Multiple myeloma-associated amyloidosis manifesting as fulminant hepatic failure.

We report a case of amyloidosis associated with K light chain multiple myeloma in a 42-year-old African American man. The patient initially had mild dyspepsia, which rapidly progressed to include anorexia, fulminant hepatic failure, and death within 9 weeks. This is only the fourth reported case of hepatic failure from myeloma-associated amyloidosis and the second reported case of light chain myeloma with amyloidosis resulting in a progressive clinical course of hepatic failure. Our patient was unique in that, despite severe disease, he had mild symptoms without laboratory abnormalities until 2 weeks prior to death.

Rapamycin inhibits hepatic stellate cell proliferation in vitro and limits fibrogenesis in an in vivo model of liver fibrosis.

BACKGROUND & AIMS: The accelerated course of hepatic fibrosis that occurs in some patients after liver transplantation is a major clinical problem. This response may be caused by the antirejection therapeutics, and in an earlier report we showed that FK-506 enhanced the fibrogenic process in in vivo and in vitro models of liver fibrosis. In the present study, the aim was to determine whether a new immunosuppressive agent, rapamycin, enhances or inhibits liver fibrosis. METHODS: Effects of rapamycin were investigated in a carbon tetrachloride model of hepatic fibrosis in rats and on hepatic stellate proliferation in vitro. RESULTS: Rapamycin inhibited extracellular matrix deposition in the rat model of fibrogenesis as determined by histological analysis, collagen content, messenger RNA levels of procollagen and transforming growth factor beta1, and tissue transglutaminase activity. Moreover, rapamycin decreased platelet growth factor-induced proliferation of hepatic stellate cells. CONCLUSIONS: These findings indicate that the new antirejection agent rapamycin inhibits hepatic fibrosis and thus may become a valuable addition to the immunosuppression armamentarium.

t(1;18)(q32.1;q22.1) associated with genitourinary malformations.

We report a male infant who has impaired penile development, hypospadias, and mild developmental delay with a 46,XY,t(1;18)(q32.1;q22.1) karyotype. Fluorescent in situ hybridization (FISH) was performed to more precisely map the translocation breakpoint. The translocation breakpoint maps to a region that has been implicated in genitourinary malformations in the 18q- syndrome. This case report suggests that a gene involved in genitourinary development maps at or near the chromosome 18 translocation breakpoint.

A role for tissue transglutaminase in hepatic injury and fibrogenesis, and its regulation by NF-kappaB.

This study was undertaken to delineate a possible role for tissue transglutaminase (tTG), an enzyme that catalyzes protein cross-linking, in hepatic fibrogenesis. Rats were treated with CCl4 solution and then killed at different stages of liver injury and fibrogenesis. Liver tTG mRNA levels were markedly increased as early as 6 h after the first injection, peaked at 4 days and 1 wk, and remained increased for 8 wk. The enzymatic activity of tTG was increased in livers of rats treated with CCl4, in a fashion that paralleled the Northern blot results. Cell isolation experiments indicated that all hepatic cell types synthesize tTG mRNA. Increased binding to the nuclear factor-kappaB (NF-kappaB) motif of the tTG promoter was found in the nuclear extracts prepared from CCl4-treated samples. These data demonstrate an increase in tTG gene expression during hepatic injury and fibrosis, suggesting a possible role for this enzyme in stabilizing the fibrotic bands during hepatic fibrogenesis. Moreover, increased NF-kappaB binding to the tTG promoter may represent one of the mechanisms by which cell injury induces tTG transcription and thus potentiates the process of fibrogenesis.

Expression of SPARC in normal and fibrotic livers.

SPARC (secreted protein, acidic and rich in cysteine)--also known as osteonectin, BM-40, and 43K glycoprotein--is secreted by endothelial cells and fibroblasts in response to culture shock. SPARC has been found in association with tissues undergoing cell proliferation, migration, and extracellular matrix remodeling. We demonstrate that normal livers from humans, rats, and mice express substantial levels of SPARC messenger RNA (mRNA). Moreover, when compared with control specimens, significantly increased levels of SPARC mRNA were found in fibrotic livers from two animal models of liver disease: murine schistosomiasis and carbon tetrachloride-induced fibrosis in rats. Fibrotic human livers also had markedly increased levels of SPARC mRNA in comparison with normal livers. We also detected an increased production of SPARC protein in the liver of animals treated with carbon tetrachloride. By immunocytochemical analysis, SPARC protein was apparent in freshly isolated Ito cells. Hybridization studies showed Ito cells to be the main source of SPARC mRNA. Extracts from a Kupffer-endothelial cell fraction exhibited traces of SPARC transcript, but expression of SPARC mRNA was absent in extracts from freshly isolated hepatocytes. These studies demonstrate the increased expression of SPARC--a protein that modulates cell shape and disrupts cell-matrix interactions--during the initial stages of hepatic fibrosis.

FK506 enhances fibrogenesis in in vitro and in vivo models of liver fibrosis in rats.

BACKGROUND/AIMS: The immunosuppressant FK506 is undergoing clinical trials in transplantation and autoimmune diseases. FK506 modulates several cytokines and exerts hepatoprotection in acute models. This study was initiated to determine whether FK506 would be beneficial as an antifibrogenic agent. METHODS: Fibrosis was induced by carbon tetrachloride administration to rats. Half of those animals were treated with FK506. The rats were killed after 8 weeks of carbon tetrachloride treatment. The livers were evaluated by histology, Northern hybridizations, and collagen quantitation. Additionally, rat fibroblasts were incubated with and without FK506 and used for Northern hybridization analysis. RESULTS: Surprisingly, FK506 exacerbated hepatic inflammation and fibrosis. Increased hepatic collagen and higher messenger RNA levels of transforming growth factor beta 1 and collagens I, III, and IV were found in the FK506-treated group. Rat fibroblasts treated with FK506 expressed higher levels of collagens I and III, fibronectin, macrophage-colony stimulating factor, tissue inhibitor of metalloprotease, and transforming growth factor beta 1 messenger RNAs. CONCLUSIONS: These findings suggest that FK506 increases the expression of extracellular matrix genes and enhances fibrosis in the rat model. While further studies are needed to elucidate these profibrogenic mechanisms, caution is indicated for the unrestricted use of FK506 in patients subject to recurrent fibrogenic stimulation.

Alterations in deoxyribonucleic acid and proteins in cerebral tissues from fetuses subject to alcohol in utero.

Critical period for intra-uterine growth retardation (IUGR), and biochemical parameters for tissue growth were studied in an animal model of Fetal Alcohol Syndrome (FAS) in rats. Our research used 40 animals, fed Lieber and DeCarli liquid diets, distributed into 4 groups: C, or control--non-alcoholic--, ad libitum; E, or alcoholic, fed ad libitum; F, or alcoholic, pair fed to E; and P, non-alcoholic, pair fed to E and F. Fetuses of group E were exposed to ethanol during the organogenic period, while those from group F exposed only during the last stage of pregnancy. Blood alcohol levels were determined both at the end of 42 days before pregnancy, and on days 3, 7, 14 and 19 of gestation. The brain content of total DNA and proteins was measured, along with the cell size of fetal tissues. Non-parametric statistics were applied, considering the litter as unit, and 5% as the significant level. Prenatal ethanol exposure was associated with a cell size, total DNA, and cerebral protein content all significantly lower (p less than or equal to 0.05) than in non-alcoholic groups. These facts strongly suggest that the critical period for growth retardation associated with FAS may be situated at the end of pregnancy, when metabolic disturbances of the brain could also arise, while major external malformations are likely to be produced during organogenesis.

Alterations in the nuclear volume of neurones from the hypothalamic magnocellular nuclei of fetuses born to rats subject to chronic alcoholism.

Previous authors have noticed alterations of the neuroendocrine system in the offspring of chronically alcoholic animals. Forty Sprague-Dawley rats, were used fed a liquid control diet and a 5%-alcohol liquid diet (Lieber and DeCarli). They were divided into four groups: Control (C), Pair Fed (P), Embryonic alcohol (E) and Fetal alcohol (F). Results obtained in the statistical analysis were as follows: from the paraventricular nucleus: between E and F, E and P, E and C, p less than 0.001. F and C p less than 0.01. P and C p less than 0.005. Between F and P there were no significant differences. From the supraoptic nucleus: E and P, E and C p less than 0.001. F and P p less than 0.025, F and C p less than 0.01. Between E and F, P and C there were no significant differences.