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Alpha-1-antitrypsin deficiency

Rare disease and only 5-10% of patients are identified.

Underdiagnosed.

Because the clinical process is indistinguishable from nonhereditary emphysema the diagnosis remains undiagnosed in approximately 90% of cases, with an interval of 5-7 years from the onset of symptoms to diagnosis.

All patients with COPD, liver disease, poorly responsive asthma, ANCA vasculitis, panniculitis, or bronchiectasis, and first- degree relatives of patients with AAT deficiency should be tested.

Predisposes to early-onset emphysema, chronic liver disease, panniculitis and vasculitis.

Clinical findings are of classic lung disease of early onset obstructed process in persons with moderate cigarette consumption and panacinar  emphysema affecting mainly the lower lobes of the lungs.

Up to 37% of patients with severe AAT deficiency have predominately upper lobe involvement, with bronchiectasis as a common x-ray findings.

1 in 3,500 live births with 100,000 severely deficient Americans.

 

One of the most common genetic diseases.

 

Most patients carry two copies of the wild type M allele of SERPINA1, which encodes AAT and have normal circulating levels of the protein.

AAT deficiency is often diagnosed late, at a point when lung disease has become irreversible.

 

95% of severe cases of AAT  deficiency result from the homozygous substitution of a single amino acid, GLU342Lys, which is present in one and 25 persons of European dissent.

 

With a mild AA deficiency amino acid GLU 264Val is  found in one and four persons in the Iberian Peninsula.

Prevalence in the US is reported to be one in 5097 individuals and is responsible for one-2% of COPD cases.

In diagnosing AAT deficiency measurement of the level of AAT in serum is performed.

AAT measurement is accompanied by a CRP level, since AAT is an acute phase reactant that increases during infection or inflammation.

A serum level higher than or equal to 1.1 g/L in the presence of a normal CRP is evidence of a normal AAT  status.

Phenotyping and genotyping along with gene sequencing can be performed when questions exist for the diagnosis.

For severe AAT deficiency, the average age a diagnosis is 46 years, but the main forced expiratory volume in one second (FEV1) and diffusing capacity of the lungs for carbon monoxide were 47% and 50% of the predicted value, respectively.

Early diagnosis can allow lifestyle changes, reduce occupational risk, provide access to new therapy, whereas delayed diagnosis is associated with poor functional status.

Smoking cessation is essential for all forms of AAT deficiency.

AAT deficiency inherited of two severe deficiency alleles at the locus alpha1 antitrypsin.

Serum level of less than 11 µmol per liter (60 mg/dL) establishes the deficiency.

Alpha 1 antitrypsin predominantly synthesized in the liver.

Clinical manifestations of lung disease associated with AAT deficiency or mainly indistinguishable from those of non-hereditary emphysema.

With AAT deficiency the number of neutrophils is increased, protease activities is unopposed, and susceptibility to infection and structural damage developed.

AAT Is synthesized within the endoplasmic reticulum and secreted to the Golgi apparatus.

AAT  levels can rise by 100% in persons with a normal proteinase inhibitor genotype (MM) during the acute phase response, but the increase is markedly attenuated in patients with severe deficiency alleles.

 

AAT is synthesized within the hepatocytes, intestinal and pulmonary alveolar cells, neutrophils, macrophages, and the cornea.

AAT Inhibits neutrophil elastase which when unopposed can cleave many of the structural proteins of the lung  as well as innate immune proteins.

In the classic loss of function concept, the Z form of AAT fails to reach the lungs in insufficient quantities and takes longer to inhibit elastase.

Oxidants in cigarettes smoke can further incapacitate Z AAT by oxidizing its active site methionine sand increasing polymerization, both of which render it unable to inhibit neutrophil elastase.

Smoking in AAY deficiency contributes to earlier and more severe lung disease.

The liver produces approximately 34 mg of a 80 per kilogram of body weight per day.

 

It has a normal plasma level of 0.9 to 1.75 mg/mL and has a half-life of 3-5 days.

Lung disease and liver disease are the most prominent disorders with AA6 deficiency, but in patients with PI ZZ  genotype neutrophilic panniculitis with painful subcutaneous nodules and neutrophil infiltrates in the subcutis occurs in less than 1%.

Are the conditions with PI ZZ  genotype include ANCA associated vasculitis, chronic kidney disease, diabetes, metabolic alterations, decreased serum triglycerides and very low density lipoproteins.

 

Alpha 1 antitrypsin is a protease inhibitor produced by the liver to protect the lung from proteolytic damage caused by neutrophil elastase.

 

Point mutations can lead to AAT accumulation in the liver and cause liver damage through a toxic gain of function process.

 

The lack of a circulating protease inhibitor predisposes homozygotes with severe deficiency to early on set emphysema.

 

Genetic variants suggest the AAT mutations confer advantage by amplification of inflammatory responses to invasive respiratory and gastrointestinal infection.

And inherited mutation in the alpha1-anti-trypsin protease inhibitor of the proteolytic enzyme elastase, with an increased risk of pulmonary and hepatic disease.

Patients commonly present in the fourth or fifth decade of life with symptoms of dyspnea and cough with or without sputum production.

Patient commonly present with symptoms of dyspnea and cough with or without sputum production, and the process may also involve other organs and present with liver cirrhosis, panniculitis, or granulomatous with polyangitis.

Classically associated with a panlobular emphysema disproportionately affecting the lung bases, in contrast to COPD related to tobacco smoke, which typically affects the upper lobes.

Secreted into the circulation from the liver.

Controls tissue degradation by the enzyme neutrophil elastase.

Relatively common in individuals of European origin.

Incidence in white newborns similar to that of cystic fibrosis.

Highly effective inhibitor of neutrophil elastase.

AAT is a serine protease inhibitor encoded by SERPINA1(PI).

The risk of emphysema increases as the imbalance of AAT levels and elastase increases.

Genotypes include M which is normal, Z or S.

MM, normal patients do not have an increased risk of emphysema

Heterozygotes individuals MZ or SZ, especially smokers are at slightly increased risk of the disease.

Homozygous ZZ is the most common genotype in those with emphysema due to alpha-1 antitrypsin deficiency, and are at high risk for lung disease, but still have detectable enzyme.

Null genotype is associated with out detectable alpha anti-trypsin proteins in the plasma, and such patients are at the highest risk of emphysema.

Most patients with alpha1-antitrypsin inherit two copies of the PI Z allele.

Patients who inherit one of the heterogeneous group of PI null alleles, result in the absence of antitrypsin production.

Patients with PI Znull heterozygotes are not distinguished from those homozygous for PI Z allele on the basis of antitrypsin levels or protein phenotype.

Z deficiency allele PI Z of SERPINA1, which encodes the serine protease inhibitor (PI) alpha1-antitrypsin causes formation of intrahepatic inclusions responsible for the development of cirrhosis.

Z deficiency allele occurs in 4% of white individuals in Northern Europe, and 1 in 2500 are homozygous for the allele.

Associated with protean clinical manifestations such as emphysema, cirrhosis, hepatoma and panniculitis.

Approximately 3% of all patients with chronic obstructive pulmonary disease have this entity.

Approximately 100,000 Americans have severe disease.

Suggested prevalence estimates of one per 1600 to 1 per 5000 individuals with severe deficient variant phenotype.

Less than 10% of patients with severe disease have been clinically recognized.

It is presumed that the Z. variant originated in northern Europe and the PI*ZZ phenotype is several times more common among Swedish individuals than among Americans.

Can occur in all ethnic groups.

Testing for this entity is encouraged in symptomatic patients with emphysema, COPD, or asthma with air flow obstruction, and it is incompletely reversible after aggressive bronchodilator treatment, individuals with unexplained liver disease, and in asymptomatic patients with persistent obstruction identified by pulmonary function tests without associated identifiable factors such as occupational exposure with cigarette smoking, and adults with necrotizing panniculitis and siblings of individuals with this process.

Most patients with severe disease have a component of reversible airflow obstruction, as demonstrated by post-bronchodilator serial testing.

Patients with severe disease may experience long diagnostic delays between their first symptom and the diagnosis, which may be as long as 5 to 7 years.

Prior to diagnosis patients with PII*ZZ disease have seen at least six physicians for the diagnosis is met, and 44% reported seeing at least three physicians before the initial diagnosis.

Cigarette smoking accelerates the mean rate of lung function decreases in individuals with severe disease.

In the National Heart, Lung, and Blood Institute Registry for individuals with severe deficiency of AAT, and the mean annual rate of forced expiratory volume in one second (FEV1) decrease was higher in active smokers than in never smokers or former smokers.

The mean rate of decrease of lung function with severe disease in patients who have never smoked, exceeds the expected rate of age-related decrease in FEV1, which is approximately 30 mL/y

In active smokers, the mean yearly decrease in the FEV1 is 109 mL and in the severe patients that never smoked or were former cigarette smokers the mean yearly decrease was 54 mL.

Radiographic evidence on plain chest x-ray nearly always shows basilar involvement.

In only 20% of patients with lung-affected disease are the upper lobes spared.

Basilar predominant patterns occur in approximately 2/3 of patients, but upper lobe predominant disease is seen in approximately 1/3 of individuals with this process.

Therefore to suspect this entity would only be present if the lower lobe predominant pattern is present, will cause a missed diagnosis in greater than 70% of cases.

Testing for alpha1 antitrypsin deficiency should be considered when symptoms of emphysema occur in patients less than 50 years of age, when there is a rapid decline in FEV1, or where there is a strong family history of COPD or liver cirrhosis.

Only curative management for alpha1-antitrypsin deficiency with severe liver disease is liver transplantation.

Liver disease is associated with accumulation of mutant AAT within hepatocytes and is exacerbated by secondary factors such as fat and alcohol.

Patients with AAT deficiency should maintain a normal body mass index and consume alcohol in limited amounts. 

Treatment for lung disease associated with AAT is the same as treatment for COPD.

Disease specific therapy for AAT deficiency is intravenous augmentation therapy with plasma-purified AAT.

Such therapy decreases the loss of lung density but no effects on other measures such as FEV1, quality-of-life or exacerbation of COPD.

The most common deficient alleles are Z and S.

A serum level of 50 mg per deciliter or less indicates that the diagnosis of alpha-1 antitrypsin deficiency.

Elevated alpha 1-anti trypsin levels in stool is a marker for protein loss.

Specific therapy for severe disease called intravenous augmentation implies the regular intravenous infusion of purified, pooled human plasma AAT.

In observational studies, augmentation therapy can slow the rate of FEV1 decrease.

Once weekly intravenous augmentation therapy is recommended.

Once weekly, 60 mg per kilogram dose is recommended for pooled human plasma AAT.

Intravenous augmentation with alpha-1 antitrypsin is associated with decreased rate of decline in lung function, especially in patients with the baseline FEV one in the moderate to severe range.

Single lung transplant can improve the quality of life and survival in selected patients with severe COPD but does not prevent progression of native lung disease.

Smoking cessation is encouraged to slow disease progression and improve survival.

Patients with AAT deficiency should be managed with spirometry, a six minute walk test, and quality-of-life questionnaires.

Patient with MZ and SZ  heterozygotes who did not smoke do not have an increased risk of lung disease, but those who do smoke have a significant increase risk as compared with relatives who are PI MM carriers.

All PI ZZ  carriers should be monitored for liver disease.

 

 

 

 

 

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