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)

To assess the pathological changes in the lungs and liver of 42 individuals who died while enrolled in the Registry of Individuals with Severe Deficiency of Alpha-1 Antitrypsin (AAT), all available histopathologic surgical or postmortem-derived specimens were reviewed by the pathologist member of the Death Review Committee. The underlying cause of death was emphysema in 34 patients and cirrhosis in 2 patients. Slides of lung were graded for emphysema, and liver specimens were graded for fibrosis, using respective pictorial scoring systems. Correlations between the degree of pathological abnormality and clinical features were evaluated. All lungs exhibited severe panacinar emphysema (mean emphysema score, 7.9 +/- 1.06 [standard deviation], where 10 represents the greatest severity) with a lower lobe predominance. Centriacinar emphysema was minimal. No correlation was found between the pathological severity of emphysema and pulmonary function measurements, and no significant correlation was found between the degree of emphysema and the degree of hepatic fibrosis. Mildly increased bronchial gland-to-wall ratio accompanied mild inflammation and goblet cell hyperplasia. There were minimal changes in small airways. Dilatation of membranous bronchioles was a frequent finding; however, bronchiectasis of larger airways was a minor feature in only 6 patients (15%). Airway morphological features did not correlate with the clinical presence of chronic bronchitis or asthma. Although the lack of correlation between liver and lung pathological changes may reflect different pathogenetic mechanisms of liver disease and lung disease, the lack of correlation between emphysema grade and lung function likely reflects the skewed sample in a series of patients with advanced lung disease.
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PMID:The bronchopulmonary pathology of alpha-1 antitrypsin (AAT) deficiency: findings of the Death Review Committee of the national registry for individuals with Severe Deficiency of Alpha-1 Antitrypsin. 1561

Congenital and neonatal viral infections usually display their acute manifestations in highly recognisable ways, for example, congenital rubella, cytomegalovirus (CMV), varicella, human immunodeficiency (HIV) and herpes simplex virus (HSV) infection. By contrast, congenital hepatitis B virus (HBV) infection may go undetected for years. Some of these are preventable, but what is not immediately apparent is that the long-term consequences are being prevented as well. The long-term consequences of congenital and neonatal infections include endocrine, immunological and cardiovascular disease, deafness, visual problems, intellectual handicap and cerebral palsy. With the survival of HIV-infected infants into adulthood the long-term consequences will soon be described. Maternally and neonatally transmitted HBV infection predisposes to carriage, liver cirrhosis and hepatocellular carcinoma in young adults. Neonatal HBV vaccination prevents adult cancer. Acquired viral infections may predispose to subsequent lung disease, malabsorption, fertility problems or neurological disability. In the prevention of acquired rubella, varicella, HBV, influenza, poliovirus, measles and hepatitis A, one should mention the added bonus of preventing secondary cases by preventing transmission from infants and children to other children and adults. Preventing paediatric HSV, HBV and HIV infection in females may even be preventing subsequent transmission to future generations. Turning to paediatric bacterial infections, vaccinating infants and young children against pertussis could not only prevent transmission to older children and adults but also break the cycle, which then transmits from adults back to infants and young children. There is evidence that disease in older age groups, including adults, has been prevented by virtue of herd immunity from paediatric vaccination, e.g. Neisseria meningitidis Group C and Streptococcus pneumoniae. The add-on benefits for other generations, including for adults, arising from the prevention of paediatric infections are considerable.
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PMID:Paediatric infections: prevention of transmission and disease--implications for adults. 1575 76

In order to evaluate the clinical manifestations, management and outcome of childhood lung abscess, a retrospective chart review of 27 pediatric patients with International Classification of Diseases, Ninth Revision-Clinical Modification (ICD-9 CM) code of 503.1 (lung abscess) from August 1987 to August 2003 was conducted. Among the 27 patients (14 males and 13 females), 30% (8/27) were primary lung abscess and 70% (19/27) had underlying chronic diseases (secondary lung abscess). The predisposing factors of the primary group (n = 8) included 6 cases of respiratory tract infection, 1 with choking during swimming, and 1 with laceration wound. The underlying diseases in the secondary group (n = 19) included 10 cases of hematologic disorder (52%), 3 of congenital heart disease, 2 of central nervous system anomalies, and 1 each of hyperimmunoglobulin E syndrome, chronic lung disease, liver cirrhosis with fistula formation, and Swyer-James syndrome. Eleven patients (41%) underwent diagnostic tapping, including echo-guided aspiration (10 cases) and computed tomography-guided percutaneous needle aspiration (1 case). Positive yield rate from aspiration of lung abscess was 63.6% (7/11). Surgical intervention was performed in 8 (42%) of the secondary group and in 1 patient from the primary group. The pathogens were identified in 11 patients (41%): 5 with oral flora, 2 with Staphylococcus aureus plus other pathogens, 1 with S. aureus alone, 1 with Pseudomonas aeruginosa plus Proteus mirabilis, 1 with P. aeruginosa alone, and 1 with Aspergillus. The average duration of parenteral antibiotic use was 40 days. Five cases (18.5%) died due to poor control of the underlying diseases, and 4 of the patients (15%) had sequelae (2 with bronchiectasis and 2 with lung fibrosis). Seventy percent of lung abscess occurred in children with underlying medical conditions. Early percutaneous aspiration has an important role in identification of pathogens. Oral anaerobes and S. aureus are the core pathogens in primary lung abscess and gram-negative pathogens should also be considered in secondary lung abscess.
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PMID:Clinical management and outcome of childhood lung abscess: a 16-year experience. 1598 68

Hepatitis C virus (HCV) infection is a chronic blood-borne disease that affects > 4,000,000 individuals in the United States. The majority of individuals with HVC infection acquire a chronic hepatitis that predisposes them to the complications of cirrhosis and hepatoma. Chronic HCV infection is, however, associated with multiple extrahepatic manifestations as well, including recently recognized effects on the lung. These include primary effects on lung function, as well as secondary effects in the settings of progressive liver disease and drug treatment for HCV. In this article, we discuss the emerging clinical data that support a role for HCV infection in lung disease, describe the multiple pulmonary manifestations of this viral infection, and outline the therapies available for specific pulmonary complications of chronic HCV infection.
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PMID:Hepatitis C virus and the lung: implications for therapy. 1623 66

A unique case of severe, multiple, microbiologically-confirmed pulmonary Mycobacterium avium-intracellulare lesions occurred in a female with decompensated liver cirrhosis, and went to cure after around 2 y despite the impossibility to deliver an effective antimicrobial chemotherapy, owing to the patient's intolerance. From an extensive literature review, we underline a possible mechanism prompting mycobacterial disease during advanced liver disease, while we retrieved only 2 described cases of possible spontaneous resolution of Mycobacterium terrae lung disease, although both were reported in patients without end-organ liver disease, who received a specific combined chemotherapy for an appreciable time period. On the other hand, while decompensated liver cirrhosis is more frequently complicated by a peritoneal localization of bacteria and very infrequently mycobacteria, the reported case represents the first severe pulmonary localization of multiple lesions due to Mycobacterium avium-intracellulare. Moreover, this extraordinary episode resolved spontaneously within the 2-y follow-up, as documented by bronchoalveolar lavage, culture, high-resolution CT scans, and scintigraphic examination.
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PMID:Multiple, severe lung infiltrates due to Mycobacterium avium-intracellulare in a patient with decompensated liver cirrhosis: Spontaneous resolution after a two-year follow-up. 1679 96

Deficiency of circulating alpha-1-antitrypsin (AAT) is the most widely recognized abnormality of a proteinase inhibitor that causes lung disease. AAT-deficiency is caused by mutations of the AAT gene that lead to AAT protein retention in the endoplasmic reticulum (ER). Moreover, the mutant AAT accumulated in the ER predisposes the homozygote to severe liver injuries, such as neonatal hepatitis, juvenile cirrhosis, and hepatocellular carcinoma. Despite the fact that mutant AAT protein is subject to ER-associated degradation (ERAD), yeast genetic studies have determined that the ubiquitination machinery, Hrd1/Der3p-cue1p-Ubc7/6p, which plays a prominent role in ERAD, is not involved in degradation of mutant AAT. Here we report that gp78, a ubiquitin ligase (E3) pairing with mammalian Ubc7 for ERAD, ubiquitinates and facilitates degradation of ATZ, the classic deficiency variant of AAT having a Z mutation (Glu 342 Lys). Unexpectedly, gp78 over-expression also significantly increases ATZ solubility. p97/VCP, an AAA ATPase essential for retrotranslocation of misfolded proteins from the ER during ERAD, is involved in gp78-mediated degradation of ATZ. Surprisingly, unlike other ERAD substrates that cause ER stress leading to apoptosis when accumulated in the ER, ATZ, in fact, increases cell proliferation when over-expressed in cells. This effect can be partially inhibited by gp78 over-expression. These data indicate that gp78 assumes multiple unique quality control roles over ATZ, including the facilitation of degradation and inhibition of aggregation of ATZ.
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PMID:Ubiquitin ligase gp78 increases solubility and facilitates degradation of the Z variant of alpha-1-antitrypsin. 1697 36

Alpha-1-antitrypsin deficiency (AATD) is a genetic disorder that manifests as pulmonary emphysema, liver cirrhosis and, rarely, as the skin disease panniculitis, and is characterized by low serum levels of AAT, the main protease inhibitor (PI) in human serum. The prevalence in Western Europe and in the USA is estimated at approximately 1 in 2,500 and 1 : 5,000 newborns, and is highly dependent on the Scandinavian descent within the population. The most common deficiency alleles in North Europe are PI Z and PI S, and the majority of individuals with severe AATD are PI type ZZ. The clinical manifestations may widely vary between patients, ranging from asymptomatic in some to fatal liver or lung disease in others. Type ZZ and SZ AATD are risk factors for the development of respiratory symptoms (dyspnoea, coughing), early onset emphysema, and airflow obstruction early in adult life. Environmental factors such as cigarette smoking, and dust exposure are additional risk factors and have been linked to an accelerated progression of this condition. Type ZZ AATD may also lead to the development of acute or chronic liver disease in childhood or adulthood: prolonged jaundice after birth with conjugated hyperbilirubinemia and abnormal liver enzymes are characteristic clinical signs. Cirrhotic liver failure may occur around age 50. In very rare cases, necrotizing panniculitis and secondary vasculitis may occur. AATD is caused by mutations in the SERPINA1 gene encoding AAT, and is inherited as an autosomal recessive trait. The diagnosis can be established by detection of low serum levels of AAT and isoelectric focusing. Differential diagnoses should exclude bleeding disorders or jaundice, viral infection, hemochromatosis, Wilson's disease and autoimmune hepatitis. For treatment of lung disease, intravenous alpha-1-antitrypsin augmentation therapy, annual flu vaccination and a pneumococcal vaccine every 5 years are recommended. Relief of breathlessness may be obtained with long-acting bronchodilators and inhaled corticosteroids. The end-stage liver and lung disease can be treated by organ transplantation. In AATD patients with cirrhosis, prognosis is generally grave.
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PMID:Hereditary alpha-1-antitrypsin deficiency and its clinical consequences. 1856 11

Alpha 1-antitrypsin deficiency is an inherited metabolic disorder that predisposes the affected individual to chronic pulmonary disease, in addition to chronic liver disease, cirrhosis, and hepatocellular carcinoma. Just over one-third of genetically susceptible adult patients with the most severe phenotype, PiZZ, develop clinically significant liver injury. The clinical presentation of liver disease is variable, and the genetic and environmental factors that predispose some individuals to liver disease while sparing others are unknown. The mechanisms of liver and lung disease are distinct and unique. This article reviews the liver disease associated with alpha 1-antitrypsin deficiency, emphasizing the genetic defect, molecular pathogenesis, natural history, and promising therapies.
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PMID:Liver disease in alpha 1-antitrypsin deficiency: a review. 1879 7

alpha(1)-Antitrypsin (AAT), a 52 kDa plasma protein, is produced mainly in the liver. It is the most abundant circulating serine proteinase inhibitor (serpin). It has also previously been called protease inhibitor to reflect its function as a general inhibitor of serine proteases. Its main physiological role is to inhibit neutrophil elastase and it contributes to the innate immune system as an anti-inflammatory protein. Severe AAT deficiency is most prevalent in northern Europeans affecting about 1 in 3000 of the population. AAT deficiency predisposes individuals who smoke to developing pulmonary emphysema in the fourth-fifth decade of adult life and to childhood cirrhosis in about 10% of cases, with the initial presentation being prolonged neonatal jaundice. The mean interval from presentation with symptoms to diagnosis in adults is about 8 years. The condition is under-recognised and under-diagnosed. The only effective current treatment for the severe liver disease that occurs in childhood currently is liver transplantation. Replacement therapy with purified AAT from human plasma is being used in clinical practice for the lung disease though it is not known whether this influences the outcome of this chronic condition. The liver pathology arises from intracellular polymerisation of mutant protein, and attenuation of polymerisation is a potential target for therapy.
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PMID:alpha1-Antitrypsin deficiency: best clinical practice. 1978 16

Alpha(1)-antitrypsin deficiency is characterized by a pathologic reduction of the serum concentration of alpha(1)-antitrypsin, the most important antiprotease in man. It is one of the most common hereditary diseases in Caucasians. Approximately 2% of obstructive airway diseases are caused by alpha(1)-antitrypsin deficiency. Patients above 35 years may develop lung emphysema, especially in the lower lobes. Symptoms are those of chronic obstructive pulmonary disease such as cough, sputum expectoration, and progressive dyspnoea. Patients with homozygous defect often develop cholestatic hepatitis in the neonatal period. However, only few adult patients develop chronic liver disease up to liver cirrhosis with an elevated risk for malignant liver tumors. The diagnostic hallmark is the reduced serum concentration of alpha(1)-antitrypsin while genetic testing proves the defect. An early recognition of the disease is decisive for prophylactic and therapeutic measures. Smoking should be stopped immediately. Treatment of lung disease includes physiotherapy, antiobstructive and antiinflammatory medication, augmentation with human alpha(1)-antitrypsin and lung surgery including lung transplantation. Liver toxins should be avoided. Besides experimental therapeutic approaches, liver disease can only be treated by liver transplantation.
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PMID:[Alpha1-antitrypsin deficiency]. 2013 85


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