Monday, September 30, 2013

Article Review (1993) - Hereditary renal amyloidosis associated with a mutant fibrinogen alpha-chain

Today's article under review is another one that was previously reviewed but only recently acquired. It was the first article discussed in the March 20, 2013 post, when I only had the abstract. This 1993 article is very important in the history of fibrinogen amyloidosis since it describes the first fibrinogen amyloidosis mutation that was discovered, so I will go ahead and write a full review here as if the previous one were never done.

Title: Hereditary renal amyloidosis associated with a mutant fibrinogen alpha-chain (1)

Authors: Benson MD, Liepnieks J, Uemichi T, Wheeler G, Correa R. (Department of Medicine, Indiana University School of Medicine, Indianapolis, USA)

Journal: Nature Genetics (1993)


Three members of a family who died with renal amyloidosis were found to share a single nucleotide substitution in the fibrinogen alpha-chain gene. The predicted arginine to leucine mutation (Arg554Leu) was proven by amino acid sequence analysis of amyloid fibril protein isolated from postmortem kidney of an affected individual. Direct genomic DNA sequencing and restriction fragment length polymorphism analysis demonstrated that all three affected individuals had the guanine to thymine 4993 transversion.
This is the first demonstration of hereditary amyloidosis associated with a variant fibrinogen alpha-chain. Variants of circulating fibrinogen may be the cause of a number of systemic amyloidoses with primarily renal involvement.

The article begins with an overview of the types of hereditary amyloidosis that were known at the time. It states that a number of families have been identified with a hereditary form of amyloidosis that is autosomal dominant where the principal organ involved is the kidney, and the amyloidosis is not caused by mutations in any of the proteins already known to cause amyloidosis.

The propositus (first identified family member) was a 50 year old Peruvian male. He developed kidney issues at the age of 36 and received a kidney transplant at the age of 40. Eight years later a renal biopsy showed amyloid deposits (primarily in the glomeruli), and he received a second kidney transplant at the age of 50. He died soon after the second kidney transplant due to septicaemia. At autopsy, his original kidneys showed much less amyloid deposition than the kidney that was first transplanted at the age of 40. There were also some amyloid deposits in the spleen but not in the liver.

A sister of the propositus died at the age of 28. She had nephrotic syndrome, and a kidney biopsy showed amyloid deposits in the glomeruli. Another sister was over 50 years old and in good health at the time this article was published.

The propositus had two sons and one daughter. One son developed azotemia at age 24, and a kidney biopsy showed amyloid deposits in the glomeruli. He died shortly after being placed on hemodialysis. The daughter and the other son of the propositus were reportedly healthy at the time this article was published.

The next section gives a technical description of how it was determined the propositus had a fibrinogen mutation. I don't understand much of it, but the oversimplified version is that after this patient's death, they analyzed a small quantity of tissue from the first transplanted kidney which had been transplanted ten years prior to his death. They isolated 7.3 mg of protein from 200 mg of kidney tissue, and then analyzed that to determine what specific protein or proteins it matched. They found that it matched part of the fibrinogen alpha-chain with the exception of one location.

This particular mutation substituted leucine for arginine at amino acid position 554 of the fibrinogen alpha chain, so it is referred to as Arg554Leu. (The most common fibrinogen amyloidosis mutation, Glu526Val, substitutes valine for glutamic acid at amino acid position 526.)

The final section of the article mentions that fibrinogen is involved in the final phase of blood coagulation, and many fibrinogen mutations have already been discovered in individuals with blood clotting disorders. Since fibrinogen is present in the blood at a relatively high concentration, it is not surprising that it could be involved in the formation of amyloid fibrils. Given the fact that other proteins have multiple mutations that can cause amyloidosis, the article states that it is likely that other fibrinogen mutations will be discovered to cause amyloidosis.


The main similarities between this mutation and the Glu526Val mutation are the presence of amyloid deposits in the glomeruli of the kidneys, and the fact that the kidneys are the primary organ affected. The main difference, based on the kindred described in this article, is that the age of onset is certainly much younger than the average age of onset with the Glu526Val mutation.

One other statement from the article that got my attention was the fact that the transplanted kidney had much heavier amyloid deposition than the original kidneys. At the time of death the patient's original kidneys had been in place for 50 years, whereas the transplanted kidney had only been in place in this patient's body for 10 years. We probably cannot draw any definite conclusions just from this patient, but it does make me wonder if something accelerates the production of amyloids as a person ages, or, since we do not know the age of the kidney donor, does something make the kidneys more susceptible to amyloid deposits as they get older? We will see in later articles that recipients of a kidney transplant who do not also get a liver transplant can expect the transplanted kidney to eventually be affected by amyloid, but the point at which it becomes clinically significant varies over a very wide range.

Now that the first fibrinogen mutation causing familial amyloidosis has been discovered, we only have to wait a year for the next mutation. That article was published in 1994 and reviewed in the March 20, 2013 blog post. The next article for review takes us all the way to 2003, describing the first patient to receive a liver-kidney transplant for fibrinogen amyloidosis.


(1) Benson MD, Liepnieks J, Uemichi T, Wheeler G, Correa R. Hereditary renal amyloidosis associated with a mutant fibrinogen alpha-chain. Nat Genet 1993; 3: 252-255.

Tuesday, September 24, 2013

One Hundred!!

Welcome longtime loyal readers, newcomers, and future readers of the blog, to post number 100! Yippeeeeeeee! I started the blog way back on September 29, 2012, which means post number 100 comes just before the one year anniversary.

I may be biased, but I think it has been a good year for the blog. I caught up on Mom's history with fibrinogen amyloidosis going back to January of 2010, created a few standalone pages that will hopefully give newcomers to this disease a relatively quick way to learn about it and make some informed decisions, and I started systematically reviewing the published medical literature related to fibrinogen amyloidosis.

One thing I do know for certain is that the spammers love the blog, because they tell me so in their comments that get automatically blocked by Blogger's spam filters. Below are some of the more flattering comments from the spammers I have received since they discovered the blog in March of this year. (Spelling, grammar and punctuation errors are accurately reproduced.) As you read through these comments, add this sentence or something similar to the end of each one: "Also, please visit my web site: [link to some web site trying to sell something]"

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After all that praise, all I can think of is Sally Field's 1985 Oscar acceptance speech. (

Let's see what happens in the next 100 posts . . .

Wednesday, September 18, 2013

Article Review (1982) - Familial Amyloidosis of Ostertag

Today's post will be a short article review on another previously reviewed article that I recently acquired. This article is from 1982 and it was briefly mentioned in the March 5, 2013 post.

Title: Familial Amyloidosis of Ostertag (1)

Authors: Lanham, Meltzer, De Beer, Hughes and Pepys (yes, that Pepys)

Journal: QJM: An International Journal of Medicine (1982)


A 23 year old Englishman presented with keratoconjunctivitis sicca and was found to have systemic amyloidosis. Five members of his family in two generations also had non-neuropathic amyloid particularly affecting the kidneys. This conforms to the Ostertag type of hereditary amyloidosis. Amyloid deposits in the proband showed permanganate-sensitive Congophilia and positive immunofluorescence staining for P component, but were negative for amyloid A and prealbumin. These observations suggested that the fibril protein in this patient was immunochemically distinct from the amyloid fibrils characterized hitherto.

This article describes yet another kindred with several family members who presented with renal amyloidosis, in which the amyloid appears to be different than that found in AL amyloidosis. The article states this family is the third one reported to have what was referred to at the time as the Ostertag type of familial renal amyloidosis. (Ostertag first published an article describing it in 1950.)

Although the symptoms of these patients are similar to those of fibrinogen amyloidosis patients, I will go ahead and spoil the ending and reveal that these patients did not have fibrinogen amyloidosis. This family was eventually found to have a lysozyme mutation, which was discovered in 1993. This article is actually the first published clinical description of that mutation. It still has some importance in the history of fibrinogen amyloidosis, since it was published at a time when these forms of familial amyloidosis that primarily affects the kidneys (with no neuropathy) were first being described.

Here is a description of each of the six cases from this family described in the article. The 23 year old patient described in the abstract is actually Case 6.

Case 1:  An aunt of Case 6 who died of renal failure at the age of 43.

Case 2:  An aunt of Case 6 who died of renal failure at the age of 38. Autopsy results showed amyloid deposits in the kidneys, spleen, lungs and liver.

Case 3:  Father of Case 6. He presented with hypertension and renal failure at the age of 33 and died three months later in renal failure. Autopsy results showed extensive amyloid deposits in the kidneys, adrenals and spleen. Amyloid to a lesser extent was found in the lungs and the liver.

Case 4:  Male cousin of Case 6. He presented at the age of 33 with hypertension and declining renal function, and started dialysis at the age of 41. A lung biopsy at that time showed amyloid deposits. At the age of 49 he had a kidney transplant but died shortly afterward due to complications. Autopsy results showed extensive amyloid deposits in the kidneys, and to a lesser extent in the lungs, liver, heart, duodenum and pylorus.

Case 5:  Female cousin of Case 6, sister of Case 5. She presented at the age of 45 with hypertension and some renal impairment. Kidney biopsy shows widespread amyloid deposits, but as of the publication of this article she was not on dialysis.

Case 6:  This patient was 23 years old when he presented with a three year history of keratoconjunctivitis sicca (dry eye syndrome). Biopsies of the lip, rectum and kidney showed extensive amyloid deposits. The kidney biopsy did show amyloid deposits in the glomeruli, which is consistent with what is seen in the kidney biopsies of patients with fibrinogen amyloidosis. Additional testing was done on the kidney biopsy tissues which showed the amyloid was not of the AL type.

The two main differences between these cases (now known to be a lysozyme mutation) and the cases of fibrinogen amyloidosis are the age of onset (and death) and the number of different organs affected. For the patients in this article, the ages of onset that we know of ranged from 23 to 45, and the ages of death ranged from 33 to 49. Those ages are considerable younger than the normal range of fibrinogen amyloidosis patients.

The number of different organs affected, especially at such young ages, is something else that is typically not found in fibrinogen patients. Although there are published reports of fibrinogen amyloidosis patients having amyloid deposits in other organs, these are typically only found long after a patient has presented with renal impairment. The lysozyme patients described in this article seemed to have amyloid deposits in multiple organs either when they initially presented (in their thirties or forties) or within a few years.

So once again the authors knew these patients had a different type of familial amyloidosis that primarily affected the kidneys and whose biochemical origin had yet to be discovered. Given what we know now about the fibrinogen and lysozyme mutations, we can see the differences between the two based on the clinical descriptions.

Next up: A milestone

[Edit 11-13-13: Corrected typo in first paragraph after Case 6 description.]


(1) Lanham, J. G., M. L. Meltzer, F. C. De Beer, G. R. V. Hughes, and M. B. Pepys. 1982. Familial amyloidosis of Ostertag. Q. J. Med. 201:25-32.

Thursday, September 12, 2013

Musical Chairs

It's time for a quick update on Mom since a couple of things are going on. First, there is good news and bad news on her lab work. The good news is that her hemoglobin is up to 11.9, so her anemia appears to be getting under control. (The lower end of the normal range for females is around 12, depending on what site you look at.) It got down to 7 last September and it was only 7.4 at the beginning of this year, so 11.9 is a major improvement.

The bad news is that her protein is low and her calcium is high. Her protein being low is likely due to her diet, so she needs to concentrate on eating more protein-rich foods, drinking protein shakes, eating protein bars, etc. Maybe I'll set up an account at for her.

Her calcium being high is a different matter. Her nephrologist, Dr. N, is concerned about that. High calcium is usually caused by a parathyroid condition (hyperparathryoidism), but he gave her a test that ruled that out. So far he has been unable to determine the cause of her high calcium, and he suspects it may be related to her amyloidosis. Dr. N has talked to Mom's hematologist, Dr. C, about it, but I do not think they have reached any conclusions yet. I may try to put him in contact with one of the doctors in Boston, since there are some more serious potential causes of high calcium and we do not want to just assume it is caused by the amyloidosis and leave it at that. Mom has her regular appointment with her internist next month, so the internist may be the doctor that has to chase down the cause of the high calcium. Determining the cause of high calcium can be difficult, since over 99% of the time (maybe not that high, depending on the source) the cause is hyperparathyroidism, which Mom supposedly does not have. So she may very well have one of the rare causes of high calcium. Hooray, another medical mystery!

Now, about the next issue . . . Do you remember that part of my August 24 post where I mentioned it had been about a month since Mom had a significant issue at dialysis, and I said I would regret making that statement? Well guess what? Something happened. They infiltrated her fistula again on Monday, September 9. Mom ended up bleeding quite a bit and some of her clothes were soaked with blood, but not quite as bad as the October 26, 2012 incident. But that's not the full story.

So how did this happen? Aren't they working on getting her started on the buttonhole technique? Yes, the buttonhole is looking good on one access, but the second access point is still under development. Everything I have read about using the buttonhole technique states that the same person should insert the needles each time, until the buttonhole is fully formed and ready to use. Doing that helps ensure that the needle is always inserted at the exact same angle, so the scar can form one narrow tunnel. That has been happening at the clinic, with the same tech (Rick) inserting Mom's needles each time. Until Monday.

Was Rick off on Monday? No, he was working at the clinic.
Didn't they put her in Rick's section like they normally do? No, they didn't.
Couldn't she call Rick over to have him insert her needles? No, Rick was exceptionally busy on Monday.

This Fresenius clinic has decided, probably with good intentions, to rotate the techs around to different bays (sections) so all of their staff can become comfortable working with any staff members, and anybody can fill in anywhere more or less equally. That seems like a reasonable goal, and it certainly has its benefits from a personnel scheduling standpoint. But this is not a factory that is making widgets. It is a clinic providing health care to people, essentially putting them on life support for a few hours at a time. They did not consider the need for Mom to have the same tech insert her needles while her buttonhole is being formed.

Rick did come over after Mom's fistula had been infiltrated on Monday and was not at all happy about it, especially since he had told them this new staff rotation plan was not a good idea. He did not want to try to get the second needle in, so Mom did not have dialysis on Monday and had to go in on Tuesday.

On Tuesday Mom spoke to the head nurse about it and stressed the need for Rick to be available to insert her needles while the buttonholes are being formed. It seemed like the head nurse just wasn't understanding what Mom was talking about, and only wanted to point out how important it was to rotate the staff around and how much better it will be for the patients. At one point she said they might have to stop offering the buttonhole technique until Rick can train some other techs how to do it. Mom eventually asked her if she needed to schedule an appointment to talk to the manager of the clinic, and the nurse told her she would talk to him.

When the manager did come in, Mom saw the head nurse immediately walk over to him and talk with him for several minutes. Then he did something Mom has never seen him do. He went up and down the rows in every bay, briefly speaking to each patient and asking how they were doing. Mom did not talk to him about her issues when he spoke to her, since she would rather do that in his office instead of in a dialysis chair. We figure the nurse talked to the manager and told him Mom was complaining about the rotation, so he talked to all the patients to see if there were any other complaints. ("You seem to be the only patient complaining about the new rotation policy, Ms. Jennings." Well, she is the only one currently developing buttonholes, so, yes, she has concerns that none of the other patients have.)

On Wednesday, Mom was once again not in Rick's area so she had to insist that Rick come over to insert the needles. Rick did not seem very pleased about this, but the needles went in fine and Mom's dialysis was completed without any issues. So now Mom is wondering if the head nurse told Rick not to give Mom any special treatment. It was disheartening to hear that Rick seemed upset about having to insert Mom's needles on Wednesday, since he seemed to really be on Mom's side on Monday. Hopefully this situation will calm down and Mom's buttonholes can get finished. She is really disgusted with the staff at the clinic and how they are dealing with this, and she is even talking about possibly having to switch to a different clinic. So stay tuned for further developments.

[11-13-13: Inserted parenthetical remark near end of third paragraph.]

Saturday, September 7, 2013

Article Reviews (1981 and 1982) - Studies and case reports of a familial form of renal amyloidosis

Today's post will review two articles that I recently obtained, one from 1981 and the other from 1982. I previously mentioned these article in the March 5, 2013 post. They are by the same authors and they discuss the same family, so I will review them together. This family was later discovered to have the fibrinogen Glu526Val mutation, making these articles the second published clinical description of what was later determined to be fibrinogen amyloidosis.

Title: Studies on the pathogenesis of a familial form of renal amyloidosis (1)

Authors: Mornaghi, Rubinstein, and Franklin (New York University Medical Center and New York Blood Center)

Journal: Transactions of the Association of American Physicians (1981)

Abstract: none

Title: Familial renal amyloidosis: Case reports and genetic studies (2)

Authors: Mornaghi, Rubinstein, and Franklin (New York University Medical Center and New York Blood Center)

Journal: The American Journal of Medicine (1982)

Rapidly progressive biopsy-proved renal amyloidosis developed in three brothers, aged 49, 52, and 55, of Irish-American origin. None had evidence of a plasma cell dyscrasia, a monoclonal serum or urine protein, or any underlying chronic disease. Immunoperoxidase staining of one pulmonary and one renal biopsy specimen was negative for Amyloid A (AA), Amyloid L (AL), and prealbumin. To investigate factors that might play a role in the disease, the subjects and 21 relatives were typed for antigens of the A, B, C, and DR loci and the linked marker genes for factor B and glyoxalase. The ability of macrophages to degrade serum amyloid A (SAA) [1] was examined. One brother yielded an intermediate AA-like produce similar to what is seen in most patients with AA or AL amyloidosis and 40 percent of normal subjects. The other two degraded SAA completely to small peptides. Analysis of the families revealed first that the disease was not linked to the major histocompatibility complex. We were unable to demonstrate a genetic relationship between processing of SAA by peripheral mononuclear cells and the human leukocyte antigen locus. Finally, the pattern of SAA degradation was not associated with the development of the disease.

Although both of these articles cover the same family and discuss the genetic testing that was done, only the 1982 article provides the medical history of the three cases of renal amyloidosis. So this review will mainly follow the 1982 article, but I will mention the 1981 article occasionally.

As stated in the abstract, this article describes three brothers who developed renal amyloidosis in their 40s and 50s.

Case 1:  This patient was a 49 year old Irish-American man who presented in September of 1978 with anemia and renal failure. A 24-hour urine collection showed 3 grams of protein. He declined a kidney biopsy at that time. He was admitted to the hospital four months later (January of 1979) due to dyspnea (labored breathing) and edema. A 24-hour urine collection showed 8.3 grams of protein and his serum creatinine level was 9.3 mg/100 ml. At some point he did have kidney and bone marrow biopsies. The kidney biopsy showed amyloid deposits, whereas the bone marrow biopsy was normal. He started hemodialysis which he was still on at the time this article (published in October 1982) was written.

Case 2:  This patient was a 52 year old brother of Case 1 who presented with hypertension in early 1976. He was found to have proteinuria and an elevated serum creatinine level. He had a kidney biopsy in June of 1976, which was positive for amyloid, localized in the glomeruli. A bone marrow biopsy was normal.

In June of 1978 he had a myocardial infarction (heart attack.) In September of 1979 he started on hemodialysis. In March of 1981 he was hospitalized and discharged a week later with a diagnosis of congestive heart failure, end-stage kidney disease, and renal amyloidosis. He was still on hemodialysis at the time this article (published in October 1982) was written.

Case 3:  This patient, a brother of Cases 1 and 2, presented in 1974 at the age of 55 with hypertension. In December of 1978 he was hospitalized with anemia. In June of 1979 he was hospitalized due to progressing renal failure and hypertension. In November of 1979 he was hospitalized and a kidney biopsy showed amyloid. In January of 1980 his serum creatinine level was 8.4 mg/100 ml and he started on hemodialysis. In June of 1980 he was admitted to the hospital due to a persistent cough and dyspnea. A lung biopsy showed amyloid deposits consistent with pulmonary amyloidosis. He was still on hemodialysis at the time this article (published in October 1982) was written.

For the most part, these three cases share a lot in common with other cases of fibrinogen amyloidosis: hypertension, proteinuria, and elevated serum creatinine level indicating kidney failure, eventually progressing to the point where dialysis is necessary. Two significant items out of the norm were the congestive heart failure in Case 2, and what is presumed to be pulmonary amyloidosis in Case 3. This is the first time I recall hearing about pulmonary amyloidosis in a person with fibrinogen amyloidosis. On the other hand, cardiac involvement is rare with fibrinogen amyloidosis, but there is a documented case in a later article. So this patient's heart may have been affected by amyloids, or he could have simply developed congestive heart failure through the "normal" means instead of amyloidosis, since amyloidosis does not prevent or cause all of the other diseases and conditions that normally occur to the body over time. In other words, you can't always blame it on the a-a-a-a-a-amyloid (apologies to Jamie Foxx).

These three brothers had an older brother who died of pneumonia at the age of 53, and they had three sisters who did not have any symptoms to indicate renal amyloidosis. Given the large size of this family, the authors were able to conduct tests on 24 family members, including the three brothers with renal amyloidosis, in an attempt to point toward some genetic causes of the amyloidosis. Both articles go into quite a bit of detail on the testing that was done, and it is way over my head, so I will try to be brief in covering them.

HLA Typing: HLA typing is commonly referred to as tissue typing. Tissue typing is important in the field of organ transplants since it gives an indication of how the recipient's body will respond to the donated (transplanted) organ. (HLA stands for Human Leukocyte Antigen.) Anyway, by comparing the HLA typing of the six siblings (three brothers and three sisters), they concluded that the evidence strongly suggests that the renal amyloidosis is not closely linked to the HLA system.

Separation of Peripheral Blood Mononuclear Cells (PBMC) and Incubation with SAA: Here is my best attempt at explaining what I think this test is. They took a quantity of blood from each family member, separated out some components, and set up experiments so they could measure how certain components (SAA, which is Serum Amyloid A) degraded over time. The authors had done previous work were they discovered a certain degradation pattern of SAA was found in almost 100% of patients with AA or AL amyloidosis. But in this case, if you have not already guessed, there was no correlation between the degradation pattern and this type of renal amyloidosis.

So these two articles document an early attempt to determine a genetic link to this type of renal amyloidosis. Although they came up empty, this additional knowledge certainly helped to support the case that this was a new type of familial amyloidosis. In fact, the authors state just that in the 1982 article: "The exact nature of this type of amyloid is still unknown, but future immunochemical studies on fibrils isolated from involved organs should provide information regarding its properties." They were right on target with that statement, and an upcoming article will show that they did a good job of predicting the future.

While they were correct in concluding this type of amyloid was different from any others previously described, the authors did reach an incorrect conclusion in the 1981 article, albeit with some caution. Here is part of the summary of the 1981 article:

". . . the disease is transmitted in a fashion which differs from most of the familial forms in that it is not inherited as an autosomal dominant trait. However, this conclusion will have to be reevaluated in years to come when the younger descendants reach the age at which amyloidosis was clinically manifested in the three propositi. It should be emphasized that these conclusions are warranted only for this unusual type of amyloidosis whose precise immunochemical nature at this time remains to be determined."

It is easy to understand how they could reach that conclusion given the data they had at the time, and the low penetrance of fibrinogen amyloidosis. Now with genetic testing available it can be clearly shown that the inheritance mode is autosomal dominant.

On a side note, one of the references listed for these articles is a 1981 article by none other than Dr. Merrill D. Benson, whose team of course discovered the first mutations for fibrinogen amyloidosis (and many others). Since 1981 was 32 years ago I wondered if that was one of Dr. Benson's first articles. Nope. According to his publications page, the first paper he co-authored was published TWENTY years before that, in 1961 (the year he earned his bachelor's degree).

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(1) Mornaghi, R., P. Rubinstein, and E. C. Franklin. 1981. Studies on the pathogenesis of a familial form of renal amyloidosis. Trans. Assoc. Am. Phys. 94:21 1-216.

(2) Mornaghi, R., P. Rubinstein, and E. C. Franklin. 1982. Familial renal amyloidosis: case reports and genetic studies. Am. J. Med. 73:609-614.