Alpha 1-antitrypsin deficiency

Chapters:

Watch video only

Introduction0:00–0:47

Alpha-1 antitrypsin deficiency is a genetic disorder in which a protein called alpha-1 antitrypsin is defective or absent.
The name “alpha-1 antitrypsin” is a holdover from when the protein was discovered – a name given before its function was actually known.
As it turns out, alpha-1 antitrypsin is a protease inhibitor that inactivates elastase - which is a type of protease, an enzyme that breaks down other proteins.
Since alpha-1 antitrypsin inactivates elastase can’t break down elastin. So alpha-1 antitrypsin deficiency leads to the opposite case - elastin breakdown - which particularly affects the lungs.
In addition, defective alpha-1 antitrypsin can cause damage to the liver. Now, in the lungs, if we zoom in on a tiny alveolus—where gas exchange happens—if there’s some sort of infection or other cause of inflammation, inflammatory cells like neutrophils arrive on the scene.

Physiology0:47–1:34

Neutrophils make an enzyme called neutrophil elastase, a protease capable of breaking down elastin, which is an extracellular matrix protein that gives elasticity and strength to lung tissues.
So while these little guys can help fight off infection by breaking down proteins of the bacteria, they can also go on to break down that precious elastin.
Fortunately, the liver makes alpha-1 antitrypsin which gets released into the blood and sent to the lungs, where it inhibits neutrophil elastase, inactivating it before it can break down the protein elastin.

Pathology1:34–4:34

Without alpha-1 antitrypsin, the opposite happens - neutrophil elastase goes unchecked, and it damages the walls of the alveoli, and without that elastin, the alveoli lose their elasticity and structural integrity.
Zooming out a bit and looking at the acinus, which is a bunch of alveoli, it just turns into one big cavity. This destruction and enlargement of the air spaces is called emphysema.
It turns out that emphysema can develop in a couple different ways, and alpha-1 antitrypsin deficiency causes pan-acinar emphysema, meaning the whole acinus is affected, and it also tends to affect the lungs’ lower lobes the most.
Another effect of unchecked inflammation in alpha-1 antitrypsin deficiency is chronic bronchitis and bronchiectasis, two conditions resulting from chronic airway inflammation.
So alpha-1 antitrypsin deficiency can lead to emphysema, bronchiectasis, and chronic bronchitis, all types of chronic obstructive pulmonary disease, or COPD.
Another, more common cause of COPD is smoking, and if someone with alpha-1 antitrypsin deficiency also smokes, they tend to get an earlier onset of COPD than they would have otherwise, an example of a gene-environment interaction.
The gene that encodes alpha-1 antitrypsin protein is called SERPINA1, which stands for serine protease inhibitor, clade A, member 1 which is located on the long arm of chromosome 14.
While some mutations in SERPINA1 completely abolish the gene’s message meaning no protein is made, others like the most common mutation, called Pi*Z, results in a misfolded alpha-1 antitrypsin protein being made.
Misfolded alpha-1 antitrypsin can aggregate and get stuck in the endoplasmic reticulum of the liver hepatocytes where it’s made, causing some of those cells to die.
Now, each wild-type, or normal, copy of alpha-1 antitrypsin protein, termed Pi*M, contributes 50% of normal alpha-1 antitrypsin or A1AT activity, meaning two normal copies gets you 100%, which just means there’s a normal amount of A1AT in the blood.
If instead they had one normal copy and one mutant copy , Z, abbreviated PiMZ, the mutated gene only contributes ~ 10% normal amounts, so these individuals only have about 60% the normal levels, which is usually enough to protect the lungs in non-smokers.
If both copies of the gene were mutant Z copies, then typically there’s only 15 - 20% of normal levels, which results in alpha-1 antitrypsin deficiency.
While there is some increased risk of lung and liver injury in PiMZ individuals, severe deficiency with two mutant genes gives such individuals a much higher risk of lung and liver disease.
Having said that, though, some people with PiZZ deficiency can live their entire lives with no lung or liver disease if their environmental exposures are minimal.

Symptoms4:34–5:46

Symptoms of alpha-1 antitrypsin deficiency typically involve the lungs and liver. The changes in the lungs that cause chronic obstructive pulmonary disease can result in shortness of breath, as well as wheezing, mucus production, and a chronic cough.
The death of liver cells can ultimately lead to cirrhosis, a process in which normal liver tissue is replaced with scar tissue.
Cirrhosis can ultimately lead to a number of complications including an inability to make coagulation factors, difficulty with detoxification leading to a buildup of waste products that can cause hepatic encephalopathy, portal hypertension that can lead to esophageal varices, and an increase in the risk of a type of liver cancer called hepatocellular carcinoma.
Although cirrhosis usually affects adults, even newborns can have complications like jaundice, or buildup of bilirubin in the blood, on account of poor excretion by the liver.
A very small minority of infants who are born with two Z genes can develop liver failure during their first years of life and require a liver transplant.
If, though, somebody has the mutant SERPINA1 that results in no A1AT, as opposed to the misfolded ones that get stuck, then they typically don’t have liver disease.

Diagnosis5:46–6:53

Diagnosis of alpha-1 antitrypsin deficiency often begins with a chest X-ray or Chest CT scan to look for hyperinflated lungs or evidence of damaged lung tissue.
In addition, pulmonary function testing can be used to measure how quickly air exits the lung, which can be slower than normal.
The level of alpha-1 antitrypsin in the blood can also be measured. Cirrhosis caused by alpha-1 antitrypsin can be diagnosed with liver ultrasound or a liver biopsy.
When evaluating a biopsy, microscopic sections of liver tissue are stained with a combination of two reagents called Periodic Acid Schiff, or PAS.
This test stains glycoproteins like alpha-1 antitrypsin a pink color. The tissue is also exposed to diastase, which is an enzyme that normally destroys many glycoproteins, but since alpha-1 antitrypsin is stuck and hidden away in the endoplasmic reticulum, diastase can’t get to it and so it’s diastase resistant.
So we say that they’d be Periodic Acid Schiff positive, or PAS positive, as well as diastase resistant. In terms of treatment, augmentation therapy is where you given intravenous infusions of normal alpha-1 antitrypsin protein purified from the blood of healthy plasma donors.

Treatment6:53–7:30

This doesn’t cure the lung disease but it does slow or halt its progression, so other therapies for chronic obstructive pulmonary disease like inhalers and supplemental oxygen are often needed as well.
Supplementing the deficient protein in the blood doesn’t fix the liver problems, since they’re caused by defective alpha-1 antitrypsin building up in the hepatocytes.
So standard treatments for cirrhosis are usually needed, like lactulose to prevent hepatic encephalopathy. Quick recap – In alpha-1 antitrypsin deficiency, the alveoli in the lungs are damaged by neutrophil elastase since there’s insufficient alpha 1 antitrypsin to counter it, causing chronic obstructive pulmonary disease, and in the liver, misfolded alpha 1 antitrypsin builds up, killing hepatocytes and leading to cirrhosis.

Review7:30–7:53