A 1-antitrypsin deficiency

Deficiency of aj-antitrypsin is also implicated in one type of liver disease (a,-antitrypsin deficiency liver... 

Figure 50-7. Scheme of causation of a,-antitrypsin-deficiency iiver disease. The mutation shown causes formation of PiZZ (MiM 107400). (a,-AT, a,-antitrypsin.)... 

A third autosomal recessive genetic disease is a -antitrypsin deficiency. Abnormalities in the a,-antitrypsin protein impair secretion from the liver, a,-Antitrypsin deficiency causes cirrhosis in children as well as adults adults usually have concomitant pulmonary disease such as chronic obstructive pulmonary disease. 

RFLPs are often a reflection of individual genetic diversity and are not related to a clinical phenotype, but occasionally they can be diagnostic of an inherited disease. This technique is relatively new yet, it has been applied to the prenatal detection of sickle cell anemia, thalassemia, phenylketonuria, a,-antitrypsin deficiency, Huntington s chorea, Duchenne muscular dystrophy, hemophilia A and B, cystic fibrosis, and several other, diseases. 

Toxicity resulting from exposure to cigarette smoke in persons afflicted with a -antitrypsin deficiency has been mentioned above (section 1.3). Avoiding cigarette smoke can prevent its destructive effects on the lungs, which result in emphysema and chronic obstructive lung disease.(9)... 

This patient illustrates a complicated clinical course of oq-antitrypsin deficiency. Our patient had liver disease that presented during infancy and developed into hepatic cirrhosis. He exhibited most of the complications of cirrhosis, including portal hypertension with ascites, hyperammonemia, malnutrition, and variceal hemorrhage. These complications of cirrhosis are not unique to a,-antitrypsin deficiency, but it is important to note the potential severity of the liver disease associated with this condition. 

Chronic obstructive pulmonary disease is a respiratory condition characterized by irreversible airway obstruction caused by chronic bronchitis or emphysema. The major symptoms of COPD include chronic cough, increased sputum production, and dyspnea. The vast majority of patients with COPD are those who are current or former heavy smokers. Other risk factors for the development of COPD include occupational exposure (dusts, chemicals) and rare genetic disorders (a -antitrypsin deficiency). The medical management of COPD includes pharmacotherapy (bronchodilators, corticosteroids, and antibiotics) in combination with interventions to reduce risk factors for disease progression (e.g., smoking cessation). Some patients require long-term administration of supplemental oxygen. 

Bile alcohols are polyhydroxy C27 sterols that serve as intermediates in the biosjmthesis of cholic acid and chenodeoxycholic acid from cholesterol (1, 2). Recently several studies have shown that increased amounts of bile alcohols namely 27-nor-5p-cholestane-3a,7a,12a,24, 25-pentol and 5P-cholestane-3a, 7a,12a,25,26-pentol are excreted (as glucuronides in urine of patients with liver diseases such as primary biliary cirrhosis (3), liver cirrhosis (4, 5) and a-antitrypsin deficiency (6). Ichimiya et. al., described the occurrence of 5P-cholestane-3a,7a,12a,26,27-pentol (5P-cyprinol) and 5P-cholestane-3a,7a,... 

Karlaganis, G., Nemeth, A., Hammarskjold, B., Strandvik, B. and Sjovall, J. (1982). Urinary excretion of bile alcohols in normal children and patients with a-antitrypsin deficiency during development of liver disease. Eur. J. Clin. Invest. 12 399-405. 

Cystic fibrosis a,-Antitrypsin deficiency Maple syrup urine disease... 

Conjugated hyperbilimbinemia is rare during the neonatal period. It can result from impaired hepatocellular function or extrahepatic obstmction. Hepatocellular defects can be caused by bacterial, viral, or parasitic infections, cystic fibrosis, a -antitrypsin deficiency, Dubin-Johnson and Rotor s syndromes, and other genetic disease. Extrahepatic obstruction can be congenital (biliary atresia) or acquired. 

Cirrhosis can develop in children as a result of a,-antitrypsin deficiency or Wilson s disease, and in adults due to haemochromatosis. o. -antitrypsin deficiency can be detected in newbt>m infants in whom there may be a prolonged period of jaundice for. several weeks. In some cases this progresses to juvenile cirrhosis. Haemochromatosis is a disorder of iron absorption, associated with deposition of iron in the hcpat(x ytes and... 

Editorial. (1977). Childhood liver disease with a,-antitrypsin deficiency. Lancet, 1, 82... 

At present, severe ai-antitrypsin deficiency liver disease can be successfully treated by liver transplantation. In the future, introduction of the gene for normal ttj-antitrypsin into hepatocytes may become possible, but this would not stop production of the PiZ protein. Figure 50-7 is a scheme of the causation of this disease. 

Carrell RW, Lomas DA Alphai-antitrypsin deficiency—a model for conformational diseases. N Engl J Med 2002 346 45. 

The protective antiprotease -antitrypsin (AAT) inhibits several protease enzymes, including neutrophil elastase. In the presence of unopposed AAT activity, elastase attacks elastin, which is a major component of alveolar walls. A hereditary deficiency of AAT results in an increased risk for premature development of emphysema. In the inherited disease, there is an absolute deficiency of AAT. In emphysema resulting from cigarettesmoking, the imbalance is associated with increased protease activity or reduced activity of antiproteases. Activated inflammatory cells release several other proteases, including cathepsins and metalloproteinases. In addition, oxidative stress reduces antiprotease (or protective) activity. 

Clinical consequence hemolysis (breakdown of circulating red blood cells) from antimalarials, sulfonamides, nitrofurantoin, and other drugs. a-1 Antitrypsin deficiency, due to variants in this circulating plasma protein Frequency 1 /3000 Northern European Caucasians Clinical consequence predisposition to emphysema in early middle age, especially in cigarette smokers, due to failure to protect against trypsinlike enzymes in lung... 

The severe form of alpha-1 antitrypsin deficiency is the result of a single nucleotide substitution that produces a single amino acid substitution. This is best described as a... 

Although ER protein degradation seems not be essential for yeast cells, the breakdown of mutated and thus malfolded ER proteins is often associated with severe diseases in human (Ciechanover, 1998 Plemper and Wolf, 1999). The importance of this process in the understanding of genetic disorders like cystic fibrosis and a 1-antitrypsin deficiency has been outlined above. In the following we will give further examples on how viruses or toxins may misuse the machinery for the ER protein degradation to interfere with cellular processes. 

Clinical pharmacology Alpha-1 antitrypsin deficiency is a chronic, hereditary, usually fatal, autosomal recessive disorder in which a low concentration of alphai-proteinase inhibitor is associated with slowly progressive, severe, panacinar emphysema that most often manifests itself in the third to fourth decades of fife. The pathogenesis of development of emphysema in alpha-1 antitrypsin deficiency is believed to be due to a chronic biochemical imbalance between elastase and alphai-proteinase inhibitor (the principal inhibitor of neutrophil elastase), which is deficient in alpha-1 antitrypsin disease. As a result it is believed that alveolar structures are unprotected from chronic exposure to elastase released from a chronic low-level burden of neutrophils in the lower respiratory tract, resulting in progressive degradation... 

Gene therapy holds great promise for the treatment of many diseases (e.g., cancer, AIDS, cystic fibrosis, adenosine deaminase deficiency, cardiovascular diseases, Gaucher disease, a 1-antitrypsin deficiency, rheumatoid arthritis, and several others) (1,2). Advances in genomics and molecular biology have revealed that almost all diseases have a genetic component. In some cases, such as cystic fibrosis or hemophilia,... 

Fig. 4.5.5 IEF pattern of a-1-antitrypsin. Sera from a control (lane 1), three CDG-I patients (CDG-Ia, CDG-Ic and CDG-Id lanes 2-4) and three CDG-II patients (CDG- , CDG-IId and CDG-IIx lanes 5-7) were analysed by IEF. The normal pattern (lane 1, left) reveals seven bands. In abnormal patterns (lanes 2-7, left to right), the position of the first additional abnormal cathodal band is indicated by an arrow. This band and also all bands below are abnormal and indicate a glycosylation deficiency...

Data are analysed by comparing the a-1-antitrypsin IEF patterns of patients suspected of having an altered transferrin protein backbone to healthy controls and patients with an already defined CDG. A normal pattern of a-1-antitrypsin in questionable patients indicates changes in the protein moiety of transferrin instead of a glycosylation deficiency. 

Correct answer = B. o1-Antitrypsin deficiency is a genetic disorder that can cause pulmonary emphysema even in the absence of cigarette use. An deficiency of a1-antitrypsin permits increased elastase activity to destroy elastin in the alveolar walls, even in nonsmokers. a1-antitrypsin deficiency should be suspected when chronic obstructive pulmonary disease develops in a patient younger than 45 years who does not have a history of chronic bronchitis or tobacco use, or when multiple family members develop obstructive lung disease at an early age. 

Hubbard, R.C., and R.G. Crystal. 1990. Strategies for aerosol therapy of a 1-antitrypsin deficiency by the aerosol route. Lung 168 Suppl 565-578. 

Factor deficiencies include disorders of fibrinogen such as afibrinogenemia and dysfibrinogenemias, prothrombin deficiency, factor V VII, X, XI, XII, and XIII deficiency, prekallikrein and high-molecular-weight kininogen deficiency, combined factor deficiencies, a2 anti-plasmin deficiency, a] antitrypsin Pittsburgh, and protein Z deficiency. 

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