4

Moath Darwish

Waseem Alhaj

Tareq Adely

Please refer to the slides for pictures.

Iron deficiency anemia

Iron absorption and regulation .1

a. only 10% of ingested iron are absorbed

duodenumtion of iron occurs in . absorpb

c. Iron from plants is a nonheme, and poorly absorbed ( vegetabeles are

not good source for iron)

d. Iron from meat is a heme and directly absorbed in the duodenum

e. The amount of iron absorbed is regulated.

(1) Hepcidin is the “master” iron regulatory hormone and determines

whether iron is absorbed or not absorbed in the duodenum and whether

iron is released from macrophages or not released.

(2) A decreased level of iron stores in the body leads to reduced

hepcidin synthesis in the liver.

• This upregulates ferroportin, causing more iron to be reabsorbed in

the duodenum to bind to transferrin and more iron to be released from

bone marrow macrophages to bind to transferrin for erythropoiesis.

(3) An increased level of iron stores In the body leads to increased

hepcidin synthesis in the liver.

• This downregulates ferroportin, causing iron accumulation in

enterocytes, which are eventually shed into the bowel. A reduced level

of ferroportin also causes iron blockade in bone marrow macrophages,

so less is released for binding to transferrin.

Epidemiology .2

a. Most common overall anemia

b. Most common nutritional deficiency worldwide

c. People at increased risk of anemia are:

(1) infants aged 1 to 2 years

• Due to inadequate intake of iron (infant's milk is poor in iron)

(2) elderly

• because they can't digest meat well

(3) teenagers

• Restricted diets with very little meat intake; decreased intake of heme

iron.

(4) low socioeconomic class.

:Pathogenesis. 3

• Decreased synthesis of heme (iron + protoporphyrin) leads to a

decreased synthesis of Hb-

.microcytic hypochromic anemia

causes.4

classification causes discussion

Non heme iron in vegetables is poorly absorbed. Not sufficient to body demand

vegetarians Decreased intake

1)daily requirement for iron on lactation and pregnancy increases. 2) Iron is required for tissue growth and expansion of blood volume in the developing fetus

1)Pregnancy/lactation

2)Infants/adolescence

Increased utilization

Gastrointestinal loss Blood loss

Absence of the villous surface in the duodenum decreases absorption of iron

Celiac, Crohn's Decreased absorption

findings Clinical .5

a. symptoms due to anemia include headache , pallor, fatigue .

b. symptoms specific to iron deficiency:

(1)glossitis and inflammation in the mouth

(2)hair loss

theory ; there is a)picaCNS manifestation (depression, insomnia , and )3(

that some brain’s enzymes contains iron.

(4)spoon nails

findings labratory .6

A. Decreased serum iron and iron saturation

B. Decreased serum ferritin

C. Microcytic and hypochromic are present with increased central area

of pallor

D. Although erythropoietin is high, low iron stores in bone marrow blunt

its effectiveness, so there is no much increase in erythroid cells.

E. Thrombocytosis

-the doctor said that the exact mechanism is unknown, but some

theories say that erythropoietin, which increases in case of anemia,

cross react to activate megakaryocytes too.

- but according to textbooks, thrombocytosis occurs as a reactive phenomenon to

a tendency or craving to eat substances other Pica:

ashes than normal food (such as clay, plaster, or

a tendency or craving to eat substances :Pica

other than normal food (such as clay, plaster, or

ashes

increase blood viscosity and prevent high-output heart failure

.

In peripheral blood smears:

1)Anisopoikilocytosis: anisocytosis RBCs of varying sizes, poikilocytosis

RBCs of varying shapes

2)Target cells: appears in abnormal hemoglobinization( thalassemia,

sickle cell anemia, iron deficiency anemia)

Iron stains blue(left); compare it to iron absence(right)

astic AnemiaMegalobl

overviewvitamin B12

eggsand meatsoluble vitamin present in -Water. 1

2. Vitamin B12 stores in the liver is sufficient to supply the body for

years, so it's deficiency due to loss of storage is rare.

3. Intrinsic factor which is released from parietal cells of the stomach

is important to absorb vitamin B12 in the ileum

4. Important in myelination of nerves.

5. It's an important Coenzyme in thymidine synthesis

encycicauses of vitamin B12 defi a.

classification causes discussion

The stages of iron deficiency in sequence are as follows: absent

iron stores; decreased serum ferritin; decreased serum iron, then

microcytic hypochromic anemia appears.

Vitamin B12 is absent in vegetables

Pure vegan diet Malnutrition Decreased intake

-Autoimmune destruction of parietal cells: this occurs in pernicious. -gastrectomy decrease intrinsic factor -Crohn disease, celiac disease interfere with the vitamin absorption.

↓Intrinsic factor

↓Terminal ileum absorption

Impaired absorption

Folic acid overview .C

and meat lesvegetabound in is f Water soluble vitamin that. 1

2. The liver contains small amount of folic acid, so deficiency due to

loss of storage is quick.

3. It's coenzyme important in thymidine synthesis

encycicauses of folic acid defib.

classification causes discussion

Low vegetables intake Malnutrition Decreased intake

In celiac disease, villi in the jejunum may be destroyed, leading to folic acid deficiency.

Celiac disease Malabsorption

1)This drug inhibits thymidine synthesis in the cell. 2)inhibits uptake of folic acid from the intestine

1)Methotrexate

2) anti-convulsant, Oral contraceptives, alcohol

Drug inhibition

There is increased utilization of folic acid in DNA synthesis

Pregnancy Increased demand

1)folic acid could be lost from serum in renal failure and

dialysis which lead to it's deficiency

2) methotrexate and vitamin b12 deficiency impair

utilization of folic acid synthesis .

anemia megaloblastic of pathogensis

1. Impaired DNA synthesis delays nuclear maturation.

this Causes a block in cell division in all rapidly dividing cells, leading

to large, immature, hematopoietic cells with a pale inactive

chromatin

2. Ineffective hematopoiesis

a. Megaloblastic precursors outside the bone marrow sinusoids are

phagocytosed and destroyed by bone marrow macrophages.

b. Megaloblastic precursors undergo apoptosis, causing

pancytopenia (anemia, neutropenia, and thrombocytopenia).

Clinical findings in vitamin B12 deficiency

1. Pernicious anemia (PA)

• there is Abnormal autoreactive T-cell response initiates direct

gastric mucosal injury also triggers formation of autoantibodies

include :

A)Type 1 antibody: antibodies block Vit B12 from binding to intrinsic

factor

B) Type 2 antibody: Antibodies that prevent the binding of vitamin

B12–intrinsic factor complexes to ileal receptors

C)type 3 antibody: Antibodies directed against the proton pump in

parietal cells( to understand this point read the extra box below)

2. Neurologic disease associated with demyelination

(A) Peripheral neuropathy with sensorimotor dysfunction

(B) weakness in the muscle that is supplied by the nerve.

findings in vitamin B12 deficiencyLaboratory

1)peripheral blood findings include

A. Pancytopenia

b. Oval (egg-shaped) macrocytes

C. Hypersegmented neutrophils

Hypersegmented neutrophils have more than five nuclear lobes•

D. giant metamyelocyte

E. large,hyper lobulated Megakaryocytes:

in vitamin B12 deficiency Bone marrow findings. 4) 2

• Megaloblastic immature nucleated cells are present with a pale

inactive chromatin pattern

•as a result of increased erythropoietic level, bone marrow cellularity

, but because impaired DNA synthesis in the cells, increase initially

decrease they undergo apoptosis and Bone marrow cellularity will

too

Clinical findings in folic acid deficiency

to vitamin B12 deficiency with the exception of neurologic Similar•

disease

Laboratory findings in folic acid deficiency

to vitamin B12 similarPeripheral blood and bone marrow findings •

deficiency

: Anemia of chronic diseases

overview-

persistentwith chronic diseasesthis condition is associated with

inflammation like tuberculosis , HIV infection, rheumatologic diseases

and malignancies

NOTE :malignancies are associated with chronic inflammation because

malignant cell activate the immune system when they go necrosis

: Pathogenesis

nt inflammation , is released during persiste atth6,-interlukin

activate hepcidin, leading to decrease iron transfer from stores and

from macrophage to erythroid cells.

:findings Laboratory

serum ferritin is increased)1

Iron stores in BM are markedly increased )2

it becomes with time, normochromic normocytic anemia, llyiatIni) 3

hypochromic microcytic anemia.

iency anemia and anemia of icbetween iron def iateHow to different

In anemia of chronic diseases, serum ferritin and ?chronic diseases

iron stores in bone marrow are high, unlike in case of iron deficiency

anemia.

iron iency anemia, we don't give icunlike iron def Treatment :

supplement , instead, we treat the underlying cause.

: Aplastic Anemia

causes)1

classificiation discussion and example

Most cases Idiopathic

Rheumatoid arthritis and viral infection Inflammation

Like chloramphenicol and gold that occur rarely drug reactions :idiosyncratic reaction

and unpredictably amongst the population

Idiosyncratic reaction to drugs

2)pathogenesis

A) due to Immunologic alterations occur in the myeloid stem

(progenitor) cells, causing T-cell activation and release of cytokines

that suppress or destroy the myeloid stem cells .

B) or due to acquired or genetic mutation that overlap with PNH.( to

understand how read the below extra box)

findings laboratory)3

a. Pancytopenia

This is due to Mutations in TERT, the gene for

the RNA component of telomerase, cause

short telomerases in congenital aplastic

anemia

b. Reticulocytopenia

c. Hypocellular bone marrow (bone marrow is filled with fat)

D.no splenomegaly

:Myelophthisic anemia

: overview

it's an infiltrative disease that cause secondary bone marrow failure

:causes

1) most commonly due to bone marrow cancer like leukemia.

2)also, it could less commonly be caused due to granuloma, which is

an aggregation of macrophages that could destroy normal bone

marrow cells.

: laboratory findings

pancytopenia)1

no splenomegaly)2

chronic renal failure

pathogenesis

Low erythropoietin level decreases erythropoiesis

bleedingUremia impairs platelet function, leading to

labtratory findings

anemia normochromic normocytic) 1:

ich RBC's have small cytoplasmic ha condition in w ,echinocytes) 2

projection (spines)

: Hypothyroidism

since Thyroxin is essential for cell metabolism, it's deficiency causes

bone marrow's cells maturation to decrease, leading to macrocytic

anemia

chronic liver diseases

laboratory findings :

A)since clotting factors are synthesized in the liver, it's diseases leads

to bleeding

B)since liver is the major organ where lipids are synthesized, it's

diseases causes impairment in lipid synthesis , which lead to

)acanthocytes( abnormal RBC's with long projection

Myelodysplastic syndrome

in blood cells in which immature cancers up ofare a gro

do not mature and therefore do not become bone marrow the[.healthy blood cells

: sisepathogen

exposure to an agent known to cause DNA damage and

.smutation

: laboratory findings

1)megaloblastic immature erythroid, myeloid and megakaryocyte.

2)hyper cellular bone marrow , with low peripheral blood count,

they become unable defective in their functionsince these cells have

to exit from bone marrow

3) Aggregates of iron in the nucleus, this condition called ring

sideroblasts; ring because they are found around the nucleus.

:Polycythemia

. of RBCs, which is full of hemoglobin massIt’s an increase in the

.of RBCs numberErythrocytosis is an increase in the

(aka primary polycythemia and rubra vera) Polycythemia vera:

Neoplastic disease of erythroid cells

:Pathogenesis

JAK-2 mutation, which is erythropoietin receptor, become very

sensitive to erythropoietin. Also there are other mutations.

.ary erythropoiesis on ita result of extramedull Splenomegaly

an increased erythropoiesis, granulopoiesis and Panmyelosis

megakaryopoiesis ( because there precursor cells also contains JAK-2)

By negative-feedback there will be a decrease in erythropoietin level.

:Clinical symptoms

Plethora, cyanosis and itching( plethora is a red skin / itching occurs

due to increased WBCs numbers and increased histamine and other

cytokines)

Sluggish circulation predisposes to thrombosis

Bleeding can also occur because platelets aren’t functioning well

Hypertension

Gout occurs when RBCs die they release uric acid which forms

crystals

:Lab findings

High HB, Hct, RBC count reticulocytes count.

High WBCs and platelets (panmyelosis)

:Secondary polycythemia

An adaptive change with no mutations

Causes:

a.chronic hypoxia, the body respond by increasing erythropoietin,

examples include : chronic lung and heart diseases, alcoholism,

smoking and high altitude.( alcohol suppresses normal respiration,

also it increases urination with subsequent high blood concentration)

b.Renal cell carcinoma: cells secrete erythropoietin

c.surreptitious: when athletes take certain drugs to increase there

performance

Secondary polycythemia is reversible and characterized with high

erythropoietin with no splenomegaly