Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

alpha 1-Antitrypsin is a major plasma protease inhibitor synthesized in the liver. Genetic deficiency of this protein predisposes the affected individuals to development of infantile liver cirrhosis or chronic obstructive pulmonary emphysema. The human chromosomal alpha 1-antitrypsin gene has been cloned and shown to contain three introns in the peptide-coding region. When the cloned alpha 1-antitrypsin gene was used as a hybridization probe to analyze Eco RI-digested genomic DNA from different individuals, two distinct bands of 9.6 kilobases (kb) and 8.5 kb in length were observed in every case. Further analysis using only labeled intronic DNA as the hybridization probe has indicated that the authentic alpha 1-antitrypsin gene resides within the 9.6-kb fragment. Thus the 8.5-kb fragment must contain another gene that is closely related in sequence to the alpha 1-antitrypsin gene. Using a series of human-Chinese hamster somatic cell hybrids containing unique combinations of human chromosomes, the alpha 1-antitrypsin gene as well as the sequence-related gene have been assigned to human chromosome 14 by Southern hybridization and synteny analysis.
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PMID:Assignment of the alpha 1-antitrypsin gene and a sequence-related gene to human chromosome 14 by molecular hybridization. 660 46

alpha 1AT should no longer be ignored by hepatologists with regard to its role in protecting the liver from injury. This protective role needs further definition with regard to protease inhibition, immunologic control, and functional inactivation. Severe deficiency of alpha 1AT clearly predisposes to definable types of liver disease not only in infants and children, but at the other end of the spectrum in elderly adults. It is unfortunate that the pathophysiology of human and animal alpha 1AT related liver injury is not as readily apparent as in pulmonology conditions. However, it is time to digest the tremendous progress that has evolved in that field in relating alpha 1AT to emphysema. Cirrhosis of the liver should be studied in relationship to the pathophysiology demonstrated by our colleagues to be important in "cirrhosis of the lung." The diagnosis of alpha 1AT deficiency and the course of the associated liver disease have been reviewed and updated. Prevention and cure have been demonstrated to be possible but neither method has universal applicability. In contrast, other potential therapeutic endeavors, although not presently proved to be efficacious, with time and research will provide methodologies for the treatment of this disorder as well as insight into mechanisms of general liver injury not previously appreciated.
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PMID:Alpha-1-antitrypsin: an ignored protein in understanding liver disease. 676 44

Homogenates of liver from cases of hepatic cirrhosis due to alpha 1-antitrypsin deficiency (PiZZ) alcoholism were analyzed for their content of various lysosomal enzymes. Also determined were the specific activities of lactate dehydrogenase, glutamate-oxaloacetate transaminase, glutamate-pyruvate transaminase, and creatine phosphokinase in the extracts of liver from cases of both kinds of hepatic cirrhosis: all of these activities were within the range of control values. Similarly, the specific activities of the following lysosomal hydrolases were unremarkable: acid phosphatase, beta-mannosidase, beta-fucosidase, beta-glucuronidase and beta-glucosidase. Hexosaminidase specific activity was increased twofold in livers from the cases of cirrhosis due to alpha 1-antitrypsin deficiency. The specific activity of alpha-mannosidase (measured at pH 4.5) in homogenates of livers from PiZZ individuals with cirrhosis and those with alcoholic cirrhosis was increased two- to four-fold. Chromatography of the high-speed supernatant fraction from homogenates of livers of cirrhotic and noncirrhotic individuals on columns of DEAE-cellulose resolved alpha-mannosidase activity into two components: under the conditions employed, acid pH optimum (pH 4.5) alpha-mannosidase did not bind to the resin, whereas intermediate pH optimum (pH 5.5) alpha-mannosidase could be eluted with 0.1 mol/l NaCl. Liver from one case of (PiZZ) alpha 1-antitrypsin deficiency and emphysema, without demonstrable cirrhosis, was found to contain normal levels of both acid alpha-mannosidase and intermediate alpha-mannosidase. However, cases of cirrhosis due to alpha 1-antitrypsin deficiency contained twice as much acid alpha-mannosidase and only one third to one fourth as much intermediate alpha-mannosidase as controls. The deficiency in hepatic intermediate alpha-mannosidase was also observed in 5 of 5 cases of alcoholic cirrhosis.
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PMID:Altered alpha-mannosidase isoenzymes in the liver in hepatic cirrhosis. 697 51

We report a 73-year-old woman with homozygous ZZ alpha-1-antitrypsin deficiency (AATD), micronodular cirrhosis, cholestatic jaundice, and emphysema. An elevated SGOT/SGPT ratio was noted in the absence of chronic alcoholism. ERCP demonstrated a normal extrahepatic biliary system and suggested obstruction of the intrahepatic ducts. An operative liver biopsy demonstrated periodic acid-Schiff-positive, diastase resistant intracytoplasmic inclusion bodies. This patient reminds us that metabolic causes of cryptogenic liver disease need to be considered, even in the elderly. We review briefly the literature concerning AATD and liver disease.
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PMID:Alpha-1-antitrypsin deficiency--a cause of cryptogenic liver disease in the elderly. 698 Feb 39

Lead, cadmium, mercury and arsenic are widely dispersed in the environment. Adults are primarily exposed to these contaminants in the workplace. Children may be exposed to toxic metals from numerous sources, including contaminated air, water, soil and food. The chronic toxic effects of lead include anemia, neuropathy, chronic renal disease and reproductive impairment. Lead is a carcinogen in three animal species. Cadmium causes emphysema, chronic renal disease, cancer of the prostate and possibly of the lung. Inorganic mercury causes gingivitis, stomatitis, neurologic impairment and nephrosis, while organic mercurials cause sensory neuropathy, ataxia, dysarthria and blindness. Arsenic causes dermatitis, skin cancer, sensory neuropathy, cirrhosis, angiosarcoma of the liver, lung cancer and possibly lymphatic cancer.
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PMID:Occupational and community exposures to toxic metals: lead, cadmium, mercury and arsenic. 716 33

Twenty-five years ago, cigarette smokers in the United Kingdom smoked plain cigarettes with an average tar yield of probably about 35 mg. Now smokers predominantly smoke filter cigarettes and average tar yields have been reduced by half. Epidemiological evidence comparing mortality in smokers of differing types of cigarettes is reviewed. Compared with smokers of higher tar plain cigarettes, smokers of lower tar filters cigarettes have a reduced mortality for lung cancer, for cancer of the buccal cavity, pharynx, larynx, oesophagus, and bladder, for chronic bronchitis and emphysema, and for cirrhosis of the liver. They also have a slightly significant. Problems of interpretation and limitations of the available evidence are discussed. No worthwhile evidence is yet available on smokers of "low tar' (0-10 mg) cigarettes and data are sparse on lifetime smokers of filter cigarettes. Continuing research is important to understand the situation fully, but the trends of lower mortality to be associated with lower tar and nicotine levels are promising.
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PMID:Mortality and type of cigarette smoked. 726 28

The putative relationship between genetic haemochromatosis and PiZ alpha 1 antitrypsin deficiency was studied using a monoclonal antibody against the PiZ variant in 67 consecutive patients with genetic haemochromatosis seen at Karolinska Hospital and Huddinge University Hospital, Stockholm over a 10 year period. Three (4.5%) of the patients with haemochromatosis were found to be PiZ homozygotes (odds ratio = 82, confidence interval = 26, 256; p < 0.0001). The prevalence of the heterozygous (PiZ) phenotype was similar to that in the general population (p = 0.937). During the ascertainment period, liver biopsy was performed in 65 (97%) of the patients; 66% (2 of 3) of the PiZ homozygotes were found to have cirrhosis compared with 10% (6/59) of the non-carriers of the PiZ variant (p = 0.039). None of the homozygous or heterozygous alpha 1 antitrypsin deficient patients had developed hepatocellular carcinoma compared with 3.4% (2 of 59) of the non-PiZ gene carriers (p = 1.0). Two of those with the homozygous phenotype had developed severe emphysema. HLA typing was performed in 18 patients, 16 (89%) of whom manifested antigens known to be linked to haemochromatosis. There were no significant differences between the PiZ gene carriers and non-carriers in mean age at onset of disease, sex distribution, or HLA type. Two of the PiZ heterozygotes had plasma alpha 1 antitrypsin concentrations below the normal range, though the group mean was lower than that of the non-PiZ carriers (p = 0.0003). The data suggest that the presence of the PiZ allele for alpha1 antitrypsin deficiency, in a double dose, is associated with genetic haemochromatosis and may contribute to the earlier onset of cirrhosis in these patients, though it does not increase the risk of hepatocellular carcinoma.
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PMID:Increased PiZ gene frequency for alpha 1 antitrypsin in patients with genetic haemochromatosis. 761 85

The association between deficiency of alpha-1-antitrypsin (A1AT) and glomerulonephritis has been only sporadically reported on, as opposed to the linkage between A1AT-deficiency and lung emphysema or hepatic cirrhosis. We describe the case of a 30-year-old man with A1AT deficiency who developed hepatic cirrhosis in early childhood, and IgA glomerulonephritis and hypertension in adult life. The IgA nephritis followed an unusual course. After three years of slight elevation of serum creatinine levels, the patient rapidly developed renal failure necessitating acute hemodialysis. The deterioration of the renal function was preceded by eruption of skin lesions, believed to represent a vasculitis. After six months of hemodialysis, the patient successfully received a transplanted kidney from his mother. The literature is reviewed with respect to the association between A1AT-deficiency and renal disease. We discuss possible underlying causes for the rapid deterioration of renal function in this patient.
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PMID:[Alpha 1-antitrypsin deficiency--not only pulmonary and hepatic involvement]. 770 89

Pulmonary complications of alpha 1-antitrypsin deficiency are most commonly manifested by panlobular emphysema. This report describes histologically proven bronchiectasis in a 21 year old man with massive haemoptysis and homozygous deficiency of alpha 1-antitrypsin. Neither panlobular emphysema nor cirrhosis of the liver were present. Bronchiectasis must be considered part of the spectrum of the pulmonary pathology that may be encountered in individuals with alpha 1-antitrypsin deficiency.
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PMID:Bronchiectasis and homozygous (P1ZZ) alpha 1-antitrypsin deficiency in a young man. 871 67

alpha 1-Antitrypsin (AAT) deficiency is associated with predisposition to developing liver cirrhosis in early childhood, and chronic degenerative lung disease in early adult life. The probable molecular basis for the disease associations is known. One of the common variants, Z, has the propensity to form polymers, a phenomenon which is concentration- and temperature-dependent. This results in accumulation of the protein in hepatocytes, the predominant tissue source of AAT, and leads to cell damage. AAT deficiency results in loss of protection in the lung against neutrophil elastase (NE) the major target for AAT. NE is capable of destroying the architecture of the lung, leading to pulmonary emphysema. The disease process is exacerbated by cigarette smoke, which is capable of oxidizing a critical methionine residue at the active site, rendering AAT an inefficient inhibitor of NE. The combination of deficiency and cigarette smoking are critical to the development of pulmonary emphysema. We have identified a mutation in an enhancer sequence which, in all probability, predisposes to disease by a novel mechanism related to diminished expression of AAT during inflammation. Our understanding of the mechanisms of disease should lead to improved therapeutic interventions.
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PMID:Molecular pathology of alpha 1-antitrypsin deficiency and its significance to clinical medicine. 782 May 38


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