May 25, 2018
Vinicio de Jesus Perez, MD is Assistant Professor of Medicine (Pulmonary and Critical Care Medicine) at the Stanford Adult PH Clinic where he trains fellows pursuing careers in PH and IPF. He is principal investigator of a research program with the ultimate goal of identifying new therapeutic targets to treat PH and IPF. In this episode, Dr. Vinicio de Jesus Perez discusses pulmonary arterial hypertension as a complication of methamphetamine use (METH-PAH).
My name is Vincinio de Jesus Perez. I am an assistant professor in the Division of Pulmonary Critical Care Medicine at Stanford University. I’m also a staff physician in the Adult Pulmonary Hypertension Clinic, also at Stanford.
Today, I would like to talk to you about how environmental and genetic factors interact to increase the risk of pulmonary hypertension in a subset of our population. I think the story with methamphetamines starts back in 2006, at least for me. Around that time I had joined the lab of Dr. Marlene Rabinovitch. I was spending some time in the pulmonary hypertension clinic. I wanted to learn how to assess, follow, treat patients with pulmonary hypertension. I remember seeing quite a few cases of patients who will come to us for pulmonary hypertension and, again, being at a time when I was trying to cover all bases, a lot of times I’m asking about drug history.
The first thing obviously when you think about PH and drug history is anorexigens, so I’m asking if they were taking weight loss agents or cocaine and a lot of the patients will venture that they had tried methamphetamines. Back then the seizure of methamphetamines, the number of meth kitchen explosions, all of that was really high, and we were just really at the epicenter of all of that. Roham Zamanian, MD and I started talking and said, “You know, there is an opportunity here.” We were starting a database. We were starting to collect blood, so Roham had taken leadership over the tissue bank. We had started the pulmonary hypertension breakthrough initiative and I had become interested in understanding genetics so I enrolled in an NIH K12 program looking at genetics of pulmonary hypertension.
I think it was fortuitous because we were at the right place at the right time. Roham started capturing very comprehensive clinical profiles of every patient with methamphetamine related pulmonary hypertension that came to the clinic. I started to take advantage of the blood samples we had on our bio-bank and I decided to conduct a study using whole exome sequencing, which is one of the next generation sequencing strategies where we can actually screen every gene in the genome. We look at the coding regions, those parts of the genes that actually become part of the protein.
Looking at mutations, disease causing variants, we started finding some really interesting candidate genes that were not necessarily your traditional PH related genes, like BMPR-2 or ALK-1, for example. While we were doing some epidemiology and clinical assessment, we started looking at a very interesting genetic candidate that we found in our whole exome stream called carboxylesterase CES1. Now, the interesting thing about that gene and the reason why we thought it will be a good way to validate the genetic data we observe in our population was that this is actually one of the genes that together with the cytochromes are involved with the detoxification of compounds, whether they’re medications, whether they are toxins, illicit substances.
This particular enzyme is important in detoxifying cocaine, heroin, methylphenidate, and some amphetamine-based compounds. With that we started looking at blood and cells and lung tissue from patients with methamphetamine PH that we had obtained at the time of transplant and, lo and behold, we started seeing the same genetic variants and ultimately ended up validating this as a susceptibility gene that when the endothelial cells, for example, are exposed to methamphetamine, if they lack this gene or if they have one of the mutations we found in our population, the endothelial cells are more likely to die out.
Now what does that mean when it comes to PH? Well, one of the things that we see commonly in patients with pulmonary hypertension and methamphetamine PH being no exception is that there is a progressive disappearance of blood vessels. Part of what we think causes that is that the endothelial cells are being damaged and they die out and ultimately there is a transition to cell growth that ultimately narrows and occludes that blood vessel. If you think about it, not everybody that takes methamphetamine develops pulmonary hypertension. If so, we will be overrun with these cases so there has to be something in this population, a genetic susceptibility or factors that increase the risk of that patient for developing the disease.
What we are proposing is that if you carry a genetic susceptibility, in this case CES1 being an example, but we found a few others that we are actively assessing. Then, you may actually have a greater risk of injuring your pulmonary circulation incapacitating the ability of cells to regenerate in the setting of injury. One of the key questions is, what happens to methamphetamine when you take it? Whether you inhale, inject, put it in your mouth? What happens when the methamphetamine hits the lung? Is it causing inflammation? How does it cause damage, it’s not been clear.
Well, what we ended up discovering is that if you give methamphetamine to endothelial cells in culture these cells can actually uptake methamphetamine. In other words, methamphetamine can make its way inside the cell and the endothelial cell has the capacity to start detoxifying methamphetamine. The endothelial cell has evolved into a system that it can actually interact and detoxify some of these compounds, methamphetamine being one but I will imagine cocaine and other compounds.
If there is anything that compromises the capacity of the endothelial cell to carry out this activity, then I think that may increase the risk of endothelial loss, vascular damage, impaired regeneration, which ultimately will result in pulmonary hypertension. Now, how does this translate into patients? Well, pulmonary hypertension is well characterized. When it comes to looking at the patients, with catheterization, they have high pressures, they meet the criteria that we currently accept for defining pulmonary arterial hypertension, the WHO Group 1.
OK fine, but what is the pathology? Does the pathology of vascular remodeling in methamphetamine PAH look the same as that we see with idiopathic, familial, and the other forms that are not being explored. Roham and I went back to our tissue bank and patients that had undergone lung transplant, we had captured some of those lungs and we decided to stain the lungs and work with our pathologist.
What we found was that, indeed, the lesions that we saw in the lungs were completely indistinguishable from what you will see in a patient with any form of PH, whether it is idiopathic, drug induced. We’re talking about a phenotype that belongs within WHO Group 1. You can make the argument that the medications that we’re currently using should also work and maybe some of the same clinical molecular pathways are shared.
The question is, is there something unique here that affects how these patients react and how these patients evolve. In our paper which we published in 2017, we actually found something really interesting. It’s that if you follow the survival of these patients, meth PAH, and you compare them with patients who are idiopathic they have a much worse survival. This is after we controlled for age, sex, social status, et cetera.
What that made us think is that if you are a methamphetamine PH patient you probably have a phenotype that is different from an idiopathic patient and you may be at a higher risk of more aggressive, a less salutary response to therapy, we don’t know. It definitely made us imagine that similar to what’s been shown with connective tissue disease; PH, HIV, PAH, these patients may just have a more aggressive phenotype that we may need to be aware of so that we can be understandably more aggressive to treat these patients.
The last thing that we found, which is of relevance to how these patients are treated, is that compared to the idiopathic PH patients there are less of these patients that are actually on IV and sub-Q therapy. The problem there, unfortunately, is that many of these patients, due to active and continued methamphetamine use, as well as poor social support and other limitations, unfortunately cannot be candidates for these therapies.
One of my most memorable, and I have to say sad, cases of methamphetamine PH was a couple of years ago. A patient of ours who arrived with a history of active methamphetamine use came with very severe PAH requiring intervention including social worker, including aggressive diagnosis. Ultimately, he was able to stop using methamphetamine. He was so severe, he was a functional Class IV, we decided to start him on IV remodulin with a Hickman catheter and he did remarkably well. His echo improved, his six minute walk, functional class, REVEAL score, it was exactly what you will like to see when you start a patient with these drugs.
However, a couple of months down the road I get called because the patient is in the emergency room and he was in cardiac arrest. When we went in, the first thing we thought of is that he had a blockage in his remodulin infusion. What we ended up doing was we unplugged the catheter, we tried to flush, and indeed there was an obstruction. We start pulling trying to see because the first thing we thought of is that maybe there’s a clot there. Instead, what we found is this white, pasty substance that was filling the inside of the catheter, which it should come as no surprise was actually methamphetamine.
The patient sadly passed away a couple of days later, but I think that tells you a couple of things. Number one, methamphetamine is a really addictive substance, it’s really hard to get rid of. Even though we had followed the patient with sporadic urine tests, for whatever reason the patient had gone back. Number two, it also made us extremely aware that these patients have to be screened and that we have to be careful. Even though a patient like this you will say, “Well, he’s a functional Class IV, patient is super sick, the medication needs to be started,” he may not necessarily benefit and even could be at high risk of potential complications not necessarily associated with the drug, associated with methamphetamine addiction.
Every time that I see a meth patient in my clinic I tell them that story. That’s my come to Jesus moment, sort of like, “Listen, just stop fooling around. You need to put life in perspective. If you keep using methamphetamine you’re going to die.” We have a policy that we don’t start patients on PH medications until we are clear that the patient is not using methamphetamine. As a matter of fact, the day they come for their catheterization, we do a urine spot because if they are on methamphetamine, which has happened, we cannot do the study.
Methamphetamine is sympathicomimetic medication so pressures are going to be worse. As a matter of fact, just stopping methamphetamine results in a remarkable improvement in pulmonary resistance and pressures. Again, you can tell this to a patient, but addiction is definitely a very poor prognostic indicator for this patient population.
My name is Vincinio de Jesus Perez and I am aware that I’m rare.
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