1. Iron deficiency anemia

2. Anemia of Chronic Disease

3. Megloblastic anemia

4. Aplastic anemia

Anemias of chronic destruction can have two generalized reasons for destruction.

What are they?

Instrinsic -- a defect exists in the RBC, itself.

Extrinisic -- Antibody or mechanically mediated destruction.

Examples of Anemias due to defects in the RBC.

Provide 5 specific examples.

Intrinic mechanisms

1. Hereditary Spherocytosis

2. G6PD deficiency

3. Sickle cell disease (hemoglobinopathies...etc)

4. Thalassemia (alpha and beta)

5. Paroxysmal Nocturnal Hemoglobinuria (PNH)

Examples of anemias involving antibody or mechanically mediated destruction.

Provide 3 examples

Extrinsic destruction

1. Warm antibody hemolytic anemia

2. Cold agglutinin immune hemolytic anemia

3. Mechanical RBC destruction (shearing forces)

Iron deficiency anemia is the most common form of anemia. What would you consider as reasons for the decreased iron levels?

(4)

1. Dietary lack (restrictive diets, chronically ill, etc...)

2. Impaired absorption

3. Increased requirement (i.e. pregnancy)

4. Chronic blood loss (menstruation, GI bleeding, IBS, etc...)

What are the main ways the body loses iron naturally?

How much iron per day should be taken to replace that loss?

Methods of loss

Sloughing of skin/epithelium

Loss of RBCs in urin and feces (menses also for women)

Daily requirements:

Men and post-menopausal women -- 1 mg/day

Menstruating women -- 2 mg/day (20-40 mg lost /menstrual cycle)

What might you find on a physical exam in a patient with iron deficiency?

(6)

1. Koilonychia (collapsed/concaved fingernails)

2. Alopecia

3. Mucosal atrophy -- tongue and gastric mucosa, for example

4. Intestinal malabsorption

5. Esophageal webs

6. Decreased Immune Response

What are the basic Red cell Indices?

(6)

Hgb -  Male: 13.5-17.5 grams/dL
          Females: 12.0-15.5 grams/dL

Hct - Male: 38.8-50.0%
        Female: 34.9-44.5%

MCV - 80 - 100 femtoliters

MCH - Hgb/RBC count =27 - 31 picograms/cell

MCHC - Hgb/Hct = 32 - 36 grams/deciliter

RDW - the variation in Red cell morphology - about 11-15%

How would red cell indices look for iron deficiency anemia?

decreased Hgb

decreased Hct

decreased MCV

decreased MCH

decreased MCHC

Increased RDW

Note: a lack of iron means that the body can't make enough hgb to fill the cells; thus, the cells are small and not very concentrated .

What Chemistry levels would you interpret to look for iron deficiency?

What results would you expect?

Serum iron -- decreased

Serum ferritin (storage form of iron) -- very decreased (<12 ug in iron deficiency)

Total Iron Binding Capacity (TIBC) -- Increased

This is a reflection of transferrin, the transport molecule of iron. If there is very little iron, then it's binding sites are mostly free. Therefore, there is a higher capacity to bind iron should there be some. This also means that there is a decrease in transferrin saturation

Treatment for Iron deficiency anemia

Simple:

1. Iron Supplement

2. Colonoscopy for people >50 to rule out colon carcinomas (bleeding)

What reasons could a hospitalized patient have for developing anemia?

hint: Think along the lines of how inflammation might cause anemia

(3)

Chronic microbial infections - ex. osteomyelitis, lung abscess, bacterial endocarditis...

Chronic immune disorders - Rheumatoid Arthritis, SLE, etc...

Neoplasms

Describe how chronic inflammation might lead to anemia in the hospitalized setting?

Just a general idea

Cytokines from infection and inflammation mediate.

Increased Hepcidin leads to decreased intestinal absorption (duodenum)

Iron is not mobilized for use, staying in bonemarrow macrophages.

RBC lifespan is reduced and is refractory to Erythropoietin

What would the RBC indices look like for Anemia of Chronic Disease?

Think about the difference between this and iron deficiency anemia.

Only a normal to decreased MCV

The bone marrow is being stingy with it's iron. Since this anemia is refractory to erythropoietin there is no great push to pump RBCs out. So they come out slowly and and smaller, with what iron they can scrounge.

The bone marrow is stainable for iron with prussian blue, whereas in I.D. anemia, it was not.

What would the iron measuring chemistry tests show for anemia of chronic disease?

Serum Iron

Ferritin

TIBC

transferrin saturation

Serum Iron - decreased (held in the tissues)

Ferritin -  normal to increased. This is the storage form so it makes sense to be increased if iron is being retained.

TIBC - decreased (iron is bound up and not put into red cells)

Transferrin Saturation - increased for the same reason as above.

How would you treat anemia of Chronic Disease?

It helps distinguish between ID anemia and ACD.

The transferrin receptors are looking for iron, they will be increased in ID anemia and not in ACD

[image]

What diagnostic tests would you perorm to test the iron cycle at each of these steps?

1. Serum iron, GI biopsy

2. Transferrin, TIBC, %saturation

3. Bone Marrow for Iron Stain

4. Red Cell count, Hgb, MCV

5. Serum Ferritin (Careful, this is increased in liver inflammation)

What is the etiology of Megaloblastic anemia?

What are reasons a person might be B12 deficient?

What are reasons a person might be Folate deficient?

(they share a couple of the same reasons)

B12 deficiency:

1. inadequate intake: limited diet

2. increased requirement: preggers, growth and development

3. defective absorption: decreased intrinsic factor (Antrum)

                                    Gastric atrophy/gastric resection     

                                    Bact. or parasitic infections

                                    Defective ILEAL mucosa

4. Defective transport: Transcobalamin II

5. Disorders of Metabolism:  enzyme deficiencies

                                            inborn errors of metab

Folate Deficiency

1. Inadequate intake: limited diet, Alcoholism, drug addiction

2. Increased requirement: Preggo, growth and development

3. Defective absorption: Defective JEJUNAL mucosa

                                     drug induced malabsorption

4. Disorders of Metabolism: inhibition of metabolic enz's. Ex. Methotrexate antagonizes Folate.

Pepsin releases B12 from food

B12 binds to R-binders (ex cobalophilins)

pancreatic proteases release B12 in Duodenum

Intrinsic Factor binds B12 in Duodenum

Complex flows to Ileum

In Ileum, B12 associates with transcobalamin II and moves into plasma

How are B12 and Folate Linked Biochemically?

What would be the immediate consequence of folate or B12 deficiency?

B12 from the diet is methylated and used to convert Homocysteine to Methionine (recall Homocysteine implicated in atherosclerosis).

Folic acid is required to methylate B12. This produces FH4, which is necessary for Thymidylate Synthase to made dTMP.

A decrease in either nutrient causes decreased dTMP synth and increased Homocysteine. Folate supplement can bypass the B12, but continued B12 deficiency leads to neurologic damage.

What is Pernicious Anemia?

How would it present clinically?

Pernicious anemia is a specific form of megaloblastic anemia caused by autoimmune gastritis that affects parietal cell-production of Intrinsic Factor -- B12 deficiency!

Clinically:

Insidious onset as body depletes B12 stores (recall, liver can store about 6 years worth of B12)

Hair is grey/white (Melanin synth impaired), Skin is lemon yellow (icteric due to RBC destruction in B.M.),

Chronic atrophic gastritis

 erythroid hyperplasia/megaloblastic RBCs

Myelin degen of dorsal and lat tracts

Blood Smear:

oval macrocytes, teardrop cells, hypersegmented Neutrophils

In what anemic condition would you see hypersegmented Neutrophils (>5 lobes)?

What Causes the megaloblastic RBC forms seen in B12/folate deficiency?

Decreased B12 leads to decreased DNA synth due to reduced FH4. DNA damage leads to destruction of developing RBCs in the medulla of the bone marrow. Stimulated erythropoietin forces the BM to make erythroid hyperplasia, which got destroyed again or spit out into circulation.

B12 deficiency also leads to demyelination from methylmalonic acid builds up (abnormal Fatty acids incorp. into neuronal lipids)

What are the key findings on a peripheral blood smear for Megaloblastic Anemia?

Hint: Consider red and white cells

Macrocytic cells (increased MCV due to immaturty of cells)

pancytopenia (decreases in all blood cell types due to inefficient DNA synthesis).

Howell-Jolly bodies (condensed nucleic acid material that wasn't properly extruded from immature cells)

Hypersegmented Neutrophils

How do you treat B12 or Folate deficiency?

B12 deficiency:

B12 injections. No oral supplements because Intrinsic factor is required.

Folate:

Oral supplements

What would you expect to see on a peripheral blood smear for a patient with Aplastic Anemia (AA)?

A dirth of cells -- red cells, white cells, plts.

What red cells are made are normochromic and normocytic (MCH and MVC), otherwise, cell precursors are being suppressed or disappeared.

This means that you won't see a good compensation -- low reticulocyte count.

There are two general categores for causes to AA.

Idiopathic

Secondary

Go!

Idiopathic: Unknown cause

Secondary: Bone Marrow injury from cytotoxic drugs, radiation therapy, hypersensitivity to a known antigen, viral infections

The most popular hypothesis is an autoimmune response to marrow stem cells (some agent may act as a hapten to generate self reactive antibodies)

What problems to you expect a person with AA to have?

Related to Red Cells

White Cells (specifically granulocytes)

Platelets

Basic lack of RBCs leads to lack of tissue oxygenation, fatiguability, pale

Decreased platelets leads to easy bruising and capillary hemorrhages -- petechiae, and bruising -- eccymosis

Lack of white cells leaves a person susceptible to infections

Don't expect Splenomegally (the spleen is an organ that could severly sequester cells to give an appearance of AA)

Fat

Mononuclear Cells (lymphocytes are not granulocytes and are implicated in antibody production in this hypothesized autoimmune disease)

Fibrous tissue

How would you treat AA?

Remove toxic drug if any are being taken

Supplement deficient products:

RBC and Plt transfusions

Provide broad spectrum antibiotics to help prevent infection

Bone Marrow transplant (some cases to actually spontaneously reverse)

Administer antilymphocyte antibodies to try and reduce the autoimmune reaction.

Paroxysmal Nocturnal Hemoglobinuria may spontaneously appear under what circumstance?

Regeneration of Bone Marrow after a bout of Aplastic Anemia.

 A mutation happens on the x-chromosome that alters PIGA, an enzyme used to make GPI anchors on the myeloid cell surfaces. These anchors help the cells avoid being lysed by complement.

What type of anemia is described by:

Anemia, Splenomegaly, intermittent jaundic.

Variable severity among patients.

Prone to bilirubin-type gallstones. May have hemolytic crises with infection, or aplastic crisis

 Possible leg ulcers

?

What are the usual defects in a cell that lead to spherocytes?

name a few different proteins

Ankyrin, Spectrin, Band 3, Band 4.2 may cause the lipid membrane to not anchor effectively to the cytoskeleton causing a membrane instability that releases portions so that the cell loses structure and size.

MCHC

Due to the decreased size of the RBCs, there is relatively more hgb per cell. Recall, MCHC = Hgb/Hct. In this case the Hct has gone down because after losing membrane the cells are smaller.

Bone Marrow Compensates with Reticulocyte production

What laboratory test checks for hereditary spherocytosis by altering the extracellular environment of a red cell?

G6PD produces what Antioxident?

This Antioxident is used to regenerate what molecule that helps eliminate oxidents that would like to damage the rbc membrane?

NADPH

Glutathione

What is a Heinz Body?

What anemias might demonstrate Heinz bodies?

A Heinze body is an aggregation of hemoglobin made insoluble wither by abnormal production or damage such as oxidation of sulfhydral groups.

They are most likely to be found in G6PD deficiencies.

They can also be found in Alpha and Beta Thalassemias

What sort of inheritance pattern does G6PD deficiency demonstrate?

X-linked.

All male RBCs are deficient while only some are deficient in females (random x-inactivation).

Thus, males are more sensitive to oxidant damage than females.

What events may cause oxidant stress in an individual with G6PD deficiency?

Drugs:

anitmalarials (ironic because this deficiency provides protection against malaria)

sulfonamides

nitrofurantoins

Foods:

FAVA BEANS

Infections:

Leukocytes generate oxidant free radicals

A shistocyte is a cell with a "bite" taken out of it by the spleen. This is an attempt by the spleen to remove precipitated Hgb (Heinz Body).

The heinz body decreases the flexibilty of the RBC membrane so it had to be removed.

Here's a classic question:

What is the mutation that causes the formation of HgbS?

A point mutation that changes the 6th amino acid of the beta chain ofHgbA from Glu to Val.

Soluble when fully oxygenated

Insoluble after deoxygenation

What are some complications of sickling?

Immediate and progressive

Sickle cell dactylitis/Hand-Foot syndrome -- toes and fingers grow at uneven rates. Caused by spotty availability of oxygen during development.

Functional asplenia leading to an autosplenectomy.

Vaso-occlusive pain crises -- could cause sores through ischemia

Renal Papillary necrosis

Infarctions (brain, kidney, retina, lung, bone)

Acute Chest Syndrome -- sickling in lung  (fever, cough, chest pain, pulmonary infiltrate)

What are the therapeutic options for someone with Sickle Cell anemia?

Analgesics and hydration for the pain crises

exchange transfusions

hydroxyurea -- increased the expression of Hgb F