Hiroshi Shijo

Effects of nifedipine on hepatic venous pressure gradient and portal vein blood flow in patients with cirrhosis

Abstract We investigated the effects of nifedipine on splanchnic haemodynamics in 13 patients with cirrhosis and portal hypertension, and in 10 control subjects using hepatic venous catheterization and pulsed Doppler ultrasound. There were no significant changes in systemic or splanchnic haemodynamics in control patients. In contrast, systemic vascodilatation, evidenced by significant decreases in mean arterial pressure and systemic vascular resistance, was observed in patients 20 min after sublingual application of 10 mg nifedipine. Moreover, hepatic venous pressure gradient and portal vein blood flow significantly increased after nifedipine administration. There was a significant correlation between the percentage increases in portal vein blood flow and in hepatic venous pressure gradient. However, no correlation was found between the percentage change in cardiac output and that in portal vein blood flow. Thus the increase in portal vein blood flow appears to be related to splanchnic arterial vasodilatation by nifedipine. Consequently, nifedipine has deleterious effects on portal haemodynamics in patients with cirrhosis. As nifedipine may potentially increase the risk of variceal haemorrhage in patients with less advanced varices, this drug should be used with caution in patients with chronic liver disease.

Combination of transileocolic vein obliteration and balloon-occluded retrograde transvenous obliteration is effective for ruptured duodenal varices

Abstract: Duodenal varices are a rare site of hemorrhage in patients with portal hypertension, but their rupture is a serious and often fatal event. We report a 65-year-old woman who presented with hematemesis and melena. She was admitted to our department because of prolonged shock, despite having received transfusion of a large volume of blood. Upper gastrointestinal endoscopy revealed nodular varices with active bleeding in the second portion of the duodenum. Endoscopic injection sclerotherapy (EIS) was performed using a tissue adhesive agent, α-cyanoacrylate monomer, with only temporary benefit. However, anemia continued to progress after the procedure. Therefore, we combined transileocolic vein obliteration (TIO) with balloon-occluded retrograde transvenous obliteration (B-RIO), using 5% ethanolamine oleate with iopamidol to obliterate the varices. Complete hemostasis was achieved without complications. Neither recurrence of varices nor further bleeding has occurred for over 3 years. We conclude that combined TIO and B-RTO, which can obstruct both the feeding and the draining vessels of duodenal varices to retain the sclerosing agent completely in the varices, is a safe and effective hemostatic measure for ruptured duodenal varices, when EIS has failed to accomplish complete hemostasis.

In situ detection of insulin-like growth factor II (IGF2) and H19 gene expression in hepatocellular carcinoma

AbstractTo assess the relationship between insulin-like growth factor II (IGF2) and H19 gene expression at the cellular level, we have examined the distribution of IGF2 and H19 mRNA by means of in situ hybridization in hepatic malignancies consisting of hepatocellular carcinoma (HCC), cholangiocellular carcinoma (CCC), and metastatic liver cancer (MLC). In HCC, 15 of 27 tumors (56%) and 11 of 27 tumors (41%) demonstrated increased IGF2 and H19 gene expression, respectively. Of 16 HCCs with increased expression of either IGF2 or H19, 10 tumors coexpressed both transcripts at comparable levels. Moreover, the spatiotemporal distribution and the cellular localization of the two gene transcripts were almost identical, suggesting the presence of a reciprocal relation between IGF2 and H19. In addition, 5 HCCs showed increased IGF2 expression without concomitant H19 expression, whereas 1 HCC showed increased H19 expression without IGF2 transcripts. However, 11 HCCs showed no IGF2 or H19 expression. On the other hand, neither IGF2 transcripts nor H19 transcripts were detected in 2 CCCs or 10 MLCs studied. The data suggest that IGF2 and/or H19 gene expression may be characteristic of some HCCs.

Influence of hepatitis b virus infection and age on mode of growth of hepatocellular carcinoma

According to the extent of hepatic involvement of the tumor and that of portal vein invasion at the time of initial diagnosis, patients with hepatocellular carcinoma (HCC) were grouped into three or four groups. Correlations among the extent of hepatic involvement, extent of portal vein invasion, and prevalence of hepatitis B surface antigen (HBsAg) and age distribution were examined. The extent of hepatic involvement of the tumor and that of portal vein invasion were significantly greater in patients with positive HBsAg compared with findings in the negative patients (P < 0.001). For cases of both positive and negative HBsAg, patients with a more extensive HCC were significantly younger. Results of the multivariate logistic regression analysis showed that hepatitis B antigenemia and younger age were statistically significant and independent positive predictors of extensive HCC. These results strongly suggest that hepatitis B surface antigenemia and age play an important role in the growth mode and the kinetics of HCC in Japanese patients.

Appearance of cross linked proteins in human atheroma and rat pre-fibrotic liver detected by a new monoclonal antibody

A new monoclonal antibody against malondialdehyde (MDA)-treated low density lipoprotein (LDL) was raised using homogenate of human atheroma as immunogen. This antibody, DLH2, was obtained by selecting the clones which did not react to native LDL but did react to copper-induced oxidized LDL (OxLDL). DLH2 showed a greater reactivity to MDA-LDL than to OxLDL. When LDL was treated with various aldehyde containing reagents, treatment of LDL with glutaraldehyde or MDA greatly increased the reactivity to the antibody, while LDL treated with 2,4-hexadienal or 4-hydroxynonenal was not reactive. Among many proteins tested, high density lipoprotein, bovine serum albumin and hemoglobin showed significant reactivity to DLH2 after they were treated with MDA or glutaraldehyde. When low density and high density lipoproteins treated with MDA were subjected to immunoblot analysis, newly formed products larger than the original apolipoproteins were detected with the antibody, suggesting that this antibody recognizes aggregated proteins with divalent short chain cross linkers. The antigenic materials were shown by immunohistochemical analysis to be present in foamy macrophages in human atheromatous lesions. DLH2 antigen did not colocalize either with apolipoprotein B. Furthermore, we found a massive accumulation of the antigenic material in Kupffer cells in the liver of rats treated with alcohol and carbonyl iron, a model of hepatic fibrosis due to oxidative stress. These results suggest the presence of cross linked proteins in damaged tissues.

Reversibility of pulmonary telangiectasia in liver cirrhosis evidenced by serial dynamic pulmonary perfusion imaging

Pulmonary perfusion Imaging with Tc-99m MAA revealed significant uptake in the lungs, brain, spleen, and both kidneys of a 48-year-old woman with liver cirrhosis and pulmonary telangiectasia associated with marked hypoxemia and cyanosis. Dynamic pulmonary perfusion imaging revealed a gradual reduction after peak uptake in both lungs. Several weeks after albumin replacement, the hypoxia and dyspnea disappeared with no change in hepatocellular function. At that time, dynamic pulmonary perfusion imaging revealed a plateau-like time-activity curve of uptake in the lungs, as compared with the findings obtained during the state of severe hypoxemia. These observations suggest that pulmonary teleangiectasia in a patient with liver cirrhosis may be due to functional vasodilatation. Serial dynamic pulmonary perfusion imaging indicates the passage of the MAA particles through the widened lumen of the pulmonary alveolar capillaries.

The natural history and prognostic factors in patients with cirrhosis and gastric fundal varices without prior bleeding.

Objectives and methods: The prognostic factors have not yet been fully evaluated in patients with cirrhosis and gastric fundal varices (FV). We investigated the natural history of 145 patients with cirrhosis and FV with no history of bleeding. Various possible prognostic factors, which include clinical, biochemical, and endoscopical variables, were analyzed using Coxs proportional hazard model. Results: Among the 145 patients with cirrhosis and FV, there were 76 patients in class A, 45 in class B and 24 class C according to Childs classification. Sixty-five patients had concomitant hepatocellular carcinoma at the time of enrollment. Seventy deaths and 34 episodes of the hemorrhage from FV occurred during the mean follow-up period of 26.4 months. The cumulative survival rates at 1, 3, and 5 years were 75, 53 and 34%, respectively. The cause of death was related to gastrointestinal hemorrhage in 18 patients (15 deaths were related to FV hemorrhage), hepatic failure in 22, hepatocellular carcinoma in 22, and other causes in eight patients. In patients with small-, medium-, and large-sized FV, the deaths related to FV hemorrhage were 4, 21 and 54%, respectively. Overall, the death related to FV hemorrhage was 21%. A multiple regression analysis using Coxs model showed hemorrhage from FV, the presence of hepatocellular carcinoma and poor Childs status were all highly significant prognostic factors. Conclusion: The natural history of the patients with cirrhosis and FV was adversely modified by the hemorrhage from FV, concomitant hepatocellular carcinoma and poor hepatic functional reserve. Since the number of deaths related to FV hemorrhage was great in patients with large-sized FV, it is important to identify high-risk large FV and its prophylactic obliteration. Further studies are needed to elucidate the efficacy of prophylactic obliteration of large-sized FV.

Reversibility of hepatopulmonary syndrome evidenced by serial pulmonary perfusion scan

SummaryA patient with liver cirrhosis who exhibited marked hypoxemia is presented. An abnormal dilatation of intrapulmonary capillaries was evidenced by perfusion lung scan, contrast-enhanced echocardiography, and histological examinations of lungs. Serial perfusion lung scan disclosed that the radioisotope uptake by extrapulmonary organs was significantly increased and uptake by both lungs was significantly decreased during the state of severer hypoxemia. Shunt quantification method revealed that intrapulmonary right-to-left shunt ratio also paralleled the extent of hypoxemia. The pathophysiology of hepatopulmonary syndrome appeared to involve a reversible intrapulmonary vascular dilatation. The perfusion lung scan could semiquantitate the severity of intrapulmonary vascular dilatation and could offer the efficient method to follow their progress.

Magnitude of activity in chronic hepatitis C is influenced by apoptosis of T cells responsible for hepatitis C virus

Background : The mechanisms of hepatitis C virus (HCV) persistence are unknown, but down‐regulation of immune response in a host is likely to play a major role in it.

Immunohistochemical evidence of insulin-like growth factor II in human small hepatocellular carcinoma with hepatitis C virus infection: Relationship to fatty change in carcinoma cells

It has recently been reported that insulin‐like growth factor II (IGF‐II) may play a role in the pathogenesis of hepatocellular carcinoma (HCC). We studied the relationship between the expression of IGF‐II and fatty change in human small HCC using immunohistochemical staining techniques. Liver biopsy specimens were obtained from 35 patients with HCC (consisting of 15 patients with fatty change and 20 patients without fatty change). All patients had serum markers for the hepatitis C virus (HCV) and histological findings obtained from non‐tumourous lesions showed liver cirrhosis or chronic active hepatitis. Immunohistochemical staining was performed using a monoclonal antibody against rat IGF‐II. A positive immunoreaction was found in 69% (24/35) of HCC. Insulin‐like growth factor II was immunodetected in 80% (12/15) of HCC with fatty change but only in 60% (12/20) of those without fatty change. In most cases, IGF‐II was not found in hepatocytes from non‐tumourous lesions. We believe this to be the first time that IGF‐II has been detected immunohistochemically in small HCC derived from HCV infection. This growth factor was more frequently immunodetected in HCC with fatty change than without. As insulin is an essential factor for the metabolism of fatty acids, IGF‐II may play an important role in both fatty degeneration and in the proliferation of HCC cells. Furthermore, immunohistochemical IGF‐II staining may contribute to the diagnosis of HCC, particularly in early stages accompanied by fatty change.