Friday, August 30, 2013

Article Review (1975) - Familial renal amyloidosis: Case reports, literature review and classification

Today's article under review is from 1975. 1975? But David, weren't you already up to 2005 in your article reviews? Why are you going back 30 years? Well, I'm glad you asked. This past weekend I visited the UT Southwestern Medical School Library to search for the articles I have been unable to find online, and oh, what a gold mine that place is. I found 12 articles on my list. It's too bad I did not visit that library earlier, especially since it is only 30 minutes from our house and I have been within walking distance of it several times in the past two years. Better late than never, as they say.

As I said, today's article under review is from 1975. I mentioned this article toward the end of the February 24, 2013 blog post, but now I can do a slightly more thorough review and even more importantly, reveal something important about these patients that was discovered long after this article was published.

Title: Familial renal amyloidosis: Case reports, literature review, and classification (1)

Authors: Fred Alexander and E. Laurence Atkins (University of Calgary Medical School)

Journal: The American Journal of Medicine (1975)


Three siblings (two brothers and a sister) of Polish origin, presented in late middle age with the features of the nephrotic syndrome and hypertension. Glomerular deposition of amyloid was found in all on renal biopsy. No amyloid was seen on rectal or gingival biopsy. Their mother and a maternal aunt died in middle age with a clinically similar disease. These cases are compared with other forms of hereditary amyioidosis which are briefly reviewed. The hereditary amyloidoses are classified with particular emphasis on neural and renal involvement.

This article, published in 1975, is one of the early articles describing familial renal amyloidosis. Although this family was not the first reported case of renal involvement in familial amyloidosis, the authors suspected there was something different about their case. Here is a very telling sentence from the first section of the article: "The syndrome in this family may represent a new variety of hereditary amyloidosis: this is the first report of familial renal amyloidosis in a non-Jewish family of Polish extraction."  It turns out the authors were correct in their suspicion, because this family was later determined to have the fibrinogen Glu526Val mutation. So this article is actually the first published clinical description of fibrinogen amyloidosis. The symptoms described in the five case reports from this family should sound familiar.

Case 1: This patient was a 58 year old man who presented in November of 1968 with hypertension and renal insufficiency. He had proteinuria and his serum creatinine was 4.8 mg/100 ml. He had seven siblings, and at the time one sister also had kidney disease and high blood pressure. His mother (Case 5 in this article) had died of kidney disease at the age of 46. He had 10 children.

A bone marrow biopsy was normal, and a kidney biopsy showed amyloid. In January of 1970 his serum creatinine had risen to 6.2 and his hemoglobin was down to 8.8 g/100 ml. Just before he died in April of 1971 at the age of 60 his serum creatinine was 18.0 and his hemoglobin was 6.0.

The kidney biopsy showed almost complete replacement of the glomeruli by amyloid. No amyloid was found elsewhere in the kidney. Post-mortem examination showed amyloid deposits in the kidneys, andrenal and spleen, but nowhere else.

Case 2: This patient was the brother of Case 1. He presented in May of 1969 at the age of 54 with proteinuria and hypertension. The proteinuria had been noted three years earlier, at the age of 51. A kidney biopsy showed the glomeruli were largely replaced by amyloid. He died of renal failure in February of 1970 at the age of 55.

Case 3: This patient was a sister of the previous two cases. Proteinuria was detected in 1960 during a pregnancy. She first became ill in 1967 with a sudden onset of edema in her legs. She was admitted to a hospital for proteinuria, hypertension and renal insufficiency in January of 1969, and died of renal failure at the age of 69. The glomeruli in the kidney biopsy specimen were almost completely replaced by material staining positively for amyloid.

Case 4: This patient was a maternal aunt of the three siblings described in the previous three cases. She first became ill in 1953 at the age of 42, and died in 1964 at the age of 53. The final diagnosis was chronic nephritis with hypertension, edema and proteinuria. There was no kidney biopsy or diagnosis of amyloidosis.

Case 5: This patient was the mother of the three siblings described in the first three cases of this article. She died in 1938 at the age of 46. The available hospital records indicate she had renal insufficiency. She was born in Poland and moved to Canada at an early age. Her parents lived to be elderly and there was no previous history of kidney disease in the family. (I think we are all familiar with that.)

The similarities of the first three cases (siblings) are then summarized:
  • A nephrotic presentation (proteinuria, edema, and hypoproteinemia (low protein in the blood))
  • Hypertension
  • Kidney biopsy showing amyloid almost exclusively within the glomeruli
  • Renal failure as the primary cause of death

The article then does a very thorough comparison of these cases of renal amyloidosis to other types of renal amyloidosis that have been previously described. I will not cover all of that here, but the main thing that differentiates these cases from most others is that the symptoms are all related to the kidney being the affected organ, and there is very little involvement of other organs. Although amyloids may affect the kidneys with other types of familial amyloidosis, kidney failure is usually not the main symptom that patients present with.

Here are a few sentences from the closing paragraph of the article, which in hindsight we know are exactly correct:

"The distinctive features of the family reported here are the pure renal symptoms  --  an insidious onset of nephrotic syndrome and hypertension. . . . We, therefore, believe that they justify inclusion as having a further variety of familial renal amyloidosis. Study of the following generation as they reach middle age will help to define this entity more clearly."

So there we have the first published description of the fibrinogen Glu526Val mutation. Since these three siblings had 15 offspring between them, and we don't know how many of the other five siblings also had the mutation or how many offspring they had, we would expect there to be several individuals in the next generation who also inherited the mutation. We can be certain there was at least one who tested positive for the mutation, since that is how they know this family has the Glu526Val mutation.

Next up are some newly found articles from the 1980s, where the cause or causes of familial renal amyloidosis are investigated.


(1) Alexander, F., and E. L. Atkins. 1975. Familial renal amyloidosis, case reports, literature review and classification. Am. J. Med. 59:121-128.

Saturday, August 24, 2013

The heartbreak of psoriasis

Today's post will just have a few updates on Mom. (No, it has nothing to do with Tegrin). You may recall she originally had a heart catheterization scheduled for July 5, but that was cancelled because she had to have emergency surgery on July 3 due to an infection at the site of her June 11 surgery, which was to take care of infection due to a piece of surgical felt that was purposely left in after her October 12, 2012 surgery to remove the peritoneal dialysis catheter that was inserted on June 28, 2012. (Yes, that was a long sentence.)

Anyway, she rescheduled the heart catheterization for Friday, August 16. The cardiologist (Dr. R) said no abnormalities were found, so that's good news. Mom's ticker should keep on ticking for awhile. They did note that her potassium level was very low, so they gave her a dose of potassium before the procedure and then another one after, while she was in recovery. Her recovery took a little longer than expected because her blood pressure was high. Her systolic blood pressure (top number) was fluctuating between 150 and 188 in recovery, but they gave her some medication (Clonidine) to get it down and it eventually stayed below 160 long enough for them to release her.

On August 21 she had a follow-up appointment with the surgeon (Dr. K) to look at the wound from the July 3 surgery. The wound itself has not totally closed up, but it is definitely smaller than it initially was and not nearly as deep. I suppose a wound of that size will simply take time to heal and will probably leave a large scar. But Mom's main concern is some bumps that have started appearing around the wound. They are like pimples in terms of their size and how they feel, only they do not have a head on them like a pimple that is ready to pop. But she can squeeze them and get some pus out of them. She showed them to Dr. K and told him she had never seen anything like it. He looked at them for awhile and then told her he has never seen anything like it either. Once again, Mom is very special. Dr. K is going to put her on some antibiotics for awhile and see how it responds.

On August 23 she had an appointment with her rheumatologist, Dr. C. Mom gives herself Humira shots in the abdomen, but she now has those pimple-like bumps on her abdomen so she asked Dr. C about that. He said to just hold off on the Humira shots until the bumps go away. He also said it looks like the bumps are a type of psoriasis that will sometimes appear near a wound or infection. I did a little Googling on that and it sounds like it is something called the Koebner phenomenon. You learn all sorts of medical terminology by following this blog, don't you?

I know I will regret this next statement, but it has been about a month since Mom had a significant issue at dialysis (the infiltration on July 22). There used to be about one issue per week, so hopefully this trend will continue. They did start the buttonhole technique last month and it seems to be going well with one access point but not the other. We will just have to wait and see how that works out. Even if it works in just one location that will still reduce the pain by half, which would be very good.

That's it for now. It's only two months until the familial amyloidosis meeting in Chicago, with over 200 patients and caregivers plus a long list of doctors and other special guests. This biennial meeting (not "biannual," like I thought until I looked it up) is an amazing chance to rub elbows with these doctors and find out the latest information regarding familial amyloidosis. You know I'll be blogging about in detail.

Sunday, August 18, 2013

Article Review (2005) - Hereditary amyloidosis in early childhood associated with a novel insertion-deletion (indel) in the fibrinogen A alpha chain gene

The article being reviewed today is a 2005 report of another new fibrinogen amyloidosis mutation. This mutation is unique for two reasons. First, the patient's symptoms were first noted at the age of 7. Second, the mutation was not inherited from either parent.

Title: Hereditary amyloidosis in early childhood associated with a novel insertion-deletion (indel) in the fibrinogen A alpha chain gene (1)

Authors: Hee Gyung Kang, Alison Bybee,Il Soo Ha, Moon Soo Park, Janet A. Gilbertson, Hae Il Cheong, Yong Choi, and Philip N. Hawkins (Seoul National University Hospital, Seoul, Korea; Sungkyunkwan University School of Medicine, Seoul, Korea; National Amyloidosis Centre, London, UK)

Journal: Kidney International (2005)

Background. Systemic amyloidosis occurring in early childhood is extremely rare, and is usually of AA type complicating chronic inflammatory diseases. We report the molecular basis of amyloidosis in a Korean girl who presented at 7 years of age with asymptomatic proteinuria and developed amyloid hepatomegaly and end-stage renal failure within 2 years.
Methods. Renal biopsy showed enlarged glomeruli virtually replaced by amyloid, but without interstitial or vascular involvement. The histologic appearance was identical to that seen in patients with hereditary fibrinogen Aa chain Glu526Val amyloidosis, and the amyloid deposits stained specifically with antibodies to fibrinogen. Mutations were sought in the genes of the amyloidogenic proteins, transthyretin, apolipoprotein AI, lysozyme and fibrinogen Aa chain genes by polymerase chain reaction (PCR) and sequencing.
Results. A unique frameshift insertion-deletion (indel) mutation was identified in one allele of her fibrinogen A alpha chain gene, which encodes a partly novel peptide and a premature stop signal, similar to the two previously reported amyloidogenic point deletions at codons 522 and 524 in this molecule. The mutation was absent in samples verified to be from her parents, indicating that it had occurred de novo.
Conclusion. This is the first description of hereditary fibrinogen A alpha chain amyloidosis in an Asian individual, and the distinctive renal histology offered a strong clue to the diagnosis. The disease is potentially curable by combined hepatorenal transplantation.

The abstract essentially tells the entire story regarding this mutation, so I will just briefly discuss some of the highlights. First, the firsts associated with this case include:
  • The first reported case of fibrinogen amyloidosis in an Asian individual.
  • The first reported case of a person under the age of 10 developing symptoms of fibrinogen amyloidosis. (The youngest reported age before this case was 12.)
  • The first reported case of a mutation causing fibrinogen amyloidosis to occur de novo, which means the mutation first occurred in this individual and was not inherited from either parent.

It is interesting that although this fibrinogen mutation is a new one, the symptoms and progression of the disease are more or less identical to those of the fibrinogen Glu526Val mutation although they occurred at least 40 years earlier in this patient's life. The renal biopsy showed enlarged glomeruli substantially replaced by amyloid deposits, and she was on peritoneal dialysis due to end-stage renal failure about two years after diagnosis. Another interesting bit of info from the article is that she had foamy urine for about a year before the proteinuria was discovered.

The mutation itself, if I understand it correctly, replaced a long section of her fibrinogen A alpha chain gene with a much shorter section. That is what the words "insertion-deletion" are referring to in the title. It is also a frameshift mutation since the remaining unchanged parts after the insertion-deletion are shifted forward in the string.

Regarding the de novo mutation, the article states that relationship testing was done to confirm that her parents were indeed her biological parents. Since neither parent had the mutation she could not have inherited it from either one, so it must have occurred first with her. She has a sister who does not have the mutation. (We would not expect the sister to have it since it was not inherited from a parent.) It would be nice to know what the status of this patient is today. This article was submitted for publication in March of 2005, and it says a combined liver-kidney transplant was being considered. One would hope that by now, eight years later, that transplant has happened and she is leading as normal a life as possible.

That's it for now . . .



(1) Kang HG, Bybee A, Ha IS, Park MS, Gilbertson JA, Cheong HI, Choi Y, Hawkins PN. Hereditary amyloidosis in early childhood associated with a novel insertion-deletion (indel) in the fibrinogen A alpha chain gene. Kidney Int 2005; 68: 1994-8.

Monday, August 12, 2013

Brigades of Oily Minions

Today's post will be a collection of miscellaneous stuff related to amyloidosis that I have run across in the past couple of months. The first item is important. The others, not so much.

CPHPC Clinical Trial Now Recruiting (in the UK)

A new clinical trial to study the effectiveness of CPHPC is officially recruiting participants in the UK as of June 28, 2013. Here is the link on the web site:

The title of this clinical trial is "A Study to Evaluate the Safety of GSK2398852 When Co-administered With GSK2315698 in Patients With Systemic Amyloidosis." Although the acronym "CPHPC" is not listed in the title, it is in the keywords at the bottom of that link. The sponsor of the trial is GlaxoSmithKline, hence the GSK numbers in the title of the study.

This trial is good news for fibrinogen amyloidosis patients, since it is for all types of systemic amyloidosis, not just AL amyloidosis. Previous testing in patients with fibrinogen amyloidosis has been promising. If you are interested and live in the UK (or if you want to move there), check out the details at the link above and see if you meet the inclusion criteria.

Grow a Spare Liver?

A July 3, 2013 article from MedlinePlus has the title "Scientists create human liver from stem cells." First I need to state that the stem cells used in this research were not embryonic stem cells, whose use is controversial (at least in the US.) There are two main forms of stem cells, embryonic (harvested from embryos) and induced pluripotent stem cells, which are taken from a person's skin or blood. Induced pluripotent stem cells (iPS cells) are the type that are harvested from AL amyloidosis patients for use in stem cell transplants.

The very short version of the article is that a team of scientists in Japan used some iPS cells to grow liver-like structures called liver buds, which were then transplanted into mice where they matured, connected to the blood vessels of the mice, and began performing many functions of a mature liver.

This is of course a long way from growing an entire human liver, but it's a start. The first practical use of this technique will likely be to study the effect of potential new drugs on the human liver. Then they might be able to grow mini-livers from the stem cells of people with liver disease, and transplant those mini-livers into those patients to take over some liver functions of the failing liver. Growing an entire liver to replace an existing liver would likely be more challenging if it is even possible, but who knows?

More Animal Amyloidosis

In the book "XIth International Symposium on Amyloidosis," which was published in 2008 and reported on the November 2006 amyloidosis symposium, I ran across this article in the section on familial amyloidosis: "Systemic amyloidosis of fibrinogen origin in the wild living stone marten (martes foina)." A marten is a small mammal in the same subfamily as weasels, ferrets and minks. Those of you with good memories may recall a previous post in which I mentioned an article titled "Familial Renal Amyloidosis in Abyssinian Cats." This article on the stone marten went into the details of how they determined that the origin of the amyloidosis in these animals was the fibrinogen alpha chain, but they did not determine whether or not it was hereditary. In any case, those of us who have tested positive for the fibrinogen amyloidosis mutation now have some more trivia to amaze and impress our friends.

Surprising Search Results

Last month someone found this blog while searching for the phrase "lean forward shampoo." I assume this person was looking for articles about the benefits of leaning forward instead of backward over a sink while getting a shampoo in a salon, when one of the hits was my July 10 post about our week on the cruise ship where I had to take Mom from the salon to the ship's medical facility because her lungs were filling up with fluid. The Internet is just full of surprises, isn't it?

A Rag Man

In case you have not figured it out yet, the title of today's post is another anagram of "fibrinogen amyloidosis." The Internet is just full of surprises, isn't it?

Tuesday, August 6, 2013

Article Reviews (2003 and 2005) - Two reviews of hereditary renal amyloidosis

It's hard to believe it has been over two months since my last article review. I suppose two emergency room visits (including one on a cruise ship), three surgeries (one of which was an emergency), two nights in the hospital, two funerals, two weeks tethered to a portable wound vacuum, and a diagnosis of skin cancer gave me something else to write about during that time. It's hard enough just writing about all that, so I can't imagine what it must be like for Mom to live through it. Once again, hopefully things will calm down for awhile.

Today's post will review two very similar articles, with the always exciting monthly blog stats at the end. Since I do not have either one of these articles, I will list their titles and abstracts first, then briefly discuss them together.

Title: Hereditary systemic amyloidosis with renal involvement (1)

Author: Philip Hawkins, National Amyloidosis Centre, London, UK

Journal: Journal of Nephrology (2003)

Hereditary systemic amyloidosis is caused by deposition of genetically variant proteins as amyloid fibrils. The types that present with renal disease are usually associated with mutations in the genes for either apolipoprotein AI, apolipoprotein AII, lysozyme or fibrinogen A alpha-chain. These diseases are inherited in an autosomal dominant manner with variable penetrance, and can present clinically at any time from the teen years to old age, though usually in mid-adult life. Hereditary amyloidosis is uncommon, but its precise characterization has major implications for patient management and genetic counseling, and it has been an extremely valuable model for elucidating the pathogenesis of amyloid deposition generally. The amyloidogenic variant proteins associated with hereditary amyloidosis are less stable than their normal wild type counterparts and even under physiological conditions can populate partly unfolded states, involving loss of tertiary or higher order structure, which readily aggregate with retention of beta-sheet secondary structure into protofilaments and fibrils. The clinical phenotype of hereditary renal amyloid is non-specific and is readily misdiagnosed as acquired AL amyloidosis. Indeed, we have lately demonstrated that five percent of patients with apparent sporadic amyloid have hereditary fibrinogen A alpha-chain amyloidosis associated with the valine 526 variant. Penetrance of this particular mutation is extremely low in most families obscuring the genetic etiology, but the renal histology is very characteristic showing substantial accumulation of amyloid within enlarged glomeruli, but none in blood vessels or the interstitium. DNA analysis is now performed routinely in UK National Amyloidosis Centre in patients with systemic amyloidosis in whom AA or AL fibril type cannot be definitively verified.

Title: Ostertag revisited: The inherited systemic amyloidoses without neuropathy (2)

Author: Merrill Benson, Indiana University School of Medicine, Indiana, USA

Journal: Amyloid (2005)

Mutations in a number of plasma proteins, including transthyretin, apolipoprotein AI, fibrinogen A alpha-chain, lysozyme, and apolipoprotein AII, are associated with hereditary systemic amyloidosis. Transthyretin amyloidosis is the most common and is usually associated with peripheral neuropathy. Mutations in the other proteins usually have no neuropathic consequences and, instead, cause principally renal and cardiac amyloidosis. Only the apolipoprotein AI glycine 26 arginine mutation may cause peripheral neuropathy and then in only some of the kindreds with this disease. This review is concerned with the non-neuropathic hereditary systemic amyloidoses. It strives to present a synopsis of the present day knowledge of these diseases including each feature of each precursor protein and its mutations; the clinical phenotype of the disease; and suggestions for treatment when feasible. The main objective is to increase awareness of these autosomal dominant diseases, enhance the chances of early diagnosis, enhance the physician's and subsequently the patient's knowledge of each disease, and finally emphasize the need for more research to find ways to treat or prevent these diseases.

These two articles, published two years apart, appear to be very similar based on the abstracts alone. They both focus on the most common familial amyloidosis types other than transthyretin (ATTR), which are apolipoprotein, fibrinogen and lysozyme, and they were published about 10 years after the first article describing the fibrinogen mutation was published. There is not much in terms of new information that we have not already covered in previous articles, but here are the highlights:

  • The inheritance mode is autosomal dominant, and penetrance (how likely a person with the mutation is to develop symptoms) is variable.
  • Hereditary renal amyloidosis is frequently misdiagnosed as AL amyloidosis because the clinical symptoms are so similar. (That article was reviewed in the May 12, 2013 blog post.)
  • A defining characteristic of the fibrinogen Glu526Val variant is the accumulation of amyloid deposits in the glomeruli of the kidneys.
The last sentence of the second abstract does a good job of summarizing the objective of these articles, which is to increase awareness of these diseases and enhance the chances of early diagnosis. A current online resource that provides a general overview, although probably not as detailed as these two published articles, is the article on familial renal amyloidosis at

That is all I have to say about these two articles since I do not have the full articles to review. The next article up for review will document yet another fibrinogen mutation, with an especially unique characteristic.

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(1) Hawkins PN. Hereditary systemic amyloidosis with renal involvement. J Nephrol. 2003;16:443–448.

(2) Benson MD. Ostertag revisited: The inherited systemic amyloidoses without neuropathy. Amyloid 2005; 12: 75-87.