Test 3: Disorders of Iron and Heme Metabolism Flashcards
The average adult has total body iron content of _______ mg
____ is found in hemoglobin
____ is found in bone marrow, liver, and spleen
3500-4000 mg
• 2/3
•1/3
Where does the majority of iron come from?
Recycling 
The minimum daily iron requirement for adults is ___ mg
1
Daily iron requirements are affected by what three things? 
- chronic blood loss
• Increase need
• Inadequate intake
Serum Fe levels exhibit both monthly and diurnal (daily) variation.
When should labs be drawn for iron studies?
First thing in the morning and fasting
Iron is ingested in foods as Fe__+ (_________) form. 
3, ferric
Stomach acid reduces Iron to Fe__+ (________) form so it can be absorbed in the gut.
2, ferrous
- gut mucosal cells oxidize back to Fe3+ form, enters the bloodstream, and is transported by transparent for distribution to buy tissues, or for storage in the bone marrow, liver, or spleen
______ atoms of ferric iron can combine to one transferrin molecule.
2
____% of iron carried by transferrin is used for heme synthesis
80
Iron not utilized by erythropoiesis is stored as _________ or _________. 
Ferritin or hemosiderin
____________ is the major form of storage iron. It is water soluble and is easily utilized by the body. Seen only via electron microscope. 
Ferritin
__________ + ___________ = ferritin
Apoferritin, Fe
____________ is not water soluble and is less readily available to the body.
Hemosiderin
This iron form represents Aggregates of iron and can be seen with Prussian blue stain
Can become available in iron deficient patients
Hemosiderin
What stain is used for hemosiderin?
Prussian blue stain for iron
What is included in the standard Fe panel?
-serum Fe
-TIBC
-Serum ferritin
-Percent transferrin saturation
This is a measure of transferrin–bound iron
Serum Fe
(NR=50 - 160 ug/dL)?
*assays has poor sensitivity for IDA, due to the disease’s various stages
Total amount of iron that can be bound by transferrin. It is effectively an indirect measurement of transferrin concentration
- total iron binding capacity (TIBC)
(NR= 250 - 400 ug/dL) 
increased TIBC means the body….
wants more iron! 
TIBC:
Add known amount access iron to patients Sera to saturate all transferrin molecules present then remove excess and…. 
Measure what remains
TIBC does what in IDA? 
???
Transferrin Increases when Fe __________. 
Decreases.
-In order for body to scavenge up any available iron atoms 
Immunoassay which evaluates body iron stores. Despite the fact that ferritin is intracellular its concentration in circulation is usually proportional to the amount of iron in storage
Serum ferritin 
What is the advantage and disadvantage of serum ferritin? 
This is the first lab test to become abnormal when iron stores decrease (Even before RBC morphology changes) 
Ferritin is an acute phase reactant so it’s elevated during any inflammatory response 
What is the normal range for serum ferritin? 
40-400 ng/mL
What might a patient’s ferritin level be with an exacerbation of SLE who also had an IDA? 
Normal
Is functionally measured as the maximum amount of iron that is Bound in plasma or serum
% transferrin saturation
(in other words, “how many transferrin molecules are full”?
How is percent transferrin saturation calculated? 
= serum iron / TIBC x 100%
What is the normal range for % transferrin saturation? 
20-55% saturation
What would percent transferrin be in IDA?
Decreased
What would percent transferrin saturation be in iron overload? 
Increased
How do the Free Erythrocyte Protoporphyrin (FEP) or Zinc  Protoporphyrin (ZPP) tests work?
-when iron is not available to be incorporated into protoporphyrin ring to form heme, access portoporphyrins form
-these excess rings complex with zinc to form zinc protoporphyrin (ZPP)
-The ZPP value correlates inversely with the ferritin level
A The worse the IDA, the _______________ the ZPP level.
Higher
More Protoporphyrin is left over to bind with zinc (due to decreased iron binding)
What is a good test to differentiate IDA from thalassemia? 
Free erythrocyte protoporphyrin (FEP) or Zinc protoporphyrin (ZPP) test *
How is FCP/ZPP test measured? And what is the normal range?
Fluorometrically
< 80 ug/dL
Measurement of transferrin receptors
Soluble transferrin receptor test 
Soluble transferrin receptors are ____________ related to the amount of body iron. 
Inversely
With the lack of intracellular iron, regulatory proteins increase the synthesis of ______________ receptors.
transferrin 
Severe IDA __________ transferrin receptors
Increases
What test can be used to distinguish IDA from anemia of chronic inflammation? 
Soluble transferrin receptor test
- soluble transferrin receptor test levels remain normal in anemia of chronic Inflammation
What is the definition of anemia according to WHO criteria for men and women? 
• Men: Hb < 13.0 g/dL or Hct < 40%
• Women: Hb < 12.0 g/dL or Hct < 36%
What are useful measurements For assessing anemia?
• MCV (mean corpuscular volume): 80-100 f
• RDW (red cell distribution width): increased value indicates
RBCs of differing sizes
• Reticulocytes: indicates the bone marrow’s ability to respond
Worldwide what is the most common type of anemia that affects 2 billion people? 
Iron deficiency anemia (IDA)

What are the three ways IDA can occur?
-State of increased physiologic demand (growth or pregnancy)
-inadequate intake (deficient diet or absorption issues)
-chronic blood loss (Ulcers, menstrual flow, parasites) 
What age does prenatal iron stores run out at?
Three months (3-6 months) 
what are common Symptoms of all severe anemia?
dyspnea and dizziness
IDA can cause the compulsive desire to eat a single food, or more commonly a non-food item. Is the term for this?
Pica
Flattened spooned fingernails
Koilonychiq (symptom of IDA)
 what are the typical RBC morphology change seen in IDA? 
Microcytic and hyperchromic
Moderate Anisocytosis and increased RDW
Pilokocytosis with codocytes, elliptocytes or ovalocytes, and dacrocytes 
And RPI less than two means? 
Bone marrow is not responding effectively
At what IDA stage does the Iron labs come back abnormal?
chem panel abnormal? 
Stage two
Not until stage three
(Very important* Look at IDA stages chart)
How iS IDA treated?
-treat underlying contributing cause
-Give oral iron supplements and treat symptoms as needed
Transfusions only given in life-threatening emergencies 
When treating ADA, retic count should increase within ______ hours reaching maximum in _______ days. 
48 hours, about 10 days
______________ population of RBCs become evident as new “iron normal” RBC‘s increase in numbers, while the old “iron deficient” RBCs die off.
Dimorphic
What is the second most common anemia? 
Anemia of chronic inflammation (Anemia of chronic disease)
-Associated with chronic infections and other states of chronic inflammation
What is the essential feature of anemia of chronic inflammation?
Sideropenia (Iron deficiency) With abundant iron stores
- Not due to bleeding, hemolysis, or bone marrow replacement by cancer or a leukemia
What is the pathophysiology of ACI? 
Appears to be due to the body withholding iron from inflamed cells, pathogenic microbes, and tumor cells, in an attempt to starve them to death
*regulated by hepcidin 
A hormone produced by hepatocytes and regulates body iron levels
-Reduces the amount of iron absorbed from intestines
-influences the ability of macrophages and parasites to retain iron
Hepcidin
When iron levels are high, hepcidin Increases, and ___________ retain iron (and vice versa) 
Macrophages
Hepcidin is also an ____________ reactant, So during Inflammation (Unrelated to iron levels), There is a decrease in iron absorption and macrophages retain iron
Acute-phase 
(Acute-phase reactant) it is an iron binding protein in neutrophilic granules (Importance in phagocytosis). During Inflammation, lactoferrin is released into plasma and scavenges available iron.
Lactoferrin
(RBCs do not have lactoferrin receptors)
Acute phase reactant that also binds iron in plasma.
Ferritin
(RBCs lack ferritin receptors)
In ACI low Iron is not the problem. What is?
Iron availability/release
What is the first test to look at when determining ACI? 
TIBC (It would be decreased, with IDA it would be increased) 
What are the clinical symptoms of ACI
-decrease serum iron and % Transferrin saturation
-Normal to increased ferritin levels
* TIBC decreased
-ZPP increased
-Transparent receptors are normal (decreased in IDA)
- Symptoms of the primary disorder
Morphology lab findings and ACI…
-Mild to moderate norm-, norm- Anemia (Sometimes look micro, hypo)
-no Reticulocytosis 
What is the treatment of ACI?
-treat the underlying condition (RA, TB, etc.)
-Can give EPO, but must also supply iron supplements concurrently (Otherwise could be fatal) 
Decreased ferritin and increased TIBC….
IDA or ACI?
IDA (opposite for ACI) 
Both IDA and ACI can be normal to decreased for MCV and MCHC. But bone marrow iron levels are decreased in which anemia?
IDA
What type of patient population would be most likely at risk for ACI? 
Hospitalized
Lead intoxication and hemachromatosis are both disorders of….
Iron metabolism
Even if MCV is normal you can have microcytic RBCs. How? 
Due to MCV being an average
Sideroblastic anemia is a diverse group of anemia that is characterized by:
-Hypochromic anemia
-Ineffective erythropoiesis
-An increase in serum and tissue iron
-The presence of ringed sideroblastic in the bone marrow
* very diverse group of disorders that can be inherited or acquired
An enzyme disorder type of anemia in which the body has adequate iron which enters normoblasts, but is unable to incorporate it into hemoglobin
- Sideroblastic anemias (SA) 
Involves abnormalities of the enzymes regulating heme synthesis
-Identify deficiencies of Delta-ALA synthetase and uroporphyrinogen decarboxalace 
Sideroblastic anemias 
What is an Identifying characteristic of Sideroblastic anemia? 
Ring sideroblastic (Iron is accumulated in the mitochondria that surround the nucleus) 
Delta ALA synthase requires __________ as a coenzyme.
Pyridoxine/pyridoxal (B6)
Normoblast Containing free Fe granules (Not yet incorporated into heme) in it’s mitochondria;  found in bone marrow (Not in peripheral blood)
Sideroblast 
Mature RBC in peripheral blood containing free iron granules (aka. Siderotic granules or pappenheimer bodies)
Siderocyte
Stain used for ringed sideroblasts?
Stain used for Pappenheimer bodies?
Prussian blue
Wrights stain
Involves a defect of delta-ALA Ssynthase, very rare, genetic
-Heme synthesis is impaired as iron enters the erythroid precursor which cannot be incorporated in the molecule because the Portoporphyrin ring cannot be formed….. Iron builds up in the mitochondria
Hereditary sideroblastic anemia 
What is the treatment for Hereditary sideroblastic anemias? 
B6 however many patients don’t respond.
Death typically due to iron overload problems
Acquired sideroblastic anemia:
actually a type of myelodysplastic disorder (Which some considered to be a preleukemia)
Refractory anemia with ringed sideroblast (RARS) -
What is the treatment for RARS? 
Treatment is rarely done because disease is usually non-progressive and non-incapacitating unless it converts to a leukemia
type of Anemia that usually follows exposure to drugs or toxins (ethanol, Alcohol, Lead, and chemotherapeutic agents)
Secondary anemia
- In alcoholics (Alcohol uses up B vitamin coenzymes so it causes a decrease in activity of heme synthesis enzymes)
What are lab findings in sideroblastic anemia
- Micro, hypo with dimorphic population (Increased RDW)
-Anisocytosis, poilkilocytosis, target cells, pappenheimer bodies, and basophilic stippling 
TIBC is ________ In sideroblastic anemias 
Normal to slightly decreased
What is increased in sideroblastic anemia? 
Serum, serum iron, percent transferrin saturation
(A lot of iron laying around and not getting used) 
What is the transferrin Receptor level usually in sideroblastic anemia?
Normal or decreased
What are Pappenheimer bodies?
Iron
Lead intoxication leads to _______________ anemia.
Sideroblastic
Lead affects what three major tissues?
-Renal
-Hemaptopoetic (Lead inhibits activity of three enzymes in heme synthesis pathway)
-Central nervous system
What are the three enzymes that lead negatively affects in heme synthesis pathway?
• BPG synthase
• Coproporphyrinogen oxidase
• Heme synthase/synthetase (aka.
Ferrochelatase.)
What are the symptoms of lead intoxication?
-abdominal pain (Lead colic)
-Constipation and vomiting
-Muscle weakness and motor disturbances
-Leadline (Blue black deposit of lead sulfide in gums near teeth or in nail beds)
-Psychiatric disturbances, seizures, coma, and permanent mental retardation (severe cases) 
-lead can cross placenta
Lab Morphology findings of lead intoxication…
Mild to moderate micro, hypo anemia in chronic exposure
Hallmark is basophilic stippling (but not always, they can be found in other anemia‘s but stippling is heavier in lead intoxication) 
What are the lab findings consistent with lead intoxication?
Normal serum iron, Ferritin and TIBC; But increased FEP* (Pathway causes an over accumulation of protoporphyrin nine) 
Lead intoxication has an increased RPI, meaning…
Anemia has a hemolytic component
What is the treatment for lead intoxication
-Remove the source of lead
-Chelation therapy
Lead intoxication interferes with incorporation of __________ in __________. 
Iron, heme 
Porphyrias result in _____________ Hematopoiesis and sideroblastic anemia
Ineffective
- Can be hereditary or acquired
Group of disorders due to an impaired production of heme. 
Porphyrias
-when an enzyme is missing, the products from earlier stages in the pathway accumulate in the blood and may be excreted in urine or feces
What conditions are associated with porphyrias?
Photo sensitivity, motor dysfunction, sensory loss, mental disturbances, and some abdominal pain
What is the most common porphyria?
Acute intermittent Porphyria*
-Missing Enzyme in prophobilinogen deaminase
-Massive buildup of porphobilinogen and ALA in urine
An inappropriate or abnormal accumulation of excess iron, resulting in tissue damage (stored in the liver, heart, and pancreas leading to organ damage)
-This can bronze skin pigmentation
Hemochromatosis
Transferrin receptors appear to be permanently “turned on”. (It may be due to mutant hepcidin. The patient cannot become hypoferrimic when needed)
- Patient absorbs normal amount of iron, but they transport more of it into the plasma
Hereditary hemochromatosis (HH) 
How common is hereditary hemochromatosis?
1:300 of northern European Caucasians
* One of the most frequent genetic diseases in this population
 Hemachromatosis is due to a mutant gene linked to the HLA-A locus of chromosome _____ called the HFE Gene. 
6
_____________ Hemachromatosis occurs secondary to other inherited hemolytic anemia‘s
Acquired
-Common characteristics are anemia, ineffective erythropoiesis, and iron overload
-Usually have multiple transfusions that leads to increased iron storage due to no mechanism for iron excretion
What are the lab findings for patients with hemachromatosis?
-increased ferritin
-Increased hemosiderin
-Free iron increases (ferrous form)
-Ferrous iron + oxygen = super oxide and free radicals leading to cell death*

all cells (except _____________) require iron, and have the potential for damage in hematochromtosis 
Mature RBCs
Meadow chroma ptosis is most commonly seen in males ages of ______ years (But infant and juvenile forms do exist)
40-60
What are the most common symptoms of hematochromotosis? 
Joint pain and chronic fatigue
Homozygous show cardiovascular disease, especially cardiac arrhythmias, liver cancer, osteoarthritis and even diabetes mellitus (Bronzed diabetes) which accounts for about 10% of all diabetes mellitus cases
(Can also Cause cases of cardiomegaly, early menopause, depression, infertility and impotence) 
What is the first lab indication of hereditary hemochromatosis?
What is the criteria for diagnosis in females and males?
Increased percent transferrin saturation
Greater than 50% for females
Greater than 60% for males
In patients with hemachromatosis serum iron is _______, And serum ferritin is_________.  Normal or _________ TIBC. 
Increased
Very elevated
Decreased
TIBC is indirect estimate of amount of __________, Does the body need to make more of this under current circumstances
Transferrin 
What two diseases are treated by aggressive therapeutic phlebotomy?
The goal is to have serum ferritin below ______ And percent transferrin saturation below _____%
-Hemachromatosis
-Polycythemia versa
(Blood cannot be donated)
50 ug/L, 80%
What is the treatment for acute poisoning in hemachromatosis?
IV administration of desferoxamine (A chelating agent used to remove iron stores)
- used when hemoglobin is less than 10 g/dL
-Not as effective as simple bloodletting
