Approach

The major manifestations of AAT deficiency are hepatic and pulmonary.

  • Panacinar emphysema and associated obstructive lung disease are the most common manifestations.[38][39] Evidence suggests that almost 60% of patients develop severe pulmonary disease.[24]

  • Bronchiectasis may occur. Up to 95% of patients with PI*ZZ AAT deficiency have radiological evidence of bronchiectasis (but PI*ZZ AAT deficiency has been found in <1% of patients who present with bronchiectasis).[40]

  • Liver disease usually initially presents as hepatitis and jaundice, although severe disease may progress to cirrhosis and hepatocellular carcinoma. Liver involvement may also be seen in neonates with AAT deficiency.[9][38]

  • Necrotising panniculitis and granulomatosis with polyangiitis are infrequent complications.

Evidence suggests that AAT deficiency may be under-recognised by physicians as a cause of lung and liver disease.[41] Further evidence demonstrates a significant time difference between the onset of clinical disease and diagnosis, with evaluation by multiple physicians in the interim.[42]

Guidelines recommend a high clinical suspicion and quantitative AAT measurement in the following scenarios:[6][38][43][44]

  • Airflow obstruction partially reversible or irreversible with bronchodilators

  • All patients with COPD[8][45]

  • All patients with adult-onset asthma[8]

  • A personal or family history of c-ANCA vasculitis (granulomatosis with polyangiitis is an infrequent complication of AAT deficiency)

  • Liver disease of unknown aetiology

  • Bronchiectasis of unknown aetiology, especially when co-existing with panacinar emphysema[38][40]

  • Panniculitis of unknown aetiology (necrotising panniculitis is an infrequent complication of AAT deficiency)

  • Adolescents and adults with a sibling who is AAT homozygous

  • Asymptomatic people with persistent obstructive pulmonary dysfunction who report smoking or occupational exposure.

Historical factors

Presenting symptoms of pulmonary manifestations are non-specific and may include shortness of breath, shortness of breath on exertion, fatigue, wheezing, cough, and/or chest tightness.

Presenting symptoms of hepatic manifestations are non-specific and may include yellowing of the skin, fatigue, bleeding, bruising, abdominal distension, abdominal pain, and/or confusion.

It is important to consider age, occupation, and smoking history in patients with symptomatic lung disease, as these factors may point to AAT deficiency. The greatest risk factor for emphysema in patients with the PI*ZZ phenotype is smoking. Lung function and survival are both affected.[24][46][47] However, some evidence suggests that ex-smokers and people who have never smoked have similar declines in lung function over time, and some smokers may never develop pulmonary symptoms.[42][48] Occupational or other exposure to gas, fumes, and/or dust has also been associated with decreased pulmonary function in patients with PI*ZZ AAT deficiency. This includes passive smoking and work with kerosene heaters.[49][50][51][52] There is limited evidence to suggest that symptomatic lung disease is more prevalent in PI*ZZ males than in PI*ZZ females. However, this result is likely to be confounded by other variables, such as smoking and occupational exposure.[20][21][22][23] The mean age at which smokers with AAT deficiency typically present with symptomatic pulmonary disease is 32 to 41 years.[24] Medical history may include asthma and/or granulomatosis with polyangiitis (an infrequent complication of AAT deficiency), and family history may reveal the presence of AAT deficiency in relatives.

Examination findings

General inspection may reveal jaundice, scleral icterus, and/or asterixis if liver disease is present. Abdominal examination may reveal hepatomegaly and/or ascites.

Respiratory examination may reveal wheeze and/or chest hyperinflation if pulmonary disease is present.

Serum AAT measurements

Serum AAT levels should be quantified in individuals with possible AAT deficiency.[1][8][53]​​​​​ However, AAT is an acute phase reactant, meaning that normal serum AAT levels can be misleading, especially in the setting of inflammatory processes.​[1][8]​​ Disease states may still be represented by borderline or even normal AAT levels, meaning such results warrant continued suspicion. Serum AAT measurement alone is not recommended for family testing after identification of a proband because it does not fully characterise the risk of disease from AAT deficiency.[38]

Some guidelines suggest genotyping for the S and Z allele is the appropriate first step for diagnostic testing of symptomatic individuals.[38]

Quantitative testing and protective threshold

Low to normal levels of AAT (<35 micromol/L) should increase suspicion and prompt further testing. Commercially available quantitative testing utilises radial immunodiffusion and nephelometry methods. Exact threshold values vary depending on testing method and regional guidance; appropriate regional guidelines should be consulted for interpretation of serum AAT levels.[6][8]​​​[9][10]​​​​

Serum AAT level measured using the purified standard developed by the US National Institutes of Health (the most common testing method in the US) are typically given in micromol/L, while AAT levels measured using commercial standards are typically given in mg/dL to differentiate them.[6] Nephelometry values less than 20 micromol/L (83-120 mg/dL) are considered deficient. Nephelometry levels below 11 micromol/L (50 mg/dL) are considered to confer inadequate protection against inflammatory lung disease; this is referred to as the 'protective threshold'.[7]

Some of the more common phenotypes result in the following serum AAT levels:

  • PI*MM: 20-48 micromol/L (150-350 mg/dL)

  • PI*MZ: 17-33 micromol/L (90-210 mg/dL)

  • PI*SS: 15-33 micromol/L (100-200 mg/dL)

  • PI*ZZ: 2.5-7.0 micromol/L (20-45 mg/dL).

Those resulting in levels below the protective threshold are more likely to result in pulmonary disease.

Phenotyping (PI-typing)

Phenotyping can be used when a quick decision is needed, whereas genotyping should be used for definitive diagnosis when available.[1]​ Low-normal plasma AAT measurements may correspond to heterozygous phenotypes that may place the individual and family members at risk for associated disease. Patients, and first-degree relatives of patients, with normal-low but protective AAT levels (12-35 micromol/L) should undergo qualitative testing through phenotyping.

Phenotyping involves the separation of AAT variants using isoelectric focusing, and can confirm the identification of characteristic deficient AAT-variant proteins. Phenotyping can reveal the presence of the actual protein variants, such as the Z protein, M (normal) protein, and S protein, as well as less common variants.[8][53]​​

Genotyping

Phenotyping can be used when a quick decision is needed, whereas genotyping should be used for definitive diagnosis when available.[1]​ Genetic testing may be performed when the actual phenotype does not correspond with the phenotype predicted by the serum AAT level.

It will demonstrate the characteristic AAT alleles responsible for the AAT-variant proteins.

For example, when a low-normal AAT level is detected, further testing with phenotyping is performed to determine the actual AAT protein variants in the serum. If only Z protein is detected, this does not correspond to a low-normal serum AAT level. In this case, additional testing may proceed to genotyping to determine the alleles present in the individual.

Polymerase chain reaction (PCR) is typically used for genotyping. Rare alleles (e.g., null or deficient variants other than Z or S) may require whole gene sequencing. Gene sequencing may also be considered if no primers are available for PCR.[8][10]​​​

Specific tests for respiratory disease

If respiratory disease is present, pulmonary function testing will demonstrate significantly abnormal results including reduced FEV1.

Chest x-ray may reveal large lung volumes and basilar predominant emphysema. [Figure caption and citation for the preceding image starts]: Chest x-ray of AAT deficiency (PA view)From the personal collection of D. Kyle Hogarth, MD, FCCP; used with permission [Citation ends].com.bmj.content.model.Caption@1ad5d69a[Figure caption and citation for the preceding image starts]: Chest x-ray of AAT deficiency (lateral view)From the personal collection of D. Kyle Hogarth, MD, FCCP; used with permission [Citation ends].com.bmj.content.model.Caption@3210f8e3

Patients with non-diagnostic results may require a chest computed tomography (CT) scan. CT is more sensitive than chest x-ray or pulmonary function tests for identifying panacinar emphysema and bronchiectasis.[8][40]​​​​ However, the absence of emphysematous changes on CT does not rule out AAT deficiency. Panacinar emphysema is predominantly seen in the lower lobes, although upper lobe-only disease has been described. A direct relationship between AAT deficiency and bronchiectasis is less clear as the presence of bronchiectasis on CT may be the result of emphysematous changes.[Figure caption and citation for the preceding image starts]: CT of advanced emphysema in a patient with AAT deficiencyFrom the personal collection of D. Kyle Hogarth, MD, FCCP; used with permission [Citation ends].com.bmj.content.model.Caption@4fd4bfb4

Exercise testing with arterial blood gas analysis in patients with emphysema is also usually abnormal and demonstrates exercise intolerance.[8][9]

Specific tests for hepatic disease

Guidelines recommend evaluation of liver function with liver function tests (LFTs) for those diagnosed with AAT deficiency, whether symptomatic or asymptomatic for hepatic disease.[38][53]​ Alpha-fetoprotein (AFP) levels are also important as part of any liver disease work-up. However, some data suggest that the sensitivity of LFTs, namely alanine aminotransferase (ALT), is only 11.9% in detecting liver disease in AAT deficiency.[54]

Patients with a phenotype associated with liver disease (e.g., PI*ZZ, PI*Mmalton, PI*Siiyama) require liver imaging, and liver ultrasound is recommended annually.[38] Liver ultrasound may also be used to monitor for signs of portal hypertension and hepatocellular carcinoma. Abdominal CT and/or magnetic resonance imaging (MRI) can also be helpful for assessing patients for liver morphology, cirrhosis, and portal hypertension, particularly in those with obesity.[53]​​

If hepatocellular carcinoma is present, LFTs may be worsening, and AFP levels may be rising.

As serum liver tests may sometimes yield inconclusive results, the European Association for the Study of the Liver recommends considering liver biopsy in patients with otherwise unexplained, recurrently elevated liver enzymes.[1]

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