L5 Heme Porphyrin metabolism and iron homeostasis
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Questions and Answers

What is primarily responsible for the impaired heme biosynthesis in sideroblastic anemia?

  • Increased iron stores
  • Genetic disorders of hemoglobin synthesis
  • Deficiency of pyridoxine (vitamin B6) (correct)
  • Excessive iron absorption

    • Which condition is NOT known to cause vitamin B6 deficiency?

  • Alcoholism
  • Hyperthyroidism (correct)
  • Chronic kidney disease
  • Chronic diarrhea

    • What is a characteristic feature of iron-deficiency anemia?

  • Macrocytic red blood cells
  • Sideroblastic red blood cells
  • Microcytic and hypochromic erythrocytes (correct)
  • Normocytic red blood cells

    • Which symptom is NOT typically associated with iron deficiency?

    <p>Macrocytic anemia symptoms</p> Signup and view all the answers

    Which of the following is TRUE regarding the progression of iron deficiency?

    <p>Iron stores diminish first, followed by circulating iron, then hemoglobin production</p> Signup and view all the answers

    What laboratory test is commonly used to assess iron deficiency?

    <p>Total iron-binding capacity (TIBC)</p> Signup and view all the answers

    Which of the following symptoms is indicative of severe vitamin B6 deficiency?

    <p>Glossitis</p> Signup and view all the answers

    Which factor does NOT contribute to iron deficiency?

    <p>Iron supplementation</p> Signup and view all the answers

    Which of the following symptoms is least likely to be present in cases of moderate lead poisoning?

    <p>Convulsions</p> Signup and view all the answers

    What is a primary effect of lead acting as a competitive inhibitor of Fe2+ in heme biosynthesis?

    <p>Accumulation of protoporphyrin IX (PPIX)</p> Signup and view all the answers

    Which treatment option for lead poisoning is a chelator that helps remove lead from the body?

    <p>Dimercaprol</p> Signup and view all the answers

    What type of anemia is caused by a deficiency of heme due to lead poisoning?

    <p>Microcytic hypochromic anemia</p> Signup and view all the answers

    Porphyrias are primarily caused by deficiencies in which type of enzymes?

    <p>Heme synthesizing enzymes</p> Signup and view all the answers

    Which of the following is a leading indicator of heavy metal poisoning?

    <p>Increased urinary excretion of d-ALA</p> Signup and view all the answers

    Which of these conditions is NOT considered an acquired disorder of heme synthesis?

    <p>Congenital porphyria</p> Signup and view all the answers

    How does the accumulation of porphyrinogens in the skin affect patients with certain porphyrias?

    <p>It results in photosensitivity</p> Signup and view all the answers

    Which form of iron does ferrochelatase incorporate into protoporphyrin IX to produce heme?

    <p>Fe2+</p> Signup and view all the answers

    What is the primary site of heme biosynthesis in the body?

    <p>Erythroid progenitor cells</p> Signup and view all the answers

    What is the consequence of high heme concentration on ALA synthase?

    <p>Inhibits ALAS by negative feedback</p> Signup and view all the answers

    Which vitamin is essential for the function of ALA synthase (ALAS) in heme biosynthesis?

    <p>Vitamin B6</p> Signup and view all the answers

    Which isoform of ALA synthase is expressed in non-erythroid cells and responds to toxins?

    <p>ALAS1</p> Signup and view all the answers

    What genetic deficiency results in X-linked sideroblastic anemia?

    <p>Deficiency of ALAS2</p> Signup and view all the answers

    Which of the following is NOT a cause of acquired disorders in heme synthesis?

    <p>X-linked deficiency</p> Signup and view all the answers

    What is the committed step for heme biosynthesis?

    <p>Synthesis of d-aminolevulinic acid</p> Signup and view all the answers

    What is the primary role of hepcidin in regulating iron levels in the body?

    <p>Decreases iron absorption by degrading ferroportin</p> Signup and view all the answers

    What condition is characterized by abnormal iron accumulation?

    <p>Hemosiderosis</p> Signup and view all the answers

    In hereditary hemochromatosis (HH), what results from mutations in the HFE gene?

    <p>Increased levels of iron absorption</p> Signup and view all the answers

    Which of the following could potentially lead to iron overload?

    <p>Frequent blood transfusions</p> Signup and view all the answers

    What effect does high iron levels have on hepcidin production?

    <p>Hepcidin production increases</p> Signup and view all the answers

    What clinical manifestation is associated with chronic hemochromatosis?

    <p>Bronzed skin pigmentation and diabetes mellitus</p> Signup and view all the answers

    Which type of iron storage protein is partially denatured and stores excess iron?

    <p>Hemosiderin</p> Signup and view all the answers

    What triggers the increased degradation of ferroportin?

    <p>High levels of hepcidin</p> Signup and view all the answers

    What causes increased unconjugated bilirubin in the blood during hemolytic jaundice?

    <p>Massive production of bilirubin due to hemolytic anemia</p> Signup and view all the answers

    In hepatocellular jaundice, which of the following findings is likely NOT present?

    <p>Increased urobilinogen in urine</p> Signup and view all the answers

    Which genetic condition is associated with increased hemolytic activity leading to jaundice?

    <p>Sickle cell anemia</p> Signup and view all the answers

    What is the most likely cause of dark urine in posthepatic jaundice?

    <p>Backup of conjugated bilirubin in circulation</p> Signup and view all the answers

    Which of the following methods is used to diagnose hemolytic jaundice?

    <p>Decreased plasma levels of haptoglobin</p> Signup and view all the answers

    What treatment is generally used for Gilbert’s Syndrome?

    <p>Small doses of phenobarbital</p> Signup and view all the answers

    In which type of jaundice is there a major issue with conjugation of bilirubin in the liver?

    <p>Hepatocellular jaundice</p> Signup and view all the answers

    Which of the following would likely increase due to hemolytic jaundice?

    <p>Urobilinogen in blood</p> Signup and view all the answers

    What is the most significant contributing factor for the expression of porphyria cutanea tarda?

    <p>Chronic alcoholism or liver damage</p> Signup and view all the answers

    Which enzyme is primarily responsible for the initial reaction of heme degradation?

    <p>Heme oxygenase</p> Signup and view all the answers

    What is the primary route through which conjugated bilirubin is excreted from the body?

    <p>Bile into the duodenum</p> Signup and view all the answers

    What percentage of urobilinogen is typically excreted in feces?

    <p>80–90%</p> Signup and view all the answers

    How does prolonged exposure to sunlight affect patients with porphyria cutanea tarda?

    <p>It exacerbates cutaneous photosensitivity</p> Signup and view all the answers

    Which of the following statements about bilirubin is accurate?

    <p>Most cells in the body generate bilirubin</p> Signup and view all the answers

    What is a key characteristic of the feces due to urobilinogen?

    <p>It has a brown-orange color from stercobilin</p> Signup and view all the answers

    What is the role of UDP-glucuronyl transferase in bilirubin metabolism?

    <p>It conjugates bilirubin to make it water soluble</p> Signup and view all the answers

    What is the primary role of heme in the human body?

    <p>Transport of oxygen</p> Signup and view all the answers

    Which symptom is commonly associated with iron deficiency anemia?

    <p>Increased fatigue</p> Signup and view all the answers

    What is the metabolic consequence of lead poisoning?

    <p>Inhibition of heme synthesis</p> Signup and view all the answers

    Which of the following best describes hemochromatosis?

    <p>A condition of abnormal iron accumulation</p> Signup and view all the answers

    What is a typical indication of jaundice due to hemolytic conditions?

    <p>Elevated levels of unconjugated bilirubin</p> Signup and view all the answers

    Which iron form is incorporated into protoporphyrin IX to form heme?

    <p>Fe2+ ferrous</p> Signup and view all the answers

    What is the rate-limiting enzyme in heme biosynthesis?

    <p>ALA synthase</p> Signup and view all the answers

    Which condition is associated with genetic deficiencies of ALAS2?

    <p>Sideroblastic anemia</p> Signup and view all the answers

    What triggers the negative-feedback inhibition of ALA synthase (ALAS)?

    <p>High heme concentration</p> Signup and view all the answers

    Which of the following is NOT a factor causing acquired disorders of heme synthesis?

    <p>Genetic mutations</p> Signup and view all the answers

    Where does most heme synthesis take place in the body?

    <p>Liver and bone marrow</p> Signup and view all the answers

    Which diagnostic marker is typically low in cases of hemolytic jaundice?

    <p>Haptoglobin</p> Signup and view all the answers

    Which vitamin is required by ALA synthase (ALAS) for its activity?

    <p>Pyridoxine (Vitamin B6)</p> Signup and view all the answers

    In hepatocellular jaundice, which component is likely to decrease in the urine?

    <p>Urobilinogen</p> Signup and view all the answers

    What is a characteristic finding of posthepatic (obstructive) jaundice?

    <p>Dark urine</p> Signup and view all the answers

    Which is an acquired disorder of heme synthesis?

    <p>Lead poisoning</p> Signup and view all the answers

    Which condition is associated with a benign inability to conjugate bilirubin?

    <p>Gilbert’s Syndrome</p> Signup and view all the answers

    What is the primary mechanism leading to pale stools in hepatocellular jaundice?

    <p>Decreased conjugated bilirubin secretion</p> Signup and view all the answers

    Which environmental factor might contribute to hemolytic anemia?

    <p>Viral infections</p> Signup and view all the answers

    Which treatment option is commonly used to stimulate bilirubin conjugation in Gilbert's Syndrome?

    <p>Phenobarbital</p> Signup and view all the answers

    What is the function of hepcidin in iron homeostasis?

    <p>Inhibits iron absorption by degrading ferroportin.</p> Signup and view all the answers

    Which condition is associated with abnormal accumulation of iron?

    <p>Hemosiderosis</p> Signup and view all the answers

    Hereditary Hemochromatosis (HH) is primarily caused by mutations in which gene?

    <p>HFE gene</p> Signup and view all the answers

    What happens to hepcidin levels when iron is detected to be low in the body?

    <p>Hepcidin levels decrease.</p> Signup and view all the answers

    Which of the following may lead to iron overload?

    <p>Frequent blood transfusions</p> Signup and view all the answers

    What effect does the degradation of ferroportin have on iron levels?

    <p>Decreases iron levels in circulation.</p> Signup and view all the answers

    What is the consequence of high hepcidin levels due to high iron concentrations?

    <p>Inhibition of ferroportin and reduced iron release.</p> Signup and view all the answers

    What skin condition may develop due to chronic hemochromatosis?

    <p>Bronze pigmentation</p> Signup and view all the answers

    What enzyme deficiency is the cause of acute intermittent porphyria?

    <p>Porphobilinogen deaminase</p> Signup and view all the answers

    Which of the following symptoms is commonly associated with acute intermittent porphyria episodes?

    <p>Severe abdominal pain</p> Signup and view all the answers

    What condition can worsen the symptoms of acute intermittent porphyria?

    <p>Drugs inducing cytochrome P-450 synthesis</p> Signup and view all the answers

    How does an acute attack of AIP lead to the accumulation of ALA and porphobilinogen?

    <p>Decreased heme availability</p> Signup and view all the answers

    What color does urine typically darken to when exposed to air due to acute intermittent porphyria?

    <p>Purple or port-wine color</p> Signup and view all the answers

    Which of the following treatments should be avoided in managing acute intermittent porphyria symptoms?

    <p>Barbiturates</p> Signup and view all the answers

    What dietary recommendation is typically made for long-term management of acute intermittent porphyria?

    <p>Carbohydrate-rich diet</p> Signup and view all the answers

    What effect does dieting have on attacks of porphyria?

    <p>It worsens the condition</p> Signup and view all the answers

    What is the main consequence of pyridoxine deficiency?

    <p>Sideroblastic anemia</p> Signup and view all the answers

    What symptom is commonly associated with iron deficiency?

    <p>Cold or abnormal sensations in extremities</p> Signup and view all the answers

    What type of anemia is characterized by microcytic and hypochromic erythrocytes?

    <p>Iron-deficiency anemia</p> Signup and view all the answers

    Which laboratory test is most indicative of iron deficiency?

    <p>Low hemoglobin levels</p> Signup and view all the answers

    What condition can result from isoniazid therapy?

    <p>Sideroblastic anemia</p> Signup and view all the answers

    What is a significant cause of iron deficiency anemia?

    <p>Celiac disease</p> Signup and view all the answers

    What dietary factor can lead to iron deficiency?

    <p>Dietary lack of iron</p> Signup and view all the answers

    Which of the following is NOT a symptom of vitamin B6 deficiency?

    <p>Frequent headaches</p> Signup and view all the answers

    Study Notes

    Porphyrin/Heme Metabolism and Iron Homeostasis

    • Marks' Basic Medical Biochemistry, 6th edition, chapter 42 (pages 939–944)
    • Biochemistry, Cell and Molecular Biology, and Genetics, Part V, chapter 36 (pages 301-312)
    • Pathologic Basis of Disease 10th Edition, chapter 14 (pages 655-658) and chapter 18 (pages 848-850)

    Learning Objectives

    • Outline the biochemical pathway and regulatory steps of heme biosynthesis
    • Describe the signs and symptoms of vitamin B6 deficiency anemia
    • Describe the signs and symptoms of lead poisoning
    • Describe the signs and symptoms of iron deficiency anemia
    • Distinguish differences in diagnosis between vitamin B6 deficiency anemia, lead poisoning, and iron deficiency anemia.
    • Describe the metabolism of bilirubin and the types of jaundice
    • Outline the types of porphyrias
    • Explain iron absorption, transport, and storage in the body
    • Explain how iron levels are regulated in the body
    • Explain diagnostic tests for iron deficiency
    • Describe the molecular and clinical findings of hemochromatosis
    • Describe the process of heme degradation and bilirubin excretion

    Hemoglobin Biosynthesis

    • Heme synthesis is coordinated with globin chain synthesis
    • Involves the coordinated use of amino acids
    • Takes place in the mitochondria

    Structure of Heme (iron protoporphyrin IX)

    • Heme is a prosthetic group for hemoglobin, myoglobin, cytochromes, cyclooxygenase, catalase, and cytochrome P-450 enzymes.
    • Protoporphyrin IX binds various metals (e.g., iron)

    Heme Biosynthesis Pathway (Detailed)

    • Succinyl CoA and glycine combine to form 8-aminolevulinate acid (ALA)
    • Two molecules of ALA condense to form porphobilinogen
    • Series of enzymatic reactions convert porphobilinogen to protoporphyrin IX
    • Iron is incorporated into protoporphyrin IX to form heme

    Heme Biosynthesis - Location and Rate-Limiting Step

    • Primarily occurs in the liver and bone marrow erythroid progenitor cells
    • ALA synthase (ALAS) is the rate-limiting enzyme and requires pyridoxine (vitamin B6)
    • Heme inhibits ALA synthase via negative feedback

    Disorders of Heme Synthesis

    • Acquired: Vitamin B6 deficiency, iron deficiency, lead poisoning
    • Congenital: Porphyrias

    8-Aminolevulinate Synthase (ALAS)

    • Two isoforms exist: ALAS1 (non-erythroid) and ALAS2 (erythroid)
    • ALAS1 expression increases in response to toxins and drugs
    • ALAS2 expression is increased by hypoxia and erythropoietin

    Effects of Lead Poisoning in Heme Biosynthesis

    • Lead inactivates ALA dehydratase and ferrochelatase enzymes
    • Acts as a competitive inhibitor of iron, preventing insertion into protoporphyrin IX
    • Increased 8-ALA and PPIX in urine indicate lead poisoning
    • Anemia, microcytic, hypochromic, and sideroblastic, due to lack of hemoglobin

    Lead Poisoning Symptoms

    • Symptoms range from mild to severe, depending on exposure levels
    • Mild: lethargy, anorexia, abdominal discomfort, arthralgia
    • Moderate: anemia, headache, abdominal cramps, peripheral neuropathy, gingival and long bone lead lines
    • Severe: convulsions, coma, encephalopathy, and renal failure

    Porphyrias

    • Caused by deficiencies in heme-synthesizing enzymes
    • Lead to accumulation of porphyrin precursors
    • Neurological symptoms (e.g., seizures, mental disturbance) and photosensitivity. Can also include skin photosensitivity

    Dietary Iron Absorption

    • Heme iron (animal products) is more readily absorbed than non-heme iron (plant products)
    • Vitamin C increases non-heme iron absorption
    • Other compounds inhibit iron absorption (e.g., antacids, polyphenols)

    Iron Homeostasis

    • Tightly regulated at cellular and systemic levels
    • Iron is shielded from oxygen by binding to proteins (e.g., ferritin, transferrin)
    • Iron regulatory proteins (IRPs) control gene expression of iron-related proteins.
    • Hepcidin regulates iron absorption and storage (particularly in macrophages)
    • Body iron stores are responsible for the level of hepcidin

    Iron Deficiency

    • Causes microcytic, hypochromic anemia
    • Symptoms: fatigue, feelings of faintness, abnormal sensations (cold or extremities), shortness of breath, immunosuppression, intellectual/behavioral problems
    • Causes: dietary lack, impaired absorption, acute blood loss, increased requirements

    Iron Deficiency Diagnosis

    • Blood tests measure hemoglobin, hematocrit, total iron-binding capacity (TIBC), ferritin, and transferrin saturation
    • Low hemoglobin, low ferritin, and high TIBC are suggestive of iron deficiency

    Tests to measure Iron Levels

    • Serum Iron: measures the amount of iron in the blood
    • Serum Ferritin: measures stored iron
    • Transferrin level (TIBC): measures the amount of transferrin in the blood
    • Transferrin saturation: calculated to evaluate the amount of iron bound to transferrin
    • Used to diagnose and monitor iron deficiency and overload

    Iron Overload (Hemosiderosis/Hemochromatosis)

    • Abnormal iron accumulation
    • Causes: genetic mutations, frequent blood transfusions, or accidental poisoning
    • Systemic damage

    Bilirubin Metabolism and Excretion

    • Breakdown of heme from red blood cells yields bilirubin
    • Bilirubin is transported to the liver, conjugated, and excreted into bile.
    • This pathway leads to the production of urobilinogen that is mostly processed into stercobilin and excreted in feces. A smaller portion is excreted in urine.

    Jaundice (Hyperbilirubinemia)

    • Increased plasma bilirubin levels
    • Caused by an imbalance between bilirubin production and excretion
    • Various causes (prehepatic, hepatocellular, and posthepatic)

    Types of Jaundice (Clinical Correlations)

    • Prehepatic: hemolytic conditions (increased RBC breakdown)
    • Hepatocellular: liver damage (impaired bilirubin processing/conjugation)
    • Posthepatic: blockage in bile ducts (impaired bilirubin excretion)

    Additional Specific Conditions

    • Neonatal Jaundice: Late onset of bilirubin conjugation, breakdown of fetal hemoglobin, or prematurity.
    • Gilbert's Syndrome: Benign, inherited liver disorder; reduced UDP-glucuronyl transferase activity

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    Description

    Test your knowledge on various types of anemia, their causes, and the effects of lead poisoning. This quiz covers key symptoms, laboratory tests, and treatment options related to impaired heme biosynthesis and iron deficiencies. Understand the critical roles of vitamin B6 and other factors in blood health.

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