Wegener's_Granulomatosis_&

Wegener's Granulomatosis and Alpha-1 Antitrypsin Deficiency (AATD) Disease

Last updated 16 February 2008

[Information below is compiled by a person without medical training. It is believed to be correct but no medical decisions should be made on the basis of this document. Ask a licensed medical professional about AAT deficiency.]

NOTE-WG patients should be tested for alpha-1 antitrypsin deficiency as soon as diagnosed or suspected.

Description

Alpha-1 Antitrypsin (AAT) Deficiency is a rare genetic disease that affects lungs and livers. It is abbreviated in literature as AATD, Alpha 1-AT Deficiency, and merely as Alpha-1. AAT is a proteinase inhibitor (Pi) needed by the body to prevent lung damage and liver damage

Demographics

AATD is more common in persons of Scandinavian, British, Spanish, and Portuguese descent, but is found in all populations. AAT protects tissues from damage due to enzymes that break down proteins. Distribution of AATD is equal between sexes. It is roughly as common as cystic fibrosis.

AAT deficiency is less rare than Wegener's granulomatosis if published estimates are valid; about 2500-3000 per million, versus WG at about 1-10 per million. As with WG, probably many AATD patients go undiagnosed.

With regard to WG, one study found 8% of WG patients had AAT deficiency.

Some estimates of unknown origin, almost certainly NOT based on hard evidence are the following numbers of Alpha-1's in U.S. and Canada, broken down by major phenotype.

PI*ZZ = 53,000

PI*SZ = 257,000

PI*SS = 346,000

PI*MZ = 7,150,000

PI*MS = 18,470,000

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Total = 26,200,000

It seems a significant number of AATD patients have been diagnosed with vasculitis. A search of Medline showed there's a number of studies that indicate AAT may play a part in some autoimmune vasculitides. The National Library of Medicine has in its Medline database a number of published studies that purport to link AATD to:

Wegener's granulomatosis
Henoch-Schonlein purpura
Temporal Arteritis (Giant Cell Arteritis)
ANCA-associated vasculitis
Chronic cutaneous vasculitis
Crohn's disease-like (milder intestinal manifestation)
Chronic Obstructive Pulmonary Disease (COPD or emphysema)

Apparently there has not been a broad investigation looking at frequency of AATD in the spectrum of autoimmune vasculitides.

Testing

CT scan-assessed lung density was 2.3-foldmore sensitive than pulmonary function testing (FEV₁ or carbonmonoxide diffusing capacity of the lung (D_L,CO)) in the evaluationof the annual progression of pulmonary emphysema

Affects

Liver damage occurs because the trypsin produced in the liver cannot be released into the blood stream.

Lung damage occurs because of neutrophil elastase released in the lungs and caused by infection or inflammation that is not neutralized by AAT.

AAT deficiency leads to damage of various organs, principally the lungs and liver. Symptoms can surface at a very early age or in adulthood and involve:

The lungs: Shortness of breath, bronchiectasis, chronic bronchitis. (Smokers are particularly likely to develop AATD early)

The liver: Jaundice, fluid in the abdomen, panniculitis, hepatocellular carcinoma, and gastro-intestinal bleeding..

Persons likely to develop AATD are identified in a WHO recommendation as those with a medical history showing:

A family history of AATD
Chronic Pulmonary Obstructive Disease (COPD)
Chronic liver disease
Asthma

Other possible indications for persons at risk for AATD (not in any special order) are:

Bronchiectasis Unexplained vasculitis Panniculitis

Wegener's Granulomatosis Unexplained liver disease Liver cancer

Patients with indications listed above may qualify to receive free testing for AATD by calling 1 877 886 2383. The results are know only to the patient thus eliminating discrimination by Insurance companies. Results will show AAT level and the phenotype.

Genetic Aspects

Only certain alleles (variant forms of the protein inhibitor) seem to contribute to vasculitis. The following is apparently the current status of what is known about alleles and AATD:<>

<>Alpha 1-AT is encoded by a polymorphic (comes in many possible shapes) gene, with over 75 alleles, resulting in various degrees of AATD.
<>Severely, medium, and non-deficient protease inhibitor (Pi) phenotypes. The most common ones involved with AATD are the PiM, PiS, and PiZ.
Alpha1-antitrypsin deficiency is not sufficient to induce ANCA positive vasculitides, and may only act as a second hit amplifying factor.

Homozygote AATs are persons in which both copies of their AAT gene are identical. Homozygotes for the PiZ variant of the alpha1-AT gene are at greater risk of developing WG than the general population. Those with only one copy of the PiZ may have a lesser deficiency of AAT.

RISK OF DEVELOPING AATD BY PHENOTYPE


AAT Genes	AATD Status	Person a Carrier ?	Serum Range
PiMM	Normal AAT Serum Level	No	20-48
PiMS	AATD,risk unclear	Yes-Note 1	??
PiMZ	Mild to moderate AATD	Yes	12-35
PiSZ	Moderate to severe AATD	Yes	8-19
PiSS	Most studies show no AATD	Yes-Note 1	15-33
PiZZ	Moderate to severe AATD	Yes	2.5-7.0
Pi Z-Null	Determine by clinical exam and testing	Yes	??
Pi Null-Null	Moderate to severe AATD	??	0.0

Note 1.

The PiS allele does not seem to contribute to the development of AATD excepting what paired with a PiZ allele in a heterozygote.

C-antineutrophil cytoplasmic antibody (cANCA) positivity in vasculitis patients is sometimes associated with the Z allele of alpha-1 antitrypsin (PiZ). P-antineutrophil cytoplasmic antibody (pANCA) positivity is sometimes associated with the S allele (PiS).

One study found an excess of PiZ and PiS alleles were associated with the development of pulmonary hemorrhage, apparently regardless of the kind of autoimmune vasculitis.

Another study described a novel form of AAT deficiency associated with the normal PiM phenotype becoming manifest only during acute illness. Information on other Pi variations does not seem to be readily available.

Treatment

AATD is considered a pre-existing condition and may not be covered by health insurance.

Treatment of the AAT damaged liver is a well-timed liver transplant. Large Volume Paracentesis may be required for liver dysfunction due to build-up of ascites (pockets of fluid in the abdomen).

There are several options for treatment of the AATD lung disease such as steroids and anti-inflammatories, for perhaps both oral and inhaled formulations. Tailored exercise programs and pulmonary rehabilitation programs are useful. Supplemental oxygen may be required for some patients, especially when flying or during exercise or therapy.

Annual influenza vaccinations are recommended as are periodic Pneumovax vaccinations. Both Hepatitis A and Hepatitis B vaccinations are recommended.

Replacement Therapy

To stop the AATD lung and liver damage, it is necessary to replace the missing AAT. The current treatment for prevention of lung damage is Bayer's "Prolastin", which is purified alpha-1 antitrypsin derived from human plasma. It is infused weekly. The Prolastin supply is limited and will be until other means of producing AAT are developed.

Prolastin use at this time appears to be limited to patients with an AAT level less than 11 μM (micromols ??). Decisions on patient applications are handled by the AAT Foundation by a working group that includes patients with AATD.

Replacement Products

Bayer started development of an alpha-1 antitrypsin produced by genetically modified sheep, and completed Phase II without significant problems. Due probably to current (July 2003) earnings problems at Bayer, the company stopped funding for PPL Therapeutics, their partner in developing transgenic AAT,.

The funding was to have been used to maintain the large number of genetically modified sheep required to proceed to the phase III clinical trial of the transgenic recombinant alpha 1 antitrypsin. PPL Therapeutics will keep a smaller number of genetically modified sheep, but not enough to go on to Phase III clinical testing of transgenic AAT at this time.

Bayer currently produces the replacement AAT (Prolastin) from plasma donations, and intends to continue that service. Prolastin is apparently available through exclusively through a non-profit company, AlphaNet http://www.alphanet.org/main.htm, that manages the distribution under contract with Bayer.

Another AAT replacement is Zemaira, made by Aventis, and also expensive. It is also distributed through AlphaNet under contract with Aventis.

Yet a third replacement product called Aralast produced by Baxter. Aralast™ is now available exclusively through specialty pharmacy providers, including Accredo Health Inc., Caremark Inc. and Coram Healthcare. It costs more than Prolastin and is in short supply.

Future Developments?

One company, GlycoFI, has identified alpha-1 antitrypsin as a product that could be produced from yeast, persumably at a cost lower than the existing three products.

There are other trials going on for inhaled products and another for a recombinant yeast. Information on trials is at http://www.alphaone.org/. Click on “Research Agenda” to see what research is planned or in progress. Click on "Clinical Trials Update" to see all the current trials for treating AATD.

Lung transplants are an increasing means of treating severe lung damage caused by AATD.

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