CASE 1

CASE 1

A 22-year-old female restricted vegetarian was seven months pregnant. She had been experiencing

frequent headaches and extreme fatigue and weakness. Following an episode of syncope, she made an

appointment with her doctor. Upon examination, her physician noted that his patient had an elevated

heart rate and pallor of the skin, mucous membranes and nail beds.

The following peripheral blood tests were performed:

Hb- 11 (13-18g/dL)

Ht – 35 (40-54%)

MCV- 75 (80-95fL)

MCH- 22 (27-32pg)

MCHC-31 (32-36g/dL)

RBC- 3.8 (4.5-6 T/L)

WBC- 5.6 (4-10 G/L)

PLT- 345 (150-450G/L)

Iron – 45 ( 50-180μg/dL)

TIBC- 580 (280-550 μg/dL)

Bilirubin – 5 ( 3-10mg/L)

1. What is TIBC and what does it describe ?

2. What is the reason for tachycardia and pallor?

3. How do you explain decreased MCV ?

4. What is the reason of low iron concentration in the blood?

5. How do you explain the prevalence of anemia in chronic inflammation.

A N E M I A - DEFINITION

Anemia is defined as a reduction in one ore more of the

major red blood cell measurements:

• Hb concentration

• Hematocrit

• RBC count

WHO criteria for anemia is:

Hb < 14 g/dl in men

< 12 g/dl in women

RED BLOOD CELLS

morphology

MEAN CORPUSCULAR VOLUME ( MCV)

80-94 fL (m3)

< 80 microcitic; > 100 macrocytic

MEAN CELL HEMOGLOBIN in RBC ( MCH)

27-34 pg

MEAN CELL HEMOGLOBIN CONCENTRATION

(MCHC)

31-37 g/dL normochromic

<31 g/dL hypochromic

Approach to anemia

anemia

check MCV

MCV < 80

microcytic

anemia

MCV 80 - 100

normocytic

anemia

MCV > 100

macrocytic

anemia

CLINICAL CONSEQENCES OF

ANEMIA I

S y p t o m s a r e d u e t o h y p o x i a

• NORMAL Hb CONCENTRATION:

women: 12-16 g/dL

men: 14-18 g/dL

optimum oxygen delivery occurs with Hb 15 g/dL

CLINICAL CONSEQENCES OF

ANEMIA II

• Fatigue

• Somnolence (sleepiness)

• Iintolerance to cold

• Pallor of skin and mucous membranes

• Hypotension due to hypoxia (vaodilators: ↑H+, ↑ lactate, ↑ CO2)

• Tachycardia (angina, arrhythmia, palpitation)

• Ringing in the ears

• Headache

• Dispnea & dyspnea at rest

• Lethargy

• Confusion

• Dizziness

MICROCYTIC ANEMIA

MCV < 80fL

• Reduced hem synthesis (syderoblastic anemia):

iron deficiency anemia (IDA)

lead exposure (rare nowedays)

porphyria ( deficency of certain enzymes in hem synthesis )

• Reduce globin production (thalassemia)

• Hemolytic anemia (e.g. hemoglobinopathies, membrane defects)

IRON DEFICIENCY ANEMIA

Iron deficiency anemia is the most

common anemia, particularly in women

and children

Approximately 20% of all women have

anemia

IRON METABOLISM

ABSORPTION

• Apoferitin – is a protein which helps iron to

absorbed in the mucosa of the proximal

small intestine (mainly duodenum)

• 5-10% of daily intake is only absorbed

IRON METABOLISM - STORAGE

MAJOR STORAGE DEPOT IS THE LIVER

Stored as ferritin and hemosyderin

F E R R I T I N

• primary storage, stored in cell cytoplasm

• release for heme synthesis

H E M O S Y D E R I N

• major long term storage form of iron in lysosomes

• slow release

IRON METABOLISM –TRANSPORT

T R A N S F E R I N

• major iron transport protein in blood (95%)

• about 30% saturated with iron (up to 50% - IDA)

• most iron bound to transferrin comes from the

breakdown of hemoglobin in liver and slpeen

• total transferrin present in plasma to bind the iron

present in plasma = TOTAL IRON-BINDING

CAPACITY (TIBC) (TIBC is the blood’s capacity to bind iron

with transferin) = iron level + LIBC (latent iron binding capacity)

IRON LOSS OF THE BODY

• Daily exfoliation of intestinal mucosa

• Menstruation

• Nails and hair cut

IRON METABOLISM

• Iron level: 55-180 ug/dL

• Transferin : 200-400mg/dL

• TIBC: 250-500ug/dL

IRON – DAILY INTAKE

• Women – 20 mg

• Men – 10 mg

• Pregnant women – 30 mg

• Infant- 10 mg

• Children (1-6 year) – 5-8 mg

• Youth (13-19 year) – 15 mg

IRON RICH FOOD

Fe 2+

• Liver

• Beef

• Lamb

• Pork

• Veal

• Chicken

• Fish

Fe 3+

• Green leafy vegetables

• Beetroot

• Prunes

IRON DEFICENCY - SYMPTOMS

• brittle nails and hair

• spoon nails (koilonychia)

• mucosal atrophyy: glossitis (smooth

erythematous tongue), dysphagia, cheilitis

ETIOLOGY OF IDA

• Blood loss ( 80%)

• Dietary deficiency

- cause in developing countries

- infants, pregnancy, adolescence

• Malabsorbtion

• Chronic inflammatory disorders

ANEMIA OF CHRONIC DISEASE

CAUSES

-chronic infections (often in children)

- chronic inflammatory disorders (obesity, uremia, autoimmune diseases)

-chronic inflammation (elder people)

- neoplastic disorders

- autoimunne disorders

PATHOMECHANISM

1. Decreased iron absorption from GI tract

2. Decreased release of iron from macrophages from RE system

3. Relative reduction in EPO (cytokines) and impaired marrow response

4. Shortened RBC survival

CASE 2

CASE 2

A 70-year-old woman presented with progressive weakness and fatigue. The symptoms had begun

about a month earlier and she no longer felt well enough to do her housework or take her daily walk.

Although her breathing was normal at rest, she was too short of breath to walk more than two or

three blocks. She had no history of recent bleeding, juandice, fever, anemia or heart disease. She had

not been exposed to medications. She had not abused alcohol and had no previous hospitalization

Finding on the physical examination were unremarkable except for mild tachycardia at rest (96), a

blood pressure of 146/84 mm Hg, pallor and the stool was negative for occult blood.

The following peripheral blood tests were performed:

Hb- 8,4 (13-18 g/dL)

Ht – 32 (40-54%)

MCV- 103 (80-95 fL)

MCH- 35 (27-32pg)

MCHC-37 (32-36 g/dL)

RBC- 3,3 (4.5-6 T/L)

WBC- 3,9 (4-10 G/L)

PLT- 110 (150-450 G/L)

Iron – 150 ( 50-180 μg/dL)

TIBC- 525 (280-550 μg/dL)

Bilirubin – 11 ( 3-10 mg/L)

Bleeding Time ( Duke) - 6 (2-5min)

1. What is the explanation for her weakness, fatigue and breathing problems?

2. What is the most probable reason for low level of RBCs, WBCs and platelets?

3. What additional blood test would be helpful ?

4. How do you explain the out of range bilirubin level ?

5. How do you explain the prolonged bleeding time?

MACROCYTIC ANEMIA

MCV > 100fL

• Abnormalities of DNA metabolism

- vitamin B12 deficiency (pernicious anemia)

- folate deficiency

- drugs (metothrexate, contraceptives)

• Lipid abnormalities

- liver disease

• Alcohol abuse (poor diet, GI complications)

MEGALOBLASTIC ANEMIA I

Abnormalities in the absorption or metabolism of folate

or cobalamine ( vit. B12).

The result is that DNA synthesis is inhibited and the cell

cycle is slowed down during erythropoesis.

Hemoglobin synthesis in cytoplasm is unchanged but

erythriblasts increase in size (megaloblasts; MCV>100fL)

and oval erythrocythes pass into the blood.

There is normal cytoplasm synthesis but, nucleus

synthesis is delayed.

MEGALOBLASTIC ANEMIA II

The formation of granulocytes and

megacaryocytes (platelets) is also disturbed

There is premature destruction of megaloblasts in

bone marrow (inefficient erythropoesis) and

shortened life-span (premature hemolysis)

COBALAMINE ( VITAMIN B12) I

Must be taken up by humans in their food.

Foods rich in cobalamine: mostly animal food: meat,

eggs, milk, fish

Daily requirement 1-5 g

Main storage – liver (enough for 3 years)

Normal absorption of vit B12 needs intrinsic factor,

produced by the gastric mucous (parietal cells).

Autoimmune disorder- antibodies vs. intrinsic factor or

parietal cells is called pernicious anemia

Site of absorption - ileum

COBALAMINE ( VITAMIN B12) II

METABOLIC FUNCTION

In cells it is metabolized to methylocobalamine

Methylcobalamine is needed to demethylation of

methyltetrahydrofolate to tethrahydrofolate (THC)

Methylcobalamin

N5-methyl-THF THF DNA synthesis

homocysteine methionine

Fatty acids synthesis (conversion of methylmalonyl CoA

to succinyl CoA).

COBALAMINE ( VITAMIN B12) III

DEFICIENCY

Intrinsic factor deficiency (pernicious anemia)

Too little uptake with food (strict vegetarian diet)

Competition for cobalamine ( broad fish tapeworms:

(Diphyllobothrium latum) in the intestinal lumen)

The symptoms of cobalamine deficiency may occur only

after years of blocked supply (great liver storage)

FOLATE I

Necessary for the synthesis of DNA (the only source of

thymidin)

Folate deficiency inhibits the rate of formation of rapidly

proliferating cells for example during erythropoesis and tumor

formation.

Daily intake – 50 g

Food source – leafy fresh green vegetables (overcooking food

destroys folate), red meats (liver); must be provided by dietary

sources

Absorption – duodenum, upper jejunum

Main storage – liver ( 2-3 months)

FOLATE DEFICIENCY

Too little folate uptake with food (fresh green

vegetables)

Increased requirement (pregnancy)

Malabsorbtion ( diseases of the small intestine e.g.

Celiac disease)

Inhibition of folate synthesis caused by cytostatic

chemotherapeutics (methotrexat, fluorouracil,

aminopterin)

Low absorption (contraceptive pills)

Folate deficiency is more commonly

encountered in clinical practice

Megaloblastic anemia is often seen as

malnutrition in the elderly, alcoholics ,

teenagers and in pregnancy

MEGALOBLASTIC ANEMIA - SYMPTOMS

H E M A T O L O G I C A L

Megaloblasts MCV →>100, reduced Hb, RBC, Ht

G A S T R O I N T E S T I N A L

Severe glossitis (inflamed red and painful tongue)

Diarrhea

N E U R O N A L (only vit. B12 deficiency → reduced fatty acids

synthesis → disturbed myelin synthesis → neuronal symptoms

Dementia

Ataxic gait (unsteady)

Psycholgical disturbances

Sensory disorders

CASE 3

CASE 3

44-year-old patient, 4 years treated with chronic immunosuppressive drugs, because of systemic lupus

erythematosus, came to the hospital with intensified following disorders such speech disorders and jaundice.

On aadmission the patient, has no circulatory and respiratory problems and no clinical signs of infection. CT

excluded bleeding into the central nervous system.

The following peripheral blood tests were performed:

Hb- 8,4 (13-18 g/dL)

Ht – 37 (40-54%)

MCV- 84 (80-95 fL)

MCH- 29 (27-32 pg)

MCHC- 34 (32-36 g/dL)

RBC- 3,3 (4.5-6 T/L)

WBC- 8.8 (4-10 G/L)

PLT- 160 (150-450 G/L)

Reticulocytes – 7.1 (0.2-2%)

Iron – 100 ( 50-180 μg/dL)

Bilirubin – 19 ( 3-10 mg/L)

LDH - 250 (140-240 U/l)

Free Hb - 85 (trace 3-10 mg/dL)

Haptoglobin - 0,4 (0.5-2 g/L)

1. Why free Hb and haptoglobin were tested?

2. What is the link between systemic lupus erythematosus and anemia?

3. What are the reasons of hemolytic anemia?

4. Why bilirubin and LDH were tested?

5. How do you explain high reticulocytes count in this case ?

6. What are the compensatory mechanisms of anemia?

Systemic lupus erythematosus (SLE) is an autoimmune

disease.

In this disease, the body's immune system mistakenly

attacks healthy connective tissue (antibodies)

Connective tissue is present in our entire body, therefore the

symptoms affect many organs

Antibodies affect the skin, joints, kidneys, brain, RBCs,

PTLs and other organs.

LUPUS ERYTROMATOUS

HEMOLITIC ANEMIA

Hemolytic anemia is a form of anemia due to hemolysis.

Hemolysis is the rupturing of erythrocytes and the release of their contents (Hb) into surrounding fluid (blood plasma).

The abnormal breakdown of (RBCs), either in the blood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular).

RBC life span below 100 days (as little as several days = definition of hemolysis)

HEMOLITIC ANEMIA

CORPUSCULAR HEMOLYTIC ANEMIA

(MAINLY INHERITED). RBCs are removed from peripheral blood by extravascular hemolysis

• spherocytosis, ovalocytosis, sicle cell anemia, talasemia

EXTRACORPUSCULAR HEMOLYTIC ANEMIA (MAINLY ACQIRED). RBCs are removed from peripheral blood by intravascular hemolysis

• blood group mismatches, malaria, snake poisoning, mechanical cause (e.g. artificial heart valves), viral infection

EXTRAVASCULAR HEMOLYSIS

INTRAVASCULAR HEMOLYSIS

JAUNDICE

Jaundice is an excess of bilirubin in blood

Bilirubin is a breakdown product of hemoglobin that it is

normally excreted into the bile

In hemolytic anemia increased red blood cell destruction

leads to the increased release of free Hb and increased

production of bilirubin

The liver is not able to remove bilirubin so fast, leading to

pigmented skin and the whites of the eyes with the

characteristic yellowish color indicative of jaundice

1. CENTRAL MECHANISMS

Increased cardiac output

Increased heart rate (tachycardia)

2. PERIPHERAL MECHANISMS

Vasodilation (reduced peripheral resistance)

Lowering blood viscosity

Increased blood flow through the heart and brain (activation of the sympathetic

nervous system →vasopresin→ relaxation of cerebral and coronary arteries and constriction of other

artheries)

Decreased blood flow through the kidneys, muscles, skin

Increased erythropoetin synthesis

3. ERYTHROCYTE MECHANISM :

Increased synthesis of 2,3 - DPG (bifosfoglicerynian) →easier oxygen transfer to the

tissues

4. TISSUE MECHANISMS :

Increased extraction of oxygen

Increased anaerobic methabolism

ANEMIA – COMPENSATORY MECHANISMS

CASE 4

CASE 4

56 year old man suffering from diabetes, was admitted to hospital because of chronic fatigue, somnolence and

poor concentration. In contrast to the previous period he could not focus his attention on anything , which

greatly hinder his business. During the night, he gets up 2-3 times to urinate. Do not drink alcohol and smoke

cigarettes.

The following peripheral blood tests were performed:

Hb - 11 (13-18 g/dL)

Ht – 32 (40-54%)

MCV - 85 (80-95 fL)

MCH - 30 (27-32 pg)

MCHC - 36 (32-36 g/dL)

RBC- 3.8 (4.5-6 T/L)

WBC- 8.1 (4-10 G/L)

PLT- 190 (150-450 G/L)

Urea – 123 (15-40 mg/dL)

Creatinin – 2,8 (0.6-1.3 mg/dL)

pH - 7.38 (7.35-7.45)

Bicarbonate – 27 (23-27 mmol/L)

Na – 142 (135-145 mmol/L)

K – 4,4 (3.8-5.0 mmol/L)

24 h urine collection – 3L (1,5-2.0 L)

Proteinuria – 500 mg/dL ( < 30 mg/ day)

Glycosuria – 200 mg/dL ( 0 mg/dL)

1. How do you explain the elevated serum creatinine and urea?

2. What is the patient daily loss of protein ?

3. How do you interpret anemia in this particular case. Is it normocytic, makrocytic or microcytic anemia?

4. How do you interpret polyuria, proteinuria and glycosuria?

5. Is diabetes melitus cause of renal failure or anemia?

NORMOCYTIC ANEMIA

MCV 80-100fL

Acute blood loss

Aplastic anemia

Chronic renal failure (EPO)

Hemolytic anemia (normocytic & microcytic)

DIABETIC NEPHROPATHY Chronic loss of kidney function due to diabetes mellitus

Diabetic nephropathy begins because of long lasting elevated

blood glucose levels which damage arterioles and nephrons

This implicated multiple changes in kidneys:

- reduced GRF

- proteinuria

- glycosuria

- polyuria (due to osmotic diuresis)

- elevated serum urea and creatinin level

- anemia

- water and electrolytes disturbances

- disturbances of acid-base balance

ANEMIA OF CHRONIC DISEASE PATHOMECHANISM OF CHRONIC RENAL FAILURE IS

CONNECTED WITH CHRONIC INFLAMMATION

CAUSES

-chronic infections (often in children)

- chronic inflammatory disorders (obesity, uremia, autoimmune diseases)

-chronic inflammation (elder people)

- neoplastic disorders

- autoimunne disorders

PATHOMECHANISM

1. Decreased iron absorption from GI tract

2. Decreased release of iron from macrophages from RE system

3. Relative reduction in EPO (cytokines) and impaired marrow response

4. Shortened RBC survival