Alpha-1 antitrypsin deficiency

Alpha‑1 antitrypsin deficiency (A1AD) is an inherited disorder characterized by low levels of a protein called alpha‑1 antitrypsin (A1AT) in the blood. This deficiency may predispose affected individuals to several diseases and most commonly manifests as chronic obstructive pulmonary disease (including bronchiectasis) and liver disease (especially cirrhosis and hepatoma), or more rarely as a skin disorder known as panniculitis. A1AD is also more frequent in individuals with Wegener’s granulomatosis, now referred to as granulomatosis with polyangiitis. 

Deficiency of A1AT allows substances that break down proteins (so‑called proteolytic enzymes) to attack various body tissues. This attack results in destructive changes in the lungs (emphysema) and may also affect the liver and skin. Alpha‑1 antitrypsin is normally released from specialized granules in a type of white blood cell (called neutrophils or polymorphonuclear leukocytes) in response to infection or inflammation. Alpha‑1 antitrypsin deficiency results in unopposed (i.e., relatively unchecked) rapid protein breakdown (protease activity), particularly in the supportive elastic structures of the lungs. Over years, this destruction can lead to progressive emphysema and is accelerated by smoking, certain occupational exposures, and probably other genetic modifiers of risk that remain incompletely understood.

Diagnosis

A1AD is caused by mutations in the SERPINA1 gene, which is responsible for the production of the alpha‑1 antitrypsin protein. This protein is normally produced in the liver and released into the bloodstream, where it functions to protect the body against the enzyme neutrophil elastase. A1AT also appears to have anti‑inflammatory effects independent of its anti‑neutrophil elastase activity. Mutations in the SERPINA1 gene lead to production of an abnormal protein that becomes trapped in the liver, resulting in low serum levels of A1AT, which may predispose the lungs to destruction by neutrophil elastase and other proteolytic enzymes (enzymes that break down proteins). In addition, the abnormal A1AT protein may accumulate in the liver and cause scarring damage. 

To date, more than 150 different mutations have been identified in the SERPINA1 gene; the most common are S and Z, while the normal version (allele) of the gene is referred to as M. The S allele causes moderately low serum levels of A1AT, and the Z allele is associated with very low serum levels of A1AT (~10–15% of normal values). Other rare variants, referred to as null variants, are associated with complete absence of A1AT in the circulation because no protein is produced.

A1AT deficiency is inherited as an autosomal codominant genetic disorder. Codominant genetic disorders occur when each inherited allele expresses some effect (such as reduced serum levels of A1AT). In general, in a codominant condition, when an individual inherits two copies of an abnormal gene for the same trait, one from each parent, the risk of disease is higher than when only one abnormal allele is inherited. Individuals who have two copies of the Z allele (ZZ) have severe A1AT deficiency and are at high risk for developing emphysema. The risk that two carrier parents will pass on the altered gene and have an affected child (ZZ) is 25% with each pregnancy, and under these circumstances the risk that the child will be a carrier like the parents is 50% with each pregnancy. Finally, the chance that a child will inherit normal genes from both parents is 25%. In autosomal conditions, the risk of inheritance is the same for males and females because the abnormal gene is not located on the sex chromosomes (X or Y). In A1AT deficiency, the SERPINA1 gene is located on the long arm of chromosome 14.

If an individual inherits one normal allele and one Z allele (MZ), the clinical risk of developing lung disease is considered low, although there may be a subgroup of these so‑called heterozygous patients who are at increased risk, particularly if they smoke. If an individual inherits one S allele and one Z allele (SZ), the risk of developing chronic obstructive pulmonary disease is also considered increased, especially in smokers.

Alpha‑1 antitrypsin deficiency most commonly occurs in North Americans or individuals of Central European origin. In the United States, approximately 100,000 people have been diagnosed with this condition. However, because most cases of A1AD are not recognized, the disorder is significantly underdiagnosed. Estimates suggest that of these estimated 100,000 individuals with severe A1AT deficiency, only 10% or fewer have been diagnosed, while the remainder either had chronic obstructive pulmonary disease (COPD) not recognized as being due to A1AD or were unaffected. Several lines of evidence indicate that A1AD is underdiagnosed:

1. Many individuals with A1AD experience substantial delays (on average 5–8 years) between the onset of symptoms (often dyspnea) and the initial diagnosis of A1AD.
2. Affected individuals often consult many physicians for A1AD‑related symptoms before the initial diagnosis is made.
3. Persistent underdiagnosis n is suggested by the fact that diagnostic delays remain long even among more recently diagnosed individuals.

The diagnosis of A1AD is based on low plasma concentrations of A1AT combined with a high‑risk phenotype (demonstrated by isoelectric focusing) or genotype (specific allele analysis, usually for the Z and S alleles and sometimes for additional alleles such as F and I and others available on commercial tests). In some cases, additional testing with A1AT gene sequencing (i.e., mapping all nucleotides that make up the A1AT gene) is required to establish a definitive diagnosis.

Because A1AD is often unrecognized, official guideline documents recommend that all individuals with fixed airflow obstruction on spirometry be tested for the disorder. In addition, all first‑degree relatives of individuals found to have severe A1AD (i.e., siblings, children, and parents), individuals with panniculitis, and individuals with unexplained liver disease or bronchiectasis should also be tested.

This disorder should be suspected when emphysema occurs in a young individual, a nonsmoker, or someone with a family history of emphysema. Suspicion of A1AD should also arise in individuals with jaundice, hepatitis, portal hypertension, hepatocellular carcinoma, or those with a family history of liver disease. As noted above, underdiagnosis may result from testing only a minority of at‑risk individuals; therefore, current testing recommendations suggest that all adults with symptomatic COPD, along with the other groups listed above, should be tested for A1AD.

Once clinical suspicion of panniculitis is raised by suggestive history and physical examination, panniculitis is diagnosed using biopsy specimens of skin lesions and blood tests to determine circulating A1AT levels and genotype.

Treatment

Treatment of emphysema associated with A1AD includes standard medications used to treat emphysema of all causes (such as inhaled bronchodilators, inhaled steroids, anticholinergics, oxygen therapy, and administration of antibiotics or phosphodiesterase‑5 inhibitors for frequent respiratory infections), as well as (in specific subgroups) A1AT‑specific therapy, known as augmentation therapy. Exercise programs (pulmonary rehabilitation) and good nutrition can help improve overall quality of daily life. It is very important for individuals with emphysema to avoid smoking, occupations that expose patients to lung irritants, and the use of non‑medical aerosol sprays. Early prevention of infection is also recommended through annual influenza vaccination and regular pneumococcal vaccination.

Specific treatment for A1AD (for individuals with established emphysema) may also include augmentation therapy, which consists of regular (usually weekly) long‑term intravenous infusion of purified, pooled human A1AT derived from human plasma into deficient individuals. Currently, six augmentation therapy products have been approved by the U.S. Food and Drug Administration: Prolastin, Aralast, Aralast NP, Zemaira, Prolastin‑C, and Glassia, of which the latter four are currently available. The best available evidence suggests that augmentation therapy may help slow the progression of lung damage due to A1AD. Augmentation therapy does not treat liver disease associated with A1AD.

In highly selected patients, lung volume reduction surgery (LVRS) or surgical removal of large confluent areas of emphysema (bullae) may be appropriate, although LVRS may provide less benefit for individuals with emphysema caused by A1AD than for individuals with emphysema without recognized genetic causes. LVRS is therefore rarely recommended for patients with A1AD.

Lung transplantation, both single and double, has been successfully performed in many patients with A1AD. This treatment option is reserved for patients with severe end‑stage lung disease who otherwise qualify as candidates for such surgery.

No specific therapy is currently available for liver disease associated with A1AD, although animal studies have shown promise for several agents that may increase the liver’s ability to degrade retained A1AT (e.g., rapamycin and carbamazepine) and have stimulated research studies in individuals with A1AD. Similarly, other approaches currently under investigation include agents that reduce production of the abnormal Z protein by liver cells, which could potentially reduce liver risk; however, much more study is required before any conclusions can be drawn regarding these research‑based approaches. At present, management of liver disease associated with A1AD focuses on symptom control. In some individuals, specialized procedures may be required, such as shunt placement to reduce pressure in hepatic blood vessels, or banding/ligation of dilated veins in the esophagus to reduce bleeding risk. Liver transplantation may be recommended for individuals with end‑stage liver disease. Transplantation of a normal liver into an individual with A1AD should correct liver abnormalities and restore blood A1AT levels to normal. However, transplantation carries risks related to the procedure itself and to immunosuppression required to prevent organ rejection.

Genetic counseling is recommended for patients and their families.

• pľúcne ochrorenie súvisiace s nedostatkom A1AD (dýchavičnosť, chronický kašeľ, tvorba hlienu, sipot, časté respiračné infekcie, problémy najmä u fajčiarov)
• ochorenie pečene spôsobené A1AD (žltý vzhľad pokožky, zväčšenie pečene, problémy s kŕmením, znížená chuť do jedla, opuch nôh alebo brucha, u dospelých cirhóza, portálna hypertenzia, chronická aktívna hepatitída, hepatocelulárny karcinóm, ospalosť)
• paniulitída - vzácna forma kožného ochorenia