Title: Misdiagnosis of Hereditary Amyloidosis as AL (Primary) Amyloidosis (1)
Authors: Helen J. Lachmann, M.B., B.Chir., David R. Booth, Ph.D., Susanne E. Booth, Alison Bybee, Ph.D., Janet A. Gilbertson, Julian D. Gillmore, M.B., B.S., M.D., Mark B. Pepys, M.D., Ph.D., and Philip N. Hawkins, M.B., B.S., Ph.D. (All from the National Amyloidosis Centre, London, UK)
Journal: New England Journal of Medicine (2002)
Background: Hereditary, autosomal dominant amyloidosis, caused by mutations in the genes encoding transthyretin, fibrinogen A α-chain, lysozyme, or apolipoprotein A-I, is thought to be extremely rare and is not routinely included in the differential diagnosis of systemic amyloidosis unless there is a family history.
Methods: We studied 350 patients with systemic amyloidosis, in whom a diagnosis of the light-chain (AL) type of the disorder had been suggested by clinical and laboratory findings and by the absence of a family history, to assess whether they had amyloidogenic mutations.
Results: Amyloidogenic mutations were present in 34 of the 350 patients (9.7 percent), most often in the genes encoding fibrinogen A α-chain (18 patients) and transthyretin (13 patients). In all 34 of these patients, the diagnosis of hereditary amyloidosis was confirmed by additional investigations. A low-grade monoclonal gammopathy was detected in 8 of the 34 patients (24 percent).
Conclusions: A genetic cause should be sought in all patients with amyloidosis that is not the reactive systemic amyloid A type and in whom confirmation of the AL type cannot be obtained.
Here is a link to the article if you would like to follow along:
This article starts with a discussion about differential diagnosis with amyloidosis, which is typically trying to determine whether a patient has AL or AA amyloidosis. Since familial types of amyloidosis are thought to be so rare, they are usually not considered in the differential diagnosis unless a patient has a family history that would indicate they may have a familial type. However, recent studies have indicated that two specific mutations associated with familial amyloidosis (the transthyretin Val30Met and the fibrinogen Glu526Val mutations) may not be as rare as previously thought.
The Methods section of the article describes the population of patients included in this study and the types of testing they did across the population. They studied 350 patients who had been referred to the National Amyloidosis Centre in the UK between 1997 and 2000 with a diagnosis of AL amyloidosis. AA amyloidosis had been ruled out for each patient, and none of the patients were aware of any family history that would indicate hereditary amyloidosis. They also studied the DNA of 50 anonymous healthy people from the general British population, and 22 additional healthy people who were first-degree relatives of patients with the fibrinogen Glu526Val mutation.
The tests performed on each of the 350 AL amyloidosis patients were:
- DNA analysis, looking for known genetic mutations in transthyretin, apolipoprotein A1, fibrinogen A alpha-chain, and lysozyme.
- Whole body SAP scintigraphy (graphical representation of amyloid load, previously discussed in this article review from 2000).
- Staining of tissue samples, specifically looking for the types of amyloid fibrils associated with the various hereditary types of amyloidosis.
The Results section of the article describes how many patients (out of 350 diagnosed with AL amyloidosis) were found to have various types of familial amyloidosis.
- 18 patients (5.1 percent) had the fibrinogen Glu526Val mutation.
- 13 patients (3.7 percent) had one of the transthyretin mutations, including three new mutations that had previously not been described.
- One patient had a known lysozyme mutation.
- One patient had a known apolipoprotein A1 mutation.
- One patient had a previously unknown apolipoprotein A1 mutation.
Adding up those numbers, that is 34 out of 350 patients who were misdiagnosed as having AL amyloidosis. So just under 10 percent of these 350 patients had a rare disease but were misdiagnosed with the wrong type of that rare disease.
Regarding the patients with the fibrinogen mutation, all 18 were of northern European ancestry and none were initially aware of any family history of amyloidosis, although one patient later discovered that her twin had died of renal failure at the age of 76. Two patients were found to be related. All 18 of these patients presented with renal dysfunction and proteinuria, and most of them had hypertension. The youngest patient initially presented while in her 30s, and the oldest presented at the age of 78.
SAP scintigraphy showed renal deposits in all 18 patients, and deposits in the spleen in all but one patient. Electrocardiogram and echocardiogram results did not suggest the presence of cardiac amyloidosis in any of the patients, and none were showing signs of neuropathy. As reported in previous articles on the Glu526Val mutation, all measurements associated with blood clotting times were normal in all of these patients.
They were able to study renal biopsy tissues from 17 of the 18 patients with the fibrinogen mutation. Apparently there are specific staining techniques that will only stain amyloid fibrils from fibrinogen. Each of these biopsy specimens did stain for fibrinogen, but the intensity of the staining varied significantly.
One piece of data that actually supported the misdiagnosis of AL amyloidosis in four of these 18 patients was a low-grade paraproteinemia, also known as monoclonal gammopathy. This condition refers to excessive amounts of paraproteins in the blood, and it is often associated with AL amyloidosis. (I have now told you more than I know about AL amyloidosis and paraprotein, so I won't go into that any further.) Three of these four patients had in fact received chemotherapy in an effort to treat what was believed to be AL amyloidosis, and not surprisingly there was no clinical response.
Regarding the 22 first-degree relatives of patients with the Glu526Val mutation, 12 of them were found to have the same mutation. All were over the age of 50 and none had proteinuria or evidence of amyloidosis on SAP scintigraphy.
The Results section (and the Discussion section) also discussed the 16 patients with mutations other than fibrinogen, but I won't go into those here.
The Discussion section of the article begins with a statement about the current clinical practices at the National Amyloidosis Centre, presumably as a result of this study. Given the variable penetrance of hereditary amyloidosis and the fact that most patients with the fibrinogen Glu526Val mutation do not have a relevant family history, they now routinely do a DNA analysis in all patients with systemic amyloidosis. This practice has already shown benefits to patients initially diagnosed with AL amyloidosis.
The article then discusses the similarities among the patients in this study with this fibrinogen mutation. They all presented with isolated renal issues, meaning they were not caused by some other disease or condition. The progress of renal dysfunction in patients with fibrinogen amyloidosis is slower than in patients with AL amyloidosis, although end stage renal failure is always reached within five years of the onset of renal issues. In two of their patients, transplanted kidneys failed within six years due to recurring amyloidosis. Two patients also exhibited some type of liver involvement long after the initial presentation with renal issues.
The article then mentions that liver transplantation is an effective treatment in types of hereditary amyloidosis in which the amyloidogenic protein is synthesized by the liver.
My initial reaction to this article is that it reinforces the need for genetic testing if you are related to someone with fibrinogen amyloidosis. Although this article showing a misdiagnosis rate of approximately 10% is from 2002, and I would hope that number has improved in the past 11 years, I am sure there is still a significant misdiagnosis rate, at least in the US. I know they still see it frequently at Mayo Clinic, and it very nearly happened to my mother since her initial kidney biopsy report did not detect fibrinogen amyloidosis although that was one of the types they looked for when staining her biopsy slides.
This article definitely indicates that fibrinogen amyloidosis affects people of northern European ancestry and is much more prevalent than previously known. In fact, before this article was published the Glu526Val mutation had been described in only five kindreds. That number more than quadruples just with the patients in this study, since it was diagnosed in 18 individuals and only two of them were related.
The clinical picture of fibrinogen amyloidosis is getting sharper with each article. Patients typically present in middle age or later with renal dysfunction with no detectable underlying cause, progressing to end stage renal failure within five years. Biopsy results show the amyloid fibrils deposited in the glomeruli of the kidney. Spleen and liver deposits may show up much later.
Regarding treatment, once again we have an article that mentions liver transplant as potentially curative. That was first mentioned in a 1996 article, reviewed here, and the first reported case of a liver-kidney transplant for fibrinogen amyloidosis was performed in 1996 and published in 2000 (reviewed here). I wonder how long we will have to wait for a liver-only transplant to occur?
The next four articles up for review include one on transplants, one case with a unique clinical presentation, and two others that provide a general overview of the current state of medical knowledge on hereditary renal amyloidosis. Unfortunately I do not have any of these four articles, so you can expect shorter reviews since all I have to go on is the abstracts and what I have learned about the specific articles elsewhere.
(1) Lachmann HJ, Booth DR, Booth SE, et al. Misdiagnosis of Hereditary Amyloidosis as AL (Primary) Amyloidosis. N Engl J Med 2002; 346: 1786-1791.