Thursday, January 30, 2014

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.

Friday, January 24, 2014

Article Review (2009) - Nephrotic Syndrome Due to an Amyloidogenic Mutation in Fibrinogen A alpha Chain

Today's article being reviewed covers a single case of fibrinogen amyloidosis, with some detailed discussion of the biopsy itself, which then expands to a discussion of the role of biopsies in determining amyloid type.


Authors: Maria M. Picken, Reinhold P. Linke (Loyola University Medical Center, Maywood, IL, USA; Reference Center of Amyloid Diseases, Martinsried, Germany)

Journal: Journal of the American Society of Nephrology (2009)

Abstract:

We identified amyloid derived from a mutant fibrinogen A alpha chain associated with one of the hereditary amyloidoses by kidney biopsy. The recognition of molecular and etiologic diversity among amyloidoses has revolutionized the management of systemic amyloidosis and necessitates precision in amyloid typing. Pitfalls and recommendations for the differential diagnosis of renal amyloid and current standards of amyloid typing are briefly discussed. Diagnosis of the amyloidosis type must be based on identification of the chemical composition of the amyloid protein in deposits and not on clinical suspicion, laboratory tests, or genetic testing. A clinical correlation is required to support but not make a diagnosis of amyloid type. If a hereditary form is detected by amyloid protein typing, then molecular studies are indicated. Conversely, in cases in which DNA sequence indicates a mutant amyloid precursor protein, protein analysis of the deposits must provide the definitive evidence. Negative or inconclusive results must be investigated further by a reference laboratory with the capability of applying more sophisticated methods.

Here is a link to the PDF of this article, if you would like to follow along:  http://jasn.asnjournals.org/content/20/8/1681.full.pdf

One of the authors of this article is Dr. Maria Picken, a leading pathologist in the field of amyloidosis who was on the panel at the 2011 and 2013 familial amyloidosis support meetings in Chicago. She is the author of the 2012 book "Amyloid and Related Disorders: Surgical Pathology and Clinical Correlations." The other author, Dr. Reinhold Linke, is an amyloidosis researcher who is the founder and owner of Amymed, a company in Germany that provides pathology services, products and training specifically for the diagnosis of amyloidosis.

The case presented in this article is a 55-year-old woman who initially presented with edema around her eyes and ankles, and weight gain. Her initial labwork showed a serum creatinine level of 2.1 mg/dl, and 24-hour urine collection showed 5.3 grams of protein. She had previously noted foamy urine. There was no known history of kidney disease in her family.

A kidney biopsy was done, and it showed amyloid deposits primarily in the glomeruli. The material stained positive with Congo red but additional immunohistochemistry analysis on that section of tissue, including staining for fibrinogen, was unable to type the amyloid. Another section of tissue (in paraffin) was anaylzed, and it stained weakly positive for light chain (AL) amyloid. This second tissue section had additional staining done for other proteins, and it was strongly positive for fibrinogen. (The article includes color photos of several of these biopsy slides, for those of you who are curious about the difference between negative, weakly positive and strongly positive.)

DNA testing confirmed that she had a fibrinogen mutation. (The article does not say which one.) This patient's younger sister and two daughters were tested for the mutation, and one daughter tested positive but is currently asymptomatic. Two years after the kidney biopsy, the patient developed kidney failure and underwent a combined liver and kidney transplant. Two years post-transplant she has normal renal function.

The next section of the article gives some basic information on amyloidosis in general, and the role of the pathologist in diagnosing it. In the past, there were only two known types of systemic amyloidosis, AL and AA. But now the hereditary types of amyloidosis, such as transthyretin, fibrinogen and apolipoprotein, are considered a third category of systemic amyloidosis. Since the kidneys are very frequently affected by systemic amyloidosis, nephrologists and renal pathologists are in a prime position to detect amyloidosis and should include amyloidosis in the differential diagnosis of proteinuria and nephrotic syndrome. The differences in treatment among the various types of systemic amyloidosis are then briefly discussed, which leads to the first mention in the article about how critical it is to accurately diagnose the type of amyloid.

The article then presents some information on fibrinogen amyloidosis, restating much of what we already know from previous articles. Patients typically present with nephrotic syndrome and hypertension, with a median age at presentation of 55. Kidney failure is the dominant clinical feature, and kidney biopsies show massive glomerular deposits with very little if any amyloid deposits elsewhere. The only other organ involvement that may become clinically significant is the spleen, which may lead to anemia or splenic rupture. Isolated kidney transplantation typically leads to recurrence of amyloid, whereas better results are achieved with combined liver and kidney transplants, since the source of the abnormal protein is eliminated.

Going back to hereditary amyloidosis in general, the article discusses the fact that hereditary amyloidosis is underdiagnosed and misdiagnosed, and offers some reasons for that:


  • Variable penetrance, which means some people with the mutation never develop symptoms. There may be no family history of hereditary amyloidosis.
  • The hereditary amyloidoses are typically late onset diseases and clinically may mimic AL amyloidosis.
  • Almost all types of amyloidosis can involve the kidneys, although to different degrees.
  • Up to 25% of patients with hereditary amyloidosis also have a plasma cell condition that is a biomarker for AL amyloidosis. I believe that means a doctor not intimately familiar with all types of amyloidosis could mistakenly diagnose someone as having AL amyloidosis because some of that patient's lab work is consistent with AL amyloidosis. (There are a few documented cases of patients indeed having both a hereditary form and AL amyloidosis.)
  • In the past, when biopsy tissue stained positive for amyloid with Congo red, but negative for AA or light chains (AL), the default diagnosis was typically "presumed" AL amyloidosis. As we know from previous articles, this is not an uncommon occurrence which has caused some patients with a hereditary form of amyloidosis to be treated as if they had AL, which means chemotherapy or a stem cell transplant.

The article then discusses the benefits and limitations of using immunohistochemistry to type amyloid. I am not going to covers those details here, but the topics include analyzing frozen tissue sections vs. those in paraffin, typing AL vs. AA, and the quality of the antibodies used during the process. The article concludes by giving the author's recommendation that a diagnosis of amyloid type must be based on the chemical nature of the amyloid deposits themselves and "not solely on clinical suspicion or on genetic testing." Restated a few sentences later: ". . . in cases in which the DNA sequence indicates a mutant amyloid precursor protein, protein analysis of the deposits must provide the definitive evidence."

Those of you with good memories may realize that this recommendation, to type the amyloid from the tissue sample even if the genetic mutation of the patient is known, is different than the answer to the question I submitted to the panel at the 2013 familial amyloidosis meeting. As I described in the November 5, 2013 blog post, I asked if it was necessary to type the amyloid in a biopsy if the patient's genetic mutation is already known. The answer given was basically no, it is not critical in that case. Dr. Picken (coauthor of this article) was at the meeting on the first day but she was not there for the question and answer session on the second day. She obviously may have given a different answer.

I suppose this subject of typing the amyloid when the genetic mutation is already known is one of those cases where there is no obvious correct answer in every case. On the one hand, if you have a fibrinogen mutation and you have had a bone marrow biopsy that did not give any indication of AL amyloidosis, it is very unlikely that amyloid deposits in your kidneys are due to anything other than fibrinogen. On the other hand, if a bone marrow biopsy shows some abnormalities (plasma cell dyscrasia), or if you have other symptoms that line up more with an amyloidosis type other than fibrinogen, maybe it is a good idea to have the amyloid in a tissue biopsy typed. At a minimum it is a discussion worth having with your doctor, and the doctors at any of the Centers of Experience (Mayo Clinic or Boston University, for instance) would certainly be willing to consult with your doctor.

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This article presents another typical case of fibrinogen amyloidosis, in terms of presentation, diagnosis, and treatment. But I do not consider the primary purpose of this article to be simply the presentation of another case. The main thing going through my mind while reading this article was how difficult it can be to get a proper diagnosis of fibrinogen amyloidosis when there is no family history of it. In fact, there are so many things working against that diagnosis that I decided to make a list. (I am going to digress from the article at this point and discuss some slightly broader ideas.)

  • Amyloidosis is rare disease. Most doctors will only see a few cases during their career, if any. Familial amyloidosis is a rare type of a rare disease. Fibrinogen amyloidosis is a rare subtype within a rare type of a rare disease.
  • Fibrinogen amyloidosis has variable penetrance. As I like to tell people, the symptoms can skip generations but the mutation cannot.
  • Other than hypertension, there are no obvious symptoms until late in the progression of the disease. People generally do not go to the doctor complaining of elevated serum creatinine levels, low GFR, or protein in their urine. (Some people may notice foamy urine, but only some of them will see a doctor about it.)
  • Even if a patient gets regular physical exams and one or more symptoms are detected relatively early, all of the symptoms of fibrinogen amyloidosis can be caused by other more common diseases or ailments. A doctor at one of the Dallas support group meetings described it this way: If a medical textbook lists 100 things that can cause a certain symptom, with the more common causes listed first, amyloidosis will be somewhere around 99th in the list.
  • Even if amyloidosis is suspected, the symptoms of fibrinogen amyloidosis are similar to the symptoms of other types of amyloidosis.
  • Some patients with amyloidosis may have biomarkers that are consistent with AL amyloidosis, thus leading to a misdiagnosis.
  • If a patient gets to point of being referred to a nephrologist for kidney issues, the nephrologist then has to go through his or her standard diagnostic process, including lab work and 24-hour urine collections, eventually deciding (hopefully) that a kidney biopsy is needed.
  • When the kidney biopsy is analyzed, Congo red staining must be done correctly to detect amyloid deposits. (I think Congo red staining is a standard procedure now, but I do not know that for certain.)
  • If amyloid is detected with Congo red staining, additional testing using immunohistochemistry is typically done to type the amyloid. Immunohistochemistry is very dependent on a number of factors which are described in this article, so it is far from a 100% reliable method. If it fails to type the amyloid, the patient may get an incorrect diagnosis of AL amyloidosis. Someone has to realize that amyloid typing still needs to occur, and suggest mass spectrometry or genetic testing.
  • Mass spectrometry is much more reliable than immunohistochemistry, but very few labs have the equipment to do that.
  • Genetic testing for the rare familial forms of amyloidosis (forms other than ATTR) is very specialized and is only done at a small number of labs. (I had difficulty getting tested even though my mutation was known.)

There are probably more items that could be added to that list. But the point is, if you are the first in your family to be diagnosed with fibrinogen amyloidosis, a lot of things had to fall into place along the way. They most likely did not happen as quickly as they could have, but they did eventually happen, which is good. I will not say anyone is lucky to have fibrinogen amyloidosis, but if you were the first in your family diagnosed with it then you are indeed fortunate to have a correct diagnosis, given all the things mentioned above that make that diagnosis difficult.

Now let's consider the person related to someone diagnosed with fibrinogen amyloidosis. If they know about it and have regular checkups, then their chances of getting a correct, early diagnosis are very good. But if they do not know about it, then they are in the same situation as anyone else on the planet and all of the items listed above are working against a correct diagnosis. That is why it is so important to inform other family members once this disease has been diagnosed. The original diagnosis was long and difficult, and there is no reason anyone else in that family should go through the same thing or risk a misdiagnosis. I could use a similar argument in support of genetic testing for potentially affected family members, but I will save that discussion for a future post or posts.

With this article review we have now reviewed the articles through 2009 (except for a few stragglers I may get to later). Things get even more interesting with fibrinogen amyloidosis in 2010, both in the medical literature and in the real world. Stay tuned!

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Citation:

(1) Picken MM, Linke RP. Nephrotic syndrome due to an amyloidogenic mutation in fibrinogen A alpha chain. J Am Soc Nephrol. 2009;20(8):1681-1685.

Sunday, January 19, 2014

Article Review (2009) - Fibrinogen Amyloidosis: A Report of 15 French Cases

Before starting today's article review I want to give a quick update on Mom since it has been almost two months since the last one. There really has not been much going on, which is actually good news. Her calcium level is hovering just below 10, which is high but still within the normal range. No new tests have been ordered, so it seems like trying to figure out the cause of her high calcium is on hold for now. She did recently change her normal dialysis appointment times from 11:00 AM (second shift) to around 6:30 AM (first shift.) That should be more convenient for her to get dialysis taken care of in the morning instead of in the middle of the day. It is early, but if she is tired then maybe she can get some sleep during dialysis.

There is another change regarding dialysis. Mom has requested to be assigned to a different nephrologist. Dr. N has not has not really been bad, but there are some things that Mom has not been pleased with so she inquired about switching a few weeks ago and was told she could do it. So we will see what the new nephrologist thinks about her blood pressure situation.

Today's article being reviewed is an abstract presented at the 2009 World Congress of Nephrology, which was held in May of 2009 in Milan, Italy. As far as I know it is not published in a book and is only available online. This is a short abstract with a correspondingly short review, in contrast to the previous one.


Authors: Laurence Vrigneaud, Jean-Philippe Delabre, Sophie Valleix, Gilles Grateau, Georges Mourad, Philippe Vanhille. (Hospital, Valenciennes, France; University Hospital, Montpellier, France; University Hospital, Paris, France)

Here is the link to this abstract online if you would like to follow along: http://www.abstracts2view.com/era_archive/view.php?nu=WCN09L_2519


As stated in the title, this abstract presents some data on 15 fibrinogen amyloidosis patients from France. I will present most of it in bullet form.



  • 8 women, 7 men
  • 7 patients had the Glu526Val mutation.
  • 6 patients had the Arg554Leu mutation.
  • 2 patients had the frameshift mutation caused by a deletion at codon 522. (Described in the 1997 article reviewed in the April 18, 2013 blog post.)

  • Mean (average) age at presentation was 48.2 years.
  • Average proteinuria was 5.8 grams per day.
  • 8 patients had high blood pressure.
  • 5 patients had microhematuria (blood in the urine).
  • 11 patients had kidney biopsies, which all showed "striking massive amyloid deposits within enlarged glomeruli."
  • 3 biopsies showed amyloid deposits in blood vessels or interstitium (between the cells).

  • 6 patients had no family history of renal disease.
  • The only patient who developed significant clinical symptoms beyond kidney disease was the one with cardiac amyloid. (That case was recently discussed in the January 6, 2014 blog post.)
  • 10 patients were on dialysis within five years of presenting.
  • 3 patients died.

  • 12 patients received kidney transplants.
  • 5 of those patients showed amyloid deposits in the transplanted kidney 4.5 years after transplant.
  • 3 patients received combined liver-kidney transplants, with no recurrence of amyloid two years after transplant.

It is interesting that only 7 out of these 15 patients (47%) had the Glu526Val mutation, since the Glu526Val mutation is the most common. In the previous article that studied 71 patients, 90% had the Glu526Val mutation. But given the small total number of patients in this group from France, one or two families with several members having the Arg554Leu mutation would be a significant percentage of the total. So I don't think we can draw any conclusions based on these numbers.

Among these patients, the typical symptoms we have seen before are proteinuria and high blood pressure. Microhematuria has been mentioned just a few times in earlier articles, so five out of 15 patients having it in this group is a bit unusual. The biopsy results are typical of fibrinogen amyloidosis, since they all showed deposits in the glomeruli and a few showed amyloid deposits elsewhere.

The data on patients who received organ transplants is in line with what we have seen in previous articles. Once again we see that a kidney transplanted without a liver can be expected to have a recurrence of amyloid, whereas a combined liver-kidney transplant seems to prevent recurrence of amyloid.

The concluding paragraph of this abstract ends with this sentence: "DNA analysis is therefore mandatory, regardless of family history, in all patients with renal amyloidosis with selective glomerular involvement, in whom AA or AL fibril type cannot be definitively confirmed." In other words, the authors recommend that in cases where a kidney biopsy shows amyloid deposits primarily in the glomeruli, and AA or AL amyloidosis cannot be confirmed, DNA analysis should be done to look for fibrinogen mutations. That makes sense based on the biopsy findings that have been reported in all the cases up to this point. There are always deposits in the glomeruli, with occasional deposits elsewhere to a lesser extent. The amyloid often cannot be typed, even with immunohistochemistry. We don't need to look any further than Mom's biopsy report to see an example of this. The diagnosis was amyloidosis, with this comment: "There is Lambda greater than Kappa staining but not significant enough to definitively state that this is AL Amyloidosis. The section stained for AA Amyloid is negative." Hindsight is always 20/20, right?

Speaking of biopsy reports, someone on the Yahoo support group recently posted a kidney biopsy report and asked if anyone could translate it. I immediately noticed how similar it was to Mom's biopsy report and offered some of my interpretation. (Bottom line is that the biopsy needs to be sent to Mayo Clinic for analysis by mass spectrometry so the amyloid can be typed.) I did not mention fibrinogen amyloidosis since I would not want to send someone down that path prematurely, but it will not surprise me at all if that is the diagnosis.

Speaking of biopsy reports again, the next article to be reviewed presents another case where the biopsy played a key role in the diagnosis of fibrinogen amyloidosis. Since one of the two authors is the pathologist on the panel at the familial amyloidosis support group meetings every two years, we can expect to get into some detail regarding biopsies.

Sunday, January 12, 2014

Article Review (2009) - Diagnosis, Pathogenesis, Treatment, and Prognosis of Hereditary Fibrinogen A alpha-Chain Amyloidosis

Today's article under review is one of the more important articles on fibrinogen amyloidosis. It follows 71 patients who were diagnosed at the National Amyloidosis Centre (NAC) in the UK. Prior to this article, the largest number of patients covered in one article was 20, from the paper presented at the XIth International Symposium on Amyloidosis in 2006. Those patients were also evaluated in the UK, and I reviewed that paper in the November 30, 2013 blog post. It should be very clear by now that fibrinogen amyloidosis is much more prevalent in the UK than in any other country.

Title: Diagnosis, Pathogenesis, Treatment, and Prognosis of Hereditary Fibrinogen A alpha-Chain Amyloidosis (1)

Authors: Julian D. Gillmore, Helen J. Lachmann, Dorota Rowczenio, Janet A. Gilbertson, Cai-Hong Zeng, Zhi-Hong Liu, Lei-She Li, Ashutosh Wechelekar, Philip N. Hawkins (National Amyloidosis Centre, London, UK; Nanjing University School of Medicine, Nanjing, Peoples Republic of China)

Journal: Journal of the American Society of Nephrology (2009)

Abstract: 

Mutations in the fibrinogen A -chain gene are the most common cause of hereditary renal amyloidosis in the United Kingdom. Previous reports of fibrinogen A -chain amyloidosis have been in isolated kindreds, usually in the context of a novel amyloidogenic mutation. Here, we describe 71 patients with fibrinogen amyloidosis, who were prospectively studied at the UK National Amyloidosis Centre. Median age at presentation was 58 yr, and renal involvement led to diagnosis in all cases. Even after a median follow-up of 4 yr, clinically significant extra-renal disease was rare. Renal histology was characteristic: striking glomerular enlargement with almost complete obliteration of the normal architecture by amyloid deposition and little or no vascular or interstitial amyloid. We discovered four amyloidogenic mutations in fibrinogen (P552H, E540V, T538K, and T525fs). A family history of renal disease was frequently absent. Median time from presentation to ESRD was 4.6 yr, and the estimated median patient survival from presentation was 15.2 yr. Among 44 patients who reached ESRD, median survival was 9.3 yr. Twelve renal transplants survived for a median of 6.0 (0 –12.2) yr. Seven grafts had failed after median follow up from transplantation of 5.8 yr, including three from recurrent amyloid after 5.8, 6.0, and 7.4 yr; three grafts failed immediately for surgical reasons and one failed from transplant glomerulopathy after 5.8 yr with no histological evidence of amyloid. At censor, the longest surviving graft was 12.2 yr. In summary, fibrinogen amyloidosis is predominantly a renal disease characterized by variable penetrance, distinctive histological appearance, proteinuria, and progressive renal impairment. Survival is markedly better than observed with systemic AL amyloidosis, and outcomes with renal replacement therapy are comparable to those for age-matched individuals with nondiabetic renal disease.

Here is a link to the PDF of the article if you would like to follow along: http://jasn.asnjournals.org/content/20/2/444.full.pdf

Note: In this review I will occasionally write "Afib" instead of "fibrinogen amyloidosis."

There is a lot of information packed into that abstract, and even more in the article. Having so much data can seem a little overwhelming, but hopefully by presenting much of the data in a more visually appealing way (bullet points) you can understand what most or all of this data means and decide what matters to you.

Before starting the review I want to define a non-medical term that appears several times in the abstract and will likely appear several times in my review. That term is "median." You may recall studying mean, median and mode in one of your math classes in school. The "mean" of a group of numbers is simply the average. For instance, to find a student's average test score you just add up all of his or her test scores and divide by the number of tests. That number is the average, or mean.

The "median" refers to the value in the middle when the test scores are sorted in order. For example, if a student's scores on five tests were:

85, 95, 68, 100, 90

We first arrange them in order:  68, 85, 90, 95, 100

And we can see that the middle value, the median, is 90. On the other hand, the mean, or average, of those five grades is 87.6. (If the number of test scores were an even number, the median would be the average of the two values in the middle.) If we know the median of a set of numbers, we know half the values are higher than the median and half the values are lower. So the median is the midpoint of a set of numbers when they are sorted in order. Unlike the average (the mean), the median is not impacted by values at one extreme or the other. But if you want to say "average" to yourself when you see the word "median," you will still get the same general idea that is being presented.

That concludes today's math lessons boys and girls. Please put away your calculators and get out your copy of today's article.

The article starts with brief histories of hereditary renal amyloidosis and fibrinogen amyloidosis. It then states that this article reports on 71 fibrinogen amyloidosis patients who were diagnosed and studied at the UK National Amyloidosis Centre between 1992 and 2007. (Later in the article it gives an ending date of February 2008.) The article has one large section in the middle where the majority of the data is presented, so there are no useful section headings to help us navigate. But it looks to me like the data can be grouped into seven categories: symptoms, diagnosis, biopsy results, genetic testing results, progression of the disease, treatment (transplants), and comparison to other diseases. I will use those categories as section headings for this review.


Symptoms
  • 100% of patients had proteinuria.
  • 72% had hypertension
  • 54% had some impairment of renal function. (The article does not say how that was measured, but the typical measurements would include serum creatinine and GFR.)
  • The median age at presentation (first visit with a doctor regarding symptoms) was 58 years old, and it ranged from 38 to 83.
  • The median time from presentation to diagnosis was 8 months, with a range from zero to 164 months. (The zero would be patients who were known to have the mutation before symptoms developed.)
  • Despite the odd number of patients, the male-female distribution was equal according to the article. (35 and 36 is close enough.)

Diagnosis
  • 64 patients were diagnosed with amyloidosis based on kidney biopsies. The other 7 patients were known to have Afib in their family and were diagnosed based on genetic testing, renal dysfunction, and SAP scintigraphy.
  • SAP scintigraphy was done on 63 of the 71 patients. It showed amyloid deposits in the kidneys of every patient who had not already reached end stage renal disease.
  • 89% of patients had amyloid deposits in the spleen. (no symptoms)
  • 21% of patients had amyloid deposits in the adrenal glands. (no symptoms)
  • At their initial evaluations, no patients had echocardiograms that indicated cardiac involvement.
  • One patient with a novel Afib mutation (discussed later) had peripheral neuropathy that a biopsy showed was due to amyloid.
  • 12 patients had been incorrectly diagnosed with AL amyloidosis. Five of those patients received chemotherapy and one received a stem cell transplant before receiving the correct diagnosis of fibrinogen amyloidosis. (For more on misdiagnosis of hereditary amyloidosis as AL amyloidosis, see the article reviewed in the blog on May 12, 2013.)
  • 46% of patients had no family history of renal disease or amyloidosis.

Biopsy Results
  • Every kidney biopsy showed amyloid deposits concentrated almost exclusively in the glomeruli.
  • Immunohistochemical staining for fibrinogen was positive in 93% of the patients with kidney biopsies. (That is surprisingly high based on what I have read in other articles.)
  • In the other 7% of cases, the patients were known to have a fibrinogen amyloidosis mutation and the overall clinical picture was typical for Afib.

Genetic Testing Results
  • 64 patients were heterozygous for the Glu526Val mutation of the fibrinogen A alpha chain. Six of those patients were from a single German family, and the rest were of British Caucasian ancestry.
  • Two British patients were heterozygous for the Arg554Leu mutation. (That was the first Afib mutation discovered, published in 1993.)
  • Four new Afib mutations were discovered at the NAC during this time period:
    • Two German sisters had the Glu540Val mutation. (I previously discussed their case toward the end of the December 30, 2013 blog post.)
    • One Chinese patient had a frameshift mutation caused by a deletion at codon 525.
    • One Chinese patient had a substitution of lysine for threonine at position 538. (Thr538Lys)
    • One Afro-Caribbean patient had a substitution of histidine for proline at position 552. (Pro552His)
  • Other than peripheral neuropathy in the patient with the Thr538Lys mutation, the clinical history and kidney biopsies of patients with these newly discovered mutations was similar to that of patients with the Glu526Val mutation.

Progression of the Disease
  • The patients were followed for a median of 4 years after diagnosis.
  • 17 of the patients died during this study. Median age at death was 67 years, with a range of 57 to 85.
  • Causes of death were:
    • Infection (6)
    • Metastatic malignancy (cancer) (3)
    • Dialysis withdrawal (2)
    • Transplant-related mortality (2)
    • Gastrointestinal blood loss (1)
    • Unknown (3)
  • The estimated median survival from presentation was 15.2 years.
  • The estimated median survival from diagnosis was 10.9 years.
  • 44 patients reached end stage renal disease (ESRD). The median age when dialysis began was 60, with a range of 36 to 82.
  • Median time from presentation with proteinuria to ESRD was 4.6 years (range 0 to 10.2).
  • Median time from diagnosis of amyloidosis to ESRD was 2 years (range 0 to 10.2).
  • Among the 23 patients with an initial estimated GFR of over 20 ml/min, the mean rate of GFR loss was 11.5 ml/min per year.
  • Thirteen of the 44 patients who reached end stage renal disease died during follow-up.
  • The estimated median survival from the start of dialysis was 8.2 years (range 0.2 to 24.8).
  • No patients developed the classic signs of cardiac amyloidosis, although various cardiac and cerebral events were reported.
  • Amyloid deposits in the liver were detected in only two patients, both of whom had presented more than 8 years previously.
  • No patients developed clinically significant autonomic neuropathy.

Transplants
  • Ten patients received kidney transplants, including two patients who received a second transplanted kidney after the first one failed. (12 transplanted kidneys total.)
  • The median follow-up after kidney transplantation was 5.8 years.
  • Five transplanted kidneys were still functioning and seven had failed. (Three failed immediately up transplantation, so that was obviously not recurrence of amyloid.)
  • The estimated median survival of the transplanted kidneys that did not fail immediately was 6.7 years (range 0.9 to 12.2).
  • Three transplanted kidneys, including two in the same patient, failed due to recurrence of amyloid after 5.8, 6.0 and 7.4 years. The fourth failed transplanted kidney did not have evidence of amyloid.
  • The longest surviving kidney transplant was 12.2 years. Surprisingly, this patient had proteinuria 7.6 years after transplant, and SAP scintigraphy shows amyloid in the transplanted kidney.
  • Seven patients received combined liver and kidney transplants. The longest survivor in this group was healthy and completely free of amyloid 11.5 years after the transplant. One patient died perioperatively (during pre-op, surgery, or recovery) due to acute necrotizing pancreatitis, and the other five patients were doing well with no evidence of recurring amyloid. Median follow-up from combined liver-kidney transplant was 24 months.

Comparison To Other Diseases
  • For these Afib patients, the median time to progress from proteinuria to end stage renal disease was 4.6 years. This is longer than untreated AL amyloidosis (7.5 to 14 months) but shorter than apolipoprotein A1 amyloidosis (8 years).
  • For these Afib patients, the estimated median survival after presentation was 15.2 years, which is significantly less than for AL amyloidosis, both untreated (less than 2 years) and treated (5 years).
  • For these Afib patients, the median survival from the start of dialysis was 8.2 years, which is longer than the median survival among all nondiabetic patients in the UK, aged 55 to 64, who commenced dialysis between 1997 and 2001.

Another interesting finding was regarding family members who were known to have the mutation but were asymptomatic. There were 23 people (not part of the 71) who were in that category, with a median age of 50 years (range 31 to 84). Out of those 23, six of them were older than the oldest family member who did have symptoms and was part of this study. They also did SAP scintigraphy on 12 of these asymptomatic patients, and their SAP scans were normal. I would have expected, especially in the older asymptomatic patients, some evidence of amyloid deposits in the SAP scans. Perhaps some day we will know why some people with the mutation develop amyloid deposits and some do not.

The results section of the article concludes by stating that combined liver and kidney transplantation typically provides a better outcome than kidney transplant alone, but it comes with additional risks associated with the surgery and recovery. Since it takes several years to realize the benefits of liver-kidney transplantation over an isolated kidney transplant, the authors state that their practice is to recommend liver-kidney transplants only in their younger, healthier patients.

The last section of the article just goes into some of the details on some of the analyses that were done as part of this study.

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With this article we have by far the largest number of fibrinogen amyloidosis patients described in one article. In terms of study size, 71 is still a small number compared to typical study sizes in most medical studies. But with a rare disease like this one you just are not going to find studies that include hundreds or thousands of patients.

Other than the four new Afib mutations that were discovered, there was not much unusual, or out of the norm, about these patients. One patient had peripheral neuropathy due to amyloid, and 21% of the patients had adrenal amyloid deposits (but no symptoms).

Let's look at the symptoms first. Every patient had proteinuria, with hypertension being the second most common symptom and renal impairment being third. Those are the three symptoms that have typically been mentioned in the previously published articles, so no real surprise there. But it is good to know that the first sign of amyloids affecting the kidneys may not be renal impairment. The median age at presentation was 58, which is comparable to the presentation ages previously reported.

In the diagnosis section we learn that 89% of these patients had amyloid deposits in the spleen, but no symptoms associated with that. Although previous articles had reported some spleen involvement (such as splenic rupture), this finding tells us that fibrinogen amyloid deposits are almost as likely to build up in the spleen as they are in the kidneys. Based on previous articles it seems like significant symptoms with the spleen only occur many years after kidney issues develop, although anemia among Afib patients seems to be rather common. There was no mention of anemia in this article.

The biopsy results of these patients all exhibited the classic Afib pattern of amyloid deposits almost exclusively in the glomeruli. As previously noted, there was a very high success rate (93%) of typing the amyloid in these biopsies using immunohistochemical staining.

There was no surprise with the genetic testing results, as 64 out of 71 patients (90%) had the Glu526Val mutation, which had already been presumed to be the most common Afib mutation. The four new mutations brings the total number of published Afib mutations up to nine according to the article.

The section on Progression of the Disease is what I suspect most people are really interested in. If you know you have the mutation, you want to know the answer to this question: "Once I develop symptoms, how long will it be before X happens?" There is no need to repeat the data here in paragraph form, but before you draw any firm conclusions from the data in this article, keep in mind the following points:

  • This study included only 71 patients, and the median length of the follow-up period was only four years. That means only about 35 of these patients had been followed for over four years.
  • If you look at the range given for each piece of data, you can see that the progression of this disease varies tremendously from patient. The median time from presentation to end stage renal disease was 4.6 years, but that varied from a low of 0 years to a high of 10.2. That means that from the time a patient presents with proteinuria, there is a 50% chance that patient will reach end stage renal disease within about four and a half years. But it could happen in less than a year, or it could take 10 years to happen.
  • The decline of GFR is an important piece of information we have not seen in previous articles. GFR (estimated glomerular filtration rate) can be thought of as a rough approximation of the amount of remaining kidney function. For example, a GFR of 35 means the kidneys are functioning at approximately 35%. Previous articles have stated that fibrinogen amyloidosis is inexorably progressive, meaning it just steadily marches on and on if left untreated. It does not go into remission like some types of cancer do. This annual decline of GFR is a measure of that progression of the disease.


In the section on transplants we learn that ten of these patients received kidney transplants and seven received combined liver-kidney transplants. Previous articles have reported the failure of kidney transplants due to recurring amyloid, and this article mentions three that failed for that reason between 5 and 8 years after the kidney transplant. This article clearly shows the benefit of liver-kidney transplant over kidney transplant, while acknowledging the increased risk of the combined transplant. As with most significant medical decisions, each patient's case will be slightly different, and what is best for one patient may not be the best for another patient. This whole subject of organ transplants is one reason I think it is so important for family members to be tested for the mutation. I would much prefer having plenty of time to learn about treatment options and the pros and cons of each, rather than being faced with a transplant decision relatively soon after being diagnosed.

In the section on comparison to other disease, the article provides some data that show fibrinogen amyloidosis compares favorably to AL amyloidosis in terms of both progression to end stage kidney disease and length of survival after presentation.

In summary, there is a lot of data presented in this article that gives us an idea of what typically happens with a patient with fibrinogen amyloidosis. But the main thing to realize is that there is a very wide range of possibilities for any category of data presented here, with no way to predict what will happen with any individual patient. We already know that some people with the mutation will never develop symptoms, and among the patients in this article, all of whom did develop symptoms, the age at which symptoms were noted ranged from 38 to 83. Once symptoms do develop we know they will progress to end stage renal disease if left untreated, but we do not know how quickly that will occur. The fact that you have a fibrinogen mutation in the first place means you are not "average," so the progression of your disease may not turn out to be "average" either.

Next up: Another report on a "large" group of patients, from another European country.

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Citation:

(1) Gillmore JD, Lachmann HJ, Rowczenio D, et al. Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis. J Am Soc Nephrol 2009; 20: 444-451.

Monday, January 6, 2014

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.

Wednesday, January 1, 2014

Happy New Year!!

Welcome to 2014 everyone. Since this is my second Happy New Year post in the history of this blog, I put two exclamation points in the title. Hopefully I'll be around long enough such that the number of exclamation points becomes ridiculous.

This post will be a quick recap of 2013, some speculation on 2014, and the always exciting monthly blog stats at the end.

First, here is what happened in the blog in 2013:
  • 73 new blog posts were written, which happens to be an average of exactly one post every five days.
  • 31 articles were reviewed in 27 blog posts.
  • Three pages were added on the right side (Welcome New Visitors, What should I do now, and Simple Glossary.)
  • 60 additional countries visited the blog, bringing the total to 79.
  • The blog received 73 spam comments, which happens to be an average of exactly one spam comment every five days.

In personal news, here is what happened in 2013:
  • Mom's dialysis transitioned from the permacath to the fistula, and eventually to using the buttonhole technique. To say dialysis has not been smooth sailing for Mom would be an understatement.
  • During 2013 Mom had the following notable medical procedures:
    • Two balloon angioplasties on her fistula
    • Permacath removed, inserted, then removed again
    • Two abdominal surgeries to address infection at the site where peritoneal dialysis catheter was removed. (One was emergency surgery, resulting in two nights in the hospital and two weeks with a wound vac.)
    • Mammogram, ultrasound and needle biopsy due to benign lump on left breast
    • Biopsy and Moh's surgery to address low grade skin cancer on right leg
    • Three (maybe four) CT scans and a bone scan
    • Heart catheterization
    • Three emergency room visits, including one on a cruise ship
  • We learned that a cousin on Mom's father's side of the family also has fibrinogen amyloidosis, solving the mystery of which side of the family it was inherited from.
  • Mom was removed from the kidney transplant list November 1, since a suitable living donor could not be located.
  • We became aware of another US family diagnosed with fibrinogen amyloidosis, and met them and members of two other affected families at the familial amyloidosis meeting in Chicago in October.

The blog will continue to primarily include article reviews and updates on Mom. Hopefully 2014 will have a little less drama for Mom, with fewer complications related to dialysis. Updates on others with fibrinogen amyloidosis, myself included, will be provided as appropriate. Naturally I will also report on any updates regarding the treatment of fibrinogen amyloidosis. We probably will not see any reports on the doxycycline or CPHPC clinical trials published in 2014, but maybe some preliminary results will be communicated.

The next post will kick off our 2014 article reviews with a couple of articles from 2008.


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

Total posts: 118 (5 in December)

Total pageviews: 10,400 (~600 in December)

Email subscribers: 6

Total number of countries that have viewed the blog: 79

No new countries viewed the blog in December.  :-(