Lamivudine in the treatment of acute hepatitis B.
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Acute Disease↗
Biomedical subjects
R Tur-Kaspa
Publications and source records attributed to R Tur-Kaspa.
Extension of transplantation free time by lamivudine in patients with hepatitis B-induced decompensated cirrhosis.
BACKGROUND: Liver transplantation for hepatitis B virus (HBV)-induced cirrhosis carries a high risk of graft reinfection and poor prognosis. Active viral replication is considered a contraindication for transplantation in most centers. Lamivudine, a new nucleoside analog, is a potent inhibitor of HBV replication that has been used safely for pretransplantation suppression of HBV replication. METHODS: We report the pattern of response to lamivudine treatment in three consecutive patients with decompensated cirrhosis due to the replicative phase of chronic HBV infection. RESULTS: In addition to virological and biochemical response, impressive clinical improvement was noted in all three patients, with disappearance of the ascites and marked improvement of synthetic liver function tests. One patient converted to anti-hepatitis B surface and is free of symptoms 20 months after initiation of treatment. The other two patients experienced significant clinical improvement for 8 to 9 months and were removed from the waiting list for transplantation. However, progressive liver disease recurred in both patients--one underwent liver transplantation and the other is a candidate for the procedure. CONCLUSION: The administration of lamivudine for pretransplantation HBV suppression was associated with impressive clinical and biochemical improvement. Lamivudine may extend the transplantation free time in such patients. The mechanism of this desirable effect should be explored.
Adult↗
Fulminant non--A-G viral hepatitis leading to liver transplantation.
BACKGROUND: All hepatotropic viruses are known to cause fulminant hepatic failure (FHF). However, in 30% to 40% of patients with FHF, the precise cause remains unknown. We aimed to better define this subgroup. METHODS: We evaluated the clinical course and outcome of 7 patients admitted during a 22-month period with fulminant viral hepatitis leading to liver transplantation; none had serologic or molecular evidence of hepatitis A, B, C, D, E, or G viral infection, thus the term non-A-G viral hepatitis. All known etiologies of FHF were excluded. RESULTS: All patients had prodromal symptoms suggestive of viral causes. Mean age was 30 years. The interval between onset of jaundice and appearance of encephalopathy was 23 days (range, 4-50 days). Five patients had grade III/IV encephalopathy. Serum alanine aminotransferase levels showed a single peak of activity. The duration between first symptoms and liver transplantation was 28 days (range, 12-71 days). Results of histological study of the explanted liver showed submassive (4 patients) or massive (3 patients) hepatocyte necrosis. In all patients, results of polymerase chain reaction analysis did not detect hepatitis B virus DNA, hepatitis C virus RNA, or hepatitis G virus RNA in the explanted liver. After transplantation, 2 patients showed (6 months later) increased liver enzyme levels of undetermined cause, and results of a liver biopsy showed mild lobular hepatitis; 1 patient had lymphoproliferative disorder (Epstein-Barr virus-originated); and 1 patient, aplastic anemia, which is known to be associated with seronegative viral hepatitis. The latter patient died, whereas the other 6 patients are alive (survival rate, 86%). CONCLUSIONS: Our patients with non-A-G viral hepatitis had a severe acute onset with progressive FHF requiring liver transplantation. There is some suggestion of recurrent viral disease after transplantation implicating other unknown viruses in the etiology.
Adolescent↗
Conversion of liver allograft recipients from cyclosporine A to FK 506 immunosuppressive therapy.
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Adult↗
Combination of interferon-alpha and ribavirin therapy for recurrent hepatitis C virus infection after liver transplantation.
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Adult↗
Mutations at vicinity of catalytic sites of hepatitis C virus NS3 serine protease gene isolated from hepatocellular carcinoma tissue.
The mechanism of hepatitis C virus (HCV) -induced hepatotocellular carcinoma (HCC) is still unknown, but in vitro studies clearly suggest that HCV proteins exert a direct effect on liver carcinogenesis. HCV NS3 serine protease is known to play a key role in the life cycle of the virus and may interact with the host cellular regulatory proteins. The aim of the present study was to conduct a genetic analysis of the HCV NS3 gene coding for the serine protease isolated from serum, tumor, and nontumor tissue of HCC patients. RNA was extracted and HCV cDNA was amplified by nested reverse transcriptase-polymerase chain reaction (RT-PCR). Sequence comparison yielded unique changes at the vicinity of the catalytic sites of the NS3 clones isolated only from HCC tissue. These changes included the insertion of a "large" and charged amino acid, substitution of a polar with a hydrophobic amino acid, and substitution of a charged with a polar amino acid. Those changes affect the electrostatic charge around the active site, and thus the activity and substrate specificity of the serine protease. This is the first study to define significant amino acid changes at the catalytic domain of the NS3 serine protease gene isolated from HCC tissue.
Amino Acid Sequence↗
Syncytial giant-cell hepatitis due to autoimmune hepatitis type II (LKM1+) presenting as subfulminant hepatitis.
Giant cell hepatitis (GCH) in adults is a rare event. The diagnosis of GCH is based on findings of syncytial giant hepatocytes. It is commonly associated with either viral infection or autoimmune hepatitis type I. A patient with GCH due to autoimmune hepatitis type II (LKM1+) is described, a combination that has not been previously reported. Corticosteroid therapy was effective in decreasing serum liver enzymes; however, the patient deteriorated rapidly and developed subfulminant hepatic failure. Although an emergency orthotopic liver transplantation was performed, the patient died because of reperfusion injury. Interestingly, only a few giant hepatocytes were noted in the explanted liver. This case stresses the association of GCH with autoimmune disorders, the possible immune mechanism involved in the formation of giant cell hepatocytes, and illustrates the rapidly progressive course and unfavorable prognosis that these patients can develop.
Adult↗
An open-label study of lamivudine for chronic hepatitis B in six patients with chronic renal failure before and after kidney transplantation.
OBJECTIVE: The course of hepatitis B virus (HBV) infection after kidney transplantation is aggressive, with a high mortality rate from liver disease mainly in patients who were serum hepatitis B e antigen (HBeAg) or HBV DNA-positive before transplantation. Lamivudine has been shown to be a potent inhibitor of HBV replication. The aim of the study was to examine the efficacy and safety of lamivudine therapy in patients with chronic renal failure and chronic HBV infection. METHODS: The study population consisted of six potential candidates for kidney or combined kidney and liver transplantation aged 25-49 yr (four patients had already undergone a kidney transplantation and developed chronic rejection). All were serum HBeAg and/or HBV DNA-positive and had been maintained on hemodialysis for 3 months to 3 yr. The duration of HBV infection was 7 months to 14 yr. Serum alanine aminotransferase (ALT) levels ranged from 72 to 610 U/L (median, 158 U/L). Liver histological evaluation showed mild to moderate chronic hepatitis (n = 4) or liver cirrhosis (n = 2). None of the patients was infected with hepatitis C or D viruses. In four patients, treatment consisted of 10 mg of oral lamivudine per day. In the other two patients, a virological and biochemical response could be achieved only when the dose was increased to 40 mg/day. RESULTS: Lamivudine treatment was associated with 1) normalization of serum ALT levels and rapid disappearance of serum HBV DNA (by hybridization) (five patients, one of whom died from sepsis); 2) seroconversion: disappearance of HBeAg (three patients) and HBsAg (two patients); 3) minor side effects: abdominal pain and nausea (one patient); 4) clinically asymptomatic lamivudine resistance 8 months after treatment (one patient); and 5) successful combined kidney and liver transplantation with no evidence of recurrent HBV infection at 6-8 months postoperatively (two patients with cirrhosis). CONCLUSIONS: Lamivudine therapy is effective as an HBV replication inhibitor in patients with chronic renal failure and HBV infection. Prospective studies of lamivudine pharmacokinetics and dosing in renal failure are needed to be able to treat patients appropriately. Although our study is small and further follow-up is needed, our data suggest that lamivudine therapy may enable selected patients with chronic hepatitis B to undergo kidney or combined kidney and liver transplantation in patients with established cirrhosis.
Adult↗
[Experience with 100 liver transplant recipients at the Rabin Medical Center and the Schneider Children's Medical Center].
Liver transplantation is the treatment of choice for end-stage liver disease. During the past 8 years we performed 102 liver transplants in 84 adults and 16 children. In the adults, 9 were combined transplants: 1 a liver-pancreas transplant for type I diabetes, and 8 liver-kidney transplants. In the children, transplants included 5 whole-livers, 5 left-lateral liver segments from living-related donors, 4 reduced-grafts of right or left lobes, and 2 split left-lateral segments. At a mean follow-up of 31 months (range 1-96) 70 were alive, 3 had died during surgery and 15 during the first postoperative months. Mortality was due to primary graft non-function (7), sepsis (10), intracranial hemorrhage (1), tumors (4), recurrent hepatitis B (2), biliary strictures (2) and chronic rejection (1). The 1- and 4-year survival rates were 79.5% and 69.6%, respectively. After transplantation, 10 developed biliary stricture (5 corrected by balloon dilatation) and 8 anastomotic stricture (7 corrected by surgery), and there were 2 multiple intrahepatic strictures. There was hepatic artery thrombosis in 5, including 4 children. In 3, grafts were salvaged by thrombectomy and 2 others underwent re-transplantation. In those who survived transplantation by more than 1-month, recurrent hepatitis B was seen in 6 of 17 (35%) and recurrent hepatitis C in 12 of 19 (63%). Thus, results of our first 100 liver transplants are similar to those reported by larger centers, showing that in an appropriate setting good results can be achieved by small transplant programs.
Adolescent↗
Association of lamivudine resistance in recurrent hepatitis B after liver transplantation with advanced hepatic fibrosis.
BACKGROUND: Orthotopic liver transplantation (OLT) in patients with hepatitis B virus (HBV) infection is known to be associated with a high recurrence rate and poor prognosis. Lamivudine, a nucleoside analogue, is a potent inhibitor of HBV replication, but it is associated with a 14-39% rate of resistance. METHODS: We report on four patients who underwent OLT for HBV infection. In all cases, the HBV infection recurred in the grafted liver and was treated with lamivudine (100 mg daily) on a compassionate-use basis. The patients were monitored closely for serum liver enzymes, hepatitis B surface antigen and HBV DNA (by hybridization). Liver biopsy was performed before and after lamivudine therapy. HBV DNA was amplified from serum for each patient and sequenced through a conserved polymerase domain, the tyrosine-methionine-aspartate-aspartate (YMDD) locus. RESULTS: All four patients exhibited lamivudine resistance 9-20 months after initiation of the drug. In all patients with a clinically mild disease, liver histology findings (12-24 months after lamivudine therapy) showed progressive fibrosis as compared to biopsies performed before lamivudine therapy, with a significant increase (> or =2 points) in the Knodell score in three patients. Moreover, two patients exhibited worsening of the necroinflammatory process. A mutation at the YMDD motif of the HBV polymerase gene was detected in all cases. CONCLUSIONS: Lamivudine resistance frequently occurs in patients with recurrent HBV infection after OLT and is associated with advanced hepatic fibrosis and necroinflammatory process. A combination of antiviral therapies may be necessary.
Adult↗
Posttransplantation lymphoproliferative disorder in liver recipients: characteristics, management, and outcome.
Posttransplantation lymphoproliferative disorder (PTLD) is a well-recognized complication of organ transplantation. The aim of this study, performed over 9 years, was to examine the histopathological findings, clinical course, and outcome of patients who, having undergone orthotopic liver transplantation (OLT), developed PTLD. The sample included 7 adult liver allograft recipients (1.7%), 4 men and 3 women, with a mean age of 53 years (range, 40 to 61 years) who developed PTLD 1 to 36 months post-OLT (mean, 6 months). Four patients received either antithymocyte globulin as primary immunosuppression or OKT3 for steroid-resistant cellular rejection. Four patients had localized hepatic tumor with or without regional lymph node involvement, 2 patients had extralymphoreticular disease (head of pancreas and chest wall), and 1 patient had spleen and lymph node involvement. All tumors were B-cell lymphomas; three polymorphic and four monomorphic. Clonality was assessed by immunostaining for kappa and lambda and gene rearrangement. Monoclonality was found in 4 patients and polyclonality in 2 (1 of whom progressed to monoclonality); in 2 patients, clonality could not be determined. Immunohistochemistry findings for the presence of the Epstein-Barr virus (EBV)-determined nuclear antigen and the latent membrane protein 1 were noted in lymphoma tissue in 6 patients. Immunosuppressive therapy was decreased in all patients. Polyclonal tumors were treated with acyclovir (1 patient is in complete remission and 1 patient died), and monoclonal tumors with systemic chemotherapy (2 patients are in complete remission and 2 patients died). One patient was treated with monoclonal antibodies (CD20) but failed to respond, and 1 patient was treated with excision and is in complete remission. The mortality rate was 43%; for the remainder, median survival is 21 months (range, 10 to 42 months). We conclude that PTLD may re-present early after OLT. EBV has a special role in the pathogenesis, combined with immunosuppressive therapy. The outcome is poor, and new therapeutic approaches are needed.
Adult↗
Differences in immunoactivation between heart and liver transplanted patients.
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Adult↗
Nitric oxide metabolites in decompensated liver cirrhosis.
High levels of nitric oxide are thought to be the cause of some of the complications associated with decompensated end-stage liver disease. To assess nitric oxide metabolism in cirrhotic patients, we measured the levels of nitric oxide metabolites (nitrosohemoglobin, methemoglobin, nitrate, and nitrite) in normal subjects, in patients with decompensated cirrhosis, in patients with renal failure (model for impaired NO metabolites excretion), and in patients with mononitrates-treated anginal syndrome (model for exogenous nitric oxide). When compared to controls, patients with decompensated cirrhosis exhibited elevated levels of nitrate only. A significant increase of nitrate was also noted in patients receiving exogenous nitrates, whereas patients with impaired excretion had significantly elevated levels of both nitrite and nitrate. In conclusion, nitric oxide metabolism in patients with decompensated cirrhosis is similar to that of patients receiving nitric oxide from an exogenous source. Renal impairment, whether alone or associated with cirrhosis, causes a change in nitric oxide metabolism. These findings may have clinical implications for nitrates treatment in patients with decompensated cirrhosis.
Adult↗
Efficacy of lamivudine in patients with hepatitis B virus precore mutant infection before and after liver transplantation.
OBJECTIVE: Hepatitis B virus (HBV) precore mutant infection is associated with a more severe liver disease and a poorer response to interferon. We evaluated the efficacy and tolerance of lamivudine to induce complete and sustained suppression of viral replication in seven patients infected with HBV precore mutant (HBeAg-/HBeAb+/HBV DNA+) (in three patients mutation at codon 1896 was detected by direct sequencing). METHODS: Of the seven patients, five had decompensated HBV cirrhosis in a replicative phase and were liver transplant candidates (Group A) and two patients underwent orthotopic liver transplantation (OLT) for HBV liver cirrhosis and developed recurrent HBV infection in the grafted liver (Group B). Lamivudine 100 mg daily was administered orally for a period of 6-75 wk. RESULTS: After 6-8 wk lamivudine therapy was well tolerated and successfully suppressed HBV replication to an undetectable serum level of HBV DNA by polymerase chain reaction in six patients. In Group A, two patients underwent successful OLT with no evidence of HBV reinfection 2-14 months later. Lamivudine was continued after OLT with no episodes of rejection. Three patients died before a suitable liver could be found (one remained serum HBV DNA+ after 6 wk of lamivudine therapy). In Group B, 9-14 months after lamivudine therapy both patients developed lamivudine resistance (increased liver enzymes, reappearance of serum HBsAg and HBV DNA [by hybridization]). In both patients liver histology had progressed and in both, mutation at codon 552 of the HBV polymerase gene was detected. CONCLUSIONS: Lamivudine is well tolerated in patients with decompensated liver cirrhosis due to HBV precore mutant infection who are liver transplant candidates. In four patients (80%) potent suppression of viral replication was detected, allowing OLT to be performed. However, post-OLT, a resistant mutant developed under lamivudine therapy. Combination therapy with other antiviral agents should be evaluated to discourage the emergence of lamivudine-resistant mutants.
Antiviral Agents↗
Mesalamine-induced granulomatous hepatitis.
A 42-yr-old man with ulcerative colitis was admitted for investigation of prolonged fever associated with cholestatic liver tests. Endoscopic retrograde cholangiopancreatography demonstrated a normal biliary tree, and liver biopsy showed granulomata. A clinical diagnosis of drug-induced granulomatous hepatitis was established as the symptoms disappeared after cessation of mesalamine therapy and recurred on rechallenge. Although the differential diagnosis of fever and hepatitis in patients with inflammatory bowel disease is wide, in this case mesalamine is the most likely cause.
Adult↗
Treatment of hepatocellular carcinoma associated with cirrhosis in the era of liver transplantation.
PURPOSE: To review the treatment of cirrhotic patients with hepatocellular carcinoma in the era of liver transplantation and to determine the most appropriate approach to the treatment of patients at different stages of disease. DATA SOURCES: A MEDLINE search of English-language articles published between 1981 and 1997 and the clinical experience of the Mount Sinai Liver Transplant Program. STUDY SELECTION: Selected studies were 1) original articles reporting results of resection and transplantation in the treatment of hepatocellular carcinoma in cirrhotic patients and 2) initial reports from major transplantation centers of multimethod therapies combining chemotherapy with transplantation. DATA EXTRACTION: Study designs were assessed with careful attention to methods and aims. Relevant data on patient population, tumor stage distribution, treatment, survival, and rate of recurrent disease were extracted and analyzed. DATA SYNTHESIS: Options for the treatment of hepatocellular carcinoma in cirrhotic patients vary according to tumor stage and severity of underlying liver disease. Resection remains an important method primarily in eastern countries, where the screening of high-risk populations has been associated with early detection of small asymptomatic lesions. Long-term survival after resection, however, is low. In western countries, liver transplantation is becoming the treatment of choice in patients with advanced cirrhosis and small, unresectable lesions; resection is reserved for cirrhotic patients with small, peripheral lesions and preserved hepatic function. Minimally invasive procedures (such as percutaneous ethanol injection and transarterial chemoembolization) have been developed to treat unresectable tumors. Transarterial chemoembolization may also be effective in patients with advanced cirrhosis and unresectable lesions who are awaiting transplantation. CONCLUSIONS: The efficacy of liver transplantation for hepatocellular carcinoma has been proven mainly in patients with advanced cirrhosis and small lesions. Future studies may clarify the role of approaches combining neoadjuvant chemotherapy with transplantation for large (stage III) tumors.
Algorithms↗
[Living-related liver transplantation--first experiences at Rabin Medical Center].
Our experience with living-related liver transplantation is described. In 2 boys and 1 girl, aged 4-4.5 years with acute, fulminating hepatitis A, the presence of very severe jaundice (bilirubin levels > 18 mg%) associated with severe coagulopathy (INR > 10) and encephalopathy indicated the need for urgent liver transplantation. In all 3 cases the left lateral hepatic segment of a matched blood type parent was transplanted. None of the donors suffered a serious complication postoperatively and all returned to full activity in 6-16 weeks. The post-transplantation course was uneventful in 1 child, but in the other 2 there was hepatic arterial thrombosis in 1 at 1 day and in the other at 8 days post-transplantation. Early detection of arterial thrombosis by Doppler sonography permitted salvage of the 2 hepatic grafts after thrombectomy and re-anastomosis. In 1 of these 2 children an anastomotic biliary stricture was found 2 months after transplantation. It was corrected at surgery and a percutaneous stent was inserted. All 3 children are alive with normal graft function at 2, 7 and 8 months post-transplantation, respectively. This initial experience indicates that living-related liver transplantation is feasible in Israel. The technique might help to solve our severe organ shortage for children awaiting liver transplantation.
Adult↗
Cavoatrial shunt: a graft salvage procedure for suprahepatic caval anastomosis obstruction after liver transplantation.
A liver transplant recipient developed the Budd-Chiari syndrome because of an obstruction of the suprahepatic inferior vena cava anastomosis. Percutaneous balloon dilatation angioplasty was not feasible. On exploration, dense retrohepatic fibrotic reaction was observed. The patient underwent successful retrohepatic cavoatrial shunt placement by means of a 16-mm, ring-enforced polytetrafluoroethylene graft. We conclude that this shunt should be considered an additional graft salvage procedure for this complication.
Arteriovenous Shunt, Surgical↗