Article Review (2012) - Amyloid diseases of the heart: Current and future therapies

It looks like I did not begin 2018 with one post per month, but maybe I can still finish the year with a total of 12 to get the average up to one per month. Since my last article review was published in August of 2016, I should probably start doing those again. I have not yet reviewed all the ones listed on the resources page and I have also found a few more that are not listed there. So this blog post will be my first article review in 18 months.

Before beginning the article review I thought I would mention that the XVIth (16th) International Symposium on Amyloidosis was recently held in Japan, and there were a couple of posters shown that were related to fibrinogen amyloidosis. One of the posters discussed the results of a small cohort of AFib patients (6) in Portugal who received kidney transplants. Although I have only seen a low-resolution picture of that poster, I suspect the results were mixed and showed rapid recurrence of amyloid in some of the transplanted kidneys, as we have seen in many of the articles I have previously reviewed.

The other poster I am aware of was titled "Fibrinogen A alpha-chain (AFib) renal amyloidosis: Is liver transplant alone sufficient? A case report." I have not yet seen a high-quality photo of that poster either, but from what I could tell of the picture posted in one of the Facebook groups, the case report was regarding the person with AFib who received a liver-only transplant at Mayo Clinic in March of 2017. The poster gave some data on this patient as recently as four months after the transplant, and it definitely showed improvement in kidney function. If I get a more readable version of that poster I will present some of that data in a future blog post.

The last bullet point in the Conclusions section of this poster was "Further studies are needed to assess long-term outcomes as well as the appropriate timing of the procedure during the course of the disease." Unfortunately there are only two patients available to study as far as we know, with one being the patient discussed in this case report and the other one being the patient who received a liver-only transplant in July of 2010. Hopefully earlier diagnosis and genetic testing of family members will lead to more AFib patients pursuing liver-only transplants in the near future.

Now to the article review . . .

Title: Amyloid diseases of the heart: Current and future therapies (1)

Authors: Dubrey, S. W. and Comenzo, R. L. (Hillingdon Hospital, Middlesex, UK; Tufts Medical Center, Boston, MA, USA)

Journal: QJM: An International Journal of Medicine (July 2012)

Abstract:

Amyloid diseases in man are caused by as many as 23 different pre-cursor proteins already described. Cardiologists predominantly encounter three main types of amyloidosis that affect the heart: light chain (AL) amyloidosis, senile systemic amyloidosis (SSA) and hereditary amyloidosis, most commonly caused by a mutant form of transthyretin. In the third world, secondary amyloid (AA) is more prevalent, due to chronic infections and inadequately treated inflammatory conditions. Much less common, are the non-transthyretin variants, including mutations of fibrinogen, the apolipoproteins apoA1 and apoA2 and gelsolin. These rarer types do not usually cause significant cardiac compromise. Occurring worldwide, later in life and of less clinical significance, isolated atrial amyloid (IAA) also involves the heart. Heart involvement by amyloid often has devastating consequences. Clinical outcome depends on amyloid type, the extent of systemic involvement and the treatment options available. An exact determination of amyloid type is critical to appropriate therapy. In this review we describe the different approaches required to treat this spectrum of amyloid cardiomyopathies.

Here is a link to the article: http://qjmed.oxfordjournals.org/content/105/7/617.long

After an introduction to the effects of amyloid on the heart and the methods of treatment, the article then has specific sections for each of the types of amyloidosis mentioned in the abstract. I will not cover any of those sections other than fibrinogen in this review.

The Fibrinogen Amyloidosis section of this article begins by stating nine fibrinogen mutations causing amyloidosis have been identified to date. (As of 2018, the number of mutations is 15 according to the data at amyloidosismutations.com.) It then presents some general information about fibrinogen amyloidosis we are very familiar with, such as the usual presentation being nephropathy leading to kidney failure if left untreated. It then mentions kidney transplantation as a treatment option, which usually leads to rapid recurrence of amyloid in the transplanted kidney.

In the section on combined liver and kidney transplantation for fibrinogen amyloidosis, the article mentions a study of nine patients in which six survived with good results. There is also a mention that a liver-only transplant may be an option to prevent progression of the disease to other organs. It does state that no patient has undergone a combined liver and heart transplant for AFib.

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There is not really any new information in this article that has not been covered in previous articles. We know fibrinogen amyloidosis initially affects kidney function, but in the later stages of the disease it can affect other organs such as the spleen, liver and heart. But I am aware of only one documented case of significant cardiac involvement in a patient with fibrinogen amyloidosis. That case was described in a 2008 article in the New England Journal of Medicine, which I reviewed in the blog on January 6, 2014. Oddly enough, that 2008 NEJM article was not listed among the references for this 2012 article for some reason.



=====Monthly Blog Status Update=====

As of January 31, 2018:

Total posts: 182 (1 in January)

Total pageviews: 82,800 (~1600 in January)

Email subscribers: 14 (unchanged)

Total number of countries that have viewed the blog: 145

No new countries viewed the blog in January.

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=====Monthly Blog Status Update=====

As of February 28, 2018:

Total posts: 182 (0 in February)

Total pageviews: 84,700 (~1900 in February)

Email subscribers: 14 (unchanged)

Total number of countries that have viewed the blog: 145

No new countries viewed the blog in February.

=====


Citation:

(1) Dubrey SW, Comenzo RL. Amyloid diseases of the heart: current and future therapies. QJM. 2012;105(7):617-631.

Article Review (2013) - Delayed diagnosis of fibrinogen A alpha-chain amyloidosis after dual heart–kidney transplantation

Today's post will be our first article review since April of this year. So much for doing reviewing one article per month, right? As you can tell from the title of this post, the patient in this case underwent organ transplantation (heart and kidney) before being diagnosed with amyloidosis. Would a proper diagnosis before the transplant have made any difference? Let's see . . .

Title: Delayed diagnosis of fibrinogen A alpha-chain amyloidosis after dual heart–kidney transplantation (1)

Authors: Tristan Legris, Laurent Daniel, Valeris Moal (Marseille, France)

Journal: Transplant International (January 2013)

There is no abstract for this article since it is actually a letter to the editors of the journal. Here is the link to the article online: http://onlinelibrary.wiley.com/doi/10.1111/tri.12002/full

This article is about a male patient who had a heart attack in 2003 at the age of 55. His heart did not do well after the heart attack, despite angioplasty and implantation of a stent. He also had indications of moderate renal failure (elevated serum creatinine and and proteinuria), but that was not explored until 2004 when it worsened. His kidneys were too small for biopsy (8 cm), and no tests could explain the kidney problems. There was also no family history of renal failure. He started hemodialysis at the end of 2004 and was placed on the waiting list for combined heart-kidney transplantation, which he received in November of 2005.

The article discusses the issues with the heart over the next few years, including receiving a pacemaker in 2010. It also states there was septum wall thickening, an impaired relaxation pattern with restrictive profile, and normal ejection fraction (65%). The article also states that the septum had a "granular sparkling appearance." (Note: Those are common findings in a patient with cardiac amyloid involvement.)

In 2011 a renal biopsy showed the presence of amyloid with congo red staining. The amyloid deposits were primarily glomerular. Immunofluorescence was positive for fibrinogen, and genetic analysis found him to have the Glu526Val mutation. Then they examined some tissue from his explanted heart (the original heart that was removed for transplant) and found mild amyloid deposits. The biopsies from his transplanted heart, however, did not show amyloid deposits.

As of the writing of this article (presumably late in 2012), the patient was doing well, with mild proteinuria. The article states that recurrence of amyloid is proven in the transplanted kidney, but only suspected in the transplanted heart.

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As far as I know this article describes the only case of heart-kidney transplantation in a patient with fibrinogen amyloidosis. It is also an unusual case for the obvious reason that the diagnosis of fibrinogen amyloidosis was made after the transplant. As to whether that would have made a difference in this case, the conclusion of the article states the following: "The diagnosis of systemic AFib amyloidosis at the time of discovery of proteinuria would have led us to discuss combined heart-liver transplantation or heart-liver-kidney transplantation."

This patient is not the first patient described in the literature with fibrinogen amyloidosis and clinically significant heart involvement. Another patient was described in two articles reviewed in the blog on January 6, 2014. That patient presented with proteinuria at the age of 48, and then reported shortness of breath at age 51. Heart biopsies at age 53 showed amyloid involvement, and he eventually received a pacemaker and an implanted defibrillator.

The recurrence of amyloid in a transplanted kidney has been described in other articles. This one occurred about six years after transplant, which is within the normal range if I remember correctly. The fact that biopsies taken from the transplanted heart were negative for amyloid is not unusual, as that often happens in cases of AL amyloidosis with heart involvement.

It is still worth noting that significant heart involvement with AFib is rare, whereas mild involvement has been noted in some patients. My assessment of the published data indicates renal involvement can be expected to precede clinically significant heart involvement by several years. This patient's heart attack at a time when he had only mild renal involvement likely means the cause of the heart attack was something other than amyloid. My understanding is that amyloid deposits in the heart cause a gradually stiffening of the heart, reducing the ability of the heart to pump blood efficiently. So please do not worry about AFib causing a heart attack.

Next up will be an update on Mom.


=====Monthly Blog Status Update===== 

As of July 31, 2015:

Total posts: 154 (1 in July)

Total pageviews: 28,100 (~800 in July)

Email subscribers: 12 (unchanged)

Total number of countries that have viewed the blog: 105

One new country visited the blog in July.

Senegal

=====

Citation:

(1) Legris T, Daniel L, Moal V. Delayed diagnosis of fibrinogen Aα-chain amyloidosis after dual heart-kidney transplantation. Transpl Int. 2013;26(1):e1-3.

Happy New Year!!!

Welcome to 2015 everyone. Since this is my third Happy New Year post in the history of this blog I put three exclamation points in the title. Hopefully I'll be around long enough such that the number of exclamation points becomes ridiculous.

Instead of being a recap of 2014, this blog post will be another Mom update since there was some additional activity in 2014. At the end of the previous update she had been released from the hospital on November 26 after being admitted on November 22 for yet another GI bleed. I mentioned at the end of that blog post that based on the average number of days between hospital visits for GI bleeds in 2014, the next one would be due around January 29 of this year. It turns out we did not have to wait that long for another hospital visit, unfortunately.

You may remember that shortly after being admitted to the hospital in November, she had an episode where her heart rate jumped up to the 140s while she was resting comfortably in the hospital bed. That did not happen again during that hospital stay, but it did happen again on December 10 and then again on December 16. In both cases she was at home, at rest, and her blood pressure was fine when her pulse went up. There was no major discomfort (unlike the episode in the hospital), so she was able to lie down, take some additional blood pressure medicine, and have the pulse come back down after a couple of hours. And then it was time for Christmas . . .

Mom was having dialysis the afternoon of Wednesday, December 24 (Christmas Eve). After being on dialysis for about an hour she started having chest pains and could feel her increased heart rate, so she called my sister Amy and asked if she could come get her and take her to the hospital. Amy suggested that Mom instead have the dialysis clinic call 911 since she was having chest pains, which does seem like an obvious thing to do with those symptoms. Amy headed to the dialysis clinic, the ambulance came for Mom, and Amy followed the ambulance to the closest hospital which was one none of us were familiar with. The ambulance did not have its siren on, so the paramedics must have determined it was not a life or death situation at this point. I believe they gave Mom a nitroglycerin tablet in the ambulance and her heart rate started to come down.

Mom arrived in the emergency room and was admitted after they did the standard stuff such as drawing blood, taking a chest x-ray, and doing an EKG. Everything looked fine but they admitted her for observation and planned to do a chemical stress test the next day. Mom had the chemical stress test Christmas morning (December 25), no abnormalities were found, and she was released that afternoon. Merry Christmas! (Fortunately we had done most of our family Christmas stuff on Tuesday of that week, so no plans had to be changed as a result of this hospital visit.)

So that is how we finished 2014, with yet another hospitalization. The next post, which will hopefully be this month, will be the 2014 recap/year in review.


=====Monthly Blog Status Update===== 

As of December 31, 2014:

Total posts: 145 (1 in December)

Total pageviews: 22,300 (~800 in December)

Email subscribers: 12 (unchanged)

Total number of countries that have viewed the blog: 101

No new countries viewed the blog in December.

=====

Article Review (2010) - Hereditary fibrinogen A alpha-chain amyloidosis: phenotypic characterization of a systemic disease and the role of liver transplantation

As promised, today's article review covers one of the more important journal articles dealing with treatment for fibrinogen amyloidosis. It reaches some conclusions and makes some recommendations we have not seen before, which exposes some disagreement among the medical community which continues to this day. I will cover this article and the points of disagreement over the next few posts, so don't worry about having to absorb everything at once.

Title: Hereditary fibrinogen A alpha-chain amyloidosis: phenotypic characterization of a systemic disease and the role of liver transplantation (1)

Authors: Arie J. Stangou, Nicholas R. Banner, Bruce M. Hendry, Mohamed Rela, Bernard Portmann, Julia Wendon, Mark Monaghan, Philip MacCarthy, Muriel Buxton-Thomas, Christopher J. Mathias, Juris J. Liepnieks, John O'Grady, Nigel D. Heaton, and
Merrill D. Benson (King's College Hospital, London, UK; Royal Brompton and Harefield NHS Trust, London; Imperial College London; King's College London; National Hospital for Neurology and Neurosurgery, London; Indiana University School of Medicine, Indianapolis, IN, USA)

Journal: Blood (2010)

Abstract:

Variants of fibrinogen A α-chain (AFib) cause the most common type of hereditary renal amyloidosis in Europe and, possibly, the United States as well. Variant fibrinogen is produced in the liver, and solitary renal allografts fail within 1 to 7 years with recurrent amyloidosis. We assessed 22 AFib patients for combined liver and kidney transplantation (LKT) and report the clinical features and outcome. Twenty-one had E526V and 1, the R554L variant. Coronary atherosclerosis was identified in 68% and systemic atheromatosis in 55%. Vascular atheroma excised at endarterectomy and endomyocardial biopsies contained purely variant fibrinogen amyloid. Half had autonomic neuropathy. Six of 9 patients who underwent LKT are alive (67%), with good allograft function and no amyloidosis at median 67 months (range, 33-155 months) of follow-up. Serial technetium-99m–labeled dimercaptosuccinic acid (99mTc-DMSA) renal scintigraphy in 2 cases of preemptive LKT demonstrated preserved native kidney residual function at 5 years. Four explanted livers were used successfully for domino transplantation. Fibrinogen amyloidosis is a systemic amyloid disease with visceral, vascular, cardiac, and neurologic involvement. LKT is curative; however, cardiovascular amyloidosis may preclude this option. Our data encourage evaluation of preemptive solitary liver transplantation early in the course of amyloid nephropathy to prevent hemodialysis and kidney transplantation.

Here is a link to the PDF of this article if you would like to follow along:  http://bloodjournal.hematologylibrary.org/content/115/15/2998.full.pdf

If you look at the hospital affiliations of the authors of this article you might notice two things. First, out of 14 authors, all but two (Dr. Benson and Dr. Liepnieks) are affiliated with hospitals in London. Second, none of those 12 authors from London are associated with the National Amyloidosis Centre in London. Keep that in mind for later.

As it says in the abstract, this article reports on 22 patients with fibrinogen amyloidosis (AFib) who were assessed for combined liver and kidney transplantation. (I am occasionally going to use the acronym "LKT" for "liver and kidney transplant" in this review to save myself some typing.) The topic of this article may seem familiar to you because there was a previous article review that also covered LKT assessments in a large number of patients (20). That article, reviewed in the November 30, 2013 blog post, was a paper presented at the XIth International Symposium on Amyloidosis in 2006. The older article covered 20 patients evaluated between 1996 and 2006, whereas today's article covers 22 patients evaluated between 1996 and 2007. Although there are only two additional patients in the current article, and six people were listed as authors on both articles, we can expect the current one to be somewhat more thorough with the details since its length is not limited like papers presented at symposia usually are. Plus, it has the benefit of about three more years of clinical experience following these patients.

Introduction

The introduction of this article lists the types of hereditary renal amyloidosis (fibrinogen, lysozyme, apolipoprotein A1 and apolipoprotein A2), and states that there are a total of 25 different mutations among those types. Fibrinogen amyloidosis (AFib) appears to be the most common type of hereditary renal amyloidosis in Europe and in the US.

Isolated kidney transplantation has been done as a treatment for the renal failure associated with AFib, but the article states it is of limited value because the transplanted kidney (often referred to as an "allograft" or simply "graft") is usually lost within 1 to 7 years due to recurrence of amyloid. Of the 18 reported kidney transplants to date, only one graft (5.5%) has survived at least 10 years. That compares poorly with the 10-year graft survival rate of 64% among all kidney transplants. This poor outcome with isolated kidney transplants led the team at King's College Hospital in London to evaluate combined liver and kidney transplantation for AFib. That would not only restore renal function but also potentially prevent recurrence of amyloid by eliminating the source of the mutant fibrinogen, the liver.

Methods

For this study, 22 AFib patients were assessed for combined liver and kidney transplantation between 1996 and 2007. One of these patients had the Arg554Leu mutation and the rest had the Glu526Val mutation. The median age at presentation was 55 years, and the median age of assessment for LKT was 57 years. Three of these patients had previously been misdiagnosed as having AL amyloidosis, with one of those receiving chemotherapy. There is a table in the article that gives some demographics and medical information on all 22 patients (age, sex, presenting features, grams per day of proteinuria, etc.) One interesting piece of information is just one patient was known to have the mutation before presenting with symptoms, but only four others had a family history of kidney problems.

The article then goes into great detail on the methods used to evaluate the patients at baseline and during follow-up. Most of that is way beyond my understanding so I am not going to try to discuss it. We are interested in the results anyway.

Results

Other than the obvious evaluation of kidney function, these patients were also evaluated for cardiac function and autonomic neuropathy. The results of those evaluations for each patient are given in a table and discussed in the results section of the article. I will just provide the highlights in bullet form here.

• 12 patients initially presented with proteinuria.
• 9 patients initially presented with hypertension or a related condition.
• 1 patient was diagnosed due to genetic testing after a family member was diagnosed.
• The median time from initial presentation to diagnosis was 23 months.
• 2 patients had liver amyloidosis.

• 15 patients had coronary atherosclerotic disease. Six of those patients had 40% to 80% narrowing of a coronary artery, without any symptoms.
• 12 patients had severe systemic vascular disease.
• 11 patients (out of 21) had abnormal echocardiograms, with findings consistent with amyloid.

• 12 patients had autonomic neuropathy affecting the heart.
• 15 patients had autonomic neuropathy affecting the GI tract.

• All kidney biopsies showed extensive amyloid deposits in the glomeruli, with minimal amyloid deposits elsewhere.
• 4 patients experienced ruptured spleens (three during transplant surgery). The removed spleens had widespread amyloid deposits.
• 3 out of the 4 heart biopsies showed substantial amyloid deposits which did stain positive for fibrinogen. 

14 of these 22 patients were initially accepted for combined liver and kidney transplant, and nine of those 14 patients had received transplants as of the time this article was written. Four of the remaining patients were removed from the list due to deteriorating health, and one patient was still on the waiting list.

The nine liver and kidney transplants (LKT) occurred between January 1996 and September 2009. At a median follow-up of 67 months, six of those nine patients are alive and well. Five of the six have good kidney function. The sixth patient developed chronic allograft nephropathy, which is the leading cause of kidney transplant failure. (Therefore it was not due to recurrence of amyloid in the transplanted kidney.) Transplant outcomes were better for patients who either had not started dialysis or had been on dialysis less than six months.

Periodic echocardiograms in 8 patients after LKT show no progression of cardiac amyloidosis, up to 12 years post transplant. The autonomic GI issues improved in all patients who received LKT. Two of these patients previously had kidney transplants, and their GI issues had continued after those transplants.

Another indicator of the success of LKT is the results of periodic SAP scintigraphy (an amyloid imaging technique I discussed in the April 30, 2013 blog post). Patients who received liver and kidney transplants showed a reduction in amyloid deposits as soon as one year post-transplant, and the patient with the longest follow-up still did not show any new amyloid deposits with SAP scintigraphy 13 years after transplant. In contrast, two of these patients had previously received kidney only transplants, and SAP scintigraphy showed their amyloid deposits progressing.

Four of the nine patients who received LKT were part of a domino liver transplant, which means their livers were transplanted into patients on the liver transplant waiting list. One of those domino recipients had SAP scans and echocardiograms for five years, with no evidence of amyloid deposits. One had normal liver and kidney function after 2.5 years, and the other two were not followed-up on after they returned to their country of origin.

Discussion 

The discussion section is where things get very interesting. It begins with some background information on fibrinogen and fibrinogen amyloidosis, and then it states that the data in this article suggest that fibrinogen amyloidosis is neither solely nephrotic (affecting the kidneys) nor solely nonneuropathic (not affecting the nervous system). So while it is true that fibrinogen amyloidosis primarily affects the kidneys, the authors of this article are saying that it should be viewed more as a systemic disease, with particular emphasis on potential cardiovascular involvement.

Remember when I mentioned that only five patients out of this series of 22 had a family history of kidney problems? Another bit of data on each patient that can be found in the same table is whether or not there was a family history of cardiovascular problems, and the table indicates that 17 of these patients did have such a family history. Of course the question that needs to be asked is whether or not the family members with cardiovascular problems also had the mutation for fibrinogen amyloidosis, and the article states that DNA testing of family members either confirmed they did have the mutation or they were obligatory carriers due to their relationship to other family members who were confirmed to have the mutation. So for this small group of 22 AFib patients, only 5 (23%) had a family history of kidney problems but 17 (77%) had a family history of cardiovascular problems.

The type of cardiovascular disease prominent among these AFib patients and their family members is described as cardiovascular atheromatous disease, which is essentially a buildup of plaque on the inner walls of the blood vessels. A reasonable question to ask is whether this buildup is due to the variant fibrinogen that is present in the bloodstream, the effects of kidney failure, or one of the other known causes of plaque buildup. Well, in the few cases where they could analyze this material that was removed from patients, biochemical analysis showed that it was indeed composed of variant fibrinogen. The article proposes that it is a combination of factors such as hypertension, hyperlipidemia (high cholesterol), and declining kidney function that may accelerate the formation of plaque deposits composed of variant fibrinogen on the inner walls of the blood vessels. Since the glomeruli in the kidneys are essentially blood vessels, that is exactly what appears to be happening the kidneys.

The article then presents three facts that point to liver transplant being curative for fibrinogen amyloidosis. They are:

• The amyloid deposits in AFib patients have been shown to be made exclusively of variant fibrinogen, unlike in ATTR amyloidosis, where the amyloid deposits consist of both mutant and wild-type (normal) transthyretin.
• Variant fibrinogen is eliminated after a liver transplant. (We learned that in the article reviewed in the December 18, 2013 blog post.)
• AFib patients who are long-term recipients of liver and kidney transplants have shown no amyloid progression at up to 12 years of follow-up.

Another related piece of data supporting the suggestion that liver transplant is curative is in the post-transplant analysis of kidney function in two transplant recipients. These patients received LKT before starting dialysis, so they had some remaining kidney function at the time of transplant. Since the native kidneys are typically left in place with a kidney transplant, the function of these native kidneys could be evaluated after transplant. They found that the native kidney function had stabilized, such that they were still providing 15% to 20% of total renal function up to five years post-transplant.
The discussion section closes with a few recommendations regarding organ transplants to treat fibrinogen amyloidosis. The third one is something we have not seen before.

• Patients with low cardiovascular risk should be considered for combined liver and kidney transplant.
• Patients with higher cardiovascular risk for liver transplant, or who have been on dialysis for a long time, should be considered for a kidney transplant.
• Patients who are in the early stages of kidney involvement due to AFib should be considered for isolated liver transplantation, to prevent progression to end stage renal failure and the progression of other systemic issues as described in this article.

Regarding the isolated liver transplantation, the article recommends that a patient listed for a liver transplant be monitored monthly to ensure the GFR remains above 50 ml/min. (Units for GFR are actually ml/min/1.73 m^2, which is not only clunky to write but is difficult to grasp intuitively. Just think of it as percentage of kidney function.) If it falls below 50 the patient should be listed for combined liver and kidney transplant. I did not realize it until I read the article again for this review, but one of the patients in this study was initially listed for an isolated liver transplant but had to be listed instead for LKT when his GFR dropped too low. He is the patient still waiting for a liver and kidney transplant at the time this article was written.

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Ok, there is a lot to talk about in that article. But since this post is long enough already I am going to save the discussion for the next article review, which is actually a short article about this article, from the same issue of the same journal.

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Citation:

(1) Stangou AJ, Banner NR, Hendry BM, et al. Hereditary fibrinogen A alpha-chain amyloidosis: Phenotypic characterization of a systemic disease and the role of liver transplantation. Blood 2010; 115: 2998-3007. 

[Edit 2-24-14: Minor typo.]

Article Review (2010) - Amyloid Heart Disease

Today's post will be a short review about a long article. But before getting to that I have quick updates on both me and Mom. First, I previously mentioned that Mom had changed her dialysis time to early in the morning. They also moved her to a different bay than the one she was in, which means a different tech will be inserting her needles. You will not be surprised to learn that the new tech is having some difficulty getting Mom's needles inserted correctly every time, which means sometimes Mom has to insist that Rick come over and help out. I do not think the new tech has infiltrated the fistula yet, but Mom's arm was hurting so much one day last week that she had to end her session early. I thought the buttonhole technique was supposed to help things go a little more smoothly, but that does not seem to be the case.

Mom has also begun to notice some signs of edema around her ankles and under her eyes. She had not thought of the puffiness around her eyes as being due to edema until she read the previous blog post, in which the patient initially presented with edema around the ankles and eyes. Hopefully she can talk to her new nephrologist about that and get them to remove more fluid during the dialysis sessions.

My update is regarding my annual physical exam I had this week. I am happy to report that I am still asymptomatic for fibrinogen amyloidosis. There was no proteinuria, my creatinine was 1.0, and my GFR was over 59. I really don't know what the right word is for how I feel right before getting the results of my lab work each year. I'm certainly not scared, probably because I already have a plan of action and I know what the next steps are likely to be. I will admit to being a little anxious to get the results each time, and I suppose there is some relief when everything looks good. But I don't get myself so worked up that I breathe a huge sigh of relief when the numbers are good. (Those of you who know me are well aware that I don't get myself worked up over much of anything.) Perhaps this is just the normal anxiety people feel when they know they have a genetic mutation for a disease but they cannot predict if or when things will start happening. Anyway, that was some free introspection for my loyal readers out there, and for my future self. ("Hey David, remember that blog post from 2014 when you said you weren't scared because you have a plan of action?")

Today's article under review focuses on amyloidosis of the heart. Since cardiac involvement is much more prevalent with other types of amyloidosis than it is with fibrinogen amyloidosis, this article only briefly mentions fibrinogen amyloidosis. But I think it is good to know this article is out there just in case you do have cardiac involvement, or to offer it to people with other types of amyloidosis who have or suspect they may have cardiac involvement. (I did that within this past week, actually.)


Title: Amyloid Heart Disease (1)

Authors: Rodney H. Falk, Simon W. Dubrey (Harvard Medical School, Boston, MA; Hillingdon Hospital Uxbridge, United Kingdom)

Journal: Progress in Cardiovascular Diseases (2010)

Abstract:

The systemic amyloidoses are an uncommon group of disorders characterized by the extracellular deposition of amyloid in one or more organs. Cardiac deposition, leading to an infiltrative/restrictive cardiomyopathy, is a common feature of amyloidosis. It may be the presenting feature of the disease or may be discovered while investigating a patient presenting with non-cardiac amyloidosis. In this article we review the features of cardiac amyloidosis and its varied manifestations. The need for a high index of suspicion and the critical importance of precise biochemical typing of the amyloid deposits is stressed in light of recent advances in therapy which can, when appropriately used, significantly improve prognosis.

Here is a link to the PDF if you would like to follow along: http://brighamandwomens.org/Departments_and_Services/medicine/services/cvcenter/Amyloidosis/Images/AmyloidReview.pdf

As I mentioned at the top of this post, this will be a rather short review, especially considering the length of the article (12 pages plus three pages of references). This article is very detailed in its descriptions of how cardiac amyloidosis affects the heart and how it is treated. I could not do it justice even if I did take the time to read it thoroughly and make sure I understand at least the basics. So I think what I will do is simply give the outline of the article based on the section headings, but only discuss a few things along the way. The first paragraph of the article is a very broad overview of amyloidosis. It mentions Congo red staining, types of amyloidosis, and organ involvement. Then it starts discussing heart involvement in particular. In the text below, section headings from the article are in bold or bold italics.

Amyloid heart disease: general overview

If a person is diagnosed with amyloidosis before cardiac symptoms develop, cardiac involvement is usually detected fairly quickly. (I would consider that good news for someone known to have fibrinogen amyloidosis, since amyloidosis should be suspected with any signs of heart abnormalities.) But if amyloidosis is isolated to the heart, a diagnosis of amyloidosis usually occurs much later in the progression of the disease, if at all. This section includes a picture of a cutaway section of a heart severely affected by AL amyloidosis, clearly showing the thickened walls.

Clinical findings

Cardiac amyloidosis is very similar to typical cases of congestive heart failure from a clinical standpoint, which is one reason the diagnosis is often missed. Doctors familiar with cardiac amyloidosis will always mention that the ejection fraction, a measure of what percentage of the blood coming into the heart is pumped out with each heartbeat, will often be normal in a heart affected by amyloid. The problem is the walls of the heart become thicker and stiffer, such that not as much blood is pulled into the heart when it expands. But the heart muscle itself is still strong enough to pump out the blood, so the ejection fraction is unaffected. The volume of blood pumped with each heartbeat is reduced, and that is the problem.

Echocardiography

This section discusses the use of echocardiography, electrocardiography, and MRI in the diagnosis of cardiac amyloidosis. An interesting figure in this section is a series of electrocardiograms over a 10-year period from a patient with one of the ATTR mutations. The decline in voltage, indicated by the size of the spikes on the graphs, is clearly evident as the years progress.

Types of amyloidosis and heart involvement
     AL amyloidosis

Treatment of AL cardiac amyloidosis
     Heart transplantation
     Prevention of sudden cardiac death

Hereditary amyloidosis
     Management of hereditary forms of amyloid heart disease

The section on hereditary amyloidosis focuses primarily on ATTR, although fibrinogen is mentioned a few times. The article does state that although fibrinogen amyloidosis almost exclusively affects the kidneys, rare cases with cardiac involvement have been reported. (It refers to one of the articles reviewed in the January 6, 2014 blog post.) Then in two different places the article states that the precursor protein for fibrinogen amyloidosis is produced in the liver, and liver-kidney transplantation has been successful.

The article states that the only specific treatment for amyloidosis due to transthyretin, fibrinogen or apolipoprotein mutations is organ transplantation. That was true at the time this article was written, but there are now some drugs available specifically for ATTR that have shown promising results in clinical trials. They were in early clinical trials at the time the article was published, but they are mentioned in the section on potential new therapies.

Senile systemic amyloid

This type of amyloidosis, which has nothing to do with becoming senile, is not due to a mutation at all. The word "senile" is used in this case to mean the second definition currently found at dictionary.com, which is: "of or belonging to old age or aged persons; gerontological; geriatric." It is a buildup of normal (wild-type) transthyretin to form amyloid deposits. About 25% of people over the age of 80 will have some amyloid deposits due to this, but it only becomes clinically significant when it affects the heart.

Potential new therapies

Secondary (AA) amyloidosis

AA amyloidosis is a buildup of amyloid in response to chronic inflammation. The amyloid is "secondary" to the inflammation. Only about 2% of AA amyloidosis cases have cardiac involvement.

Isolated atrial amyloid

This is a disease of the elderly caused by a buildup of a substance (atrial natriuretic peptide, or ANP) that is produced by the heart. The article states that up to 95% of people in their 80s will have this to some extent. So if you need something to worry about as you get older, I suppose this would be one of the more rational things to worry about, given its prevalence. You're welcome.

Summary

The summary is rather short, given the length of the article. I did notice one sentence in the summary regarding genetic testing that I thought was worth repeating here: "The identification of a patient with familial amyloidosis should lead to genetic counseling and, possibly, genetic screening of offspring, as new therapies, currently in clinical trials, may offer a way to prevent or delay the onset of the disease, and early detection in offspring may permit better disease management." So if someone tells you they are not interested in genetic testing because there is no treatment available other than an organ transplant, be sure to inform them that is no longer true.

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Although this article does not really add anything to what we already know about fibrinogen amyloidosis from earlier articles, as I said earlier I think it is good to know this article is out there should the need arise, either for yourself or for someone else. It is also interesting to see some discussion of early clinical trials in an article published four years ago, even though they were not applicable to fibrinogen amyloidosis.

Speaking of clinical trials, the next article up for review is about a clinical trial that is applicable to fibrinogen amyloidosis.

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Citation:

(1) Falk RH, Dubrey SW. Amyloid heart disease. Prog Cardiovasc Dis. 2010;52(4):347-361.

Article Reviews (2008) - Cardiac Amyloidosis with the E526V Mutation of the Fibrinogen A alpha-chain

Today's article review will cover two articles from 2008 that appear to be about the same patient. This is the first reported case of cardiac amyloidosis in a patient with fibrinogen amyloidosis. As if kidney failure is not enough to be concerned with, now we add the possibility of heart involvement. I will talk about that some more at the end of this review, including some correspondence I had with the author of one of these articles and with one of the Boston doctors.

Title: Myocardial involvement in fibrinogen A-alpha chain amyloidosis (1)

Authors: G. Gahide, F. Roubille, J. C. Macia, V. Garrigue, H. Vernhet (Centre Hospitalo-Universitaire de Montpellier, Montpellier, France) 

Journal: European Journal of Internal Medicine (November 2008)


Title: Cardiac Amyloidosis with the E526V Mutation of the Fibrinogen A alpha-chain (2)

Authors: Georges Mourad, Jean-Philippe Delabre, Valerie Garrigue (University of Montpellier Medical School, Montpellier, France)

Journal: New England Journal of Medicine (December 2008)


I will be reviewing these two articles together since they are about the same patient. When I need to refer specifically to one article I will refer to them as the November article and the December article.

The December article is freely available online, and here is a link to the PDF: http://www.nejm.org/doi/pdf/10.1056/NEJMc0805012. I found that article in November of 2010, based on the download date on my PDF version. But for some reason I did not find the November article until last month. It is not freely available online, but here is the PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/19013365.

The December article begins with these two sentences: "Proteinuria developed in a 48-year-old man in 2003. He mother had died 10 years earlier from renal amyloidosis." That really got my attention the first time I read this article because at the time I was 48 and I knew my mother had fibrinogen amyloidosis.

Here is what I believe is the chronology of this patient, based on information from both of these articles. (I am not positive I have the ages or the sequence of events exactly correct, as it was difficult to reconcile the timelines in both articles.)

Age 48:  Proteinuria (over 7 grams per 24 hours). Creatinine clearance and GFR were normal.

A kidney biopsy showed amyloid deposits in the glomeruli. He was originally diagnosed with AL amyloidosis, but familial amyloidosis was suspected since his mother had died from renal amyloidosis. Genetic testing showed he had the Glu526Val mutation for fibrinogen amyloidosis. (Note: Since his mother died around 1993, she died before the first article on the Glu526Val mutation was published.)

Age 51:  Patient reported dyspnea (shortness of breath), which gradually got worse. He had no family history of heart disease.

Age 53: Patient referred for a myocardial hypertrophy (thickening of the heart muscle). Echocardiogram and MRI showed various heart issues, so multiple heart biopsies were obtained from the affected area(s). Those biopsies showed amyloid, but more importantly, the tissue stained specifically with antifibrinogen antibodies, indicating the amyloid was due to fibrinogen.

Patient received a pacemaker, and then an implanted defibrillator.

Both articles give details on the heart issues found with this patient. I am not going to repeat or summarize those here, since they are way beyond my comprehension. The November article has four images from the cardiac MRI, and it does stress how valuable MRI can be when evaluating cardiac amyloidosis.

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These two articles discuss an unusual case of clinically significant heart involvement in a patient with fibrinogen amyloidosis. The articles do not state what his kidney function was after he initially presented with proteinuria at the age of 48, so perhaps we can assume it was less clinically significant than the cardiac issues.

What does all this mean for those of us with a fibrinogen amyloidosis mutation? Do we need to start having periodic echocardiograms or cardiac MRIs now, even if we have no kidney issues? Is it possible to have heart involvement before kidney involvement? Do we just not worry about cardiac amyloidosis until we start having heart issues? These were some of the questions I had after the first time I read the December article. Since the prognosis for cardiac amyloidosis is rather poor if left untreated I have been very interested in this topic for the past three years, so I will give you my current opinion on the subject. Keep in mind that I am not a doctor and all of this is subject to change as more data becomes available, so the best thing to do is discuss it with your doctor.

One thing I did to help answer some of my questions was send an email to the primary author of the December article, Dr. Mourad. Going over my old emails, it looks like I sent that email in February of 2011, the day after I found out I had the Glu526Val mutation. I explained my situation and asked him two questions, and he replied the following day. The first question was about some data from the article, which stated about 40 cases of fibrinogen amyloidosis had been reported since it was first described in 1993. (Remember this article was from 2008.) I asked if that was 40 cases in France, Europe, or globally. He said it was 40 cases reported in the international literature at the time they wrote the article.

In my other question I asked him what he would recommend someone with the mutation who is asymptomatic do proactively before renal symptoms develop, such as getting an echocardiogram. He said he would recommend checking for proteinuria and hematuria annually or every two years, as well as getting an echocardiogram every year or two.

In October of 2012 I became curious about this subject again for some reason, so I sent Dr. Berk in Boston an email with the same general question regarding periodic echocardiograms for someone who has the mutation but is asymptomatic, vs. someone who does have kidney involvement. He said there are no consensus guidelines, but the focus of periodic checkups should be on renal function. He did say periodic echocardiograms or measurements of cardiac biomarkers should suffice, with additional studies as appropriate.

I also asked Dr. Berk about having an echocardiogram done outside of a Center of Experience such as Boston or Mayo Clinic, because I had heard or read that detecting amyloid on an echocardiogram can be easily missed by someone with very little training or experience with cardiac amyloidosis. He said echocardiogram reports tend to reflect the familiarity of the person reading the echocardiogram with amyloidosis, and he would recommend having echo images reviewed by a cardiologist well versed in amyloid.

One thing I have learned over the years is that cardiac amyloidosis can be difficult to diagnose and often goes undiagnosed because the symptoms are so similar to those caused by other more common heart ailments. Unlike declining kidney function, which has early warning biomarkers such as proteinuria, GFR, and serum creatinine level, there are no biomarkers that are considered clear early warning signs of cardiac amyloidosis. It requires more of an overall assessment, including tests like echocardiogram or MRI.

Based on all that, I do not think a person with fibrinogen amyloidosis needs to be overly concerned about possible cardiac involvement. Keep in mind that these articles from 2008 are the only published account of cardiac amyloidosis in a patient with fibrinogen amyloidosis. (There are some later articles that indicate some degree of cardiac involvement may be more common than previously thought, but it generally does not become clinically significant.) Another important fact from this 2008 case is that this patient had proteinuria for three years before he had any signs of heart trouble. As long as you are getting an annual physical exam and there are no kidney or heart issues, I do not think there is a need to go looking for cardiac involvement.

The situation changes once kidney issues appear, however. At that point it may make sense to talk to your doctor about getting an echocardiogram to serve as a baseline measurement if nothing else. I do not think it is urgent by any means, and if you start investigating a liver or combined liver and kidney transplant, you may have an echocardiogram as part of that evaluation anyway. If you are evaluated at Mayo Clinic or Boston you will almost certainly have an echocardiogram done there.

The situation definitely changes if heart issues develop to the point where you are referred to a cardiologist. That is where the patient really needs to be their own advocate and talk to their cardiologist about amyloidosis. You do not necessarily have to become well-versed in the medical terminology such that you are comfortable talking about ejection fraction, wall-thickening, and the classic sparkly appearance of amyloid on echocardiograms. At a minimum, you need to make sure your cardiologist understands that cardiac amyloidosis can mimic other more common heart ailments, and suggest that he or she consult with an experienced cardiologist at either Boston or Mayo Clinic (or perhaps another Center of Experience if not in the US.)

When I went to Mom's cardiologist appointments with her earlier this year, I had a good discussion with him and felt like he was aware of what to look for. I did bring a copy of the December article for him to keep and review at his leisure if he wanted to. (No need to make him scan it over quickly during the appointment, just to hand it back and say he does not need a copy.)

Given the rarity of the diagnosis in this case (fibrinogen amyloidosis with cardiac involvement), there simply is not a lot of experience to generate any firm guidelines on how to proceed. Each patient's case will be different, and based on the data we have it will not be an issue at all for most patients. My goal here is to make people aware of the possibility so they can decide for themselves what they are comfortable doing. Some people may decide not to do anything until they have heart issues, whereas others may want to get a baseline echocardiogram before reaching the age of 40 while they are asymptomatic. Either approach can be considered reasonable.

In summary, my opinion is that there is no need to panic about possibly having cardiac involvement if you have a fibrinogen amyloidosis mutation. You do need to be aware of the possibility, especially if and when you develop kidney issues, since kidney issues will very likely occur first. At that point it may make sense to be proactive and get an echocardiogram before heart issues develop. That is certainly something to discuss with your doctor at that point. If you do develop heart issues, you want to make sure you are under the care of a cardiologist who either has some familiarity with amyloidosis, or will consult with a cardiologist who does.

The next article up for review is one of the more important ones published to date regarding fibrinogen amyloidosis, as it reports on 71 patients. Yes, 71. I have not looked at this article in a year or two, but you can probably expect a lengthy post (maybe even a two-parter) with lots of data.

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Citations:

(1) Gahide G, Roubille F, Macia JC, Garrigue V, Vernhet H. Myocardial involvement in fibrinogen A-alpha chain amyloidosis. Eur J Intern Med. 2008;19(7):e54-56.

(2) Mourad G, Delabre JP, Garrigue V. Cardiac amyloidosis with the E526V mutation of the fibrinogen A alpha-chain. N Engl J Med. 2008;359(26):2847-2848.