Alpha-1 Antitrypsin Deficiency

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Gene: SERPINA1 (HGNC:8941)
• Mode(s) of Inheritance: Autosomal Recessive
• Literature Search: 08/26/2024
• Curation Status: Released (2.0.0)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
SERPINA1	alpha 1-antitrypsin deficiency (0013282)	613490	Moderate Actionability

Actionability Assertion Rationale

• The majority of the experts agreed with the assertion of moderate. It was noted that there is uncertainty regarding the penetrance of the pulmonary features of this condition in an unselected non-smoking population. In addition, it is noted that although smoking cessation is effective in slowing disease progression, non-smokers are still known to develop both the pulmonary and hepatic features of this condition.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Morbidity and mortality from lung disease / AAT augmentation therapy	2	3D	1A	2	8DA
Morbidity and mortality from lung disease / Avoidance of environmental exposures including cigarette smoke	2	3D	2C	2	9DC
Morbidity and mortality from liver disease / Surveillance by specialist to guide management including consideration of liver transplant	2	2A	3A	1	8AA

Severity of Outcome

Prevalence of the Genetic Condition

Epidemiological studies show that alpha-1 antitrypsin deficiency (AATD) is one of the most prevalent genetic disorders in humans. AATD occurs in approximately 1 in 1500 to 7000 individuals. Severe A1AT deficiency is most commonly found in individuals of European ancestry, yet it affects all ancestral subgroups worldwide. Approximately 1-2% of all individuals with chronic obstructive pulmonary disease (COPD) have AATD.

Clinical Features (Signs / symptoms)

AATD is characterized by an increased risk for development of several disorders primarily involving the lungs, liver, and, less frequently, the skin. Pulmonary involvement can include recurrent respiratory infections, chronic bronchitis, bronchiectasis, emphysema, and COPD, presenting as shortness of breath, cough, and wheezing. Liver disease can include cholestatic jaundice, hepatitis, unexplained increase in aminotransferases, hepatomegaly, fibrosis, cirrhosis, hepatocellular carcinoma, and liver failure. Skin findings can include panniculitis, granulomatosis, and C-ANCA-positive vasculitis. Other features include weight loss and fatigue.

Natural History (Important subgroups & survival / recovery)

Severity of disease depends on genotype as well as environmental exposures. Variants in SERPINA1 have been divided into four classes:

• The family of normal variants is designed PI*M

• Deficiency alleles PI*Z and PI*S

• Null alleles

• Dysfunctional alleles (Tier 4)Within the first three decades of life, liver disease is the major threat and pulmonary dysfunction is not common. Liver disease has never been reported in individuals with AATD due to homozygous null alleles. Liver disease may occur throughout a person’s life. In children, liver disease may present only transiently or may be persistent, progressing to fibrosis and cirrhosis requiring liver transplant. Cholestatic jaundice and hepatitis can be observed in some newborns, while later during childhood individuals may experience an unexplained increase in aminotransferases, hepatomegaly, or on rare occasions, cirrhosis, and liver failure. Adults may show asymptomatic changes in transaminases, cirrhosis, and hepatocellular carcinoma. Liver disease in adults may occur in the absence of a history of neonatal or childhood liver disease. Emphysema is the most common manifestation of AATD. Pulmonary disease affects males and females equally, and the approximate age of diagnosis is 40-45 years. Individuals with null alleles are at risk of the most severe form of the associated disease, including emphysema. Individuals with the Pi*ZZ genotype have a high risk of emphysema, Pi*SZ have an increased risk for emphysema, and Pi*SS is not associated with a significant risk of emphysema. Active smoking is the most important additional risk factor for the development and course of lung function deficits and COPD. Individuals with AATD who smoke develop COPD 10-20 years earlier than smokers without AATD and they have a median survival time approximately 15 years less than individuals with AATD who are not smokers. Lung disease progression is more rapid than in non-AATP patients with COPD. However, smoking cessation can “normalize” this progression to that of AATD in never-smokers. Mortality in individuals with AATD results primarily from respiratory diseases, followed by liver complications. Reported standardized mortality ratios vary from 3.6 to 6.3 compared with the general population.

Likelihood of Outcome

Mode of Inheritance

Autosomal Recessive

Prevalence of Genetic Variants

>1-2 in 100

Worldwide the prevalence of PI*ZZ genotype is 0.003%, prevalence of PI*SZ genotype is 0.02%, and PI*SS genotype is 0.08%.

Tier 3

>1-2 in 100

Over 90% of individuals with AATD have the PI*ZZ genotype. However, there are hundreds of rare and ultra-rare genotypes that result in AATD. Worldwide it has been estimated that there are 3.4 million individuals with deficiency allele combinations (PI*ZZ, PI*SZ, or PI*SS genotypes), and ≥116 million carriers of deficiency alleles (PI*MZ and PI*MS). The null allele occurs in a frequency of 0.00017.

Tier 3

Unknown

The PI*Z allele is most common in northern Europe and nearly absent among Africans and Eastern populations. AATD is always associated with non-PI*Z alleles in Asian populations.

Tier 3

>1-2 in 100

Among 15,484 ethnically diverse individuals screened for AATD carrier status, 1,178 carriers (7.6%) were identified, for an estimated carrier frequency of approximately 1 in 13.

Tier 3

Penetrance (Includes any high-risk racial or ethnic subgroups)

>= 40 %

A systematic review of disease burden in AATD included 38 studies with sample sizes ranging from 19 to 422,506 individuals. Mean age ranged from 39.9 to 69.6 years across 29 studies. Data on smoking status were reported in 17 studies; in 15 of these, most individuals were current or former smokers (52-84%). PI*ZZ was the most identified genotype, and was the only genotype identified in 10 studies. Pulmonary morbidity was commonly reported, and included COPD with a prevalence of 36.3-75.8%, emphysema (14.4-53.8%), and bronchiectasis (3.8-73.1%). Liver fibrosis was the most reported hepatic morbidity, with a wide variation in prevalence (1-88%) in those with AATD. Advanced liver fibrosis was reported in 0.5-25.6% and cirrhosis was seen in 4-11%. Panniculitis was reported in <1-8.6% of individuals with AATD across three studies.

Tier 1

5-39 %

A systematic review and meta-analysis of liver fibrosis prevalence in adults with AATD included 5 studies with a total of 1,359 individuals. In PI*ZZ individuals, the pooled prevalence of significant liver fibrosis (≥F2) was 22.1% and advanced fibrosis (F3-F4) was 8.13%.

Tier 1

>= 40 %

A systematic review of liver disease in AATD included 28 papers with a total of 1536 children under the age of 16 years. Most included children had PI*ZZ genotype (75.1%). Seven papers with a total of 626 participants reported the outcomes of adult populations. About half (55.1%) had PI*ZZ genotype. Reported prevalences were:

Pediatric studies

• Liver transplant 16.5%

• Cirrhosis 7.5%

• Portal hypertension 6.9%

• Jaundice 1.9%

• Abnormal LFTs/prolonged PT 9.0%

• Hepatocellular carcinoma 0.0%

Adult studies

• Liver transplant 14.7%

• Cirrhosis 10.5%

• Portal hypertension 3.4%

• Jaundice Not reported

• Abnormal LFTs/prolonged PT 3.6%

• Hepatocellular carcinoma 1.3%

Tier 1

>= 40 %

Risk of emphysema by genotype:

PI*ZZ: 80-100%

PI*SZ: 20-50%

PI*SS: Background

Null-Null: 100%

Tier 3

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown

No relative risk estimates were found.

Expressivity

The clinical impact of AATD is highly variable. Individuals with lung disease vary in presentation and subsequent decline. Heterogeneity in lung disease is only partly explained by exposure to known risk factors, such as cigarette smoke.

Tier 2

The spectrum of AATD-related disorders and their ages of onset are quite broad.

Tier 3

Phenotypic expression varies within and between families. Variable disease expressivity in individuals with the PI*ZZ genotype suggests the existence of other as-yet unidentified genetic disease modifiers.

Tier 4

Intervention Effectiveness

Patient Management

Individuals with AATD should be referred to a pulmonologist/specialist center for management of treatment.

Tier 2

The initial assessment of an individual with AATD should begin with a medical history and physical exam with special focus on pulmonary, liver and skin disease. The initial assessment should include spirometry, pulmonary volumes, carbon monoxide diffusion capacity (DLCO), arterial blood gas analysis, and 6-minute walk test. Chest X-ray should be carried out during the initial assessment. High-resolution CT of the chest is recommended, if available, for detecting and quantifying the presence of emphysema.

Tier 2

Pneumococcal vaccination and annual influenza vaccinations are recommended.

Tier 2

Recommendations on the use of augmentation therapy in individuals with AATD are conflicting. One guideline does not recommend augmentation therapy for AATD. Other guidelines recommend discussion of augmentation therapy if individuals meet specific criteria, which vary by guideline. Criteria for augmentation therapy include age (aged 18 or older), severity of AATD (AAT concentration ≤50-57 mg/dl), smoking status (non-smokers or ex-smokers), documented COPD due to emphysema, genotype (PI*ZZ or null alleles, some guidelines also recommend therapy for Pi*SZ genotype), forced expiratory volume (FEV1) predicted value, and no immunoglobulin A deficiency. Augmentation therapy is only indicated in individuals with pulmonary involvement. One guideline also recommends augmentation therapy for individuals with necrotizing panniculitis. Serum immunoglobulin tests are recommended to identify immunoglobulin A deficiency before initiating therapy.

Tier 2

Two systematic reviews on the effectiveness of augmentation therapy were found.

• One meta-analysis included five studies (one randomized controlled trial, four nonrandomized studies) with a total of 1509 individuals with AATD on augmentation therapy. Among all individuals, augmentation was associated with a 23% slow decline in FEV1. The protective effect of augmentation was primarily attributable to the subset of individuals with baseline FEV1 of 30 to 65% of predicted. Statistically significant effects could not be demonstrated in the subsets with baseline FEV1 <30% or >65% of predicted. (Tier 1)

• A systematic review and meta-analysis on treatment of lung disease in AATD included three randomized controlled trials of augmentation therapy with a total of 320 adult participants conducted over two to three years. Annual deterioration in lung density on CT was less on augmentation (p=0.002), demonstrating a slower rate of emphysema progression. There was no significant difference in annual FEV1% predicted decline or DLCO. There was a small, statistically significant increase in annual exacerbations on treatment (p=0.02). Small and nonsignificant changes in health status were observed in both groups. Mortality data were reported by one trial with one death on treatment and three on placebo. The systematic review also included six observational studies with a total of 2,610 participants. The largest observational study analyzed data from 1,129 individuals. Overall mortality was 18.1%; it was significantly higher for individuals who never received augmentation therapy, as opposed to sometimes or always (p<0.001). All studies that reported FEV1 data demonstrated a statistically significant slow in FEV1 decline after starting augmentation, though this was not seen in individuals with FEV1 <30% predicted.

Tier 1

Vaccination against hepatitis A and B is recommended.

Tier 3

In the therapeutic approach of patients with emphysema due to AATD, international COPD recommendations should be followed for smoking cessation, symptomatic treatment, referral to rehabilitation programs, exercise, diet, and vaccination.

Tier 2

All individuals with alleles leading to AAT accumulation in the liver must undergo an initial assessment of liver changes by abdominal ultrasound (or Fibroscan) and serum tests. The serum liver assessment should include transaminases (AST and ALT), alkaline phosphatase, GGT, bilirubin, albumin, coagulation tests, platelets, fat soluble enzymes, and alpha-fetoprotein.

Tier 2

Liver transplant is the only effective treatment for severe liver disease due to AATD.

Tier 4

A systematic review identified 12 studies (6 pediatric, 6 pediatric and adult) of liver transplant as a treatment for AATD. The studies included 425 children who underwent liver transplantation for AATD. Genotypes were reported in 297 children; 95.6% were Pi*ZZ. The median ages ranged from 1.9 to 6 years (range 1-17 years). Outcomes following liver transplantation were reported in 8 studies. Five-year survival ranged from 74% from transplant data in the 1980s to 92% in two studies published since 2000. Most studies report an excellent quality of life in survivors, with no recurrence of AATD in the liver, no pulmonary complications, and favorable outcomes compared with other indications for liver transplantation. The studies included 656 adults who underwent liver transplantation for AATD. Genotypes were reported in 130 participants and were Pi*ZZ in 73.8% and Pi*SZ in 18.5%. Median ages ranged from 34 to 54 years. Outcomes following liver transplantation were included in four studies. Five-year survival was 80% in the most recent study published in 2013. Survivors report an excellent quality of life and had no recurrence of liver or lung disease.

Tier 1

Surveillance

A respiratory functional assessment is suggested at the end of adolescence and afterwards at 2-to-3-year intervals. Respiratory monitoring should include spirometry with bronchodilator test every year, annual plethysmography and carbon monoxide diffusion capacity, and chest CT repeatedly as per medical indication.

Tier 2

Liver monitoring should include physical examination including focused exam for signs of liver disease, laboratory assessment and abdominal ultrasound every 6 to 12 months (or more frequently as clinically indicated). The serum liver assessment should include transaminases (AST and ALT), alkaline phosphatase, GGT, bilirubin, albumin, coagulation tests, platelets, fat soluble enzymes, and alpha-fetoprotein.

Tier 2

Circumstances to Avoid

Every effort should be made to prevent exposure to tobacco smoke. Exposure to passive smoking is a serious problem negatively affecting pulmonary function in pediatric patients with AATD. Educational programs whose purpose is to eliminate passive exposure to tobacco smoke play an important role.

Tier 2

Ensure smoking is stopped if the patient is a smoker.

Tier 2

One study compared quit attempts between adult smokers who tested negative and positive for AATD (n=199 participants, 9% with AATD). Smokers with AATD were significantly more likely to report a 24-hour quit attempt than those without AATD (59% vs. 26%). However, there were no differences in actual abstinence at 3 months.

Tier 3

In an AATD registry study 25 respondents with AATD were smokers at the time of diagnosis, with a subsequent reported quit rate of 92% (23/25).

Tier 5

One study identified 61 children with AATD on neonatal screening and followed them and a control group through age 18-20 years to assess smoking habits. There was no difference in parental smoking between the groups. Rates of smoking were significantly lower in young adults with AATD (88% never smoked) than controls (65% never smoked, p<0.05).

Tier 3

In a cohort of 482 individuals with AATD not receiving augmentation therapy 79.2% of individuals with COPD were current or past smokers. Individuals without COPD were more likely to have never smoked (p<0.0001). Smoking cessation can “normalize” progression to that of never smokers. For the 87 individuals without established COPD, there was no significant difference in decline rate in FEV1 between never and ex-smokers.

Tier 3

Individuals with AATD should avoid exposure to inhaled irritants, in the workplace and at home.

Tier 2

Occupational exposures including exposure to environmental pollutants used in agriculture, mineral dust, gas, and fumes should be avoided.

Tier 4

Excessive use of alcohol should be avoided.

Tier 4

A systematic review of AATD-associated liver disease reported that increased alcohol intake has not consistently been shown to be a risk factor or cofactor for development of liver disease in AATD.

Tier 1

Nature of Intervention

Nature of Intervention

Interventions consist of avoidance of smoking and environmental irritants, vaccines to prevent lung and liver infection, non-invasive lung function tests, and imaging procedures. Augmentation therapy consists of lifelong, weekly administration of an intravenous infusion of purified human AAT extracted from a pool of donor plasma. Augmentation therapy is generally safe and well tolerated, with very few adverse effects. In a study of 443 treated individuals over six years the following adverse reactions were noted, nausea and vomiting (4.7%), hives (4.1%), fever (3.8%), dyspnea (3.8%) and anaphylactic reaction (0.9%). In another study of 747 treated individuals over seven years the following adverse reactions were noted, headaches (47%), dizziness (17%), nausea (9%), and dyspnea (9%). The main limitation for this therapy is the very high cost and lack of availability in many countries. Liver transplant is the only effective treatment for severe liver disease due to AATD.

Context: Adult Pediatric

Chance to Escape Clinical Detection

AATD remains widely and persistently under-diagnosed and misdiagnosed by healthcare providers. This disease is often misdiagnosed as asthma, COPD, or cryptogenic liver disease. Many individuals with AATD remain undiagnosed either because of a lack of clinical manifestation of their deficiency or through being unrecognized by their treating physicians.

Context: Adult Pediatric

Tier 4

A five to eight-year delay between the onset of the first symptom and the recognition of AATD has been found in studies performed over a time span of 18 years. Diagnostic delay is associated with worsened clinical status at the time of initial diagnosis.

Context: Adult Pediatric

Tier 3

It has been reported, based upon allelic frequencies, that less than 10% of individuals with AATD are diagnosed.

Context: Adult Pediatric

Tier 3

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			SERPINA1			613490	0013282

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