2.5 Purine, Pyrimidine Metabolism & the Porphyrias

[!NOTE] MRCP Part 1 Blueprint Focus: Inborn errors of metabolism and metabolic biochemistry constitute high-yield questions on the exam. Candidates must distinguish between enzyme deficiencies in purine catabolism, acute vs cutaneous porphyrias, glycogen storage diseases, sphingolipidoses, and amino acid catabolism disorders based on clinical presentation, biochemical markers, and histology.

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Purine & Pyrimidine Metabolism: Pathways & Clinical Pathology

Purines (adenine, guanine) and pyrimidines (cytosine, thymine, uracil) are essential for nucleic acid synthesis, energy transfer (ATP, GTP), and intracellular signaling.

                     Purine Salvage and Degradation Pathways
       AMP                                   IMP                                   GMP
        │                                     │                                     │
        ▼                                     ▼                                     ▼
    Adenosine                             Inosine                               Guanosine
        │ (Adenosine Deaminase)               │                                     │
        ▼                                     ▼                                     ▼
     Inosine ──────────────────────────> Hypoxanthine                            Guanine
                                              │                                     │
                                              │ (Xanthine Oxidase)                  │
                                              ▼                                     ▼
                                           Xanthine <───────────────────────────────┘
                                              │
                                              │ (Xanthine Oxidase)
                                              ▼
                                          Uric Acid (Excreted in Urine)

Purine Salvage versus De Novo Synthesis

Purines can be synthesised de novo from 5-phosphoribosyl-1-pyrophosphate (PRPP) in an energy-costly pathway, or reclaimed from dietary nucleic acids and cellular turnover via the purine salvage pathway:

• Hypoxanthine-Guanine Phosphoribosyltransferase (HGPRT): Converts hypoxanthine to IMP and guanine to GMP, consuming PRPP.
• Adenine Phosphoribosyltransferase (APRT): Converts adenine to AMP, consuming PRPP.

Gout and Hyperuricaemia

Uric acid is the poorly soluble end-product of purine degradation, formed sequentially from hypoxanthine to xanthine, and xanthine to uric acid by xanthine oxidase.

• Pathophysiology: Hyperuricaemia (serum urate >420 micromol/L [>7.0 mg/dL]) leads to precipitation of monosodium urate (MSU) crystals in synovial joints and avascular tissues.
• Crystal Characteristics: Synovial fluid polarized light microscopy reveals needle-shaped crystals with strong negative birefringence (crystals appear bright yellow when aligned parallel to the slow axis of the red compensator filter, and blue when perpendicular).
• Mechanisms: Approximately 90% of gout cases stem from renal underexcretion (reduced glomerular filtration, volume depletion, or drug interference: thiazide diuretics, loop diuretics, ciclosporin, low-dose aspirin, alcohol which generates lactate competing for proximal tubular excretion). Approximately 10% stem from overproduction (myeloproliferative disorders, tumor lysis syndrome, severe psoriasis, PRPP synthetase hyperactivity).

Lesch-Nyhan Syndrome

• Genetics: X-linked recessive, total deficiency of HGPRT on Xq28.
• Biochemical Pathogenesis: Absent HGPRT prevents hypoxanthine and guanine salvage. Unconsumed PRPP accumulates to supranormal concentrations, acting as an allosteric feed-forward activator of amidophosphoribosyltransferase (the rate-limiting enzyme of de novo purine synthesis). This causes massive, uncontrolled purine synthesis and degradation into uric acid.
• Clinical Presentation:
  • Metabolic / Renal: Severe hyperuricaemia, urate nephrolithiasis, obstructive uropathy, and orange "sand" (sodium urate crystals) noted in infant diapers.
  • Neurological: Severe extrapyramidal movement disorder: choreoathetosis, dystonia, and spastic cerebral palsy-like motor impairment emerging in the first year (due to basal ganglia dopamine deficiency).
  • Behavioral: Classic hallmark is compulsive self-mutilation (severe biting of lips, tongue, and fingertips; head-banging) and aggressive outbursts.

Adenosine Deaminase (ADA) Deficiency

• Pathophysiology: Autosomal recessive inborn error accounting for ~15-20% of cases of Severe Combined Immunodeficiency (SCID). ADA normally deaminates adenosine to inosine and deoxyadenosine to deoxyinosine.
• Molecular Toxicity: Absent ADA causes massive accumulation of intracellular deoxyadenosine, which is phosphorylated to toxic levels of dATP. Elevated dATP allosterically inhibits ribonucleotide reductase, starving dividing cells of deoxyribonucleotides (dNTPs) and arresting DNA replication. Immature T and B lymphocyte progenitors in the thymus and bone marrow are exquisitely sensitive, undergoing widespread apoptosis.
• Clinical Features: Severe, recurrent opportunistic bacterial, viral, and fungal infections (e.g., Pneumocystis jirovecii, disseminated cytomegalovirus, intractable Candida thrush), profound lymphopenia with absent T, B, and NK cells, failure to thrive, and absent thymic shadow on chest radiograph.

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The Porphyrias: Neurovisceral Attacks vs Cutaneous Photosensitivity

Porphyrias are inborn errors of the 8-step heme biosynthetic pathway. Heme is synthesized in all nucleated cells, predominantly in erythroid bone marrow (80%, for haemoglobin) and hepatocytes (15-20%, for cytochrome P450 enzymes).

                        Heme Biosynthesis Pathway & Enzymatic Blocks
  Glycine + Succinyl-CoA
        │ (ALA Synthase: rate-limiting; ALAS-1 in liver, ALAS-2 in bone marrow)
        ▼
  delta-Aminolevulinic Acid (ALA)
        │ (ALA Dehydratase)
        ▼
  Porphobilinogen (PBG)
        │ (PBG Deaminase / HMB Synthase) ───[Block: Acute Intermittent Porphyria / AIP]
        ▼
  Hydroxymethylbilane (HMB)
        │ (Uroporphyrinogen III Synthase) ──[Block: Congenital Erythropoietic Porphyria / CEP]
        ▼
  Uroporphyrinogen III
        │ (Uroporphyrinogen Decarboxylase) ─[Block: Porphyria Cutanea Tarda / PCT]
        ▼
  Coproporphyrinogen III ──> Protoporphyrinogen IX ──> Protoporphyrin IX ──> Heme (via Ferrochelatase)

Acute Intermittent Porphyria (AIP)

• Pathophysiology: Partial (~50%) deficiency of PBG deaminase. Symptoms are triggered when hepatic ALAS-1 is induced. Fasting (via PGC-1alpha induction) or CYP-inducing drugs (which consume free hepatic heme, relieving feedback repression on ALAS-1) trigger a massive influx of precursors into the pathway, accumulating neurotoxic ALA and PBG.
• Clinical Manifestations (The 5 "P"s):
  1. Painful abdomen: Severe, diffuse, poorly localized, colicky pain out of proportion to physical signs (soft, non-tender abdomen).
  2. Polyneuropathy: Motor-predominant axonal peripheral neuropathy, typically starting with proximal upper limb weakness (wrist drop, shoulder girdle paresis), which can progress to quadriplegia and diaphragmatic respiratory paralysis.
  3. Psychiatric manifestations: Confusion, anxiety, psychosis, visual hallucinations, and agitation.
  4. Port-wine urine: Colorless when freshly voided; PBG polymerizes to porphobilin upon light/air exposure, turning urine deep red/brown/black.
  5. Precipitated by drugs: Barbiturates, carbamazepine, phenytoin, rifampicin, sulphonamides, nitrofurantoin, alcohol, low-calorie diets, and cyclical progesterone in the luteal phase of the menstrual cycle.
  • Autonomic instability (sinus tachycardia, hypertension) and hyponatraemia (due to SIADH or vomiting) are frequent.
• Diagnosis: Markedly elevated urinary PBG (quantitative ion-exchange chromatography) during an acute attack.
• Management: Immediate cessation of porphyrinogenic medications. Administer IV Hemin (hematin), which reconstitutes the hepatic heme pool, directly suppressing ALAS-1 transcription. Administer high-dose intravenous dextrose (300 g/day), which suppresses ALAS-1 via insulin-mediated FoxA2/PGC-1alpha downregulation.

Porphyria Cutanea Tarda (PCT)

• Pathophysiology: Deficiency of uroporphyrinogen decarboxylase (UROD). Uroporphyrinogen accumulates in the liver and circulates to the dermis. The conjugated tetrapyrrole rings absorb long-wave ultraviolet A light (Soret band ~400-410 nm), generating singlet oxygen and reactive radicals that damage capillary basement membranes.
• Clinical Features: Chronic blistering on sun-exposed sites (dorsa of hands, forearms, face). Fragile skin that sloughs with minor friction, producing weeping erosions, atrophic scarring, and milia (tiny subepidermal keratin cysts). Facial hypertrichosis (temporal/malar hair growth) and hyperpigmentation. Tea-colored urine that fluoresces coral-pink under Wood's lamp (365 nm UVA).
• Associations: Strongly linked with Hepatitis C virus (HCV) infection, hepatic iron overload (HFE C282Y mutations), chronic alcohol abuse, and exogenous oestrogens.
• Management: Serial venesection (therapeutic phlebotomy) to deplete hepatic iron stores (target ferritin <50 micrograms/L), restoring UROD activity. Low-dose oral chloroquine or hydroxychloroquine (100 mg twice weekly) forms water-soluble complexes with porphyrins, enhancing renal clearance. Direct-acting antivirals for HCV.

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