Real causes of fatigue in thalassemia (minor)

Hi,

It's been a while since my last visit here. Yet I am still looking for answers.

So, we may safely assume that thalassemia sufferers are fatigued due to thalassemia.
But what would be the cause of that fatigue?

By finding what the causes are, we could convince doctors, researchers and other people
once and for all that this fatigue is real.

Of course in case of thalassemia major and intermedia the situation is a bit different - there is
additonal iron overload, ROS production etc. These mechanisms do not apply to thalassemia
minor.

As far as I can figure out:
1. Vitamin depletion.
Because of continuous production of erythrocytes different vitamins get used up faster than in "normal" people. Consecutive deficiency causes fatigue as different parts of body do not work
as they should and get fatiqued.
Vitamin deficiency can be easily alleviated by taking supplements (especially vitamins B complex)

2. Underoxygenation of tissues.
With unsufficient oxygen supply tissues do not have energy and experience different other problems, for example acidification.
But in case of sufficient hemoglobin (mine is 15,3 g/dl) underoxygenation should not be a problem, or is it?

Obvious solution to this problem is bringing hemoglobin to normal level (which may not be easy), taking antioxidants (they stop erythrocyte breakdown so they help increase hemoglobin) and taking vitamin E which makes blood thinner and erytrhocytes more flexible allowing better penetration of tissues.
Acidification may be fought by eating fruit or taking baking soda/sodium citrate.

3. Provoking inflammation/releasing different substances signalling brain that fatigue should be felt.
It is feasible that after erythrocytes break down there are certain substances released that cause inflammation (cytokines). Also the intracellular machinery may be somehow detected and this signals the brain to stop activity by inducing fatigue (strain -> broken cells -> necessity to stop the strain).
For example muscle cells release additionally endorphines, which cause this pleasant feeling of relaxation but also make you tired and a little dizzy.

Anyone has any idea of specific substance that can be released by erythrocytes breaking down?

4. Other disorders caused by thalassemia minor like allergies.
Well, as a matter of fact I think thalassemia's involvement in causing other disorders is highly overrated but I mention it for the sake of the accuracy (I read such a statement in one of the threads). However my personal opinion is that simply all people get sicker due to pollution etc.

5. Bone pain.
Bone pain caused by bone marrow overproduction.

6. Heme/hemoglobin conundrum...
The first four items are kind of well recognized, this one is purely speculative.

This is the kind of question that can be answered probably only by a doctor/geneticist. If you are one or have a contact with one, you might want to pursue this question.

So I was wondering...

In case of beta-thalassemia (or alpha-thalassemia) one of hemoglobin chains is damaged.
Is it possible that this hemoglobin chain is used in different locations within the body?
Damaged hemoglobin in different locations would lead to impaired function and that would lead to fatigue (and other problems).

Possible different locations of hemoglobin:
- myoglobin in muscles
- complex III in electron transport chain
- complex IV (cytochrome c oxidase) in electron transport chain
- cytochrome c in electron transport chain

The question is if any parts of these compounds are expressed by the same genes as a particular hemoglobin? If so, we may have the answer.

This all gets even more complicated because of heme which is encoded by a different gene.
If it is the heme that is a common part of the above compounds, one would rather have porphyria and not thalassemia.

All in all this is all quite complicated (and I am not describing this correctly, I know) and a person is needed that knows exactly which part of the given compound is coded by a particular gene.

Why this kind of idea?
I have beta-thalassemia minor but I also have (metabolic) myopathy.
This means erythrocytes break down but also muscle cells break down. This is weird - it is much more likely that these two are interconnected somehow than they are not. So it is likely that the cause is the same for both of these disorders. So I am looking for this connection but I can't find any.

This kind of connection in general might cause fatigue.

**
Another question is: what is the most important cause of the above.
Another question is: what fatigue itself really is - there are many theories about that and how this connects with thalassemia.


If you have any ideas or comments, please reply.

Regards,
Bigg

I read an article about COPD - and am wondering if chronic anemia and long term oxygen deprivation can cause COPD like fatigue symptoms.

And if so, can pulmonary rehab help where one takes oxygen and exercises to rebuild muscle and stamina?

I am always fatigued and have extremely less muscle strength. When I push my limits, I get so severely fatigued that I'm forced to rest and i recover in few days. Anti inflammatory pills help my fatigue when I am actually taking them for migraines.

The chronic fatigue over many years, allows me to do less and lesser work, probably that further reduces stamina and muscle too. At the times I'm tired i struggle to breathe too, which may have affected my lung capacity. So naturally i feel tired faster and feel i'm worse with age.

You might want to look into sub clinical B12 deficiency and Chronic fatigue syndrom.  Many thal minors have bad B12 levels due to various reasons.

Yes,
I had vit. B12 deficiency. It was normal, clinical deficiency with lab test results below normal.
I had vit. B6 deficiency. It was normal, clinical deficiency with carpal tunnel syndrome in all joints and tendonitis.
I had vit. D deficiency. It was normal, clinical deficiency with lab test results below normal, actually below detection level, so the deficiency was most severe.

The symptoms of all of these were terrible, many times I developed strange symptoms that simply made me think that it's time to die. Tiredness, paresthesia, inflammation, dryness of musous membranes (dry to the blood), neverending cold, etc.

Now all of these deficiencies are gone, supplementation in place. I take full multivitamin, omega-3, magnesium, alpha-lipoic acid (btw. this one is good as a remedy for item 2, it causes vasodilation, so the blood flow should be better), carnitine, and a few other supplements.

And quite ridiculous, none of these deficiencies was diagnosed by a doctor, none of the supplements was recommended by a doctor.
This all probably means that blood and muscle breakdown caused these deficiencies. There was a lot of demand for the vitamins...

Each of the supplements helped me considerably, enabling me to function somehow.
Unfortunately this is still not exactly normal functioning and as such it justifies looking for the gist of the matter over and over again. Actually it got me quite bored and impatient. But what else can I do...

This "common hemoglobin gene affecting both blood and muscles" theory would explain both disorders.
Of course there may be any other gene affected... like vitamin transporter etc.
Something that would affect blood and muscles.
There was a theory that it might be g6pdh deficiency - lab tests confirmed that's not it.
So I'm still looking...

First of all, it is impossible to determine the exact mechanism of how thalassemia causes fatigue in the human body. There are just so much that we do not understand, and it will differ from various individuals as well. The only thing we can do is take some supplements and implement lifestyle changes in terms of the foods we eat and exercise properly to accommodate our condition.

I too have beta thalassemia minor like you, and have researched a bit on how to deal with it. Looking at the bright side, you have to realize that our thalassemic condition was actually meant to be a defense mechanism against malaria. Normally, people with beta thalassemia minor don't experience symptoms. That was the case with me as a child, I was perfectly healthy and active, but as I grew older bad nutrition and poor exercise habits caused some symptoms like fatigue to manifest.

I have compiled some supplement advice from Andy posted in the supplement section: http://i.imgur.com/N4ICU.png
There are 2 promising drug trials currently in development, the HQK-1001 and ACE 536 for beta thalassemia.

The fatigue from the slight anemia was significantly reduced after I took supplements and followed a paleo diet. It is important not to consume processed foods or wholegrains/milk/rice/beans that contains chemicals like Leptin and Gluten that causes gut irritation. When your stomach cannot digest and absorb nutrients properly, you'll feel fatigued more easily.
http://www.fourhourworkweek.com/blog/2010/09/19/paleo-diet-solution/

You can also incorporate more spicy foods that contain curcumin in your diet, as research shows that it improves the oxidative stress in beta-thalassemic individuals.
http://www.ncbi.nlm.nih.gov/pubmed/19900435
Then there's the standard drinking of water daily, as that will help cleanse your system and stimulate blood cell turnover rates. Green tea will also help as a powerful anti-oxidant.
Look up a list of super foods like blueberries that are powerful anti-oxidants and incorporate them into your diet.

Vitamin D levels are also very important. http://jackkruse.com/the-sunshine-of-your-life/
I checked my vitamin D levels and had 27.3, and the optimal levels are around 50. So I've been taking liquid vitamin D supplements of at least 5000IU every day, and will be rechecking my levels soon.

As for exercise, since our gene defects affects the production of beta globin proteins which results in excessive destruction of red blood cells, we need to reproduce them more rapidly. The process is called Erythropoiesis, which is regulated by the hormone erythropoietin. About 2.4 million new erythrocytes are produced per second for a normal person, the number is probably higher for us. There are some supplements that could help boost erythropoietin, click on this link: http://i.imgur.com/VZJrc.png

Testosterone is known to boost erythropoiesis and hemoglobin production as well. http://www.ncbi.nlm.nih.gov/pubmed/18160461 So it makes sense to exercise your entire body during each workout to elicit a maximal hormonal/testosterone response. http://www.fourhourworkweek.com/blog/2007/04/29/from-geek-to-freak-how-i-gained-34-lbs-of-muscle-in-4-weeks/

Please note that I am not an expert, these are just my personal experiences. Hope this helps!

Did you figure out the cause for your B12 deficiency?  Did you test methylmalonic acid(MMA), homocysteine and gastrin?  Did you test for genetic methylation issues related with MTHFR? 

What specific products did you use for your B12 deficiency?

Check this forum for some other ideas related to chronic fatigue syndrom:

http://forums.phoenixrising.me/forumdisplay.php?49-Detox-Methylation-B12-Glutathione-Chelation-...

Addition to item 2: underoxygenation may also be caused by higher (and in some cases lower, but lower seems to help in some cases) affinity of hemoglobin for oxygen. High affinity will cause hemoglobin not to release oxygen where it is necessary. I know this is the case for some specific variants of hemoglobins, but I don't know if this is true in general for beta thalassemia. Is the most of thalassemias characterised by this high affinity or just the opposite? That is a question.

***
I just got today the result of vit. D test.
My 4th test of this vitamin in 4 years. The previous result was 27 (almost in normal range).
The current result is 22.7 so this means dicrease of concentration. Bummer.
I thought that spending almost half a year in the sun and taking vit. D, but not
too high doses, would be sufficient. The problem is also that I get mild hypercalcemia
when the doses are higher though still not that high (like 2000-3000 iu).
I was wrong - this is not sufficient.
So we could end the discussion with this - too low level may be the sole cause of my
problems (although I doubt it). And I should supplement and wait for the results.

***
But I'd like to continue the discussion. This may lead to finding out the cause for me...
and for others.
Right now I don't think it is not even worth it to do additional tests.
A few years ago I've been ordering a lot of tests. These did not bring any added value
for me. This was because there was no good interpretation and no matching tests
to symptoms.
For example I did blood tests and I pointed out my microcytosis many time during visit
at GP office.
I wanted to be referred to hematologist. There was no reaction to this. Finally I went to
hematologist and paid for the tests from my own pocket.
Same applied to vitamin D and vitamin B12. And practically all other things/tests/diagnoses.
Doctors may take credit for maybe 1 in 10 of diagnoses.

> First of all, it is impossible to determine the exact mechanism of how thalassemia causes fatigue in the human body.
But naming the causes may help find one particular cause and help order particular test. This will be probably a group of causes.

***
> I have compiled some supplement advice from Andy
All of these supplements are taken, except of resveratrol. I can't see any benefits of it for me. The problem with resveratrol is that it probably has moderate long term effect but only after you take
other supplements, especially antioxidants. If you do not follow the supplementation recommendations to the letter, it's no use taking resveratrol. And that was the case with me, so
I kind of don't exactly know if it is effective for me. But beside that I see a few important problems:
resveratrol is especially important for thal majors and you can spend money a lot better than on
resveratrol. Many brands of resveratrol seem to be ineffective due to the problems of formulation and absorption.

> You can also incorporate more spicy foods that contain curcumin
I also tried curcumin. There are also a few problems with it: no short-term action and no clear benefit for thal minors. On the plus side, it's quite cheap. It would be the simplest thing in the world
to take it with food not as an additional supplement... but unfortunately in Europe it is not that common. I practically don't know of any food containing curcumin.

These are my doubts, feel free to correct me if I am wrong.

Right now I am supplementing antioxidants:
- normal multivitamin, so vitamin C etc. although in quite small doses
- natural vitamin E in high doses
- CoQ10 in high doses
- L-carnitine in high doses
- green tea
- grape seed extract
- alpha lipoic acid
- arginine

I think I've got it pretty well covered right now. But I must admit that it is so well covered for about a month now, and I can see the positive results. It is ridiculous that I tried many of these supplements separately (or rather in groups, I wanted to try them out) and only all of them work well.

BTW. I also tried Pycnogenol. I haven't come across Pycnogenol at this forum. Boy, this stuff is strong! I could literally feel it's action in my muscles and in my veins. Unfortunately after the second day of using the side effects started to be severe: my BP dropped to the level where I was falling asleep while standing. It is so strong that it took a whole week to "regain conciousness". I was inspired to take it by the fact that it is believed that it's not resveratrol but polyphenols are responsible for the benefits of wine and the French paradox. Pycnogenol contains these polyphenols. Of course it did not work for me, so I started taking grape seed extract - these are also polyphenols.
If anyone would like to try pycnogenol, it is possible to buy generic version which is usually called "pine bark extract". Well, all in all, it has not very good aftertaste and the awareness that you have to ingest bark is also troublesome...

> Testosterone is known to boost erythropoiesis and hemoglobin production as well
I would say that I take all of the mentioned supplements boosting testosterone.
But I must say that the ultimate (yet safe) testosterone booster is a combination of HMB (β-Hydroxy β-methylbutyric acid), L-arginine and L-ornithine. I take this combination on and off.
It helps especially with muscles.

> Did you figure out the cause for your B12 deficiency?
I guess it was the same as for the other vitamins. Too high demand and too low supply (caused probably by poor absorption).

> Did you test methylmalonic acid(MMA), homocysteine and gastrin?
Homocysteine not tested although the doctor wanted to order it. Funny thing considering that they never ever want to order anything. However I said it'd be better to test it after bringing vit. B12 to normal level, otherwise the result would be above normal range because of vit. b12 def anyway, so what was the point? But after bringing vit. b12 to normal level nobody cared about testing homocysteine. Is it worth it to do it now, from my own pocket?
The most important thing is that the B12 level is quite high - 450 (normal range: 200 - 900) and I took shots and take it sublingually so I don't care about intrisic factor (I assume you meant intrisic factor not gastrin).
Regarding methylmalonic acid - it was actually tested when my urine was tested for all organic acids produced by muscles. It was within normal range... And it was interesting twist of action - from vitamin b12 to muscles... very interesting.

I just got today the result of vit. D test.
My 4th test of this vitamin in 4 years. The previous result was 27 (almost in normal range).
The current result is 22.7 so this means dicrease of concentration. Bummer.
I thought that spending almost half a year in the sun and taking vit. D, but not
too high doses, would be sufficient. The problem is also that I get mild hypercalcemia
when the doses are higher though still not that high (like 2000-3000 iu).
I was wrong - this is not sufficient.
So we could end the discussion with this - too low level may be the sole cause of my
problems (although I doubt it). And I should supplement and wait for the results.
-----

It seems you already know these are very low results. You should consider anything below 50 as a low value.  The levels you are taking are very low and I am not surprised you are not making much progress.  In order to address the hypercalcemia you should be taking vit K2 MK4, so that the newly absorbed calcium goes to the right places.  It is a good idea to take Magnesium along with vitamin D and test you Ca and Mg levels along with vit D.


> Did you test methylmalonic acid(MMA), homocysteine and gastrin?
Homocysteine not tested although the doctor wanted to order it. Funny thing considering that they never ever want to order anything. However I said it'd be better to test it after bringing vit. B12 to normal level, otherwise the result would be above normal range because of vit. b12 def anyway, so what was the point? But after bringing vit. b12 to normal level nobody cared about testing homocysteine. Is it worth it to do it now, from my own pocket?
The most important thing is that the B12 level is quite high - 450 (normal range: 200 - 900) and I took shots and take it sublingually so I don't care about intrisic factor (I assume you meant intrisic factor not gastrin).
Regarding methylmalonic acid - it was actually tested when my urine was tested for all organic acids produced by muscles. It was within normal range... And it was interesting twist of action - from vitamin b12 to muscles... very interesting.

------

Your B12 levels are still low.  Results below 550 are considered deficient in Japan and the lab ranges in Europe and the US are extremely low and inaccurate.  Check the forum i linked to for the best supplement brands.  Certain sub-lingual brands are the best for this condition.  Gastrin is tested to estimate the HCL levels in your gut which are associated with absorption of vitamins (not only vitamin B12), so you might need HCL supplementation and Enzymes.  High homocysteine levels are related to low B12 or low Folic acid(B9).  MMA is specifically related to low B12.  You might have issues with your methylation cycle as a thal minor.  Have you tested RBC folate?


You still need to address better your B12 and vit D levels as well as rule out Folate deficiency before you continue in your investigations.

You still need to address better your B12 and vit D levels as well as rule out Folate deficiency before you continue in your investigations.

Yes, this sounds like a plan. But first the supplementation with vit. B12 and D and only after that some tests...

This discussion is fascinating and tells me that patients are taking their condition much more seriously than the medical industry that tends to dismiss thal minors without any thought.

I want to address one specific problem in thalassemia that is finally being given its due importance with thal majors but still ignored in thal minor. Bigg has touched on this with his discussion about erythrocytes.
http://www.thalassemia.com/thal_intro_2.html

Beta thalassemia results in an excess of alpha globins, which leads to the formation of alpha globin tetramers (a4) that accumulate in the erythroblast (immature red blood cell). These aggregates are very insoluble and precipitation interferes with erythropoiesis, cell maturation and cell membrane function, leading to ineffective erythropoiesis and anemia.

Even though this quote is in the context of beta thal major, the same thing happens in thal minor, although to a lesser extent. This is a vicious cycle that feeds itself and adds to the destruction of red blood cells by the creation of more red cells. Efforts to improve the quality of red blood cells and reduce ineffective erythropoiesis seem to be the best approach. The "precipitation" produced also makes me wonder if Bigg is onto something when he suggests that this may be a contributor to other physical problems like the breakdown of muscle cells.

There are many excellent suggestions in this thread regarding supplements, and the use of natural herbs and spices that have strong medicinal properties does help those who develop a good program for themselves, as we see in the posts in this thread. For those considering this approach, please be patient and think long term. We are talking about natural supplements and foods, not drugs, and it takes time to show results, but they do appear in the long run, often in very subtle ways. I recently started using wheatgrass extract after a long break, and once again I am convinced that wheatgrass does have amazing properties. One thing I noted was my telling myself much less often when I wake up in the morning, "I'm so tired. " This was a subtle thing that I noticed and is typical of what is seen after re-starting a discontinued supplement that seems to be having no effect. You don't see any dramatic immediate effects from natural methods but the effects are real, so think long term. The goal of optimizing the production of red blood cells will pay off in the long term. It will not eliminate all of the problems associated with thal minor but it will help.

I do not believe that a significant deficiency of vitamin D will respond to low doses of D. In my own case, it took a year at 5000 IU daily to bring my level from 19 to over 30. My level of 19 was after two years of using 2000 IU daily. Periodic testing is necessary to assess your progress, but I strongly recommend doses higher than 2000 IU daily. My doctor recommends I continue to take 5000 IU once weekly even during the summer time when I do get a lot of sun. The difference in my life is amazing. I just wish I could get more D from sunshine. My long time winter depression has vanished and I no longer feel as though I am holding my breath for months on end. My immune system is also improved and I recover quickly when I do get sick. After many years of alopecia, I even have some stubble growing and have to shave occasionally. Even my nails grow faster now. I am wondering if my health would have been much different had I remained in Florida and continued to work outdoors, as all my issues began after I was no longer exposed to the sun for 6 to 8 hours daily.

This discussion is fascinating and tells me that patients are taking their condition much more seriously than the medical industry that tends to dismiss thal minors without any thought.

I want to address one specific problem in thalassemia that is finally being given its due importance with thal majors but still ignored in thal minor. Bigg has touched on this with his discussion about erythrocytes.
http://www.thalassemia.com/thal_intro_2.html

Quote

Beta thalassemia results in an excess of alpha globins, which leads to the formation of alpha globin tetramers (a4) that accumulate in the erythroblast (immature red blood cell). These aggregates are very insoluble and precipitation interferes with erythropoiesis, cell maturation and cell membrane function, leading to ineffective erythropoiesis and anemia.

Even though this quote is in the context of beta thal major, the same thing happens in thal minor, although to a lesser extent. This is a vicious cycle that feeds itself and adds to the destruction of red blood cells by the creation of more red cells. Efforts to improve the quality of red blood cells and reduce ineffective erythropoiesis seem to be the best approach. The "precipitation" produced also makes me wonder if Bigg is onto something when he suggests that this may be a contributor to other physical problems like the breakdown of muscle cells.

Thank you so much for your insights Andy. After reading that article, I was wondering if there exists some natural food that can help detox the excess of alpha globins.
Could beets be such a food? The "treatment" section on the wiki for thalassemia states the following:

The antioxidant indicaxanthin, found in beets, in a spectrophotometric study showed that indicaxanthin can reduce perferryl-Hb generated in solution from met-Hb and hydrogen peroxide, more effectively than either Trolox or Vitamin C. Collectively, results demonstrate that indicaxanthin can be incorporated into the redox machinery of β-thalassemic RBC and defend the cell from oxidation, possibly interfering with perferryl-Hb, a reactive intermediate in the hydroperoxide-dependent Hb degradation.

In addition, according to the WHFoods website for beets: http://www.whfoods.com/genpage.php?tname=foodspice&dbid=49

The betalin pigments present in beets have repeatedly been shown to support activity in our body's Phase 2 detoxification process. Phase 2 is the metabolic step that our cells use to hook activated, unwanted toxic substances up with small nutrient groups. This "hook up" process effectively neutralizes the toxins and makes them sufficiently water-soluble for excretion in the urine. One critical "hook up" process during Phase 2 involves an enzyme family called the glutathione-S-transferase family (GSTs). GSTs hook toxins up with glutathione for neutralization and excretion from the body. The betalains found in beet have been shown to trigger GST activity, and to aid in the elimination of toxins that require glutathione for excretion.

Since betalin pigments in beets can convert toxins to be sufficiently water soluble, it is possible that it can convert excess alpha globin aggregates that are normally insoluble so that it can be flushed out of our systems? This would help prevent them from interfering with erythropoiesis.

This was posted in another thread but has relevance to this discussion.

DAMHA    Beet juice & green tea
From my humble experience as a one who has a severe form of B-Thal minor ( Hb 10.5-11.5), I would like to share with you that I found  a really great benefit on energy level with drinking GREEN TEA and BEET JUICE. They really improve fatigue and exhaustion and improve mental power (not only as anti-oxidants but beet juice is well known to increase brain blood flow.

I believe Umair has also previously posted about beets. I would like to hear from more people about any experience using beets in thals.

When my thal was not yet diagnosed, the standard anemia advice was iron supplements or beets.  My hemoglobin is always below 10, sometimes as low as 8.3.

My B12 and D are above normal, that doesn't seem to help my fatigue.

When i'm tired, i'm also light headed. Has anyone tried medicines that can help blood circulation to the brain? It would be good if beets can help the same.

I have some postural issues too, so i'm more tired on my feet. And then my face gets really pale.  Cinnarizine helps for a few hours, seems to reduce the 'fatigue'. Even anti inflammatory pills help. I do agree that its possible inflammation makers are released, and cause fatigue so we are forced to rest. Possibly to decrease the rate of rbc breakdown and increase erythropoiesis.

About erythropoeisis, if one already has enough RBC's, does it make sense to increase it further? Taking folic acid keeps my RBC count in the upper end.

I have always felt that the fatigue and extra exertion needed to function properly, also reduces hemoglobin. Taking more bed-rest definitely reduces fatigue. the warmth feeling reduces too, which makes me feel it slows down the rate of rbc destruction.  Has anyone tried a lot of bed rest to increase hemoglobin faster?

I plan to try this myself, as hemoglobin is down to 9. Will try the beets as well.

Even if  cant clearly understand what fatigues me, I keep researching to see what helps me.

I tend to sleep alot. I even fall asleep at the computer quite often. I was receiving iron infusion treatments, but they were never absorbed very well, even though I went for them two to three times a week. Then I asked the doctor if I could take multivitamin and iron tablets. She said to give it a try. My hemoglobin jumped higher than it ever had during the infusion treatments and even the percentage of iron absorbed increased. Lately though, that has changed and even though my hemoglobin is high (a little more than 14.2) the percentage of iron absorbed is even below the low they show on the blood test results. I have been using my parents' cast iron cookware and it seems to help alot. Can anyone suggest what I might do to get back on track with the absorption again? Thanks!

Try taking a vitamin C supplement of 500-1000 mg along with any iron supplement and any iron rich foods. It will aid in iron absorption.