The HBx protein from hepatitis B virus coordinates a redox-active Fe-S cluster.

The viral protein HBx is the key regulatory factor of the hepatitis B virus (HBV) and the main etiology for HBV-associated liver diseases, such as cirrhosis and hepatocellular carcinoma. Historically, HBx has defied biochemical and structural characterization, deterring efforts to understand its molecular mechanisms. Here we show that soluble HBx fused to solubility tags copurifies with either a [2Fe-2S] or a [4Fe-4S] cluster, a feature that is shared among five HBV genotypes. We show that the O2-stable [2Fe-2S] cluster form converts to an O2-sensitive [4Fe-4S] state when reacted with chemical reductants, a transformation that is best described by a reductive coupling mechanism reminiscent of Fe-S cluster scaffold proteins. In addition, the Fe-S cluster conversions are partially reversible in successive reduction-oxidation cycles, with cluster loss mainly occurring during (re)oxidation. The considerably negative reduction potential of the [4Fe-4S]2+/1+ couple (-520 mV) suggests that electron transfer may not be likely in the cell. Collectively, our findings identify HBx as an Fe-S protein with striking similarities to Fe-S scaffold proteins both in cluster type and reductive transformation. An Fe-S cluster in HBx offers new insights into its previously unknown molecular properties and sets the stage for deciphering the roles of HBx-associated iron (mis)regulation and reactive oxygen species in the context of liver tumorigenesis.

Liver haematoma as a presentation of peliosis hepatis.

Peliosis hepatis (PH) is an uncommon, benign hepatic vascular condition involving liver lesions consisting of dilated sinusoidal spaces that ultimately lead to numerous blood-filled cavities within the liver parenchyma. We detail the case of a 62-year-old woman who presented with a large hepatic haematoma resulting from intracystic haemorrhage. She was subsequently diagnosed with PH via arteriogram. Her symptoms were successfully treated surgically with open fenestration. Patient's postoperative course was unremarkable, with no recurrence of symptoms to date.

Peliosis hepatis in a kidney transplant recipient with manifestation as massive ascites and liver dysfunction: case report.

We report a case of 59-year-old woman who received a kidney transplant 7 years earlier without evidence of viral hepatitis history. She was asymptomatic initially and a newly developed nodule, ∼2.3 cm in size, was discovered in the right liver during routine sonographic examination. Computerized tomography-guided biopsy was inconclusive at that time. However, the lesion grew to 6.8 cm and bilobular multiple nodules developed with concomitant massive ascites and hyperbilirubinemia months later. Laparoscopy showed typical bluish-reddish-blackish nodules. Needle-biopsy histology showed severe sinusoid dilation and dropout of centrilobular hepatocytes consistent with peliosis hepatis. Reticulin staining also demonstrated disruption of sinusoidal reticulin fibers. We tried to withdraw possible offending drugs to anticipate regression of peliosis, but it failed and liver dysfunction progressed, leaving liver transplant as the last resort in such rare circumstances.

Peliosis hepatis: microscopic and macroscopic type, time pattern, and correlation with liver cell apoptosis in a model of toxic liver injury.

Macroscopic and microscopic types of peliosis hepatis, time pattern, and correlation with hepatocyte and sinusoidal cell apoptosis were investigated. Male Wistar rats were injected with a dose of cadmium (6.5 mg CdCl(2)/kg body weight, intraperitoneally; group I). Putrescine (300 micromol/kg body weight, intraperitoneally; group II) was injected at 2, 5, and 8 hours and vascular endothelial growth factor (VEGF; 400 ng/animal, intravenously; group III) at 2 hours. Animals from each group were humanely killed 0, 6, 12, 24, 48, or 60 hours after cadmium intoxication. Liver tissue was histologically assessed for necrosis, apoptosis, and peliosis. Apoptosis was also quantified by the TUNEL assay for hepatocytes and nonparenchymal liver cells. The discrimination between hepatic cell subpopulations was done histochemically. Sinusoidal cell apoptosis and macroscopic peliosis hepatis evolved in a monophasic pattern and correlated closely. Putrescine or VEGF administration totally reversed macroscopic peliosis. Putrescine exerted a major protective effect on hepatocytes, whereas the protective effect of VEGF was more pronounced for nonparenchymal liver cells. Microscopic peliosis also evolved in a monophasic pattern preceding macroscopic type. The extent of the lesion was reduced by putrescine and almost totally reversed by VEGF. Macroscopic peliosis progresses as a compound lesion closely correlating with nonparenchymal cell apoptosis. Both hepatocyte and nonparenchymal cell injury are prerequisites for the genesis of the lesion. Microscopic peliosis precedes macroscopic peliosis and up to a degree seems to be independent of initial hepatocyte injury, but it seems to depend on nonparenchymal cell injury.

Excessive tumor-elaborated VEGF and its neutralization define a lethal paraneoplastic syndrome.

Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen and key regulator of both physiologic and pathologic (e.g., tumor) angiogenesis. In the course of studies designed to assess the ability of constitutive VEGF to block tumor regression in an inducible RAS melanoma model, mice implanted with VEGF-expressing tumors sustained high morbidity and mortality that were out of proportion to the tumor burden. Documented elevated serum levels of VEGF were associated with a lethal hepatic syndrome characterized by massive sinusoidal dilation and endothelial cell proliferation and apoptosis. Systemic levels of VEGF correlated with the severity of liver pathology and overall clinical compromise. A striking reversal of VEGF-induced liver pathology and prolonged survival were achieved by surgical excision of VEGF-secreting tumor or by systemic administration of a potent VEGF antagonist (VEGF-TRAP(R1R2)), thus defining a paraneoplastic syndrome caused by excessive VEGF activity. Moreover, this VEGF-induced syndrome resembles peliosis hepatis, a rare human condition that is encountered in the setting of advanced malignancies, high-dose androgen therapy, and Bartonella henselae infection. Thus, our findings in the mouse have suggested an etiologic role for VEGF in this disease and may lead to diagnostic and therapeutic options for this debilitating condition in humans.

Peliosis hepatis. Hallazgos por resonancia magnética: informe de un enfermo / Peliosis hepatis. Resonance magnetic imaging fidings in a case

La presencia de hepatomegalia por lesiones ocupativas de espacio, de diferente tamaño e intesidad en T1 e hiperintensas en T2 por resonancia magnética debe incluír en las posibilidades diagnosticas a la peliosis hepatis especialcente cuando coexistan antecedentes de ingestión crónica de esteroides, anticonceptivos, neoplasias o SIDA. Se describen los hallazgos clínicos y por diferentes métodos de imagen de un enfermo con esta patología

Ultrastructural lesions of the liver in human peliosis. A report of 12 cases.

Ultrastructural lesions of the liver were studied in 12 patients with peliosis hepatis. This vascular lesion consisted of cavities filled with red blood cells and sometimes lined with an endothelial barrier; the cavities were due to cystic dilatation of the space of Disse and/or sinusoidal lumen. The passage of red blood cells through the endothelial barrier was occasionally demonstrated. Other striking alterations included the presence of numerous blebs on the sinusoidal membrane of the hepatocytes and the existence of multiple cellular layers lining the sinusoids. Perisinusoidal fibrosis appeared on follow-up biopsies in 3 patients. There was no major abnormality of the hepatocytes or of the hepatic venules. These findings suggest that alterations of the sinusoidal barrier might constitute the primary event in peliosis, although secondary changes to increased pressure and hypoxia within the lobules cannot be excluded.

Peliosis hepatis as a late and fatal complication of thorotrast liver disease. Report of five cases.

Five autopsy cases of peliosis hepatis occurring as a late complication of thorotrast (ThO2) liver disease are described. The liver contained many blood-filled cystic spaces of various sizes. Marked sinusoidal dilatation, disruption of cell cords and reticulin fiber framework, and cystic dilatation of sinusoids seem to represent the developmental stages of peliosis hepatis in sequence. Of the five cases, two had no other liver disease except for hepatic fibrosis, and the other three had associated neoplasms, such as angiosarcoma, hepatocellular carcinoma, cholangiocarcinoma, benign hemangioma, and their combinations. Peliosis hepatis seemed to have directly contributed to the patient's death in four cases. The most characteristic clinical feature was the fulminant terminal course with massive ascites, deep jaundice, and hepatic failure, often accompanied by hepatorenal syndrome and tendency to hemorrhage. Liver function study suggested progressive hepatic insufficiency with reduction in serum albumin, prothrombin and the clearance rate for test dyes, and increase in bilirubin. Clinical diagnosis was almost impossible without biopsy.