Alpha-1 Antitrypsin Deficiency

CORAM S VOLUME 5 Coram LLC is a leading national provider of home infusion services, including alternate site of care and specialty pharmacy distribution. 12450 East Arapahoe Road, Suite A, Centennial, CO 80112 720.568.3436 For the branch nearest you, visit coramhc.com. Alpha-1 Antitrypsin Deficiency Alpha-1 antitrypsin, also referred to as A1P1, AAT deficiency, AAT, genetic or inherited emphysema or simply alpha-1 is the most common genetic cause of emphysema in adults. The liver also produces alpha-1-antitrypsin. Deficiency of the protein results in destruction of hepatocytes and, ultimately, cirrhosis. AAT may also affect the skin, the feature of which is panniculitis, an inflammation of the fat under the skin. Diagnosis of AAT is typically missed or delayed, disallowing the opportunity for early treatment and maintenance of pulmonary and hepatic function. This continuing education offering will define AAT and its clinical manifestations and review both pharmacologic and nonpharmacologic therapy options. Pathophysiology Trypsin is a normally occurring enzyme whose primary function is to break down protein to aid digestion. Per the normal negative feedback loop as seen in the illustration, when trypsin is no longer needed it is important that its production cease and continued breakdown not occur. Thus, the body generates antitrypsin, specifically alpha-1 antitrypsin (AAT). Alpha-1 antitrypsin is a protease inhibitor it inhibits the action of trypsin. AAT protects tissues from the enzyme s inflammatory cells, especially the neutrophil elastase. Without alpha-1 antitrypsin (i.e. a deficiency), elastase is free to break down elastin, an important contributor to lung elasticity. Elastin breakdown results in destruction of lung, leading to such complications such as emphysema or COPD. In emphysema, the alveoli break down and block the area, preventing the exchange of air. These patients can inhale sufficiently, but they cannot effectively exhale. Such emphysema can occur as a result of the deficient level of alpha-1 antitrypsin. In fact, alpha-1 antitrypsin is the most common genetic cause of emphysema in adults. The result is progressive, irreversible, chronic obstructive lung disease (COPD). With the mutated gene there is also impaired secretion from the liver. Either the gene is targeted for destruction or it doesn t polymerize but stays in the endoplasm where it will destroy liver tissue. Liver damage is less common than lung damage but can be seen in both children and adults. Alpha-1 antitrypsin is the most common cause of liver disease in the pediatric population. The only available treatment for liver damage, however, is liver transplant. Pattern of Heredity Alpha-1 antitrypsin is an autosomal recessive disorder. Since it is recessive, a person can only inherit the disease when he or she inherits a defective gene from both parents. Refer to the diagram illustrating the pattern of heredity. Consider M as the normal gene, Z or S as abnormal. In C O N T I N U I N G E D U C A T I O N P R O G R A M

this diagram, the grandfather is a heterozygote (formerly referred to as a carrier) he has one normal gene and one abnormal gene. He will not have the disease but, if matched with another heterozygote, could pass it on. In this case the grandmother does have the disease (ZZ). Refer to the middle row. Two of the children inherited a Z from mom and a Z from dad and therefore have the disease. The third inherited the M from dad and the Z from mom, so is a heterozygote. In the next generation you see a person who is neither afflicted or a heterozygote. She inherited the M gene from both parents. A person who inherits the normal gene from both parents will present with normal serum level and function of alpha-1 antitrypsin. Heterozygotes typically have lower than normal serum alpha-1 antitrypsin levels, but do not manifest symptoms of the disease. If a person inherits the Z gene from both parents, he or she is a PiZZ, the most severe form of the deficiency. There are about 75 different phenotypes of alpha-1 antitrypsin deficiency. Most common are the M, Z, S and null phenotypes. The presence of an SZ or null gene also indicates disease. The incidence of the most common phenotype, ZZ, is about 1 in 3,000 in the US, similar to the incidence of cystic fibrosis. This equates to approximately 100,000 individuals. Unfortunately, only about 10% of those patients, or 10,000 persons, are ever diagnosed. Given the fact that an estimated 3% of patients with emphysema or COPD are likely to have AAT, that is another nearly 1M patients not diagnosed. Alpha-1 antitrypsin deficiency is most common in Caucasians, less common in the African American population and rare in the Asian population. About 1 in 37 persons are heterozygotes. Alpha-1 antitrypsin deficiency mimics the symptoms of such respiratory diseases as asthma, allergies, COPD or chronic bronchitis. Misdiagnosis is all too common with an average of 7 to 10 years from symptom development to actual diagnosis. Unfortunately, by the time diagnosis is made, much opportunity to prevent lung or liver damage is missed. And, since alpha-1 antitrypsin deficiency is so rare, many community practitioners are not aware of and do not test for alpha-1 antitrypsin deficiency. Clinical Presentation Patients typically present with an insidious but progressive shortness of breath at a relatively early age, increased airflow obstruction, year-round allergy symptoms and a chest x-ray revealing hyperinflation of the bases of the lungs and a symmetrical loss of lung tissue vascularity. Patients also present with such symptoms as pursed-lip breathing and chronic, often productive, cough. About 20-30% of alpha-1 patients have concomitant bronchitis, up to a third of the patients also have asthma. There is a significantly increased risk of lung tissue damage in patients who smoke and/or are exposed to toxins or pollutants. About 12-15% of patients with alpha-1 present with liver involvement as well. Alpha-1 is the most common form of liver disease in children and the most common genetic reason for liver transplant in pediatrics in general. Of children with PiZZ phenotype: Up to 25% develop cirrhosis and Serum Concentration (µm) 60 50 40 30 20 10 0 portal hypertension and succumb to complications before age 12 Another 25% will die of the same process by age 20 Approximately 25% have liver fibrosis but minimal hepatic dysfunction and can live to adulthood 25% show no evidence of progressive disease Approximately 12-15% of adult patients with the ZZ phenotype present with liver disease. The risk increases in those persons who abuse alcohol or are exposed to environmental or occupational toxins. Some patients may present with the skin condition panniculitis. Panniculitis is an inflammation of fat beneath the skin, often developing after an incident of trauma, which causes skin to harden and form lumps, lesions and patches. Panniculitis is treatable with augmentation therapy. Diagnosis As mentioned above, the ZZ phenotype is the most severe phenotype and accounts for 95% of symptomatic patients with AAT deficiency. There are a number of other variant phenotypes as well, with their own symptom profiles. The chart below illustrates the impact of the various phenotypes on the serum Range of Alpha-1 PI serum concentrations by genotype MM MS SS MZ SZ ZZ Alpha -1 Antitrypsin Pi Type 11 µm protective threshold 2 VOLUME 5

How Alpha-1 is Inherited therapy will not prevent or reverse lung damage. It should, however, slow the damage and functional decline and enhance survival. Augmentation therapy has also been shown to decrease infection rates. It is reserved for the most symptomatic patients. levels of alpha-1 antitrypsin. The MM phenotype presents with normal serum ATT levels while at the other end of the spectrum is ZZ which has significantly low levels and is the most symptomatic. In addition to assessing serum levels, diagnosis of alpha-1 antitrypsin deficiency is supported by several other tests. A chest x-ray shows the typical abnormalities at the base of the lungs. Pulmonary function tests (PFTs), an exercise test and arterial blood gas (ABG) measurement all indicate the degree of lung dysfunction. Liver function tests (LFTs) identify the presence and severity of liver dysfunction. As stated above, alpha-1 antitrypsin deficiency looks like emphysema but it is important to determine the actual type of emphysema in order to support effective treatment. With acquired emphysema the serum alpha-1 antitrypsin levels are normal. It is usually associated with a smoking history, primarily affects the upper lobes of the lungs and is diagnosed in an older population. Whereas with alpha-1 emphysema, serum levels are low, it is primarily the base of the lungs that are affected and is early onset. Patients may present with co-morbid condition such as asthma or pulmonary infection, but are also at risk for such complications as cor pulmonale (enlargement of the right ventricle of the heart as a response to increased resistance in the lungs), pulmonary hypertension (high blood pressure that affects only the arteries in the lungs and the right side of the heart), and hypoxemia. Pharmacologic Treatment Pharmacologic treatment options include bronchodilators to lessen airway obstruction, anti-infectives which should be administered early and aggressively in order to minimize the risk of damage to lung tissue, and augmentation replacement therapy. Augmentation is just that it augments low serum levels of alpha-1 antitrypsin with additional alpha-1 antitrypsin. Augmentation therapy is indicated in patients with established airflow obstruction as well as in lung transplant patients during times of rejection or dysfunction, infection or exacerbation. Increasing the serum levels of alpha-1 antitrypsin is not a cure for the disease. Augmentation Augmentation therapy is the only FDA-approved treatment for alpha- 1antitrypsin deficiency. It consists of weekly IV infusions of alpha-1 antitrypsin derived from human plasma. The therapy is administered IV at 60 mg/kg of body weight, typically over 60-80 minutes. Augmentation therapy has an approximate 6 day half-life, thus weekly infusions are required to maintain serum levels and keep the patients symptom-free. While the first dose is administered in a monitored setting, it is generally expected that patients be able to selfinfuse in their homes. Some patients may be best treated in an Ambulatory Infusion Suite (AIS). As with any home infusion therapy, patient education, return demonstration, compliance and response to therapy must be monitored. Augmentation therapy is generally well-tolerated. Serious side effects are rare although such side effects as drowsiness, dizziness, headache, cold symptoms, pain, bleeding, or a warm, tingling feeling at the injection site, and gastrointestinal symptoms have been reported in a small percent of patients. Augmentation Therapy Options Aralast NP Glassia Prolastin Zemaira continued on back CONTINUING EDUCATION 3

continued from page 3 Non-pharmacologic Treatment In addition to pharmacologic interventions, pulmonary rehabilitation, lifestyle changes and current immunizations are important. Smokers must stop smoking and should avoid lung irritants. Patients should aerobically exercise. Strategies to support nutrition are also important. Patients are often so fatigued that even eating is a challenge and malnutrition is a risk. Symptomatic Alpha-1 patients should be evaluated in terms of their oxygen levels. Lung Transplant Lung transplant may be an option when the patient s pulmonary function has declined to a point where therapies are no longer viable. At 84.1, 60.6, and 47.6 percent at 1, 3 and 5 years respectively, survival rates for AAT patients are comparable to that with other disease states for transplant. 1 In general, routine post-transplant augmentations therapy is not recommended, as insufficient supportive data is available. However, given the detection of significant increase in elastase activity measured in the bronchoalveolar lavage of post-transplant patients during symptomatic respiratory episodes, many clinicians support the use of augmentation therapy during episodes of lung inflammation, including chronic rejection and infection. Liver Transplant For patients with liver disease, liver transplant is the only option. Augmentation therapy does not have an impact. Screening The option for testing patients for alpha-1 antitrypsin is a sensitive issue. Certainly, ethical principles must be considered. It is essential that patients make an autonomous decision based on accurate information, including of the risks and benefits of knowing/not knowing. It is recommended that family members already displaying symptoms be told that the test is available and discuss their options with their healthcare providers or a genetic counselor. Regardless of the ultimate decision a family member makes, it is important that everyone understand their risks and at least know to make lifestyle changes. The World Health Organization (WHO), the American Thoracic Society (ATS), and the European Respiratory Society (ERS) each recommend alpha-1 screening for all patients with COPD, bronchiectasis, or asthma that is not controlled with usual medications. It should also be considered and screened for in patients with emphysema developing before age 45, pneumonia unresponsive to antibiotics, unexplained liver disease and signs of panniculitis or a specific form of vasculitis. Siblings and offspring of persons with alpha-1 or patients with a history of a family member who dies of unknown lung or liver disease should also be screened. Coram CE Department 720.568.3436 CEDept@Coramhc.com coramhc.com 12450 East Arapahoe Road, Suite A, Centennial, CO 80112 2014 Coram LLC COR16019-0714

Healthline Self-Assessment Quiz Alpha-1 Antitrypsin Deficiency LEARNING OBJECTIVES To understand the clinical disease state of Antitrypsin Deficiency, treatment options and screening. LEARNING GOAL At the end of this program, the reader will be able to: 1. Define Alpha-1 Antitrypsin Deficiency 2. Identify the three primary systems affected by Alpha-1 Antitrypsin Deficiency 3. Describe clinical manifestations of AAT lung disease 4. Identify augmentation therapy options 5. List non-pharmaceutical therapy interventions SELF-ASSESSMENT QUESTIONS In the Quiz Answers section on the next page, circle the correct answer for each question. To obtain two (2.0) contact hours toward CE credit, the passing score is 100%. Return your Self-Assesment Quiz to Coram via email, fax or mail. See the next page for details on how to return to your quiz. Please allow approximately seven days to process your test and receive your certificate upon achieving a passing score. 1. A deficiency of alpha-1 antitrypsin: a. Primarily affects primarily the lung, liver and skin b. Allows elastase to breakdown elastin c. Results in the most common genetic cause of emphysema in adults d. A and C e. All of the above 2. Alpha-1 antitrypsin is the most common cause of liver disease in the pediatric population. 3. The only available treatment for liver damage is liver transplant. 4. Symptoms of alpha-1 antitrypsin deficiency are clearly differentiable from those of, for example as asthma, allergies, COPD or chronic bronchitis. 5. Which AAT phenotype presents with the lowest levels of alpha-1 antitrypsin: a. MM b. MZ c. Null d. ZZ 6. Augmentation therapy provides additional alpha-1 antitrypsin to enhance low or absent levels. 7. Augmentation therapy a. Will reverse lung damage b. Should enhance survival c. Decreases infection rates d. Is applicable for use in all phenotypes e. A, B and D f. C and D g. B and C 8. Augmentation therapy is typically required in the first three months post-lung transplant. 9. AAT screening should be considered for all of the following EXCEPT: a. Any patient with COPD, bronchiectasis, or asthma. b. Patients with early onset emphysema developing (before age 45) c. Pneumonia unresponsive to antibiotics d. Unexplained liver disease e. Signs of panniculitis f. Siblings and offspring of persons with alpha-1 or patients with a history of a family member who dies of unknown lung or liver disease should also be screened 10. It is essential that patients make an autonomous decision regarding AAT screening based on accurate information, including of the risks and benefits of knowing/not knowing.

VOLUME 5 CORAM S CONTINUING EDUCATION PROGRAM Alpha-1 Antitrypsin Deficiency QUIZ ANSWERS Circle the correct answers below to receive 2.0 Continuing Education credits. 1. a b c d e 2. a b 3. a b 4. a b 5. a b c d 6. a b 7. a b c d e f g 8. a b 9. a b c d e f 10.a b Provider approved by the California Board of Registered Nursing, Provider #15200. Coram LLC is approved by the Delaware Board of Nursing, Provider Number DE-14-010517. Coram LLC is approved by The Commission for Case Manager Certification to provide continuing education credit to CCM board certified case managers. This Healthline is approved by the above accreditations for 2.0 contact hours. To obtain Continuing Education credits, please complete this information in full. Please print clearly. Name: Address: City: State: Zip: License Number (required to receive CEs): RN LPN Certified Case Manager Employer: Work Phone: Coram Representative: Was this material: Useful in your practice? Yes No Comprehensive enough? Yes No Well organized? Yes No Date: Coram offers other Continuing Education booklets on home care topics. Contact your local Coram Representative for more information. I would like my certificate mailed to the address provided above. I would like my certificate emailed to me at: (ex: john.smith@coramhc.com) RETURN THIS PAGE TO CORAM VIA: Mail: Coram s Healthline Department 12450 E Arapahoe Road, Suite A Centennial, CO 80112 Fax: 949.462.8990 Email: CEDept@coramhc.com 2014 Coram LLC COR16019-1214