Alpha 1 antitrypsin deficiency causes, symptoms, diagnosis, treatment, pathology

Summary

Alpha-1 antitrypsin deficiency is a genetic disorder where the alpha-1 antitrypsin protein, a protease inhibitor, is defective or absent, leading to lung and liver diseases. The lack of this protein allows neutrophil elastase to damage lung tissue, causing emphysema and chronic bronchitis, which are types of COPD. Liver issues arise from misfolded alpha-1 antitrypsin accumulating in hepatocytes, potentially leading to cirrhosis. The condition is diagnosed through imaging, pulmonary function tests, and blood level measurements. Treatment includes augmentation therapy and managing COPD and liver complications, but it does not cure the disease.

Takeaways

• 🧬 Alpha-1 antitrypsin deficiency is a genetic disorder affecting the protein alpha-1 antitrypsin, which is crucial for preventing lung and liver diseases.
• 🛡️ Alpha-1 antitrypsin acts as a protease inhibitor, neutralizing proteases like neutrophil elastase that can break down proteins, including elastin in lung tissues.
• 🚨 In the absence of alpha-1 antitrypsin, neutrophil elastase can damage lung tissue, leading to a loss of elasticity and structural integrity of the alveoli, causing emphysema.
• 💨 Emphysema caused by alpha-1 antitrypsin deficiency is pan-acinar, affecting the entire acinus and predominantly impacting the lower lobes of the lungs.
• 🚭 Smoking exacerbates the effects of alpha-1 antitrypsin deficiency, leading to an earlier onset of chronic obstructive pulmonary disease (COPD).
• 🧬 The gene responsible for encoding alpha-1 antitrypsin is called SERPINA1, and mutations in this gene can lead to the production of misfolded proteins or no protein at all.
• 🧬 The most common mutation, PiZ, results in misfolded alpha-1 antitrypsin that can aggregate and cause liver damage due to accumulation in hepatocytes.
• 🌟 Alpha-1 antitrypsin deficiency is a recessive disease, requiring two mutant copies of the gene (ZZ) for the disease to manifest.
• 🏥 Diagnosis of alpha-1 antitrypsin deficiency can involve chest imaging, pulmonary function testing, and blood level measurements of the protein.
• 🛠️ Treatment options include augmentation therapy to replace alpha-1 antitrypsin in the blood and standard treatments for cirrhosis if liver problems are present.

Q & A

What is alpha-1 antitrypsin deficiency?

Alpha-1 antitrypsin deficiency is a genetic disorder where the protein alpha-1 antitrypsin is defective or absent, leading to lung and liver diseases.

What is the role of alpha-1 antitrypsin in the body?

Alpha-1 antitrypsin is a protease inhibitor that inactivates proteases like trypsin and neutrophil elastase, preventing the breakdown of proteins, especially elastin in the lungs.

How does alpha-1 antitrypsin deficiency affect the lungs?

Without alpha-1 antitrypsin, neutrophil elastase breaks down elastin in the lungs, damaging the alveoli, leading to a loss of elasticity and structural integrity, and causing emphysema.

What type of emphysema is caused by alpha-1 antitrypsin deficiency?

Alpha-1 antitrypsin deficiency causes panacinar emphysema, which affects the whole acinus and tends to impact the lower lobes of the lungs the most.

How can alpha-1 antitrypsin deficiency lead to chronic bronchitis?

Unchecked inflammation due to alpha-1 antitrypsin deficiency can result in increased mucus production and narrowing of the airways, leading to chronic bronchitis.

How does smoking affect individuals with alpha-1 antitrypsin deficiency?

If someone with alpha-1 antitrypsin deficiency smokes, they are likely to experience an earlier onset of COPD due to the combined effects of genetic and environmental factors.

What is the gene responsible for encoding alpha-1 antitrypsin protein?

The gene that encodes the alpha-1 antitrypsin protein is called SERPINA1, which stands for serine peptidase inhibitor, clade A, member 1.

What is the most common mutation associated with alpha-1 antitrypsin deficiency?

The most common mutation associated with alpha-1 antitrypsin deficiency is the PiZ mutation, which results in a misfolded alpha-1 antitrypsin protein.

How does alpha-1 antitrypsin deficiency affect the liver?

Misfolded alpha-1 antitrypsin can aggregate and get stuck in the endoplasmic reticulum of liver hepatocytes, causing cell death and potentially leading to cirrhosis.

What are the typical symptoms of alpha-1 antitrypsin deficiency in the lungs and liver?

Symptoms of alpha-1 antitrypsin deficiency in the lungs include shortness of breath, wheezing, mucus production, and chronic cough. In the liver, it can lead to cirrhosis, which has various complications such as difficulty in making coagulation factors, hepatic encephalopathy, and an increased risk of hepatocellular carcinoma.

How is alpha-1 antitrypsin deficiency diagnosed?

Diagnosis of alpha-1 antitrypsin deficiency often starts with a chest X-ray or CT scan to look for hyper-inflated lungs or damaged lung tissue. Pulmonary function testing and measuring the level of alpha-1 antitrypsin in the blood can also be used. For liver issues, a liver biopsy can be performed, and the tissue can be tested for PAS positivity and diastasis resistance.

What is the treatment for alpha-1 antitrypsin deficiency?

Augmentation therapy, which involves replacing alpha-1 antitrypsin in the blood, is one treatment option. However, it does not cure the disease, and other therapies for COPD, such as supplemental oxygen, may also be needed. Liver problems due to alpha-1 antitrypsin buildup require standard treatments for cirrhosis, like using lactulose to prevent hepatic encephalopathy.

Outlines

00:00

😷 Alpha-1 Antitrypsin Deficiency and Its Effects

Alpha-1 antitrypsin deficiency is a genetic disorder where the alpha-1 antitrypsin protein, a protease inhibitor, is defective or absent, leading to lung and liver diseases. This protein normally prevents proteases like neutrophil elastase from breaking down elastin, a protein important for lung elasticity. When absent, proteases damage lung tissue, causing emphysema characterized by enlarged air spaces. The condition affects the lower lung lobes predominantly and can lead to chronic bronchitis, contributing to chronic obstructive pulmonary disease (COPD). The genetic aspect involves mutations in the SERPINA1 gene, which may either delete the gene's message or result in misfolded proteins that cause liver damage. The disease is recessive, and symptoms include shortness of breath, wheezing, and chronic cough due to COPD, and liver cirrhosis due to cell death in the liver.

05:00

🧬 Diagnosis and Treatment of Alpha-1 Antitrypsin Deficiency

Diagnosing alpha-1 antitrypsin deficiency involves chest X-rays or CT scans to identify lung damage, pulmonary function tests to measure airflow, and blood tests to measure the protein's levels. Liver cirrhosis due to the buildup of misfolded alpha-1 antitrypsin can be confirmed with a liver biopsy, where the liver cells are stained with periodic acid and Schiff reagents, revealing diastasis-resistant alpha-1 antitrypsin. Treatment options include augmentation therapy, which replaces the deficient protein in the blood, and supplemental therapies for COPD such as supplemental oxygen. Liver issues are treated with standard cirrhosis therapies, like lactulose to prevent hepatic encephalopathy. The video concludes with a recap of the disease's impact on lung function and liver health, and a reference to Osmosis.org for further educational resources.

Keywords

💡alpha-1 antitrypsin deficiency

Alpha-1 antitrypsin deficiency is a genetic disorder where the protein alpha-1 antitrypsin is either defective or absent. This protein is crucial as it acts as a protease inhibitor, preventing the breakdown of other proteins. In the context of the video, this deficiency leads to lung and liver diseases because the absence of alpha-1 antitrypsin allows proteases like neutrophil elastase to damage lung tissue, causing conditions like emphysema and chronic bronchitis, which are types of chronic obstructive pulmonary disease (COPD).

💡protease

A protease is an enzyme that breaks down other proteins. In the video, proteases play a dual role: while they are beneficial for fighting infections by breaking down bacterial proteins, they can also cause harm by breaking down essential proteins like elastin in the lungs. Neutrophil elastase, a type of protease, is particularly highlighted as it can lead to lung damage in the absence of alpha-1 antitrypsin.

💡neutrophil elastase

Neutrophil elastase is a protease enzyme produced by immune cells called neutrophils. It is capable of breaking down elastin, an extracellular matrix protein that provides elasticity and strength to lung tissues. The video explains that when alpha-1 antitrypsin is deficient, neutrophil elastase can cause damage to the alveoli, leading to emphysema.

💡emphysema

Emphysema is a lung condition characterized by the destruction and enlargement of air spaces, which reduces the lungs' ability to transfer oxygen to the blood. The video describes how alpha-1 antitrypsin deficiency leads to a specific type called panacinar emphysema, affecting the entire acinus (functional unit of the lung) and tending to impact the lower lobes of the lungs the most.

💡chronic bronchitis

Chronic bronchitis is a condition resulting from unchecked inflammation, leading to increased mucus production and narrowing of the airways. The video script mentions that alpha-1 antitrypsin deficiency can result in chronic bronchitis, which, along with emphysema, contributes to the development of chronic obstructive pulmonary disease (COPD).

💡COPD

COPD, or chronic obstructive pulmonary disease, is a collective term for progressive lung diseases that include emphysema and chronic bronchitis. The video emphasizes that alpha-1 antitrypsin deficiency can lead to both emphysema and chronic bronchitis, which are types of COPD. Smoking is also mentioned as a common cause of COPD, and individuals with alpha-1 antitrypsin deficiency who smoke may experience earlier onset of COPD.

💡SERPINA1

SERPINA1 is the gene that encodes for the alpha-1 antitrypsin protein. Mutations in this gene can lead to the production of either no protein or a misfolded protein, as explained in the video. The script discusses how different mutations can affect the functionality of alpha-1 antitrypsin, with the most common mutation, PiZ, resulting in misfolded protein that can cause liver damage.

💡misfolded protein

A misfolded protein refers to a protein that has not folded correctly into its functional shape. In the context of alpha-1 antitrypsin deficiency, the video describes how the PiZ mutation leads to the production of misfolded alpha-1 antitrypsin proteins that aggregate and become stuck in the endoplasmic reticulum of liver cells, causing liver damage and potentially leading to cirrhosis.

💡cirrhosis

Cirrhosis is a liver disease where normal liver tissue is replaced with scar tissue, which impairs liver function. The video explains that in alpha-1 antitrypsin deficiency, misfolded alpha-1 antitrypsin proteins accumulate in liver cells, leading to cell death and the development of cirrhosis. This can result in various complications, including an inability to produce necessary proteins, difficulty detoxifying the body, and an increased risk of liver cancer.

💡augmentation therapy

Augmentation therapy is a treatment for alpha-1 antitrypsin deficiency that involves replacing the missing alpha-1 antitrypsin protein in the blood. The video mentions that while this therapy does not cure the disease, it can help manage symptoms. However, it does not address liver problems caused by the buildup of misfolded alpha-1 antitrypsin in liver cells.

💡lactulose

Lactulose is a medication used in the treatment of cirrhosis, specifically to prevent hepatic encephalopathy, a condition characterized by confusion and altered consciousness due to liver failure. The video script notes that standard treatments for cirrhosis, such as lactulose, may be necessary alongside augmentation therapy for individuals with alpha-1 antitrypsin deficiency.

Highlights

Alpha-1 antitrypsin deficiency is a genetic disorder affecting the protein alpha 1-antitrypsin, leading to lung and liver disease.

Alpha 1-antitrypsin is a protease inhibitor that prevents the breakdown of proteins by proteases.

Neutrophil elastase, an enzyme from immune cells, breaks down elastin in the lungs, affecting their elasticity and strength.

The liver produces alpha 1-antitrypsin to inhibit neutrophil elastase, protecting lung tissues.

Without alpha 1-antitrypsin, neutrophil elastase damages the alveoli, causing emphysema.

Alpha-1 antitrypsin deficiency leads to pan acinar emphysema, affecting the entire lung and predominantly the lower lobes.

Unchecked inflammation from the deficiency can also result in chronic bronchitis.

Alpha-1 antitrypsin deficiency can cause both emphysema and chronic bronchitis, which are types of COPD.

Smoking can exacerbate COPD in individuals with alpha 1-antitrypsin deficiency, leading to earlier onset.

The gene responsible for alpha 1-antitrypsin is called SERPINA1, with mutations impacting the protein's function.

The most common mutation, PiZ, results in misfolded alpha 1-antitrypsin that can aggregate in the liver.

Having one normal and one mutant gene (PiMZ) results in about 60% of normal alpha 1-antitrypsin levels.

Two mutant Z copies lead to alpha 1-antitrypsin deficiency, with only 15-20% of normal levels.

Symptoms of alpha 1-antitrypsin deficiency include shortness of breath, wheezing, and chronic cough.

Liver complications can lead to cirrhosis, which has several severe health implications.

Diagnosis of alpha 1-antitrypsin deficiency involves chest imaging, pulmonary function testing, and blood level measurements.

Liver cirrhosis caused by misfolded alpha 1-antitrypsin can be diagnosed with a liver biopsy and specific staining tests.

Treatment options include augmentation therapy to replace alpha 1-antitrypsin in the blood and standard treatments for cirrhosis.

Transcripts

alpha-1 antitrypsin deficiency is a

genetic disorder in which a protein

called alpha 1-antitrypsin is defective

or absent and this causes lung and liver

disease trips ins are a type of protease

which is an enzyme that can break down

other proteins

so this antitrypsin protein is a

protease inhibitor and inactivate strip

sins thereby preventing protein

breakdown the alpha one is just a letter

and number combination given before its

role was known

now in the lungs if we zoom in on a tiny

alveolus which is where gas exchange

happens when there's some sort of

infection or other cause of inflammation

immune cells like neutrophils arrive on

the scene

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 it 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 just like

it inhibits trypsin in activating it

before it can break down the elastin

without alpha 1-antitrypsin the opposite

happens neutrophil elastase goes

unchecked and it damages the walls of

the alveolus and without that elastin

the alveolus loses its elasticity and

structural integrity

zooming out a bit and looking at the

hacen s 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 Asness 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 resulting from increased

mucus production in narrowing of the

Airways so alpha-1 antitrypsin

deficiency can lead to both emphysema

and chronic bronchitis which are the two

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

now the gene that encodes alpha

1-antitrypsin protein is called sir Pina

one which stands for serpent peptidase

inhibitor clade a member one while some

mutations in Serafina one completely

delete the genes message meaning there's

no alpha one antitrypsin protein others

like the most common mutation called Piz

results in a miss folded alpha one

antitrypsin protein being made miss

folded alpha one 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 the

alpha 1-antitrypsin gene termed M

contributes 50% of normal alpha

1-antitrypsin activity meaning its

codominant and two normal copies gets

you a hundred percent normal activity

which just means that there's a normal

amount of alpha 1-antitrypsin in the

blood if instead they had one normal

copy in one mutant copy z abbreviated

PMZ

the mutated gene only contributes about

10% of normal amounts so these

individuals only have about sixty

percent the normal levels in their blood

which is actually usually enough to

protect the lungs in non-smokers

if both copies of the gene were mutant Z

copies though then typically there's

only about fifteen to twenty percent of

normal levels which results in alpha

1-antitrypsin deficiency since you need

both mutant copies for the disease this

makes alpha 1-antitrypsin deficiency a

recessive disease symptoms of alpha

1-antitrypsin deficiency typically

involved the lungs in the liver the

changes in the lungs that cause chronic

obstructive pulmonary disease result in

shortness of breath as well as wheezing

mucus production and chronic cough the

death of liver cells can ultimately lead

to cirrhosis a process in which normal

liver tissues replaced with scar tissue

cirrhosis can 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 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 because of

poor excretion by the liver if though

somebody has the mutant subpoena one

gene that results in no alpha

1-antitrypsin protein as opposed to the

miss folded ones that gets stuck then

they typically don't have any liver

disease diagnosis of alpha 1-antitrypsin

deficiency often starts at the chest

x-ray or chest CT scan to look for

hyper-inflated lungs or evidence of

damaged lung tissue in addition

pulmonary function testing can be used

to measure how quickly air exits the

lungs which can be slower than normal

the level of alpha 1-antitrypsin in the

blood can also be measured cirrhosis

caused by misfolded alpha 1-antitrypsin

can be diagnosed with a liver biopsy

liver cells are treated with

accommodation of two reagents called

periodic acid and Schiff or pas this

test stains glycoproteins like alpha

1-antitrypsin a pink color the tissue is

also exposed to dye a space which is an

enzyme that normally destroys alpha

1-antitrypsin but since alpha

1-antitrypsin stuck and hidden away in

the endoplasmic reticulum dye states

can't get to it and destroy it and so we

say that it's diastasis resistant so we

say that they be periodic acid in shift+

or pas positive as well as diastasis

resistant

in terms of treatment augmentation

therapy is where you replace

alpha-1 antitrypsin in the blood

although this doesn't cure the disease

so other therapies for chronic

obstructive pulmonary disease like

supplemental oxygen are often needed as

well giving someone the deficient

protein in the blood doesn't fix the

liver problems since these are caused by

defective alpha-1 antitrypsin building

up in the hepatocytes so standard

treatments for cirrhosis are often

needed like using lactulose to prevent

hepatic encephalopathy all right as a

quick recap an alpha 1-antitrypsin

deficiency the alveoli the lungs are

damaged by neutrophil elastase since

there's no alpha 1-antitrypsin to

counter it and this causes chronic

obstructive pulmonary disease also in

the liver misfolded alpha 1-antitrypsin

builds up which kills the hepatocyte sin

leads to cirrhosis

what's up everyone thanks for watching

that video on alpha 1-antitrypsin

deficiency if you want to learn a little

bit more about that topic you should

head over to osmosis org we've got a

bunch of flashcards quiz questions

scheduling tools basically anything in a

med student or student in the medical

field you see that fly alright see you

guys

you