Emphysema: Pathogenesis B

00:00 Alright, so, now, if that’s centrilobular, let us now move into our 2nd sub-type. This is Panacinar. When was the last time you’ve heard of Pan? Mitral regurgitation and you’ve heard of pansystolic. What does that mean? Throughout, pan means throughout in general. Now, this is panacinar and what that basically represents is the fact that the entire acinus has now become damaged. Now this is a big problem.

00:31 How important is this? Quite, why? Take a look, most common homozygous, what does that mean? Both genes have been affected.

00:39 In Caucasians, one of the most common homozygous genetic mutations in Caucasians.

00:48 What are some of the other ones that you know of? You definitely know about Down, trisomy 21 and you know about cystic fibrosis chromosome 7, how popular are those? Unfortunately, quite in the Caucasian population. So, what is this that we’re talking about? Now, before you get into details understand the concept. Let’s start from the start real quick. Remember those neutrophils that were recruited when smoking, what did they release? That enzyme? Good, it was a elastase, wasn’t it? This elastase was then released and what is it that normally neutralizes elastase? Good, that’s your alpha-1 antitrypsin. In centrilobular, there is no genetic mutation, was there? In centrilobular. What about panacinar? Yes there is.

01:31 So, there is absolutely nothing protecting the lung from elastase. So here comes some neutrophils.

01:37 Now, I’m going to first give you a non-smoker. A non-smoker who shows up with FEV1/FVC ratio, decreased pulmonary function test, dyspnoea is taking place, on chest X-rays we find a barrel chest. Non-smoker, age there? Maybe about 45. So without any smoking your patient has now gone into emphysema but this is the panacinar type and with the panacinar type you know, well you’re thinking, Caucasian patient? Mostly likely alpha-1 antitrypsin deficiency. So, what is this gene? Well, look at the gene here. Normally it’s called PI. What does PI stand for? Protease inhibitor. What's a protease? An enzyme.

02:23 Which enzyme? The enzyme from the neutrophil? Yup, that enzyme from the neutrophil. What was that called? Elastase. So, now you have to know a few names don’t you? So, that neutrophil releasing that proteolytic enzyme, protease known as elastase and PI stands for protease inhibitor. I think that’s a beautiful name, appropriately done.

02:44 Okay, so what happens now? Well, you pick up mutations. What’s homozygous mean? Both genes. For every “z” that you pick up, you have further deficiency of alpha-1 antitrypsin. You have both mutations taking place, you have two "z’s" what does that mean to you? This is homozygous, alpha-1 antitrypsin deficiency. That means not a single alpha-1 antitrypsin is being produced properly. Why did I emphasize the term “properly”? You’ll see why, okay? So, now, you have no proper amount of, or properly formed alpha-1 antitrypsin.

03:26 So who wins this battle automatically? Elastase, and kills off the entire lung. Are we done? No. What other organ is highly dependent on this protective mechanism? The liver. The liver is. So therefore, in a patient, panacinar, this is a big deal with homozygous. You know about homozygous for example, there’s a difference between sickle cell trait and sickle cell disease. What is sickle cell disease? That’s homozygous, is'nt it? That’s haemoglobin S, is'nt it? That’s haemoglobin S. Anyhow, so PIZZ, there’s no alpha-1 antitrypsin and so, not only is the lung being damaged from apex to base, but as is the liver, and with the liver you’re worried about this patient going on to what? Cirrhosis, nothing protecting it.

04:13 Now, I’m going to walk you through this properly formed type of alpha-1 antitrypsin and why that’s important to you clinically. Childhood hepatitis evolving into cirrhosis in adulthood will reveal protein globules, stop there. Okay, from henceforth, when you think of the term “hepatitis”, do not think viral only. Think about all the different reasons why you can have hepatitis. Hepatitis alcohol, hepatitis autoimmune, hepatitis nash, hepatitis Wilson’s disease, hepatitis viral? Hepatitis here, alpha-1 antitrypsin deficiency. All that hepatitis means is inflammation that’s it, okay. But many causes of hepatitis.

04:54 So, as a child, you were never born, as a homozygous, you were never born with the enzyme. So, your liver is already damaged you call that hepatitis. With all that damage taking place, what’s that again? Fibrosis.

05:09 Eventually, what are you going to result in? A type of micronodule type of cirrhosis.

05:12 Cirrhosis is my point. And when you have cirrhosis taking place, I told you "properly", you don’t have properly formed alpha-1 antitrypsin. What is an enzyme? A protein. A protein is formed in what organelle in your cell? Good, rough endoplasmic reticulum. Okay, now, my point is this. So now, you can’t form an alpha-1 antitrypsin because of the deficiency, enzyme deficiency, genetic mutation. But is the liver desperate enough to produce alpha-1 antitrypsin? It is desperate, it needs it so that it can protect the liver and maintain homoeostasis. So, it tries but when it tries it produces what? A protein globule in the, read the full statement here, hepatocyte endoplasmic reticulum upon liver biopsy. Is that clear? Why is there protein globule being formed? Because you are trying to form, who is? The liver is trying to form your alpha-1 antitrypsin, but doesn’t produce properly so within your hepatocyte and endoplasmic reticulum you end up finding a protein globule.

06:16 That is the full picture of panacinar and how it’s strictly associated with your genetic mutation being homozygous.

06:22 Now, your patient here I told you was a non-smoker at the age of 45. Well, could you have a patient with panacinar and this type of alpha-1 antitrypsin deficiency as a smoker? Sure.

06:33 So, if they're smoker and they have alpha-1 antitrypsin deficiency homozygous type, how old do you think he or she is when they then present with panacinar emphysema? 35? That’s crazy. That’s ridiculously young to be developing such an issue with your lung and such.

06:52 Okay. Now, a couple other things here. So paraseptal is where we are. This is distal acinar emphysema.

06:58 What does it do? Results in destruction of the alveolar duct, it may occur alone, in combination with any of the above 2 types referring to your, well, centrilobular or panacinar. When your patients are affected with paraseptal emphysema alone, it usually results in spontaneous pneumothorax. What does that mean? Okay. So, the type that we just looked at earlier was the proximal type and with the proximal type you’re in the respiratory bronchiole, are we clear? Go back and take a look at the definition, proximal.

07:29 With this you can have a centrilobular type of pattern without alpha-1 antitrypsin deficiency, but if there is alpha-1 antitrypsin deficiency that is panacinar, we just talked about all of these. If the distal portion is affected now you’re distal from the respiratory bronchiole.

07:44 Where are you? You’re one step closer to the alveoli so affecting the alveolar duct and maybe even the alveoli. If that happens then you’re weakening the parenchyma. What may then happen? Rupture. When you have rupture taking place in your lungs, what happens? You’ve lost your negative pressure, right? Because anything outside of the lung, what happens to your pressure? It automatically becomes positive, are we clear? What’s your best analogy? When was your birthday? Well, during your birthday, maybe you got balloons. If you didn’t, then I’m sorry, I don’t know what to tell you. But anyhow, so you know what a balloon is. You’re blowing it up That’s your lung, okay? How do you keep it open? Well, as long as you have negative intrapleural pressure, you keep it expanded. Are we clear? Then you take a pin, you ever have this? Aren’t you one of those maybe mischievous little dudes or dudettes, and what were you doing? You're going around popping balloons.

08:42 Alright. So this is what you’re doing in spontaneous pneumothorax. That needle, you pop the balloon, what happens to balloon which is your lung? Collapses. That’s spontaneous pneumothorax, that is the best method of explaining in simple terms as to what spontaneous pneumothorax is. So, when you have distal, your alveolar duct which is undergoing massive destruction, please understand that you might then introduce spontaneous pneumothorax, you then tell me as to what you can expect upon percussion of your chest. Will it be tympanic or will be dull? Your lung just collapsed for Pete’s sake, this is all empty, so upon percussion it will be tympanoc. Obviously, I’m exaggerating but it will be tympanic, is that clear?