Thursday, March 31, 2016

Article Review (2011) - The Case: Proteinuria in a patient with diabetes

Today's post will be an update on me, followed by a short review of an article published in 2011 that I recently found online, and then the always exciting monthly blog stats.

As you may recall from the previous post, at my last physical exam my doctor confirmed I am slightly anemic, and no sources of bleeding were found during an endoscopy and colonoscopy in February. Since then I have had some more blood work done per orders from the gastroenterologist, and I have viewed those results online but have not met with the doctor about them. In my uneducated opinion it looks like I do have iron deficiency anemia. Although all of the numbers related to red blood cells improved slightly from where they were in January, the only one that moved from out of range to within range was hematocrit. Hemoglobin was still low at 12.6 g/dL. Some new numbers from this round of testing were also out of range, specifically ferritin, which was 6 ng/mL (normal range is 20 to 380), and total iron, which was 26 mcg/dL (normal range is 50 to 180).

I also did a more thorough review of the journal articles I have related to fibrinogen amyloidosis, looking not only for mentions of anemia but also spleen. Several articles mention involvement of the spleen in more advanced cases of AFib, possibly causing anemia that is resistant to treatment. Most of the AFib cases mentioned in the articles either do not mention anemia or hemoglobin as part of the patient's initial presentation, or they say the patient's hemoglobin was normal. But I did find two cases where the patients did have anemia when they initially presented with kidney issues.

So it is not unheard of for an AFib patient to have anemia early in the progression of the disease. Maybe I am so special I developed anemia before developing kidney issues. Of course this is all speculation at this point. But I very clearly remember a comment Dr. Benson made during one of the familial amyloidosis meetings in Chicago, when he was discussing the typical progression of symptoms of the various types of familial amyloidosis. He said sometimes you see a patient who hasn't read the book, and their symptoms are not consistent with the typical pattern.

Moving on to the article review, this article appeared in the "Make Your Diagnosis" section of the journal "Kidney International" in 2011.

Title: The Case: Proteinuria in a patient with diabetes (1)

Authors: Srikanth Kunaparaju, Chidi Okafor, Helen Cathro, Vijay Bhola, F. Jackson Ballenger and Mitchell H. Rosnerl (Virginia, USA)

Journal: Kidney International (April 2011)

Here is a link to the PDF file if you would like to follow along:

A 49-year-old Caucasian man with type 2 diabetes, hypertension, hyperlipidemia and obesity, and no known renal disease presented with 2 weeks of headache and visual disturbances, and a 6-month history of frothy urine. Diabetes had been diagnosed 3 years previously and had been under excellent control; the most recent Hgb A1c was 7.1%. There was no history of end-organ involvement secondary to diabetes, including retinopathy and neuropathy. Serum and urine protein electrophoresis with immunofixation demonstrated no monoclonal proteins.

The abstract is essentially the first paragraph of the article. The only additional information in the first paragraph is that there was no family history of kidney disease. Additional testing found that this patient's serum creatinine was 4.55 mg/dL, which was significantly higher than his creatinine level of 1.22 the previous year. A 24-hour urinalysis study also showed 10.0 grams of protein. A renal ultrasound showed the kidneys were of normal size, so a biopsy was done.

The kidney biopsy was very similar to other fibrinogen amyloidosis biopsies. It was Congo Red positive and it showed obliteration of all glomeruli with very little amyloid elsewhere. The antibody-specific staining intensity was not strong enough for a definitive diagnosis of fibrinogen amyloidosis, so the biopsy tissue was submitted for mass spec analysis. That analysis showed fibrinogen, and genetic testing confirmed the Glu526Val mutation.

The article then gives some basic information about fibrinogen amyloidosis, which there is no need to repeat here. It also states that since fibrinogen is synthesized exclusively in the liver, a liver or liver-kidney transplant is required for long-term success. Near the end of the article there is one sentence that summarizes the purpose for this article. "The rapid progression of renal disease, high levels of new-onset proteinuria, and well-controlled diabetes should suggest a diagnosis other than diabetic nephropathy." In other words, although diabetes is often the cause of kidney disease, nephrologists should not always assume that is the case without looking a little further. If the renal disease progresses rapidly, the patient develops proteinuria, and the diabetes is well-controlled, there may be an underlying cause of the kidney disease that should be investigated.

Next up will likely be a review of a very recent, very special article.

=====Monthly Blog Status Update=====

As of February 29, 2016:

Total posts: 164 (1 in February)

Total pageviews: 37,600 (~800 in January)

Email subscribers: 14 (unchanged)

Total number of countries that have viewed the blog: 110

One new country viewed the blog in February:



(1) Kunaparaju S, Okafor C, Cathro H, Bhola V, Ballenger FJ, Rosner MH. The Case: Proteinuria in a patient with diabetes. Kidney International.79(7):793-794.

Edit 4-1-16: Corrected Total pageviews in Monthly Blog Status Update

Tuesday, March 1, 2016

Signs, signs, very subtle signs?

Today's post will be a health update on me, followed by the always exciting monthly blog stats at the end. (Monthly blog stats will now include a hyperlink to the Wikipedia page of any new country visiting for the first time, since we could all use an occasional world geography lesson. You're welcome.) This ended up being a rather long post, but a large portion of it in the middle can easily be skipped. (Hopefully there are no strange formatting issues with this post, since there is a chart. If it just doesn't look quite right, check the web site. I will eventually make it look correct there on the blog.)

I had my annual physical examination in February, and my kidney function is still fine. Creatinine was 1.0 mg/dL (normal range 0.6 to 1.5) and GFR was 77 (normal range is anything over 59.) No proteinuria was detected. So all of that is obviously good news and my kidneys do not appear to be affected by amyloidosis yet. However, there was a bit of other news during this doctor visit. After my doctor walked into the exam room and we exchanged pleasantries, the first thing he said was that I seem to be a little anemic. I think my exact words were, "As a matter of fact, I was hoping to discuss that with you." And then I handed him the piece of paper I brought with me that contained this chart:
Hemoglobin chart

(Incidentally, my wife rolled her eyes at me and groaned a little when I told her about handing my chart to the doctor. You would think being married to an engineer for 23 years would prepare her for stuff like that. Maybe not.)

Before I discuss that chart, I need to back up a bit. (If you would rather skip the backstory and get back to the chart, just scroll down until you see the chart again in this post.) In early 2013, my wife was diagnosed with hereditary hemochromatosis, a blood disorder that causes the body to retain excessive amounts of iron. This buildup of iron can adversely affect many different organs if it is not reduced. How does one reduce the amount of iron in the body? By simply giving blood. So my wife was looking at the prospect of needing to give blood periodically until her iron levels returned to normal. She does not like needles and was not looking forward to giving blood, so I decided to start giving blood also, sort of as a show of support and so I could tell her what to expect. I had also known for some time that men are more likely to have excessive iron levels than premenopausal women are, so donating blood would also serve to reduce my iron levels if they were high.

In May of 2013 I gave my first blood donation since 1981. Before a person is allowed to donate blood their hemoglobin level is checked by analyzing a few drops of blood from a finger poke. My hemoglobin measured 15.9 for this donation, which is well within the normal range and very close to the reading at my physical examination in January of that year. I donated blood two more times in 2013, and twice in 2014, and the lowest hemoglobin reading was 14.8. It was 14.4 at my physical examination in January of 2014, and 13.6 at my exam in January of 2015. The paperwork from my doctor's office indicated the normal range was 13.5 to 18.0, so 13.6 was at the low end of the normal range.

There were two items in my lab results from January of 2015 that were out of range, however. My doctor did not say anything about them during the appointment, but I did some research on my own to find out what they were. The first was MCH, which stands for Mean Corpuscular Hemoglobin. It is a calculation of the average amount of hemoglobin inside a single red blood cell. The normal range is 27 to 34 pg (picograms), and mine was 26.2 pg. The second lab result that was out of range was RDW, which is Red cell Distribution Width. It is a calculation of the variation in the size of red blood cells. The normal range is 10 to 15%, and mine was 15.5%. A low MCH and a high RDW can both be caused by iron deficiency anemia. Ok, that's interesting. Let's see what they are next year.

I continued to give blood in 2015, with donations in February and March. I was not watching my hemoglobin closely until I tried to donate in June of 2015. My hemoglobin at that time was 11.8, which is below the minimum allowable level of 12.0. Ok, that's really interesting. Now you have my attention. They said I could try again in a week, but I decided to wait a month. My hemoglobin was high enough to donate in July (12.6) and September (12.5), but not high enough in November (11.4) or December (11.4).

Looking back at my donation attempts in 2015, it does seem odd that I would continue trying to give blood with my hemoglobin levels so low. In retrospect I think there were two reasons for that. First, I like data. (See engineer comment above.) Most biomarkers will fluctuate between readings, and it is the trend that really matters. So I realized more data points would make the trend, if there was one, more visible. Second, I do not think I was fully aware that 13.5 was the lower limit of the normal range during this time, at least not initially. If 12.0 is the cutoff for blood donations, that was good enough for me. I knew from dealing with Mom's anemia that 10.0 was an important threshold.

Now we enter 2016. The place where I donate blood gives the donor three options for donating. They are:

  • Whole blood. This is the simplest and quickest option, and it is what most people are familiar with. The donor fills up a bag with blood, and then they are done.
  • Double red blood cells. This option takes a little longer than donating whole blood because the donor is connected to a machine that draws out some blood, spins it in a centrifuge to separate the red blood cells from other components, and then pumps those other components back into the donor. That draw and return process is repeated several times until enough red blood cells are collected. The blood collection agencies like to receive this type of donation because they get twice as many red blood cells per donation (hence the name) and there is less processing for them to do after receiving the donation.
  • Platelets. This option takes a little longer than double reds. It is similar to the double red procedure in that the donor is connected to a machine and the blood components are separated, but instead of collecting red blood cells the machine collects platelets and returns the other blood components, including red blood cells, to the donor.

Before 2016 I had only donated whole blood or double red blood cells. I decided toward the end of 2015 to try to give platelets instead, due to my low hemoglobin. I was finally able to donate platelets in January of 2016, about two weeks before I had a blood draw for my upcoming physical exam in February. My hemoglobin at the time of the blood donation was 12.7.

That brings us up to January of 2016, just before my annual physical. I gathered all my hemoglobin readings from the blood donation center, and my lab results from the last four years, and created the chart I showed at the top of the post, which I will show again here, just because.

Hemoglobin chart

As you can see in the chart, there was a slight dip in my hemoglobin readings that bottomed out early in 2014, but after going back up close to almost 16.0, the steady decline started around the middle of 2014. It may or may not be leveling off around the 12.0 mark right now. So I printed this chart and the associated data to show my doctor.

I explained to Doctor S. what was going on with the blood donations, and that my most recent donation was platelets, with my last whole blood donation occurring in September. He asked if I have had a colonoscopy recently and I told him I have one scheduled in two weeks as a three-year followup. He suggested I get an endoscopy done at the same time since I'll be under anesthesia anyway, so they can also check for sources of bleeding in my stomach, such as ulcers.

He said it wasn't just my hemoglobin that was low, but there was another reading that has to do with the size of the red blood cells, and it showed they were smaller than normal. The way we left it at the end of that appointment is that he would see me in a year, pending the results of the colonoscopy and endoscopy. Naturally when I got home I looked at all my lab results and did a little research on the ones that were out of range. I found this link at Lab Tests Online, which had all the info I needed on one page: In a typical CBC (Complete Blood Count) there is a group of seven biomarkers that deal specifically with the red blood cells. Six of those seven were out of range at my 2016 physical. The complete results are below. For each one I give my lab results followed by the normal range in parenthesis. (Note: The normal range given here is from my doctor's office. Other clinics and web sites may publish different "normal" ranges, but they will all be relatively close.)

  • RBC 5.04 M/uL (4.2 - 5.8)
  • Hemoglobin 12.0 g/dL (13.5 - 18.0)
  • Hematocrit 38.2% (40.0 - 54.0)
  • MCV 75.8 fL (80.0 - 102.0)
  • MCH 23.8 pg (27.0 - 34.0)
  • MCHC 31.4 g/dL (32.0 - 36.0)
  • RDW 18.4% (10.0 - 15.0)

I decided not to give a description of each of those biomarkers here since they are available at various resources online such as the Lab Tests Online link I gave above, but here is my attempt at a summary of what all those numbers mean: I have plenty of red blood cells (RBC), although the volume of my red blood cells as a percentage of the total volume of my blood (hematocrit) is a little low, and the amount of oxygen carried in my red blood cells (hemoglobin) is a little low. The average size of my red blood cells (MCV) is low, as is the average amount (MCH) and concentration (MCHC) of hemoglobin inside my red blood cells. And finally, the variation in size of my red blood cells (RDW) is greater than normal. Iron-deficiency anemia can cause each one of those to be out of range in the direction mine are out of range.
It sure sounds like there is a lot wrong with me, doesn't it? I'm glad I feel perfectly fine with no apparent loss of energy. No sources of bleeding were found during my endoscopy and colonoscopy. Pending some biopsy results, the gastroenterologist recommended some more blood work and then possibly some more fun tests to look for abnormalities in the GI tract. (I might get to enjoy my first barium shake. Yummy!) So the big question, of course, is this:

Is this anemia my first symptom of fibrinogen amyloidosis?

Well, I don't know. I honestly think that question will only be answered in retrospect some months or years after today. The journal articles often mention anemia being present in patients with fibrinogen amyloidosis, but is the anemia a result of the reduced kidney function? Mom's anemia started about two years after her reduced kidney function was initially discovered, so that leads me to believe her anemia was due to the kidney disease and not a direct result of the fibrinogen amyloidosis. Another AFib patient I asked also had kidney problems before anemia. But, given so few patients and so many other factors involved, this could very will be my first symptom. I suppose we will see how things develop. It is easy to blame amyloidosis for any systemic problem, but we have to remember that people without amyloidosis develop anemia all the time. I do want the doctors to continue looking for the cause of the anemia, and I have already started trying to increase the iron in my diet. Hopefully we can get it under control without iron supplements. I suppose I should stop donating blood for a while, too. Depending on how things go with any upcoming tests, I hope to have an update this summer if not sooner.

=====Monthly Blog Status Update=====

As of January 31, 2016:

Total posts: 163 (1 in December)

Total pageviews: 36,800 (~1900 in January)

Email subscribers: 14 (unchanged)

Total number of countries that have viewed the blog: 109

One new country viewed the blog in January: