Microcytic Anaemia

Overview

Microcytic anemia is characterized by low hemoglobin and low mean corpuscular volume. It is very important to confirm the cause of anemia, starting with a peripheral blood smear and an Iron panel. Patients with severe or symptomatic anemia (Hb < 7g/dL, Hb < 8g/dL is CAD) should get fluid resuscitation and pRBCs.

Microcytic anemia

Disorder	MCV	Iron	TIBC	Ferritin	RDW	Hepcidin
IDA	Very Low	Low	High	Low	Wide	Normal
Anemia of chronic disease	Normal/Low	Low	Low	High	Normal	High
Thalassemia	Very low	Normal/High	Normal/High	High	Normal	Normal
Sideroblastic anemia	Low	High	Low/Normal	High	Normal	Normal

Chelators

Iron	Deferoxamine, Deferasirox
Mercury	Dimercaprol
Lead	Succimer, Dimercaprol, EDTA
Copper	Penicillamine
Zinc	EDTA

• Causes of microcytic anemia STAILS
  • Defective globin chain
    • Sickle cell disease
    • Thalassemia
  • Defective heme synthesis
    • Anemia of chronic disease (second most common cause)
    • Iron deficiency anemia (IDA, most common cause)
    • Lead poisoning
    • Sideroblastic anemia
• Signs and Symptoms of Anemia
  • Fatigue
  • Weakness
  • Malaise
  • Pallor
• Iron Panel
  • Measures of Extracellular iron
    • Serum Iron: amount of free iron in the serum
    • Total Iron Binding Capacity: Indirect measure of transferrin which transports iron in serum.
  • Measures of Intracellular iron
    • Serum ferritin: amount of ferritin (iron stores) in the body. Also an acute phase reactant. It is elevated in inflammation and decreases in IDA.

Iron Deficiency Anaemia

Iron deficiency anemia is the most common cause of Iron deficiency anemia. It usually has some unusualy symptoms e.g. Pica. Most cases of IDA are non-emergent. It is important to determine the underlying cause. Most patient are treated with iron supplementation.

Seen in upto 14% of menstruating women.

Plummer-Vinson synrome; A rare triad of IDA, esophageal webs and resultant dysphagia.

• Causes of IDA
  • Excess loss
    • Menorrhagia
    • Overt loss (epistaxis, hemorrhoids)
    • Occult GI loss (Upper or Lower Bleed – PUD, colon cancer)
    • Occult hematuria
    • Blood Donation
  • Increased requirment
    • Pregnancy
    • Lactation
    • Prematurity
    • Growth
  • Low absorption
    • Malabsorption (Gastrectomy, Autoimmune disease, Coeliac disease, Crohn’s disease)
  • Poor dietary intake
• What are the factors that favor iron absorption and those that reduce it?
  • Factors that favour iron absorption
    • Haem iron
    • Ferrous form (Fe2+)
    • Acids (HCl, vitamin C)
    • Solubilizing agents (e.g. sugars, amino acids)
    • Reduced serum hepcidin
    • Ineffective erythropoiesis
    • Pregnancy
    • Hereditary hemochromatosis
  • Factors reducing iron absorption
    • Inorganic iron
    • Ferric form (Fe3+)
    • Alkalis – antacids, pancreatic secretions
    • Precipitating agents – phytates, phosphates, tea
    • Increased serum hepcidin
    • Decreased erythropoiesis
    • Inflammation
    • Calcium (due to chelation of iron)
• Iron absorption and the role of hepcidin in iron metabolism
  • Occurs in the duodenum and upper jejunum
  • Dietary iron is released from ingested food in the stomach by gastric acid and pepsin
  • Gastric acid converts ferrous iron to its ferric form
  • Insoluble non-heme Ferric iron (Fe3)* is mainly reduced to ferrous iron (Fe2+) by ferrireductase (Duodenal Cytochrome B reductase). It then enters enterocytes via the **divalent metal transporter 1 (**DMT-1)
  • Iron-containing heme enters the enterocyte via the heme carrier protein 1 (HCP1). Heme oxygenase breaks down heme within the enterocyte, releasing Fe2+, CO and biliverdin
  • **Mucin-bound Fe3+**is absorbed into the enterocyte via the integrin receptor in the alkaline environment of the duodenum
  • Iron is either stored in enterocytes as ferritin or transported by mobileferrin to the basolateral side of the cell
    • Hephaestin (ferric reductase) converts Fe3+ → Fe2+
  • Ferroportin transfers iron into plasma where it reaches its target bound to transferrin
    • Transferrin binds 2 Fe2+ ions
  • The enzyme hepcidin regulates intestinal absorption of iron
    • Hepcidin is synthesized in the liver
    • Its production is regulated by the human hemochromatosis protein (HFE; High Fe2+ protein)
      • IDA, Anemia, hypoxia increases Hepcidin
      • Fe overload, inflammation
    • Increased body iron stores (plasma transferrin saturation, IL-6) → increased HFE protein → increased hepcidin → prevention of iron absorption and release from macrophages
      • Binds to and inhibits ferroportin on macrophages, hepatocytes and enterocytes
    • Iron deficiency (Erythroblasts, Hypoxia, EPO, Matripase) → decreased hepcidin → increased iron absorption
• Signs and Symptoms of
  • Signs and symptoms of anemia:
    • Fatigue, lethargy
    • Pallor (primarily in highly vascularized mucosa e.g. the conjunctiva)
    • Cardiac: tachycardia, angina, dyspnea on exertion, pedal edema and cardiomyopathy in severe cases
  • Koilonychia (specific for IDA but is rarely seen in high-income countries), brittle nails and hair loss
  • Pica, dysphagia (associated with Plummer-Vinson syndrome)
  • Angular cheilitis (Stomatitis)
  • Atrophic glossitis: erythematous, edematous, painful tongue with loss of tongue papillae (smooth, bald appearance)
  • Associated with Plummer-Vinson syndrome
    • Triad of IDA, postcricoid dysphagia, and upper esophageal webs
    • Associated with an increased risk of esophageal squamous cell carcinoma and glossitis
• Investigations
  • Complete Blood Count
    • Low HCT
    • Decreased Hb
    • Decreased MCV
    • Decreased MCH
    • RDW increased (anisocytosis – differentiates IDA from thalassemia)
  • Peripheral Blood Film
    • Microcytic hypochromic red cells
    • Target cells and pencil-shaped poikilocytes
  • Reticulocyte count: Low
  • Bone Marrow studies
    • Diminished stores
    • Dimorphic features (due to treatment)
  • Iron panel
    • Low serum iron (no iron in blood)
    • Low ferritin (no need for ferritin)
    • Increased Total Iron Binding Capacity (TIBC) / Transferrin
    • Increased serum transferrin receptor
  • Stool for ova and cyst
  • Colonoscopy and Gastroscopy
  • Coeliac serology
• Treatment
  • Treat the underlying cause
  • PO Iron supplementation (Ferrous sulphate) 200mg q8h
    • Raises Hb by 1g/dL/week
    • Continue for 3 months after Hb normalizes to replenish stores
    • Side effects include nausea, abdominal discomfort, diarrhoea or constipation and
  • Parenteral Iron Supplementation (for patients with malabsorption etc.)
  • Recheck Iron in 3 weeks

Sideroblastic Anaemia

Sideroblastic anaemia is caused by the defective incorporation of iron into protoporphyrin (the final step in the synthesis of heme). It is an umbrella term referring to multiple disorders with different etiologies.

• Causes of sideroblastic anemia
  • Inherited
    • X-linked sideroblastic anemia due to delta-ALA-synthase gene defect
  • Acquired
    • Vitamin B6 deficiency
    • Excess alcohol intake
    • Copper deficiency
    • Heavy metal toxicity (Lead, Copper, Zinc)
      • Lead paint on walls
    • Drugs (Isoniazid, Chloramphenicol)
• Patient History
  • Excess Alcohol intake
  • Heavy metal toxicity (Lead inhibits ALA dehydratase and ferrochelatase)
  • Vitamin B6 deficiency (INH for Tuberculosis)
• Signs and symptoms
  • Fatigue, pallor, malaise, weakness
  • Excess alcohol
    • Past History
    • Hepatomegally
    • Jaundice etc.
  • Lead poisoning
    • Lead lines on metaphyses of long bones
    • Encephalopathy and Erythrocyte basophilic stippling
    • Abdominal colic
    • Drop (wrist and foot)
  • Vitamin B6 deficiency
    • Cheilitis, Glossitis, Conjunctivitis
• Investigations ****
  • Complete Blood count
    • Low Hb (iron is not able to bind protoporphyrin)
  • Peripheral Blood Film
    • Basophilic stippling of RBCs (the “stipples” are iron granules)
    • Normocytes or macrocytes (more common in acquired etiologies)
  • Serum iron studies
    • High ferritin (to bind the intracellular iron that cannot bind protoporphyrin)
    • High iron (Iron is backed up – the only anaemia with elevated iron levels)
    • High transferrin saturation
    • Normal or low TIBC (transferrin is not affected by this disease)
  • BMA (Prussian blue staining)
    • Ringed sideroblasts
• Treatment
  • Treat underlying cause
  • Pyridoxine supplementation (co-factor for delta-ALA synthase. Accelerates hemoglobin synthesis)
  • Dimercaprol, EDTA, Succimer (paediatric) for Lead poisoning
  • Transfusion if symptomatic

Anaemia of Chronic Disease

This is the most common cause of anemia in hospitalized patients. Anaemia of chronic disease occurs when the body tries to “hide” iron away from serum (away from potential bacteria). Technically, it is due to impaired utilization of iron. During inflammation, hepcidin causes sequestration of iron and transferrin is reduced to decrease total amount of extracellular iron.

• Some causes of anemia of chronic disease other etiologies can cause this kind of anemia?
  • Chronic liver disease
  • Chronic kidney disease
  • Heart Failure
  • Infections (Viral, bacterial, parasitic, fungal)
  • Chronic infection (Tuberculosis)
  • Autoimmune diseases (Rheumatoid Arthritis, Systemic Lupus Erythematosis)
  • Malignancy (Lung cancer, Breast cancer, lymphoma)
• Pathophysiology of anemia of chronic disease
  • Inflammation causes the production of cytokines (IL-1 and IL-6) which stimulates hepatocytes to produce hepcidin.
  • The following mechanisms are responsible for the resultant anaemia:
    1. Poor utilization of iron in erythropoiesis
    2. Cytokine-induced shortening of RBC survival
    3. Decreased production and response to erythropoietin
  • Hepcidin
    • Hepcidin reduces iron absorption and decreases iron release from macrophages to erythroid precursors in the bone marrow (by downregulating ferroportin and increasing apoferritin)
  • Production of inflammatory cytokines
    • TNFa and IL-1 from activated macrophages, and IFN-y from activated T-cells impairs proliferation of erythroid progenitor cells
    • This occurs through
      • Diminished response to erythropoietin
      • Decreased production of EPO by the kidney
  • Lactoferrin
    • Neutrophil lactoferrin is released into plasma during inflammation
    • It scavenges iron at the expense of transferrin and becomes bound to macrophages and hepatocytes which salvage the iron
    • RBCs are deprived of plasma iron since they lack lactoferrin receptors
  • Ferritin
    • Increased levels of ferritin in inflammation bind iron
    • Developing RBCs lack ferritin receptors and are thus deprived of iron
  • All these lead to reduced erythrocyte survival and lifespan
• Investigations
  • Full Blood Count
    • Low Hb
    • Normal MCV (early), Low MCV (late)
    • Normal MCH (late stage)
    • Leukocytosis
    • Thrombocytosis
  • Reticulocyte count – no reticulocytosis
  • Peripheral blood film
    • Normocytic normochromic red blood cells (early phase)
    • Microcytic hypochromic red blood cells may be seen in the coexisting Iron deficiency (Late stage)
  • Iron studies
    • Low serum iron (iron is sequestered in cells)
    • Low total iron binding capacity (TIBC = low transferrin)
    • Normal or low transferrin saturation
    • High serum ferritin (to hold sequestered iron)
    • Decreased reticulocyte hemoglobin (Iron restricted erythropoiesis)
    • Normal soluble transferrin receptor (normal intracellular iron)
  • Bone marrow study: if other cytopaenias are abundant
    • Abundant stores of iron in macrophages – Haemosiderin laden-macrophages
• Treatment
  • Treat the underlying cause (usually entails steroids for chronic inflammatory diseases)
  • Supplemental B12, Folate
  • Transfusion is rarely necessary
  • Erythropoietin analogous (Epoietin, Darbepoietin) if there is underlying chronic kidney disease

Thalassemia

Thalassemia is a disorder of globin production. It presents as microcytic anemia with a relatively normal iron study. The definitive diagnosis of thalassemia is hemoglobin electrophoresis. Iron supplementation is generally contraindicated in Thalassemia (iron is fine, the problem is with globin synthesis)

α-thalassemia: a disorder of alpha globin production due to deletion of alpha globin genes. 4 genes code for alpha-globin. The severity of the disease is worse with more alpha genes missing

αα/αα: normal

αα/α-: silent carrier

α-/α- or αα/—: α-thalassemia trait (minor symptoms)

α-/—: HbH disease (β4 tetramer w/major symptoms)

—/—: Hemoglobin Barts (stillbirth)

β-thalassemia: a disorder of beta globin production due to a **point mutation at a splice site **or promoter sequence. 2 genes code for beta globin. A β gene may be fully functional (β), low function (β), or non-functional (β0)

β**-thalassemia minor**: a patient has one normal gene and one mutated gene

β**-thalassemia major (Cooley’s anemia)**: a patient has two mutated genes

• Signs and symptoms
  • Weakness, fatigue, malaise and pallor
  • Splenomegaly
  • Bony abnormalities (jaw, frontal bone)
  • Fractures
• Investigations
  • Complete Blood Count
    • Low Hb (may be normal)
    • Low MCH (out of proportion to the anemia – Mentzer index < 13)
  • Hemoglobin electrophoresis
  • Genetic testing
• Treatment
  • Tranfusion for highly symptomatic patient or Hb < 7 g/dL
    • Keep Hb > 9 g/dL
  • Iron chelation therapy (Deferoxamine, Deferasirox) in patient who have had repeat tranfusions (and are at risk of iron overload syndrome)
  • Splenectomy in case of hypersplenism
• Long-term complications
  • Gallstones
  • Infections
  • Ulcers
  • Hypersplenism
  • Thrombosis
  • Cardiac complications from hemochromatosis

α-thalassemia

α-thalassemia is more common among black individuals (Trans: α-/α-) and asians (cis: αα/—).

β-thalassemia

β-thalassemia is more common among Mediterraneans (Italians, Greeks)

• BETA THAL D
  • Basophlilic stippling
  • Excess iron transfusion
  • Transplant bone marrow (curative)
  • A (HbA decreased or absent)
  • Tower skull and bony abnormalities
  • Heart failure
  • Anisocytosis
  • Liver and spleen enalrgement
  • Deferoxamine for iron chelation