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?

It binds and transports bilirubin to the liver (D) Signup and view all the answers

How is heme converted to bilirubin observed visually?

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

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

Heme (A) Signup and view all the answers

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

Accumulation of heme precursors (B) Signup and view all the answers

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

High-affinity site (A) Signup and view all the answers

Which condition is associated with unconjugated hyperbilirubinemia?

Hemolytic anemias (D) Signup and view all the answers

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

Enterohepatic urobilinogen cycle (A) Signup and view all the answers

What can cause urobilinogen to be excreted in the urine?

Excessive bile pigment formation (A) Signup and view all the answers

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

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

Which liver disease is commonly associated with predominantly conjugated hyperbilirubinemia?

Various types of hepatitis (B) Signup and view all the answers

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

Diazotized sulfanilic acid (C) Signup and view all the answers

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

Gilbert syndrome (D) Signup and view all the answers

What happens to residual urobilinogens in the colon?

They are oxidized to colored urobilins (B) 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?

Bilirubin diglucuronide (D) Signup and view all the answers

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

Uptake by the liver (A) Signup and view all the answers

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

Induce conjugation of bilirubin (D) Signup and view all the answers

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

UDP-glucuronosyltransferase (B) Signup and view all the answers

What occurs in human plasma when bilirubin conjugates exist abnormally?

They are predominantly monoglucuronides (C) Signup and view all the answers

What process follows the reduction of biliverdin to bilirubin?

Conjugation with glucuronic acid (A) Signup and view all the answers

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

Heme oxygenase (C) Signup and view all the answers

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

Uptake, conjugation, secretion (C) 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?

Dubin-Johnson syndrome (A) Signup and view all the answers

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

Unconjugated bilirubin (C) Signup and view all the answers

What type of hyperbilirubinemia occurs due to overproduction of bilirubin?

Retention hyperbilirubinemia (B) Signup and view all the answers

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

Conjugated bilirubin (D) Signup and view all the answers

What is choluric jaundice characterized by?

Presence of bile pigments in urine (B) Signup and view all the answers

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

Conjugation (A) Signup and view all the answers

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

It is converted to urobilinogen (B) Signup and view all the answers

Which condition occurs exclusively with unconjugated bilirubin in excess?

Acholuric jaundice (D) Signup and view all the answers

What is a major cause of posthepatic jaundice?

Gallstone obstruction (B) Signup and view all the answers

How is the bilirubin levels characterized in obstructive jaundice?

Increased direct bilirubin (D) Signup and view all the answers

What differentiates choluric jaundice from acholuric jaundice?

Presence of bilirubin in the urine (B) Signup and view all the answers

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

Decreased urine urobilinogen (C) Signup and view all the answers

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

Bilirubin UDP-glucuronosyltransferase activity (C) Signup and view all the answers

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

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

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

They are markedly elevated (B) Signup and view all the answers

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

Markedly elevated levels (C) Signup and view all the answers

What is the primary cause of cholestatic jaundice?

Extrahepatic obstructive jaundice (B) Signup and view all the answers

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

Type I Crigler-Najjar syndrome (B) Signup and view all the answers

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

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

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

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

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

Retained UDP-glucuronosyltransferase activity (C) Signup and view all the answers

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

Hepatic jaundice (D) Signup and view all the answers

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

Prehepatic jaundice (C) Signup and view all the answers

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

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

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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