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Heme: Synthesis, Degradation, Jaundice, and Iron

Tier 3 · #24 of 33 · moderate yield · topic 4.4 — every high-yield fact from the book chapter, exam-ready.

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  1. Front
    What is the rate-limiting enzyme of heme synthesis?
    Back
    ALA synthase (ALAS)
  2. Front
    Which two molecules condense to form delta-aminolevulinic acid (ALA) in the first step of heme synthesis?
    Back
    Succinyl-CoA and glycine
  3. Front
    In which subcellular compartment does ALA synthase operate?
    Back
    The mitochondrial matrix
  4. Front
    Which cofactor does ALA synthase require?
    Back
    Pyridoxal phosphate (PLP) , the active form of vitamin B6
  5. Front
    How does heme regulate ALAS1 (the liver isoform) when heme levels are high?
    Back
    Heme feedback-inhibits ALAS1 : blocks its transcription , decreases its mitochondrial import , and accelerates its degradation
  6. Front
    Which ALA synthase isoform is the ubiquitous liver form regulated by heme feedback?
    Back
    ALAS1
  7. Front
    Which ALA synthase isoform is erythroid-specific and regulated by iron?
    Back
    ALAS2
  8. Front
    Why do drugs like barbiturates trigger porphyria attacks?
    Back
    They induce cytochrome P450 enzymes, which consume heme ; the resulting heme demand upregulates ALAS1 , overloading a defective downstream pathway
  9. Front
    Which enzyme condenses two ALA molecules into porphobilinogen (PBG) , and where does this occur?
    Back
    ALA dehydratase (ALAD) , in the cytoplasm
  10. Front
    Lead poisoning inhibits ALA dehydratase by displacing which metal ion at its active site?
    Back
    Zinc
  11. Front
    What lab finding accumulates in urine when lead inhibits ALA dehydratase ?
    Back
    ALA (delta-aminolevulinic acid)
  12. Front
    Which enzyme polymerizes four PBG molecules into the linear tetrapyrrole hydroxymethylbilane ?
    Back
    Hydroxymethylbilane synthase (HMBS) , also called PBG deaminase
  13. Front
    A defect in hydroxymethylbilane synthase (HMBS/PBG deaminase) causes which porphyria ?
    Back
    Acute intermittent porphyria (AIP)
  14. Front
    Which enzyme produces the correct asymmetric isomer uroporphyrinogen III , and what disease results from its deficiency?
    Back
    Uroporphyrinogen III synthase ; deficiency causes congenital erythropoietic porphyria (CEP) , forming the useless symmetric isomer UROgen I
  15. Front
    Why is uroporphyrinogen III (not isomer I) the critical branch point of heme synthesis?
    Back
    Only the asymmetric UROgen III isomer continues productively toward heme ; UROgen I is biologically useless
  16. Front
    A deficiency of uroporphyrinogen III decarboxylase causes which porphyria — the most common one?
    Back
    Porphyria cutanea tarda (PCT)
  17. Front
    Porphyria cutanea tarda is often acquired. Name triggers that suppress uroporphyrinogen decarboxylase .
    Back
    Alcohol , hepatitis C , estrogen use , and iron overload
  18. Front
    Which enzyme catalyzes the final step of heme synthesis, inserting Fe2+ into protoporphyrin IX ?
    Back
    Ferrochelatase
  19. Front
    Which oxidation state of iron must ferrochelatase insert into protoporphyrin IX ?
    Back
    Ferrous Fe2+ (the reduced form); ferric Fe3+ is inactive for this step
  20. Front
    Besides ALA dehydratase , which late heme-synthesis enzyme is also inhibited by lead ?
    Back
    Ferrochelatase (creating a double block, early and late )
  21. Front
    A defect in ferrochelatase itself causes which porphyria ?
    Back
    Erythropoietic protoporphyria (EPP)
  22. Front
    In any porphyria , which metabolites accumulate relative to the deficient enzyme?
    Back
    The substrates immediately upstream of the enzymatic block
  23. Front
    Which accumulated intermediate is directly neurotoxic and drives the acute neurovisceral porphyria attack?
    Back
    ALA (delta-aminolevulinic acid)
  24. Front
    What is the diagnostic urine test of choice during an acute porphyria attack?
    Back
    Markedly elevated urine PBG (porphobilinogen)
  25. Front
    Name the four acute hepatic porphyrias by their deficient enzymes.
    Back
    ADP ( ALA dehydratase ), AIP ( HMBS ), HCP ( coproporphyrinogen oxidase ), VP ( protoporphyrinogen oxidase )
  26. Front
    Why does the luteal phase of the menstrual cycle trigger AIP attacks?
    Back
    High progesterone upregulates ALAS1 transcription , increasing ALA/PBG that the deficient HMBS cannot clear
  27. Front
    What is the treatment for an acute porphyria attack, and how does it work?
    Back
    IV hemin — it replenishes the hepatic heme pool and feedback-inhibits ALAS1 , shutting down the pathway
  28. Front
    Cutaneous porphyrias : why does porphyrin accumulation cause photosensitivity?
    Back
    Porphyrins absorb visible (especially blue) light and generate reactive oxygen species that damage skin
  29. Front
    Which porphyria causes nonblistering burning pain on light exposure (vs. PCT 's blistering skin fragility)?
    Back
    Erythropoietic protoporphyria (EPP)
  30. Front
    Why is protoporphyrin in EPP excreted in bile rather than urine?
    Back
    Protoporphyrin is hydrophobic (lipid-soluble) ; it can also cause progressive liver damage
  31. Front
    What blood smear finding is the classic clue to lead poisoning ?
    Back
    Basophilic stippling
  32. Front
    In lead poisoning , why is urine ALA elevated but PBG normal?
    Back
    Lead inhibits ALA dehydratase , so ALA accumulates but cannot be converted to PBG
  33. Front
    Where in the body are senescent red blood cells (≈120-day lifespan) cleared and heme degraded?
    Back
    Macrophages of the reticuloendothelial system (RES) — spleen, liver, and bone marrow
  34. Front
    Which enzyme opens the heme ring, and what cofactors does it use?
    Back
    Heme oxygenase , using molecular oxygen (O2) and NADPH
  35. Front
    Heme oxygenase produces which gas as a byproduct — one of the only endogenous CO sources?
    Back
    Carbon monoxide (CO)
  36. Front
    What green tetrapyrrole is the direct product of heme oxygenase opening the ring?
    Back
    Biliverdin
  37. Front
    Which enzyme reduces biliverdin to bilirubin , and what cofactor does it use?
    Back
    Biliverdin reductase , using NADPH
  38. Front
    Cloze: Unconjugated (indirect) bilirubin is water-{{insoluble}} and therefore cannot be excreted in {{urine}}.
    Back
    insoluble ; urine
  39. Front
    What carrier protein transports water-insoluble unconjugated bilirubin through the blood to the liver?
    Back
    Albumin
  40. Front
    What neurotoxic condition results when lipid-soluble unconjugated bilirubin enters the neonatal brain?
    Back
    Kernicterus
  41. Front
    Which hepatic enzyme conjugates bilirubin , and with what molecule?
    Back
    UDP-glucuronosyltransferase (UGT) , conjugating bilirubin with two molecules of glucuronic acid
  42. Front
    What is the product of bilirubin conjugation by UGT , and what physical property does it gain?
    Back
    Bilirubin diglucuronide (conjugated/direct bilirubin); it becomes water-soluble
  43. Front
    Complete absence of UGT causes which lethal disorder (without liver transplant)?
    Back
    Crigler-Najjar syndrome type I
  44. Front
    Partial UGT reduction causing benign mild jaundice during fasting or illness is which syndrome?
    Back
    Gilbert syndrome
  45. Front
    In the intestine, gut bacteria reduce conjugated bilirubin to which colorless compound?
    Back
    Urobilinogen
  46. Front
    Which urobilinogen derivative gives stool its brown color?
    Back
    Stercobilin
  47. Front
    Which urobilinogen derivative spills into urine and gives it a yellow color?
    Back
    Urobilin
  48. Front
    In complete biliary obstruction, why does stool become clay-colored (acholic)?
    Back
    No bilirubin reaches the gut, so no stercobilin is formed
  49. Front
    Pre-hepatic (hemolytic) jaundice : which bilirubin fraction is elevated?
    Back
    Unconjugated (indirect) bilirubin
  50. Front
    Why is there no bilirubin in the urine in pre-hepatic (hemolytic) jaundice ?
    Back
    Unconjugated bilirubin is bound to albumin and cannot pass the glomerular filter
  51. Front
    What happens to urobilinogen levels in pre-hepatic (hemolytic) jaundice ?
    Back
    Increased fecal and urinary urobilinogen (more bilirubin reaches the gut)
  52. Front
    Name the lab markers of hemolysis seen with pre-hepatic jaundice .
    Back
    Elevated LDH, low haptoglobin, and reticulocytosis
  53. Front
    Why does physiologic neonatal jaundice occur, and why is its mechanism classified as hepatic?
    Back
    Neonates have low UGT activity at birth, so unconjugated bilirubin transiently accumulates
  54. Front
    How does phototherapy clear neonatal bilirubin without requiring conjugation?
    Back
    It converts bilirubin to water-soluble photoisomers that can be excreted directly
  55. Front
    Post-hepatic (obstructive) jaundice : which bilirubin fraction rises and appears in urine?
    Back
    Conjugated (direct) bilirubin — water-soluble, causing dark urine (bilirubinuria)
  56. Front
    Which serum enzymes are markedly elevated in the cholestatic pattern of obstructive jaundice ?
    Back
    Alkaline phosphatase (ALP) and gamma-GT
  57. Front
    Which jaundice type shows markedly elevated ALT/AST (transaminases)?
    Back
    Hepatic jaundice (hepatocellular damage)
  58. Front
    Why does the body have no mechanism to excrete excess iron , and where is iron balance therefore controlled?
    Back
    There is no dedicated iron excretion pathway ; all iron balance is controlled at the level of intestinal absorption
  59. Front
    Which transporter absorbs intact heme iron across the duodenal enterocyte ?
    Back
    HCP1 (heme carrier protein 1)
  60. Front
    Non-heme dietary iron is ferric (Fe3+); which brush-border enzyme reduces it to Fe2+ for absorption?
    Back
    Duodenal cytochrome b (Dcytb)
  61. Front
    How does vitamin C affect non-heme iron absorption?
    Back
    It promotes the reduction of Fe3+ to Fe2+ (via Dcytb ), enhancing non-heme iron absorption
  62. Front
    Which transporter carries Fe2+ across the enterocyte apical (brush border) membrane?
    Back
    DMT-1 (divalent metal transporter 1)
  63. Front
    What is the only known mammalian iron exporter, found on the basolateral enterocyte membrane?
    Back
    Ferroportin
  64. Front
    Which ferroxidase oxidizes Fe2+ to Fe3+ as iron exits the enterocyte for loading onto transferrin ?
    Back
    Hephaestin (or ceruloplasmin in plasma)
  65. Front
    What is the major iron transport protein in the blood?
    Back
    Transferrin
  66. Front
    How do cells take up iron from transferrin ?
    Back
    Via transferrin receptors (TfR) : the complex is endocytosed, iron released in the acidic endosome, and transferrin/TfR recycled to the surface
  67. Front
    What protein handles long-term, non-toxic iron storage by holding thousands of iron atoms?
    Back
    Ferritin
  68. Front
    Why is low serum ferritin the most specific single test for iron deficiency ?
    Back
    Ferritin directly reflects total body iron stores and falls only when stores are genuinely depleted
  69. Front
    When can ferritin be falsely normal or elevated despite true iron deficiency ?
    Back
    Ferritin is an acute-phase reactant — inflammation, infection, liver disease, or malignancy raises it nonspecifically
  70. Front
    In iron overload , ferritin is degraded into which insoluble golden-brown storage aggregate?
    Back
    Hemosiderin
  71. Front
    Which liver peptide hormone is the master regulator of systemic iron levels?
    Back
    Hepcidin
  72. Front
    How does hepcidin lower iron availability when stores are full or during inflammation?
    Back
    It binds ferroportin and causes its internalization/degradation , blocking iron absorption and trapping iron in macrophages
  73. Front
    Inappropriately low hepcidin signaling causing unregulated iron absorption is the basis of which inherited disease (and its most common gene)?
    Back
    Hereditary hemochromatosis ; most commonly due to HFE gene mutations
  74. Front
    Trapping of iron in macrophages by elevated hepcidin during inflammation underlies which anemia?
    Back
    Anemia of chronic disease
  75. Front
    Into which two broad flavors are the porphyrias classified, and what accumulates in each?
    Back
    Acute (neurovisceral) = ALA/PBG accumulate ; cutaneous (photosensitive) = later porphyrins accumulate
  76. Front
    A porphyria presenting with abdominal pain, psychosis, and neuropathy (no skin findings) is which broad type?
    Back
    Acute (neurovisceral) porphyria
  77. Front
    Which accumulated metabolite is characteristic of congenital erythropoietic porphyria (CEP) ?
    Back
    UROgen I isomers
  78. Front
    Which metabolite accumulates in porphyria cutanea tarda (PCT) ?
    Back
    Uroporphyrin III
  79. Front
    Which metabolite accumulates in hereditary coproporphyria (HCP) ?
    Back
    Coproporphyrin III
  80. Front
    Which metabolites accumulate in variegate porphyria (VP) ?
    Back
    Protoporphyrin and coproporphyrin
  81. Front
    Which porphyria is characteristically common in South Africa?
    Back
    Variegate porphyria (VP)
  82. Front
    Which porphyria presents with severe blistering from infancy plus red urine?
    Back
    Congenital erythropoietic porphyria (CEP)
  83. Front
    Which porphyria can produce BOTH acute attacks and blistering skin lesions?
    Back
    Hereditary coproporphyria (HCP) ; variegate porphyria (VP) also does both
  84. Front
    Besides condensing succinyl-CoA and glycine into ALA , what small molecule does the ALA synthase reaction also release?
    Back
    CO2 (the irreversible condensation releases CO2)
  85. Front
    In an acute porphyria attack, why does the urine classically turn dark red on standing?
    Back
    Porphyrins in the urine are photooxidized on exposure to light/air
  86. Front
    What is the inheritance pattern of acute intermittent porphyria (AIP) ?
    Back
    Autosomal dominant with low penetrance
  87. Front
    Which enzyme converts coproporphyrinogen III to protoporphyrinogen IX (and where)?
    Back
    Coproporphyrinogen oxidase , in the mitochondria
  88. Front
    Which enzyme oxidizes protoporphyrinogen IX to protoporphyrin IX ?
    Back
    Protoporphyrinogen oxidase (PPOX)
  89. Front
    A deficiency of coproporphyrinogen oxidase causes which porphyria ?
    Back
    Hereditary coproporphyria (HCP)
  90. Front
    A deficiency of protoporphyrinogen oxidase (PPOX) causes which porphyria ?
    Back
    Variegate porphyria (VP)
  91. Front
    In lead poisoning , which erythrocyte porphyrin finding (from the ferrochelatase block) is elevated?
    Back
    Erythrocyte zinc-protoporphyrin / free erythrocyte protoporphyrin
  92. Front
    In hepatic (hepatocellular) jaundice , which bilirubin fraction(s) can be elevated?
    Back
    Both fractions : uptake failure raises unconjugated , secretion failure raises conjugated (hepatocellular damage tends to raise both)
  93. Front
    Trace the compartmental shuttle of heme synthesis (start to finish).
    Back
    Mitochondria -> cytoplasm -> back to mitochondria
  94. Front
    Which heme-synthesis steps occur in the cytoplasm (between the two mitochondrial phases)?
    Back
    ALA dehydratase through uroporphyrinogen III decarboxylase ( ALA -> PBG -> HMB -> UROgenIII -> coproporphyrinogen III )
  95. Front
    Name common causes of pre-hepatic (hemolytic) jaundice .
    Back
    Hereditary spherocytosis, G6PD deficiency, sickle cell, malaria, autoimmune hemolytic anemia
  96. Front
    Name common causes of post-hepatic (obstructive) jaundice .
    Back
    Common-bile-duct gallstones, pancreatic head cancer, cholangiocarcinoma, primary sclerosing cholangitis
  97. Front
    Name common causes of hepatic jaundice .
    Back
    Viral hepatitis, alcoholic liver disease, cirrhosis, drug-induced hepatotoxicity
  98. Front
    How many iron-binding sites does transferrin carry, and which derived parameter is measured clinically?
    Back
    Two iron-binding sites ; transferrin saturation is the measured parameter
  99. Front
    A normal/elevated ferritin with a LOW transferrin saturation should raise suspicion for what combined picture?
    Back
    Iron deficiency coexisting with an inflammatory/acute-phase state (ferritin falsely normal)
  100. Front
    ADP (ALA dehydratase deficiency porphyria) produces a clinical picture resembling which non-porphyria toxidrome, and why?
    Back
    Lead poisoning — both block ALA dehydratase , so isolated ALA accumulates and drives acute neurovisceral symptoms
  101. Front
    Which acute porphyria has NO skin (photosensitivity) involvement — a key discriminator from the cutaneous and mixed porphyrias?
    Back
    Acute intermittent porphyria (AIP)
  102. Front
    In which hepatocyte organelle does UDP-glucuronosyltransferase (UGT) conjugate bilirubin ?
    Back
    The smooth endoplasmic reticulum (smooth ER)
  103. Front
    Acute intermittent porphyria (AIP) attacks are more common in which sex?
    Back
    Women (linked to hormonal triggers — progesterone in the luteal phase upregulates ALAS1 )

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