Alpha-1 antitrypsin deficiency is a genetic disorder that causes liver disease. Vitamin D deficiency may worsen alpha-1 antitrypsin deficiency symptoms.

Alpha-1-Antitrypsin Deficiency

Overview

Alpha-1 antitrypsin (AAT) is a protease inhibitor formed in the liver. It is carried to the lungs, where it&rsquo;s also formed in restricted quantities by macrophages and bronchial epithelial cells. The purpose of AAT is to shield the respiratory tract from the enzymes released by the white cells as a typical immune function.

Alpha-1 antitrypsin deficiency, also known as AAT deficiency, is a hereditary disorder. The common symptoms of this deficiency include breathing difficulties and jaundiced, or yellow, skin, and a potential to cause serious lung or liver disease. Although there is no cure yet, there are treatments that help with symptomatic management.

Smokers with AAT inadequacy tend to develop the disease 10 or more years earlier than people who don&#39;t smoke<a href="#accrodion">[6]</a>. AAT deficiency is a hereditary disorder affecting approximately 3.4 million people worldwide<a href="#accordion">[1]</a>. 
&nbsp;

The disorder is inherited from the parents and it causes damage to the lungs and liver. Lung symptoms are often similar to those seen in emphysema, such as a chronic cough, shortness of breath, and wheezing. Once the liver is affected, symptoms similar to cirrhosis such as <a href="https://merisehat.pk/disease/jaundice-65">jaundice</a> and throwing up of blood present themselves indicating the poor functioning of the organ.

While treatments help to lower the risk of lung damage, quitting smoking is by far the most effective way to prevent serious complications from developing.

AAT deficiency affects approximately 1 in 3,000 people in the UK<a href="#accordion">[7]</a>, and approximately 1 in 25 northern Europeans are carriers<a href="#accordion">[8]</a>. 
&nbsp;

Signs and Symptoms

Not everyone who has AAT deficiency (AATD) gets the attributable disease<a href="#accordion">[2]</a>. The form of mutation associated with AATD determines how the disease manifests. However, the majority of AATD-related symptoms are limited to the respiratory system. 
&nbsp;

The 2 primary clinical presentations of AATD are:

<ol>
	<li>&nbsp;Liver ailments (such as cirrhosis and chronic hepatitis) are caused by an unusual buildup of AAT within the liver cells, i.e., hepatocytes and hepatoma</li>
	<li>&nbsp;<a href="https://merisehat.pk/disease/emphysema">Emphysema</a> is caused by the loss of the proteolytic protection of the lung. 
	&nbsp;</li>
</ol>

Other, less frequent, presentations include:

<ol>
	<li>&nbsp;Panniculitis, which is the hardening of the skin and painful lumps or patches begin to appear on the skin, too</li>
	<li>&nbsp;Cytoplasmic anti-neutrophil cytoplasmic antibody-associated vasculitis. 
	&nbsp;</li>
</ol>

Symptoms usually appear between the ages of 20 and 40<a href="#accordion">[9]</a>, including shortness of breath especially during exercise. A delayed diagnosis means most people do not even realize they have the disease until they are an adult. At this stage, individuals with AATD also begin to wheeze or make a whistling sound whenever they breathe, and they may develop lung infections as well. 
&nbsp;

Other red flags that help detect AATD include:

<ul>
	<li>Feeling exhausted</li>
	<li>Racing heart while getting up</li>
	<li>Loss of weight 
	&nbsp;</li>
</ul>

If AATD has progressed and there are issues with the liver, the patient will experience the following symptoms:

<ul>
	<li>Yellowish eyes or skin</li>
	<li>Swollen abdomen or legs</li>
	<li>Coughing up blood 
	&nbsp;</li>
</ul>

A newborn baby may have the following:

<ul>
	<li>Jaundice with the characteristic yellow tint on the skin or in the eyes</li>
	<li>Yellow colored urine</li>
	<li>Difficulty in gaining weight</li>
	<li>Swollen liver</li>
	<li>Nasal or umbilical stump bleeding. 
	&nbsp;</li>
</ul>

Causes

AATD is an autosomal co-dominant condition. If a person is diagnosed with it, then that means they inherited the condition from their parents through faulty genes. Additionally, it means that there may be individuals who have the genes but remain asymptomatic or have a mild form of the disease.

The faulty genes reduce the level of AAT protein in the blood. As a result, it may accumulate in the liver rather than enter the bloodstream. The accumulation of AAT in the liver induces liver ailment, whereas the deficiency of AAT protein in the blood causes lung disease. 
&nbsp;

Diagnosis

The diagnosis for AATD is frequently missed because it&rsquo;s so similar to other more common ailments, like asthma, COPD, or chronic cough. It is recommended to include AATD in the differential diagnosis of the following diseases<a href="#accordion">[11]</a>:

<ul>
	<li>Cystic Fibrosis</li>
	<li>Autoimmune Hepatitis</li>
	<li>Bronchiectasis</li>
	<li>Primary Ciliary Dyskinesia (Kartagener Syndrome)</li>
	<li>Chronic Obstructive Pulmonary Disease (COPD), including emphysema and bronchitis</li>
	<li>Viral Hepatitis 
	&nbsp;</li>
</ul>

If a patient presents any signs of lung ailment, the doctor may advise a number of diagnostic tests<a href="#accordion">[10]</a>:

<ul>
	<li>A Blood Test To Determine AAT Levels - The laboratory evaluation measures serum alpha-1-antitrypsin levels. Normally, it should be 100-190 mg/dL; levels less than 57 mg/dL are thought to accelerate lung damage<a href="#accordion">[12]</a></li>
	<li>&nbsp;Gene Testing - Testing includes ultra-modern AAT proteotype analysis using liquid chromatography-tandem mass spectrometry to distinguish normal M variants from specific AAT disease variants, for example, Z and S variants.</li>
	<li>An arterial blood gas (ABG) test to measure the blood&#39;s oxygen and carbon dioxide levels</li>
	<li>An X-ray and CT scan of the chest to look for signs of lung damage</li>
	<li>An electrocardiogram and an echocardiogram to detect changes in heart</li>
	<li>A pulse oximetry test to determine the oxygen saturation level</li>
	<li>A pulmonary function test to determine lung functioning.</li>
	<li>Liver ultrasound</li>
	<li>Noninvasive MRI-based technique to detect liver fibrosis (MR elastography)</li>
	<li>In some instances, a liver ultrasound and biopsy will also be performed. If the AAT levels are low, but the liver and lung function tests are normal, then the patient may not require treatment; however, they will be routinely monitored with repeat testing over time<a href="#accordion">[6]</a>. 
	&nbsp;</li>
</ul>

Please Note

<ul>
	<li>X-rays and CT scans of the chest for traditional emphysema primarily reflect damage to the upper lungs. However, in case of AATD-related emphysema, changes will usually occur in the lower lung.</li>
	<li>If there&rsquo;s a family history of AATD and COPD, please consult a medical professional. 
	&nbsp;</li>
</ul>

Treatment

<h5>Lung Conditions From Alpha-1</h5>

These are treated depending on the symptoms. Usually bronchodilators and pulmonary rehabilitation are recommended. Any or a combination of the following treatments can also be advised: 
&nbsp;

<ul>
	<li>Medications - The mainstay of treatment include inhaled corticosteroids and<a href="https://my.clevelandclinic.org/health/treatments/17575-bronchodilator"> </a>bronchodilators. These aid in reducing inflammation.&nbsp; 
	&nbsp;</li>
	<li>Oxygen Therapy - Depending on the damage to the lungs, patients might require supplemental oxygen. 
	&nbsp;</li>
	<li>Pulmonary Rehabilitation - This includes physical therapy and breathing exercises to help the patient with troubled breathing.&nbsp; 
	&nbsp;</li>
	<li>Lung Transplant -&nbsp;AAT deficiency accounts for approximately 12% of all lung transplant operations for emphysema. Some patients with advanced lung disease benefit from lung transplantation. Due to a lack of available donor lungs, single lung transplants are more common even though double lung transplant patients have better outcomes. The 5-year survival rate after lung transplant is around 50%, with bronchiolitis obliterans being the leading cause of death post-transplant. 
	&nbsp;</li>
	<li>Lung Volume Reduction Surgery -&nbsp;In patients with typical emphysema, lung volume reduction surgery (LVRS) improves exercise capacity and alleviates dyspnea, but the study is less clear as far as AATD is concerned. One study found that bilateral LVRS was beneficial in AAT-deficient patients with emphysema, but functional measurements (except the 6-minute walk test) returned to baseline after 6-12 months<a href="#accordion">[3]</a>. 
	&nbsp;</li>
	<li>Emphysema Due To Very Low Levels Of Alpha 1 - In this case augmentation therapy is recommended. In this treatment option supplemental normal AAT is provided to the patient through an infusion. It is important to mention that augmentation therapy can&rsquo;t reverse the lung damage, it can help slow down the progression of emphysema. 
	&nbsp;</li>
</ul>

There are 3 possible AAT augmentation therapy<a href="#accordion">[1]</a>:

(1) Intravenous human plasma-derived augmentation therapy

(2) Augmentation therapy by inhalation

(3) Recombinant AAT augmentation therapy

&nbsp;

<ul>
	<li>Intravenous Human Plasma-Derived Augmentation Therapy</li>
</ul>

Intravenous administration of purified human AAT concentrate has been shown to elevate lung AAT levels in AAT-deficient patients. Patients who received IV doses once a week increased anti-neutrophil elastase capacity in lung epithelial lining fluid by 60-70%. A purified preparation was formed and demonstrated to be biologically active. As a result, the treatment was approved by the US Food and Drug Administration in 1988.

&nbsp;

<ul>
	<li>&nbsp;Augmentation Therapy By Inhalation</li>
</ul>

In people with AAT deficiency, aerosol application of AAT boosts AAT concentration and anti-elastase activity in the lower respiratory tract in a dose-dependent manner. Preliminary data suggest that administering aerosolized AAT one or two times every day may result in long-term anti-elastase protection of the lungs. 
&nbsp;

<ul>
	<li>Recombinant AAT Augmentation Therapy And Synthetic Elastase Inhibition</li>
</ul>

Despite the fact that several AAT recombinant forms have been formed and that recombinant secretory leukoprotease inhibitors and many synthetic low molecular weight elastase inhibitors are being studied, their clinical effectiveness has not been recorded. At present, the data only suggests a lowered overall mortality and a reduced rate of FEV<a href="#accordion">[1]</a>&nbsp;decline in augmentation therapy recipients. 
&nbsp;

<h5>Liver Damage From&nbsp;Alpha-1</h5>

<ul>
	<li>Usually symptomatic management is provided, however a definitive cure can be achieved through liver transplant alone.</li>
	<li>Liver transplantation is accepted as a curative procedure in children and adults who have end-stage liver disease<a href="#accordion">[5]</a>. 
	&nbsp;</li>
</ul>

<h5>Other Measures </h5>

<ul>
	<li>Smoking cessation therapy</li>
	<li>Quitting alcohol</li>
	<li>Vaccinations to prevent pneumonia and viral hepatitis 
	&nbsp;</li>
</ul>

Please Note 
Individuals with symptoms may require life-long treatment, and early diagnosis may decrease the clinical and economic burden of advancing lung degradation. 
&nbsp;

Complications of AATD include:

<ul>
	<li><a href="https://merisehat.pk/disease/copd">COPD</a></li>
	<li><a href="https://merisehat.pk/disease/emphysema">Emphysema</a></li>
	<li>Bronchiectasis</li>
	<li><a href="https://merisehat.pk/disease/pulmonary-hypertension">Pulmonary hypertension</a></li>
	<li><a href="https://merisehat.pk/disease/cirrohsis">Cirrhosis</a></li>
	<li>Liver Cancer</li>
	<li>Panniculitis</li>
	<li><a href="https://merisehat.pk/disease/pneumonia">Pneumonia</a> 
	&nbsp;</li>
</ul>

In severe cases, it might lead to:

<ul>
	<li>Heart failure</li>
	<li>Respiratory failure</li>
	<li>Liver failure 
	&nbsp;</li>
</ul>

The following risk factors are associated with the development of AATD<a href="#accordion">[4]</a>: 
&nbsp;

<ul>
	<li>Patients with known AAT deficiency pass the gene to their kids.</li>
	<li>Patients with AAT insufficiency have chronic lung ailment due to smoking.</li>
	<li>Patients with AATD are more vulnerable to lung ailments due to exposure to dust, fumes, or other toxic substances. 
	&nbsp;</li>
</ul>

In accordance with the Global Initiative for Chronic Obstructive Lung Disease guidelines, all individuals with COPD, should be tested for AAT inadequacy regardless of their age or ethnicity<a href="#accordion">[6]</a>. Besides, screening is recommended in case of family history for correct identification of the condition. That is, if a patient has a parent or sibling with AAT inadequacy, screening helps control lung or liver issues from progressing.

Also, the common standards of the European Respiratory Society and American Thoracic Society suggest that siblings of people with AAT inadequacy be tested as well. Other first-degree relatives or partners could be tested, but this is not routinely advised.

A diagnosis of AATD does not guarantee that it will lead to emphysema. It&rsquo;s possible to lower the risk of developing this lung ailment by not smoking, eating a healthy diet, and exercising regularly. It&rsquo;s also essential to take the medications as directed by the doctor in order to slow the progression of the disease. 
&nbsp;

Emerging Liver‐Directed Therapies For AATD

There are no treatments as yet that specifically treat AATD-related liver disease. However, research is being done on treatment plans that target various pathways in the pathophysiology of the condition.

For example, autophagy is a process whereby the cells get rid of misfolded proteins. It is one of the realistic strategies for the body to eliminate the Z mutant AAT. Animal models have been used to study autophagy stimulants, such as sirolimus, carbamazepine, and rapamycin, and they have proved to be effective during the trials. However, no human experiments have taken place for the same<a href="#accordion">[5]</a>. 
&nbsp;

Moreover, the oligonucleotide treatment conducted in mice models promises to lower the circulating AAT as well as reduce the aggregated hepatic AAT. Studies have shown both short- and long-term beneficial positive impact on liver fibrosis. Although human trials could not be completed due to toxicity associated with carrier vehicles in non-human studies, the RNA inhibition technology has demonstrated some encouraging outcomes in lowering ZZ mutant protein production in humans. Currently, drugs based on small interfering RNA are actively being tested in phase 2 trials<a href="#accordion">[5]</a>.

Another therapy works on the fact that chemical chaperones facilitate correct protein folding. The issue is that there&rsquo;s quite a significant amount of AAT generated every day and, therefore, ensuring 1:1 binding stoichiometry would similarly require a sizable quantity of chaperones to be supplied to the endoplasmic reticulum. At present, human phase 2 trials of novel small-molecule chaperones are underway by Vertex Corporation and they seem to be promising for both liver and lung disease<a href="#accordion">[5]</a>. 
&nbsp;

Key Points

<ul>
	<li>Alpha-1 antitrypsin (AAT) is a protein formed in the liver and circulated in the blood. It helps protect the lungs and liver from protease-mediated destruction.</li>
	<li>A lack of AAT protein is a two-fold condition: 1, it affects the lungs and triggers emphysema along with asthma, chronic bronchitis, and COPD; 2, it affects the liver and results in cirrhosis, liver scarring, liver failure, and liver cancer.</li>
</ul>

<ul>
	<li>A family doctor may test for AATD if they suspect the patient has the condition, especially if the patient has been diagnosed with COPD. They may also do it as part of family screening. In case the test result comes back positive, they may refer the individual to a specialist for genetic counseling and further tests.</li>
	<li>At present, there is no cure for AATD. Symptoms determine treatment. The primary goal of AATD treatment is to prevent or hinder lung/liver ailment advancement. 
	&nbsp;</li>
</ul>