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AIM: The vasopressin V2 receptor antagonist tolvaptan has been used for the treatment of cirrhotic patients with ascites; however, no predictor of efficacy and prognosis has been developed. We evaluated candidate predictors of response to tolvaptan treatment. METHODS: This was a single-center retrospective study. Overall, 97 Japanese cirrhotic patients (60 men, median age 63 years), who were hospitalized for ascites treatment including oral tolvaptan coupled with conventional diuretics, were enrolled. The efficacy of tolvaptan was defined as a urination increase of ≥500 mL or a urine volume ≥2000 mL/day on the day following treatment. The prognosis of tolvaptan treatment was evaluated by the post-treatment survival time by Kaplan-Meier analysis. RESULTS: Tolvaptan therapy was effective in 67% of cirrhotic patients. Patients showed -1.5 (-17.2 to +6.2) kg change in body weight and 40% achieved ≥2.0 kg reduction in body weight after 1 week of treatment. Platelet counts, urine sodium (Na) level, and urine Na/potassium (Na/K) ratio were higher, and the blood urea nitrogen (BUN)/creatinine (Cr) ratio was lower, in cases showing a response to tolvaptan. The combination of a BUN/Cr ratio ≥17.5 and urine Na/K ratio <3.09 was predictive of being non-responsive to tolvaptan, and the response rate in these patients was only 39% (P < 0.01). The mean post-treatment survival duration was significantly longer in patients who responded to tolvaptan therapy. CONCLUSIONS: Urinary BUN and Na excretion were predictive of a response to tolvaptan, and tolvaptan treatment may improve the prognosis of cirrhotic patients.
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Poorly controlled diabetes mellitus (DM) patients sometimes show serum transaminase elevations due to steatohepatitis. However, we experienced four cases with type 1 DM with sharp elevations in serum transaminases that could not be explained by steatohepatitis alone and showed bright liver. They were diagnosed with glycogenic hepatopathy (GH) clinicopathologically. The four patients had a median age of 22.5 years (range, 19-29 years) and 12.5 (4-15)-year histories of type 1 DM and showed marked increases in serum transaminases (aspartate aminotransferase, 698 U/L [469-2763 U/L]; alanine transaminase, 255 U/L [216-956 U/L]). Diabetes mellitus control was poor and hemoglobin A1c was 12.7% (11-16.5%). Three cases had a past history of diabetic ketoacidosis. Hepatomegaly and hyperdense liver were seen on computed tomography scans. Magnetic resonance imaging showed low intensity in T2-weighted images. The pathological findings revealed pale and swollen hepatocytes and glycogenated nuclei. The architecture of the liver was preserved, and steatosis and fibrosis were mild. The cytoplasm of hepatocytes stained densely positive with periodic acid-Schiff, and the positive staining disappeared after diastase digestion, suggesting glycogen deposition. No other cause of hepatitis was evident, and the diagnosis was GH. Elevated transaminases improved within 1 month with good glycemic control. Transaminase elevations were observed several times in three cases with poor glycemic control. Glycogenic hepatopathy is rare, but extremely high serum elevations of transaminases are important to identify clinically. Despite showing a good clinical course in general, GH sometimes recurs and requires strict glycemic control. Clinicians should be aware of and recognize GH when dealing with uncontrolled DM patients.
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AIM: Recently, the short-term efficacy of the vasopressin V2 receptor antagonist tolvaptan for the treatment of ascites in cirrhosis was reported. However, the long-term effects remain unknown. Here, we report the clinical features of decompensated cirrhosis treated using long-term tolvaptan therapy, and evaluate its safety and efficacy. METHODS: Fifty-five cirrhotic patients hospitalized due to ascites, despite receiving appropriate diuretic treatment, were treated with tolvaptan. We excluded 35 patients due to liver transplant (20.0%), death (28.6%), poor general status (14.3%), improved ascites (5.7%) or other reasons (31.4%). In 20 cases treated with tolvaptan for 6 months, total body water (TBW) and extracellular fluids (ECW) were measured using bioelectric impedance analysis (BIA) with an InBody720. RESULTS: The median age of the 20 patients was 64 years (range, 48-90), and 60% were male. The etiology of cirrhosis included hepatitis C (45%), alcohol-induced (20%) and other (35%). The percentage of patients with Child-Pugh class A, B and C was 0%, 40% and 60%, respectively. Biochemical findings revealed that serum creatinine levels and estimated glomerular filtration rate were not affected during 6 months of treatment with tolvaptan, and there was no renal disturbance. The median serum sodium levels were increased from 138 to 139 mEq/L, but serious adverse events related to renal and liver function were not observed. Data also revealed that long-term treatment reduced the BIA-estimated ECW/TBW ratio. CONCLUSION: Long-term tolvaptan treatment was a safe and effective treatment for decompensated cirrhosis.
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Primary hyperoxaluria (PH) is a rare, autosomal recessive disorder characterized by overproduction of oxalate caused by a deficiency in a hepatic enzyme. The excess oxalate combines with calcium in the kidneys to form deposits of calcium oxalate, which can lead to nephrocalcinosis and renal failure. PH type 1 (PH1), the most common form of this disease, is caused by a deficiency of the liver-specific enzyme alanine/glyoxylate aminotransferase (AGT). Liver transplantation is performed as a definitive therapy for PH to correct the enzyme defect. Usually, liver depositions are limited and liver function is normal without fibrosis. Here, we report an adult case of liver cirrhosis caused by PH1. A 28-year-old woman was admitted to our hospital under suspicion of PH1 and the presence of nephrocalcinosis. The patient had suffered from kidney stone recurrences from 17 years of age, and was initiated on hemodialysis due to renal failure at the age of 27 years. The serum level of oxalic acid was high, whereas the AGT level in the liver tissue was decreased. Thus, the patient was definitively diagnosed with PH1. Although she had normal liver function, surface nodularity and splenomegaly were detected by computed tomography, suggesting liver cirrhosis. The native liver showed micronodular cirrhosis and portal fibrosis. Several arterioles were filled with rhomboid and polyhedral refractile oxalate crystals and various portal tracts showed these crystals. Our case suggests that long-term oxalosis can lead to liver cirrhosis; thus, PH should be considered one of the causes of liver cirrhosis.
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BACKGROUND: There have been few reports on hepatocellular carcinoma (HCC) in nonalcoholic steatohepatitis (NASH) and the natural history of NASH. Accordingly, we assessed the clinical features of HCC in NASH, the risk factors for HCC, and natural history of NASH with advanced fibrosis. PATIENTS AND METHODS: There were 34 NASH patients with HCC and 348 NASH patients without HCC. To clarify the clinical features of NASH patients with HCC and to determine the risk factors for HCC, we compared NASH patients with HCC with those without HCC. Univariate and multivariate logistic regression models were used for statistical analysis. A prospective cohort study of the outcomes of 137 NASH with advanced fibrosis was started in 1990. The impact of baseline risk factors on the development of HCC and survival was evaluated by Cox regression analysis. RESULTS: In total, 88% of patients with HCC had advanced fibrosis, with a median age of 70 years. Older age, low level of AST, low grade of histological activity, and advanced stage of fibrosis were risk factors for HCC. A prospective cohort study showed that the 5-year cumulative incidence of HCC was 7.6%, and the 5-year survival rate was 82.8%. HCC was the leading cause of death. CONCLUSIONS: The present study confirmed that older age and advanced fibrosis were important risk factors for HCC, and that HCC was the major cause of mortality in NASH patients with advanced fibrosis. Regular screening for HCC is thus extremely important for NASH patients with advanced fibrosis.
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Carcinoma Hepatocelular/etiología , Hígado Graso/patología , Neoplasias Hepáticas/etiología , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Niño , Estudios de Cohortes , Femenino , Humanos , Cirrosis Hepática/complicaciones , Cirrosis Hepática/patología , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Factores de Riesgo , Tasa de Supervivencia , Adulto JovenRESUMEN
AIM: Ornithine carbamoyltransferase (OCT) is reported to be a liver-specific marker for the evaluation of hapatocellular damage. In this study, we investigated its clinical significance in non-alcoholic steatohepatitis (NASH). METHODS: Serum OCT levels were measured by the ELISA (enzyme-linked immunosorbent assay) method. One hundred and twenty patients with NASH (18 liver cirrhosis induced by NASH and 9 NASH combined with hepatocellular carcinoma) were measured. RESULTS: The serum levels of OCT and the ratios of OCT : alanine amino transferase (ALT) and OCT : aspartate amino transferase (AST) were increased in parallel with the progression of NASH. Especially, OCT and both ratios were markedly increased in hepatocellular carcinoma. As for the relationship between fibrosis grade and OCT, the serum OCT levels and the ratio of OCT : ALT levels were increased in parallel with liver fibrosis. In NASH patients with ALT within normal range, about 30% showed elevation of OCT. CONCLUSION: Serum OCT levels and the ratios of OCT : ALT and OCT : AST increase in parallel with the progression of NASH. It was suggested that OCT is a useful marker in the progression of NASH.
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AIM: Because the procedure of balloon-occluded retrograde transvenous obliteration (B-RTO) causes extensive thrombosis of the major shunt that connects the spleen and gastric/renal venous systems, an increase in portal pressure is unavoidable. The aim of the present study was to assess the long-term outcome of B-RTO, including changes in esophageal varices. METHODS: B-RTO was conducted in 22 patients with gastric varices, who were divided according to the severity of esophageal varices at baseline; there were no esophageal varices (n = 7), F(1) varices (n = 11), and F(2) varices (n = 4). The outcome measures included the development/worsening of esophageal varices after B-RTO and survival rates. RESULTS: The cumulative bleeding-free probability for all 22 patients at 3 years after B-RTO was 100%. The overall 3-year survival was 94.4%. Seven patients who had no esophageal varices prior to B-RTO did not develop any after the procedure. Seven (63.6%) of the 11 patients with stage F(1) esophageal varices prior to B-RTO showed no changes in the varices after B-RTO, while two patients progressed to F(2) varices and two developed F(3) varices. The cumulative treatment-free probability of the esophageal varices at 24 months after B-RTO was 100% for patients without esophageal varices at baseline, 80.8% for patients with pre-existing F(1) varices, and 75% for those with pre-existing F(2) varices. CONCLUSION: Although the B-RTO procedure is considered useful for the treatment of gastric varices, changes in hemodynamics due to obliteration of this major shunt must be taken into account and observed closely.
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The patient was a 23-year-old man who was diagnosed with severe hypoxemia and liver dysfunction after suffering from sudden difficulty breathing. At 2 years of age, he had been diagnosed with hypopituitarism, and had received hormone-replacement until he was 18 years of age. Echocardiography using micro bubbles and pulmonary scintigraphy indicated intrapulmonary shunt and a liver biopsy showed steatohepatitis. He was diagnosed with hepatopulmonary syndrome associated with nonalcoholic steatohepatitis. Hormone-replacement therapy was re-started. After 5 months, a second liver biopsy revealed the amelioration of nonalcoholic steatohepatitis, which improved his respiratory condition. This case suggested that early effective therapy for chronic liver diseases might improve the pathological and clinical conditions of hepatopulmonary syndrome.
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Síndrome Hepatopulmonar/complicaciones , Síndrome Hepatopulmonar/tratamiento farmacológico , Terapia de Reemplazo de Hormonas/métodos , Hipopituitarismo/tratamiento farmacológico , Hipopituitarismo/etiología , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/etiología , Corticoesteroides/uso terapéutico , Adulto , Hormona del Crecimiento/uso terapéutico , Humanos , Masculino , Testosterona/uso terapéutico , Hormonas Tiroideas/uso terapéutico , Resultado del Tratamiento , Adulto JovenRESUMEN
Objective Hyponatremia is frequently observed in patients with decompensated liver cirrhosis and it is also related to a poor prognosis. The vasopressin V2-receptor antagonist tolvaptan is used to treat cirrhotic patients with ascites and increases the serum sodium (Na) level. In this study, we investigated (i) whether or not correction of the Na level improves the prognosis of cirrhotic patients with ascites and (ii) predictors of normalization of the serum Na level after tolvaptan therapy. Methods This was a single-center retrospective study. A total of 95 Japanese cirrhotic patients (60 men, median age 63 years) were enrolled and received tolvaptan orally after hospitalization for ascites treatment. The serum Na level was monitored during the period of tolvaptan treatment. The laboratory data and survival rates of patients who achieved serum Na levels of <135 and ≥135 mEq/L after 1 week were compared. Results Patients showed serum Na levels of 136 (121-145) mEq/L, and 42.1% had a serum Na level of <135 mEq/L. Among patients with an initial serum Na level <135 mEq/L, 60.0% achieved a normal level after 1 week, and the survival rate was significantly higher in patients with a normalized serum Na level (p<0.01). The pretreatment brain natriuretic peptide (BNP) level was predictive of achieving a serum Na level of ≥135 mEq/L (odds ratio: 0.87, 95% confidence interval: 0.316-0.987, p<0.05). Conclusion Normalization of the Na level after one week was associated with a favorable outcome of tolvaptan therapy, and Na correction improved the prognosis.
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Antagonistas de los Receptores de Hormonas Antidiuréticas/uso terapéutico , Ascitis/complicaciones , Benzazepinas/uso terapéutico , Hiponatremia/complicaciones , Hiponatremia/tratamiento farmacológico , Cirrosis Hepática/complicaciones , Anciano , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Sodio/sangre , Tolvaptán , Resultado del TratamientoRESUMEN
A 26-year-old woman, who had had Turner syndrome from age 10 years old, had diarrhea, fever, joint pain, and erythema in the lower left leg. She was given a diagnosis of Crohn's disease, erythema nodosum, and Hashimoto disease. Systemic steroid therapy was very effective for both intestinal and skin lesions. It has been reported that half of inflammatory bowel disease patients with Turner syndrome have 46XiX (q) type chromosome abnormality, and this case also has this type of abnormality.
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Enfermedad de Crohn/etiología , Eritema Nudoso/etiología , Enfermedad de Hashimoto/etiología , Síndrome de Turner/complicaciones , Adulto , Antiinflamatorios/administración & dosificación , Enfermedad de Crohn/tratamiento farmacológico , Eritema Nudoso/tratamiento farmacológico , Femenino , Humanos , Prednisolona/administración & dosificación , Síndrome de Turner/genéticaRESUMEN
A 56-year-old man was diagnosed with aplastic anemia and paroxysmal nocturnal hemoglobinuria at 43 years of age and treatment with cyclosporin A was started. Liver cirrhosis, ascites, and thrombus in the hepatic veins were found at 56 years of age and Budd-Chiari syndrome (BCS) was diagnosed according to angiography findings. He was treated with diuretics and paracentesis was performed several times, but with limited efficacy. A Denver® peritoneovenous shunt (PVS) was inserted into the right jugular vein; his ascites and renal function improved immediately and his general condition has remained good for 12 months since starting the above treatment regimen. A PVS is a treatment option for ascites due to BCS.
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Anemia Aplásica/complicaciones , Ascitis/cirugía , Síndrome de Budd-Chiari/cirugía , Hemoglobinuria Paroxística/cirugía , Trombosis de la Vena/cirugía , Ascitis/complicaciones , Síndrome de Budd-Chiari/complicaciones , Hemoglobinuria Paroxística/complicaciones , Humanos , Cirrosis Hepática/complicaciones , Masculino , Persona de Mediana Edad , Derivación Peritoneovenosa , Resultado del Tratamiento , Trombosis de la Vena/complicacionesRESUMEN
Re-infection by the hepatitis C virus (HCV) occurs rapidly after liver transplantation (LT), and spontaneous clearance of HCV is rare under immunosuppressive conditions. Here, we report on two patients who underwent LT to treat liver cirrhosis and hepatocellular carcinoma. The immunosuppressants prescribed were short-term corticosteroids, tacrolimus, and mycophenolate mofetil. A 50-year-old woman underwent LT, with her brother as the donor. She acquired HCV of serological type 1 after LT; the HCV RNA level was 6.0 logIU/mL. Corticosteroids were discontinued within 24 days, with a total dose of 669 mg (adjusted) prednisolone (PSL). The serum alanine aminotransferase (ALT) level increased to 700 U/L by day 55 post-LT. Surprisingly, HCV RNA was not detected on day 87. A 52-year-old man underwent LT, with his sister as the donor. He became rapidly re-infected with HCV of serological type 2; the HCV RNA level was 6.9 logIU/mL. Corticosteroids were given for 24 days, with a total dose of 827 mg (adjusted) PSL. The serum ALT level increased continuously and his HCV cleared 115 days after LT. Both donor and recipient had the major IL28B genotype. HCV was eliminated spontaneously, even under immunosuppressive conditions, after PSL discontinuation without interferon treatment. Minimal use of immunosuppressants and the presence of hepatitis may have contributed to HCV clearance. However, it is important to evaluate additional relevant cases.
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Hepacivirus , Hepatitis C/virología , Huésped Inmunocomprometido , Trasplante de Hígado , Remisión Espontánea , Corticoesteroides/administración & dosificación , Carcinoma Hepatocelular/cirugía , Femenino , Humanos , Inmunosupresores/administración & dosificación , Cirrosis Hepática/cirugía , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Rapid seroconversion from hepatitis B surface antigen (HBsAg) to anti-HBs antibody is seen in most patients with fulminant hepatitis B. It is unclear whether viral mutation or host immune background is responsible for such enhanced host reaction to hepatitis B virus (HBV). To investigate interaction between virus mutation and host immune background, we established a mouse model of hepatitis B using liposome-mediated gene transfer. METHODS: A mixture of liposomes and full-length viral DNA derived from hepatitis B patients was injected into three strains of purebred mice intrahepatically. After injection, HBsAg and antibody in liver and serum were serially measured. RESULTS: Three days after transfection, viral transcript and antigen were detected in the liver and serum. Ten days after transfection with wild-type DNA, hepatitis B surface antibody was detectable in two of the three strains. Mice that did not produce antibody after transfection with wild-type DNA produced a high amount of serum antibody against surface antigen when transfected with fulminant hepatitis-associated DNA. CONCLUSIONS: The present results are consistent with previous clinical observations of rapid HBsAg seroconversion in patients with fulminant hepatitis B. Further studies are needed to determine which mutations are responsible for differences in immunogenicity between HBV strains.
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Encefalopatía Hepática/inmunología , Anticuerpos contra la Hepatitis B/inmunología , Antígenos de Superficie de la Hepatitis B/inmunología , Virus de la Hepatitis B/genética , Hepatitis B/inmunología , Hepatitis B/patología , Mutación , ARN Viral/análisis , Animales , Formación de Anticuerpos , Secuencia de Bases , Modelos Animales de Enfermedad , Femenino , Encefalopatía Hepática/fisiopatología , Anticuerpos contra la Hepatitis B/análisis , Antígenos de Superficie de la Hepatitis B/análisis , Virus de la Hepatitis B/inmunología , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos BALB C , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Fulminant non-A, non-B, non-C hepatitis has a high mortality rate, making the identification of its causative agent imperative. Cytomegalovirus, Epstein-Barr virus, human herpesvirus-6, and herpes simplex virus are all members of the herpesviridae family that are associated with fatal hepatic failure. We investigated the involvement of herpesviridae and hepatitis virus in the pathogenesis of fulminant hepatitis. METHODS: The study participants consisted of 11 patients with fulminant hepatitis and 11 with acute hepatitis negative for known hepatitis viral markers and any other liver diseases. Viral DNA was extracted from liver tissues and amplified. In situ hybridization was then performed for 1 patient to detect viral DNA and RNA, and viral protein was localized by monoclonal antibodies. RESULTS: Human herpesvirus-6 was detected in liver tissues from seven patients, (five children and two adults) with fulminant hepatitis and two patients with acute hepatitis. Two patients with fulminant hepatitis also had cytomegalovirus in the liver. Although Epstein-Barr virus and herpes simplex virus were detected in the patients with fulminant hepatitis, they were not specific to these patients. In situ hybridization in one of the patients localized DNA and RNA of human herpesvirus-6 in hepatocyte nuclei, and an envelope antigen of this virus was detected in hepatocyte cytoplasm. CONCLUSIONS: Human herpesvirus-6 was frequently detected in Japanese pediatric patients with fulminant non-A, non-B, non-C hepatitis. Although the significance of human herpesvirus-6 in liver pathogenesis remains unclear, this virus may replicate in hepatocytes in some patients with acute onset hepatitis.
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Fallo Hepático/virología , Hígado/virología , Adulto , Niño , ADN Viral/análisis , Femenino , Virus de Hepatitis/aislamiento & purificación , Herpesviridae/aislamiento & purificación , Herpesvirus Humano 6/aislamiento & purificación , Humanos , Inmunohistoquímica , Hibridación in Situ , Lactante , Japón/epidemiología , Masculino , Persona de Mediana Edad , Reacción en Cadena de la PolimerasaRESUMEN
BACKGROUND: To analyze the mechanisms of mutant escape, we established a murine model of hepatitis B virus (HBV) infection and studied the interaction of the envelope protein of the virion with various kinds of anti-hepatitis B antibody. METHODS: Mutation from glycine to arginine at aa145 was introduced into replication-competent DNA of HBV. The resulting mutant HBV DNA was transfected into cultured hepatoma cells and livers of mice using liposome-mediated gene transfer. Then, interactions between the antigenic envelope protein (in culture or in circulation) and anti-hepatitis B antibody were examined. RESULTS: Mutant envelope protein escaped human hepatitis B immunoglobulin, rabbit polyclonal anti-hepatitis B surface antigen (HBsAg) antibody, and monoclonal anti-a antibody in vitro and in vivo. There was a difference in the degree of inhibition between hepatitis B immunoglobulin and the other two antibody types in vitro. Transfection with an HBV construct containing a mutation in the a-loop resulted in levels of HBsAg in circulation and seroconversion to anti-HBs antibody that were similar to those produced by a wild-type construct. CONCLUSIONS: The degree of escape by the mutant envelope protein differed according to antibody type. Of the three types of antibody used in this study, HBV immunoglobulin was least affected by mutation in the a-loop. There appears to be no correlation between antigenicity and immunogenicity of the escape mutant, and the a-loop mutant may cause hepatitis with the usual serum viral markers.
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Antígenos de Superficie de la Hepatitis B/genética , Virus de la Hepatitis B/genética , Animales , Western Blotting , Antígenos de Superficie de la Hepatitis B/inmunología , Virus de la Hepatitis B/inmunología , Inmunoglobulinas/inmunología , Hígado/citología , Ratones , Modelos Animales , Datos de Secuencia Molecular , Mutación , TransfecciónRESUMEN
Several studies have reported the presence of hepatitis B virus (HBV) DNA in peripheral blood mononuclear cells (PBMCs). However, the mode of existence, infectivity and replication competence of HBV DNA in PBMCs remain unclear. To clarify these questions, we assayed for covalently closed circular DNA (cccDNA) and integrated HBV DNA in PBMCs from ten patients who had recovered from acute self-limited hepatitis B (AHB) and 14 chronic hepatitis B (CHB) patients. HBV DNA was detected in all six CHB patients who were positive for hepatitis B e antigen (eAg), and cccDNA was detected in five. HBV DNA was detected in seven of the eight CHB patients who were negative for eAg, and cccDNA was detected in three. HBV DNA and cccDNA was also detected in five and two of the ten AHB patients, respectively. Integrated HBV was not detected in PBMCs of any patients. HBV DNA presence and replication competence in PBMCs are associated with eAg-positive phenotype. Sequence analysis revealed that the source of HBV DNA differed between PBMCs and serum. Even in patients who have recovered from AHB, replicable HBV may persist in PBMCs.
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Clinical manifestations and viral sequences of core promoter and precore/core region were compared among various genotypes of hepatitis B virus (HBV) in 25 patients with acute hepatitis. The genotype in patients with acute hepatitis was distributed differently from that among chronic hepatitis patients in Japan, which are predominantly genotypes B and C. Of 25 patients with acute hepatitis, 14 had genotype A, five genotype B and six genotype C. Serum total bilirubin levels were significantly higher in patients with genotype A than in those with genotype C. Prothrombin time was shorter in patients with genotype B than those with genotype A or C. Total bilirubin was lower in patients with short duration of acute hepatitis. The serum ALT value remained above 1000 IU/l for over 10 days in 79% of patients with genotype A. This prolonged duration of hepatitis in patients with genotype A may contribute to hyperbilirubinemia. Sequence analysis revealed no difference in the number of mutations in precore/core regions among the three genotypes. Although the double mutation, A-T and G-A at 1762 and 1764, respectively, was found in two patients each with genotype A and C, these mutations were not related to the hepatitis B e antibody (HbeAg)/hepatitis B e antibody (HbeAb) phenotype. Two of seven patients with thymidine at 1858 also had a G to A mutation at 1896. Thus, the difference in the genotype little influenced the HBeAg/HBeAb phenotype in acute hepatitis patients. Understanding the viral genotypes in acute HBV infection may be valuable in predicting the clinical course of acute hepatitis B (AHB).
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We describe lamivudine therapy for acute hepatitis B (AHB) with prolonged high alanine aminotransferase (ALT) and HBV DNA. Three male patients (27-31 years old) had prolonged high ALT, bilirubinemia, and prolonged prothrombin time for over 10 days. Lamivudine was administered at a dose of 150 mg per day because of the threat of acute liver failure. All three patients tolerated the drug well. Serum HBV DNA levels quickly became undetectable, and both the ALT level and liver function tests normalized within 1 month in all three patients. HBeAg and HBsAg disappeared during the clinical course of AHB, and HBsAb was not detected in two of the three patients during the 1-year follow-up. Direct sequence analysis revealed no significant substitution of amino acids in the precore and core regions, including the HLA class II epitope. Lamivudine might prevent the progression of severe AHB to fulminant liver failure, and it appears to modify the clinical course of the disease.
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AIM/BACKGROUND: There is an increasing evidence that certain hepatitis B virus (HBV) strains may contribute to the pathogenesis of fulminant hepatitis B (FHB). Recently, we reported that genotypes of HBV influence the clinical course of acute self-limited hepatitis B (AHB). In this study, we compared clinical features of FHB between different HBV genotypes and compared the prevalence of each genotype between FHB and AHB patients. METHODS: The subjects consisted of seven patients with FHB and 25 patients with AHB. The core promoter and precore region were directly sequenced following polymerase chain reaction, and genotype was determined by restriction fragment length polymorphism analysis of the S gene. RESULTS: Of the seven FHB patients, one had genotype A, one had genotype B, four had genotype C, and one had genotype D. Six of the seven FHB patients were infected by heterosexual contact; one FHB patient who was not infected by heterosexual contact had genotype C. All four FHB patients with genotype C had a short duration clinical course. In one patient with genotype A, the time from onset of hepatitis to hepatic coma was 30 days. These results are similar to those of the patients with AHB, in which clinical course was longer in patients with genotype A than in patients with genotype C. CONCLUSION: Viral genotype can be used to predict the clinical course of both FHB and AHB.
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A 50-year-old woman patient began receiving lamivudine because of acute exacerbation of chronic hepatitis B. She also suffered from adult-onset Still's disease and had received prednisolone for 5 years. Lamivudine was effective for treatment of the first flare. Fifteen months after lamivudine treatment was started, a breakthrough due to lamivudine-resistant strain M5521 occurred. Between 10 and 12 months after the breakthrough, flare with jaundice occurred 3 times. We decided interferon would not be suitable, because it could induce activation of Still's disease. Prolonged lamivudine therapy is only recommended in cases of hepatitis B in which there is no alternative treatment.