What is Alpha-1?

Alpha-1 Antitrypsin Deficiency (Alpha-1) is a condition that is passed on from parents to their children through genes. This condition may result in serious lung and/or liver disease at various ages in life.

Alpha-1 antitrypsin is a protein that is produced mostly in the liver. Its primary function is to protect the lungs from neutrophil elastase. Neutrophil elastase is an enzyme that normally serves a useful purpose in lung tissue-it digests damaged or aging cells and bacteria to promote healing. However, if left unchecked, it will also attack healthy lung tissue. Alpha-1 antitrypsin, in sufficient amounts, will trap and destroy neutrophil elastase before it has a chance to begin damaging the delicate lung tissue. Consequently, if an individual doesn't have enough alpha-1 antitrypsin, the enzyme goes unchecked and attacks the lung.

Most people have two normal copies of the alpha-1 antitrypsin gene that make the protein. Some people may have one normal copy and one damaged copy of the gene; they are considered Alpha-1 Carriers. Individuals with two damaged copies of the gene have the severe deficiency of the alpha-1 antitrypsin protein and considered to have "Alpha-1" and are referred to as "Alphas".

Alpha-1 Carriers with only one abnormal gene can produce enough protein to stay healthy, especially if they do not smoke. However, people with two damaged copies of the gene can't produce enough alpha-1 antitrypsin, which can cause several conditions. They are often diagnosed with emphysema as their primary disease. Other common diagnoses include COPD (chronic obstructive pulmonary disease), asthma, chronic bronchitis, and bronchiectasis. Alphas are usually quite susceptible to lung infections. In the Alpha-1 patient, any of these conditions can cause further damage if they aren't treated right away.

Another disease that some Alpha patients develop is cirrhosis of the liver. This scarring of healthy liver tissue affects Alpha-1 infants, as well as 12% to 15% of adult Alphas. Unfortunately, there is no cure for cirrhosis of the liver, regardless of its cause. Cirrhosis can be managed as a chronic condition if caught early and protective steps are taken. Still, a liver transplant is currently the only option available for advanced disease.

More rarely, Alphas may also have a disease known as panniculitis. Panniculitis is an inflammation in the fatty tissue under the skin. It can occur in both children and adults.

Alphas and physicians regularly speak of a patient's "primary disease." This means the principal way the deficiency is manifested in a given patient, whether in the lungs, the liver, or the skin.

How Do You Get It?

 

Since Alpha-1 Antitrypsin Deficiency is an inherited disorder, it occurs when both parents pass on a abnormal gene to their child. A father and mother who are both carriers (MZ) could expect to have a 50% chance of having a carrier, and a 25% chance of having either a healthy or a deficient child.

With the birth of each child, the same percentages apply. Therefore, it is entirely possible for a MZ father and a MZ mother to have four children, all of which are ZZ or all of which are MM. Or on the other hand, it is possible for this same father and mother to have 1 ZZ child, 2 MZ child and 2 MM child as the percentages imply.

If one parent has the ZZ genotype, and the other has two normal copies of the gene (MM), all of their children will have the MZ genotype.

For information on who should be tested, please visit the Alpha-1 Foundation website: Get Tested

How is Alpha-1 Diagnosed?

Although Alpha-1 is one of the most common genetic disorders in the world, it is often misdiagnosed. Many times patients are told they have asthma, bronchitis, symptoms related to stress, emphysema caused by smoking, or simply chronic obstructive pulmonary disease of unknown cause.

The most common indicators of Alpha-1 include shortness of breath, a chronic cough, and abnormal liver test results. If you have any of these symptoms there is a simple blood test that can detect alpha-1 antitrypsin levels. This test is also recommended if you have relatives, especially siblings, who have been diagnosed with alpha-1, or if there is a family history of early emphysema, with or without smoking.

The laboratory test measures alpha-1 antitrypsin levels in blood, which are usually reported within Australia using grams per litre (g/L), however alternative measures are milligrams per 100 ml (mg%) and micromoles per liter (µM/L). All measurements provide the same basic information on how much alpha-1 antitrypsin is in the blood.

People with two healthy copies of the alpha-1 gene produce the most alpha-1 antitrypsin, and people with no copies of the gene at all produce the least. In addition, environmental factors can affect how much alpha-1 antitrypsin is in the blood. An individual's genetic makeup (genotype) combines with environmental factors to determine their phenotype. Here are the more common phenotypes and their corresponding blood alpha-1 levels.

Phenotype

g/L

mg%

µM/L

MM (two normal copies)

1.10 - 3.50

110 - 350

20.2 - 64.4

MZ (one normal copy, one deficient copy)

0.74 - 2.10

74 - 210

13.6 - 38.6

SS (two marginally deficient copies)

1.00 - 2.00

100 - 200

18.4 - 36.8

SZ (one deficient copy, one marginally deficient copy)

0.75 - 1.20

75 - 120

13.8 - 22.1

ZZ (two deficient copies)

0.20 - 0.45

20 - 45

3.68 - 8.28

NULL (two nonfunctional copies)

0

0

0

Table data source: American Thoracic Society / European Respiratory Society Statement: Standards for the Diagnosis and Management of Individuals with Alpha-1 Antitrypsin Deficiency > page 925 > Table 3, adjusted where test results are known for Australian patients.

 

Alpha-1 levels of 0.8 g/L (80 mg% or 14.7 µM/L) or less put you at greatest risk of developing alpha-1 related emphysema. Smokers with intermediate deficiency levels (0.80 to 1.60 g/L) are also at increased risk of lung disease.

Of 13 testing laboratories around Australia, as at 3 December 2016 the published reference ranges for Alpha-1 Antitrypsin levels had an average low of 0.94 g/L, and an average high of 1.98 g/L.

A couple of user-friendly online conversion calculators exist:

In the table above, M refers to the normal gene. Over 75 combinations of gene variations (alleles) have been identified, some of which can cause Alpha-1. The S, Z and Null genes are the most common ones that cause alpha-1 deficiencies. ZZ is the most common allele that causes lung disease.

The Null gene is one that produces no detectable levels of alpha-1. Alphas with the Null-Null phenotype are at the greatest risk of developing emphysema, yet none have suffered liver damage as a result of their Alpha-1

For more information on Alpha-1 testing, please see page numbered 5 of the AAA booklet. You may also find helpful:

Newly Diagonised Alphas

Welcome to the Alpha-1 Association of Australia (AAA).

You may be here because you or a family member has just been diagnosed with Alpha-1. Perhaps your doctor didn't tell you much about it, or didn't know much about it. At this point you have more questions than you have answers. The AAA is here to help you understand the diagnosis and provide you with the education and support to empower you in coping with Alpha-1.

A serious genetic (inherited) diagnosis can leave you feeling afraid and unsure of what to do next. This can be a very difficult time for you and your family. It is often overwhelming to think about the care, the treatment options, possible lifestyle changes and the effects this will have not only on your life, but on your immediate family. A diagnosis of Alpha-1 could impact your family including brothers, sisters, children and grandchildren and possibly your extended family members.


You may be experiencing uncertainty, anger, fear, guilt, grief, and frustration. These are all normal feelings. Your next step is to learn how to cope with these feelings. You accomplish this through a step-by-step process of:

  • Education:
    Knowledge is the key to understanding the diagnosis of Alpha-1. The AAA provides information about treatement, diagnonsis, family inheritance / risk factors, testing options, health management and other resources.

 

  • Medical Care:
    The AAA can help you find a specialist in the treatment of Alpha-1.

 

  • Support:
    We can support your endeavour in dealing with your recent diagnosis through our website, and by helping you to connect to other members by joining our online discussion forums.

 

You're not alone! The AAA is here to help answer questions, refer you to appropriate physicians, provide you with literature, refer you to other resources, and connect you with other Alphas who have faced this diagnosis and who are taking charge of their health and their life!

Alpha-1 - Important Facts

  • Although hard data about the prevalence of Alpha-1 in Australia doesn't yet exist, due to the absence of any comprehensive population or other study, it is estimated that about 1 in every 9 people carry a defective Alpha-1 gene, and that Alpha-1 affects 1 out of around 300 people. (Frederick J de Serres, PhD, 2002).
  • Early respiratory-related symptoms of Alpha-1 are often misdiagnosed as asthma, with an accurate diagnosis often taking several doctors and several years.

 

Common Signs and Symptoms of Alpha-1

Family history of lung disease or liver disease

Symptoms:

  • Shortness of breath
  • Wheezing or non-responsive asthma
  • Coughing with or without sputum (phlegm) production
  • Recurring respiratory infections
  • Rapid deterioration of lung function
  • Unexplained liver problems and /or elevated liver enzymes

For information on Alpha-1 testing in Australia, please see page 5 of the AAA's information booklet.

Alpha1 Liver Disease

 

Alpha-1 liver disease can affect infants, children, and adults. It can result in a mild bump in some liver enzymes that returns to normal in a few weeks or it can lead to liver failure and the need for a liver transplant. Just as a simple blood test can establish the diagnosis of Alpha-1, liver disease due to Alpha-1 is usually detected by a simple panel of blood tests. If more advanced liver problems appear, then your doctor may recommend such tests as an ultrasound, an abdominal CT scan, or a liver biopsy.

A liver biopsy can evaluate the severity of the liver injury and can help evaluate whether other liver conditions are contributing to your liver problems. Liver biopsy carries with it an extremely small but potentially serious risk of side effects such as bleeding and so it's reserved for patients with ongoing liver problems. When a liver biopsy from an individual with Alpha-1 is examined under a microscope the liver cells appear filled with granules which are actually abnormal alpha-1 antitrypsin protein that can't be cleared from the liver. These granules are present even in individuals who don't have Alpha-1 related liver disease.

How Does Alpha-1 Liver Disease Develop?

The causes of liver disease in Alpha-1 are less well understood than the causes of lung disease in this condition. Most Alpha-1 liver research suggests that Alpha-1 liver cell damage is caused by misfolded abnormal alpha-1 antitrypsin protein build up in each cell's endoplasmic reticulum, the part of the cell that manufactures proteins. This misfolded protein gets stuck in the endoplasmic reticulum and is unable to move along a pathway leading out of the liver cell and into the blood. Scientists believe that this blockage, combined with other genetic and environmental factors, leads to the liver injury of Alpha-1. Still unknown is why most people with Alpha-1 never develop significant liver disease!

Adult Liver Symptoms Summary

    Liver-affected adults with Alpha-1 may experience some or all of the following symptoms. All symptoms should be reported to your doctor:
  • itching
  • jaundice (yellow skin and/or whites of eyes)
  • esophageal hemorrhaging (vomiting up blood)
  • ascites (water retention in abdomen)
  • edema (water retention in ankles/feet)
  • fatigue
  • weight loss
  • nausea, vomiting
  • abdominal pain
  • abnormal liver function tests
  • black stool, fresh blood in the stool
  • chronic nose bleeds
  • water in the lungs
  • various infections
  • faster than normal breathing
  • gastrointestinal bleeding
  • depression
  • confusion
  • digestive problems

Children's Liver Symptoms Summary

    Liver-affected children with Alpha-1 may experience some or all of the following symptoms. All symptoms should be reported to the child's doctor.
  • jaundice at birth
  • foul-smelling stools
  • enlarged spleen, abdomen
  • small liver
  • cirrhosis
  • portal hypertension
  • varices of the esophagus (swollen blood vessels in the esophagus)
  • slow to gain weight
  • slow eating
  • vomiting, nausea
  • problems nursing
  • itching
  • pale stools-almost white
  • abnormal bile flow
  • liver inflammation
  • reflux
  • loss of appetite
  • lack of energy
  • elevated liver enzymes

Treatment Options

There is no specific treatment for Alpha-1 associated liver disease. Clinical care primarily consists of treating biochemical abnormalities and providing supportive measures, which address symptoms. Preventing potential complications is also vital. It is extremely important to avoid cigarette smoking and known liver toxins such as alcohol. Additionally, a healthy diet is essential.

Liver transplantation is sometimes a necessary life-saving measure. Fortunately, studies indicate that only a small percentage of the liver affected Alpha-1 community require liver transplantation. Clinical centers have observed that a number of patients with severe liver dysfunction have a low rate of disease deterioration and are able to live a relatively normal life for long periods of time. When a liver transplant is performed, the donor liver makes normal alpha-1 antitrypsin and releases it into the blood, thus, in a practical sense, the affected individual no longer has Alpha-1!

While living related donor liver transplantation is becoming more popular as understanding and techniques improve, it is rarely used as an option for Alpha-1 patients since family members of individuals with Alpha-1 liver disease may well have one or two abnormal genes. However, family members who do not carry a deficient gene for Alpha-1 can be considered for living donor transplantation and Alphas have had successful living donor transplants from friends.

Much research is currently being done to evaluate ways of protecting the liver from injury or even to trick the liver into releasing the alpha-1 antitrypsin protein trapped within the liver cells. If successful such a treatment could lead to a cure for Alpha-1.

Alpha-1 Lung Disease

Alpha-1 antitrypsin protects the delicate tissues of the lungs by binding to neutrophil elastase, a protein released by white blood cells which digests bacteria and other foreign objects in the lungs. When a person who is deficient of Alpha-1 antitrypsin inhales irritants, or contracts a lung infection, the neutrophil elastase released in the lungs continues digesting irritants unchecked, eventually destroying healthy lung tissue. The eventual result of the destruction of healthy lung tissue by neutrophil elastase is emphysema.

However, Alpha-1 Antitrypsin Deficiency emphysema (also known as "genetic" or "inherited" emphysema) is different than emphysema caused by smoking ("acquired" emphysema). In emphysema caused by smoking the damage usually affects the upper portion of the lungs. In the Alpha-1 patient, the lower regions of the lungs are first affected. With either cause, the lungs are hyperinflated due to air trapping caused by the destruction of the lung tissue, and the diaphragms are flattened due to the hyperinflation of the lungs.

Emphysema is a lung disease caused by the destruction of the delicate walls of small air sacs (alveoli). With this destruction, air sacs lose their elasticity and form larger, inefficient sacs that cannot properly exchange oxygen and carbon dioxide with the bloodstream. In addition, it becomes harder to breathe since each drawn breath inflates the lungs, but the lungs do not return to normal with the exhaled breath. This causes air to become trapped, leading to over-inflation of the air sacs. Emphysema caused by Alpha-1 is a progressive disease-the destructive action continues until the lungs can no longer bring in oxygen to the bloodstream.

Alpha-1 emphysema usually causes symptoms in people while they are in their 30's or 40's. While there is no cure for Alpha-1, there are treatments available for the symptoms, as well as augmentation therapy, which may slow down or halt the destruction. Patients with more severe or advanced Alpha-1 lung disease may be candidates for lung transplantation.

Many people with Alpha-1 also have chronic bronchitis. With this, the lung lining becomes swollen and congested with mucus, restricting air flow. The bronchi (air passages) often go into bronchospasms, which are contractions of the muscles which further reduce air flow. This often results in a chronic cough.

Panniculitis in Alpha-1

 

The following article is a reprint from the Alpha-1 Foundation Research Registry Update Spring/Summer Issue 2007 and represents the most comprehensive information on Alpha-1 associated Panniculitis.

See also Alpha-1 Foundation > Newly Diagnosed > Learning About Alpha-1 > Panniculitis.


Panniculitis in Alpha-1 Antitrypsin Deficiency

James K. Stoller, MD, MS

Panniculitis is an uncommon manifestation of alpha-1 antitrypsin deficiency. This brief paper will discuss the definition of panniculitis, the variety of potential causes, current understanding of the mechanism of panniculitis, its signs and symptoms, and available experience with treatment.

Panniculitis is an inflammation of the panniculus, which is the fibro-fatty tissue layer that lies underneath the outermost or superficial layers of our skin. This layer of the skin resembles a honeycomb, with globules of fat separated by walls, or septae. In anatomic terms, panniculitis is categorized as either being septal (involving the walls separating the fatty sections of the panniculus) or lobular (affecting the fat globules or collections themselves).

Like most medical conditions, panniculitis can arise from many underlying causes. Alpha-1 Antitrypsin Deficiency is one of those causes. Among the other potential causes are a group of diseases known as connective tissue disease (which include conditions causing diffuse body inflammation, such as systemic lupus erythematosus and rheumatoid arthritis), underlying so-called lymphoproliferative diseases (like lymphoma), pancreatic disease, gout, kidney dysfunction, so-called atheroembolism (in which clots from blood vessels find their way to the fibro-fatty layer of the skin), and even adverse reactions to some drugs, including corticosteroids.

Panniculitis manifests as characteristically red nodular spots on the skin which may break down and ulcerate, causing an oily discharge. While these nodular blotches may occur anywhere on the body, common sites include the thighs and buttocks and areas subject to trauma.

Conditions that may precipitate the development of such nodules include trauma (including rigorous exercise), intravenous injections, cryosurgery on the skin (which is surgery involving freezing the skin). The lesions of panniculitis may go on to develop deep ulceration with tissue breakdown, called necrosis. Such necrotic nodules are usually painful to the touch.

Panniculitis is felt to be due to inflammation of the fibro-fatty layer of the skin, presumably mediated by unopposed protein breakdown. In Alpha-1-related panniculitis, the mechanism of panniculitis resembles that believed to cause the development of emphysema, namely the unopposed breakdown of tissue by the absence of alpha-1 antitrypsin, allowing proteases within the body to affect structures underlying the skin (in the case of panniculitis) or the support matrix of the lung (in the case of emphysema).

Panniculitis is an uncommon complication of Alpha-1 Antitrypsin Deficiency. It was first described in a patient in France in 1972 by Dr. Warter and colleagues. These physicians described a young woman with severe deficiency of alpha-1 antitrypsin who developed characteristic red nodular, painful skin ulcers. Since that original report, fewer than 50 cases of panniculitis in individuals with Alpha-1 Antitrypsin Deficiency have been reported in the medical literature, establishing that panniculitis is a very uncommon complication of Alpha-1 Antitrypsin Deficiency. For example, in the National Heart, Lung, and Blood Institute Registry of Individuals with Severe Deficiency of Alpha-1 Antitrypsin, only a single participant reported having panniculitis. In various reports specifically about panniculitis and Alpha-1, only 28 patients had been described through 1997. Tallying all reported cases through 2003 shows a total of 44 individuals with panniculitis complicating Alpha-1 Antitrypsin Deficiency described in the medical literature.

Importantly, panniculitis in Alpha-1 can accompany various phenotypes (or genetic types of Alpha-1 Antitrypsin Deficiency), some with severe deficiency of serum levels of alpha-1 antitrypsin (e.g., including PI*ZZ and PI*SNull) and others with only mild deficiency (e.g., PI*MZ and PI*MS). In one series by Humbert and colleagues, of the 26 patients with panniculitis and Alpha-1 Antitrypsin Deficiency described, 62% were PI*ZZ, 15% were PI*MZ, 8% were PI*MS, and 4% were PI*SNull; in the remaining 8%, the phenotype was not stated. The reported experience suggests that panniculitis occurs equally among men and women and that the mean age of onset is approximately 40 years old.

Various therapies have been tried and evaluated to treat panniculitis, including corticosteroids, antibiotics (including doxycycline and dapsone), full plasma exchange, and intravenous pooled human plasma alpha-1 antitrypsin (more popularly called augmentation therapy). Of these various treatments, augmentation therapy has been the most dramatically successful. Several reports describe resolution of panniculitis after as few as three doses of intravenous augmentation therapy. The dose of augmentation therapy for panniculitis is the same as that for established emphysema, 60 mg/kg once weekly.

In summary, panniculitis can be both an annoying and also potentially disabling complication of Alpha-1 Antitrypsin Deficiency. Panniculitis is thankfully very uncommon and is amenable to effective treatment with existing approaches for Alpha-1, including augmentation therapy. Undoubtedly, the spectrum of treatment choices for panniculitis will grow along with ongoing research regarding optimal therapy of individuals with Alpha-1 Antitrypsin Deficiency and with the development of new treatment options.

Treatments

Augmentation Therapy

Augmentation therapy consists of weekly intravenous (IV) infusions of Alpha-1 Antitrypsin derived from human plasma. It is used to increase the concentration of the protein in blood and lungs. Augmentation therapy is the only TGA-approved treatment for Alpha-1 Antitrypsin Deficiency. Your respiratory specialist can determine if you are an appropriate candidate for such therapy.
Read more...

Drug and Other Therapies

This is among the most important types of medical therapy for the newly diagnosed individual with Alpha-1 Antitrypsin Deficiency. Although these are most relevant to lung-affected individuals, all Alphas have risks to their lungs. Some of the therapies listed are relevant for all Alpha-1 patients.

For information on Alpha-1 testing, please see page 5 of the AAA booklet.
Read more...

Surgical Options

Organ Transplantation of the lung or liver
Read more...

Participate in Research

 There are many ways that Alphas of all ages and all phenotypes (ZZ, MS, MZ, SS, SZ, etc) can help to advance research and improve the quality of life for Alphas now and in the future. Some studies may be as simple as a self administered questionnaire or participating in a focus group. Others may be a one-time or periodic visits to a physician, or participation in a clinical trial for new therapy. Your participation in research can make a long-lasting impact on the life of Alphas.

The participation by Alphas in research studies and clinical trials is vital to the approval process for new treatments and, eventually, a cure for Alpha-1.

See our Clinical Trials page for details of past and present trials available for participation by Australian residents. 

Booklets

 The AAA has produced an information booklet which contains more detail about A1AD, and a poster for raising awareness. You can access the booklet and poster by clicking on the images below. The poster may be printed locally in A3 or A4 size. Please encourage your family doctor or respiratory physician to put a poster on display in the surgery or patient waiting area! For more information about A1AD, see our Links section.