2. Microcytic anemia

Question 1

Definition of microcytic anemia

Answer 1

Anemia with MCV < 80fL

Question 2

Mechanism of microcytic anemia

Answer 2

Insufficient hemoglobin production

Question 3

Diseases that present with microcytic anemia

Answer 3

1. Defective heme synthesis:
   a. Iron deficiency anemia (the most common)
   b. Lead poisoning
   c. Anemia of chronic disease (late phase)
   d. Sideroblastic anemia
2. Defective globin chain:
   a. Thalassemia

IRON LAST
IRON - Iron deficiency
L - Lead poisoning 
A - Anemia of chronic disease 
S - Sideroblastic anemia 
T - Thalassemia

Question 4

Epidemiology of Iron deficiency anemia

Answer 4

1. Most common form of anemia worldwide
2. Prevalence highest in:
   a. Children up to 5 years of age
   b. Young women of child-bearing age (due to menstrual blood loss)
   c. Pregnant women

Question 5

Etiology of Iron deficiency anemia

Answer 5

1. Iron losses:
   a. Bleeding
   i. Gastrointestinal bleeding
   - Occult gastrointestinal malignancy (e.g., colon cancer)
   - Hookworm infestation (e.g., Ancylostoma spp., Necator americanus)
   - Peptic ulcer disease
   - Increased risk with NSAID use
   ii. Menorrhagia
   iii. Hemorrhagic diathesis (e.g., hemophilia, von Willebrand disease)
   b. Meckel diverticulum
2. Decreased iron intake:
   a. Chronic undernutrition
   b. Cereal-based diet
   c. Strict vegan diet
3. Decreased iron absorption:
   a. Achlorhydria/hypochlorhydria (e.g., due to autoimmune or H. pylori infection-induced atrophic gastritis)
   b. Inflammatory bowel disease, celiac disease
   c. Surgical resection of the duodenum
   d. Bariatric surgery
4. Increased demand:
   a. Pregnancy
   b. Lactation
   c. Growth spurt
   d. Erythropoietin (EPO) therapy

Question 6

Pathophysiology of Iron deficiency anemia

Answer 6

Iron deficiency → ↓ binding of iron to protoporphyrin (last reaction in heme synthesis) → ↓ production of hemoglobin

Question 7

Clinical presentation of Iron deficiency anemia

Answer 7

1. Signs and symptoms of anemia:
   a. Fatigue, lethargy
   b. Pallor (primarily seen in highly vascularized mucosa, e.g., the conjunctiva)
   c. Cardiac: tachycardia, angina, dyspnea on exertion, pedal edema, and cardiomyopathy in severe cases
2. Brittle nails, koilonychia (spoon-like nail deformity) , hair loss
3. Pica, dysphagia
4. Angular cheilitis: inflammation and fissuring of the corners of the mouth
5. Atrophic glossitis: erythematous, edematous, painful tongue with loss of tongue papillae (smooth, bald appearance)
6. IDA can be associated with Plummer-Vinson syndrome (PVS)
   a. Triad of iron deficiency anemia, postcricoid dysphagia, and upper esophageal webs (Thin membranes of normal esophageal tissue protrude into the esophagus causing symptoms such as dysphagia, odynophagia, and food impaction)
   b. Associated with an increased risk of esophageal squamous cell carcinoma and glossitis

DIEd Plumm 
D - Dysphagia 
I - Iron deficiency anemia 
C - Carcinoma of the esophagus 
E - Esophageal web 
P - Plummer-Vinson syndrome

Question 8

Lab studies for Iron deficiency anemia

Answer 8

1. CBC
   a. ↓ Hemoglobin
   i. Women: nonpregnant < 12 g/dL; pregnant < 11 g/dL
   ii. Men: < 13 g/dL
   b. ↓ Hematocrit
   c. ↑ Platelet count (reactive thrombocytosis)
2. RBC indices
   a. ↓ MCV
   b. ↓ MCH
   c. Normal or ↓ reticulocyte count
   d. ↑ RDW
3. Peripheral blood smear
   a. anisocytosis
   b. hypochromasia
4. Iron studies
   a. ↓ serum ferritin
   b. ↓ Serum iron
   c. ↑ Serum transferrin and total iron binding capacity (TIBC)

Question 9

Etiology of lead poisoning

Answer 9

1. Battery manufacturing, metallurgy, corrosion inhibition
2. Drinking water (contaminated by lead plumbing) or contaminated sources
3. Lead-containing paint (common source of exposure in children) from:
   i. Antique or imported toys
   ii. Walls of older homes

Question 10

Pathophysiology of lead poisoning

Answer 10

Inhibition of aminolevulinate dehydratase and ferrochelatase → heme synthesis disruption → ↑ protoporphyrin and ↑ aminolevulinic acid in RBCs

Question 11

Clinical presentation of lead poisoning

Answer 11

1. Nervous system
   a. Polyneuropathy, encephalopathy, headache
   b. Demyelination of peripheral nerves → peripheral neuropathy → paralysis of muscles supplied by the radial or peroneal nerve (wrist/foot drop)
   c. Cognitive impairment, memory loss
   d. Acute encephalopathy: persistent vomiting, ataxia, seizures, coma
2. Kidneys: nephropathy, renal cell carcinoma
3. Red blood cells: symptoms of anemia
4. Other:
   i. Purple-blue line on the gums (lead line or Burton line)
   ii. Severe abdominal pain (lead colic)
   iii. Constipation

Children are especially susceptible to the neurologic effects of lead poisoning

ABCDEFGH 
A: Anemia 
B: Basophilic stippling 
C: Constipation 
D: Demyelination 
E: Encephalopathy 
F: Foot drop 
G: Gum deposition / Growth retardation / Gout 
H: Hyperuricemia / Hypertension

Question 12

Lab studies for lead poisoning

Answer 12

1. Blood lead level (BLL) measurement
2. Basophilic stippling of erythrocytes on peripheral blood smear (lead inhibits RNA degeneration)
3. Microcytic, hypochromic anemia (lead inhibits heme synthesis)
4. Ring sideroblasts in bone marrow

Question 13

Definition of Anemia of chronic disease

Answer 13

Anemia due to chronic inflammation

Question 14

Epidemiology of Anemia of chronic disease

Answer 14

Second most common anemia

Question 15

Pathophysiology of Anemia of chronic disease

Answer 15

Inflammation → increase in cytokines (esp. IL-6) and hepcidin → results in the outcomes listed below:

1. Reduced iron release from macrophages in the reticuloendothelial system and reduced intestinal iron absorption → reduced iron available systemically
2. Reduced response (of production) to erythropoietin (EPO) and relative reduction of EPO levels → reduced RBC synthesis
3. Reduced erythrocyte survival and lifespan

Question 16

Etiology of Anemia of chronic disease

Answer 16

1. Inflammation (e.g., rheumatoid arthritis, systemic lupus erythematosus)
2. Malignancy (e.g., lung cancer, breast cancer, lymphoma)
3. Chronic infections (e.g., tuberculosis)

Question 17

Lab studies for Anemia of chronic disease

Answer 17

1. CBC: normocytic anemia (early phase) → microcytic anemia (later phase)
2. Low iron
3. Low iron saturation
4. Low total iron binding capacity (TIBC)
5. High serum ferritin
6. Low reticulocyte count

Question 18

Definition of Sideroblastic anemia

Answer 18

Anemia caused by defective heme metabolism, which leads to iron trapping inside the mitochondria

Question 19

Etiology of Sideroblastic anemia

Answer 19

1. Inherited: X-linked sideroblastic anemia due to a δ-ALA-synthase gene defect
2. Acquired:
   a. Vitamin B6 deficiency
   b. Lead poisoning
   c. Alcohol use disorder
   d. Drugs (e.g., chloramphenicol, isoniazid , linezolid)
   e. Copper deficiency
   f. Myelodysplastic syndrome
   g. Malignancy

Question 20

Lab studies for Sideroblastic anemia

Answer 20

1. CBC: microcytic anemia
2. Serum iron studies
   a. High ferritin
   b. High iron
   c. High transferrin saturation
   d. Normal/low TIBC
3. Peripheral blood smear
   a. Basophilic stippling of RBCs
   b. Normocytes/macrocytes (more common in acquired etiologies)
4. Prussian blue staining of bone marrow: ringed sideroblasts

Question 21

Definition of Thalassemias

Answer 21

Thalassemias are a group of hereditary hemoglobin disorders characterized by mutations on the α- or β-globin chains (resulting in alpha or beta thalassemia).

Question 22

Epidemiology of Thalassemias

Answer 22

1. Beta thalassemia: most commonly seen in people of Mediterranean descent
2. Alpha thalassemia: most commonly seen in people of Asian and African descent
   - Thalassemia provides partial resistance against malaria.

Question 23

Etiology of Beta thalassemia

Answer 23

1. Cause: gene mutations
   - Beta thalassemia: usually due to point mutations in promoter sequences or splicing sites
   - β-globin locus - short arm of chromosome 11
2. Inheritance pattern: autosomal recessive

In a normal cell, the β-globin chains are coded by a total of two alleles. Thus, there are two main forms of the disease.

a. Beta thalassemia minor (trait): one defective allele
b. Beta thalassemia major (Cooley anemia): two defective alleles
c. Sickle cell beta thalassemia: a combination of one defective β-globin allele and one defective HbS allele

Question 24

Etiology of Alpha thalassemia

Answer 24

1. Cause: gene mutations
   - Alpha thalassemia: usually due to deletion of at least one out of the four existing alleles
   - The α-globin gene cluster is located on chromosome 16
2. In a normal cell, the α-globin chains are coded by a total of four alleles
   a. Silent carrier (minima form): one defective allele (-α/αα)
   b. Alpha thalassemia trait (minor form)
   - Two defective alleles (-α/-α or –/αα)
   - Cis-deletion is common amongst Asian populations, whereas trans-deletions are more common in African populations
   - Children of parents with a two-gene deletion in cis are at higher risk of developing Hb Bart.
3. Hemoglobin H disease (intermedia form): three defective alleles (–/-α) → results in excessive production of pathologically altered HbH
4. Hemoglobin Bart disease (major form): four defective alleles (–/–) → results in excessive production of pathologically altered Hb Bart (consists of four γ-chains (γ-tetramers))

Question 25

Pathophysiology of Thalassemias

Answer 25

1. Inefficient erythropoiesis → anemia
   a. Beta thalassemia minor and major: faulty β-globin chain synthesis → ↓ β-chains→ ↑ γ-,δ-chains → ↑ HbF and ↑ HbA2.
   - HbF protects infants up to the age of 6 months, after which HbF production declines and symptoms of anemia appear.
   b. Alpha thalassemia intermedia (HbH disease) and alpha thalassemia major (Bart disease): faulty α-globin chain synthesis → ↓ α-chains → impaired pairing of α-chains with β-chains and γ-chains→ ↑ free β-, γ-chains → ↑ HbH, ↑ Hb-Bart’s
   c. In minor and minima forms, production of the affected chain is reduced, but enough is produced to prevent severe anemia.
2. Increased hemolysis: One of the chains (either α or β) is reduced → compensatory overproduction of other chains → excess globin chains precipitate and form inclusions within RBCs → erythrocyte instability with hemolysis
3. Anemia → ↑ erythropoietin → bone marrow hyperplasia and skeletal deformities

Question 26

Clinical presentation of Beta thalassemia

Answer 26

1. Minor variant: unremarkable symptoms (low risk of hemolysis, rarely splenomegaly)
2. Major variant
   a. Severe hemolytic anemia that often requires transfusions → secondary iron overload due to hemolysis, transfusion, or both → secondary hemochromatosis
   b. Hepatosplenomegaly
   c. Growth retardation
   d. Skeletal deformities (high forehead, prominent zygomatic bones, and maxilla)
   e. Transient aplastic crisis (secondary to infection with parvovirus B19)
3. Sickle cell beta thalassemia
   a. Features of sickle cell disease
   b. Severity depends on the amount of β-globin synthesis.

Question 27

Clinical presentation of Alpha thalassemia

Answer 27

1. Silent carrier: asymptomatic
2. Alpha thalassemia trait: mild hemolytic anemia with normal RBC and RDW
3. Hemoglobin H disease
   a. Jaundice and anemia at birth
   b. Chronic hemolytic anemia that may require transfusions → secondary iron overload due to hemolysis, transfusion, or both → secondary hemochromatosis
   c. Hepatosplenomegaly
   d. Skeletal deformities (less common)
   e. Compared to thalassemia beta, symptoms in adults are generally less severe.
4. Hb-Bart’s hydrops fetalis syndrome (most severe variant of alpha thalassemia)
   a. Intrauterine ascites and hydrops fetalis, severe hepatosplenomegaly, and often cardiac and skeletal anomalies
   b. Incompatible with life (death in utero or shortly after birth)

Question 28

Lab studies for Thalassemia

Answer 28

1. CBC
   a. Characteristic finding: microcytic hypochromic anemia
   b. Normal RDW
   c. Higher RBC count than IDA
2. Hemolysis evaluation
   a. Coombs test: negative
   b. ↓ Haptoglobin, ↑ LDH, ↑ reticulocytes
   c. Hyperbilirubinemia
3. Peripheral blood smear findings include:
   a. HbH inclusion bodies
   b. Target cells
   c. Teardrop cells
   d. Anisopoikilocytosis
   e. Erythroblasts
4. Detection of haemoglobin variants : Hb-electrophoresis
5. Genetic studies

Question 29

Imaging studies for Thalassemia

Answer 29

1. Skull X-ray
   a. Indication: assessment of craniofacial abnormalities
   b. Findings include:
   i. High forehead
   ii. Prominent zygomatic bones and maxilla (referred to as “chipmunk facies”)
   iii. Hair-on-end (also known as “crew cut”) sign
2. CXR
   a. Indication: suspected extramedullary hematopoiesis in the thorax
   b. Findings include:
   i. Mediastinal or pulmonary masses
   ii. Subperiosteal extension in the ribs (also known as “rib within a rib”)
3. MRI spine: Evaluate mass effect symptoms due to extramedullary hematopoietic pseudotumors