Unit 21 Question Bank
Format note: the TMU Biochemistry paper gives five suggested
answers (A–E), not four — these MCQs match that. Items tagged TMU 2019 or
TMU 2020/21 come from the real papers. Answers are verified against Harper's
Illustrated Biochemistry; the "marking schemes" in the source folder are other students'
answer sheets, not official, so they are never used as the authority.
0 / 25 answered
1The essential difference between purine and pyrimidine ring biosynthesis is that ( ).
Answer: B
Harper's states it directly: unlike in purine biosynthesis, where PRPP serves as a scaffold for assembly of the purine ring, PRPP participates in pyrimidine biosynthesis only SUBSEQUENT to assembly of the pyrimidine ring — it joins at OMP. Both pathways are cytosolic.Harper's ch.33, p.352
2The overall determinant of the rate of de novo purine nucleotide biosynthesis is ( ).
Answer: C
And PRPP concentration depends on the availability of ribose 5-phosphate — from the pentose phosphate pathway — and on PRPP synthase, feedback inhibited by AMP, ADP, GMP and GDP. Hold the rule “whenever PRPP rises, purine synthesis rises and urate follows” and von Gierke disease and Lesch-Nyhan both become deducible.Harper's ch.33, p.350
3Which set of donors contributes atoms to the purine ring?
Answer: D
Note the practical consequence Harper's draws: several reactions of IMP biosynthesis require folate derivatives and glutamine — consequently, antifolate drugs and glutamine analogs inhibit purine biosynthesis. Option B is the pyrimidine pair; option E is the urea cycle.Harper's ch.33, p.349 · TMU Lecture 20 slide 34
4The committed step of de novo purine synthesis is catalysed by ( ).
Answer: E
Feedback inhibited by AMP and GMP — the end products of the pathway. Note that human brain tissue has a low level of this enzyme and hence depends in part on exogenous purines, and erythrocytes and polymorphonuclear leukocytes cannot synthesise 5-phosphoribosylamine at all.Harper's ch.33, pp.349–350
5The parent purine nucleotide from which both AMP and GMP arise is ( ).
Answer: A
IMP is a precursor both of AMP and of GMP. XMP and AMPS (adenylosuccinate) are the intermediates on the two branches; UMP and OMP belong to the pyrimidine pathway.Harper's ch.33, p.350
6Which statement about the IMP branch point is correct?
Answer: B
This cross-regulation serves to balance the biosynthesis of purine nucleoside triphosphates by decreasing the synthesis of one purine nucleotide when there is a deficiency of the other. It is not feedback inhibition but reciprocal funding — each branch is paid for in the currency of the other.Harper's ch.33, p.351
7Aspartate provides the ( ) of AMP, and glutamine the ( ) of GMP.
Answer: C
A precise pair worth memorising as a unit. Note the recurring theme: aspartate donates a nitrogen and leaves as fumarate here, exactly as it does at argininosuccinate lyase in the urea cycle (Unit 20). Same trick, different pathway.Harper's ch.33, Summary p.357
8Hypoxanthine-guanine phosphoribosyltransferase converts ( ).
Answer: D
The salvage reaction, of the form Pu + PRPP → Pu-RP + PPi. Salvage requires far less energy than de novo synthesis, and its failure is Lesch-Nyhan syndrome. Option A describes adenine phosphoribosyltransferase for the adenine half only; option E is adenosine deaminase.Harper's ch.33, p.350
9Which cells are MOST dependent on salvage rather than de novo purine synthesis?
Answer: E
They cannot synthesise 5-phosphoribosylamine and therefore utilise exogenous purines. The brain is also partly dependent, having a low level of PRPP glutamyl amidotransferase — which is exactly why an HGPRT defect produces a neurological syndrome. Liver is the major site of de novo synthesis and supplies the rest.Harper's ch.33, p.350
10Carbamoyl phosphate synthase II differs from carbamoyl phosphate synthase I in that it ( ).
Answer: A
Compartmentation thus provides an independent pool of carbamoyl phosphate for each process. CPS-II is inhibited by UTP and purine nucleotides but activated by PRPP; the N-acetylglutamate requirement belongs to CPS-I of the urea cycle.Harper's ch.33, p.352
11Aspartate transcarbamoylase, the second enzyme of pyrimidine synthesis, is ( ).
Answer: B
The classic textbook allosteric enzyme. Note that option C is the regulation of CPS-II — the two enzymes are adjacent in the pathway and are regulated by different signals, so keep them apart. CTP is the end product, hence its inhibitory role.Harper's ch.33, p.354
12Ribonucleotide reductase acts on ( ) and requires ( ).
Answer: C
Two design points. It acts at the diphosphate level, giving a single gateway between the RNA and DNA worlds; and the enzyme complex is functional only when cells are actively synthesizing DNA. Its controls exist to achieve balanced production of dNTPs — an unbalanced pool is mutagenic.Harper's ch.33, p.352
13The only reaction of pyrimidine nucleotide biosynthesis requiring a tetrahydrofolate derivative is catalysed by ( ).
Answer: D
And it does not merely use the folate — it consumes it: tetrahydrofolate is oxidized to dihydrofolate, which must be reduced back by dihydrofolate reductase before synthesis can continue. That dependence on recycling is precisely what methotrexate exploits.Harper's ch.33, p.353
14Methotrexate kills dividing cells by ( ).
Answer: E
Dividing cells, which must generate TMP and dihydrofolate, are especially sensitive to inhibitors of dihydrofolate reductase. The effect is called thymineless death — and note that thymine appears in DNA only, so there is no alternative source. The toxicity (marrow, gut mucosa, hair follicles) is the mechanism. Option A is 5-fluorouracil.Harper's ch.33, pp.353–354
15Which drug is a GLUTAMINE analog that blocks purine biosynthesis?
Answer: A
Azaserine (reaction 5) and diazanorleucine (reaction 2) are the two glutamine analogs. 6-mercaptopurine is a purine analog converted to a nucleotide; mycophenolic acid inhibits IMP dehydrogenase, the GMP branch — which is why it is used as an immunosuppressant, lymphocytes being especially dependent on de novo synthesis.Harper's ch.33 · TMU Lecture 20 slide 68
16The end product of purine catabolism in humans is uric acid because ( ).
Answer: B
In mammals other than higher primates, uricase converts uric acid to the water-soluble product allantoin. Losing that one enzyme is why humans, alone among most mammals, get gout — the pathway stops one step short of solubility.Harper's ch.33, p.354
17Which enzyme acts TWICE in the conversion of hypoxanthine to uric acid?
Answer: C
Hypoxanthine → xanthine → uric acid, both steps catalysed by xanthine oxidase — which is why allopurinol, a single inhibitor, blocks the last two steps at once. The accumulating hypoxanthine and xanthine are considerably more soluble than urate and are excreted harmlessly.Harper's ch.33, p.355
18The pKa of uric acid is 5.8. The clinical consequence is that ( ).
Answer: D
Two deductions follow. Urine is acidic, so uric acid precipitates there as stones — and alkalinising the urine is rational therapy. And peripheral joints are cooler, solubility falls with temperature, which is why classical gout strikes the first metatarsophalangeal joint. One number, two clinical facts.Harper's ch.33, Summary p.357
19Most cases of gout are due to ( ).
Answer: E
A qualification candidates routinely omit. Genetic defects in PRPP synthase — an elevated Vmax, increased affinity for ribose 5-phosphate, or resistance to feedback inhibition — do present clinically as gout, but they are the minority. Urate crystals are diagnostic, and sodium urate crystallising in soft tissues and joints causes the inflammatory reaction, gouty arthritis.Harper's ch.33, p.354
20Lesch-Nyhan syndrome is characterised by ( ).
Answer: A
Understand the paradox rather than memorising it: salvage normally consumes PRPP, so the accompanying rise in intracellular PRPP results in purine overproduction. The patient both fails to recycle purines and makes too many new ones. And because the brain depends partly on salvage, a disease of urate chemistry produces a neurological syndrome.Harper's ch.33, pp.354–355
21Adenosine deaminase deficiency causes immunodeficiency because ( ).
Answer: B
Why lymphocytes specifically? Because they have the highest ADA activity and must undergo enormous clonal proliferation — a general block on DNA precursors falls hardest on the cells that divide most. Both T and B cells are sparse and dysfunctional; in purine nucleoside phosphorylase deficiency, T cells are severely deficient but B-cell function is apparently normal.Harper's ch.33, p.355
22Why does pyrimidine overproduction cause so little clinical trouble?
Answer: C
A structural answer, not a physiological one: a pyrimidine is a single small ring that can be opened into soluble fragments, whereas a purine is a fused bicyclic system that ends as insoluble urate. β-aminoisobutyrate excretion increases in leukemia and severe x-ray exposure — though many people of Chinese or Japanese ancestry excrete it routinely.Harper's ch.33, pp.355–356
23Ornithine transcarbamoylase deficiency causes orotic aciduria because ( ).
Answer: D
Compartmentation normally keeps the two carbamoyl phosphate pools separate; when the urea cycle blocks at reaction 2, the wall is breached. The result is increased excretion of orotic acid, uracil and uridine, and the mild orotic aciduria is increased by high-nitrogen foods. A single patient linking Units 20 and 21.Harper's ch.33, p.356
24Only which form of bilirubin can cross the blood-brain barrier and cause kernicterus?
Answer: E
Due to its hydrophobicity, only unconjugated bilirubin can cross the blood-brain barrier. The mirror-image rule follows from the same property: because of its water-solubility, only conjugated bilirubin can appear in urine — so choluric jaundice occurs only in regurgitation (obstructive) hyperbilirubinemia. Two solubilities, two diseases.Harper's ch.31, p.332
25A patient has increased urinary urobilinogen with NO bilirubin in the urine. This suggests ( ).
Answer: A
Reason it out from solubility. Haemolysis raises unconjugated bilirubin, which cannot appear in urine — but the extra bilirubin that is conjugated and excreted yields more urobilinogen. Conversely, in complete obstruction bilirubin has no access to the intestine, so no urobilinogen is present in the urine while conjugated bilirubin does appear. Conjugated bilirubin in urine WITHOUT urobilinogen means obstruction.Harper's ch.31, pp.333–334
1 PRPP (5-phosphoribosyl-1-pyrophosphate) — 2′+
An important precursor of both purine and pyrimidine nucleotides (and of some amino acids), formed from ribose 5-phosphate + ATP by PRPP synthase.
The overall determinant of the rate of de novo purine nucleotide biosynthesis is the concentration of PRPP, which depends on the availability of ribose 5-phosphate — from the pentose phosphate pathway — and on PRPP synthase, feedback inhibited by AMP, ADP, GMP and GDP.
Its role differs between the two pathways: in purine synthesis it is the scaffold on which the ring is built; in pyrimidine synthesis it joins only after the ring is complete.
Because it is common to both, PRPP synthase is the pivot of the coordinated, mole-for-mole regulation of purine and pyrimidine synthesis.Harper's ch.33, pp.350–354
The overall determinant of the rate of de novo purine nucleotide biosynthesis is the concentration of PRPP, which depends on the availability of ribose 5-phosphate — from the pentose phosphate pathway — and on PRPP synthase, feedback inhibited by AMP, ADP, GMP and GDP.
Its role differs between the two pathways: in purine synthesis it is the scaffold on which the ring is built; in pyrimidine synthesis it joins only after the ring is complete.
Because it is common to both, PRPP synthase is the pivot of the coordinated, mole-for-mole regulation of purine and pyrimidine synthesis.Harper's ch.33, pp.350–354
2 The purine salvage pathway — 3′+
Reactions that convert purines, their ribonucleosides and their deoxyribonucleosides to mononucleotides, and which require far less energy than de novo synthesis.
Mechanism 1 — phosphoribosylation by PRPP: Pu + PRPP → Pu-RP + PPi, catalysed by adenine phosphoribosyltransferase (adenine → AMP) and hypoxanthine-guanine phosphoribosyltransferase (HGPRT) (hypoxanthine → IMP, guanine → GMP).
Mechanism 2 — phosphoryl transfer from ATP: Pu-R + ATP → PuR-P + ADP, catalysed by adenosine kinase and deoxycytidine kinase.
Significance: liver is the major site of de novo synthesis and supplies purines to tissues incapable of it — brain (low PRPP glutamyl amidotransferase) and erythrocytes and polymorphonuclear leukocytes (cannot make 5-phosphoribosylamine). Failure of HGPRT causes Lesch-Nyhan syndrome.Harper's ch.33, p.350
Mechanism 1 — phosphoribosylation by PRPP: Pu + PRPP → Pu-RP + PPi, catalysed by adenine phosphoribosyltransferase (adenine → AMP) and hypoxanthine-guanine phosphoribosyltransferase (HGPRT) (hypoxanthine → IMP, guanine → GMP).
Mechanism 2 — phosphoryl transfer from ATP: Pu-R + ATP → PuR-P + ADP, catalysed by adenosine kinase and deoxycytidine kinase.
Significance: liver is the major site of de novo synthesis and supplies purines to tissues incapable of it — brain (low PRPP glutamyl amidotransferase) and erythrocytes and polymorphonuclear leukocytes (cannot make 5-phosphoribosylamine). Failure of HGPRT causes Lesch-Nyhan syndrome.Harper's ch.33, p.350
3 Gout — 3′+
A metabolic disorder of purine catabolism in which serum urate exceeds the solubility limit, sodium urate crystallizes in soft tissues and joints, and causes an inflammatory reaction — gouty arthritis. Urate crystals are diagnostic.
Why humans are susceptible: humans lack uricase, which in other mammals converts uric acid to the soluble product allantoin, so uric acid is the end product of purine catabolism in humans. Its pKa is 5.8 — relatively insoluble as the free acid at acidic pH, more soluble as sodium urate near neutrality, which explains both uric acid stones in acid urine and deposition in cool peripheral joints.
Causes: various genetic defects in PRPP synthase — elevated Vmax, increased affinity for ribose 5-phosphate, or resistance to feedback inhibition — cause overproduction; but most cases of gout reflect abnormalities in renal handling of uric acid. Secondary hyperuricemia accompanies cancer, psoriasis and von Gierke disease.
Treatment: allopurinol, which inhibits xanthine oxidase, so that the more soluble hypoxanthine and xanthine are excreted instead.Harper's ch.33, pp.354–355
Why humans are susceptible: humans lack uricase, which in other mammals converts uric acid to the soluble product allantoin, so uric acid is the end product of purine catabolism in humans. Its pKa is 5.8 — relatively insoluble as the free acid at acidic pH, more soluble as sodium urate near neutrality, which explains both uric acid stones in acid urine and deposition in cool peripheral joints.
Causes: various genetic defects in PRPP synthase — elevated Vmax, increased affinity for ribose 5-phosphate, or resistance to feedback inhibition — cause overproduction; but most cases of gout reflect abnormalities in renal handling of uric acid. Secondary hyperuricemia accompanies cancer, psoriasis and von Gierke disease.
Treatment: allopurinol, which inhibits xanthine oxidase, so that the more soluble hypoxanthine and xanthine are excreted instead.Harper's ch.33, pp.354–355
4 Lesch-Nyhan syndrome — 2′+
An overproduction hyperuricemia characterized by frequent episodes of uric acid lithiasis and a bizarre syndrome of self-mutilation, reflecting a defect in hypoxanthine-guanine phosphoribosyl transferase (HGPRT), an enzyme of purine salvage.
Mechanism of the overproduction: salvage normally consumes PRPP; when HGPRT fails, the accompanying rise in intracellular PRPP results in purine overproduction. The patient therefore both fails to recycle purines and makes too many new ones.
The neurological features follow from the fact that brain has a low level of PRPP glutamyl amidotransferase and depends in part on exogenous purines. Causative mutations include deletions, frameshift mutations, base substitutions and aberrant mRNA splicing.Harper's ch.33, pp.354–355
Mechanism of the overproduction: salvage normally consumes PRPP; when HGPRT fails, the accompanying rise in intracellular PRPP results in purine overproduction. The patient therefore both fails to recycle purines and makes too many new ones.
The neurological features follow from the fact that brain has a low level of PRPP glutamyl amidotransferase and depends in part on exogenous purines. Causative mutations include deletions, frameshift mutations, base substitutions and aberrant mRNA splicing.Harper's ch.33, pp.354–355
5 Jaundice (icterus) — 3′+
The yellow discolouration of tissues caused by hyperbilirubinemia. Hyperbilirubinemia is a blood level exceeding 1 mg/dL (17 μmol/L); when the concentration reaches 2 to 2.5 mg/dL, bilirubin diffuses into the tissues, which turn yellow.
Two mechanisms: retention hyperbilirubinemia, from overproduction (unconjugated), and regurgitation hyperbilirubinemia, from reflux into the bloodstream because of biliary obstruction (conjugated).
Three anatomical categories:
• Prehepatic — haemolytic anaemias; ↑ indirect (unconjugated), urine urobilinogen increased, urine bilirubin ABSENT (acholuric)
• Hepatic — hepatitis, cirrhosis; both fractions rise; ALT and AST markedly elevated
• Posthepatic — gallstone in the common bile duct, cancer of the head of the pancreas; ↑ direct (conjugated), urine bilirubin PRESENT (choluric), urine urobilinogen absent, pale stools, alkaline phosphatase elevated
Only unconjugated bilirubin crosses the blood-brain barrier — hence kernicterus; only conjugated bilirubin appears in urine.Harper's ch.31, pp.332–334
Two mechanisms: retention hyperbilirubinemia, from overproduction (unconjugated), and regurgitation hyperbilirubinemia, from reflux into the bloodstream because of biliary obstruction (conjugated).
Three anatomical categories:
• Prehepatic — haemolytic anaemias; ↑ indirect (unconjugated), urine urobilinogen increased, urine bilirubin ABSENT (acholuric)
• Hepatic — hepatitis, cirrhosis; both fractions rise; ALT and AST markedly elevated
• Posthepatic — gallstone in the common bile duct, cancer of the head of the pancreas; ↑ direct (conjugated), urine bilirubin PRESENT (choluric), urine urobilinogen absent, pale stools, alkaline phosphatase elevated
Only unconjugated bilirubin crosses the blood-brain barrier — hence kernicterus; only conjugated bilirubin appears in urine.Harper's ch.31, pp.332–334
6 Bilirubin conjugation — 2′+
The hepatic conversion of nonpolar bilirubin to a water-soluble form for excretion, by transfer of two glucuronosyl moieties from UDP-glucuronate, catalysed by bilirubin UDP-glucuronosyl transferase of the endoplasmic reticulum, giving bilirubin diglucuronide.
It is the second of the three stages of hepatic bilirubin catabolism: uptake by the liver, conjugation with glucuronic acid, and secretion in the bile — of which secretion, via the multispecific organic anion transporter (MOAT), is probably rate-limiting.
Clinically: conjugated bilirubin is “direct” bilirubin (assayed without added methanol); indirect = total − direct = unconjugated. Defects of the transferase give Gilbert syndrome (~30% activity retained, harmless), Crigler-Najjar type I (complete absence, over 20 mg/dL, often fatal within 15 months, no response to phenobarbital) and type II (partial, responds to phenobarbital).Harper's ch.31, pp.331–333
It is the second of the three stages of hepatic bilirubin catabolism: uptake by the liver, conjugation with glucuronic acid, and secretion in the bile — of which secretion, via the multispecific organic anion transporter (MOAT), is probably rate-limiting.
Clinically: conjugated bilirubin is “direct” bilirubin (assayed without added methanol); indirect = total − direct = unconjugated. Defects of the transferase give Gilbert syndrome (~30% activity retained, harmless), Crigler-Najjar type I (complete absence, over 20 mg/dL, often fatal within 15 months, no response to phenobarbital) and type II (partial, responds to phenobarbital).Harper's ch.31, pp.331–333
1
Describe the de novo biosynthesis of purine nucleotides and its regulation.
8′
Where, and from what
Purine nucleotides are synthesised in the cytosol. They are formed from amphibolic intermediates and are thus dietarily nonessential. The defining structural feature is that the ring is assembled directly ON the ribose — PRPP serves as the scaffold, in contrast to pyrimidine synthesis where the ring is completed first.
The sources of the ring atoms
- Glycine — C4, C5 and N7, an entire fragment
- Glutamine — N3 and N9
- Aspartate — N1
- CO₂ — C6
- N¹⁰-formyl-tetrahydrofolate — C2 and C8
Hence Harper's remark that several reactions of IMP biosynthesis require folate derivatives and glutamine — consequently, antifolate drugs and glutamine analogs inhibit purine biosynthesis.
The pathway
Ribose 5-phosphate + ATP → PRPP (PRPP synthase). PRPP + glutamine → 5-phosphoribosylamine — the committed step, catalysed by PRPP glutamyl amidotransferase. Eleven further reactions, several carried out by multifunctional catalysts whose adjacent active sites channel the intermediates, build the ring to give inosine monophosphate (IMP).
IMP is a precursor both of AMP and of GMP:
- To AMP: IMP + aspartate + GTP → adenylosuccinate (adenylosuccinate synthase) → AMP + fumarate. Aspartate provides the 6-amino group.
- To GMP: IMP + NAD⁺ → XMP (IMP dehydrogenase) → GMP, using glutamine and ATP. Glutamine provides the 2-amino group.
Regulation — three levels
The rationale is explicit: biosynthesis of IMP is energetically expensive — in addition to ATP, glycine, glutamine, aspartate and reduced tetrahydrofolate derivatives all are consumed — so it is of survival advantage to closely regulate purine biosynthesis in response to varying physiologic need.
- 1 · PRPP supply. The overall determinant of the rate is the concentration of PRPP. PRPP synthase is feedback inhibited by AMP, ADP, GMP and GDP.
- 2 · The committed step. AMP and GMP feedback inhibit PRPP glutamyl amidotransferase.
- 3 · The branch point. AMP inhibits adenylosuccinate synthase; GMP inhibits IMP dehydrogenase. Further, AMP synthesis requires GTP and GMP synthesis requires ATP — cross-regulation that balances the biosynthesis of purine nucleoside triphosphates by decreasing the synthesis of one when there is a deficiency of the other. AMP and GMP also inhibit HGPRT.
Coordination with pyrimidines
Purine and pyrimidine biosynthesis parallel one another quantitatively, mole for mole — as they must, since DNA and RNA pair them 1:1. PRPP synthase, which forms a precursor essential for both processes, is feedback inhibited by both purine and pyrimidine nucleotides.
Salvage — the cheaper alternative
Salvage reactions require far less energy than de novo synthesis. Pu + PRPP → Pu-RP + PPi, by APRT and HGPRT; or Pu-R + ATP → PuR-P + ADP, by adenosine kinase. Liver is the major site of de novo synthesis and supplies purines for tissues incapable of it — brain, erythrocytes and polymorphonuclear leukocytes.
Marking guide: cytosolic location and PRPP as scaffold 1 · ring atom donors, at least four correct 2 · committed step named 1 · IMP as the branch point with both products 1.5 · at least two levels of regulation 1.5 · the cross-regulation of the two branches 1.
2
Discuss the formation, transport and excretion of bilirubin, and the causes of jaundice.
10′
Formation
Catabolism of the heme ring, initiated by the mitochondrial enzyme heme oxygenase, produces the linear tetrapyrrole biliverdin; subsequent reduction of biliverdin in the cytosol forms bilirubin. This occurs in the reticuloendothelial system; the iron is released and reutilized and the globin degraded to amino acids.
Since 1 g of hemoglobin yields about 35 mg of bilirubin, human adults form 250 to 350 mg of bilirubin per day — principally from haemoglobin, but also from ineffective erythropoiesis and other heme proteins. The process can be watched: the purple colour of the heme in a hematoma slowly converts to the yellow pigment of bilirubin.
Transport
Bilirubin is only sparingly water-soluble, but bilirubin bound to serum albumin is readily transported to the liver. Albumin's high-affinity site binds approximately 25 mg per 100 mL of plasma; beyond that, bilirubin is loosely bound, detaches and diffuses into tissues. Antibiotics and certain other drugs can compete with and displace bilirubin from the high-affinity site — clinically important in the newborn.
Hepatic handling — three stages
- Uptake at the sinusoidal surface by a large capacity, saturable facilitated transport system; bilirubin then binds cytosolic glutathione S-transferase (ligandin), preventing its return to the blood.
- Conjugation by bilirubin UDP-glucuronosyl transferase of the endoplasmic reticulum, transferring two glucuronosyl moieties from UDP-glucuronate to give bilirubin diglucuronide. This is what makes the pigment water-soluble.
- Secretion into bile by the multispecific organic anion transporter (MOAT), an ATP-binding cassette transporter — probably rate-limiting for the entire process.
In the gut
Bacterial β-glucuronidases remove the glucuronosyl moieties, and reduction by the fecal flora forms colorless tetrapyrroles called urobilinogens. Small portions are reabsorbed and reexcreted via the enterohepatic urobilinogen cycle; most are oxidized in the colon to coloured urobilins and excreted in the feces.
The two solubilities — the key to everything clinical
Due to its hydrophobicity, only unconjugated bilirubin can cross the blood-brain barrier, so encephalopathy (kernicterus) occurs only with unconjugated bilirubin. Because of its water-solubility, only conjugated bilirubin can appear in urine, so choluric jaundice occurs only in regurgitation hyperbilirubinemia.
The laboratory follows the same division: “direct” bilirubin (assayed without added methanol) is bilirubin glucuronide — conjugated; “indirect” = total − direct = unconjugated.
Jaundice
Hyperbilirubinemia exceeds 1 mg/dL (17 μmol/L); at 2 to 2.5 mg/dL bilirubin diffuses into the tissues, which turn yellow — jaundice or icterus.
| Prehepatic (haemolysis) | Hepatic (hepatitis) | Posthepatic (obstruction) | |
|---|---|---|---|
| Serum bilirubin | ↑ Indirect | ↑ both | ↑ Direct |
| Urine urobilinogen | Increased | Decreased if micro-obstruction | Absent |
| Urine bilirubin | Absent (acholuric) | Present if micro-obstruction | Present (choluric) |
| Fecal urobilinogen | Increased | Decreased | Trace to absent, pale stools |
| Enzymes | — | ALT, AST ↑↑ | Alkaline phosphatase ↑ |
The common causes of posthepatic obstruction are a stone in the common bile duct and cancer of the head of the pancreas.
Inherited and neonatal disorders
- Neonatal “physiologic jaundice” — accelerated hemolysis plus an immature hepatic system for uptake, conjugation and secretion. If unconjugated bilirubin exceeds the albumin binding capacity (20–25 mg/dL) it penetrates the blood-brain barrier, causing kernicterus and mental retardation. Treated by phototherapy with blue light, which converts some to biliary-excretable derivatives, and by phenobarbital.
- Gilbert syndrome — about 30% of transferase activity retained; harmless.
- Crigler-Najjar type I — complete absence of the transferase; over 20 mg/dL, brain damage, often fatal within the first 15 months; phenobarbital has no beneficial effect. Type II retains some activity and responds to large doses of phenobarbital.
- Dubin-Johnson syndrome — conjugated hyperbilirubinemia from a mutation in the secretion protein; benign. Rotor syndrome is similarly benign and conjugated.
- Toxic hyperbilirubinemia — chloroform, carbon tetrachloride, acetaminophen, hepatitis virus, cirrhosis, Amanita mushroom poisoning.
Marking guide: heme oxygenase → biliverdin → bilirubin 1.5 · albumin transport 1 · the three hepatic stages with conjugation named 2 · gut conversion to urobilinogen 1 · the solubility rule for kernicterus and choluria 2 · the three categories of jaundice with at least four correct laboratory findings 2 · one inherited disorder 0.5.