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Anemia

Anemia of chronic disease, also referred to as anemia of inflammatory response, is a common condition seen in chronic illness.1) Anemia is not due to iron deficiency, nor will it be helped by iron supplements. In fact, iron supplements are counterproductive because iron is “crucial” to the survival and multiplication of pathogens.2)

Standard measures of iron status, such as ferritin, total iron-binding capacity, and serum iron are directly affected by chronic disease. In contrast, soluble transferrin receptor (sTfR) is elevated in iron deficiency but is not appreciably affected by chronic disease.

An adaptive response to infection

Excessive and misplaced iron promotes an array of neurodegenerative and endocrine diseases as well as cardiomyopathy, arthropathy, neoplasia and infection. Vertebrates maintain an iron withholding defense system designed to prevent accumulation of redox-active (free) iron in sensitive sites and to sequester the metal in innocuous packages.

Eugene D. Weinberg, “Iron Withholding: A Defense Against Disease”3)

The low levels of blood cells characteristic of anemia of chronic disease (ACD) are relatively common among autoimmune conditions4) and obesity.5) A related hallmark of ACD is increased uptake and retention of iron within cells.6) For many physicians, ACD should be treated as a cause of illness, but the condition serves to protect the host against further infection including those that may drive autoimmuneA condition or disease thought to arise from an overactive immune response of the body against substances and tissues normally present in the body processes. In their New England Journal of Medicine review, Weiss and Goodnough write that despite treatment guidelines, “anemia of chronic disease remains underrecognized and undertreated.” Anemia should be actively managed, they put forth, because the condition “has been associated with a relatively poor prognosis” and is associated with suboptimal oxygen delivery.7)

However, Zarychanski and Houston state ACD is fundamentally an adaptive physiologic response which benefits the patient during times of infection8) with Baker and Ghio offering a similar argument.9) As a nutrient that is essential for the function of many microbes, increased iron availability promotes microbial growth.10) For example, Mycobacteria synthesize molecules that have several times higher affinity for iron than their host counterparts, they also synthesize molecules for efficient storage of excess iron.11) Further, moderation of iron inside a host is a threat to mycobacterial persistence.

Further, the ability of a particular species of bacteria to glean iron from its host is often a good indicator of its virulence. It is logical then that the body sequesters iron in response to an infection: Kemna et al. showed that injecting human volunteers with lipopolysaccharides, a component of the cell walls of gram-negative bacteria, leads to a significant decrease in serum iron.12) In iron-deficient conditions, blood plasma is moderately effective at inhibiting bacterial growth.13) 14) 15)

It might otherwise seem reasonable for a clinician to directly manage ACD using iron supplements or other antianemic therapies: fatigue and shortness of breath can be very unpleasant. However, administering this type of short-time palliation may lead to poorer outcomes. The possibility that ACD is an adaptive response by the host to microbes raises the specter that artificially resolving anemia subverts the immune response allowing microbes to spread by subverting the immune response and consequently allowing microbial infections to proliferate, thus, making the question of what ultimately causes autoimmune diseases all the more urgent.

Tests

  • serum ferritin – The protein in the blood that stores iron for later use by the body. Serum ferritin is also an acute phase reactant and will rise rapidly in the face of inflammationThe complex biological response of vascular tissues to harmful stimuli such as pathogens or damaged cells. It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue.. May be high in anemia of chronic disease, especially if the liver is involved. Macrophages, a type of phagocyte, are the cells responsible for accreting ferritin. Described further here.
  • serum iron – The amount of iron being carried by transferrin in the blood plasma. On its own, serum iron provides no useful information. Serum iron has a diurnal variation that can be as much as 30% within a single individual. It is sensitive to the day's dietary iron intake and is affected by all the confounding diseases listed above. A low serum iron picked up as an incidental finding has a very low specificity for iron deficiency. Described further here.
  • total iron binding capacity (TIBC) – Shows if there is the “right amount” of iron in the blood. TIBC helps measure the ability of transferrin to carry iron in the blood. TIBC is typically measured along with serum iron to evaluate people suspected of having either iron deficiency or iron overload. The iron concentration divided by TIBC gives the transferrin saturation, which is a more useful indicator of iron status than iron or TIBC alone. The TIBC test measures the amount of iron that the blood would carry if the transferrin were fully saturated. Since transferrin is produced by the liver, the TIBC can be used to monitor liver function and nutrition. Described further here.
  • soluble transferrin receptor (sTfR) – Relatively new test. While standard measures of iron status such as ferritin, total iron-binding capacity, and serum iron are directly affected by chronic disease sTfR is elevated in iron deficiency but is not appreciably affected by chronic disease. A good way to verify anemia of chronic desease because it is not affected by inflammation. Should be considered for anemic patients whose differential diagnosis includes iron deficiency and anemia of inflammatory disease.
  • hemoglobin (HGB) – The iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates. The effect of locking up iron stores is to reduce the ability of the bone marrow to produce red blood cells. These cells require iron for their massive amounts of hemoglobin which allow them to transport oxygen.
  • hematocrit (HCT) – A measure of the number of red blood cells and the size of red blood cells. It gives a percentage of red blood cells found in whole blood. Most automated cell counters measure the hemoglobin directly, but the hematocrit is calculated. Generally, therefore, it is probably more reliable to base clinical decisions on the hemoglobin concentration.
  • erythropoietin (EPO) – Erythropoietin is not a routine test. It is ordered primarily to help differentiate between different types of anemia and to determine whether the amount of erythropoietin being produced is appropriate for the level of anemia present. Low EPO in patients on olmesartanMedication taken regularly by patients on the Marshall Protocol for its ability to activate the Vitamin D Receptor. Also known by the trade name Benicar. might largely be due to better blood flow and oxygenation in kidneys since the olmesartan blocks the angiotensin II receptors. This would have an effect superimposed on anemia of chronic disease which is caused by immunopathologyA temporary increase in disease symptoms experienced by Marshall Protocol patients that results from the release of cytokines and endotoxins as disease-causing bacteria are killed..

Management

Transient decrease in hemoglobin and hematocrit are common in the early phases of the MP. My use of lab tests is to help determine pace of therapy.

Greg Blaney, MD

Male and females patients whose HGB falls to 11 and/or whose HCT falls to 28, should work with their doctors to slow down their immune response. Changes may be evident in as soon as several weeks. It may take several years for anemia blood markers to return to a normal range. Doctors should use their judgement regarding the frequency of testing to monitor anemia.

Other treatments

Iron

As iron supplements are usually well tolerated by patients so many doctors will not bother to definitively diagnose iron deficiency anemia. They will use iron supplements as a therapeutic probeA brief trial of the Marshall Protocol to see if it will generate an immunopathological response. The "gold standard" for testing whether a patient is a good candidate for the MP. and retest HGB and HCT to see it they are effective. Before patients agree to taking an iron supplement, talk with your doctor about further testing to determine if they have anemia of chronic disease.

As explained above, patients should not take iron supplements in an effort to increase hemoglobin and hematocrit. Iron will only help pathogens multiply. Increasing iron in a patient's diet would likewise be counterproductive.

See also Stress hormones promote iron availability.

Blood transfusions

Blood transfusions should not routinely be given, as anemia of patients on the MP is rarely improved by transfusions and carries with it an increased risk of infection from the donated blood. Transfusions may be warranted by, for example, dangerously low hemotocrit and hemoglobin, at the discretion of the treating physician.

Erythropoiesis-stimulating agents

Although they are not without risk and we do not recommend them, erythropoiesis-stimulating agents (Aranesp, Epogen or Procrit) may be necessary if HCT and HGB are extremely low and do not respond quickly to measures to reduce your immune system reaction. ESAs (Procrit and Epogen) do increase red blood cells but they also have serious side effects and we don't know how they might affect the immune system. The decision to treat is based on risk and benefit.

Doctors using these drugs are advised “to maintain the lowest hemoglobin level consistent with avoiding the need for transfusions.” It isn't necessary to maintain a normal HGB and HCT while patients are recovering on the MP.

A randomized controlled trial of critically ill patients showed erythropoiesis-stimulating agents did not reduce overall mortality.16)

Epidemiological studies

In a 10 year follow up study from Chile, infants who already had high levels of hemoglobin proteins in their blood and were fed iron-fortified formula ended up with lower scores on tests of thinking and memory than those given low-iron formula.17)

Patients experiences

My red blood count has risen into the normal range without any kind of iron or vitamin supplemenation.

NorCalJim in phase 3

When I was diagnosed with hypothyroidism (from Hashimoto's thyroiditis) I had iron-deficiency anaemia. Doctor ordered me to take iron supplements for a month before he even gave me any thyroxine. BIG mistake. (Not his fault, but had we only known about the MP…) My iron levels came up, yes, I guess because I was ingesting enough to feed myself and all those iron-hungry bacteria! The awful part was I felt more fatigued than ever before and my arthritic joints hurt more than ever before. I was depressed, in pain and had to give up my work as a massage therapist after 25 years.

Once I started thyroxine my life turned around, as I got most of my energy back and my thinning hair started growing back - but my arthritis was as bad as ever.

Fast forward 1 year - I found the MP and began phase one. Within days of starting mino I began to experience a metallic taste in my mouth. Could that metallic taste be … metal? Can't prove it, but my ferritin levels shot through the roof! You can read my phase 1 posts on my thread: http://www.marshallprotocol.com/forum20/5902-1.html

I reckon all those iron-sequestering CWD monsters were dying and giving up all the iron back into my bloodstream. After a couple of months, my ferritin levels came down to normal again and the metallic taste went away at the same time.

So there you have it.

Claudia, MarshallProtocol.com

Notes and comments

<DiseaseHierarchy>

Anemia of chronic disease equals: -ferritin normal or high -iron low -normal to low soluble transferrin receptor (sTfR) -normal to low total iron-binding capacity (TIBC)

Given iron’s role as a key microbial nutrient, it may be that patients receiving blood plasma have significantly increased mortality as was reported in a randomized controlled trial(9971864) and why an

Exp Mol Med. 2011 Feb 28;43(2):121-8. Iron mediates endothelial cell damage and blood-brain barrier opening in the hippocampus after transient forebrain ischemia in rats. Won SM, Lee JH, Park UJ, Gwag J, Gwag BJ, Lee YB. Source Neuroscience Graduate Program, Brain Disease Research Center, Institute for Medical Science, Department of Pharmacology, Ajou University School of Medicine, Suwon, Korea. Abstract Blood cells are transported into the brain and are thought to participate in neurodegenerative processes following hypoxic ischemic injury. We examined the possibility that transient forebrain ischemia (TFI) causes the blood-brain barrier (BBB) to become permeable to blood cells, possibly via dysfunction and degeneration of endothelial cells in rats. Extravasation of Evans blue and immunoglobulin G (IgG) was observed in the hippocampal CA1-2 areas within 8 h after TFI, and peaked at 48 h. This extravasation was accompanied by loss of tight junction proteins, occludin, and zonula occludens-1, and degeneration of endothelial cells in the CA1-2 areas. Iron overload and mitochondrial free radical production were evident in the microvessel endothelium of the hippocampus before endothelial cell damage occurred. Administration of deferoxamine (DFO), an iron chelator, or Neu2000, an antioxidant, blocked free radical production and endothelial cell degeneration. Our findings suggest that iron overload and iron-mediated free radical production cause loss of tight junction proteins and degeneration of endothelial cells, opening of the BBB after TFI. PMID: 21278483

Nat Rev Immunol. 2011 Apr;11(4):264-74.Platelets and the immune continuum. Semple JW, Italiano JE, Freedman J. Source 1] Toronto Platelet Immunobiology Group, Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, 30 Bond Street, Toronto, Ontario, Canada, M5B 1W8. [2] Departments of Pharmacology, Medicine and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. [3] Canadian Blood Services, Toronto, Ontario, Canada. Abstract Platelets are anucleate cells that are crucial mediators of haemostasis. Most immunologists probably don't think about platelets every day, and may even consider these cells to be 'nuisances' in certain in vitroA technique of performing a given procedure in a controlled environment outside of a living organism - usually a laboratory. studies. However, it is becoming increasingly clear that platelets have inflammatory functions and can influence both innate and adaptive immune responses. Here, we discuss the mechanisms by which platelets contribute to immunity: these small cells are more immunologically savvy than we once thought.

PMID: 21436837

According to the textbook “An Introduction to Human Disease: Pathology and Pathophysiology Correlations” by Leonard V. Crowley,Bone Marrow Suppression, Damage, or Infiltration “Many conditions may depress bone marrow functions. Chronic diseases of all types may impair hematopoiesis and lead to mild or moderate anemia, which is called the anemia of chronic disease. … The most common cause of this type of anemia is chronic infection, but other chronic diseases and some malignant tumors may also be responsible.”

GI bleeding

A simple outpatient two minute check of your stool for blood would rule out your doctor's concerns pertaining to bleeding into the gut.NIH: Fecal occult blood test

Hi Kas, I think you are probably stuck with the anemia until your kidneys heal with the MP because those of us with bad kidneys have at least two factors leading to anemia. Below is something I have posted elsewhere.

Anemia

Several factors may contribute to the anemia observed for MPers with low kidney function. The production of new RBC is promoted by the cytokineAny of various protein molecules secreted by cells of the immune system that serve to regulate the immune system.,or hormone, erythropoetin (EPO). In adults it is synthesised by the renal peritubular cells, regulated by the level of blood oxygenation. The mechanism is a negative feedback whereby an EPO transcription factor HIF-1 (for hypoxia-inducible factor) is inactivated by oxygen. Anemia may begin to develop when around 50% of kidney function is lost.

People who develop low kidney function and anemia on starting the MP would have had significant damage beforehand: but the effect on RBC production could have been masked because anoxia in the tubulointerstitial region would be giving greater stimulus to EPO production (Ref 1). The anoxia derives from the action of angiotensin II to constrict the efferent arterioles with consequent limitation on the blood supply to the tubulointerstitial cells(Ref 1).

With this action blocked by olmesartan, blood flow through dilated arterioles would greatly improve, reducing the anoxia and the stimulus to EPO production. Onset of overt anemia would follow: but ongoing damage to the tubulointerstitial cells would lessen. A recent study reported improved renal oxygenation in humans with kidney disease on treatment with olmesartan: but was then withdrawn (Ref 8).

Another factor lowering RBC levels is anemia of chronic disease (ACD) (Ref 9). ACD can result from immune activation anywhere in the body. Inflammatory cytokinesAny of various protein molecules secreted by cells of the immune system that serve to regulate the immune system. trigger processes to limit iron availability, blunt the action of EPO and inhibit the differentiation and production of erythroid progenitor cells. Thus it will occur as a result of the immune activation associated with the MP.

Lowering olmesartan might improve the RBC levels but at the cost increasing the anoxia and and impeding the healing in the kidneys.

for reference links, see full post by Jigsaw

References

2)
Iron acquisition, assimilation and regulation in mycobacteria.
Banerjee S, Farhana A, Ehtesham NZ, Hasnain SE
Infect Genet Evol11p825-38(2011 Jul)
3)
Iron withholding: a defense against disease.
Weinberg ED, Miklossy J
J Alzheimers Dis13p451-63(2008 May)
5)
Iron deficiency in early childhood in the United States: risk factors and racial/ethnic disparities.
Brotanek JM, Gosz J, Weitzman M, Flores G
Pediatrics120p568-75(2007 Sep)
6) , 7)
Anemia of chronic disease.
Weiss G, Goodnough LT
N Engl J Med352p1011-23(2005 Mar 10)
9)
Iron homoeostasis in rheumatic disease.
Baker JF, Ghio AJ
Rheumatology (Oxford)48p1339-44(2009 Nov)
11)
Iron acquisition, assimilation and regulation in mycobacteria.
Banerjee S, Farhana A, Ehtesham NZ, Hasnain SE
Infect Genet Evol11p825-38(2011 Jul)
12)
Time-course analysis of hepcidin, serum iron, and plasma cytokine levels in humans injected with LPS.
Kemna E, Pickkers P, Nemeth E, van der Hoeven H, Swinkels D
Blood106p1864-6(2005 Sep 1)
14)
Intravenous iron therapy in renal failure: friend and foe?
Afzali B, Goldsmith DJ
J Nephrol17p487-95(2004 Jul-Aug)
15)
The critical role of iron in some clinical infections.
Bullen JJ, Ward CG, Rogers HJ
Eur J Clin Microbiol Infect Dis10p613-7(1991 Aug)
16)
Efficacy and safety of epoetin alfa in critically ill patients.
Corwin HL, Gettinger A, Fabian TC, May A, Pearl RG, Heard S, An R, Bowers PJ, Burton P, Klausner MA, Corwin MJ
N Engl J Med357p965-76(2007 Sep 6)
17)
Iron-Fortified vs Low-Iron Infant Formula: Developmental Outcome at 10 Years.
Lozoff B, Castillo M, Clark KM, Smith JB
Arch Pediatr Adolesc Medp(2011 Nov 7)
home/diseases/anemia.txt · Last modified: 02.05.2017 by sallieq
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