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Questions and Answers
What is the common cause of hepatocellular jaundice?
What is the condition that causes a defect in the ability of hepatocytes to secrete conjugated bilirubin into the bile?
What causes unconjugated hyperbilirubinemia in neonates?
What is the treatment for Crigler-Najjar syndrome?
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Which liver disease occurs when the flow of bile from the liver is reduced or blocked?
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What causes Dubin-Johnson syndrome?
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What is the condition that can occur in newborns due to transiently low UDP-glucuronyl transferase?
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What is the result of impaired hepatocellular storage of conjugated bilirubin leaking into plasma causing hyperbilirubinemia?
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What is the impact of perivenous hepatocytes being exposed to lower oxygen tension and lower nutrient and hormone levels than periportal hepatocytes?
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Study Notes
Heme Metabolism
- Heme is a tightly bound prosthetic group of hemoglobin, myoglobin, cytochrome P450, catalase, and many other proteins.
- It comprises one ferrous ion (Fe2+) in the center and protoporphyrin IX (a tetrapyrrole ring).
Heme Synthesis
- Heme is synthesized principally in the bone marrow for erythrocytes and in the liver for cytochrome P450.
- The process involves the condensation of two molecules of aminolevulinic acid (ALA) to form porphobilinogen.
- The enzyme ALAS1 (aminolevulinate synthase 1) is the rate-limiting step of heme synthesis in the liver, and ALAS2 is responsible for heme synthesis in the bone marrow.
Regulation of Heme Synthesis
- Hemin, the oxidized form of heme, acts as a feedback inhibitor of ALAS1 in the liver.
- Low iron inhibits ALAS2 expression in erythroid cells.
- Erythropoietin induces ALAS2 expression in the bone marrow.
Porphyrias
- Defects in heme synthesis can lead to porphyrias, a group of rare genetic disorders.
- Accumulation of porphyrin precursors in the blood and urine is a hallmark of porphyrias.
- Symptoms include abdominal pain, cutaneous photosensitivity, and neurological abnormalities.
Classification of Porphyrias
- Hepatic porphyrias: e.g., porphyria cutanea tarda, acute intermittent porphyria.
- Erythropoetic porphyrias: e.g., erythropoietic protoporphyria, congenital erythropoetic porphyria.
Heme Degradation and Excretion
- Heme is degraded to bilirubin in macrophages and then transported to the liver for excretion in the bile.
- Bilirubin is conjugated with glucuronic acid in the liver and secreted into the bile as a diglucuronide adduct.
Disorders of Heme Degradation
- Jaundice occurs when bilirubin levels in the blood and skin increase, often due to defects in heme degradation and excretion.
- Examples of disorders include Crigler-Najjar, Gilbert's, Dubin-Johnson, and Rotor syndromes.
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Description
Test your knowledge about the next steps in porphyrin synthesis where cytosolic 2 ALA are condensed to porphobilinogen by ALA dehydratase, generating characteristic side chains and linkers for macrocyclic porphyrin formation. Also includes side-chain modification, decarboxylation, oxidation, and linker oxidation steps.
