Alpha 1 Antitrypsin Deficiency

Alpha 1 antitrypsin deficiency or α1-antitrypsin deficiency is an inherited disorder that may cause lung disease and liver disease.

The signs and symptoms of the condition and the age at which they appear vary among individuals. It is an autosomal-codominant condition with more than 120 alleles identified. Out of them, PiZZ is responsible for nearly all cases of alpha 1 antitrypsin deficiency causing emphysema and liver disease.

It is one of the most common inherited disorders among white people. The median time between the observation of symptoms and diagnosis is approximately 8 years.

Alpha 1 antitrypsin deficiency has been identified in all populations, but it is most common in individuals of Northern Europe. About 1-5% of patients diagnosed as chronic obstructive pulmonary disease are estimated to have alpha 1 antitrypsin deficiency.

Women and men are affected in equal numbers with this disease.

It was first described by Laurell and Eriksson in 1963.

The condition is often underdiagnosed because its presentation is similar to other respiratory illnesses.

Pathophysiology of Alpha 1 Antitrypsin Deficiency

Alpha1-antitrypsin is the prototype member of the serine protease inhibitor superfamily of proteins. Alpha1 antitrypsin deficiency is caused by mutations in the SERPINA1 gene located in the long arm of chromosome 14.

Alpha 1 antitrypsin is produced in the liver. One of the functions of this enzyme is to protect the lungs from neutrophil elastase, an enzyme that can digest connective tissue. It also causes inhibition of several neutrophil-derived proteases like trypsin, elastase, proteinase 3, cathepsin G. [Therefore, alpha 1-antiprotease is a better term]

The genetic defect alters the configuration of the alpha 1-antitrypsin molecule and prevents its release from hepatocytes resulting in a decrease in serum levels of alpha 1-antitrypsin.

This leads to a low concentration of alpha 1-antitrypsin in alveoli and hence normal protection rendered by alpha 1 antitrypsin against proteases such as neutrophil elastase is reduced.

The lungs are continuously exposed to airborne pathogens, which results in an immune response characterized by the local release of oxidants and proteases like neutrophil elastase. Alpha1-antiprotease or alpha 1 antitrypsin keeps these proteases in check and protect the lungs from unregulated protease activity that could cause alveolar wall destruction.

In individuals with alpha 1 antitrypsin deficiency, alveoli lack antiprotease protection leading to unopposed neutrophil elastase digestion of band collagen in the alveolar walls resulting in progressive emphysema.

There is also evidence that alpha1-antiprotease may inhibit alveolar cell apoptosis and protect against emphysema in the absence of neutrophilic inflammation.

In the liver, accumulation of excess alpha1-antitrypsin in hepatocytes due to defective secretion causes the destruction of these cells, and ultimately liver disease.

Serum levels of alpha 1 antitrypsin greater than 11 µmol/L appear to be protective. Emphysema develops in most individuals with serum levels less than 9 µmol/L.

Genetics

SERPINA1 is the gene on chromosome 14 that encodes the protein Alpha 1-antitrypsin.

Over 75 mutations of the SERPINA1 gene have been identified.

M allele is the normal allele which produces normal levels of alpha 1-antitrypsin. This gene is denoted as PiMM

The most common type of allele for alpha 1 antitrypsin deficiency is Z allele which is formed by mutation in exon 5 [single base-pair substitution] to produce allele Z which causes alpha 1-antitrypsin deficiency. If both the alleles are substituted, it is denoted as PiZZ.

Other genotypes associated with severe alpha1-antitrypsin deficiency include PiSZ, PiZ/Null, and PiNull.

[Null means that a copy of allele is not functional at all and would not produce the enzyme].

Most patients with clinical disease are homozygous SS or ZZ or heterozygous MS, MZ, or SZ.

The levels of alpha 1 antitrypsin in different phenotype are

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

Patients with the null gene for alpha 1-antitrypsin will not produce any alpha 1-antitrypsin and almost all of them develop emphysema by 30 years of age.

It is noteworthy that patients with null gene do not develop the liver disease because due to lack of production, accumulation of alpha1-antitrypsin in the hepatocytes does not occur.

Contributory Factors

• Cigarette smoking
  • Accelerates the onset of symptomatic disease by 10 years
  • Causes an increase in the number of neutrophils and neutrophil elastase in the alveolus
  • Inactivates the remaining small amounts of antitrypsin enzyme.
• Infections
• Exposures to dust and fumes – causes inflammation which can also cause the recruitment of neutrophils to the alveoli.

Associated conditions with Alpha 1 Antitrypsin Deficiency

Following conditions are associated with alpha 1 antitrypsin deficiency, occurring due to reduced levels in blood, lungs, and accumulation of mutated molecule in the liver

• Cirrhosis
• Chronic obstructive pulmonary disease (COPD)
• Pneumothorax
• Asthma
• Granulomatosis with polyangiitis
• Pancreatitis
• Gallstones
• Bronchiectasis
• Pelvic organ prolapse
• Primary sclerosing cholangitis
• Autoimmune hepatitis
• Emphysema, predominantly involving the lower lobes and causing bullae
• Secondary membranoproliferative glomerulonephritis
• Cancer
  • Hepatocellular carcinoma (liver)
  • Bladder carcinoma
  • Gallbladder carcinoma
  • Lymphoma
  • Lung cancer

Presentation of Alpha 1 Antitrypsin Deficiency

The major manifestation of alpha 1-antitrypsin deficiency in the first 2 decades of life is liver disease. Pulmonary manifestations appear later.

The disease could present as neonatal jaundice and hepatitis in newborns, cholestatic jaundice in infants and in children as hepatic cirrhosis or liver failure.

Alpha1-antitrypsin deficiency is a leading condition requiring liver transplantation in children.

Adults with alpha-1 antitrypsin deficiency usually develop symptoms of lung disease between ages 20 and 50. The disease peaks in the fifth decade of life. Smokers with disease present a decade early. Severe forms of the disease may present as early as the third decade.

Adults may develop liver disease – (jaundice, cirrhosis) and are also at risk of developing a type of liver cancer called hepatocellular carcinoma.

Rarely, people with alpha 1 antitrypsin deficiency may develop panniculitis, characterized by hardened skin with painful lumps or patches. This can occur at any age.

Not every individual with alpha 1 antitrypsin deficiency develops clinically significant disease.

The common presenting symptoms are

• Shortness of breath
• Wheezing
• Rhonchi
• Rales.
• Cough with sputum production
• Unintentional weight loss
• Recurring respiratory infections
• Fatigue

Patients may have been recurrently treated for asthma or respiratory infections without being diagnosed for alpha 1 antitrypsin deficiency.

Eventually, emphysema develops and dyspnea is the symptom that dominates the clinical presentation.

Initially, the dyspnea is evident only with strenuous exertion but over time it limits even mild activities. By the time dyspnea becomes the dominant manifestation and a diagnosis is established, usually, several years have passed.

Patients with Alpha 1 antitrypsin deficiency frequently develop dyspnea 20-30 years earlier (at age 30-45 years) than do smokers with emphysema and normal alpha1-antitrypsin levels.

Depending on the severity, physical examination may reveal the following features: (though these are not specific findings)

• Increased respiratory work
  • Tachypnea
  • Scalene and intercostal muscle retraction
  • Tripod position.
• Airflow obstruction
  • Pursed-lip breathing
  • Wheezing
  • Pulsus paradoxus.
• Hyperinflation
  • Barrel chest
  • Increased percussion note
  • Decreased breath sound intensity
  • Distant heart sounds.

Mild to moderate disease may not have any findings.

Approach to Diagnosis

Alpha 1 antitrypsin deficiency remains undiagnosed in many patients. It is estimated that about 1% of all COPD patients actually have alpha 1 antitrypsin deficiency.

Thus, testing should be performed for all patients of

• Emphysema at an early age <45 years
• Emphysema in a patient with the absence of a recognized risk factor [smoking or occupational exposure]
• Emphysema of the lower lungs
• Asthma with persistent airflow obstruction after treatment
• Unexplained liver disease
• Necrotizing panniculitis
• Antiproteinase 3-positive vasculitis (antineutrophil cytoplasmic antibody [C-ANCA]–positive vasculitis)
• Bronchiectasis without a clear cause
• Family history of emphysema, bronchiectasis, liver disease, or panniculitis.
• A sibling with the disease

The initial test performed is serum alpha 1 antitrypsin deficiency level. A low-level of alpha 1 antitrypsin deficiency confirms the diagnosis and warrants further assessment with phenotyping and genotyping.

Differential Diagnoses

• Autoimmune Hepatitis
• Bronchiectasis
• Bronchitis
• Chronic Obstructive Pulmonary Disease
• Cystic Fibrosis
• Emphysema
• Kartagener Syndrome
• Viral Hepatitis

Lab Studies

Serum alpha 1-antitrypsin levels

Serum alpha 1-antitrypsin levels are used to identify the disease and determine the level of the enzyme. The study is most commonly performed by nephelometry.

Normal serum alpha 1-antitrypsin levels are 100-300 mg/dL [20-60 µmol/L]. Levels less than 80 mg/dL [11 µmol/L] suggest a significant risk for lung disease.

Serum alpha 1-antitrypsin concentration alone has a low sensitivity for detecting alpha 1 antitrypsin deficiency. Phenotyping is required to confirm alpha 1-antitrypsin deficiency.

Phenotyping

Phenotyping is done in patients with low serum levels of alpha 1 antitrypsin.

Isoelectric focusing is the most commonly used method to definitively detect the alpha 1-antitrypsin phenotype.

A free Alpha-1 Test Kit (finger-stick test) from the Alpha-1 Research Registry is available [ associated with the Alpha-1 Association].

Functional assay of alpha 1-antiprotease

This test is rarely required. It is done in patients with clinical features that are highly suggestive of alpha 1 antitrypsin deficiency but whose serum levels are within the reference range.

It measures the ability of the patient’s serum to inhibit human leukocyte elastase, a rare defect.

Genotyping

It uses DNA extracted from circulating mononuclear blood cells and is done by DNA amplification techniques.

Liver Function Tests

These should be done in patients with low or borderline levels of alpha 1-antitrypsin.

It includes measurement of serum transaminases, bilirubin, albumin, and routine clotting function (activated partial thromboplastin time and international normalized ratio).

Imaging Studies

Chest radiography

• Hyperlucency because of destruction of healthy tissue, certain areas being affected more than others.
• Loss of the normal rich pattern of branching blood vessels.
• Basilar emphysema [smoking causes apical emphysema]

High-resolution CT scanning

High-resolution CT scanning of the chest demonstrates widespread hypoattenuating areas resulting from a lack of lung tissue. Smaller and fewer pulmonary vessels are noted.

Mild forms of alpha 1-antitrypsin disease can be missed on CT but in moderate disease, the panlobular nature of the process and the characteristic lower zone predominance can be noticed.

Severe forms may be indistinguishable from severe centrilobular emphysema.

Hepatomegaly, cirrhotic changes or hepatocellular carcinoma may be detected on CT abdomen.

Pulmonary Function Tests

• Spirometry for forced vital capacity (FVC) and forced expired volume in 1 second (FEV₁)
• Determination of lung volume by plethysmography

BODE Index

Body mass index, airflow obstruction, dyspnea, and exercise capacity index is a 4-step evaluation of patients with chronic obstructive lung disease to determine the severity of the disease.

Treatment of Alpha 1 Antitrypsin Deficiency

Preventing or slowing the progression of lung disease is the major goal. This is achieved by

• Decreasing any proinflammatory stimuli in the alveolus – smoking, asthma, or respiratory infection
• Improving pulmonary functions
• Augmenting or replacing the deficient enzyme

To decrease the risk of liver disease, vaccination against hepatitis A and B is administered.

Quitting smoking

No treatment for emphysema has a greater effect on survival than quitting smoking.

Improvement of Lung function

• Metered-dose inhalers of short-acting beta-adrenergic agents and ipratropium bromide bronchodilators
• Long-acting inhaled beta-adrenergic drugs and anticholinergics
• Inhaled corticosteroids
• Oral corticosteroids for acute exacerbation
• Theophylline – May lessen the degree of dyspnea

Preventing Respiratory Infections

Aggressive treatment of infections may help decrease the potential for additional lung injury. Periodic vaccination for Pneumonia and influenza vaccination and early antibiotic therapy for all exacerbations with purulent sputum should be done.

Pulmonary Rehabilitation

• Education
• Exercise conditioning
• Breathing training
• Chest physical therapy
• Respiratory muscle training
• Psychological support

Reducing Hypoxemia

Oxygen supplementation increases exercise capacity, improves performance, decreases dyspnea with exercise, and improves sleep quality.

Stable patients with resting hypoxia benefit most if they wear their oxygen mask continuously.

Enzyme Replacement or Augmentation Therapy

IV augmentation therapy is the only treatment specific for alpha 1-antitrypsin deficiency.  Currently, three preparations – Prolastin, Aralast and Zemaira are available.

Weekly IV infusions of alpha 1-antitrypsin protein concentrate restore serum and alveolar alpha 1-antitrypsin concentrations to protective levels.

There are no firm guidelines for augmentation therapy yet. Most of the doctors recommend it in following conditions:

• Serum level below the threshold protective value
• The patient has one or more of the following:
  • Signs of significant lung disease: chronic productive cough or an unusual frequency of lower respiratory infection
  • Airflow obstruction
  • Accelerated decline of FEV₁
  • Evidence of emphysema on chest x-ray or CT

Use of alpha 1-antitrypsin augmentation in patients after lung transplantation for alpha 1-antitrypsin deficiency is not supported by evidence yet.

Augmentation therapy is not appropriate for liver-affected patients.

Surgery

Two surgical approaches may help selected patients with emphysema due to alpha 1-antitrypsin deficiency.

Volume Reduction Surgery

Volume-reduction surgery in selected patients with severe emphysema and significant air trapping leads to symptomatic improvement. The surgery reduces severely affected 20-35% of each lung. Spirometry and exercise tolerance generally improve and dyspnea generally is diminished.

However, the duration of improvement seems to be brief.

Lung transplantation

This is indicated in patients who are at high risk of early mortality but are not very ill.

Liver transplantation

Liver transplantation is the definitive treatment for advanced liver disease.

Follow Up

• Measuring pulmonary function regularly
• Repeat influenza vaccination yearly
• Pneumococcal vaccination every 5 years
• Periodic evaluation of liver function in PiZZ type individuals
• Ultrasound monitoring every 6-12 months to detect early fibrotic changes and hepatocellular carcinoma in cases of established liver disease.

Prognosis & Complications

Complications may include pneumothorax, pneumonia, acute exacerbation of airflow obstruction, and respiratory failure.

Patients diagnosed with screening often have a prognosis like that of healthy people. Patients diagnosed after symptoms have established have a worse prognosis.

Poor prognosis is found in

• Severe airflow obstruction
  • FEV₁ >50%, 5-year mortality rate is 4%
  • FEV₁ 35-49%, 5-year mortality rate is 12%
  • FEV₁ < 35, 5-year mortality rate is 50%
• Significant bronchodilator response (>12% and >200 mL)
• Smoking
• Male sex

Help Resources

Several organizations are there to offer patients and family members education, support and opportunities to participate in research about alpha 1 antitrypsin deficiency.

Alpha 1 National Association

The Alpha-1 National Association offers a telephone hotline (1-800-4ALPHA-1), a national newsletter (Alpha-1 News), and local support groups that provide information and support for patients, their families, and their caregivers.

Address

3300 Ponce de Leon Blvd.

Coral Gables, FL 33134 USA

Phone: (305) 567-9888

Toll-free: 877218772287321

Website: http://www.alpha1.org/

Alpha-1 Research Registry

The Alpha-1 Research Registry (A1RR) is a confidential database of individuals diagnosed with or identified as carriers of, alpha-1 antitrypsin deficiency.  The registry was established in 1997 by the Alpha-1 Foundation to facilitate research towards improved treatment and, ultimately, a cure for this disorder. It is located at the Medical University of South Carolina in Charleston.

Address

c/o Medical University of South Carolina

96 Jonathan Lucas St., Suite 812-CSB, MSC 630

Charleston, SC 29425-6300 USA

Phone: (843) 792-0260

Toll-free: (877) 886-2383

Website: http://www.alphaoneregistry.org

American Liver Foundation

The American Liver Foundation is a national, voluntary, non-profit organization dedicated to the prevention, treatment, and cure of hepatitis and other liver diseases through research, education and advocacy. Established in 1976, ALF provides a national helpline, educational information and programs, physician referrals, extensive scientific research grants, and a nationwide network of chapters and support groups.

Address

39 Broadway, Suite 2700

New York, NY 10006 USA

Toll-free: (800) 465-4837

Website: http://www.liverfoundation.org

American Lung Association

The American Lung Association (ALA) is a national, non-profit, voluntary health organization dedicated to the prevention, cure, and control of all types of lung diseases such as asthma, emphysema, tuberculosis, and lung cancer. This is accomplished through programs of community service, public health education, advocacy, and research. The ALA was established in 1904 as the National Association for the Study and Prevention of Tuberculosis.

As the number of tuberculosis cases declined over the years, the association widened its focus to include other forms of lung disease and in 1973, changed its name to the American Lung Association. The association offers assistance through support groups, genetic counseling, patient networking, referrals, and the development and dissemination of educational materials. Such materials include reports, brochures, audiovisual aids, and Spanish language materials.

Address

1301 Pennsylvania Ave NW

Suite 800

Washington, DC 20004 USA

Phone: (202) 785-3355

Toll-free: (800) 586-4872

Website: http://www.lungusa.org

Childhood Liver Disease Research and Education Network

The Childhood Liver Disease Research and Education Network (ChiLDREN) is a non-profit, collaborative team of doctors, nurses, research coordinators, medical facilities and patient support organizations, all working together to perform important research in 8 rare cholestatic childhood liver diseases, to educate and train physicians and scientists, and to provide important information about the diseases to parents, patients and the public. The ChiLDREN Network has clinical sites and research labs in the US and Canada, and also includes a research lab in London. These sites are working together to improve the lives of children and families dealing with rare liver diseases. The ChiLDREN Network combines the Biliary Atresia Research Consortium (BARC) and the Cholestatic Liver Disease Consortium (CLiC), as well as new studies on cystic fibrosis liver disease (CFLD). The ChiLDREN Network was developed to support the discovery of new diagnostics, etiologic, and treatment options for children with liver disease, and those who undergo liver transplantation. The Network also supports training for the next generation of investigators in rare, pediatric liver diseases.

Address

c/o Joan M. Hines, Research Administrator

Children’s Hospital Colorado

Aurora, CO 80045

Phone: (720) 777-2598

Email: [email protected]

Website: http://www.childrennetwork.org

Children’s Liver Disease Foundation

Children’s Liver Disease Foundation (CLDF) is a UK charity which takes action against the effects of childhood liver disease, providing information, emotional support, research funds and a voice for all affected children, young people and families in the United Kingdom.

Address

36 Great Charles Street

Birmingham, B3 3JY United Kingdom

Phone: (121) 212-3839

Email: [email protected]

Website: http://www.childliverdisease.org

COPD-ALERT

The COPD-ALERT is a non-profit organization that offers a nationwide support and advocacy group for patients suffering from chronic obstructive pulmonary disease (COPD) and their caregivers. It is also open to medical professionals and other interested individuals/organizations. COPD has foreign members as well. Membership is free. COPD is a disease characterized by progressive airflow limitations caused by an abnormal inflammatory reaction to the chronic inhalation of particles.

Address

3210 N. Leisure World Blvd.

Ste. 614

Silver Spring, MD 20906

Phone: (301) 598-6693

Website: http://www.copd-alert.com

Genetic and Rare Diseases (GARD) Information Center

Established by the National Human Genome Research Institute (NHGRI) and the Office of Rare Diseases (ORD) at the National Institutes of Health, the Genetic and Rare Diseases Information Center gives health care providers and their patients immediate access to experienced information specialists who can supply current and accurate information about more than 6,000 genetic and rare diseases in English and Spanish. Information specialists answer calls Monday through Friday from 12 p.m. to 6 p.m. EST. Bilingual information specialists can speak with Spanish-speaking callers. All information requests are completely confidential.

Address

PO Box 8126

Gaithersburg, MD 20898-8126

Phone: (301) 251-4925

Toll-free: (888) 205-2311

Website: http://rarediseases.info.nih.gov/GARD/

March of Dimes Birth Defects Foundation

The March of Dimes Birth Defects Foundation (MODBDF) is a national, non-profit organization that was established in 1938. The mission of the foundation is to improve the health of babies by preventing birth defects, premature birth and infant mortality. The March of Dimes funds programs of research, community services, education, and advocacy. Educational programs that seek to prevent birth defects are important to the foundation and, to that end; it also produces a wide variety of printed informational materials and videos. The Pregnancy & Newborn Health Education Center is staffed by trained health information specialists who provide researched information on pregnancy issues, complications and risks, newborn care, birth defects, genetic diseases and related topics as well as referrals to relevant organizations and support groups.

The March of Dimes Birth Defects Foundation has added an email and website for Spanish speaking individuals.

Address

1275 Mamaroneck Avenue

White Plains, NY 10605

Phone: (914) 997-4488

Website: http://www.marchofdimes.com