Diffuse glutamine synthetase overexpression restricted to areas of peliosis in a ß-catenin-activated hepatocellular adenoma: a potential pitfall in glutamine synthetase interpretation.

Hepatocellular adenomas have recently been classified into four subtypes based on molecular findings: hepatocyte nuclear factor 1α (HNF1α) inactivated, inflammatory/telangiectatic, ß-catenin activated, and unclassifiable. ß-catenin-activated adenomas have the potential for malignant transformation and are thus important to recognize. Diffuse glutamine synthetase immunohistochemical positivity has been shown to be a reliable surrogate marker for ß-catenin activation, though variations in staining patterns may be difficult to interpret. We report a case of a peliotic adenoma that was morphologically consistent with a ß-catenin wild-type hepatocellular adenoma but harbored a ß-catenin mutation by molecular analysis. The tumor lacked nuclear ß-catenin positivity and demonstrated a hitherto undescribed pattern of glutamine synthetase overexpression restricted to areas of peliosis with mostly negative staining in non-peliotic areas. This pattern was initially interpreted as physiologic and may represent a potential pitfall in glutamine synthetase interpretation.

Alcohol binging causes peliosis hepatis during azathioprine therapy in Crohn's disease.

Patients with inflammatory bowel disease have normal life expectancy and, due to modern immunosuppressive therapies, also a normal quality of life. Since mostly young people are affected, their social behaviour suits this environment. Alcohol binging is an increasingly disturbing factor among young people. We describe a patient with Crohn's disease, treated with azathioprine, who developed peliosis hepatis after three epsiodes of alcohol binging. Liver toxicity was not observed previously during the course of the treatment. Azathioprine-induced peliosis hepatis is thought to be idiosyncratic in humans. From animal studies, however, it is clear that hepatic depletion of glutathione leads to azathioprine toxicity to the sinusoidal endothelial cells. Damage of these cells causes peliosis hepatis. Since alcohol binging leads to hepatic glutathione depletion, we conclude that in our patient the episodes of binging have reduced liver gluathione content and therefore this has increased azathioprine toxicity causing peliosis hepatis. The problem of alcohol binging has not yet been addressed in IBD patients undertaking immunosuppressive therapy. This should be reviewed in future considerations regarding patients advice.

Expression of cell adhesion molecules and their beta1 and beta2 integrin ligands in human liver peliosis.

The expression of the following cell adhesion molecules and their beta1 and beta2 integrin ligands was investigated in the liver tissue from 3 patients with non-bacillar peliosis using light and electron microscope immunohistochemistry: intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, platelet endothelial cell adhesion molecule-1 (PECAM-1), leukocyte function-associated antigen-1 (LFA-1), macrophage antigen-1 (Mac-1), and very late antigen-4 (VLA-4). We found a parallel enhancement of the adhesion molecules expression in the dilated sinusoids and cavities in all 3 cases with peliosis. Mononuclear blood cells were detected in the sinusoids and sometimes perisinusoidally. These cells were mainly ICAM-1-, LFA-1-, and VLA-4-positive. At the ultrastructural level, ICAM-1-positive immune deposits were observed on the membrane of sinusoidal endothelial cells, Kupffer cells, and hepatocytes. The expression of cell adhesion molecules on liver sinusoids in peliosis is probably triggered by factors released from damaged endothelial cells and hepatocytes. The prevalence of the ICAM-1/LFA-1 and VCAM-1/VLA-4 patterns of mononuclear blood cell/sinusoidal cell interactions could support the macrophage-induced or lymphocyte-induced type of liver injury. PECAM-1 was also included in the non-specific immune response in peliosis. The presence of erythrostasis or thrombosis in liver sinusoids could participate in the induction of adhesion molecule expression in peliosis.

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced accumulation of biliverdin and hepatic peliosis in rats.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a widespread, persistent, and highly toxic environmental pollutant. The most TCDD-sensitive and the most TCDD-resistant rat strains (Long-Evans [Turku/AB] and Han/Wistar [Kuopio], respectively) were crossbred to separate the alleles of two genes (Ahrand an unidentified gene "B") mediating resistance against TCDD toxicity. During crossbreeding, a new type of toxicity in livers of both sexes was detected, characterized macroscopically by intense dark green to black color and swelling that appeared most frequently after a large dose (300 micro g/kg or more as a single intragastric dose) and a follow-up period of more than three weeks. Therefore, studies were undertaken to identify the causative pigment chemically and to examine the hepatotoxicity histologically. The pigment fractions were separated by thin layer chromatography and then analyzed by HPLC and electrospray mass spectrometry. The pigment was found to consist of biliverdin and several biliverdin-related compounds. In liver histopathology carried out on male rats, progressive sinusoidal distension and hepatic peliosis with membrane-bound cysts were seen. The clinical manifestations of pigment accumulation were recorded most often in intermediately resistant rat lines such as line B (homozygous for the gene B), but never occurred in rats expressing only the Han/Wistar (Kuopio)-type Ah receptor with an altered transactivation domain structure.

Immunohistochemical localization of collagen type III and type IV, laminin, tenascin and alpha-smooth muscle actin (alphaSMA) in the human liver in peliosis.

The expression of collagen types III and IV, laminin, tenascin, and hepatic stellate cells (HSCs) activation marker alphaSMA was evaluated immunohistochemically in the liver of three patients with non-bacilar peliosis. Peliosis was attributed to tuberculosis, endometriosis treated with anabolic androgenic steroids, and to pheochromocytoma. Ultrastructural examination of the lesions of the liver revealed cavities that were sometimes lined with sinusoidal endothelial cells or hepatocytic microvilli. In liver sinusoids around cavities, cystic dilatation of the space of Disse and an abundance of amorphous matrix were observed. At this location, HSCs were transformed into transitional cells or myofibroblasts. Extracellular matrix proteins (ECM) were increased in the dilated sinusoids around cavities perisinusoidally and in the wall of cavities themselves. AlphaSMA was also increased. Ultrastructural immunohistochemistry revealed strong intracellular deposits of collagen type IV, laminin, and alphaSMA in HSCs. Laminin immunoreactivity was also noted in the endocytic vesicles in the cytoplasm of a monocyte. These findings suggest that enhanced ECM accumulation and the transformation of HSCs into myofibroblasts constitute a secondary event in peliosis and an attempt of the liver to restrict and remove sinusoidal dilatation.

Evidence of a leading role for VEGF in Bartonella henselae-induced endothelial cell proliferations.

Bartonella henselae causes the vasculoproliferative disorders bacillary angiomatosis (BA) and bacillary peliosis (BP). The pathomechanisms of these tumorous proliferations are unknown. Our results suggest a novel bacterial two-step pathogenicity strategy, in which the pathogen triggers growth factor production for subsequent proliferation of its own host cells. In fact, B. henselae induces host cell production of the angiogenic factor vascular endothelial growth factor (VEGF), leading to proliferation of endothelial cells. The presence of B. henselae pili was associated with host cell VEGF production, as a Pil- mutant of B. henselae was unable to induce VEGF production. In turn, VEGF-stimulated endothelial cells promoted the growth of B. henselae. Immunohistochemistry for VEGF in specimens from patients with BA or BP revealed increased VEGF expression in vivo. These findings suggest a novel bacteria-dependent mechanism of tumour growth.

Peliosis-like ultrastructural changes of the hepatic sinusoids in human chronic hypervitaminosis A: report of three cases.

In addition to hypertrophy of Ito cells and perisinusoidal fibrosis, previously unrecognized ultrastructural abnormalities of the hepatic sinusoids were observed in three patients with chronic hypervitaminosis A: 1) large areas of communication between the sinusoidal lumina and the perisinusoidal spaces, allowing extravasation of blood cells; 2) marked dilation of the perisinusoidal spaces; and 3) swelling and clarification of endothelial cells. Most of these changes, along with some other sinusoidal barrier alterations previously reported in chronic hypervitaminosis A (i.e., bleb formation on the sinusoidal membrane of the hepatocytes and the presence of multiple cellular layers lining the sinusoids), are strikingly similar to those observed in peliosis hepatis. The present findings suggest that sinusoidal barrier abnormalities might constitute a major event in the pathophysiology of vitamin A-induced liver injury as well as of peliosis hepatis.