Successful liver transplantation in a patient with splanchnic vein thrombosis and pulmonary embolism due to polycythemia vera with Jak2v617f mutation and heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a rare complication of heparin treatment resulting in a severe acquired thrombophilic condition with an associated mortality of about 10 %. We report the first case of successful urgent liver transplantation (LT) in a patient with end-stage liver disease due to a Budd-Chiari syndrome, portal vein thrombosis and pulmonary embolism due to acquired thrombophilia associated to polycythemia vera carrying JAK2V617F gene mutation and HIT in the acute phase. Lepirudin was used to provide anticoagulation in the LT perioperative period that was performed without haemorrhagic and thrombotic complications despite the donor received heparin during liver explantation.

JAK2V617F mutation in patients with splanchnic vein thrombosis.

BACKGROUND: Splanchnic vein thrombosis can be the presenting manifestation of myeloproliferative neoplasms. However, the diagnosis of a myeloproliferative neoplasm in these patients is often problematic, and more objective criteria are needed. AIM: To determine the frequency of the mutation JAK2V617F in patients with splanchnic vein thromboses. METHODS: A consecutive series of 108 adult patients with portal vein thrombosis (n = 77) and Budd-Chiari syndrome (n = 31) referred for hemostasis evaluation was retrospectively studied, with a median follow-up of 51 months (1-104). RESULTS: One or more prothrombotic risk factors were present in 63% of the patients. Twenty-four (22%) out of the 108 patients presented the JAK2V617F, including 2 cirrhotic patients. Most had a low mutated allele burden (median 16.5%). JAK2V617F was present in all four patients with a previous diagnosis of a myeloproliferative neoplasm. In nine JAK2V617F-positive patients, the diagnosis of a myeloproliferative neoplasm was made at the thrombosis work-up, during follow-up or after JAK2V617F detection. Among the other 11 patients carrying the mutation, 2 patients have died, 4 had no evidence suggesting a myeloproliferative neoplasm, 1 had a normal bone marrow biopsy, and the other 4 could not be persuaded to undergo a biopsy. Among the patients without an overt myeloproliferative neoplasm, 15 out of 99 (15%) presented the JAK2V617F mutation. None of the JAK2V617F-negative patients have developed signs of a myeloproliferative neoplasm during follow-up. CONCLUSIONS: Our findings suggest that JAK2V617F occurs in a high proportion of patients with splanchnic vein thrombosis, and reinforces the diagnostic utility of JAK2V617F testing in this setting.

JAK2V617F and prothrombin G20210A gene mutations in a patient with Budd-Chiari syndrome and essential thrombocythemia.

Myeloproliferative disorders and the inherited thrombophilias have been described as the main causes underlying the Budd-Chiari syndrome. Moreover, the presence of the JAK2V617F was associated with a higher frequency of Budd-Chiari syndrome in patients who have overt or even latent myeloproliferative disorder. We herein describe a 28-year-old woman who was diagnosed with Budd-Chiari syndrome and later developed an overt myeloproliferative disorder. The patient was found to carry both the JAK2V617F and the prothrombin G20210A mutation in the heterozygous form. The significance of the chronology of diagnosis is highlighted.

Low burden of a JAK2-V617F mutated clone in monoclonal haematopoiesis in a Japanese woman with Budd-Chiari syndrome.

Approximately one-half of the cases of Budd-Chiari syndrome (BCS) are caused by bcr/abl negative chronic myeloproliferative disorders (CMPDs). Furthermore, a mutation in the Janus kinase protein (JAK2-V617F) is detected in half of the patients with BCS. However, whether the JAK2 mutation is the primary event leading to CMPDs and BCS is controversial. We present a report concerning a young woman who suffered from BCS prior to the onset of CMPDs. Analysis of X-chromosome inactivation patterns in this patient, using the human androgen receptor gene demonstrated monoclonal haematopoiesis in her granulocytes. In contrast, she had a low burden of a JAK2-V617F mutation positive clone among granulocyte populations. These results suggest that the JAK2-V617F mutation occurs after the onset of monoclonal haematopoiesis; thus the V617F mutation of JAK2 may not be the primary event in the induction of BCS.

Occurrence of the JAK2 V617F mutation in the Budd-Chiari syndrome.

Myeloproliferative diseases represent a major risk factor for Budd-Chiari syndrome. In 32 patients with Budd-Chiari syndrome, the JAK2 V617F mutation was detected, in heterozygous state, in 11 individuals (34.4%; 95% confidence interval: 18.6-53.2). Eight patients with (72.7%; 95% confidence interval: 39.0-94.0) and six without (28.6%; 95% confidence interval: 11.3-52.2) the JAK2 V617F mutation had a diagnosis of myeloproliferative diseases before or at the occurrence of the venous thrombotic event. In three patients carrying the JAK2 V617F mutation, a myeloproliferative disease was not detected. Determination of the JAK2 V617F mutation may be useful to recognize patients with Budd-Chiari syndrome with or at risk for the subsequent development of overt myeloproliferative diseases.

Transaminitis after pancreatic islet transplantation.

BACKGROUND: An asymptomatic, self-limited transaminitis uniformly follows pancreatic islet transplantation (PIT) performed through portal vein (PV) infusion. The underlying cause and significance of this transaminitis is unclear. STUDY DESIGN: Records of all patients with insulin-dependent diabetes mellitus who had undergone PIT at our institution were reviewed. All PITs were performed in conjunction with a remote pancreatic islet isolation center and done through percutaneous transhepatic PV infusion. Alanine aminotransferase (ALT) levels, serum glucose concentrations, insulin requirements, and color-flow Doppler ultrasonography examinations of the right upper quadrant were assessed before and after PIT. RESULTS: Eleven patients have undergone a total of 26 PITs. An elevated ALT level occurred in all 11 patients (100%) after the first PIT, with the median post-PIT peak ALT level reaching 187 IU/L. Transaminitis was less frequent and less marked after the second PIT. A negative correlation between viability of the pancreatic islets transplanted (r = -0.44, p = 0.03) and a positive correlation between the ratio of maximum to initial PV pressure (r = 0.41, p = 0.04) were seen with the subsequent ALT peak. Color-flow Doppler ultrasonography examinations showed no occurrences of PV thrombosis or intrahepatic hematoma. Finally, the degree of transaminitis did not correlate with post-PIT insulin requirements, indicating that post-PIT transaminitis cannot be used to measure allograft rejection or function. CONCLUSIONS: Transaminitis after PIT is common and self-limited. Post-PIT transaminitis does not signal acute rejection or serious procedure-related complications such as PV thrombosis or intrahepatic hematoma.

Hyperhomocysteinemia and the MTHFR C677T mutation in Budd-Chiari syndrome.

Hyperhomocysteinemia (HH) is a factor that predisposes individuals to thrombosis, and the C677T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) is known to give increased plasma homocysteine. However, little is known about their roles in Budd-Chiari syndrome (BCS). This study evaluated the roles of HH and the MTHFR C677T mutation in patients with BCS. We compared 41 BCS patients with 80 sex- and age-matched healthy controls. The mean plasma homocysteine level was significantly higher in patients with BCS (20.15 +/- 5.78 micromol/L) compared with normal controls (15.80 +/- 6.58 micromol/L), P < 0.01. HH (>19.5 micromol/L in men and >15.0 micromol/L in women) was detected in 15 (36.59%) patients and in 14 (17.5%) controls (odds ratio [OR], 2.72; 95% confidence internal [CI], 1.17-6.32). The prevalence of the mutated MTHFR 677TT genotype and the 677T allele in normal controls was 10.0% and 31.3%, respectively. The mutant 677T homozygotes and alleles were more frequent in patients with BCS than in controls (22.0% vs. 10.0%, 0.025 < P < 0.05; 45.1% vs. 31.3%, 0.025 < P < 0.05). The relative risk of BCS among the carriers of 677TT was significantly increased (OR, 3.3; 95% CI, 1.1-10.0). The mutant MTHFR heterozygous 677C/T carriers were not significantly increased in patients with BCS compared with controls (46.3% vs. < 2.5%, P > 0.05). The relative risk OR of BCS among carriers of 677C/T was 1.6 (95% CI, 0.7-3.6). This study suggests that both HH and the homozygous C677T mutation in the MTHFR gene are important risk factors of BCS.

'Tissue' transglutaminase release from apoptotic cells into extracellular matrix during human liver fibrogenesis.

Enhanced apoptosis characterizes several pathologies affecting human liver. This study sought to determine whether apoptosis is involved in the formation of fibrotic lesions occurring in hepatic disease. The expression of Bcl-2 was analysed, and of 'tissue' transglutaminase (tTG), a cross-linking enzyme which recent evidence suggests plays a role in the formation of fibrotic lesions in experimental settings. Regardless of the degree of liver injury, tTG abnormally accumulated in the liver cells adjacent to fibrotic tissue. Many cells showing DNA fragmentation and morphological features of apoptosis were also observed near fibrotic lesions. Bcl-2 was detected predominantly in infiltrating lymphocytes within the liver tissue. Marked staining for both tTG protein and chromatin was also observed in the acellular fibrotic tissue, which suggested an active release of intracellular macromolecules from the dying cells into the extracellular matrix. This study indicates that fibrogenesis in the liver is associated with the release of tTG from dying cells. By cross-linking extracellular matrix proteins, this enzyme might play a role in the formation of fibrotic lesions.

Overexpression of cytochrome P-450 isoforms involved in aflatoxin B1 bioactivation in human liver with cirrhosis and hepatitis.

Studies were carried out to test the hypothesis that inflammatory liver disease increases the expression of specific cytochrome P-450 isoenzymes involved in aflatoxin B1 (AFB) activation. The immunohistochemical expression and localization of various human cytochrome P-450 isoforms, including CYP2A6, CYP1A2, CYP3A4, and CYP2B1, were examined in normal human liver and liver with hepatitis and cirrhosis. The constitutive expression of CYP3A4 in normal liver showed a characteristic pattern of distribution in centrilobular hepatocytes, whereas CYP1A2, CYP2A6, and CYP2B1 were expressed uniformly throughout the liver acinus. In sections of liver infected with hepatitis B virus (HBV) or hepatitis C virus (HCV), the expression of CYP2A6 was markedly increased in hepatocytes immediately adjacent to areas of fibrosis and inflammation. CYP3A4 and CYP2B1 were induced to a lesser degree, and expression of CYP1A2 was unaffected. In HBV-infected liver, double immunostaining revealed that overexpression of CYP2A6 occurred in hepatocytes expressing the HBV core antigen. In HCV-infected liver, CYP2A6, CYP3A4, and CYP2B1 were overexpressed in hepatocytes with hemosiderin pigmentation. These results suggest that alterations in phenotypic expression of specific P-450 isoenzymes in hepatocytes associated with hepatic inflammation and cirrhosis might increase susceptibility to AFB genotoxicity.

A homogeneous assay system of aspartate aminotransferase iso-enzymes using proteases and application for clinical evaluation of myocardial infarction.

We designed a rapid, homogeneous assay for human aspartate aminotransferase (AST) isoenzymes, by a selective proteolysis of soluble AST (s-AST), using chymotrypsin and protease 401. The linearity of mitochondrial (m-AST) was elongated up to 4000 U/l. m-AST values from the human liver, and determined by a homogeneous assay using protease 401 or chymotrypsin, were relative to those obtained using an immunoprecipitation method. In perioperative patients or those with an acute myocardial infarction, the peaks of s-AST and m-AST values were noted 13 h and at 57 h after ictus, respectively, whereas the peak of ratio between was seen 6 h after ictus. In the case of Budd-Chiari syndrome, the maximum levels of the two AST activities were evident 14 days after hospitalization and the peak of ratio between them was seen after 7 days. We propose that this homogeneous assay can serve as a diagnostic tool for early phase detection of myocardial infarction and of Budd-Chiari syndrome.