Friday, January 24, 2014

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

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

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

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


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

Here is a link to the PDF of this article, if you would like to follow along:

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

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

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

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

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

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

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

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

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

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

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


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

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

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

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

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



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

No comments: