Saturday, December 31, 2016

Familial or Hereditary?

Hello, loyal blog readers. This final post of the year will have an update on my health and a few other minor things going on in the world of amyloidosis.

First, it looks like I may not have a type of familial amyloidosis after all. I may actually have a type of hereditary amyloidosis instead. "But David, isn't familial the same thing as hereditary?" Generally speaking those two terms are synonymous and often used interchangeably. However, in terms of describing amyloidosis it turns out there is a need to make a distinction between the two.

According to the article Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification: International Society of Amyloidosis 2016 Nomenclature Guidelines (1), in July of 2016, the Nomenclature Committee of the International Society of Amyloidosis met to make recommendations regarding the nomenclature for amyloid fibril proteins and the clinical classification of the amyloidoses. These recommendations are necessary to standardize how to refer to the various types of amyloidosis. For instance, this committee recommended that the term "senile systemic amyloidosis" be replaced with "wild-type ATTR amyloidos" now that the wild-type TTR protein is known to be the cause of that disease.

Regarding "familial" vs. "hereditary" the committee made the following recommendation:

The terms “hereditary amyloidosis” and “familial amyloidosis” refer to different entities. The term “hereditary amyloidosis” should be used when there is a mutation in the fibril protein gene itself, e.g. ATTR, ALys or AFib. The term “familial amyloidosis” should be used when the syndrome occurs in a familial setting due to mutations in genes expressing non-amyloid proteins, e.g. AA amyloidosis.

So if the mutation is in a gene that expresses an amyloid protein, such as fibrinogen, that is considered hereditary amyloidosis. On the other hand, if the mutation is in genes that do not express amyloid proteins, that is considered familial amyloidosis. I do not know enough about what are now considered familial types to go into any more detail on those or discuss how they differ from hereditary types like AFib, so I will just leave it at that and try to use "hereditary" instead of "familial" going forward.


Speaking of familial, I mean hereditary amyloidosis, the next meeting in Chicago has been scheduled for October 28 and 29 of 2017. You can find more information about this meeting and register for it at this link: http://amyloidosissupport.org/support_groups/familial.html. I plan on arriving Friday, October 27, in time for the Friday night meet and greet.

Regarding my health, you may recall from the previous blog post that in October my hemoglobin had increased to 14.3 (within normal range) and my ferritin had increased to 15 (still a little low). I continued taking two iron supplements per day and saw my hematologist, Dr. C, on December 16. My hemoglobin increased to 15.3 and my ferritin increased to 28.1. The normal range for ferritin is 22 to 415, so my ferritin was back in the normal range, as were all the other measurements of things like red blood cell size. So I am going to stop taking the iron supplements on January 1 and see where my numbers are at my annual physical exam in February of 2017.

Next month's post will be the 2016 wrap-up.

=====Monthly Blog Status Update=====
As of November 30, 2016:

Total posts: 172 (1 in October)

Total pageviews: 51,400 (~1300 in November)

Email subscribers: 14 (unchanged)

Total number of countries that have viewed the blog: 132

One new country viewed the blog in November:

Bosnia & Herzegovina
=====


(1) Sipe JD, Benson MD, Buxbaum JN, et al. Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines. Amyloid. 2016;23(4):209-213.

Wednesday, November 30, 2016

Dallas Support Group Meeting: November 12, 2016

Greetings, loyal blog readers. Long time no see. You may have noticed I did not have a new post in October. No need to fear, though. Although things are a little crazy here for a number of reasons, making it all too easy to put the blog on the back burner, everything is fine.

Today's post will be an update on my anemia situation, followed by my account of the Dallas support group meeting in November. Since I did not post anything in October, the end of this post will have the monthly blog stats for not just one but two months. Bonus!

In the previous post I mentioned that I started taking iron supplements in September at the recommendation of my hematologist, Dr. C. In September my hemoglobin had increased slightly to 13.3, but my ferritin was 5, which is very low. (Normal for men is 18 to 270.) I saw Dr. C in October after one month of taking the iron supplements, and my hemoglobin had increased to 14.3, which is within the normal range. My ferritin was still a little low at 15, but that definitely indicates the iron supplements are working and my iron storage is improving. Dr. C wants me to continue taking the iron supplements and see him again toward the end of December. So all that is good news. Hopefully I can stop taking the iron supplements in December and everything will be back to normal for my next annual physical exam in February or March of 2017.

The Dallas support group meeting was held on November 12, 2016. There were 22 attendees, including the guest speaker, Dr. Gonsalves from Mayo Clinic in Rochester. Fourteen of the 22 attendees were amyloidosis patients, with about half of those being diagnosed with AL amyloidosis. There were a few localized and some ALECT2 patients, and unless I missed hearing about someone's diagnosis, I think I was the only familial patient there.

Dr. G's presentation focused primarily on AL amyloidosis and current clinical trials, but it did include some slides about ALECT2, which he spent some time discussing since there were three ALECT2 patients at the meeting. ALECT2 is a relatively new type of amyloidosis that may turn out to be the third most common type. An interesting fact about ALECT2 is that it seems to have a genetic component although it does not appear to be the result of an inherited mutation like ATTR or fibrinogen amyloidosis. I suspect we will start hearing much more about ALECT2 in the general amyloidosis discussions going forward.

That's all for now. See you next month. Maybe . . .


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

As of September 30, 2016:

Total posts: 171 (1 in September)

Total pageviews: 48,300 (~1700 in September)

Email subscribers: 14 (unchanged)

Total number of countries that have viewed the blog: 131

One new country viewed the blog in September:

Turkmenistan

=====


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

As of October 31, 2016:

Total posts: 171 (0 in October)

Total pageviews: 50,000 (~1700 in October)

Email subscribers: 14 (unchanged)

Total number of countries that have viewed the blog: 131

No new countries viewed the blog in October.
=====

Friday, September 30, 2016

Tony Stark

This blog post will just be an update on me followed by the always exciting monthly blog stats at the end. But before getting to that, I need to let everyone know that it is time to start making plans to attend the next mega-gigantic-colossal familial amyloidosis support group meeting in Chicago, scheduled for the last weekend in October of 2017. Details will be available at this link: http://amyloidosissupport.org/support_groups/familial.html.

In the previous blog post I mentioned that my primary physician drew some blood on August 25 to see what my anemia situation was. On September 2 I found out that my hemoglobin was actually up a little to 13.3 (compared to 12.6 in March) but some of the other numbers still indicated an issue with iron storage. My primary physician recommended I see a hematologist, and I chose to see Dr. C, the same hematologist/oncologist that Mom saw when she had breast cancer and when she was first diagnosed with amyloidosis.

My hematologist appointment was September 9. I told Dr. C about the fibrinogen amyloidosis and the fact that anemia often develops in AFib patients after the kidney problems appear, and I do not have any kidney problems yet. He said he thinks my iron deficiency anemia was really caused by the blood donations last year that got my hemoglobin low. My ferritin level, which is an indication of how much iron the body is storing, is at 5. That is very low compared to the low end of the normal range, which is around 20. He explained that although the hemoglobin is on the rise, my body is having a very difficult time recovering and bringing the iron storage levels back into the normal range, which is not unusual. Often it needs a boost, which I do recall from when Mom's hemoglobin started dropping below 10.

Dr. C suggested I start taking iron supplements, and then if my iron situation does not resolve itself quickly enough they can do an iron infusion via IV to bring the iron levels back up. So I started taking an iron supplement the following day (one tablet per day), and then increased it to two tablets per day a week later. He said some people are unable to take two tablets per day due to the side effects (primarily constipation), but so far my side effects are negligible. I will have some more lab work done on October 13 to see how things are going.

That's all for now. See you next month.

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

As of August 31, 2016:

Total posts: 170 (1 in August)

Total pageviews: 46,500 (~1800 in August)

Email subscribers: 14 (unchanged)

Total number of countries that have viewed the blog: 130

Two new countries viewed the blog in August:

Martinique
Trinidad & Tobago

=====

Wednesday, August 31, 2016

Article Review (2013) - Renal Transplantation in Systemic Amyloidosis -- Importance of Amyloid Fibril Type and Precursor Protein Abundance

Today's post will be a quick update on me, followed by an article review, ending with the always exciting blog status update at the end.

As mentioned in the previous post, on July 28 I had my second capsule endoscopy due to a malfunction with the first one. The gastroenterologist, Dr. E, called me early the next week and said no abnormalities were found. We then discussed what the next step should be, and we agreed that I would see my primary physician to discuss whether to refer me to a hematologist, have me start taking an iron supplement, or do something else.

I saw my primary physician on Thursday, August 25, and as I expected he wanted to do some blood work to see where my hemoglobin level is now. I asked him to also have my creatinine and GFR measured with that blood work and explained why. My most recent lab work was done in March of this year, so this set of numbers will give another data point 5 to 6 months after that. I do not have those results yet, so we will have to wait until the next blog post to see what happens next. Now to the article review . . .

Title: Renal Transplantation in Systemic Amyloidosis  --  Importance of Amyloid Fibril Type and Precursor Protein Abundance (1)

Authors: Pinney, Lachmann, Sattianayagam, Gibbs, Wechalekar, Venner, Whelan, Gilbertson, Rowczenio, Hawkins, and Gilmore (UK National Amyloidosis Centre, London, UK; UCL Centre for Nephrology, London, UK)

Journal: American Journal of Transplantation (February 2013)

Abstract:

Renal transplantation remains contentious in patients with systemic amyloidosis due to the risk of graft loss from recurrent amyloid and progressive disease. Outcomes were sought among all patients attending the UK National Amyloidosis Centre who received a renal transplant (RTx) between January 1978 and May 2011. A total of 111 RTx were performed in 104 patients. Eighty-nine percent of patients with end-stage renal disease (ESRD) due to hereditary lysozyme and apolipoprotein A-I amyloidosis received a RTx. Outcomes following RTx were generally excellent in these diseases, reflecting their slow natural history; median graft survival was 13.1 years. Only 20% of patients with ESRD due to AA, AL and fibrinogen amyloidosis received a RTx. Median graft survival was 10.3, 5.8 and 7.3 years in these diseases respectively, and outcomes were influenced by fibril precursor protein supply. Patient survival in AL amyloidosis was 8.9 years among those who had achieved at least a partial clonal response compared to 5.2 years among those who had no response (p = 0.02). Post-RTx chemotherapy was administered successfully to four AL patients. RTx outcome is influenced by amyloid type. Suppression of the fibril precursor protein is desirable in the amyloidoses that have a rapid natural history.

Here is a link to the article: http://onlinelibrary.wiley.com/doi/10.1111/j.1600-6143.2012.04326.x/full

As stated in the abstract, this article reviews the results of renal transplants among UK National Amyloidosis Centre patients between January of 1978 and May of 2011. There were 111 transplants among 104 patients with various types of systemic amyloidosis. The breakdown among the five different types of systemic amyloidosis that were represented is as follows:


AL (primary) - 25 patients
AA (secondary) - 43
AFib (fibrinogen) - 19
AApo (Apolipoprotein A1) - 14
ALys (Lysozyme) - 3


The main focus of this article is to document the results of these kidney transplants and see how the type of amyloid protein and the presence of that protein post-transplant affects how well the transplanted kidney performs. In this review I will only be focusing on the results of the AFib patients.


The introduction of the article provides some basic information about the various types of amyloidosis. It mentions three important points about fibrinogen amyloidosis that differentiate it from the other types:

 - AFib presents with proteinuria and progressive decline in kidney function, usually leading to end-stage renal disease within five years of diagnosis.

 - The fibrinogen alpha-chain is synthesized only in the liver.

 - Since fibrinogen alpha-chain is only synthesized in the liver, liver transplantation completely eliminates the mutant fibrinogen molecules from being produced.


Here are some of the statistics regarding the 19 AFib patients included in this study:

 - There were a total of 21 renal transplants among the 19 patients, indicating some transplanted kidneys failed.

 - Nine patients received combined liver and kidney transplants. (One of those was after a transplanted kidney developed amyloid.)

 - Amyloid did reoccur in seven patients who received kidney transplants, but not in any of the patients who received combined liver and kidney transplants.

 - 4 of the 10 patients who received kidney transplants had died as of the writing of the article. None of those deaths were known to be due to surgical complications. 

 - 3 of the 9 patients who received combined liver and kidney transplants died due to surgical complications.


The discussion section of the article mentions again that liver transplantation removes all of the mutant fibrinogen from the blood, preventing the ongoing accumulation of amyloid in the kidneys. But it states that the risk of combined liver and kidney transplant must be considered when deciding on kidney only vs. combined liver and kidney. This article does not mention anything about liver only transplantation, which is not surprising since it was published in 2013 and came out of the NAC in London.

=====


This article does not really give us any new information on fibrinogen amyloidosis itself, but it does provide some statistics (from a small population) on the mortality of two treatment options (kidney transplant vs. combined liver and kidney transplant). That serves as a helpful reminder that although we hear about organ transplants quite frequently in the amyloidosis community, organ transplants are certainly not without risk.

Next up will hopefully be an update on me.

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

As of July 31, 2016:

Total posts: 169 (1 in July)

Total pageviews: 44,600 (~2300 in July)

Email subscribers: 14 (unchanged)

Total number of countries that have viewed the blog: 128

One new country viewed the blog in July:

Seychelles

=====

Citation:

(1) Pinney, J. H., Lachmann, H. J., Sattianayagam, P. T., Gibbs, S. D. J., Wechalekar, A. D., Venner, C. P., Whelan, C. J., Gilbertson, J. A., Rowczenio, D., Hawkins, P. N. and Gillmore, J. D. (2013), Renal Transplantation in Systemic Amyloidosis—Importance of Amyloid Fibril Type and Precursor Protein Abundance. American Journal of Transplantation, 13: 433–441. 

Monday, August 1, 2016

Not so hard to swallow

Today's post will just be an update on what has been going on with me over the past two months. The last thing I mentioned was that nothing was found on the small bowel follow through exam I had on May 11, and the next test the doctor wanted to do was a capsule endoscopy (swallowing a pill camera) to examine my small intestine.

I had the capsule endoscopy on June 27. Before swallowing the pill camera, the nurse wrapped a wide belt around my waist with pads built into it, similar to the pads used on the chest when they do an EKG. This belt has a cable coming out of it that plugs into a receiver the patient wears with a shoulder strap for the duration of the test. So I looked like I was carrying a small purse all day. Then she had me activate the system by touching one gold band of the camera (shown below) with two fingers of one hand and the other gold band with two fingers of the other hand.


MiroCam MC1000-W Capsule Endoscope and US Quarter Dollar Coin

Once the system is activated it is time to swallow the camera. Although it is rather large (10.8 mm x 24.5 mm) I found it quite easy to swallow. It did not feel like there was a lump in my throat or anything like that. I had to wear the belt and receiver for 12 hours and then I could remove it and return the equipment to the doctor's office the next morning.

Three days later the doctor's office called me with the results. Drumroll please . . . 

It did not work so I have to repeat the test. Yes, I get to repeat the capsule endoscopy. I was actually not surprised when I heard that because when we were trying to activate it the nurse said she never heard the tones from the receiver that it is supposed to emit when the camera is activated. She got another nurse to try it as well, and she never heard the tones either but she believed it was already activated. I did not have a good feeling about it and walked away from the office fully expecting to have to repeat it, which meant going through the bowel prep as well, which is similar to the prep for a colonoscopy. So I really was not surprised when I heard that news. And now I know how Mom felt that year she had to have so many colonoscopies.

I had capsule endoscopy number two on July 28. The same nurse hooked me up, but once again we did not hear any tones from the receiver to indicate it was activated. She got another nurse in the office to help, and we did hear the tones that time. (And there was much rejoicing.) Exactly twelve hours later the receiver beeped 8 times and all the lights on it turned off, so I have a much better feeling about that one. I should get those results in August. I suspect it will also come back normal, so I am looking forward to seeing what the doctor wants to try next, if anything. Hopefully he will want some more blood work first so he can see what my hemoglobin is and I can see how my kidneys are doing.

In other news, a total of ten family members went on the Caribbean cruise Mom had planned for the family just a month before she died. It started out as a high school graduation gift for two of her grandsons who graduated this year, but then it evolved into Mom paying for everyone to go. After Mom's passing there was never any doubt that she would still want us to go, so we did and everyone had a great time. We sailed on the sister ship of the one we sailed on in 2013, so it brought back many memories of that trip, including taking Mom to the medical facility one night when she needed to have an emergency dialysis session due to excessive fluid. (http://www.fibrinogenamyloidosis.com/2013/07/cruising-along-on-dialysis.html)

I even had an opportunity to visit the medical facility on this year's cruise as well. The phone in our cabin rang one night around 10 PM and it was the teen center informing me that my son needed to go to the medical facility due to a severe nosebleed caused by getting hit in the face with a soccer ball while he was playing soccer. They asked if I wanted to come up and get him or just meet them at the medical facility. I told the caller I would meet them at the medical facility since I was all too familiar with how to get there. Fortunately the nosebleed was already stopped by the time I arrived and no further medical care was needed. It was nice to visit the medical facility for a less dire situation than my previous visit.

Hopefully the next blog post will have the results of capsule endoscopy number two.


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

As of June 30, 2016:

Total posts: 168 (1 in June)

Total pageviews: 42,300 (~1000 in June)

Email subscribers: 14 (unchanged)

Total number of countries that have viewed the blog: 127

Four new countries viewed the blog in June:

Cote d'Ivoire (Ivory Coast)
Albania
Qatar
Kuwait
=====

Edit August 1, 2016: Changed "May" to "June" in one of the Blog Status Updates.

Friday, July 1, 2016

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

Monday, May 30, 2016

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.

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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.

Sunday, May 1, 2016

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.

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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.