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.

=====

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.

=====

=====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 Reviews (2012 and 2013) - Laser microdissection and mass spectrometry-based proteomics

Today's post will be two article reviews. These two articles are very similar and also quite technical, so there is no need to cover them in separate posts.

Those of you following the always exciting monthly blog stats might like to know that May of 2016 had more new countries visit the blog than in all of 2015, and it also had the most new countries in one month since May of 2013. I do not think this sudden uptick is due to increased global awareness of fibrinogen amyloidosis, but is instead due to a more global infiltration of spammers and automated programs that register as visits. In any case, it's fun to keep track of it. On to the articles . . .

First article

Title: Laser microdissection and mass spectrometry-based proteomics aids the diagnosis and typing of renal amyloidosis

Authors: Sanjeev Sethi, Julie A. Vrana, Jason D. Theis, Nelson Leung, Anjali Sethi, Samih H. Nasr, Fernando C. Fervenza, Lynn D. Cornell, Mary E. Fidler and Ahmet Dogan (Mayo Clinic, Minnesota, USA and Drexel University College of Medicine, Pennsylvania, USA)

Journal: Kidney International (July 2012)

Abstract:

Accurate diagnosis and typing of renal amyloidosis is critical for prognosis, genetic counseling, and treatment. Laser microdissection and mass spectrometry are emerging techniques for the analysis and diagnosis of many renal diseases. Here we present the results of laser microdissection and mass spectrometry performed on 127 cases of renal amyloidosis during 2008–2010. We found the following proteins in the amyloid deposits: immunoglobulin light and heavy chains, secondary reactive serum amyloid A protein, leukocyte cell-derived chemotaxin-2, fibrinogen-a chain, transthyretin, apolipoprotein A-I and A-IV, gelsolin, and b-2 microglobulin. Thus, laser microdissection of affected areas within the kidney followed by mass spectrometry provides a direct test of the composition of the deposit and forms a useful ancillary technique for the accurate diagnosis and typing of renal amyloidosis in a single procedure.

Second article

Title: Mass Spectrometry Based Proteomics in the Diagnosis of Kidney Disease

Authors: Sanjeev Sethi, Julie A. Vrana, Jason D. Theis, and Ahmet Dogan (Mayo Clinic, Minnesota, USA)

Journal: Current Opinion in Nephrology and Hypertension (May 2013)

Abstract:

Purpose of review: Laser microdissection (LMD) and mass spectrometry (MS) is a new technique that consists of dissection of glomeruli, tryptic digestion of dissected material, analysis by MS and generation of a protein profile using different algorithms. The review focuses on the use of this methodology as an ancillary technique in a clinical laboratory for the diagnosis of kidney diseases.

Recent findings: LMD/MS is used in the diagnosis and typing of kidney diseases with organized deposits such as amyloidosis. Uncommon and familial forms of renal amyloidosis are diagnosed and typed on the basis of the presence of specific amyloidogenic proteins. LMD/MS is used to confirm and identify immunoglobulins and complement factors in immune complex mediated and complement-mediated proliferative glomerulonephritis, respectively. In particular, LMD/MS can detect monoclonal immunoglobulins in cases of equivocal immunofluorescence studies in monoclonal immunoglobulins-associated glomerulonephritis. LMD/MS can detect specific complement factors of the alternative pathway and terminal pathway in complement-mediated glomerulonephritis.

Summary: LMD/MS is currently used for diagnosis and typing of amyloidosis. In addition, LMD/MS is useful in determining the type of immunoglobulins and complement factors in immune complex and complement-mediated glomerulonephritis, respectively.

Here are the online links to these two articles if you would like to follow along:
http://www.kidney-international.org/article/S0085-2538(15)55509-9/fulltext

http://journals.lww.com/co- nephrolhypertens/Abstract/2013/05000/Mass_spectrometry_based_proteomics_in_the.5.aspx


As you can probably tell from the titles alone, and definitely from the abstracts, these two articles are a bit more technical in nature than most of the previously reviewed articles on the blog. Both articles go into quite a bit of detail on two relatively new techniques for analyzing tissue samples to determine the type of amyloidosis and, as discussed in the second article, to diagnose other kidney diseases. I will not be covering these two articles in any detail, but I will instead focus on the sections that are relevant to the diagnosis of fibrinogen amyloidosis.

First, some definitions of a few words in the titles:

Proteomics is the study of the entire complement of proteins produced by an organism. For the purposes of this discussion, humans are the organism.

Laser Microdissection is a technique for isolating and separating a specific portion of biopsy tissue. We have seen photos of biopsies stained with Congo Red, for instance, in which a well-defined portion of the tissue is that apple green color. Laser microdissection cuts out just that portion so it can be analyzed further.

Mass Spectrometry, in oversimplified terms, is a method of breaking down and analyzing a tissue sample to determine the protein components that are present. In the typical process of staining a biopsy with various stains (immunohistochemistry), each stain will react to a different protein. So if the pathologist is looking for 20 different proteins, 20 different stains must be applied. Mass spectrometry, on the other hand (often referred to a mass spec), is a process to identify all of the proteins with one process. It is a complicated, multi-step process that involves some sophisticated software to analyze the results. It is not an exact, precise method, however, as the results are given in terms of probabilities that each protein is present, and only those with a greater than 90% probability are considered to be identified.

The 2012 article is a retrospective analysis of 127 cases of renal amyloidosis analyzed by laser microdissection and mass spectrometry between 2008 and 2010 at Mayo Clinic. Of those 127 cases, seven were identified as fibrinogen amyloidosis. In the analysis of the fibrinogen cases, it was noted that both mutated and wild-type (non-mutated) fibrinogen were detected in the samples. If I understand that correctly, that means the amyloid deposits consist of both types of fibrinogen molecules. That is interesting because the data on AFib patients who have had liver transplants indicates that the wild-type fibrinogen does not add to the existing amyloid deposits (unlike in the case of ATTR). So maybe the presence of mutated fibrinogen allows for both mutated and wild-type fibrinogen to contribute to the buildup of amyloid deposits. But once there is no more circulating mutated fibrinogen, the wild-type fibrinogen can no longer attach to the existing deposits.

The Discussion section of the 2012 article lists several advantages of laser microdissection/mass spectrometry over the conventional methods of amyloid typing:

1. It is one test to identify the protein vs. a series of tests, as in immunohistochemistry.
2. It is performed on only the involved tissue (as identified by Congo red staining).
3. It is performed on paraffin-embedded material and does not require frozen material.
4. It is better at typing problematic cases, such as heavy-chain (AH) amyloidosis.
5. It is useful for typing familial types of amyloidosis.
6. Again regarding the familial types, it can identify the specific genetic mutation.
7. It can detect amyloid even before a tissue sample is positive for Congo red staining.
8. It can prevent misdiagnosis of familial cases of amyloid as AL or AH amyloid, especially in those cases where the familial amyloidosis patient also has a monoclonal gammopathy.

The 2013 article has much of the same information regarding laser microdissection and mass spectrometry. Since amyloidosis is only one of the five or six kidney diseases discussed in this article, it does not have as much detail on the various types of amyloidosis. But it does specifically mention fibrinogen amyloidosis as one of the hereditary types for which laser microdissection/mass spectrometry is very useful for determining the type.

=====

At the familial amyloidosis meeting in Chicago last October, one of the doctors mentioned that Mayo Clinic does mass spec on all kidney biopsies. That seems like a good indicator that the doctors at Mayo are confident in the results of mass spec. I am sure it reduces the chances of misdiagnosis of amyloid type, and for the rare types it helps reach a diagnosis more quickly than would otherwise occur if they only used the older techniques.

The question for someone like me who has not yet had a kidney biopsy is this: If and when I do develop symptoms that warrant having a kidney biopsy, should I request that it be sent to Mayo Clinic for analysis by mass spec? I am leaning toward answering that question with a "yes," given how rare this disease is. Plus, it makes Mayo Clinic aware of the patient, which may help establish a dialog between Mayo Clinic and the patient's local doctors for future consultation.

In the next blog post I might have the results of my capsule endoscopy. Or maybe not.

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

As of May 31, 2016:

Total posts: 167 (1 in May)

Total pageviews: 41,300 (~1500 in May)

Email subscribers: 14 (unchanged)

Total number of countries that have viewed the blog: 123

Seven new countries viewed the blog in May:

Bahrain
Brunei
Congo (DRC)
French Polynesia
Mauritius
Niger
Rwanda
=====

(1) Sethi S, Vrana JA, Theis JD, et al. Laser microdissection and mass spectrometry-based proteomics aids the diagnosis and typing of renal amyloidosis. Kidney Int. 2012;82(2):226-234.


(2) Sethi S, Vrana JA, Theis JD, Dogan A. Mass spectrometry based proteomics in the diagnosis of kidney disease. Curr Opin Nephrol Hypertens. 2013.

Edit 7-1-16: Corrected country count in blog stats

Article Review (2013) - Fibrinogen A alpha-chain amyloidosis: Report of the first case in Latin America

Today's post will be a quick update on me, then the article review, and then the monthly blog stats.

Regarding my anemia, I had a small bowel follow through exam on May 11. That is a procedure in which the patient drinks a barium solution (after fasting at least 8 hours), and then a series of x-rays are taken to follow the solution through the stomach and small intestines, looking for any signs of leakage. The doctor's office contacted me two weeks later and said no abnormalities were found, so the next test they will schedule is a capsule endoscopy. You can expect a blog post about that in June or July.

On to the article review, in which fibrinogen amyloidosis makes an appearance on yet another continent.

Title: Fibrinogen A alpha-chain amyloidosis: Report of the first case in Latin America (1)

Authors: Juliana Reis Machado, Marcos Vinícius da Silva, Precil Diego Miranda de Menezes Neves, Flavia Aparecida de Oliveira, Rosana Rosa Miranda Corrêa, Willians Vinícius Dutra Rodrigues, Merril Benson, and Marlene Antônia dos Reis (Brazil and USA)

Journal: Amyloid (March 2013)

Here is a link to the PDF file (not public) if you would like to follow along:  http://informahealthcare.com/doi/pdf/10.3109/13506129.2012.763029

Abstract:

Background: Hereditary fibrinogen A alpha-chain (AFib) amyloidosis affects different organs, especially the kidneys. No case of this disease has been reported in Latin America.

Case report: A 52-year-old previously healthy Brazilian woman presented with a seven-month history of proteinuria in the absence of hematuria. The patient had normal blood pressure and reported no other symptoms. A renal biopsy was obtained and light microscopy revealed the presence of Congo red positive deposits (apple-green birefringence under polarized light) only in the glomerular compartment. These deposits were strongly immunoreactive to fibrinogen in all glomeruli. Electron microscopy showed the presence of organized deposits compatible with AFib. The diagnosis was confirmed by DNA analysis of the AFib gene, which demonstrated a Glu526Val mutation in one allele.

Conclusion: This first description of hereditary AFib amyloidosis in Latin America highlights the need to include this type of amyloidosis in the differential diagnosis, especially in Brazil where the degree of miscegenation is high.

After a brief introductory paragraph providing some basic information on the different types of amyloidosis, this specific case is described. The patient was a 52-year-old previously healthy Brazilian woman who presented with proteinuria in 2006. There was no family history of kidney disease. In 2009 a 24-hour urine collection showed 2 grams of protein, which increased to 3.7 grams seven months later. There were no other urinary symptoms and her blood pressure was normal.

After ruling out some of the more common kidney diseases (glomerulopathies), a kidney biopsy was performed. The article gives a very detailed description of the biopsy results, some of which I will summarize here:

• Various stains were used, with Congo Red indicating the presence of amyloid.
• Most glomeruli had large amyloid deposits.
• Immunofluorescence was positive for fibrinogen.

Based on the biopsy results they made the diagnosis of fibrinogen amyloidosis That diagnosis was confirmed by DNA analysis which showed the patient had the Glu526Val mutation.The last thing mentioned about the patient is that she still has proteinuria without edema, and her blood pressure and renal function are still normal.

The discussion section of the article goes into some more detail about the various types of hereditary amyloidosis, and states that ATTR and gelsolin types have been previously reported in Brazil. Some background on fibrinogen amyloidosis and where it has been reported is then provided, followed by a few sentences regarding organ transplant as a treatment option. The article concludes by stating that this type of amyloidosis needs to be included in the differential diagnosis, especially in Brazil where the degree of miscegenation (mixed-race sexual relations) is high.

=====

There are a couple of interesting things about this case I want to mention. The initial presentation of proteinuria is very common among AFib patients, but what I find really unusual is that this patient still had normal kidney function at the time this article was written. Given the publication date of 2013, we can assume the article was written in 2012, perhaps 2011 at the earliest. So five years or more after the initial presentation with proteinuria, the patient still only had proteinuria with presumably normal creatinine and GFR levels. That is a very slow progression compared to other reported cases.

The other interesting thing about this case is that the biopsy results gave a rather clear indication of fibrinogen amyloidosis. We know that usually is not the case unless mass spectrometry is used, so this patient is very fortunate the pathologists did a thorough job analyzing the biopsy with immunofluorescence. We have to wonder how many cases of AFib have gone undiagnosed or misdiagnosed in Brazil.

There have now been published reports of fibrinogen amyloidosis cases in North and South America, several European countries, Asia, and Australia. I do not think there have been any published reports of an AFib patient in Africa, although I do know of one patient in Africa (with English heritage) as of the writing of this blog post. So it is safe to say that fibrinogen amyloidosis has now been diagnosed in at least one person living on each continent with permanent human inhabitants.

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

As of April 30, 2016:

Total posts: 166 (1 in April)


Total pageviews: 39,700 (~1200 in April)


Email subscribers: 14 (unchanged)


Total number of countries that have viewed the blog: 116


Three new countries viewed the blog in April:


Ethiopa
Netherlands Antilles
Mayotte
=====

Citations:

(1) Machado JR, Silva MV, Neves PD, et al. Fibrinogen A alpha-chain amyloidosis: report of the first case in Latin America.Amyloid. 2013;20(1):52-55.

Article Review (2016) - Liver transplant alone without kidney transplant for fibrinogen A alpha-chain (AFib) renal amyloidosis

Today's post will be a review of a very recently published article. This article, which is actually a Letter to the Editor in the most recent issue of Amyloid, is very special for two reasons. First, it presents the case of the first, and as far as I know, the only instance (as of the date of this blog post) of a fibrinogen amyloidosis patient receiving a liver transplant without also receiving a kidney transplant. Second, the patient in this case is our very own Cathy T., who has attended all four of the familial amyloidosis meetings in Chicago and has corresponded with some of you she has not met in person. She is now famous in the annals of medical history.

Title:  Liver transplant alone without kidney transplant for fibrinogen A alpha-chain (AFib) renal amyloidosis (1)

Authors: Oren Fix, Peter Stock, Brian Lee, and Merrill Benson (Seattle, WA, USA; San Francisco, CA, USA; Indianapolis, IN, USA)

Journal:  Amyloid

The opening paragraph of the article gives a basic introduction to fibrinogen amyloidosis. Regarding treatment options, it states that a kidney transplant will prolong life but without liver transplantation the transplanted kidney may develop amyloidosis within one to five years.

The patient in this case was a female who presented with hypertension and proteinuria of 3.4 grams per day at the age of 58. Creatinine progressed from 1.39 mg/dl to 1.97 mg/dl over a 10-month period. A renal biopsy was analyzed with mass spectrometry which showed the amyloid deposits to be fibrinogen, and DNA analysis showed that she had the Glu526Val mutation. Regarding the transplant, the article states: "Despite recommendations to proceed with combined liver and kidney transplantation the patient elected to have only liver transplantation."

She was listed for a liver transplant in March of 2010 and underwent liver transplantation in July of that year. (It is not stated in the article, but she was the middle patient of a domino liver transplant, which means her liver was transplanted into the liver of another patient on the liver transplant list.) Just prior to the transplant her creatinine was up to 2.85 mg/dl, then rose to 3.77 immediately after the transplant, and then went back down to 2.12 when she was discharged from the hospital one week later.

Four months after the transplant rejection of the transplanted liver was successfully treated and she is now on two immunosuppressant drugs, tacrolimus and azathioprine. Five and a half years post-transplant her serum creatinine level is 1.8 mg/dl and she does not have proteinuria. "The patient's kidney function, which had deteriorated considerably prior to transplantation, stabilized after liver transplantation and she has enjoyed several years of good health." Below is a chart from the article showing her creatinine level since her initial diagnosis. (Hopefully the chart appears correctly if you are receiving the post via email. It does extend past the right edge of the page when viewed on the web site.)

The article then discusses some of the earlier results of organ transplantation for treating AFib. As previously mentioned, with kidney transplantation alone recurrence of amyloid in the transplanted kidney is the norm, with failure almost always occurring within 10 years. On the other hand, patients who received liver and kidney transplants appear to have long term success with no recurrence of amyloid, with those who have been on dialysis less than six months (or not at all) having better survival rates than those on dialysis more than six months. The article then spends a paragraph explaining that unlike with ATTR, liver transplantation does halt the progression for AFib because the amyloid deposits in AFib consist solely of the mutant fibrinogen.

The article then offers the following recommendations for liver transplantation in patients with AFib:

• Liver transplantation should not be considered until the onset of amyloidosis has been documented.
• Liver transplantation should be recommended before renal function deteriorates to the point where dialysis or a kidney transplant is needed.
• Liver transplantation should be recommended before renal function deteriorates to the point where major surgery may jeopardize the patient's native kidneys.

The article suggests two biomarkers for when liver transplantation should be considered:

• Creatinine greater than or equal to 1.5 mg/dl, or

• Proteinuria greater than 2 grams per day 

The results of the present case suggest a possible reversal of renal manifestations of amyloid deposition. (In other words, the kidney issues caused by amyloid deposits improved.) Similar improvements in organ function have been observed in cases of AL amyloidosis patients treated with chemotherapy or stem cell transplantation.

The article closes with two points in favor of early liver transplantation for patients with AFib:

• Choosing a combined liver and kidney transplant will usually lead to a much longer wait due to the shortage of donor kidneys.
• The native kidney function will likely improve after an early liver transplant, and the progression of the disease will almost certainly be halted.

================

For such a short article there is definitely a lot of important information here. First, if you want to learn some more details about Cathy's journey from diagnosis to liver transplant and how they came to that decision, you can check out the blog she was keeping at the time. Here is a link to the first post, from September of 2009:  http://cathyandlon.blogspot.com/2009/09/just-beginning_22.html. Her blog has not been updated since October of 2011, but we can't really fault her for that since she has twenty times as many grandchildren as I have.

Although Cathy's liver transplant was briefly mentioned in an article published in 2012 (reviewed in the blog on July 12, 2014), this article from 2016 is the first time her case has been presented in the medical literature. Based on the results of this one case (no proteinuria; creatinine stabilized and slowly trending down; survival over five years so far), this liver transplant was certainly a success. But that does not necessarily mean a liver transplant is the right course of action for everyone, and there are drug treatments currently in clinical trials that should be considered, depending on your location. So I want to try to go through the typical progression of the disease and discuss what treatment options seem most appropriate as of the writing of this blog post. Many factors are involved when deciding on treatment options so as always, seek professional medical advice, preferably from an experienced amyloidosis specialist.

I am going to divide the progression of fibrinogen amyloidosis into stages, starting with Stage Zero. This staging system is my own creation I came up with while typing this blog post. I should also mention that many factors regarding the overall health of the patient must be evaluated to determine whether a specific patient is a good candidate for an organ transplant of any type. But for the purpose of defining these various stages and the treatment options, I will assume the patient is otherwise healthy with no conditions that would exclude the patient from being considered for an organ transplant.

Stage Zero  --  The earliest stage of the progression of the disease is when a patient has a fibrinogen amyloidosis mutation (whether the patient is aware of the mutation or not) but there are no symptoms. A patient in this stage is considered asymptomatic, which Dictionary dot com defines as "showing no evidence of disease." There is no treatment available at this stage, although it is reasonable to imagine that some day there may be a drug available that can be taken proactively to prevent the buildup of fibrinogen amyloid deposits in the kidneys, much like some people take a daily aspirin today to reduce the risk of heart attacks and strokes.

Stage One  --  The next stage is when kidney function initially deteriorates to the point where one or more biomarkers (creatinine, proteinuria, and GFR) are outside the normal range but organ transplantation is not yet considered appropriate. There is certainly not a medical consensus regarding at what point organ transplantation becomes appropriate, and it could be argued that as soon as any of these biomarkers are outside the normal range an organ transplant should be considered.

It is important at this stage that a kidney biopsy is done to confirm the kidney issues are caused by fibrinogen amyloidosis and not one of the many other potential causes of reduced kidney function. An organ transplant to address fibrinogen amyloidosis should obviously not be pursued until confirming the cause of the patient's kidney issues.

Another treatment option to consider at this stage or any of the later stages is one of the drug treatments currently in clinical trials that will hopefully be proven effective and considered standard treatment some day. The most well known of these is the CPHPC plus anti-SAP antibody being tested in England. I will have more to say about that in a future article review.

Stage Two  --  The next stage is when kidney function has deteriorated to the point where a liver transplant without a kidney transplant is considered appropriate. As I mentioned earlier, there is no consensus on exactly where this point is, and some may consider Stage One to be very short or non-existent. There is also not a consensus regarding whether a liver-only transplant is ever considered appropriate, since so little information is available regarding that option. Since I have discussed that subject in previous blog posts I will not go into much detail here. But there are indications that more people in the medical community are in favor of a liver-only transplant under the right conditions. There should also be more opportunities for that transplant option as asymptomatic carriers of the mutation are diagnosed early in the progression of the disease.

Stage Three  --  The next stage is when kidney function has deteriorated to the point where a liver-only transplant is not considered appropriate due to the potential harm to the kidneys. At this stage a liver plus kidney transplant is the better transplant option. The fibrinogen amyloidosis is "cured" with the liver transplant, and renal function is restored with the kidney transplant.

When my mother tried to get a liver transplant she was told that her kidney function was too low to consider it, because the immunosuppressants given after a liver transplant are very hard on the kidneys and they do not want to risk causing a patient to go on dialysis. The doctor told us the threshold at this particular transplant center was 30% kidney function. I do not know if that number varies among the transplant centers. Cathy T. was very likely at Stage Three when she received her liver transplant, as the article notes that the recommendation was for a combined liver plus kidney transplant.

Stage Four  --  The next stage is when dialysis begins for the patient. A general rule of thumb is that dialysis begins when a patient's kidney function gets below 10%, but that will vary from patient to patient, with the decision on when to start dialysis being very dependent on the patient's overall health and how they are feeling.

At this stage a combined liver plus kidney transplant can still be an appropriate option, but as stated in the article, patient survival is better for patients who have been on dialysis less than six months than it is for patients who have been on it for longer periods of time. At some point a combined liver plus kidney transplant may no longer be appropriate as the patient's health declines, which moves the patient to the next stage.

Stage Five  --  The next stage is when the only appropriate organ transplant option for the patient is a kidney transplant, which will restore the patient's renal function but does not stop the amyloid production in the liver. The transplanted kidney will eventually start failing again due to  amyloid buildup, but how long that will take is very unpredictable. Nevertheless, a kidney transplant is still an appropriate option for some patients as it will allow them to stop dialysis as long as the transplanted kidney is functioning.

Stage Six  --  The next stage is when no organ transplant options are appropriate, and the only renal replacement therapy available is dialysis.

=====

Keep in mind that this staging system is my own creation, and since I just came up with it today there is a good chance I will modify it later. Also note that not all patients will transition through every stage. A patient could potentially go from Stage Zero to Stage Six due to health issues that prevent that patient from having an organ transplant. But the important thing to remember is that this is a progressive disease and the clock is always ticking once symptoms begin. The window of opportunity for each transplant option may be short, which is why it is best to learn about the options sooner rather than later. This subject fits into a larger discussion about the pros and cons of genetic testing, which I do intend to discuss in a series of blog posts at some point.

I should also state that any decision about organ transplantation is a difficult one. An organ transplant is a very major surgery with significant risk, especially a liver transplant. Everyone must make that decision on their own after consulting with medical professionals, family members, and others. My goal here is to give people enough time and resources to make an informed decision.

In closing, this is a very important article for anyone interested in the treatment options for fibrinogen amyloidosis. I feel it is so important that I plan on including it in the short list near the top of the Fibrinogen Amyloidosis Resources page. The fibrinogen amyloidosis community should be very thankful that Cathy and her husband Lon fought as hard as they did to make this transplant happen, and that it turned out so well although it went against the established protocols at the time. I hope AFib LTR #1 (Liver Transplant Recipient) has many more years as a living testament to the success of this treatment option, and I hope to report on LTR #2 (with permission) before the end of this calendar year.

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

As of March 31, 2016:

Total posts: 165 (1 in March)

Total pageviews: 38,400 (~800 in March)

Email subscribers: 14 (unchanged)

Total number of countries that have viewed the blog: 113

Three new countries viewed the blog in March:

Gibraltar
Macedonia (FYROM)
Angola
=====

Citation:

(1) Fix OK, Stock PG, Lee BK, Benson MD. Liver transplant alone without kidney transplant for fibrinogen Aα-chain (AFib) renal amyloidosis. Amyloid. 2016:1-2.

Article Review (2011) - The Case: Proteinuria in a patient with diabetes

Today's post will be an update on me, followed by a short review of an article published in 2011 that I recently found online, and then the always exciting monthly blog stats.

As you may recall from the previous post, at my last physical exam my doctor confirmed I am slightly anemic, and no sources of bleeding were found during an endoscopy and colonoscopy in February. Since then I have had some more blood work done per orders from the gastroenterologist, and I have viewed those results online but have not met with the doctor about them. In my uneducated opinion it looks like I do have iron deficiency anemia. Although all of the numbers related to red blood cells improved slightly from where they were in January, the only one that moved from out of range to within range was hematocrit. Hemoglobin was still low at 12.6 g/dL. Some new numbers from this round of testing were also out of range, specifically ferritin, which was 6 ng/mL (normal range is 20 to 380), and total iron, which was 26 mcg/dL (normal range is 50 to 180).

I also did a more thorough review of the journal articles I have related to fibrinogen amyloidosis, looking not only for mentions of anemia but also spleen. Several articles mention involvement of the spleen in more advanced cases of AFib, possibly causing anemia that is resistant to treatment. Most of the AFib cases mentioned in the articles either do not mention anemia or hemoglobin as part of the patient's initial presentation, or they say the patient's hemoglobin was normal. But I did find two cases where the patients did have anemia when they initially presented with kidney issues.

So it is not unheard of for an AFib patient to have anemia early in the progression of the disease. Maybe I am so special I developed anemia before developing kidney issues. Of course this is all speculation at this point. But I very clearly remember a comment Dr. Benson made during one of the familial amyloidosis meetings in Chicago, when he was discussing the typical progression of symptoms of the various types of familial amyloidosis. He said sometimes you see a patient who hasn't read the book, and their symptoms are not consistent with the typical pattern.

Moving on to the article review, this article appeared in the "Make Your Diagnosis" section of the journal "Kidney International" in 2011.

Title: The Case: Proteinuria in a patient with diabetes (1)

Authors: Srikanth Kunaparaju, Chidi Okafor, Helen Cathro, Vijay Bhola, F. Jackson Ballenger and Mitchell H. Rosnerl (Virginia, USA)

Journal: Kidney International (April 2011)

Here is a link to the PDF file if you would like to follow along: http://www.kidney-international.org/article/S0085-2538(15)54882-5/pdf

Abstract:

A 49-year-old Caucasian man with type 2 diabetes, hypertension, hyperlipidemia and obesity, and no known renal disease presented with 2 weeks of headache and visual disturbances, and a 6-month history of frothy urine. Diabetes had been diagnosed 3 years previously and had been under excellent control; the most recent Hgb A1c was 7.1%. There was no history of end-organ involvement secondary to diabetes, including retinopathy and neuropathy. Serum and urine protein electrophoresis with immunofixation demonstrated no monoclonal proteins.

The abstract is essentially the first paragraph of the article. The only additional information in the first paragraph is that there was no family history of kidney disease. Additional testing found that this patient's serum creatinine was 4.55 mg/dL, which was significantly higher than his creatinine level of 1.22 the previous year. A 24-hour urinalysis study also showed 10.0 grams of protein. A renal ultrasound showed the kidneys were of normal size, so a biopsy was done.

The kidney biopsy was very similar to other fibrinogen amyloidosis biopsies. It was Congo Red positive and it showed obliteration of all glomeruli with very little amyloid elsewhere. The antibody-specific staining intensity was not strong enough for a definitive diagnosis of fibrinogen amyloidosis, so the biopsy tissue was submitted for mass spec analysis. That analysis showed fibrinogen, and genetic testing confirmed the Glu526Val mutation.

The article then gives some basic information about fibrinogen amyloidosis, which there is no need to repeat here. It also states that since fibrinogen is synthesized exclusively in the liver, a liver or liver-kidney transplant is required for long-term success. Near the end of the article there is one sentence that summarizes the purpose for this article. "The rapid progression of renal disease, high levels of new-onset proteinuria, and well-controlled diabetes should suggest a diagnosis other than diabetic nephropathy." In other words, although diabetes is often the cause of kidney disease, nephrologists should not always assume that is the case without looking a little further. If the renal disease progresses rapidly, the patient develops proteinuria, and the diabetes is well-controlled, there may be an underlying cause of the kidney disease that should be investigated.

Next up will likely be a review of a very recent, very special article.

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

As of February 29, 2016:

Total posts: 164 (1 in February)

Total pageviews: 37,600 (~800 in January)

Email subscribers: 14 (unchanged)

Total number of countries that have viewed the blog: 110

One new country viewed the blog in February:

Madagascar
=====

Citation:

(1) Kunaparaju S, Okafor C, Cathro H, Bhola V, Ballenger FJ, Rosner MH. The Case: Proteinuria in a patient with diabetes. Kidney International.79(7):793-794.

Edit 4-1-16: Corrected Total pageviews in Monthly Blog Status Update

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.

=====

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.

Article Review (2007) - New insights into systemic amyloidosis: the importance of diagnosis of specific type

It looks like I have once again waited until the last minute to get a monthly blog post written. Fortunately today's article review will be rather short since this article only briefly mentions fibrinogen amyloidosis. In the interest of completeness I still need to review it, but first, a partial update on Mom.

In the previous update on Mom (February 13, 2015) she had just started using her new CPAP machine and her cardiologist had prescribed a change in her medication to control her heart palpitations. What has happened since then?

On March 12 she had a regularly scheduled appointment with Dr. K to check on her fistula. He said there was some blockage that had gone from moderate to severe, so she needed to have another balloon angioplasty to open up those blockages. This was not an emergency and it is just something that happens over time as a fistula ages and gets used. She had the procedure on March 17 and it went fine.

On Friday, March 20 Mom started having heart palpitations toward the end of dialysis and had to be taken home. Her pulse rate got as high as 155 bpm. Fortunately she did not feel any chest pain this time and she recovered quickly from it. Based on this episode and the one that put her in the hospital on Christmas Eve last year, we think these heart palpitations can be induced at dialysis when they try to remove too much fluid from her, or remove it too fast. So she will have to make sure any dialysis tech that gets her set up is aware of those limitations.

Since Mom is back on the list for a kidney transplant she has to be evaluated annually by the pre-transplant group. She had an appointment on March 25 where they did an echocardiogram and went over her medical records. That was an interesting discussion to say the least, so I will continue that story with the next blog post. Now it is time for a short article review.

Title: New insights into systemic amyloidosis: the importance of diagnosis of specific type (1)

Author: Maria Picken (Loyola University Medical Center, Illinois, USA)

Journal: Current Opinion in Nephrology and Hypertension (2007)

Abstract:

Purpose of review: This review aims to summarize recent developments in the area of systemic amyloidoses with emphasis on pathologic diagnosis.

Recent findings: In recent years, management of amyloidosis has shifted from a purely supportive approach to quite diverse, radical and aggressive treatments. The central issue is the understanding that treatment of systemic amyloidoses depends on the molecular type of the amyloid protein. In the United States and the Western world, AL-amyloidosis is the most prevalent type of systemic amyloidosis, but hereditary amyloidoses are being diagnosed with increasing frequency; genetics also plays a role in a subset of familial AA amyloidoses. The biggest challenge is in the diagnosis of AL-type with confidence and in differentiation of AL and hereditary amyloidoses. While careful clinico-pathologic correlation is recommended for all patients with amyloidosis, it is, in itself, not a substitute for amyloid typing.

Summary: The diagnosis of the amyloid type ultimately depends on the examination of the amyloid protein within the deposits. The role of immunohistochemistry – the current standard of care in amyloid typing – is evolving with emergence of alternative biochemical methods. Amyloid, being essentially a protein disorder, presents an attractive venue for the application of proteomics methodologies, despite their inherent complexities.

Here is a link to the article (not freely available) if you would like to follow along: http://journals.lww.com/co-nephrolhypertens/Abstract/2007/05000/New_insights_into_systemic_amyloidosis__the.5.aspx

The author of this article, Maria Picken, is a well-known pathologist in the amyloidosis community. We have seen her name at least twice in previous article reviews, and she has also been on the panel at the familial amyloidosis support meetings that are held every two years in Chicago. You might say she literally wrote the book on pathology as it relates to amyloidosis, because she was not only one of the editors of the book Amyloid and Related Disorders, she also wrote five of the 33 chapters in the book.

This article from 2007 gives a broad overview of the different types of amyloidosis and the importance of properly typing the amyloidosis before deciding on a treatment. I will not go over that since it has been discussed in previous articles. Regarding methods of typing by analyzing biopsy tissue, mass spectrometry was very new at the time this article was published, so the article focuses primarily on immunohistochemistry, which is staining for specific proteins. Again, I will not go over that here because it has been covered in previous articles.

What I will discuss here is a couple of paragraphs that specifically relate to fibrinogen amyloidosis. Here is the first one, in the section of the article that gives an overview of the various types of familial amyloidosis.

Amyloid derived from the fibrinogen A alpha chain (AFib) appears to be the most common form of hereditary amyloidosis in the UK and northern Europe. Amyloid deposits in AFib are quite unique in that they appear to selectively target glomeruli and lead to their complete obliteration, with sparing of the extraglomerular compartments. Renal failure rapidly develops.

We have seen similar descriptions of fibrinogen amyloidosis deposits in other articles (such as the article from the previous article review), but hearing it from a pathologist with as much experience as Dr. Picken does give some weight to the statement.

In the section of the article on treatment of systemic amyloidosis there is a discussion of liver transplantation for patients with transthyretin amyloidosis (ATTR). Due to the risks associated with liver transplantation, it was initially only offered to patients in whom the disease had progressed. But it has since been recognized that better results can be obtained by performing liver transplantation earlier in the progression of the disease. (We are still talking about ATTR here.) Then there is this bit of information I have not seen before regarding liver transplantation for ATTR:

Interestingly, heavy amyloid deposits in the kidneys, especially in the glomeruli, may portend a poor outcome for liver transplantation. Thus, kidney biopsy has been proposed as an outcome predictor for liver transplantation.

First, the article that reported those outcomes was for liver transplantation in patients with the Val30Met ATTR mutation. It was not for liver transplantation in general. But it does make sense based on what I learned when Mom was denied a liver transplant, because the medicine required post-transplant is very hard on the kidneys. The less kidney function there is remaining before the transplant, the more likely there is to be compromised kidney function after the transplant, leading to complications. This is another reason why it is better to start thinking about organ transplantation as soon as possible. Time is of the essence if you decide to pursue a liver-only transplant.

The article then mentions that hepatorenal transplantation (combined liver-kidney) has been successful in treating patients with fibrinogen, apolipoprotein A1 and apolipoprotein A2.

As I mentioned in the beginning of this review, this article does not give us much new information about fibrinogen amyloidosis. It does serve to further support the statement that fibrinogen amyloidosis deposits tend to concentrate in the glomeruli. Unfortunately, given the rarity of amyloidosis in general, very few pathologists will analyze enough biopsies to be able to make that determination. And even if they do suspect fibrinogen amyloidosis when looking at a biopsy, it still needs to be properly typed with one of the more advanced methods.

The next post will reveal what was learned when Mom discussed her medical records with the pre-transplant group, and what unfolded after that.

=====Monthly Blog Status Update===== 

As of March 31, 2015:

Total posts: 150 (1 in March)

Total pageviews: 24,200 (~600 in March)

Email subscribers: 12 (unchanged)

Total number of countries that have viewed the blog: 101

No new countries viewed the blog in March.

=====

Citation

(1) Picken MM. New insights into systemic amyloidosis: the importance of diagnosis of specific type. Curr Opin Nephrol Hypertens. 2007;16(3):196-203.