Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019209 (hepatomegaly)
 5,798 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three cases of a syndrome featuring massive splenomegaly, gross generalized lymphadenopathy, and moderate hepatomegaly are reported. Spleen weights ranged from 800 to 2400 g. Gradual depletion of lymphoid germinal centers, and prominent infiltration of the splenic and lymph node cords with plasma cells, immunoblasts and actively dividing B cells were the most distinctive histological features. The liver in two cases showed portal infiltrates. A marked hypergammaglobulinemia, a decrease in blood cholesterol level and hematological abnormalities related to hypersplenism were observed. The condition begins early in life and runs a chronic course, of up to 25 years. There was a family history in only one instance. Since there was no generalized immunodeficiency nor local depletion of T cells or dendritic reticulum cells, a failure in the local regulation of the immune response and possible cytokine production is postulated. This condition underlines the pivotal role of the local organization of the germinal centers in cellular cooperation and in the carrying out and regulation of the immune response.
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PMID:The disappearance of germinal centers in chronic lymphadeno-hepato-splenomegaly syndrome in childhood: report of three cases. 271 99

Gaucher disease, the most common form of lysosomal storage disease, is the result of autosomal recessive inheritance of a lysosomal enzyme glucocerebrosidase deficiency, which produces defective hydrolysis of glucosylceramide that accumulates in reticuloendothelial (tissue macrophage) cells. The current review focuses on Type 1 (the nonneuronopathic) or adult Gaucher disease and defines the clinical manifestations (splenomegaly, hepatomegaly, bony lesions, and clinical metabolic dysfunction) in relationship to the known enzymatic defect. The clinical diversity and variability in symptoms and signs, the age at onset of the clinical manifestations and their rate of progression, and the heterogeneity of the organs involved are reviewed. Extensive delineation of the nature of the enzyme defect and the recent molecular characterization of the enzyme mutants has not provided an explantation for the remarkable clinical phenotypic heterogeneity. Enzyme assays now provide an excellent method for diagnosis. Effective enzyme replacement therapy emphasizes the value of early diagnosis and has altered the costs and potential risks of older therapeutic indications for splenectomy or cytokine therapy. Enzyme efficacy raises questions about the specific indications for replacement treatment and the most desirable rate and duration of enzyme delivery.
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PMID:Gaucher disease: a heterogeneous clinical complex for which effective enzyme replacement has come of age. 809 3

We demonstrate in this study the cytotoxic effects of inorganic arsenicals, arsenite and arsenate, and organic arsenic compounds, monomethylarsonic acid (MAA), dimethylarsinic acid (DMAA), and trimethylarsine oxide (TMAO), which are metabolites of inorganic arsenicals in human bodies, using murine macrophages in vitro. Inorganic arsenicals, both arsenite and arsenate, are strongly toxic to macrophages, and the concentration that decreased the number of surviving cells to 50% of that in untreated controls (IC50) was 5 or 500 microM, respectively. These inorganic arsenicals mainly caused necrotic cell death with partially apoptotic cell death; about 80% of dead cells were necrotic, and 20% were apoptotic. The inorganic arsenicals also induced marked release of an inflammatory cytokine, tumor necrosis factor alpha (TNF alpha), at cytotoxic doses. This strong cytotoxicity of an inorganic arsenical, arsenite, might be mediated via active oxygen and protease activation because it was inhibited by the addition of some antioxidant reagents, such as superoxide dismutase (SOD), catalase, and GSH, or by a peptide inhibitor of interleukin-1 beta-converting enzyme (ICE). It is likely that these immunotoxic effects of inorganic arsenicals may evoke both immunosuppression and inflammation, and they may be central factors causing carcinogenesis and severe inflammatory responses, such as hepatomegaly and splenomegaly, in chronic arsenicosis patients who daily ingested arsenic-contaminated well water. In contrast, the cytotoxic effects of methylated arsenic compounds were lower than those of inorganic arsenicals. The IC50 value of DMAA was about 5 mM, and MAA and TMAO had no toxicity even at concentrations over 10 mM. Additionally, these methylated chemicals suppressed the TNFalpha release from macrophages. DMAA induced mainly apoptotic cell death in macrophages as indicated by cellular morphological changes, condensed nuclei, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL), and DNA fragmentation. However, the cytotoxicity of DMAA might be induced via a different mechanism from that of inorganic arsenicals because it was not abolished by the additions of SOD, catalase, or ICE inhibitor. Conversely, GSH enhanced the toxicity of DMAA. These data suggest that methylation of inorganic arsenicals in mammals plays an important role in suppression of both severe immunosuppression and inflammatory responses caused by inorganic arsenicals.
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PMID:Inorganic and methylated arsenic compounds induce cell death in murine macrophages via different mechanisms. 954 97

Sezary cell leukemia (SCL) is a rare T cell neoplasia that has been suggested to be a variant of T-prolymphocytic leukemia (T-PLL). Both disorders have an aggressive clinical course, lymphocytosis with characteristic morphology, lymphadenopathy, hepatomegaly, characteristic cytogenetic abnormalities and mature T cell phenotypes. Skin lesions, however, are mainly found in T-PLL. We describe a patient with T-PLL/SCL, who atypically presented with severe seropositive polyarthritis and skin lesions, responding to treatment with human CD52 antibody, CAMPATH-1H and pentostatin. Meningeal leukemia and an assumed myocardial infiltration subsequently developed. Polyarthritis is common in T large granular lymphocyte leukemia and adult T cell lymphoma-leukemia, but both entities could be ruled out in the present case. In rheumatoid arthritis, an expansion of CD4+ and/or CD8+ T lymphocytes is well documented and this phenomenon is believed to be of pathogenetic importance. We speculate that the T cell clone in the present case had special homing properties or cytokine effects resulting in synovitis.
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PMID:Seropositive polyarthritis and skin manifestations in T-prolymphocytic leukemia/Sezary cell leukemia variant. 1075 96

Endotoxin has been identified as a principal mediator of sepsis, often with resulting multiple organ failure. Although interferon gamma (IFN-gamma) has a central role in controlling bacterial infection through the activation of macrophages and T lymphocytes, it can also enhance the harmful effects of the inflammatory response. To examine the role of IFN-gamma in lipopolysaccharide (LPS)-induced injury, we administered LPS (20 or 800 microg/mouse) alone or as low-dose LPS (20 microg/mouse) 7 days after heat-killed Propionibacterium acnes (P. acnes) injection into wild-type C57BL/6 (B6) mice or IFN-gamma-deficient (GKO) mice (B6 background). Although low-dose (20 microg) LPS alone had no effect on survival, the administration of 800 microg LPS alone resulted in 100% mortality in both B6 and GKO mice without significant hepatic mononuclear cellular infiltration or differences in elevated plasma tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), and IL-12 levels. In contrast, mortality after low-dose (20 microg) LPS challenge in P. acnes-primed B6 mice was 100%, but 0% in GKO mice. In vivo plasma cytokine (IFN-gamma, TNF-alpha, IL-6, and IL-12) levels and in vitro cytokine production by hepatic mononuclear cells were significantly higher in B6 mice compared with GKO mice. Associated hepatic mononuclear cellular infiltration, multifocal liver necrosis, hepatomegaly, and splenomegaly were found in B6 mice, but not in GKO mice. Finally, the anti-inflammatory NK1.1+CD4+ cell proportion of hepatic infiltrating mononuclear cell numbers 7 days after P. acnes administration was significantly reduced in B6 compared with GKO mice, whereas the proportion of inflammatory NK1.1+CD4- cells was increased. In conclusion, these data suggest that IFN-gamma mediates P. acnes-primed low-dose LPS injury through the hepatic infiltration of mononuclear cells and the subsequent elevation of inflammatory cytokines after LPS challenge, whereas the lethal effects of high-dose LPS alone does not depend on the presence of IFN-gamma.
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PMID:The resistance of P. acnes--primed interferon gamma-deficient mice to low-dose lipopolysaccharide-induced acute liver injury. 1191 26

Attenuated Salmonella strains have shown excellent efficacy as mucosal vaccine delivery systems. In the present report, several recombinant strains of Salmonella enterica serovar Typhimurium, engineered to express defined murine cytokines, were used to study their potential immunoregulatory capacity in the mouse model of typhoid fever. Specifically, recombinant strains expressing IL-2 (known as GIDIL2) or TNF-alpha (GIDTNF) were compared with the parental, non-cytokine-secreting, strain (BRD509) for their ability to induce a variety of immune responses in susceptible BALB/c mice. Our findings indicate that bacterially-expressed cytokines are functional in vivo and do induce a unique pattern of responses, quite distinct from that induced by BRD509 organisms. Both the type and magnitude of specific immune parameters were affected. These included the capacity to induce an inflammatory response resulting in a state of profound splenomegaly and hepatomegaly, activation of individual immune cells (particularly macrophages and other myeloid lineage cells), and the induction of nitric oxide (NO) secretion. Furthermore, a structural analysis using light as well as electron microscopy was undertaken to examine the host cellular response to infection with the different bacterial strains. The results indicate that cytokine expression by the invading pathogen can dramatically influence host immunity from a very early stage following infection. These findings may well have important consequences for the potential utilization of bacterial vector-encoded cytokines in immunoregulation in different disease settings.
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PMID:Cytokine expression by attenuated intracellular bacteria regulates the immune response to infection: the Salmonella model. 1200 71

Hepatomegaly and alterations in hepatic function are common to all patients with sickle-cell disease. In these patients, hepatic sickling is a manifestation of severe intrahepatic vaso-oclusive crises, even at levels of 25 % HbS and hematocrits of more than 45-50 %, which in 10 % of cases can lead to acute hepatic failure (AHF). AHF can be due to a variety of causes, including hematologic malignancies, but T cell lymphoma, which is usually secondary to diffuse hepatic infiltration and ischemia, is an exceptional cause, although other mechanisms can be involved. Cytokines released by lymphomas have recently been implicated as a cause of AHF.We describe a black girl with sickle cell disease, who developed AHF due to T cell lymphoma without lymphomatous infiltration of the liver. The only mechanism found to explain the clinical findings was release of cytokines by lymphoma. In patients with AHF of unknown etiology we propose early liver biopsy, because prognosis depends on the presence or absence of hepatic tumour infiltration. If AHF develops in a patient with diagnosed malignant disease, cytokine release may be the cause of AHF. Consequently, early diagnosis of the underlying disease and provision of liver support, as well as direct removal of inflammatory mediators from the circulation by exchange transfusion or other methods, should be the main priorities.
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PMID:[Acute liver failure due to T cell lymphoma without hepatic infiltration]. 1262 21

Adiponectin has recently been shown to be a promising candidate for the treatment of obesity-associated metabolic syndromes. Replenishment of recombinant adiponectin in mice can decrease hyperglycemia, reverse insulin resistance, and cause sustained weight loss without affecting food intake. Here we report its potential roles in alcoholic and nonalcoholic fatty liver diseases in mice. Circulating concentrations of adiponectin decreased significantly following chronic consumption of high-fat ethanol-containing food. Delivery of recombinant adiponectin into these mice dramatically alleviated hepatomegaly and steatosis (fatty liver) and also significantly attenuated inflammation and the elevated levels of serum alanine aminotransferase. These therapeutic effects resulted partly from the ability of adiponectin to increase carnitine palmitoyltransferase I activity and enhance hepatic fatty acid oxidation, while it decreased the activities of two key enzymes involved in fatty acid synthesis, including acetyl-CoA carboxylase and fatty acid synthase. Furthermore, adiponectin treatment could suppress the hepatic production of TNF-alpha and plasma concentrations of this proinflammatory cytokine. Adiponectin was also effective in ameliorating hepatomegaly, steatosis, and alanine aminotransferase abnormality associated with nonalcoholic obese, ob/ob mice. These results demonstrate a novel mechanism of adiponectin action and suggest a potential clinical application of adiponectin and its agonists in the treatment of liver diseases.
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PMID:The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. 1284 63

The multifunctional cytokine interleukin 6 (IL-6) is expressed in a wide variety of disease states and pathologic processes. Mice deficient in IL-6 display abnormal and delayed liver regeneration and repair. Currently, IL-6 is thought to influence liver growth indirectly by priming hepatocytes to respond to growth factors such as hepatocyte growth factor (HGF) by inducing expression of HGF and by inhibiting hepatocyte apoptosis, as distinct from the direct mitotic effects of IL-6 on myeloid and other cell types. Here, we show that systemic administration of IL-6 using CHO cell tumors in nude mice results in dramatic hepatomegaly and hepatocyte hyperplasia in the absence of liver injury. Liver mass and liver to body mass ratios increased to 2 to 3 times normal because of proliferation of hepatocytes. Liver growth was associated with high levels of serum IL-6 and with activation of the IL-6-signaling pathway, including increased expression of IL-6 receptor-alpha/gp80, activation of the signal transducer and activator of transcription-3 (STAT-3), and mitogen-activated protein kinase (MAPK/ERK)-signaling pathways and induction of downstream target genes, including c-myc. HGF receptor and transforming growth factor alpha (TGF-alpha)/epidermal growth factor (EGF) receptor activation were decreased in hypertrophied livers, suggesting that IL-6-induced liver growth was independent of these known hepatocyte mitotic pathways. In conclusion, we suggest that IL-6 may function as a direct hepatic mitogen in vivo and, furthermore, that IL-6 warrants closer examination as a potent liver growth factor with potential clinical utility for increasing liver mass following injury.
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PMID:Massive liver growth in mice induced by systemic interleukin 6 administration. 1288 76

A prospective study of clinical and cytokine profiles of 107 infants with dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS) was conducted. Fever, petechiae on the skin, and hepatomegaly were the most common clinical findings associated with DHF/DSS in infants. DSS occurred in 20.5% of the patients. Hemoconcentration and thrombocytopenia were observed in 91.5% and 92.5% of the patients, respectively. Serologic testing revealed that almost all of the patients (95.3%) had primary dengue virus infections. These data demonstrate that clinical and laboratory findings of DHF/DSS in infants are compatible with the World Health Organization's clinical diagnostic criteria for pediatric DHF. The present study is the first to report evidence of production of cytokines in infants with DHF/DSS and to describe the difference between the cytokine profile of infants with primary dengue virus infections and children with secondary infections. Overproduction of both proinflammatory cytokines (interferon-gamma and tumor necrosis factor-alpha) and anti-inflammatory cytokines (interleukin-10 and -6) may play a role in the pathogenesis of DHF/DSS in infants.
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PMID:Dengue hemorrhagic fever in infants: a study of clinical and cytokine profiles. 1472 86


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