting for the stage of fibrosis. Importantly, TE measurements were not influenced by the degree of steatosis. CONCLUSIONS: TE is more suitable for the identification of patients with advanced fibrosis than of those with cirrhosis or significant fibrosis. In patients in whom likelihood ratios are not optimal and do not provide a reliable indication of the disease stage, liver biopsy should be considered when clinically indicated. Necro-inflammatory activity, but not steatosis, strongly and independently influences TE measurement in patients who do not have cirrhosis.

ADMA correlates with portal pressure in patients with compensated cirrhosis.

BACKGROUND: Chronic liver diseases are frequently complicated by portal hypertension, an important component of which is the increased intrahepatic vascular resistance, in part related to endothelial dysfunction. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, is an established mediator and marker of endothelial dysfunction. We therefore investigated the possible implication of ADMA in chronic liver diseases-induced portal hypertension. MATERIALS AND METHODS: We studied 39 consecutive patients with compensated hepatitis C virus (HCV) related chronic liver diseases. All patients underwent hepatic venous pressure gradient (HVPG) measurement, and simultaneous blood sampling from the hepatic vein and the pulmonary artery, for ADMA and nitrite/nitrate (NOx) plasma level determinations. RESULTS: A positive correlation between HVPG and ADMA concentrations in hepatic veins (ADMA-h) was found (r = 0.77, P < 0.0001). Moreover, a negative correlation between HVPG and NOx concentrations in the hepatic veins (NO-h) (r = -0.50, P = 0.005), and between ADMA-h and NO-h was observed (r = -0.40, P = 0.02). ADMA concentrations in pulmonary artery (ADMA-p) (0.55 +/- 0.13 micromol L(-1)) were significantly higher than in hepatic veins (0.47 +/- 0.09 micromol L(-1)) (P < 0.0001). CONCLUSIONS: These results suggest that ADMA may play a pathophysiological role in portal hypertension by contributing to the relative intrahepatic NO deficiency typical of endothelial dysfunction.

Review article: the pathogenesis of fibrosis in non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis has been recognized as a significant cause of end-stage liver disease and hepatic decompensation. Despite the growing interest in this condition, the molecular mechanisms underlying the development of fibrosis in this setting are only partially understood. In this article, the cellular and molecular basis of fibrosis in chronic liver disease are briefly outlined. In addition, mechanisms specifically operating in the context of fatty liver and steatohepatitis are examined, including: insulin resistance, oxidative stress, and inflammation. Finally, recent developments indicating the possible contribution of cytokines derived from adipose tissue (adipokines) to liver fibrosis is discussed.

Adipokines and liver fibrosis.

Liver fibrosis involves different cell types, and should be regarded as a "wound healing" response that occurres in conditions of chronic liver injury and is characterized by inflammation, activation of matrix-producing cells, matrix deposition and remodeling, and epithelial cell regeneration or an attempt thereof. Liver damage may be caused by several agents or conditions, resulting in different degrees and types of tissue inflammation and in activation of matrix-producing cells, such as the hepatic stellate cells (HSC). HSC undergo a phenotypic transition (known as "activation") to myofibroblast-like cells that synthesize different extracellular matrix components. Obesity is associated with the development of NASH, and has been indicated as an independent factor for the progression to fibrosis. In liver diseases, the biologic actions of the adipokines, such as leptin, adiponectin and resistin, released by adipocytes or locally produced by liver and/or inflammatory cells, may contribute to clarify the mechanisms of progression in NASH. The clinical and experimental findings accumulating on this class of molecules could represent the basis to devise a better management strategy for the patients with chronic liver disease.

Update on ascites and hepatorenal syndrome.

Ascites is the most common complication occurring during liver cirrhosis. Even if a significant decrease in renal clearance may be observed in the first step of chronic active liver disease, renal impairment, at times complicated by the typical signs of hepatorenal syndrome, occurs only in patients with ascites, especially when tense and refractory. Experimental and clinical data seem to suggest a primary sodium and water retention in the pathogenesis of ascites, in the presence of an intrahepatic increase of hydrostatic pressure, which, by itself, physiologically occurs during digestion. Abnormal sodium and water handling leads to plasma volume expansion, followed by decreased peripheral vascular resistance and increased cardiac output. This second step is in agreement with the peripheral arterial vasodilation hypothesis, depicted by an increase in total blood volume, but with a decreased effective arterial blood volume. This discrepancy leads to the activation of the sympathetic nervous and renin-angiotensin-aldosterone systems associated with the progressive activation of the renal autacoid systems, especially, that of the arachidonic acid. During advanced cirrhosis, renal impairment becomes more sustained and renal autacoid vasodilating substances are less available, possibly due to a progressive exhaustion of these systems. At the same time ascites becomes refractory inasmuch as it is no longer responsive to diuretic treatment. Various pathogenetic mechanisms leading to refractory ascites are mentioned. Finally, several treatment approaches to overcome the reduced effectiveness of diuretic therapy are cited. Paracentesis, together with simultaneous administration of human albumin or other plasma expanders is the main common approach to treat refractory ascites and to avoid a further decrease in renal failure. Other effective tools are: administration of terlipressin together with albumin, implantation of the Le Veen shunt, surgical porto-systemic shunting or transjugular intrahepatic portosystemic stent-shunt, or orthotopic liver transplantation, according to the conditions of the individual patient.

Hemodynamic, renal, and endocrine effects of acute inhibition of nitric oxide synthase in compensated cirrhosis.

To assess whether an increased production of nitric oxide is involved in the circulatory and renal alterations of cirrhosis, we evaluated systemic hemodynamics (echocardiography), renal hemodynamics, and sodium handling (lithium clearance method), plasma renin activity (PRA), aldosterone (PAC), and norepinephrine in 7 patients (3 men, mean age 65 +/- 2 years) with compensated cirrhosis, portal hypertension, and hyperdynamic circulation during intravenous N(G)-monomethyl-L-arginine (L-NMMA) (3 mg/kg bolus plus 0.05 mg/kg. min for 120 minutes) or placebo (the vehicle) in a randomized, placebo-controlled, crossover study. Administration of L-NMMA resulted in significant reductions in plasma and urinary nitrite levels and plasma cyclic guanosine monophosphate (cGMP), indicating effective inhibition of nitric oxide synthase. L-NMMA also significantly reduced cardiac index (-13%) and increased systemic vascular resistance (+26%), arterial pressure (+9%), renal blood flow (+12%), glomerular filtration rate (+12%), and sodium excretion (+25%). Changes in sodium excretion were caused by both enhanced filtered sodium load and reduced sodium reabsorption in the proximal tubule. Plasma norepinephrine significantly decreased in response to L-NMMA, and there was a trend for reductions in PRA and PAC. Placebo had no appreciable effect on any of the measured parameters. These results indicate that in patients with compensated cirrhosis, portal hypertension and hyperdynamic circulation inhibition of nitric oxide synthase corrects the altered systemic hemodynamics and improves renal function and sodium excretion.

Ascites and hepatorenal syndrome.

Ascites is a frequent complication of chronic liver disease with severe portal hypertension. Moreover, in the presence of tense ascites, renal dysfunction and hepatorenal syndrome may occur. Unfortunately, there is no explanation that thoroughly describes the complex relationship between the liver and kidney in either physiological or pathological conditions. Nevertheless, available evidence indicates that early sodium and water retention precedes decompensation, characterized by hyperdynamic circulation. The best approach to the treatment of these patients should be aimed at the prevention of ascites formation. An accurate sequential treatment is indicated in patients with ascites. In the case of hepatorenal syndrome, the only definitive approach is liver transplantation.