Talking Tall Rounds: Overview of ATTR Amyloidosis – Pathophysiology & Types
Talking Tall Rounds: Overview of ATTR Amyloidosis – Pathophysiology & Types
Welcome to the Talking Tall Rounds series, brought to you by the Sydell and Arnold Miller Family Heart, Vascular and Thoracic Institute at Cleveland Clinic.
Mazen Hanna, MD:
Good morning, everyone. Welcome to Cleveland Clinic Tall Rounds. Today's Tall Rounds are going to be about the diagnosis of ATTR amyloidosis. We're going to start this Tall Rounds as we usually do with a case by our advanced fellow Dr. Jeremy Brooksbank.
Jeremy Brooksbank, MD:
So, let's get started with the case today. So, we've got a 64-year-old African American female who just has a medical history of hypertension, been relatively well controlled over the years. However, several years back in 2010, she had bilateral carpal tunnel surgery and a couple of years later she tore a rotator cuff. Now she finds herself seeing cardiology in 2023 being evaluated for possible redo carpal tunnel surgery as part of preoperative evaluation.
Her medications were listed below, and like I said, her hypertension's been relatively well controlled. You take a look at her electrocardiogram, not too much to write home about. Normal sinus rhythm, but there is sort of, you can kind of get a sense of some lowish voltages in the limb leads. You look back at an emergency department visit that she had for a shortness of breath some time ago, and her NT-proBNP was a thousand, but she'd gotten sent home and no one really looked further into it. She had felt otherwise okay.
Here's her echocardiogram that you obtained in the clinic. You see that her septum is a little on the generous side and that the base of the heart doesn't appear to be squeezing quite normally. You see the septum is 1.2 centimeters with a posterior wall thickness of 0.9 centimeters. Remember, she is female, so that is abnormal. Here we see an apical four chamber view where we can really appreciate that the apex of the heart has much better systolic function than the base of the heart does. And then we take a look at her strain imaging, and we see that the sort of classic bullseye pattern of apical sparing that we see often in cardiac amyloidosis. So unfortunately, as part of this echo, it was actually ordered as a stress echo protocol because this was preoperative for surgery. There was some concern about possible lateral ischemia, which was called on this study but wasn't called that there was some concern for amyloidosis.
And this patient, you can see here, has a restrictive filling pattern at rest which worsens with stress. And so, she goes for her carpal tunnel surgery intraoperatively. Here's the specimen. We see the H and E stain on the left with the extracellular protean deposition, and then we see Congo Red stain over on the right with the classic apple green birefringence positive on pathologic specimen for amyloidosis and then underwent mass spectrometry, which confirmed that this was TTR subgroup. Gets a pyrophosphate scan at that point, which is certainly positive. And then when you talk to the patient more and they actually end up in Amyloid Clinic, turns out her mother has known hereditary ATTR amyloidosis and had been followed at an outside institution for a number of years. She was positive for the classic genetic variant for this, had no evidence of AL on outside testing.
But this case really highlights that there were many, many points in the cascade and over the years where this diagnosis could have been made and finally was made at the time of a repeat carpal tunnel surgery. So, lots to highlight in making this diagnosis as expeditiously as possible, especially now that we have treatments.
Mazen Hanna, MD:
Very interesting case and highlights the importance of diagnosing this condition as early as we can. I'm going to move us forward with the overview of ATTR cardiac amyloidosis, pathophysiology and types.
And I think we should start with a definition of amyloidosis, which is a protein misfolding disorder. So normally our proteins are in a folded shape and some proteins can pathologically misfold into more linear structures and then aggregate into these amyloid fibrils which are rigid, non-branching, insoluble, and deposit extracellularly in tissues and organs, causing dysfunction. They have a characteristic appearance under electron microscopy and regardless of the precursor protein that leads to the amyloid fibril, what they all have in common is when stained with Congo Red and viewed under polarized microscopy, you get this apple green birefringence pattern.
Now though there's 30 different types of amyloid diseases. There are really two main types that affect the heart. You have AL or light chain amyloidosis, which is a bone marrow plasma cell clone issue or ATTR or transthyretin amyloidosis, which is due to the liver derived protein TTR. Either way, these amyloid fibrils deposit extracellularly between myocytes causing stiffening of the organ. Now, although there are these rare other types of cardiac amyloidosis on the left, well over 95 percent of the time, it's either going to be AL or ATTR, and you should tailor your workup to these two types.
So as far as the pathology of amyloid, the deposition is diffuse affecting both the left ventricle and the right ventricle. The LV is typically non-dilated. At times, there can be a small chamber leading to low fixed stroke volume. The atrial universally involved, you get direct deposition and thickening of the inter atrial septum. You can impair atrial contraction. The conduction system can be involved, the AV valves can be moderately thickened and, in some patients, due to deposition in the intramural coronary arteries, you can get microvascular ischemia.
These patients present us with cardiac and non-cardiac clues. Cardiac wise, most of these patients are going to present with dyspnea or heart failure. I put hypertrophic cardiomyopathy in quotes because this often can be a misdiagnosis. Low flow, low gradient aortic stenosis in the elderly, atrial fib or cardio embolic stroke, complete heart block, needing a pacemaker, and at times angina with normal coronaries. But there's these non-cardiac symptoms and clues that when seen in conjunction with a cardiac presentation can strengthen suspicion in particular orthopaedic manifestations, which we'll talk about shortly.
So, AL amyloidosis is a rare disease. There are about 7,000 new cases annually in the United States. The median age of diagnosis is 63 and historically has had a dismal prognosis when presenting with heart failure. That has certainly changed now. Nonetheless, it is a multisystem disease in which the amyloidogenic light chain forming the fibrils most commonly deposits in the heart and in the kidneys and the kidneys causes mainly glomerular disease with proteinuria, at times nephrotic.
The other main type is not rare. We think it's more common than we previously thought, and that's ATTR or transthyretin amyloidosis. Now transthyretin is a liver-derived protein. When it's secreted by hepatocytes it is a tetramer, four identical monomers, and ultimately either due to aging or some destabilizing mutation, this tetrameric structure can dissociate ultimately into the monomers, which misfold aggregate into amyloid fibrils, which ultimately deposit in the heart and/or nerves. And the neuropathy is peripheral neuropathy and autonomic neuropathy and of course orthopaedic ligaments and soft tissues.
Now within transthyretin amyloidosis, there's two subtypes. One is the wild type. In this type, there's no mutation of the TTR gene, it is not hereditary. Median age of diagnosis is in the mid-seventies, most commonly white males and it's much more common than we once thought. We believe that up to 10% of patients with HFpEF and increased wall thickness actually have TTR cardiac amyloidosis. The other is the variant type. In this case, there is a mutation in the TTR gene that causes a single amino acid substitution. It's hereditary, autosomal dominant inheritance, and the age and the organs involved depends on the specific variant. The most common variant in the United States is valine 122 isoleucine, which is seen in African Americans and causes late onset cardiac amyloidosis. The only way to distinguish these two is by a simple blood or saliva test, TTR gene testing to determine if you're wild type or variant.
Now, we always teach the fellows to ask these questions in patients with heart failure increased wall thickness. "Has the patient had carpal tunnel syndrome, typically bilateral or surgery spinal stenosis, biceps tendon rupture or rotator cuff tear?" This is because these soft tissue and ligamentous issues often present sometimes years before the cardiac manifestations. This is an example of an old, ruptured bicep tendon in a patient with wild-type TTR. Probably about 30 percent of these patients have this if you ask, and probably up to 40 to 50 percent have carpal tunnel and spinal stenosis.
As far as the variants, there's been over 150 mutations described. There's several that cause mainly cardiac, several that cause mainly neurologic manifestations, but most are a mixed phenotype. The one you should be aware of is the valine 122 isoleucine variant. Three and a half percent of African Americans are heterozygous carriers for this, putting them at risk for late onset cardiac amyloidosis. And then there is this Irish mutation. Unfortunately, you'll see in some of the reports PV 142I because they added a signal peptide. So hopefully you'll recognize that's the same variant. So, it's the echo that prompts the suspicion. What we're looking at is increased septal and posterior wall thickness amongst other findings. Typically, we start to suspect amyloid when the septum and posterior wall are equal to or greater than 1.2 centimeters. We typically have heard that this is a disease of HFpEF, but actually many of these patients have mid-range EF, and about a quarter of them can have lower EF. Other echocardiographic clues include thickening of the right ventricle. So biventricular thickening is a very important finding. Pericardial effusion, thickened mitral and tricuspid valve, thickened inter atrial septum, low stroke volume, and of course due to the stiffening of the myocardium, varying degrees of diastolic dysfunction and restrictive filling.
The other clue can be found on longitudinal strain imaging. Here we're looking at deformation at various segments of the left ventricle and the longitudinal strain is near normal or less involved in the apex than it is at the mid and base progressively. So, when you look at the polar map, you'll get this apical sparing pattern or bullseye pattern, which can be highly suggestive of cardiac amyloid. And when you look at strain and hypertrophic cardiomyopathy, typically it's reduced at the septum. In hypertensive heart disease you typically will not see apical sparing. So, this can be a very useful clue that you're dealing with cardiac amyloid.
As far as the electrocardiogram, we always say look at the electrocardiogram in conjunction with the echocardiogram. What you're looking at is decreased voltage as opposed to increased voltages when you see in true LVH. This is the classic low voltage EKG that you see less than five in the limb leads, pseudo infarct pattern. But the truth is only about 30 percent of patients with ATTR meet low voltage criteria. And in fact, LVH criteria in EKG is seen about 10 percent of biopsy proven ATTR. What you're really looking for is the discordance between the voltage on the EKG and the degree of LV wall thickening. And conduction disease is very common, typically a first-degree AV block or an IVCD right bundle, left bundle. When you look at the whole picture, this conduction disease can also be a clue.
Two phenotypes to be aware of. About a quarter of patients with wild-type ATTR cardiac amyloidosis have asymmetric septal hypertrophy. And a small subset of those can have dynamic LVOT outflow obstruction. And then you'll hear a little more about low flow, low gradient stenosis and the elderly concomitant ATTR can be seen in 10 to 15 percent of patients. So, the traditional diagnostic approach used to be to go directly to a heart biopsy, you determine if they have amyloid, and you determine the type. Heart biopsy is a procedure through the right internal jugular vein. We take about four or five pieces from the intraventricular septum. We quote a risk of less than 1 percent of RV perforation and tamponade. I think it'd be very safely done in the right hands. And what you see on the H and E is these pink amorphous areas are the amyloid and the other areas are the myocytes.
Here we have two renowned pathologists, Rene Rodriguez and Carmela Tan, and they use Thioflavin S instead of Congo Red. They feel it's more sensitive and specific. This very light blue is the amyloid, but it's very important for a pathologist not to stop and just tell us there's amyloid in the heart. We need to know the type. We can either use immunohistochemistry and when it's unclear with immunohistochemistry, we send it for mass spectrometry, and we do that in-house here at the Cleveland Clinic. Luckily, most of the cases you can arrive at the diagnosis noninvasively with a constellation of labs and imaging findings.
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