Heme Metabolism
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Questions and Answers

What are the principal types of porphyrias categorized based on?

  • Severity of symptoms
  • Genetic predisposition
  • Location in the body
  • Clinical features (correct)

Which of the following drugs can induce porphyria by affecting heme levels?

  • Aspirin
  • Griseofulvin (correct)
  • Ibuprofen
  • Acetaminophen

What is the daily bilirubin production for human adults?

  • 600 to 700 mg
  • 250 to 350 mg (correct)
  • 400 to 500 mg
  • 100 to 200 mg

What is the role of serum albumin in bilirubin transport?

<p>It binds and transports bilirubin to the liver (D)</p> Signup and view all the answers

How is heme converted to bilirubin observed visually?

<p>As a purple color during hematoma healing (C)</p> Signup and view all the answers

What substance is primarily derived from hemoglobin when converting to bilirubin?

<p>Heme (A)</p> Signup and view all the answers

What results from the derepression of ALAS1 synthesis in porphyria patients?

<p>Accumulation of heme precursors (B)</p> Signup and view all the answers

Which site on albumin has a higher binding capacity for bilirubin?

<p>High-affinity site (A)</p> Signup and view all the answers

Which condition is associated with unconjugated hyperbilirubinemia?

<p>Hemolytic anemias (D)</p> Signup and view all the answers

What is the process by which urobilinogens are reabsorbed and recirculated?

<p>Enterohepatic urobilinogen cycle (A)</p> Signup and view all the answers

What can cause urobilinogen to be excreted in the urine?

<p>Excessive bile pigment formation (A)</p> Signup and view all the answers

How does the presence of urobilinogens affect the color of feces?

<p>They can lead to fecal discoloration upon oxidation (A)</p> Signup and view all the answers

Which liver disease is commonly associated with predominantly conjugated hyperbilirubinemia?

<p>Various types of hepatitis (B)</p> Signup and view all the answers

What reagent is commonly used in the colorimetric method for bilirubin measurement?

<p>Diazotized sulfanilic acid (C)</p> Signup and view all the answers

Which of the following is NOT a cause of conjugated hyperbilirubinemia?

<p>Gilbert syndrome (D)</p> Signup and view all the answers

What happens to residual urobilinogens in the colon?

<p>They are oxidized to colored urobilins (B)</p> Signup and view all the answers

What is the primary substance that most of the bilirubin excreted in the bile of mammals is converted into?

<p>Bilirubin diglucuronide (D)</p> Signup and view all the answers

What is the first step in the hepatic catabolism of bilirubin?

<p>Uptake by the liver (A)</p> Signup and view all the answers

What role do certain drugs, such as phenobarbital, play in bilirubin metabolism?

<p>Induce conjugation of bilirubin (D)</p> Signup and view all the answers

Which enzyme is primarily responsible for the conjugation of bilirubin with glucuronic acid?

<p>UDP-glucuronosyltransferase (B)</p> Signup and view all the answers

What occurs in human plasma when bilirubin conjugates exist abnormally?

<p>They are predominantly monoglucuronides (C)</p> Signup and view all the answers

What process follows the reduction of biliverdin to bilirubin?

<p>Conjugation with glucuronic acid (A)</p> Signup and view all the answers

Which component is necessary for the conversion of ferric heme into biliverdin?

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

What is the complete sequence of bilirubin metabolism in the liver?

<p>Uptake, conjugation, secretion (C)</p> Signup and view all the answers

What condition is characterized by a blood concentration of bilirubin reaching 2 to 2.5 mg/dL, leading to yellowing of tissues?

<p>Dubin-Johnson syndrome (A)</p> Signup and view all the answers

Which type of bilirubin is capable of crossing the blood–brain barrier?

<p>Unconjugated bilirubin (C)</p> Signup and view all the answers

What type of hyperbilirubinemia occurs due to overproduction of bilirubin?

<p>Retention hyperbilirubinemia (B)</p> Signup and view all the answers

Which bilirubin type appears in urine as a result of biliary obstruction?

<p>Conjugated bilirubin (D)</p> Signup and view all the answers

What is choluric jaundice characterized by?

<p>Presence of bile pigments in urine (B)</p> Signup and view all the answers

Which process primarily affects the transfer of bilirubin from blood to bile?

<p>Conjugation (A)</p> Signup and view all the answers

What occurs in the intestine when conjugated bilirubin is processed by specific bacteria?

<p>It is converted to urobilinogen (B)</p> Signup and view all the answers

Which condition occurs exclusively with unconjugated bilirubin in excess?

<p>Acholuric jaundice (D)</p> Signup and view all the answers

What is a major cause of posthepatic jaundice?

<p>Gallstone obstruction (B)</p> Signup and view all the answers

How is the bilirubin levels characterized in obstructive jaundice?

<p>Increased direct bilirubin (D)</p> Signup and view all the answers

What differentiates choluric jaundice from acholuric jaundice?

<p>Presence of bilirubin in the urine (B)</p> Signup and view all the answers

Which laboratory result is significantly different in hepatitis compared to obstructive jaundice?

<p>Decreased urine urobilinogen (C)</p> Signup and view all the answers

In type II Crigler-Najjar syndrome, what is retained?

<p>Bilirubin UDP-glucuronosyltransferase activity (C)</p> Signup and view all the answers

What is a typical serum bilirubin level range for normal patients?

<p>Direct: 0.1-0.4 mg/dL (A)</p> Signup and view all the answers

What typically occurs to alanine aminotransferase and aspartate aminotransferase levels in hepatitis?

<p>They are markedly elevated (B)</p> Signup and view all the answers

What can be an indication of obstructive liver disease according to alkaline phosphatase levels?

<p>Markedly elevated levels (C)</p> Signup and view all the answers

What is the primary cause of cholestatic jaundice?

<p>Extrahepatic obstructive jaundice (B)</p> Signup and view all the answers

Which condition is characterized by the complete absence of hepatic UDP-glucuronosyltransferase activity?

<p>Type I Crigler-Najjar syndrome (B)</p> Signup and view all the answers

What is the outcome of having around 30% of bilirubin UDP-glucuronosyltransferase activity in Gilbert syndrome?

<p>It is harmless and requires no treatment. (B)</p> Signup and view all the answers

What is the effect of phototherapy in Type I Crigler-Najjar syndrome?

<p>It slightly reduces plasma bilirubin levels. (B)</p> Signup and view all the answers

Which manifestation is associated with Type II Crigler-Najjar syndrome compared to Type I?

<p>Retained UDP-glucuronosyltransferase activity (C)</p> Signup and view all the answers

What type of jaundice occurs due to liver diseases such as hepatitis or cancer?

<p>Hepatic jaundice (D)</p> Signup and view all the answers

What type of bilirubin-related condition could result from hemolytic anemias?

<p>Prehepatic jaundice (C)</p> Signup and view all the answers

What distinguishes conjugated hyper-bilirubinemia from other types of jaundice?

<p>It is a result of liver damage affecting bilirubin conjugation. (D)</p> Signup and view all the answers

Flashcards

Porphyria Variations

Different types of porphyrias involve varying levels of heme, its precursors, or its metabolites, leading to specific affects on certain cells and organs.

Porphyria Classification

Porphyrias can be classified as acute or cutaneous depending on their main symptom manifestation.

Porphyria Diagnosis

Diagnosing porphyria involves considering a patient's medical history, family history, physical exam, and specific lab tests.

Drug-Induced Porphyria

Certain drugs can induce the production of cytochrome P450, which can lead to a porphyria attack by depleting heme levels.

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Porphyria Attack Mechanism

When heme levels are depleted, the body tries to make more, leading to an increase in potentially harmful heme precursors that can cause symptoms.

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Bilirubin Transport

Bilirubin, a breakdown product of heme, is not water soluble but can be transported in the blood bound to serum albumin.

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Albumin and Bilirubin

Albumin has high-affinity and low-affinity binding sites for bilirubin, ensuring efficient transportation.

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Heme to Bilirubin Conversion

The conversion of heme to bilirubin can be observed visually as the purple color of a hematoma slowly changes to yellow.

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Bilirubin Transfer

The process of bilirubin being transferred from blood to bile, involving three major steps: uptake, conjugation, and secretion.

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Unconjugated Bilirubin

The form of bilirubin that is produced by the breakdown of heme.

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Conjugated Bilirubin

The form of bilirubin that has been conjugated with glucuronic acid by the liver, making it water-soluble.

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Hyperbilirubinemia

A condition where the blood concentration of bilirubin is elevated, resulting in yellowing of tissues called jaundice.

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Retention Hyperbilirubinemia

A type of hyperbilirubinemia caused by overproduction of bilirubin, often due to increased breakdown of red blood cells.

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Regurgitation Hyperbilirubinemia

A type of hyperbilirubinemia caused by a blockage in the bile ducts, leading to the buildup of conjugated bilirubin.

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Kernicterus

A condition caused by the buildup of unconjugated bilirubin in the brain, leading to brain damage.

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Choluria

The presence of bile pigments in the urine, a sign of regurgitation hyperbilirubinemia.

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Bilirubin conjugation

The process where bilirubin is converted to a water-soluble form by attaching glucuronic acid to it.

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Bilirubin UDP-glucuronosyltransferase

An enzyme found in the liver that plays a crucial role in the conjugation process.

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Bilirubin diglucuronide

The primary form of bilirubin excreted in the bile of mammals.

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Obstructive jaundice

A type of jaundice where the obstruction occurs in the bile ducts.

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Unconjugated hyperbilirubinemia

A type of jaundice that arises due to the inability to conjugate bilirubin properly.

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Uptake of bilirubin by the liver

The process by which the liver takes up bilirubin from the bloodstream.

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Secretion of bilirubin in the bile

The process by which conjugated bilirubin is secreted into the bile.

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Hepatic catabolism of bilirubin

The catabolism of bilirubin in the liver involves three stages: uptake, conjugation, and secretion.

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Urobilinogen

A substance formed from the breakdown of heme in the intestines, which is then excreted in the feces.

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Enterohepatic Urobilinogen Cycle

A cycle involving the reabsorption of urobilinogen in the intestines and its re-excretion in the bile.

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Bilirubin Assay

The measurement of bilirubin in the blood serum, used to diagnose liver function.

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Diazotized sulfanilic acid method

A colorimetric method used to measure bilirubin in the blood, relying on a color change reaction.

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Direct bilirubin

A form of bilirubin that is already attached to glucuronic acid and can be directly measured in the blood.

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Indirect bilirubin

A form of bilirubin that is not yet attached to glucuronic acid and needs to be reacted with diazotized sulfanilic acid for measurement.

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Cholestatic Jaundice

A type of jaundice caused by a blockage of bile flow, either from outside the liver (extrahepatic) or within the liver (intrahepatic).

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Glucuronosyltransferases

A family of enzymes responsible for adding a glucuronic acid molecule to bilirubin, making it water-soluble and easier to excrete.

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Gilbert Syndrome

A genetic condition where the activity of the enzyme responsible for bilirubin conjugation is reduced, resulting in mild jaundice.

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Type I Crigler-Najjar Syndrome

A severe congenital jaundice caused by a complete absence of bilirubin conjugation activity, leading to high bilirubin levels and potential brain damage. Often fatal in early childhood.

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Type II Crigler-Najjar Syndrome

A milder form of Crigler-Najjar syndrome where some bilirubin conjugation activity remains, resulting in less severe jaundice. Often treatable with phototherapy.

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Jaundice

Yellowing of the skin and whites of the eyes caused by high levels of bilirubin in the blood.

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Pre-Hepatic Jaundice

A condition where bilirubin is not properly conjugated, leading to high levels of unconjugated bilirubin in the blood. Often caused by hemolytic anemia.

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Hepatic Jaundice

A type of jaundice caused by liver damage or disease. Bilirubin may be unable to be conjugated or excreted due to liver malfunction.

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Elevated Conjugated Bilirubin

Elevated levels of conjugated bilirubin indicate a blockage in the bile ducts.

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Common Causes of Obstructive Jaundice

A gallstone or head of the pancreas cancer blocks the common bile duct.

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Crigler-Najjar Syndrome

Caused by lack of the enzyme UDP-glucuronosyltransferase, resulting in inability to conjugate bilirubin.

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Study Notes

Porphyrins & Bile Pigments

  • Heme is synthesized from porphyrins and iron
  • Bile pigments and iron are products of heme degradation
  • Porphyrias are diseases caused by abnormalities in porphyrin biosynthesis
  • Jaundice is an elevated level of plasma bilirubin, either from overproduction or excretion failure
  • Porphyrins are cyclic compounds formed from four pyrrole rings linked by methyne bridges
  • Porphyrins can form complexes with metal ions, such as iron in heme and magnesium in chlorophyll.
  • Proteins with heme are ubiquitous. Hemoglobin and myoglobin are examples with oxygen-transport/storage function
  • Heme biosynthesis is initiated by the condensation of succinyl-CoA and glycine
  • The key regulated enzyme in hepatic heme biosynthesis is ALA synthase.
  • Porphyrinogens are colorless tetrapyrroles, while porphyrins are colored.
  • Porphyrin synthesis occurs in both the cytosol and mitochondria.
  • ALA dehydratase (porphobilinogen synthase) catalyzes the condensation of two molecules of ALA forming porphobilinogen. ALA dehydratase is a zinc metalloprotein and is sensitive to lead.
  • The key regulated enzyme, ALA synthase (EC 2.3.1.37), catalyzes the condensation of succinyl-CoA and glycine to form 8-aminolevulinate (ALA)
  • Hydroxymethylbilane synthase (uroporphyrinogen I synthase, EC 2.5.1.61) involves head-to-tail condensation of four molecules of porphobilinogen forming hydroxymethylbilane.
  • The subsequent reaction of cyclizing hydroxymethylbilane to form uroporphyrinogen III, is catalyzed by the cytosolic enzyme uroporphyrinogen III synthase (EC 4.2.1.75).
  • The four acetate moieties of uroporphyrinogen III undergo decarboxylation to methyl groups, forming coproporphyrinogen III.
  • Coproporphyrinogen III enters mitochondria and is sequentially converted to protoporphyrinogen III, then protoporphyrin III.
  • Iron is incorporated into protoporphyrin III forming heme by ferrochelatase (heme synthase, EC 4.99.1.1).
  • Humans express two isozymes of ALA synthase; ALAS1 is ubiquitous, while ALAS2 is found in erythrocyte precursors.
  • Heme is regulated by ALAS1; it is feedback-inhibited by heme.
  • Heme biosynthesis proceeds mostly in erythroid cells and hepatocytes.

Heme Synthesis

  • Heme is synthesized from succinyl coA and glycine
  • The key regulated enzyme is ALA synthase
  • Four molecules of porphobilinogen produce a linear tetrapyrrole, hydroxymethylbilane
  • Hydroxymethylbilane is subsequently cyclized to form the isomer uroporphyrinogen III, where the methylene bridges are involved in conjugation
  • Further reactions produce coproporphyrinogen III, then protoporphyrinogen III, and then protoporphyrin
  • Incorporation of iron by ferrochelatase forms heme.

Porphyrias

  • Porphyrias are genetic disorders of heme biosynthesis.
  • Porphyrias can either affect the erythropoietic lineage or the hepatic lineage.
  • There are various types of porphyrias each with their own characteristic clinical presentation.
  • Some common symptoms include abdominal pain, neuropsychiatric effects and photosensitivity
  • Porphyrias result from defects in specific enzymes of heme synthesis
  • Diagnostic tests involve laboratory analysis of body fluids for the accumulation of porphyrin precursors.
  • Treatment for porphyrias is mostly symptomatic

Bilirubin Metabolism

  • Bilirubin is the end product of heme breakdown
  • Bilirubin is produced from heme degradation in reticuloendothelial cells
  • This process has steps including heme degradation by heme oxygenase and reduction of biliverdin to bilirubin.
  • Unconjugated bilirubin is relatively insoluble
  • Conjugated bilirubin is more water-soluble.
  • Bilirubin is primarily conjugated and excreted in the bile.
  • In mammals, bilirubin is primarily transported bound to serum albumin
  • Bilirubin is removed from albumin and transported to hepatocytes.
  • Bilirubin is conjugated by binding with glucuronic acid and secreted into the bile.
  • In the intestine bacteria convert conjugated bilirubin to urobilinogens.
  • Urobilinogens are reabsorbed and excreted in the urine or reenter the circulation
  • Bilirubin is primarily metabolized in the liver
  • Jaundice occurs with increased levels of bilirubin in the blood, causing yellowing.
  • There are different types of jaundice
  • Obstruction in the biliary system is often associated with conjugated hyperbilirubinemia

Hyperbilirubinemia

  • Hyperbilirubinemia is elevated blood bilirubin.
  • Hyperbilirubinemia may result from accelerated hemolysis or in cases of liver dysfunction.
  • Bilirubin transport/uptake, conjugation, or secretion defects are other potential causes of jaundice.
  • Different types of jaundice arise from different causes.
  • Increased levels of bilirubin leads to tissue discoloration
  • Treatment of hyperbilirubinemia depends on the cause.

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Harper's Illustrated Biochemistry, 31st Ed. PDF - Porphyrins & Bile Pigments

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