Liver support systems as perioperative care in liver transplantation-historical perspective and recent progress in Japan.

A meta-analysis of the efficacy of artificial liver support (ALS) systems for fulminant hepatic failure (FHF) by the Cochrane Hepato-Biliary Group suggested that all ALS systems previously developed are ineffective for FHF. This supports the view that the only treatment of choice for FHF is immediate liver transplantation. Plasma exchange, in combination with high-volume hemodiafiltration or high-flow continuous hemodiafiltration using large pore membranes, which was excluded from the Cochrane meta-analysis because of the lack of randomized control trials, has become a standard ALS system in Japan. This system is safe, and it efficiently removes more low and middle molecular weight toxic substances than other methods by using a large volume of buffers (more than 200 L per session), resulting in recovery from coma in patients with severe FHF comparable to an ahepatic state. These artificial liver support systems are effective tools for sustaining patients with FHF in a favorable condition until liver function recovers or liver transplantation becomes available.

Artificial liver support system using large buffer volumes removes significant glutamine and is an ideal bridge to liver transplantation.

BACKGROUND: Fulminant hepatitis is an intractable disease of varying etiology. Artificial liver support (ALS) is used to control serious symptoms of fulminant hepatitis, such as brain edema, which may induce postoperative neurological deficits. PATIENTS AND METHODS: ALS was evaluated in 12 patients with fulminant hepatitis who had been placed on an ALS system comprising plasma exchange and online hemodiafiltration. Six of 12 patients fell into an ahepatic state, the absolute indication for liver transplantation. The effects of ALS were evaluated on the basis of improvements in clinical symptoms, removal of glutamine (Gln), and brain computed tomography. RESULTS: All 12 patients regained consciousness with ALS and 5 survived; 7 died despite recovering from hepatic coma. The ALS systems sustained patients in an ahepatic state for more than 2 weeks. The median estimated plasma equivalent volume of removed Gln was 17.9 L (range, 6.7-64.3 L). There was a significant relationship between total buffer volume and the plasma equivalent volume of removed Gln. CONCLUSION: Plasma exchange combined with hemodiafiltration using large buffer volumes is a promising and effective bridging method to liver transplantation.

Efficacy of interferon Beta combined with cyclosporine induction and intensified therapy for retreatment of chronic hepatitis C.

OBJECTIVE: Hepatitis C virus (HCV) infection is a major burden after liver transplantation. There is no effective treatment for these patients, therefore management is challenging. Cyclophilins are essential host factors for HCV replication. We have reported herein the efficacy of divided administration of interferon (IFN) beta plus cyclosporine for chronic hepatitis C patients who failed pegylated (Peg)-IFN or IFN combined ribavirin treatment. PATIENTS AND METHODS: We prospectively enrolled 59 patients (median age, 63 years) with genotype 1b who failed to respond to the combinations of IFN plus ribavirin or Peg-IFN plus ribavirin. Our treatment involved induction, intensified, and maintenance therapies. The induction therapy prescribed intravenous 1 MU IFN beta every 4 hours for the first 3 days, 1.5 MU IFN beta every 6 hours for the next 4 days, and then 2 MU IFN beta every 8 hours for 3 weeks. The intensified therapy was the induction therapy shortened to 2 weeks. The maintenance therapy involved Peg-IFN alpha 2b and ribavirin. Cyclosporine was given 4 times daily during the induction and intensified therapies. Ribavirin was given twice daily during the maintenance phase. RESULTS: The end treatment and sustained virological response rates in the present study were 73% (43/59) and 59% (35/59), respectively. The relapse rate was 19% (8/43). Sixteen percent of patients (3/19) were nonresponders. All adverse effects were reversible. The treatment protocol was well tolerated. CONCLUSION: Our protocol should be effective for patients who have failed previous combination therapies.

Interferon combined with cyclosporine treatment as an effective countermeasure against hepatitis C virus recurrence in liver transplant patients with end-stage hepatitis C virus related disease.

Hepatitis C virus (HCV) is the most common cause of end-stage liver disease in transplant recipients. Progression of recurrent HCV infection is accelerated. Cyclosporine is not only an immunosuppressive drug, but also an anti-HCV drug. We reported here the beneficial effect of combined interferon and cyclosporine treatment for chronic hepatitis C. We recommend this protocol for established HCV-related graft disease.

A simple method for evaluating prothrombin time in severe liver disease.

A measurement of prothrombin time by a new, whole blood capillary system was evaluated for use in severe liver disease, such as fulminant and chronic hepatic failure. The measurement required a single drop of fresh, whole blood and was easily performed at bedside. Results were available within 5 minutes after collection of the blood samples. Good correlation was observed between prothrombin time values determined by the rapid method and those determined with the laboratory method (r = .89). The laboratory method was used as a reference. The whole blood system may be especially helpful in emergency situations, when central laboratory services are not available.

Interferon and cyclosporin A in the treatment of fulminant viral hepatitis.

The prognosis of fulminant hepatitis due to non-A, non-B virus infection and acute reactivation of hepatitis B virus in HB carriers is generally poor, and the treatment of choice in Western countries is recognized as liver transplantation. In countries such as Japan where liver transplantation is not readily available, however, these intractable types of fulminant hepatitis have to be treated medically. Based on the assumption that persistent replication of causal viruses and enhanced host immune responses, especially cellular immunity, to eradicate the viruses are the key mechanism in progressive liver cell destruction and the poor prognosis, we attempted a combination treatment with interferon and cyclosporin A for these types of fulminant viral hepatitis. Subjects in the present study consisted of 1 patient with acute severe hepatitis without coma and 13 patients with coma (13 with fulminant hepatic failure) due to non-A, non-B virus and acute reactivation of hepatitis B virus. The patients were given interferon-beta, 300 x 10(4) U daily, and cyclosporin A, at an initial dose of 3 mg/kg, with tapering. Fourteen patients with coma received artificial liver support that we devised. The patient with acute severe hepatitis survived, showing histologically remarkable liver regeneration. Eight of the 14 patients with hepatic coma, all of whom were indications for liver transplantation according to the criteria of the King's College group, survived. Decreased transaminase level, increased liver volume, and histological liver regeneration were observed in all the survivors. The combination of interferon and cyclosporin A is worth attempting in fulminant hepatitis caused by non-A, non-B virus and acute reactivation of hepatitis B virus in HB carriers.

Studies on serum immunoreactive prolyl 4-hydroxylase in liver diseases--its elevation both in hepatocellular damage and cholestatic diseases.

The concentration of serum immunoreactive prolyl 4-hydroxylase (S-IRPH) was determined in patients with various liver diseases by the radioimmunoassay developed previously. S-IRPH values were elevated in acute hepatitis (p less than 0.01), hepatocellular carcinoma (p less than 0.05), metastatic liver neoplasm (p less than 0.01) and cholestatic diseases (p less than 0.001), but no significant elevation was seen in chronic hepatitis or liver cirrhosis. The mean value of S-IRPH was highest in cholestatic diseases, and next highest in acute hepatitis. In addition to acute hepatitis, S-IRPH was increased in other conditions of hepatocellular damage such as exacerbation of chronic hepatitis or immediately after transcatheter arterial embolization of hepatocellular carcinoma. In cases of hepatocellular damage S-IRPH varied concurrent with cytoplasmic enzyme (AST, ALT and LDH) levels and in cases of cholestatic diseases with biliary enzyme (Al-P and gamma GTP) levels. These properties appear to be unique among serum enzymes. The characteristics of S-IRPH were considered to be related to its unique subcellular localization within the cell, ie the membrane of rough endoplasmic reticulum.

Case report: fulminant hepatitis C viral infection after allogeneic bone marrow transplantation.

The authors describe two patients with acute leukemia who died of fulminant hepatitis caused by hepatitis C virus (HCV) after an allogeneic bone marrow transplant, the first such cases reported in Japan. Both had developed posttransfusion hepatitis during chemotherapy to induce remission and for consolidation. Six months after blood transfusion, the blood serum of each patient was positive for HCV antibody and HCV RNA. In each case, there was a transient improvement in liver function after the transplant. However, within 5 months of receiving the transplant and coincident with the withdrawal of cyclosporin A, each patient developed an acute exacerbation of hepatitis. The fulminant hepatitis in our patients may, therefore, have been caused by the reactivation of HCV induced by the immunosuppressive therapy followed by a reconstitution of the immune system.

[Reversible posterior leukoencephalopathy in a patient receiving cyclosporin therapy].

We reported a case of reversible posterior leukoencephalopathy syndrome (RPLS) that occurred during cyclosporin A (CyA) therapy for fulminant hepatitis. A 22-year-old man was given an intravenous drip of interferon-beta, metylprednisolone sodium succinate and CyA, and also received plasma exchange and hemodiafiltration. On the 7th day of the intravenous CyA therapy, in which its dose had been increased from 60 mg/day to 84 mg/day, he became somnolent and had headache, double vision, hallucination and then a generalized tonic-clonic seizure. The blood CyA concentration increased to a level as high as 455 ng/ml. Brain computed tomography (CT) scan without contrast medium revealed symmetric low-density areas in the bilateral occipital white matter and partly in the cortex. T2-weighted magnetic resonance imaging (MRI) showed an increased signal intensity, and single-photon emission CT using 99 mTc showed a hypoperfusion of cerebral blood flow in those areas. After CyA administration was changed to 100 mg/day orally to decrease its uptake in the blood, his consciousness and vision recovered within 4 weeks. Then abnormalities in MRI findings completely disappeared. On the basis of the clinical course and time-sequential change of serum CyA level in this patient, he was diagnosed as having RPLS caused by CyA therapy. Recently, the number of cases of RPLS has increased in the Western countries. However, there are few reports of RPLS after CyA therapy in Japan. From this case, we emphasize that careful following up the patient's neurological findings during CyA therapy is very important and that a cranial MRI is an essential tool for the diagnosis of RPLS.

[Overview of hepatitis C virus from its discovery to now].

Hepatitis C was first recognized as a form of viral hepatitis that was distinct from disease caused by hepatitis A virus and hepatitis B virus. The etiologic agent of hepatitis C was proposed to be a small, enveloped virus based on demonstrations of its transmissibility to chimpanzees, electron microscopic studies, and sensitive to chloroform. Successful molecular cloning of viral genome in the late 1980's led to the development of assay for serological diagnosis of HCV and it is currently estimated that at least 170 million people are chronically infected with the hepatitis C virus. HCV evades host antiviral defenses by mechanisms that remain to be identified and establishes a persistent infection in a majority of patients. Persistent infection of HCV is a leading cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Therefore development of antiviral treatment for HCV is an urgent worldwide health problem. Although much has been learned about HCV genome organization, polyprotein processing, protein function and structure, many key questions remain to be answered. Major efforts of Japanese investigators should now be directed at establishing cellular system and animal models appropriate for dissecting the various steps in HCV replication cycle and strategies for blocking them.

[Effects of intraarterial infusion chemotherapy on liver function in patients with hepatocellular carcinoma].

Periodic infusion chemotherapy from the reservoir implanted by direct arterial puncture (Seldinger method) was performed in 21 cases of hepatocellular carcinoma. The effectiveness of treatment in terms of efficacy and liver function in about 12 patients who survived more than 6 months was investigated. Owing to the progressive liver atrophy and liver dysfunction with ascites, some cases had to delay infusion treatment. Thus, it is necessary to check liver function regularly.

[Effects of intra-arterial infusion chemotherapy with radiation therapy for advanced hepatocellular carcinoma].

Eight cases were treated with periodic arterial infusion therapy from reservoir and four cases with arterial infusion therapy plus 30 Gy's radiation therapy for hepatocellular carcinoma (HCC). The anatomical extent of the tumor was E3 and E4, respectively. We evaluated these forms of therapy from the viewpoint of tumor characteristics, survival time and therapeutic effects. There was no effective case of life prolongation and most of the reservoir only treated cases died a short time after therapy. But no severe complication was observed in reservoir plus radiation cases. One case showed a response, and another case tumor necrosis. The results indicate that this method is effective for advanced HCC.

[Treatment of fulminant hepatitis with highly reliable artificial liver support and administration of interferon].

We treated 10 patients with viral fulminant hepatitis (FH) and subacute hepatitis (SH) by highly reliable artificial liver support (ALS), the combination of plasma exchange (PE) and hemodiafiltration (HDF) using polymethyl methacrylate (PMMA) membrane. All patients regained clear consciousness by the ALS. Even the patients with long term hepatic failure up to for 108 days were sustained in a favorable clinical condition. Five patients finally survived. Interferon was administered to one case with type B FH with positive HBeAg, four cases with NANB FH and SH who were assumed to have persistent viral replication. Two of them showed favorable clinical responses and definite liver regeneration was confirmed. The intensive liver support which can sustain patient with severe fulminant hepatic failure accompanied by the administration interferon is believed to be the most effective treatment for FH and SH especially caused by NANB virus in our country.

[A close association of prognosis with effect of interferon in HBV carriers developing acute severe exacervation].

We have treated 19 HBV carriers who developed acute severe exacerbation using interferon and immunosuppressive agents. Of these 14 patients developed fulminant hepatic failure. Of 10 patients with positive result for serum HBV DNA polymerase before the start of te treatment, five patients in whom HBV DNA polymerase turned negative and one patient whose HBV DNA polymerase level fluctuated in a low abnormal range after the start of the treatment survived. While, four patients whose HBV DNA polymerase level remained high after the start of interferon treatment died. Thus, it is suggested that suppression of HBV virus replication is closely related to prognosis in HB carriers developing acute severe exacervation of hepatitis.

[Serial hepatic and splenic volumetry in acute severe hepatitis].

In this study, we elucidate a relationship between final outcome and changes in hepatic and splenic volume in patients with acute severe hepatitis. The subjects were 40 patients: 10 with sever acute hepatitis (prothrombin time < 40%) and 30 with fulminant hepatic failure (acute type in 12 and subacute type in 18). Liver and spleen volume were measured by CT initially on hospitalization and subsequently 1 to 40 days after hospitalization, and the scans were analyzed retrospectively. Liver volume decreased in 15 of 26 survivors, and all 14 non-survivors. Among 15 survivors and 14 non-survivors whose liver volume decreased, spleen volume increased in none of the survivors, whereas it increased in 11 of the 14 non-survivors. In survivors there was a close parallelism between changing rates of the liver volume and that of the spleen volume (r = 0.82, p < 0.0001). These observations suggest that the decrease of liver volume accompanied by that of spleen volume implies a good prognosis, while the decrease without such accompaniment implies a bad prognosis.

[IFN combined cyclosporin A therapy].

Current therapy of chronic hepatitis C with a 6 months course of alpha interferon shows limited effectiveness for patients with chronic hepatitis C. In particular more effective therapy is needed to treat patients who have high serum level of group 1-HCV RNA. We previously reported that a combination of interferon and cyclosporin A was more effective than interferon monotherapy. We also examined whether CsA has an antiviral effect on HCV using cultured human hepatocyte cell line. Propagation of HCV seems to be inhibited by CsA in a dose dependent manner. Further study is needed to clarify the action of cyclosporin A.

[Interferon treatment of type C fulminant hepatitis].

On the contrary to Western countries, there are a substantial number of patients with type C fulminant hepatitis (FH) including coinfection on type A and type B hepatitis in Asian countries. The pathogenesis of FH is not fully understood, however, recent clinical observations suggest that enhanced host immune responses contribute to hepatocyte destruction in type C FH. In contrast to type B FH, type C FH is characterized by gradual and continuous liver necrosis probably duo to persistent infection of hepatitis C virus. Administration of interferon with immunosuppressive agents is the treatment of choice. Prognosis may be improved if the treatment is started in the early stage of the disease.

[Causal relationship between GBV-C and fulminant hepatitis].

GBV-C is recently discovered RNA virus which appeared to be member of Flaviviridae. We previously reported the possible involvement of GBV-C in the etiology of fulminant hepatitis(FH). It is still controversial whether GBV-C cause FH. So far, the only reliable tool for the diagnosis of GBV-C is the detection of the viral genome using PCR. Detection of GBV-C in serum of patient with FH dose not necessarily mean that GBV-C is causal virus. Serial quantification of serum GBV-C RNA in patient with FH may reveal a pathogenetic role of GBV-C. Further study is needed to elucidate the relationship between FH and a specific strain of GBV-C.