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Causes for non-symptomatic hyperferritinemia in lymphoma patients
Lymphoma Inflammation and Iron Overload Disorders

        By Susan S. Gallant
==============================================================

Table of Contents:
Hyperferritinemia
Ferritin
Defining Lymphoma  Inflammation
Medical Studies in Cancer Inflammation
Diagnostic Phlebotomies
Reducing Iron Stores
Potential Causes for Hyperferrinemia in the non-symptomatic lymphoma patient
What tests help to determine underlying cause of hyperferritinemia?
Conclusion


Hyperferritinemia

Hyperferritinemia or High Ferritin Levels: 
   * "Hyper-," excessive, above, or beyond.
   * "ferritin," an intracellular iron storage protein and transporter for
iron.
   * "-emia," suffix meaning "blood condition."
Many causes provoke elevated serum ferritin levels (Fe), some like
inflammation have no direct relationship with body iron stores.  Ferritin can
be considered a marker for non-Hodgkin's lymphoma (NHL)(1), and around 50% of
NHL patients can have elevated ferritin levels.  

Hyperferrinemia should not be ignored or dismissed.  The appropriate action
to take is to determine the cause of the hyperferritinemia and apply the
correct treatment to correct levels.

There are several lab test that might help distinguish between elevated
ferritin indicating inflammation and elevated ferritin indicating high iron
storage.   A full iron profile should be taken first including Serum Ferritin
(sFt), Serum Iron (Fe), Total Iron Binding Capacity (TIBC), and Transferrin
Saturation (%TS or %Sat).   Another test is called the Glyco-Ft(2) test that
separately measures the glycosylated ferritin measuring iron and the
non-glycosylated form of serum ferritin due to inflammation.  This test, has
been used in research, but it is not commercially available.  A new test
called a "Serum Transferrin Receptor (sTfR)" is now available which is a
helpful tool in distinguishing between inflammation, iron overload, and
anemia of chronic diseases.  Correct diagnosis, however, may not be this
simple.


Ferritin

Ferritin consists of a shell of protein surrounding a cavity in which the
iron can be deposited.(3)  Generally, the level of  ferritin molecules in the
blood is a direct measure of iron storage.  Iron is a required nutrient which
can be harmful in high concentrations.  To prevent excess iron from damaging
cells, it is stored in ferritin. 

Ferritin level (sFt) is clinically used as a parameter to evaluate the iron
storage pool in a whole body since ferritin production is increased or
decreased in response to overall iron stores; 1 ng/mL of serum ferritin
equates to about 8-10 mg of storage iron.   Serum ferritin (sFt) is a test
which not only determines iron in the body, but also inflammation.

Serum ferritin is present in two forms:
     1.  A glycosylated form that results from active secretion by intact
cells.  Glycosylated (secreted) ferritin binds to concanavalin A (Con A)
through the glucose and/or mannose residues of the molecule. 
     2.  A non-glycosylated (non-secreted), tissue type ferritin that is
directly released by damaged malignant cells lacks the glucose of
glycosylated ferritin and does not bind to concanavalin A (Con A). Tumors
secrete ferritin because they need it in the blood to support cell
proliferation. Changes in inflammation produce changes in ferritin levels,
but they do not reflect changes in iron stores.


Defining Lymphoma  Inflammation

"Inflammation" is a normal, protective response of body tissues to irritation
or injury.  Take a wound as an example.  Inflammation signs are redness,
heat, swelling, and pain.  Blood vessels restrict to prevent bleeding, and
then increase to promote healing and new growth.  When healing has occurred,
inflammation "turns off" and the body's clean up crew or defense system comes
to dispose of the accumulated debris by the macrophages.

Cancer inflammatory episodes can produce only moderate increases in ferritin
level, typically an increase of 50 or total reading of serum ferritin (sFt)
not exceeding a 300 ng/mL.(4)  Serum ferritin values greater than 300 ng/mL
in persons with or without inflammation or anemia indicate that the tissues
contain excessive amounts of iron deposits.(5) 

Lymphoma is an inflammatory cancer, and inflammation is necessary to support
lymphoma progression.   Cancer inflammation is similar to wound inflammation
but more complex. Malignant lymphoma tumors can manipulate the body's
inflammation process to promote their own angiogenic growth (blood vessel
formation).  They turn on the inflammation process and then block it from
turning off like it's designed to do when it accomplishes its job such as
wound healing or fighting an infection.  The main point to understand is that
lymphoma inflammation can included angiogenesis leading to disease
progression.  So, try to do something to stop it such as taking an
anti-inflammatory drug like Celebrex or aspirin or by reducing body iron
stores.


Medical Studies in Cancer Inflammation

Although a background in biology and biochemistry are helpful in
understanding complex processes such as disease inflammation, even our
leading researchers today are trying to fully comprehend malignant
inflammations.  One study interpretation found increased levels of serum
ferritin in cancer patients possible of exerting adverse effects on the host
immune response and perhaps an inhibitory effect on production of new blood
cells.(6)   Another study considers it as a common and non-specific response
finding no use in serum ferritin assay for either diagnosis or monitoring of
malignant disease.(7) Yet another study found that serum ferritin was found
normal in NHL of low malignancy and only a few NHL high malignant patients
who showed high concentration of serum ferritin.(8) 

Malignant lymphoma cells can release cytokines causing an "inflammation." 
These cytokines are proteins that communicate with other cells.  They can
hijack the body's defense system which is meant to protect us against viruses
and bacteria and use our immune system to promote tumor growth through
neovascularization and angiogenesis.  These reactions can manifest symptoms
of disease progression such as fevers (in the absence of an infection), night
sweats, malaise, or fatigue.  Such action will generate the expression of
COX-2 which can be treated with aspirin, other nonsteroidal anti-inflammatory
agents such as Celebrex.

Patients with highly malignant tumors frequently present abnormally high
ferritin levels.  This is because tumor cell activity can "falsely elevate"
the serum ferritin measurement to give a high reading by secreting ferritin
from the cancerous tumors.  Ferritin level will return to normal with
clinical remission.(9) 
Some researchers have concluded that part of the serum ferritin in
hematopoetic malignancies is from non-secreted ferritin tissue derived from
tumor cell destruction called "lysis."(10)

Studies have shown that elevated serum ferritin levels due to inflammation in
cancer patients are associated with a poor prognosis, potentially for several
reasons:
     1.  Harmful biological effects of tumor ferritins on WBC functions. (11)
     2.  Prolonged inflammation also hinders the production of red blood
cells by the bone marrow.  Since iron cannot be properly made into hemoglobin
during inflammation, it accumulates unused in the marrow tissue.


Diagnostic Phlebotomies

Diagnostic bleedings called phlebotomies or phlebs are identical to blood
donations. They are basically a method of assuming a diagnosis of iron
overload and proceeding with deiorning phlebs.  A patient ability to
withstand aggressive diagnostic phlebs of up to 500 mL weekly for up to six
weeks without withstanding anemia has been considered evidence of
hemochromatosis, whether hereditary or not. 

Blood donations are associated with a decrease in serum ferritin.  A person
with a normal iron load could not sustain many bleedings without becoming
anemia.  One study showed that normal men purposely consuming a high iron
diet could not compensate for a monthly blood loss rate of 164 +/- 34 mL per
month, and that is only about 1/3 of a single normal blood donation (500 mL)
or four normal donations per year.12)   Another study showed that one unit
per year halved the serum ferritin level in many males. Normal donations are
500 mL and 70 days apart.  Average male donors while depleting their iron
stores can donate 2-3 units of 500 mL per year without an appreciable
incidence of iron deficiency, and woman only about half that amount. 


Reducing Iron Stores

The preferred treatment for reducing iron stores is by therapeutic
phlebotomies.  Patients unable to withstand the bloodletting phlebotomy
treatments are alternately prescribed drug treatment like Desferal
(deferoxamine).

Cancer cells actually have low levels of iron themselves and increase their
transferrin receptors to try and get more iron to support cell growth.  If
the cancer cells succeed in getting their demand for iron met, their
continued growth will demand even larger quantities of iron which will
eventually be diverted from red blood cells leading to anemia of chronic
diseases (ACD).  Cancer tumors cannot get iron when it is in the form of
ferritin, so the body's system of encasing iron in ferritin is actually
protecting it from cancerous growth. 

Reducing body iron stores is an effective means of controlling cancer's
growth and such are the teaching of modern day researcher Eugene D.
Weisenberg, PhD at the University of Indiana.  Weisenberg has recommended
maintaining ferritin at 80 for effective control of cancer.  Iron stores in
the cancer patient, however, need constant monitoring because too much
reduction can lead to anemia of chronic diseases (ACD).  Also, remember that
reducing excess iron can theoretically reduce excessive inflammation, but it
cannot stop it because the inflammatory cytokines are expressed by the cancer
tumors.

Iron stores in the cancer patient should be minimized because:

1.  High iron stores increase cancer growth through cell proliferation.
2.  Low iron stores retard cancer growth and restrict the cancer cells
ability to secrete
      non-glycosylated ferritin thus inhibiting cancer inflammation.
3.  High iron stores support heart disease processes.
4.  High iron stores contribute as a risk factor to liver disease and other
organ damage.
5.  High iron stores support free radical activity.
6.  High iron storage levels are of no health benefit.

However, finding a doctor to prescribe therapeutic phlebotomies for a cancer
patient without iron overload who wishes to reduce iron stores to control
cancer will be a definite challenge for any person with cancer.


Potential Causes for Hyperferrinemia in the non-symptomatic lymphoma patient:

1.  Lymphoma inflammation - moderate increases in ferritin level can be due
to inflammatory episodes, typically an increase of 50 or total reading of
serum ferritin (sFt) not exceeding 300.(13)  Ferritin molecules that appear
in serum during inflammation contain less iron than normal.(14)  Generally,
inflammation is accompanied by a reduction in transferrin saturation (%SAT or
%TS).

2.  Iron Overload Disorders.  There are actually a number of iron overload
disorders, hereditary hemochromatosis (HH) is one of them.  A body with
excess iron is usually inflamed to varying degrees.  As toxic levels or iron
are removed, the inflammation is also reduced.  Much of the high number in
the serum ferritin test reflects inflammation, and when iron is removed, it
"relieves" the body of this "irritant" which is reflected in a sudden drop in
the ferritin level.  Macrophages are the body's clean up crew or defense
system.  An excess of iron can overburden macrophanges so that they can no
longer function normally.  Hepatocellular injury (liver cell injury) can
cause false elevation.  Ferritin can increase if the liver is irritated in
any way - disease, high iron, or infection.  Late diagnosis HH can typically
be 1000 to 1500 serum ferritin (sFt) and higher.  Generally, HH is 
accompanied by an elevation in transferrin saturation (%TS or % SAT).  Iron
loading is associated also with moderate depression of a third variable,
serum transferrin receptor (sTfR).  The ratio of sTfR/sFt, apparently
independent of inflammation, is significantly reduced in persons with high
levels of iron.

3.  Anemia of chronic disease (ACD) - A condition of impaired iron
utilization where functional iron (hemoglobin) is low, but tissue iron (such
as in storage) is normal or high. ACD is seen in chronic malignant disease
conditions.  Symptoms are inflammation, infection, fatigue, and cancer. 
Tests will show low hemoglobin but elevated ferritin.  Transferrin iron
saturation percentage low, total iron binding capacity (TIBC) low,
transferrin low, and the serum transferrin receptor normal.


What tests help to determine underlying cause of hyperferritinemia?

1. Iron Screening:  Serum Iron, TIBC, and %Sat.

2. Genetic testing: Hemochromatosis (HH), iron overload, can be genetically
confirmed approximately 95% of the time.

3. Liver Biopsy:  An expensive and invasive procedure with some health risks.
Generally, this has been replaced by the genetic test.

4. Serum Transferrin Receptor (sTfR):  A relatively new test helpful in
distinguishing between inflammation, iron overload, and anemia of chronic
diseases.  High levels indicate iron deficiency.  Normal levels are found in
anemia of chronic disease.  Low levels indicate iron overload.

5. Liver Function Tests:  High ferritin can be attributable to liver disease.

6. Bone Marrow Biopsy:  Not appropriate for hyperferritinemia alone, but
potentially helpful if performed for another of patient's health condition. 
Prussian Blue iron stains provide a good correlation between iron content in
the marrow and serum ferritin

7. CAT Scans or MRI: Not appropriate for hyperferritinemia alone, but
potentially helpful if performed for another of patient's health condition.

8. Inflammation Markers:
    a.  Erythrocyte Sedimentation Rate (ESR, Sed Rate)
    b.  C-Reactive Protein (CRPC)

9.  Red Cell Ferritin:  (Normal range, 5 - 48 attograms/RBC)  Less than 5
shows iron deficiency.  Over 50 shows iron utilization.  Red cell ferritin is
a residue of erythroblast ferritin.  It indicates iron status uninfluenced by
inflammation, infection, tissue necrosis, or tumors.  It may be more reliable
than serum ferritin as an indicator of iron status in inflammatory diseases.

10.  Diagnostic Phlebotomies:  A series of four to six phlebs weekly at 500
mL as long as HCT>35% so that anemia is avoided.


Conclusion

The more I understand of the inflammatory process, the more I cannot believe
that the medical community has not tried to block inflammation as a simple
method of cancer control long ago. 

So, why isn't ferritin level checked in all cancer patients?   Why when the
lymphoma patient presents a case of hyperferritinemia to their oncologist
would they told to go home and forget about it?  Good questions.  No answers.

You don't believe that could happen?  Wrong.  Read "Terry's Story."  I'll
post that next.  For now I will tell you, I didn't forget it.  I got
treatment for my husband, and he's doing pretty well.



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