hematology exam 3 review disorders of iron and heme metabolism + IDA, SA, and ACI

Iron is an essential element for all living organisms Because it:

Cellular growth, oxygen transport, and proliferation of

RBCs

When oxygen tensions drops,

Receptors in the kidney can sense the change in oxygen tension/concentration- making more EPO to release into the bone marrow

When EPO is released into the bloodstream, the bone marrow responds to this by

allowing for the early release of reticulocytes, increases the number of mature erythrocytes, and increases the rate of maturation of erythroid precursors - so there’s accelerated release effect into peripheral blood.

Reticulocyte Production Index, a calculation which indicates

whether or not bone marrow is responding adequately to anemia.

Normal bone marrow response can increase erythropoiesis by? And for how long would it take for compete response to occur?

6-8 fold; a full week

disorders that present with an increase in circulating RBC (increased Hct)

Erythrocytosis and Polycythemias

disorders that present with a decrease in circulating RBCs (decreased Hct)

Anemias

Physiologic Adaptations in Anemia, how does it affect the Oxy. dissociation curve?

Hypoxia occurs due to decrease in O2-carrying capacity.

Diffusion causes ↑ O2 release by Hgb- shifts the oxy dissociation curve to the right. (decreased O2 affinity of Hgb)

The body increases 2,3-DPG production to further help with off-loading oxygen.

Via selective vasoconstriction, RBCs are rerouted to areas where there is highest oxygen demand, and this requires increased cardiac output. In severe anemia, this can even cause tachycardia. (inc heart rate)

With anemia, what is its relationship with vasoconstriction?

RBCs are rerouted to areas where there is highest oxygen demand, and this requires increased cardiac output. In severe anemia, this can even cause tachycardia. (inc heart rate)

Absolute anemia definition and examples

true decrease in red cell mass; impaired RBC production, blood loss or accelerated RBC destruction or hemolysis

Relative anemia definition and examples

apparent decrease in red cell mass not from true hematologic disorder; fluid shifts (ex in pregnancy) or diluted blood from (IV)

Retic count test: Schilling’s test

tests for B12 in urine

CBC tests

Hgb, Hct, MCV, MCH,MCHC, RDW

To test for anemia, a high reticulocyte counts indicates that there is

shortened RBC survival

A low reticulocyte count when testing for anemia indicates what is happening to RBCs

decreased RBC production

Normal hemoglobin values for adults

males: 13.5-18.0 g/dL and Females 12.0-15.0 g.dL

Anemia types: Acute blood loss, hemolytic anemias, early stage aplastic anemias, myelopthisic anemia, stem-cell related anemia display what RBC morphology?

normocytic, normochromic

what types of anemia conditions would normocytic and normochromic RBCs indicate?

Acute blood loss, hemolytic anemias, early-stage aplastic anemias, myelophthisic anemia, stem-cell related anemia

Macrocytic and normochromic RBCs would indicate what anemia conditions?

MCV=high, MCH=high, MCHC=normal

megaloblastic anemia, anemia of liver disease, chronic aplastic anemia, acute hemolytic anemia w/ shift retics

Anemia of chronic inflammation has what type of RBC morphology?

microcytic and normochromic; MCV=low, MCH= normal , MCHC= normal

microcytic and normochromic; MCV=low, MCH= normal , MCHC= normal 

indicates what anemia condition?

Anemia of chronic inflammation

iron deficiency anemia, thalassemia, lead poisoning, porphyrias, sideroblastic anemia would show what RBC morphology

microcytic, hypochromic; MCV,MCH, MCHC= all are low

Average adult has total body iron content of

3500- 4000 mg

2/3 of iron is stored as

Hemoglobin

1/3 iron found in

Bone marrow, liver, and spleen

Stain used for iron

Prussian blue stain

Minimum daily requirement (MDR) of iron for adults is

1mg

Daily requirements of iron are affected by

• Chronic blood loss

• Increased need

• Inadequate intake

Serum Fe levels. Exhibit both

Monthly and diurnal (daily) variation, so draw labs for Fe studies first thing in am, & fasting!

Apotrensferrin

Iron not bound to transferrin (review to check)

Iron is ingested in foods as

Fe3+ Ferric

Total Iron Binding Capacity (TIBC)

total amount of iron that can be bound by transferrin. It is effectively an indirect measurement of transferrin concentration.

Normal range for TIBC?

NR = 250- 400 ug/dL

Most common type of anemia

Iron deficiency anemia (IDA)

When does IDA occur?

whenever Fe loss or need exceeds Fe intake

conditions when IDA could develop?

1. States of increases physiologic demand

2. Inadequate intake

3. Chronic blood loss

Chronic blood loss could occur in the following, leading to IDA:

a. Increased menstrual flow

b. Chronic bleeding - gastric ulcers, GI carcinoma

c. Frequent blood donation

d. Chronic hemolysis - malaria, paroxysmal nocturnal hemoglobinuria

e. Hookworm infestation - Necator americanus, Ancylostoma duodenale

Common symptoms of all SEVERE anemias:

dyspnea (shortness of breath) & dizziness

Characteristic IDA symptom - pica, what is pica?

(the persistent, compulsive desire to eat a single food, or more commonly, a nonfood item

laundry starch, dirt, clay, cigarette butts, ice, etc

Characteristic IDA symptom – koilonychia, what is it?

flattened, spooned fingernails

Moderate aniso with ↑ RDW; why?

Microcytes

Heme lab findings in IDA?

Microcytic Hypochromic anemia

With IDA, Blood smear shows

poikilocytosis w/ codocytes, elliptocytes or ovalocytes, and dacrocytes

Developing red blood cell

Sideroblasts

Sequential Changes in Development of Fe Deficiency (More Assays)

Paste chart

IDA treatment

First, treat underlying contributing cause

>Give oral Fe supplements & treat symptoms as needed. (Transfusions only given in life- threatening emergencies!)

>Retic count should increase within 48_h_rs_., reaching maximum in ~10 days.

>Dimorphic population of RBCs becomes evident as new “Fe normal" RBCs increase in #, while the old “Fe deficient" RBCs die off.

Dimorphic population is referred to as?

A variation in size (ie. anisocytosis)

Anemia of Chronic Inflammation

The 2nd most common anemia - associated with chronic infections

Central feature of anemia of chronic inflammation is

sideropenia (iron deficiency) with abundant iron stores

Anemia from chronic inflammation is NOT due to

bleeding, hemolysis, or bone marrow replacement by cancer or a leukemia

What does cause anemia of chronic inflammation?

Appears to be due to the body withholding Fe from inflamed cells, pathogenic microbes, & tumor cells, in an attempt to starve them to death!

Hepcidin function

Decreasing iron secretion

Main hormone responsible for anemia of chronic inflammation

Hepcidin

What produces Hepcidin?

hepatocytes, macrophages, intestinal enterocytes

Hepcidin is also an acute-phase reactant, so during inflammation (unrelated to iron levels), there is

a decrease in iron absorption and macrophages retain iron.

Most important acute phase reactant in ACI

Hepcidin

Lactoferrin (acute-phase reactant) is a

iron-binding protein in neutrophilic granules (importance in phagocytosis). During inflammation, lactoferrin is released into plasma and scavenges available iron. RBCs do not have lactoferrin receptors

Ferritin (acute-phase reactant) also binds

iron in plasma. RBCs lack ferritin receptors.

Treatment of ACI

• First, treat the underlying condition

• Can give EPO, but must also supply iron supplements

concurrently

• Taking iron supplements (without EPO) could be harmful, even fatal

With anemia of chronic infection, what is the main concern regarding iron?

Iron availability / release

Clinical Symptoms of ACI

• Decreased serum iron and % Tf saturation

• Normal to increased ferritin levels

• TIBC decreased

• ZPP increased

• TfR (transferrin receptors) are normal (increased in IDA)

• Also includes symptoms of the primary disorder.

Lab Findings in ACI

• Mild to mod. normo-, normo- anemia (but can sometimes look micro-, hypo-) (depending upon on how blocked Fe release is.)

• No reticulocytosis (body somehow knows it isn’t really Fe deficient)

how do you tell the difference between IDA & ACI?

IDA- ferritin dec and TIBC inc (opposite for ACI)

ACI- inc bone marrow Fe lvls

IDA dec bone marrow Fe lvls

What type of patient population would

be most likely at risk for ACI

Individuals who have been hospitalized for a long time

Sideroblastic anemias - diverse group of anemias characterized by

• hypochromic anemia

• ineffective erythropoiesis

• an increase in serum and tissue iron

• the presence of ringed sideroblasts in the bone marrow.

Characteristic ringed sideroblast In SA

sideroblasts in which iron is accumulated in the mitochondria that surround the nucleus)

-Visible w/ Prussian blue stain

abnormalities of the enzymes regulating heme synthesis In SA

Identified deficiencies of δ-ALA synthetase and uroporphyrinogen decarboxylase

*Delta ALA synthetase requires pyridoxine/pyridoxal (Vitamin B6) as a coenzyme.

Sideroblastic anemia (SA) is caused by

inability to make protoporphyrin IX, the body has adequate iron which enters normoblasts, but is unable to incorporate it into hemoglobin

When patient has lots of iron but their body doesn’t have the enzymatic capacity to use it, what anemia is this

Sideroblastic anemia

Sideroblastic Anemias (SA) etiology

Etiology – typically follows exposure to drugs or toxins (i.e. antitubercular therapy, ethanol [most common culprit*], chloramphenicol, alcohol, lead, and chemotherapeutic agents

How to identify Sideroblast on bone marrow smear

Use the Prussian blue stain

Siderocyte

mature RBC in peripheral blood containing free Fe granules (aka. siderotic granules or Pappenheimer bodies)

Hereditary SA involves a defect of

δ-ALA synthetase

Idiopathic definition

Unknown cause

80% of iron carried by transferrin is used for ?

synthesis of heme

how many atoms of ferric iron can bind to one transferrin molecule?

2

relationship between iron and the stomach?

The low pH of the stomach reduces ferric iron (Fe3+) to ferrous iron (Fe2)

Gut mucosal cells work to absorb iron when it leaves the stomach by 

oxidizing ferrous iron (Fe2+) BACK to ferric form (Fe3+), where it enters the bloodstream then is transported by transferrin for distribution to body tissues or stored in the spleen/liver/bone marrow

Why is hemosiderin not as used compared to ferritin for iron storage?

Hemosiderin is not water soluble and less readily available in the body

Fe without ferritin is what?

Apoferritin

When Transferrin concentration increased, what happens to iron? and why?

Iron decreases so that the body can scavenge up any available Fe atoms

Because of the inverse relationship between Transferrin and Fe, what happens to TIBC if a patient has Iron deficiency anemia (IDA)?

TIBC increases

Porphyrias are a

group of disorders due to an impaired production of heme; Results in ineffective hematopoiesis and sideroblastic anemia

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

Acute Intermittent Porphyria: most common porphyria

• Missing enzyme is porphobilinogen deaminase

• Massive build up of porphobilinogen and ALA in urine

What are Pappenheimer bodies?

Iron

Lead (Pb) Intoxication leading to SA

Acquired condition,

May be chronic or acute

• Occurs in both adults (occupational exposure) & children (excessive exposure to pre-1970 Pb- containing paint, which tastes? Sweet

• Improperly glazed cooking pottery & vehicle emissions (even in soil near highways) can affect all age groups.

Lead (Pb) affects three major tissues

renal, hematopoietic, & central nervous system.

Pb inhibits activity of 3 enzymes in heme synthesis pathway, which are

PBG synthase

• Coproporphyrinogen oxidase

• Heme synthase/synthetase (aka. Ferrochelatase.) Last enzyme in pathway!

Lead Intoxication Lab Findings

Mild to moderate micro-, hypo- anemia in chronic exposure (but can be normo- normo- otherwise).

• Normal serum Fe, ferritin, & TIBC; but increased FEP! (Since inability to link heme & Fe together at the last step in the pathway causes an over- accumulation of protoporphyrin IX.)

• Hallmark is basophilic stippling (but not always!)

Lead intoxication interferes with

Incorporation of iron in heme

Hemochromatosis

An inappropriate (or abnormal) accumulation of excess iron, resulting in tissue damage

• Excess iron is stored in the liver, heart, and pancreas – leading to damage of these organs

• This can cause bronze skin pigmentation

Hereditary Hemochromatosis (HH)

One of the most frequent genetic diseases in

Northern European Caucasians (1:300)

• Tf Receptors appear to be permanently “turned on”. (It may also be due to mutant hepcidin – the patient cannot become hypoferremic when needed.)

• Patients absorb normal amount of iron, but they transport more of it into the plasma

Acquired Hemochromatosis

occur secondary to other inherited hemolytic anemias

• Common characteristics are anemia, ineffective erythropoiesis, and iron overload

• Usually have multiple transfusions...leads to increased iron storage due to no mechanism for iron excretion

Hemochromatosis: When excess iron is present:

• Increased ferritin

• Increased hemosiderin

• Free iron increases (ferrous form)

• Ferrous iron + oxygen = superoxide & free radicals....leading to cell death

desferoxamine

Treatment option for hemochromatosis that is chelating agent used to reduce iron stores).; not as effective as simple bloodletting and is used when hemoglobin is less than 10 g/dL

Differentiation of Fe Metabolism Disorders