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:

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:

Netherlands Antilles


(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: 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:

Macedonia (FYROM)


(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.