Alpha-1 antitrypsin deficiency

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Alpha-1 antitrypsin deficiency
Other namesα1-antitrypsin deficiency
intravenous infusions of A1AT protein[2]
PrognosisLife expectancy ~50 years (smokers), nearly normal (non-smokers)[3]
Frequency1 in 2,500 (Europeans)[1]

Alpha-1 antitrypsin deficiency (A1AD or AATD) is a

lung infections.[1][2] Complications may include chronic obstructive pulmonary disease (COPD), cirrhosis, neonatal jaundice, or panniculitis.[1]

A1AD is due to a mutation in the

genetic tests.[2]

Treatment of lung disease may include

pneumococcus, and hepatitis is also recommended.[2] Life expectancy among those who smoke is 50 years while among those who do not smoke it is almost normal.[3]

The condition affects about 1 in 2,500 people of European descent.

Asians it is uncommon.[1] About 3% of people with COPD are believed to have the condition.[5] Alpha-1 antitrypsin deficiency was first described in the 1960s.[6]

Signs and symptoms

Individuals with A1AD may develop

shortness of breath (on exertion and later at rest), wheezing, and sputum production. Symptoms may resemble recurrent respiratory infections or asthma.[8]

A1AD may cause several manifestations associated with liver disease, which include impaired liver function and cirrhosis. In newborns, alpha-1 antitrypsin deficiency can result in early onset jaundice followed by prolonged jaundice. Between 3% and 5% of children with ZZ mutations develop life-threatening liver disease, including liver failure.[9] A1AD is a leading reason for liver transplantation in newborns.[9] In newborns and children, A1AD may cause jaundice, poor feeding, poor weight gain, hepatomegaly and splenomegaly.[9]

Conditions associated with alpha-1 antitrypsin deficiency, occurring due to paucity of AAT in circulation allowing uninhibited inflammation in lungs, and accumulation of mutated AAT in the liver

Apart from COPD and chronic liver disease, α1-antitrypsin deficiency has been associated with necrotizing panniculitis (a skin condition) and with granulomatosis with polyangiitis in which inflammation of the blood vessels may affect a number of organs but predominantly the lungs and the kidneys.[10]

Genetics

Serpin peptidase inhibitor, clade A, member 1 (SERPINA1) is the gene that encodes the protein alpha-1 antitrypsin. SERPINA1 has been localized to chromosome 14q32. Over 75 mutations of the SERPINA1 gene have been identified, many with clinically significant effects.[11] The most common cause of severe deficiency, PiZ, is a single base-pair substitution leading to a glutamic acid to lysine mutation at position 342 (dbSNP: rs28929474), while PiS is caused by a glutamic acid to valine mutation at position 264 (dbSNP: rs17580). Other rarer forms have been described [citation needed].

Pathophysiology

Photomicrograph of a liver biopsy from a patient with alpha-1 antitrypsin deficiency. The PAS with diastase stain shows the diastase-resistant pink globules that are characteristic of this disease.
See also: Alpha-1 antitrypsin

A1AT is a glycoprotein mainly produced in the

hypersecretion of mucus that can develop into chronic bronchitis.[15] Both conditions are the makeup of chronic obstructive pulmonary disease (COPD).[16]

Normal blood levels of alpha-1 antitrypsin may vary with analytical method but are typically around 1.0-2.7 g/L.

oxidizing essential methionine residues to sulfoxide forms, decreasing the enzyme activity by a factor of 2,000.[citation needed
]

With A1AT deficiency, the pathogenesis of the lung disease is different from that of the liver disease, which is caused by the accumulation of abnormal A1AT proteins in the liver, resulting in liver damage.

incomplete penetrance), despite the presence of accumulated mutated protein in the liver.[9] Therefore, additional factors (environmental, genetic, etc.) likely influence whether liver disease develops.[9]

Diagnosis

Emphysema due to alpha-1 antitrypsin deficiency
Computed tomography of the lung showing emphysema and bullae
in the lower lobes of a subject with type ZZ alpha-1 antitrypsin deficiency. There is also increased lung density in areas with compression of lung tissue by the bullae.

The gold standard of diagnosis for A1AD consists of blood tests to determine the phenotype of the AAT protein or genotype analysis of DNA.[9] Liver biopsy is the gold standard for determining the extent of hepatic fibrosis and assessing for the presence of cirrhosis.[9]

A1AT deficiency remains undiagnosed in many patients. Patients are usually labeled as having COPD without an underlying cause. It is estimated that about 1% of all COPD patients actually have an A1AT deficiency. Testing is recommended in those with COPD, unexplained liver disease, unexplained bronchiectasis, granulomatosis with polyangiitis or necrotizing panniculitis.[10] American guidelines recommend that all people with COPD are tested,[10] whereas British guidelines recommend this only in people who develop COPD at a young age with a limited smoking history or with a family history.[19] The initial test performed is serum A1AT level. A low level of A1AT confirms the diagnosis and further assessment with A1AT protein phenotyping and A1AT genotyping should be carried out subsequently.[11]

As

immunoturbidimetric method. Thus, protein electrophoresis is useful for screening and identifying individuals likely to have a deficiency. A1AT is further analyzed by isoelectric focusing (IEF) in the pH range 4.5-5.5, where the protein migrates in a gel according to its isoelectric point
or charge in a pH gradient. Normal A1AT is termed M, as it migrates toward the center of such an IEF gel. Other variants are less functional and are termed A-L and N-Z, dependent on whether they run
heterozygote with two different copies of the gene may have two different bands showing on electrofocusing, although a heterozygote with one null mutant that abolishes expression of the gene will only show one band. In blood test results, the IEF results are notated as, e.g., PiMM, where Pi stands for protease inhibitor and "MM" is the banding pattern of that person.[citation needed
]

Other detection methods include use of

enzyme-linked-immuno-sorbent-assays in vitro and radial immunodiffusion
. Alpha-1 antitrypsin levels in the blood depend on the genotype. Some mutant forms fail to fold properly and are, thus, targeted for destruction in the
polymerize, thereafter being retained in the endoplasmic reticulum. The serum levels of some of the common genotypes are:[citation needed
]

  • PiMM: 100% (normal)
  • PiMS: 80% of normal serum level of A1AT
  • PiSS: 60% of normal serum level of A1AT
  • PiMZ: 60% of normal serum level of A1AT
  • PiSZ: 40% of normal serum level of A1AT
  • PiZZ: 10–15% (severe alpha-1 antitrypsin deficiency)

Treatment

Main article: Alpha-1 antitrypsin § Medical use

Treatment of lung disease may include

pneumococcus, and hepatitis is also recommended.[2]

People with lung disease due to A1AD may receive intravenous infusions of alpha-1 antitrypsin, derived from donated human plasma. This augmentation therapy is thought to arrest the course of the disease and halt any further damage to the lungs. Long-term studies of the effectiveness of A1AT replacement therapy are not available.[20] It is currently recommended that patients begin augmentation therapy only after the onset of emphysema symptoms.[11] As of 2015 there were four IV augmentation therapy manufacturers in the United States, Canada, and several European countries. IV therapies are the standard mode of augmentation therapy delivery.[citation needed]

Liver disease due to A1AD does not include any specific treatment, beyond routine care for chronic liver disease.

Nonsteroidal antiinflammatory drugs (NSAIDs) should also be avoided, as these medications may worsen liver disease in general, and may particularly accelerate the liver injury associated with A1AD.[9] Augmentation therapy is not appropriate for people with liver disease. If progressive liver failure or decompensated cirrhosis develop, then liver transplantation may be necessary.[9]

Epidemiology

Distribution of PiZZ in Europe

People of Northern

homozygous.[citation needed
]

Another study detected a frequency of 1 in 1550 individuals.[21] The highest prevalence of the PiZZ variant was recorded in the northern and western European countries with mean gene frequency of 0.0140.[21] Worldwide, an estimated 1.1 million people have A1AT deficiency and roughly 116 million are carriers of mutations.[21]

A1AD is one of the most common genetic diseases worldwide and the second most common metabolic disease affecting the liver.[22]

History

A1AD was discovered in 1963 by

University of Lund in Sweden.[23]
Laurell, along with a medical resident, Sten Eriksson, made the discovery after noting the absence of the α1 band on protein electrophoresis in five of 1500 samples; three of the five patients were found to have developed emphysema at a young age.[citation needed]

The link with liver disease was made six years later, when Harvey Sharp et al. described A1AD in the context of liver disease.[24]

Research

Recombinant and inhaled forms of A1AT treatment are being studied.[25]

References

  1. ^ a b c d e f g h i j k l m n o p q "alpha-1 antitrypsin deficiency". Genetics Home Reference. January 2013. Retrieved 12 December 2017.
  2. ^ a b c d e f g h i j k l m n "Alpha-1 antitrypsin deficiency". GARD. 2016. Retrieved 12 December 2017.
  3. ^
    ISBN 9780199556373
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  4. PMID 28364818
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  5. ^
    PMID 22536580.{{cite journal}}: CS1 maint: numeric names: authors list (link
    )
  6. ISBN 9781848151154
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  7. ^
    ISBN 978-0-7216-0187-8
    .
  8. ^ Vestbo J (2013). "Diagnosis and Assessment" (PDF). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. Global Initiative for Chronic Obstructive Lung Disease. pp. 9–17. Archived from the original (PDF) on 28 March 2016. Retrieved 9 August 2019.
  9. ^
    S2CID 52883809
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  10. ^
    PMID 28848891
    .
  11. ^
    PMID 19553648
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  12. PMID 3260605
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  13. S2CID 53017522
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  14. ISBN 9780123740014
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  15. PMID 21147616
    .
  16. ^ "Emphysema". Mayo Clinic. Mayo Foundation for Medical Education and Research (MFMER). Retrieved 16 November 2021.
  17. PMID 22912357
    . Retrieved 17 January 2014.
  18. PMID 29446109
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  19. ^ "Chronic obstructive pulmonary disease in over 16s: diagnosis and management". www.nice.org.uk. National Institute for Health and Care Excellence. December 2018. Retrieved 11 August 2019.
  20. PMID 27644166
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  21. ^
    PMID 14760160
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  22. ISBN 978-0323609623
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  23. doi:10.1080/00365516309051324
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  24. PMID 4182334
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  25. PMID 38112023
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External links

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