Biochemistry of Disease

Biochemical pathways underlie virtually all human disease. Understanding the enzyme defect, accumulated substrate, or deficient product in an inborn error of metabolism, or the dysregulated signalling in a complex disease, allows mechanistic understanding of clinical presentation, diagnosis, and treatment.

Phenylketonuria (PKU)

PKU is an autosomal recessive inborn error of amino acid metabolism caused by deficiency of phenylalanine hydroxylase (PAH), which normally converts phenylalanine (Phe) to tyrosine using tetrahydrobiopterin (BH4) as cofactor. Without PAH, phenylalanine accumulates in blood and brain; it is transaminated to phenylpyruvate and reduced to phenyllactate and phenylacetate (collectively "phenylketones" — excreted in urine, giving characteristic musty odour). Tyrosine becomes conditionally essential. Elevated phenylalanine is neurotoxic: it competitively inhibits large neutral amino acid transporters (LAT1) at the blood-brain barrier, reducing uptake of other aromatic amino acids (tryptophan, tyrosine) needed for neurotransmitter synthesis (serotonin, dopamine, norepinephrine). It also inhibits PKC and impairs myelination. Untreated: severe intellectual disability, seizures, hypopigmentation (tyrosine is needed for melanin synthesis via tyrosinase), eczema. Newborn screening (Guthrie test, then tandem MS) detects elevated Phe on filter paper blood spot. Treatment: low-phenylalanine diet (restrict natural protein, supplement with Phe-free amino acid formula) continued lifelong. Sapropterin (synthetic BH4) is effective in BH4-responsive PAH variants. Pegvaliase (PEGylated phenylalanine ammonia lyase) is an enzyme substitution therapy.

Maternal PKU: uncontrolled hyperphenylalaninaemia during pregnancy causes teratogenic effects on the fetus (who has normal PAH) — microcephaly, congenital heart disease, intellectual disability, IUGR. Strict dietary control before conception is essential.

Galactosaemia

Classic galactosaemia is caused by deficiency of galactose-1-phosphate uridylyltransferase (GALT), the second enzyme in the Leloir pathway for galactose metabolism. Galactose → galactose-1-phosphate (galactokinase) → glucose-1-phosphate + UDP-galactose (GALT) → enters glycolysis/glycogen synthesis. Without GALT, galactose-1-phosphate accumulates — it is toxic to liver, brain, kidneys, and lens. Alternative pathway: aldose reductase converts galactose → galactitol (a polyol), which accumulates in the lens, causing cataracts (osmotic damage). Clinical presentation in neonates: jaundice, hepatomegaly, E. coli sepsis (galactose-1-phosphate impairs neutrophil function), cataracts, hypoglycaemia. Treatment: immediate removal of galactose from diet (no breast milk — lactose = glucose + galactose; use soya or casein hydrolysate formula). Despite treatment, long-term outcomes include intellectual disability, speech problems, and premature ovarian insufficiency in females (mechanism unclear, possibly direct toxicity to gonads). GALT and GALK deficiency are screened by newborn screening. Epimerase deficiency is a milder variant.

Diabetes Mellitus Biochemistry

Type 1 DM: autoimmune destruction of pancreatic beta cells (T-cell mediated, anti-GAD and anti-islet cell antibodies) → absolute insulin deficiency. Without insulin: GLUT4 not translocated → reduced glucose uptake in muscle and adipose. Adipose HSL is uninhibited → unrestrained lipolysis → elevated plasma NEFA → hepatic beta-oxidation → excess acetyl-CoA → ketogenesis. Simultaneously, low malonyl-CoA (insulin normally activates ACC) relieves CPT-I inhibition. Glucagon unopposed → glycogenolysis + gluconeogenesis → hyperglycaemia. Hyperglycaemia osmotic diuresis → dehydration. Diabetic ketoacidosis (DKA): blood glucose >11 mmol/L, pH <7.3, bicarbonate <15, positive ketones. Treatment: IV fluids, insulin infusion, potassium replacement (insulin drives K+ into cells). Type 2 DM: insulin resistance (defective post-receptor signalling, reduced IRS-1 phosphorylation, impaired Akt activation, reduced GLUT4 expression/translocation) in muscle, liver, and adipose. Initially compensated by beta cell hypersecretion; progressive beta cell failure leads to frank hyperglycaemia. Chronic hyperglycaemia causes glycation of proteins (HbA1c formed non-enzymatically — used clinically to assess 3-month glucose control). Advanced glycation end-products (AGEs) accumulate on long-lived proteins (collagen, lens crystallin), activating RAGE receptors and promoting inflammation. Polyol pathway: glucose → sorbitol (aldose reductase, NADPH-consuming) → fructose (sorbitol dehydrogenase, NAD+-consuming). In hyperglycaemia, polyol accumulation causes osmotic damage (cataracts, neuropathy) and depletes NADPH (reducing antioxidant capacity). Protein kinase C activation by diacylglycerol (elevated in hyperglycaemia) impairs endothelial function. Hexosamine pathway: excess glucose → glucosamine-6-phosphate → O-GlcNAc modifications on transcription factors and signalling proteins, impairing insulin signalling. Microvascular complications (retinopathy, nephropathy, neuropathy) and macrovascular disease (atherosclerosis) arise from these mechanisms.

Atherosclerosis: Lipid Mechanisms

Atherosclerosis begins with endothelial injury (turbulent flow, oxidative stress, hypertension, smoking). Modified (oxidised) LDL (oxLDL) accumulates in the arterial intima. oxLDL is taken up by macrophages via scavenger receptors (SR-A, CD36) — unlike LDLR, scavenger receptors are not downregulated by cholesterol, so macrophages become foam cells (lipid-laden). Foam cells secrete cytokines (TNF-α, IL-1β, IL-6, MCP-1) perpetuating inflammation. Smooth muscle cells migrate from media to intima, proliferate, and secrete extracellular matrix (fibrous cap formation). Plaque grows: lipid core (necrotic core of dead foam cells + extracellular lipid) surrounded by fibrous cap. Vulnerable plaques: thin fibrous cap (metalloproteinase degradation), large lipid core, high inflammatory cell infiltration → prone to rupture → thrombus → MI/stroke. Statins reduce LDL and have pleiotropic anti-inflammatory effects (reduce oxLDL, stabilise plaques). PCSK9 inhibitors markedly reduce LDL. Lipidomics reveals that specific oxidised phospholipids (lysophosphatidylcholine) are particularly atherogenic.

Gout: Purine Catabolism Disorder

Gout results from hyperuricaemia (serum urate >360 μmol/L in women, >420 μmol/L in men) and deposition of monosodium urate (MSU) crystals in joints (classically the first metatarsophalangeal joint — podagra). Uric acid is the end product of purine catabolism in humans (most other mammals have uricase, which converts urate to soluble allantoin): AMP → IMP → inosine → hypoxanthine → xanthine → uric acid; GMP → guanosine → guanine → xanthine → uric acid. Xanthine oxidase catalyses the last two steps. Causes of hyperuricaemia: increased purine turnover (haematological malignancies, tumour lysis syndrome, psoriasis), reduced urate excretion (renal disease, thiazides, aspirin at low doses — competes with urate secretion at OAT1), enzyme defects (HGPRT deficiency — Lesch-Nyhan syndrome: failure of purine salvage pathway → purine de novo synthesis ↑; PRPP synthetase overactivity). Pathogenesis of gout: MSU crystals are phagocytosed by neutrophils → NLRP3 inflammasome activation → caspase-1 → IL-1β maturation and release → acute inflammatory arthritis (hot, red, swollen, exquisitely tender joint). Chronic tophaceous gout: urate deposits in soft tissues. Treatment: colchicine/NSAIDs/corticosteroids (acute attack); allopurinol or febuxostat (xanthine oxidase inhibitors, reduce uric acid synthesis); probenecid (uricosuric). Rasburicase (recombinant uricase) for tumour lysis syndrome prevention.