Disorders of Iron Kinetics, Heme Metabolism, and Erythrocyte Destruction

General Concepts in Iron and Heme Metabolism

• Anemia Classication:

  • Anemias of impaired production: Lack of raw materials for hemoglobin assembly.

  • Iron-restricted anemias: Iron is the limiting factor (e.g., IDA and AI).

  • Porphyrias: Blockage in protoporphyrin production leads to accumulation of precursors.

  • Sideroblastic anemias (SAs): Failure to incorporate iron into protoporphyrin, oen due to mitochondrial defects.

• Iron Compartments:

  • Storage: Ferritin in bone marrow macrophages and hepatocytes.

  • Transport: Serum transferrin.

  • Functional: Hemoglobin, myoglobin, and cytochromes.

Iron Deciency Anemia (IDA)

• Etiology:

  • Inadequate Intake: Approximately $1\text{ mg}$ of iron is lost daily via desquamated skin and intestinal epithelium. IDA develops if replacement fails.

  • Increased Need Relative to Supply: Rapid growth (infancy, adolescence), pregnancy (needs nearly $1200\text{ mg}$), and erythropoietin treatment (functional iron deciency).

  • Impaired Absorption: Celiac disease; IRIDA (matriptase-2 mutations leading to high hepcidin); reduced stomach acidity (gastrectomy, PPIs) which prevents conversion of $Fe^{+3}$ to absorbable $Fe^{+2}$.

  • Chronic Blood Loss: GI bleeding (ulcers, tumors, parasites), menorrhagia, repeated blood donations, and intravascular hemolysis (e.g., PNH).

• Pathogenesis Stages:

  • Stage 1 (Storage Depletion): Decreased serum ferritin; no anemia or RBC morphological changes; healthy appearance.

  • Stage 2 (Transport Iron Depletion): Exhausted storage pool; decreased serum iron; increased TIBC; increased soluble transferrin receptor (sTfR) and free erythrocyte protoporphyrin (FEP); decreased reticulocyte hemoglobin content; still no frank anemia.

  • Stage 3 (Functional Iron Depletion): Frank microcytic hypochromic anemia (MCV < 80\text{ fL}, MCHC < 32\text{ g/dL}); elevated RDW (> 15\%).

• Symptoms: Fatigue, weakness, pallor, glossitis (sore tongue), angular cheilosis, koilonychia (spooning of nails), and pica (cravings for ice, dirt, or starch).

• Treatment: Ferrous sulfate ($6\text{ months}$ or more). Reticulocytes increase in $5$ to $10$ days; hemoglobin rises in $2$ to $3$ weeks.

Anemia of Inammation (AI)

• Etiology: Central feature is sideropenia in the face of abundant iron stores (functional iron deciency).

• Pathophysiology:

  • Hepcidin: An acute phase reactant upregulated by $IL-6$ from Kuper cells via the JAK-STAT pathway. Hepcidin binds ferroportin, causing its degradation and blocking iron release from macrophages/enterocytes.

  • Lactoferrin: High-avidity iron-binding protein in neutrophil granules; released to scavenge iron from bacteria but sequesters it from erythroblasts.

  • Cytokines: $TNF-\alpha$, $IL-1$, and $IFN-\gamma$ suppress erythroid progenitors and decrease EPO production.

• Laboratory Findings: Low serum iron, low TIBC (unlike IDA), and normal to high serum ferritin. sTfR is typically normal.

• Diagnosis Modification: The ratio of $sTfR/\log(\text{ferritin})$ is < 1 in AI and > 2 in coexistent IDA/AI.

Sideroblastic Anemias (SAs)

• Hallmark: Ring sideroblasts in the bone marrow (iron-laden mitochondria encircling the nucleus detectable by Prussian blue stain).

• Hereditary Forms:

  • X-linked (XLSA): Mutations in $ALAS2$ (erythroid form of aminolevulinic acid synthase 2). Uses pyridoxine ($Vitamin B_6$) as a cofactor.

  • Pearson Marrow-Pancreas Syndrome: Mitochondrial DNA deletions; maternal inheritance; typically macrocytic anemia and pancreatic insuciency.

• Acquired Forms:

  • Primary: Clonal (Myelodysplastic neoplasms).

  • Secondary: Bone marrow toxins like alcohol, lead poisoning, and antitubercular drugs.

• Lead Poisoning:

  • Mechanism: Inhibits ALA dehydratase (elevating ALA) and ferrochelatase (preventing iron incorporation into protoporphyrin).

  • Morphology: Punctate basophilic stippling (due to inhibition of pyrimidine $5'\text{-nucleotidase}$ causing ribosome aggregation).

Porphyrias

• Denition: Hereditary or acquired deciencis of enzymes in the heme synthetic pathway.

• Clinical Manifestations: Photosensitivity (due to uorescence of accumulated porphyrins in skin), hemolytic anemia, and autouorescence of RBCs under uorescent microscopy.

• Hematologically Signicant: Congenital Erythropoietic Porphyria (CEP), Erythropoietic Protoporphyria (EPP), and X-linked Erythropoietic Protoporphyria (XLEPP).

Iron Overload and Hemochromatosis

• Hereditary Hemochromatosis (HH):

  • Type 1 (HFE-Associated): Most common in northern Europeans ($0.5\% \text{ homozygous}$). Mutation in $HFE$ gene impairs hepcidin regulation.

  • Juvenile (Type 2A/2B): Mutations in hemojuvelin ($HJV$) or hepcidin ($HAMP$); rapid iron accumulation in teens.

• Acquired Overload: Transfusion-related hemosiderosis (each unit of RBCs adds $200$ to $250\text{ mg}$ of iron) and iron-loading anemias (erythroid hyperplasia suppresses hepcidin via erythroferrone).

• Phenotype: "Bronzed diabetes" (skin pigmentation, liver cirrhosis/carcinoma, diabetes mellitus, and congestive heart failure).

• Diagnosis: Transferrin saturation (TS > 45\%), ferritin (> 300\text{ ng/mL} for men), and genetic testing.

• Treatment: Lifelong therapeutic phlebotomy for HH ($500\text{ mL}$ weekly initially) or iron chelators (deferoxamine, deferasirox) for transfusion-dependent patients.

Megaloblastic Anemias (Defects of DNA Metabolism)

• Etiology: Impaired DNA synthesis leading to nuclear-cytoplasmic asynchrony (nucleus lags behind cytoplasm).

• Vitamin Roles:

  • Folate: Carries methyl groups for amino acid and nucleotide metabolism (conversion of dUMP to dTMP).

  • Vitamin B12 (Cobalamin): Cofactor for methionine synthase and methylmalonyl CoA mutase.

• Pathology: The "Folate Trap" occurs in $B_{12}$ deciency because folate is trapped as $5\text{-methyl THF}$. Misincorporation of uracil into DNA leads to strand breaks and apoptosis in bone marrow (ineective hematopoiesis).

• Absorption of $B_{12}$: Requires intrinsic factor (IF) from gastric parietal cells to bind and transport to ileal receptors (cubam complex). Transported in plasma as holotranscobalamin.

• Causes of $B_{12}$ Deciency:

  • Pernicious Anemia (PA): Autoimmune destruction of parietal cells; lacks IF. Highly specic antibody: anti-intrinsic factor.

  • Others: Gastrectomy, $D. latum$ (sh tapeworm) infection, and H. pylori.

• Laboratory Findings:

  • CBC: MCV ($100$ to $150\text{ fL}$), pancytopenia, oval macrocytes.

  • WBC: Hypersegmented neutrophils (> 5\% ve-lobed or $1$ six-lobed).

  • Biochemical: Elevated indirect bilirubin and LDH; elevated homocysteine (both deciencies); elevated methylmalonic acid (MMA) (only in $B_{12}$ deciency).

• Systemic Eects: Neural tube defects (folate); subacute combined degeneration of the spinal cord and psychosis ($B_{12}$).

Bone Marrow Failure

• Aplastic Anemia:

  • Denition: Pancytopenia with a hypocellular bone marrow (< 25\% \text{ cellularity}).

  • Acquired: $70-85\%$. Idiopathic (autoimmune T-cell destruction of stem cells) or Secondary (radiation, drugs like chloramphenicol, benzene, or viruses).

  • Inherited (Fanconi Anemia): Chromosome instability disorder; positive diepoxybutane (DEB) breakage test; physical anomalies (absent thumbs).

  • Inherited (Dyskeratosis Congenita): Telomere maintenance defect; triad of abnormal skin pigmentation, dystrophic nails, and oral leukoplakia.

  • Inherited (Shwachman-Bodian-Diamond): Pancreatic insuciency and cytopenia.

• Pure Red Cell Aplasia (PRCA): Selective decrease in erythroid precursors; normal WBC/PLT.

  • Diamond-Blackfan Anemia (DBA): Congenital PRCA; elevated erythrocyte adenosine deaminase.

• Congenital Dyserythropoietic Anemia (CDA): Characterized by multinucleated erythroblasts and "Swiss cheese" heterochromatin (CDA I).

• Myelophthisic Anemia: Bone marrow inltration by tumor or brosis; causes a leukoerythroblastic blood picture (teardrop cells, NRBCs, immature myeloid cells).

Hemoglobinopathies and Thalassemias

• General Classication:

  • Structural (Qualitative): Altered amino acid sequence (e.g., Hb S, Hb C, Hb E).

  • Thalassemias (Quantitative): Reduced production of normal globin chains.

• Sickle Cell Anemia (Hb SS):

  • Mutation: $[\beta 6 (A3) Glu \to Val]$.

  • Pathophysiology: Deoxygenated Hb S polymerizes into tactoids, distorting RBCs. Causes vasoocclusive crisis (VOC), acute chest syndrome (ACS), and autosplenectomy.

  • Management: Hydroxyurea (induces Hb F via BCL11A repression), Voxelotor (increases $O_2$ anity), and CRISPR-Cas9 (gene editing).

• Hemoglobin C (Hb CC):

  • Mutation: $[\beta 6 Glu \to Lys]$.

  • Morphology: Hexagonal "Washington Monument" crystals.

• Hemoglobin E (Hb EE):

  • Mutation: $[\beta 26 Glu \to Lys]$. Common in Southeast Asia; manifests as a microcytic anemia with many target cells.

• Thalassemia Classication:

  • $\beta\text{-Thalassemia}$: Most common are point mutations. Minor ($\beta/\beta^+$ or $\beta/\beta^0$) shows increased $Hb A_2$ ($3.5\% - 7.0\%$); Major shows severe ineective erythropoiesis and "hair-on-end" skull X-rays.

  • $\alpha\text{-Thalassemia}$: Primarily large deletions.

    • $1\text{ deletion}$: Silent carrier.

    • $2\text{ deletions}$: Trait (microcytosis).

    • $3\text{ deletions}$: Hb H Disease ($\beta_4$ tetramers; golf-ball inclusions on supravital stain).

    • $4\text{ deletions}$: Hydrops Fetalis (Hb Bart; $\gamma_4$ tetramers; fatal in utero).

Hemolysis Mechanisms

• Macrophage-Mediated (Extravascular): RBCs cleared by the spleen; causes spherocytes and increased indirect bilirubin/urobilinogen.

• Fragmentation (Intravascular): RBCs rupture in circulation; causes schistocytes, decreased haptoglobin, hemoglobinuria, and hemosiderinuria.

• Salvage Systems: Haptoglobin binds hemoglobin dimers; hemopexin binds metheme; CD163 (macrophage) and CD91 (hepatocyte) are the respective receptors.

• Nonimmune Causes: TTP (ADAMTS13 deciency), HUS (Shiga toxin or complement defect), and DIC (clotting factor consumption).