Physiology

Maintaining proper levels of heme and its breakdown products is crucial for overall health. Imbalances can lead to a variety of disorders

Normal States

• Normal Heme Synthesis: Balanced production of heme to meet the body’s needs
• Normal Heme Degradation: Efficient breakdown and excretion of heme and its products
• Normal Bilirubin Levels: Proper conjugation and excretion of bilirubin, preventing accumulation in the body
• Normal Iron Levels: Appropriate absorption, transport, and storage of iron to support heme synthesis

Normal Heme Synthesis

• Sufficient production of hemoglobin in red blood cells for oxygen transport
• Adequate synthesis of myoglobin in muscle cells for oxygen storage
• Proper production of cytochromes in mitochondria for electron transfer
• Balanced synthesis of heme-containing enzymes for various metabolic processes

Normal Heme Degradation

• Efficient breakdown of aged or damaged red blood cells
• Effective conversion of heme to biliverdin and bilirubin
• Appropriate conjugation of bilirubin in the liver
• Proper excretion of bilirubin in bile
• Balanced production of urobilinogen in the intestine and its excretion in feces and urine

Normal Bilirubin Levels

• Total Bilirubin: 0.3-1.0 mg/dL (5.1-17.1 μmol/L)
• Direct (Conjugated) Bilirubin: 0.0-0.3 mg/dL (0-5.1 μmol/L)
• Indirect (Unconjugated) Bilirubin: 0.2-0.8 mg/dL (3.4-13.7 μmol/L)
• These levels indicate proper bilirubin production, conjugation, and excretion

Normal Iron Levels

• Serum Iron: 60-170 μg/dL (10.7-30.4 μmol/L)
• Total Iron-Binding Capacity (TIBC): 240-450 μg/dL (42.9-80.6 μmol/L)
• Transferrin Saturation: 20-50%
• Ferritin: 20-200 ng/mL in women, 20-500 ng/mL in men
• These levels indicate proper iron absorption, transport, and storage

Abnormal States

• Porphyrias: Accumulation of porphyrins and porphyrin precursors
• Jaundice and Hyperbilirubinemia: Accumulation of bilirubin
• Iron Deficiency Anemia: Insufficient iron levels
• Hemochromatosis: Excessive iron absorption and accumulation
• Lead Poisoning: Exposure to lead
• Anemia of Chronic Disease: Chronic inflammatory conditions
• Other conditions

Porphyrias

• Definition: Genetic disorders caused by deficiencies in enzymes of the heme synthesis pathway, leading to the accumulation of porphyrins and porphyrin precursors
• Pathophysiology: Enzyme deficiencies result in the buildup of specific porphyrins and porphyrin precursors in tissues and body fluids
• Laboratory Findings: Elevated levels of porphyrins and porphyrin precursors in urine, blood, and feces
• Symptoms: Abdominal pain, neurological dysfunction, photosensitivity
• Specific States
  • Acute Intermittent Porphyria (AIP): Deficiency in porphobilinogen deaminase (PBGD)
    • Elevated ALA and PBG in urine during acute attacks
    • Abdominal pain, neurological symptoms
  • Porphyria Cutanea Tarda (PCT): Deficiency in uroporphyrinogen decarboxylase (UROD)
    • Elevated uroporphyrins in urine
    • Photosensitivity, skin lesions

Jaundice and Hyperbilirubinemia

• Definition: Yellowing of the skin and mucous membranes due to elevated bilirubin levels
• Pathophysiology
  • Pre-hepatic (hemolytic): Excessive red blood cell breakdown
  • Hepatic: Liver dysfunction affecting bilirubin conjugation or excretion
  • Post-hepatic (obstructive): Blockage of bile ducts preventing bilirubin excretion
• Laboratory Findings: Elevated total bilirubin levels, with varying proportions of conjugated and unconjugated bilirubin
• Symptoms: Yellowing of skin and eyes, dark urine, pale stools
• Specific States
  • Pre-Hepatic (Hemolytic Jaundice): Excessive red blood cell breakdown
    • Elevated total bilirubin, primarily unconjugated
    • Normal liver function tests
    • Causes: Hemolytic anemia, transfusion reactions
  • Hepatic Jaundice: Liver dysfunction
    • Elevated total bilirubin, with varying proportions of conjugated and unconjugated bilirubin
    • Abnormal liver function tests (AST, ALT, alkaline phosphatase)
    • Causes: Hepatitis, cirrhosis, drug-induced liver injury
  • Post-Hepatic (Obstructive Jaundice): Blockage of bile ducts
    • Elevated total bilirubin, primarily conjugated
    • Elevated alkaline phosphatase and gamma-glutamyl transferase (GGT)
    • Causes: Gallstones, tumors

Iron Deficiency Anemia

• Definition: Anemia caused by insufficient iron levels, leading to impaired heme and hemoglobin synthesis
• Pathophysiology: Inadequate iron intake, absorption, or increased iron loss leads to reduced heme synthesis
• Laboratory Findings
  • Decreased red blood cell count, hemoglobin, and hematocrit
  • Low serum iron and ferritin levels
  • Elevated total iron-binding capacity (TIBC)
  • Decreased transferrin saturation
• Symptoms: Fatigue, weakness, pale skin, shortness of breath

Hemochromatosis

• Definition: A genetic disorder characterized by excessive iron absorption and accumulation in tissues
• Pathophysiology: Mutations in genes regulating iron absorption lead to iron overload
• Laboratory Findings
  • Elevated serum iron and ferritin levels
  • Decreased total iron-binding capacity (TIBC)
  • Increased transferrin saturation
• Symptoms: Fatigue, joint pain, abdominal pain, liver damage, diabetes
• Specific States
  • Hereditary Hemochromatosis: Genetic mutations leading to increased iron absorption
    • Elevated serum iron and transferrin saturation
    • Elevated ferritin
    • Liver damage, diabetes, skin pigmentation
  • Secondary Iron Overload: Due to transfusions or other causes
    • Elevated serum iron and ferritin
    • Transfusion history

Lead Poisoning

• Definition: Exposure to lead, which inhibits enzymes in the heme synthesis pathway
• Pathophysiology: Lead inhibits ALA dehydratase and ferrochelatase, disrupting heme synthesis
• Laboratory Findings
  • Elevated blood lead levels
  • Elevated zinc protoporphyrin (ZPP) in red blood cells
  • Anemia
• Symptoms: Abdominal pain, constipation, neurological symptoms, developmental delays in children

Anemia of Chronic Disease

• Definition: Anemia associated with chronic inflammatory conditions
• Pathophysiology: Inflammation leads to increased hepcidin production, which reduces iron absorption and release
• Laboratory Findings
  • Decreased red blood cell count, hemoglobin, and hematocrit
  • Normal or elevated ferritin levels
  • Decreased serum iron and total iron-binding capacity (TIBC)
  • Decreased transferrin saturation
• Symptoms: Fatigue, weakness

Other Conditions

• Sideroblastic Anemia: Impaired heme synthesis in bone marrow
  • Elevated serum iron and ferritin
  • Ringed sideroblasts in bone marrow
• Plumbism (Lead Poisoning): Disruption of heme synthesis by lead
  • Elevated blood lead levels
  • Abdominal pain, neurological symptoms

Key Terms

• Porphyrias: Genetic disorders of heme synthesis
• Jaundice: Yellowing of the skin and eyes due to elevated bilirubin
• Hyperbilirubinemia: Elevated bilirubin levels in the blood
• Iron Deficiency Anemia: Anemia due to insufficient iron
• Hemochromatosis: A genetic disorder of iron overload
• Lead Poisoning: Disruption of heme synthesis by lead
• Total Bilirubin: A measure of all bilirubin in the blood
• Direct (Conjugated) Bilirubin: Bilirubin that has been conjugated in the liver
• Indirect (Unconjugated) Bilirubin: Bilirubin that has not been conjugated in the liver
• Serum Iron: A measure of iron in the blood
• Total Iron-Binding Capacity (TIBC): A measure of the blood’s capacity to bind iron
• Transferrin Saturation: The percentage of transferrin that is bound to iron
• Ferritin: A protein that stores iron
• Porphyrins: Intermediates in heme synthesis
• ALA (δ-Aminolevulinate): A precursor in heme synthesis
• PBG (Porphobilinogen): A precursor in heme synthesis
• ZPP (Zinc Protoporphyrin): Accumulates in red blood cells when heme synthesis is impaired