Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have developed a transgenic mouse strain, Z#2, which represents a model for alpha 1-protease inhibitor (alpha 1-antitrypsin: alpha 1-Pi)-associated liver disease (Dycaico et al., 1988). Fifteen percent of human infants with alpha 1-Pi disease develop non-viral hepatitis which is sometimes associated with growth retardation. Such hepatitis and growth retardation tend to occur in a subset of families with other alpha 1-Pi affected members who have had non-viral hepatitis. The Z#2 mouse strain exhibits non-viral hepatitis and growth retardation. This phenotype is more pronounced in transgenic offspring of crosses between Z#2 mice and DBA/2J inbred mice, and less pronounced in transgenic offspring of crosses between Z#2 and CBA/J inbred mice. Such phenotypic differences resemble the phenotypic differences seen in human families with alpha 1-Pi-associated liver disease.
 ...
PMID:Neonatal growth delay in alpha-1-antitrypsin disease. Influence of genetic background. 261 43

Circulating alpha 1-antitrypsin is synthesized primarily in the liver and secreted into the bloodstream, where it serves as the major protease inhibitor. The PiZ variant of alpha 1-antitrypsin is associated with decreased levels of the protein in sera as a result of its retention within hepatocytes. Homozygosity for the variant allele predisposes individuals to the development of pulmonary emphysema and an increased risk for liver disease. We and others have previously demonstrated that the normal PiM human alpha 1-antitrypsin gene can be properly expressed in the livers of transgenic mice. The PiZ variant of the human alpha 1-antitrypsin gene was introduced into the germline of mice to determine whether the mutant protein would accumulate in mouse hepatocytes and if such accumulation would result in the development of liver damage in an animal model. As expected, the mutant human protein was abundantly synthesized in the livers of the transgenic animals and accumulated within the rough endoplasmic reticulum of hepatocytes as it does in human patients. PiZ mice developed significantly more liver necrosis and inflammation than PiM transgenic mice or control littermates. The degree of liver damage was correlated with the amount of PiZ alpha 1-antitrypsin accumulated in the liver of the different pedigrees of mice. Although 40% of PiZ mice tested were seropositive for mouse hepatitis virus (MHV), the degree of liver damage was not influenced by the MHV seropositivity; rather, it was related only to the presence of accumulated PiZ protein.
 ...
PMID:Accumulation of PiZ alpha 1-antitrypsin causes liver damage in transgenic mice. 278 98

The reactivity of alpha-1-antitrypsin (AAT) with Lens culinaris agglutinin (LCA) was studied by crossed immuno-affinity electrophoresis of the sera of 246 subjects from 6 groups (acute virus hepatitis, chronic hepatitis, liver cirrhosis, hepatocellular carcinoma (HCC), carcinoma metastatic to the liver and normal controls). Two species of AAT (LCA-reactive and -nonreactive species) were detected on crossed immuno-affinity electrophoresis in a gel containing LCA. The percentages of LCA-reactive species of AAT in neoplastic diseases of the liver were significantly higher than those in benign liver diseases and normal controls. There was no correlation between the percentage of LCA-reactive species of AAT and serum AAT concentration in any group. Furthermore, in studying 15 pairs of serum samples before and after the subsequent development of HCC, the percentage of LCA-reactive species of AAT after HCC occurrence was significantly higher than that before, although there was no statistically significant difference between the serum AAT concentration before and after development of the disease. The latter 15 patients were all of the normal protease inhibitor phenotype (PiMM) and no change in phenotype was observed before and after the development of HCC. The results indicate that measurement of the reactivity of AAT with LCA can be a useful marker for the diagnosis of HCC and carcinoma metastatic to the liver, especially when serum concentrations of alpha-foetoprotein or other tumour markers are within the normal ranges.
 ...
PMID:The reactivity of alpha-1-antitrypsin with Lens culinaris agglutinin and its usefulness in the diagnosis of neoplastic diseases of the liver. 282 74

Homozygous deficiency of alpha-1 antitrypsin is the most common inborn error or metabolism in Europe. Severe deficiency of this major protease inhibitor in serum is associated with chronic obstructive lung disease, chronic liver disease in adults and neonatal hepatitis. An overview is given of the role of heredity, and the diagnostic criteria and clinical and histological findings in this disorder. Emphysema seems to be caused by the free elastolytic activity of white cells, leading to the degradation of elastin. The pathophysiology of liver disease - less well understood - is discussed with special emphasis on the importance of heterozygous alpha-1 antitrypsin deficiency. Exogenous noxae seem to play an important role in the pathogenesis of heterozygous deficiency. In view of the 7% frequency of heterozygous alpha-1 antitrypsin deficiency in the European population and the role of noxae in the development of pulmonary and liver diseases, improved prophylaxis is mandatory.
 ...
PMID:[Alpha 1-antitrypsin deficiency: a review with special reference to the significance of heterozygous deficiency]. 300 60

In a six-month multicenter feasibility and safety study, 20 patients, who all had a congenital deficiency of alpha-1-protease inhibitor (A1PI) of the PiZ phenotype accompanied by a chronic obstructive lung disease, were treated with human-plasma-derived A1PI. A weekly dose of 60 mg/kg, administered intravenously, was shown to be sufficient to maintain patient serum levels above the threshold limit of 35 percent, the serum level of healthy persons of the MZ phenotype. This is supposed to be the minimal effective level for protection against the elastolytic attack of the lung and, therefore, satisfies one of the most important criteria of feasibility of long-term replacement therapy. The global concentration in serum or bronchiolar lavage fluid A1PI including active and inactivated A1PI was measured immunologically by rate nephelometry and radial immunodiffusion. The functional activity of A1PI, expressed as free inhibitor activity against trypsin and leukocyte elastase, confirmed that the infused A1PI remained mostly in its active form in the circulation. Reported adverse reactions were moderate and did not require alteration to the schedule of the infusions and/or the dose and rate of administration. Antibodies to A1PI as measured by the Ouchterlony method did not develop. Laboratory and physical signs of possible hepatitis virus contamination were not observed. The long-term replacement therapy, therefore, appears to be safe.
 ...
PMID:Replacement therapy for alpha-1-protease inhibitor deficiency in PiZ subjects with chronic obstructive lung disease. 328 88

alpha 1-Antitrypsin, the major serum protease inhibitor, is a glycoprotein synthesized in the liver. Severe deficiency results in protease-antiprotease imbalance, which predisposes to severe emphysema at a young age. Reduced serum levels reflect inadequate release of alpha 1-antitrypsin by the liver, which may be caused by specific defects in biosynthesis. The deficiency is inherited, with multiple codominant alleles at a single autosomal locus. Homozygous individuals, with severely reduced alpha 1-antitrypsin levels, have dyspnea, pulmonary function abnormalities, and respiratory disability from emphysema, usually in the fifth decade of life, with smokers being affected one decade earlier. Heterozygous individuals have intermediate alpha 1-antitrypsin levels and a more benign clinical course. Heterozygous smokers may have mild pulmonary function abnormalities, but these are of uncertain clinical significance. Hepatic involvement with transient neonatal hepatitis and cirrhosis with subsequent liver failure in adulthood represent the major extrapulmonary manifestations, occurring in 10% of homozygous individuals.
 ...
PMID:alpha 1-Antitrypsin deficiency. 632 84

Alpha 1-protease inhibitor (alpha 1 PI), also called alpha 1-antitrypsin, may be useful for replacement therapy in a number of chronic or acute disorders. The risk associated with the possible presence of hepatitis virus can be greatly reduced by pasteurization at 60 degrees C for 10 h. A series of thermal denaturation profiles was obtained in the presence of various protein stabilizers using the increase in 1,8-anilinonaphthalene sulfonate fluorescence that accompanies protein denaturation. A parallel series of experiments was conducted to evaluate each additive for its capacity to protect the biological activity of alpha 1 PI. As much as 92% of the inhibitory activity against elastase and trypsin could be recovered after pasteurization in buffer containing citrate (1.2 M) and either EDTA (0.5 M) or gluconate (1.2 M). Loss of activity was not affected by protein concentration. In conclusion, conditions have been developed to protect the bulk of alpha 1 PI from denaturation during pasteurization, and this should give an added impetus to efforts to test the efficacy of this protein in various clinical conditions.
 ...
PMID:Thermal denaturation of alpha 1-protease inhibitor. Stabilization by neutral salts and sugars. 640 63

Experimental autoimmune hepatitis was induced in C57BL/6 mice by immunization with syngeneic liver protein and adjuvant. Hepatitis was characterized by marked cellular infiltrates, but hepatic necrosis was mild to moderate. A small dose of endotoxin (25 micrograms/mouse) produced lethal hepatitis with elevation of serum transaminase levels in these mice. The endotoxin-induced reactions were completely inhibited by i.p. administration of FUT-175 (5 mg/kg), a synthetic protease inhibitor, 1 h before the endotoxin injection. In vitro experiments showed that two-thirds of the inflammatory infiltrates were monocyte/macrophages. Cytotoxicity against syngeneic hepatocytes was significantly increased by the addition of endotoxin (25 micrograms/ml), but the same dose of endotoxin alone had no effect on the viability of hepatocytes. The endotoxin-induced increase in cytotoxicity was prominent in the glass-dish adherent (monocyte/macrophage enriched) fraction and was also demonstrated after depletion of T-cells. However, elevated cytotoxicity did not occur when FUT-175 (> 1 x 10(-7) M) was present throughout the assay period. These results seem to indicate that the hepatotoxic effects of endotoxin are mediated, at least in part, by monocytes or macrophages infiltrating the liver following immunization of liver proteins. Our results also suggest that FUT-175 has protective effects against endotoxin-induced hepatotoxic reactions.
 ...
PMID:Protective effects of FUT-175 on acute massive hepatic necrosis induced in mice following endotoxin injection and immunization with liver proteins. 815 Nov

The deficiency of alpha 1-antitrypsin, a strong protease inhibitor, is known to cause pulmonary emphysema, neonatal hepatitis and liver cirrhosis. Among 75 variants reported so far, amino acid or DNA variations have been determined in about 30 variants. Many are caused by single base substitutions which then cause single amino acid replacements. In most of the null variants, base substitutions, base deletions or base insertions make stop codons appear somewhere beyond the mutation sites, which cause truncated proteins. Only several variants, including PiZ and PiMmalton, characterized as having cytoplasmic globules in hepatocytes, cause liver diseases. Recent analyses on the tertiary structure of alpha 1-antitrypsin have elucidated the mechanism of the formation of insoluble polymers in PiZ patients. The accumulation theory seems more relevant to the mechanism of the liver damage than the protease-antiprotease imbalance theory.
 ...
PMID:[Genetic analyses of alpha 1-antitrypsin deficiency]. 846 63

Hepatic explant specimens from 171 patients with cirrhosis were examined to determine the incidence of periodic acid-Schiff (PAS)-positive diastase-resistant globules (PDRGs) in end-stage hepatic disease and whether the globules bear a specific relationship to the alpha1-antitrypsin (A1AT) phenotype or to causes of hepatic disease other than A1AT deficiency. PAS-positive diastase-resistant globules were detected in 17 (10%) of the hepatic explant specimens, and the globules in all of these cases were strongly immunoreactive for A1AT. In the 17 patients with PDRGs, the cirrhosis was attributed preoperatively to A1AT deficiency (3 patients), ethanol abuse, viral hepatitis, or both (10 patients), cryptogenic cirrhosis (3 patients), and autoimmune hepatitis (1 patient). The A1AT isoelectric phenotypes classified according to the protease inhibitor (Pi) nomenclature for 16 of these patients were as follows: Pi ZZ (3 patients), Pi SS (1 patient), Pi MZ (8 patients), and Pi MM (4 patients). Because PDRGs were seen in a variety of A1AT phenotypes, serum electrophoretic analysis, not histologic examination, is required for the correct diagnosis of an A1AT abnormality. Furthermore, although PDRGs were seen in a variety of hepatic diseases, the majority of patients with globules had an undetected A1AT abnormality. Accordingly, on identification of hepatocytic PDRGs, the clinician should be alerted to the possibility of an unsuspected A1AT abnormality even in the presence of other causes of hepatic disease.
 ...
PMID:Hepatocytic globules in end-stage hepatic disease: relationship to alpha1-antitrypsin phenotype. 916 67


<< Previous 1 2 3 4 5 Next >>