(a) A 32-year-old male is brought to the emergency department following a road traffic accident. His clinical examination shows…

(a) Erb–Duchenne palsy after a road traffic accident (15 marks)

(i) Site of the lesion (5 marks). The signs (adducted, medially rotated arm, extended elbow, pronated forearm, and sensory loss on the lateral forearm) and the MR finding of an upper plexus injury point to the upper trunk of the brachial plexus (roots C5 and C6), at Erb's point, 2–3 cm above the clavicle behind the posterior border of sternocleidomastoid, where the two roots unite. It is injured by a forced downward traction of the shoulder with the head bent to the opposite side, as when a motorcyclist lands on the shoulder. The diagram marks the lesion.

(ii) Anatomical basis of the motor and sensory loss (10 marks). C5 and C6 supply the shoulder abductors and lateral rotators and the elbow flexors and supinators, mainly through the axillary, suprascapular, musculocutaneous and radial nerves.

• Arm adducted: deltoid and supraspinatus (abduction) are paralysed, so the adductors (pectoralis major, latissimus dorsi, teres major), which are supplied from lower roots, act unopposed.
• Arm medially rotated: infraspinatus and teres minor (lateral rotators) are paralysed, so the medial rotators (subscapularis, pectoralis major, latissimus dorsi) win.
• Elbow extended: biceps, brachialis and coracobrachialis (musculocutaneous, C5–C6) are paralysed, so triceps (radial nerve, C6–C8) extends the elbow without opposition.
• Forearm pronated: biceps and supinator (the supinators) are paralysed, so pronator teres and pronator quadratus (median nerve, C6–C7 and C8–T1) are unopposed. Brachioradialis is also paralysed. The limb takes the "waiter's tip" position.
• Sensory loss: the C5 and C6 dermatomes. The lateral forearm is supplied by the lateral cutaneous nerve of the forearm, the continuation of the musculocutaneous nerve (C5–C6), and there is also loss over the lateral arm (upper lateral cutaneous nerve of the arm from the axillary nerve, C5) and the thumb and index finger (C6).
• The biceps and brachioradialis reflexes are lost, while hand function (C8, T1) is preserved.

(b)(i) Proteins regulating iron absorption, transport and storage (10 marks)

Absorption. Dietary non-haem iron (Fe³⁺) is reduced to Fe²⁺ by duodenal cytochrome b (Dcytb) with vitamin C, and enters the duodenal enterocyte through the divalent metal transporter 1 (DMT1) at the apical membrane. Haem enters by the haem carrier protein or endocytosis, and haem oxygenase releases its iron. The iron leaves the cell across the basolateral membrane through ferroportin, the only known cellular iron exporter, and is oxidised to Fe³⁺ by hephaestin (ceruloplasmin in plasma).

Transport. Transferrin carries Fe³⁺ in plasma (two sites per molecule, about 30% saturated). The transferrin receptor 1 (TfR1) on cells binds the diferric transferrin, and the complex is taken up by receptor-mediated endocytosis. In the acidified endosome the iron is released, reduced by STEAP3 and taken to the cytosol by DMT1, and the receptor and apotransferrin are recycled.

Storage. Ferritin, a shell of 24 H and L subunits, stores iron as Fe³⁺ (the H chain has ferroxidase activity), which makes it non-toxic, and its plasma level reflects the stores. Haemosiderin is a partly degraded, insoluble form stored in macrophages in iron overload.

Regulation.

• Hepcidin: the liver peptide hormone, made in response to iron and inflammation (IL-6), and suppressed by iron deficiency, hypoxia and erythropoietic drive (erythroferrone). It binds ferroportin and causes its internalisation and degradation, so intestinal absorption and macrophage iron release fall. Deficiency of hepcidin (or the HFE/TfR2/hemojuvelin signals that raise it) causes haemochromatosis; excess in chronic disease causes anaemia of chronic disease.
• IRE–IRP system (post-transcriptional): in iron deficiency, the iron regulatory proteins bind the iron-responsive elements of mRNA. At the 5′ UTR of ferritin (and ferroportin) mRNA this blocks translation, and at the 3′ UTR of TfR1 and DMT1 mRNA it stabilises the message. Iron loading reverses this, so there is more ferritin and fewer receptors.

(b)(ii) Biochemical role of vitamin B6 and the pellagra-like state in its deficiency (10 marks)

Role. Vitamin B6 (pyridoxine, pyridoxal, pyridoxamine) is converted by pyridoxal kinase to its active coenzyme, pyridoxal phosphate (PLP), which forms a Schiff base with the substrate amino group and acts as an electron sink. It is needed for:

• Transamination: alanine and aspartate aminotransferases (ALT, AST).
• Decarboxylation: formation of GABA from glutamate, dopamine from DOPA, serotonin from 5-hydroxytryptophan, histamine from histidine.
• The first step of haem synthesis (ALA synthase) from glycine and succinyl-CoA.
• Trans-sulfuration (cystathionine β-synthase and γ-lyase), converting homocysteine into cysteine.
• Glycogen phosphorylase, sphingolipid synthesis (serine palmitoyltransferase), and dehydratases and racemases.
• Tryptophan metabolism, through kynureninase (explained below).

Deficiency (isoniazid or long-term drugs, alcoholism) causes convulsions (less GABA), sideroblastic anaemia, peripheral neuropathy, dermatitis and homocysteinaemia.

Why B6 deficiency resembles pellagra. Niacin, and hence NAD, is made in the body from tryptophan by the kynurenine pathway: tryptophan → kynurenine → 3-hydroxykynurenine → 3-hydroxyanthranilate → quinolinate → nicotinate mononucleotide → NAD. The step that cleaves 3-hydroxykynurenine to 3-hydroxyanthranilate is done by kynureninase, a PLP-dependent enzyme. In B6 deficiency the enzyme is inactive, so 3-hydroxykynurenine builds up and is diverted to xanthurenic acid (excreted in urine, the basis of the tryptophan-load test), and too little niacin and NAD is formed. The patient therefore develops niacin deficiency, the dermatitis, diarrhoea and dementia of pellagra, though the diet contains niacin and tryptophan.

(c)(i) Functions and regulation of growth hormone (10 marks)

Functions. GH (191 amino acids, from the somatotrophs of the anterior pituitary) acts directly and through insulin-like growth factor 1 (IGF-1, made mainly in the liver under GH control).

• Growth-promoting (mainly through IGF-1): proliferation of chondrocytes at the epiphyseal plates and longitudinal bone growth; growth of muscle and viscera; protein synthesis with amino-acid uptake, nitrogen retention and less urea formation.
• Metabolic (mainly direct): lipolysis, with more free fatty acids and ketogenesis (fat-sparing); an anti-insulin (diabetogenic) effect, with less glucose uptake by muscle and fat, insulin resistance and more hepatic glucose output; retention of sodium, potassium and phosphate, and more calcium absorption.

Regulation of secretion. Secretion is pulsatile (every 3–4 hours) and is highest during the first slow-wave sleep of the night.

• Hypothalamic GHRH stimulates the somatotrophs (Gs, cAMP), and somatostatin inhibits them. The gastric peptide ghrelin stimulates release (GH secretagogue receptor).
• Feedback: IGF-1 inhibits the pituitary and stimulates somatostatin, and GH itself has a short-loop feedback on the hypothalamus.
• Stimuli: hypoglycaemia, fasting, amino acids (arginine), exercise, stress, deep sleep, puberty (sex steroids), L-dopa, clonidine and glucagon.
• Inhibitors: hyperglycaemia and raised free fatty acids, obesity, excess glucocorticoids, hypothyroidism, ageing, REM sleep.

(c)(ii) Insulin action at the receptor level (5 marks)

The insulin receptor is a heterotetramer of two extracellular α subunits, which bind insulin, and two transmembrane β subunits with intrinsic tyrosine kinase activity, held together by disulfide bonds. It is a receptor tyrosine kinase.

• Insulin binds the α subunits, changes the conformation, and the β subunits autophosphorylate each other on tyrosine residues, which activates the kinase.
• The kinase phosphorylates the insulin receptor substrates (IRS-1 and IRS-2) and Shc, which act as docking sites.
• PI3-kinase–Akt (PKB) pathway (metabolic effects): translocation of GLUT4 to the membrane in muscle and fat, activation of glycogen synthase (through inhibition of GSK-3), protein synthesis (mTOR), and inhibition of lipolysis and gluconeogenesis.
• Ras–MAPK pathway (growth and gene expression).
• Termination: the insulin–receptor complex is internalised by endocytosis, insulin is degraded in the endosome, and the receptor is recycled or degraded (down-regulation). Phosphatases such as PTP1B dephosphorylate it, and serine phosphorylation of IRS causes insulin resistance.