1. Iron de ciency anemia
De nition: Most common form of anemia worldwide.
Classi cation of anemia in general:
- microcytic: iron, thalassemia, sideroblastic, lead poisoning, anemia of chronic disease
- macrocytic: B12, folate
- normocytic: acute blood loss anemia, occult bleeding, anemia of chronic disease, hemolytic
anemia, chronic kidney disease, aplastic anemia
Etiology:
- due to inadequate intake of iron with the diet
- decreased absorption ( e.g. atrophic gastritis, in ammatory bowel disease
- increased demand ( e.g. during pregnancy)
- increased loss ( e.g. GIT bleeding, menorrhagia)
- based on age
- Infants
- Exclusive intake of nonforti ed cow's milk
- Exclusive breastfeeding after 6 months of age
- Children
- Malnutrition (mainly developing countries)
- Meckel diverticulum
- Excessive intake of cow's milk (> 24 ounces/700 mL per day): In addition to low iron
content, the calcium and proteins in cow's milk disrupt iron absorption.
- Adolescence: menarche/menstruation
- Adults (20–50 years)
- Menorrhagia or pregnancy (females)
- Peptic ulcer disease (males)
- Adults > 50 years:
- Colon polyps/carcinoma in developed countries
- Hookworm (Ancylostoma duodenale, Necator americanus) in developing countries
- based on underlying mechanisms
- Iron losses
- Bleeding
- 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
- Menorrhagia
- Hemorrhagic diathesis (e.g., hemophilia, von Willebrand disease)
- Meckel diverticulum
- Dialysis-dependent renal failure
- Frequent blood donation
- Decreased iron intake
- Chronic undernutrition
- Cereal-based diet
- Strict vegan diet
- Decreased iron absorption
- Achlorhydria/hypochlorhydria (e.g., due to autoimmune or H. pylori infection-induced
atrophic gastritis)
- In ammatory bowel disease, celiac disease
- Bariatric surgery
- Increased demand
- Pregnancy
- Lactation
- Growth spurt
- EPO therapy
flfi fi fi fi fl
,Clinical features:
- signs and symptoms of anemia: fatigue, pallor, cardiac: tachycardia, agnina, dyspnea on
exertion, pedal edema
- Brittle nails, koilonychia, hair loss
- pica, dysphagia
- angular cheilits
- atrophic glossitis
Diagnostics:
- Diagnosis of IDA requires the presence of anemia (low hemoglobin or hematocrit) and evidence
of low iron stores (usually determined by serum ferritin and iron levels).
- Typically manifests as microcytic, hypochromic anemia with anisocytosis, low serum ferritin,
and low serum iron levels
- labs
- Complete blood count with di erential
- ↓ Hemoglobin: anemia is typically de ned as a hemoglobin level less than 2 standard
deviations below normal (for age and sex) [1]
- ♂: < 14 g/dL
- ♀: < 12 g/dL
- ↓ Hematocrit
- RBC: initially normal; decreased (with prolonged de ciency)
- ↓ Mean corpuscular volume: microcytic
- ↓ Mean corpuscular hemoglobin: hypochromic
- Normal or ↓ reticulocyte count
- ↑ Red cell distribution width : di erentiates IDA from anemia of chronic disease and
thalassemia trait (where the RDW is usually normal)
- Iron studies
- ↓ Serum ferritin
- ↓ Serum iron
- ↑ Serum transferrin and total iron binding capacity (TIBC)
- ↓ Transferrin saturation (< 20%)
- ↑ Serum free erythrocyte protoporphyrin
- Peripheral blood smear:
- Anisocytosis
- Increased zone of central pallor
- Bone marrow biopsy (rarely indicated): in patients with suspected IDA and nondiagnostic iron
studies, low bone marrow iron is diagnostic of IDA
- evaluation of underlying cause: DD
DD:
ff ff fi fi
, Low ferritin and iron levels in combination with an elevated TIBC are diagnostic of iron
de ciency anemia.
Increased ferritin does not rule out iron de ciency anemia. It can be increased in response
to simultaneousin ammation.
Treatment:
- Dietary modi cations
- Infants and young children: restrict cow's milk intake, use iron-forti ed formula, introduce
iron-rich foods (pureed form)
- Adults: increase consumption of iron-rich diet (meats, iron-forti ed food, fresh green leafy
vegetables)
- Oral iron therapy:
- Indicated in all patients with IDA (if tolerated)
- Should initially be administered for 3–6 months [6]
- Adverse e ects: gastrointestinal discomfort, nausea, constipation, black discoloration of
stool
- Absorption may be enhanced by simultaneous consumption of vitamin C (e.g., with lime
juice).
- Foods (e.g., tea, cereals) and drugs (e.g., calcium, antacids, PPIs) that decrease intestinal
absorption of iron should be avoided.
- Parenteral iron therapy
- Indicated in
- Nonadherence/intolerance to oral iron therapy
- Intestinal malabsorption
- Patients with Hb < 6 g/dL who decline blood transfusions
- Available forms (ferric preparations): iron dextran, sodium ferric gluconate, and iron sucrose
- Adverse e ects:
- Thrombophlebitis
- Iron dextran can cause myalgia, arthralgia, headaches, and, rarely, anaphylactic shock
within 1–2 days of infusion.
- Blood transfusion
- See transfusion
- Recommended for severe anemia (Hb < 7 g/dL)
- Treat the underlying disease (e.g., antihelminthics for hookworm, OCPs for menorrhagia)
fi ff fi fl fi fi fi
, 2. Macrocytic and megaloblastic anemias.
Vitamin B12 anemia
Etiology:
- Malabsorption
- ↓ Intrinsic factor
- Pernicious anemia: most common cause of vitamin B12 de ciency
- Atrophic gastritis (e.g., secondary to H. pylori infection)
- Gastrectomy
- ↓ Reduced uptake of IF-vitamin B12 complex in terminal ileum: e.g., Crohn's disease, celiac
disease, pancreatic insu ciency, surgical resection of the ileum
- Malnutrition: e.g., chronic alcoholism, anorexia nervosa, or strict vegan diets
- Increased demand: e.g., during pregnancy, breastfeeding, sh tapeworm (Diphyllobothrium
latum) infections, and leukemia
Pathophysiology:
- Physiological function: Vitamin B12 is a water-soluble cofactor for enzymatic reactions of DNA
synthesis (via methionine synthase) and odd-chain fatty acid metabolism (via methylmalonyl
CoA mutase). A de ciency of vitamin B12 leads to enzyme dysfunction.
- Dysfunctional methionine synthase (normally converts homocysteine to methionine, thereby
demethylating N5-methyl-THF to THF)
- → ↓ Tetrahydrofolate (THF) → ↓ DNA synthesis → large, nucleated hematopoietic cells,
including megaloblasts → megaloblastic precursors undergo apoptosis or are phagocytosed
by macrophages → pancytopenia (including megaloblastic anemia)
- → ↓ Methionine → neuropathy
- → ↑ Homocysteine → endothelial damage → predisposes to cardiovascular disease
- Dysfunctional methylmalonyl CoA mutase
- Methylmalonyl CoA cannot be converted to succinyl CoA → accumulation of methylmalonyl
CoA and its precursor propionyl CoA, as well as their associated odd-chain fatty acids,
which cannot be completely metabolized
- Propionyl CoA replaces acetyl CoA in neuronal membranes → demyelination → neurological
manifestations
fi ffi fifi
De nition: Most common form of anemia worldwide.
Classi cation of anemia in general:
- microcytic: iron, thalassemia, sideroblastic, lead poisoning, anemia of chronic disease
- macrocytic: B12, folate
- normocytic: acute blood loss anemia, occult bleeding, anemia of chronic disease, hemolytic
anemia, chronic kidney disease, aplastic anemia
Etiology:
- due to inadequate intake of iron with the diet
- decreased absorption ( e.g. atrophic gastritis, in ammatory bowel disease
- increased demand ( e.g. during pregnancy)
- increased loss ( e.g. GIT bleeding, menorrhagia)
- based on age
- Infants
- Exclusive intake of nonforti ed cow's milk
- Exclusive breastfeeding after 6 months of age
- Children
- Malnutrition (mainly developing countries)
- Meckel diverticulum
- Excessive intake of cow's milk (> 24 ounces/700 mL per day): In addition to low iron
content, the calcium and proteins in cow's milk disrupt iron absorption.
- Adolescence: menarche/menstruation
- Adults (20–50 years)
- Menorrhagia or pregnancy (females)
- Peptic ulcer disease (males)
- Adults > 50 years:
- Colon polyps/carcinoma in developed countries
- Hookworm (Ancylostoma duodenale, Necator americanus) in developing countries
- based on underlying mechanisms
- Iron losses
- Bleeding
- 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
- Menorrhagia
- Hemorrhagic diathesis (e.g., hemophilia, von Willebrand disease)
- Meckel diverticulum
- Dialysis-dependent renal failure
- Frequent blood donation
- Decreased iron intake
- Chronic undernutrition
- Cereal-based diet
- Strict vegan diet
- Decreased iron absorption
- Achlorhydria/hypochlorhydria (e.g., due to autoimmune or H. pylori infection-induced
atrophic gastritis)
- In ammatory bowel disease, celiac disease
- Bariatric surgery
- Increased demand
- Pregnancy
- Lactation
- Growth spurt
- EPO therapy
flfi fi fi fi fl
,Clinical features:
- signs and symptoms of anemia: fatigue, pallor, cardiac: tachycardia, agnina, dyspnea on
exertion, pedal edema
- Brittle nails, koilonychia, hair loss
- pica, dysphagia
- angular cheilits
- atrophic glossitis
Diagnostics:
- Diagnosis of IDA requires the presence of anemia (low hemoglobin or hematocrit) and evidence
of low iron stores (usually determined by serum ferritin and iron levels).
- Typically manifests as microcytic, hypochromic anemia with anisocytosis, low serum ferritin,
and low serum iron levels
- labs
- Complete blood count with di erential
- ↓ Hemoglobin: anemia is typically de ned as a hemoglobin level less than 2 standard
deviations below normal (for age and sex) [1]
- ♂: < 14 g/dL
- ♀: < 12 g/dL
- ↓ Hematocrit
- RBC: initially normal; decreased (with prolonged de ciency)
- ↓ Mean corpuscular volume: microcytic
- ↓ Mean corpuscular hemoglobin: hypochromic
- Normal or ↓ reticulocyte count
- ↑ Red cell distribution width : di erentiates IDA from anemia of chronic disease and
thalassemia trait (where the RDW is usually normal)
- Iron studies
- ↓ Serum ferritin
- ↓ Serum iron
- ↑ Serum transferrin and total iron binding capacity (TIBC)
- ↓ Transferrin saturation (< 20%)
- ↑ Serum free erythrocyte protoporphyrin
- Peripheral blood smear:
- Anisocytosis
- Increased zone of central pallor
- Bone marrow biopsy (rarely indicated): in patients with suspected IDA and nondiagnostic iron
studies, low bone marrow iron is diagnostic of IDA
- evaluation of underlying cause: DD
DD:
ff ff fi fi
, Low ferritin and iron levels in combination with an elevated TIBC are diagnostic of iron
de ciency anemia.
Increased ferritin does not rule out iron de ciency anemia. It can be increased in response
to simultaneousin ammation.
Treatment:
- Dietary modi cations
- Infants and young children: restrict cow's milk intake, use iron-forti ed formula, introduce
iron-rich foods (pureed form)
- Adults: increase consumption of iron-rich diet (meats, iron-forti ed food, fresh green leafy
vegetables)
- Oral iron therapy:
- Indicated in all patients with IDA (if tolerated)
- Should initially be administered for 3–6 months [6]
- Adverse e ects: gastrointestinal discomfort, nausea, constipation, black discoloration of
stool
- Absorption may be enhanced by simultaneous consumption of vitamin C (e.g., with lime
juice).
- Foods (e.g., tea, cereals) and drugs (e.g., calcium, antacids, PPIs) that decrease intestinal
absorption of iron should be avoided.
- Parenteral iron therapy
- Indicated in
- Nonadherence/intolerance to oral iron therapy
- Intestinal malabsorption
- Patients with Hb < 6 g/dL who decline blood transfusions
- Available forms (ferric preparations): iron dextran, sodium ferric gluconate, and iron sucrose
- Adverse e ects:
- Thrombophlebitis
- Iron dextran can cause myalgia, arthralgia, headaches, and, rarely, anaphylactic shock
within 1–2 days of infusion.
- Blood transfusion
- See transfusion
- Recommended for severe anemia (Hb < 7 g/dL)
- Treat the underlying disease (e.g., antihelminthics for hookworm, OCPs for menorrhagia)
fi ff fi fl fi fi fi
, 2. Macrocytic and megaloblastic anemias.
Vitamin B12 anemia
Etiology:
- Malabsorption
- ↓ Intrinsic factor
- Pernicious anemia: most common cause of vitamin B12 de ciency
- Atrophic gastritis (e.g., secondary to H. pylori infection)
- Gastrectomy
- ↓ Reduced uptake of IF-vitamin B12 complex in terminal ileum: e.g., Crohn's disease, celiac
disease, pancreatic insu ciency, surgical resection of the ileum
- Malnutrition: e.g., chronic alcoholism, anorexia nervosa, or strict vegan diets
- Increased demand: e.g., during pregnancy, breastfeeding, sh tapeworm (Diphyllobothrium
latum) infections, and leukemia
Pathophysiology:
- Physiological function: Vitamin B12 is a water-soluble cofactor for enzymatic reactions of DNA
synthesis (via methionine synthase) and odd-chain fatty acid metabolism (via methylmalonyl
CoA mutase). A de ciency of vitamin B12 leads to enzyme dysfunction.
- Dysfunctional methionine synthase (normally converts homocysteine to methionine, thereby
demethylating N5-methyl-THF to THF)
- → ↓ Tetrahydrofolate (THF) → ↓ DNA synthesis → large, nucleated hematopoietic cells,
including megaloblasts → megaloblastic precursors undergo apoptosis or are phagocytosed
by macrophages → pancytopenia (including megaloblastic anemia)
- → ↓ Methionine → neuropathy
- → ↑ Homocysteine → endothelial damage → predisposes to cardiovascular disease
- Dysfunctional methylmalonyl CoA mutase
- Methylmalonyl CoA cannot be converted to succinyl CoA → accumulation of methylmalonyl
CoA and its precursor propionyl CoA, as well as their associated odd-chain fatty acids,
which cannot be completely metabolized
- Propionyl CoA replaces acetyl CoA in neuronal membranes → demyelination → neurological
manifestations
fi ffi fifi
