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Station 39: AMYLOIDOSIS What is meant by amyloid? SpoilerAmyloid is an abnormal fibrillar protein that is deposited in the extracellular tissue. The proteins are deposited in a rigid, mesh-like, sheet structure. What is amyloidosis or amyloid degeneration? SpoilerAmyloidosis is a life-threatening condition in which there is deposition of abnormal fibrillar proteins known as amyloid in the extracellular tissue. Why do amyloid deposits in chronic infection not resolve? SpoilerHumans are susceptible to the complications of the amyloid protein because they have no enzyme that can break this structure down. What are the common sites of amyloid deposition? SpoilerBased on the clinical features of AL and AA amyloidosis common sites of amyloid deposition include: Kidneys (leading to proteinuria and nephrotic syndrome) Heart (leading to restrictive cardiac disease and arrhythmias) Liver (Hepatomegaly) Spleen (Splenomegaly) Nervous System (Peripheral neuropathy, carpal tunnel syndrome, autonomic neuropathy) Gastro-intestinal tract (Macroglossia, bleeding, poor absorption) What are the different types of amyloid protein? SpoilerAL protein (associated with Multiple Myeloma/Immunocyte dyscrasias, i.e., Primary amyloidosis) AA protein (associated with Chronic inflammatory conditions e.g., T.B., Rheumatoid arthritis, Secondary amyloidosis) β₂ or microglobulin (Aβ₂m) protein (associated with Chronic renal failure or dialysis, i.e., Hemodialysis-associated amyloidosis). Note: Familial amyloidosis is also mentioned, caused by a mutation in transthyretin. Which type of amyloidosis occurs in chronic inflammation? SpoilerAA amyloidosis (or Secondary amyloidosis) occurs in chronic inflammation. Examples of chronic inflammatory conditions include: -Rheumatoid arthritis (commonest cause of AA amyloid in the UK) -Inflammatory bowel disease -Tuberculosis (T.B.) -Bronchiectasis -Osteomyelitis -Renal cell carcinoma What are the main clinical findings in amyloidosis? SpoilerThe clinical features depend on the type (AL vs. AA) and organs involved. The patient description in your prompt suggests AL amyloidosis due to the presence of: -Progressive ankle swelling / Pitting pedal oedema (suggests kidney/cardiac involvement) -Frothy urine / 3+ Proteinuria (Kidney involvement: Proteinuria and nephrotic syndrome) -Fatigue -Numbness in his feet (Nervous system involvement: Peripheral neuropathy) -Large, firm tongue / Macroglossia (Gastro-intestinal tract involvement) -Hepatomegaly (Liver involvement) How is amyloidosis classified? SpoilerAmyloidosis is classified by the protein and the system involved. Classification by Protein Involved (Systemic/Generalized Amyloidosis) • AL amyloid (Immunocyte dyscrasias with monoclonal B-cell proliferations like Multiple myeloma) • AA amyloid (Chronic inflammatory conditions) • Familial amyloidosis (Autosomal dominant disorder, commonly caused by a mutation in transthyretin) Classification by Clinical Type • Primary Amyloidosis: Associated with Immunocyte dyscrasias (e.g., Multiple myeloma), involving the AL protein. • Secondary Amyloidosis: Associated with Chronic inflammatory conditions (e.g., T.B., bronchiectasis), involving the AA protein. • Haemodialysis-associated amyloidosis: Associated with Chronic renal failure or dialysis, involving the β₂-microglobulin (Aβ₂m) protein. How to test for amyloidosis? SpoilerBlood and urine tests may provide hints about the diagnosis, but the gold standard for detecting amyloid deposits is to perform Congo red staining on a tissue sample, which appears apple-green when viewed with a polarizing microscope. Laser microdissection followed by mass spectrometry can determine the type of amyloid in virtually 100% of cases.

Stem A 65-year-old lady, presented with long standing goitre, malaise & chronic fatigue. FBC & full biochemical profile reviewed as part of her assessment & MAC showed low T3 & T4, high TSH along with macrocytic anaemia. What's the most likely clinical diagnosis? SpoilerHypothyroidism Describe the physiological regulation of thyroid hormones SpoilerThe physiological regulation of thyroid hormones involves a complex feedback loop involving the hypothalamus, pituitary gland, and thyroid gland: Hypothalamus – TRH: Releases thyrotropin‑releasing hormone (TRH), stimulating the pituitary. Pituitary – TSH: TRH triggers release of thyroid‑stimulating hormone (TSH), which stimulates the thyroid gland. Thyroid – T3 & T4: TSH stimulates production and release of thyroxine (T4) and triiodothyronine (T3). Negative feedback: High levels of T3/T4 inhibit TRH and TSH release, maintaining balance. What are differences between T3 & T4 SpoilerT3 is more biologically active than T4. T4 has greater protein‑binding capacity than T3. Talk about Synthesis of T3 & T4 SpoilerIodide ions enter thyroid follicular cells via active pumping. Iodide is converted to iodine by TPO (thyroid peroxidase). Iodine combines with tyrosine to form MIT (monoiodotyrosine) and DIT (diiodotyrosine). MIT + DIT = T3 DIT + DIT = T4 Signs of hypothyroidism SpoilerWeight gain Memory loss Cold intolerance Constipation Myxoedema Bradycardia Muscle weakness Pretibial oedema Dry skin Causes of hypothyroidism Primary hypothyroidism SpoilerIatrogenic -Surgery -Radioiodine therapy -Drugs Autoimmune (Hashimoto’s) Iodine deficiency Idiopathic Genetic defects in thyroid development Thyroid hormone resistance syndrome (THRB) (rare) Congenital biosynthetic defect (dyshormonogenetic goitre) (rare) Transient thyroiditis (De Quervain’s thyroiditis) Infiltrative (amyloidosis, sarcoidosis) Secondary hypothyroidism SpoilerPituitary failure (rare) Hypothalamic failure (rare) If hypothyroidism is due to hypopituitarism, how could TFT differ? SpoilerThis will be secondary hypothyroidism: Low TSH Low T3 and T4 From the FBC findings given, explain the cause SpoilerPatient has macrocytic anaemia due to antibodies directed against parietal cells, which are responsible for secretion of intrinsic factor that helps in absorption of vitamin B12. I.e. autoimmune hypothyroidism associated with pernicious anaemia. She was put on medical therapy; she is not compliant. Which teams should be involved? SpoilerEndocrinologist Her GP Family members Problems associated with emergency surgery in hypothyroid patients SpoilerPre‑operative Anaemia Increased risk of ischaemic heart disease Increased sensitivity to medications, anaesthetic drugs, and narcotics Intra‑operative Airway compromise Coagulopathy Post‑operative Myxoedema coma Delayed recovery Poor wound healing How to improve compliance with thyroid replacement therapy SpoilerDiscuss with the patient the reason for non‑compliance Communication with GP and family members Medical follow‑up Simple regimen: single dose in the early morning

MRCS B Prostate Gland Stem: A 68-year-old man presents to his GP with a 6-month history of increasing urinary frequency, nocturia, and a weak urinary stream with hesitancy. He denies any haematuria or weight loss. On examination, his abdomen is soft and non-tender, with no palpable bladder. What are the superior and inferior relations of the prostate gland? SpoilerSuperior – neck of the bladder Inferior – external urethral sphincter Describe the zonal anatomy of the prostate. Which zone is most commonly affected by carcinoma, and which by benign hyperplasia? SpoilerPeripheral zone – largest zone, most common site of prostate carcinoma, palpable on DRE Transition zone – surrounds the urethra, most common site of benign prostatic hyperplasia Central zone – surrounds the ejaculatory ducts What is the arterial supply to the prostate? SpoilerInferior vesical artery, from the anterior division of the internal iliac artery. What is the venous drainage of the prostate and how is it implicated in prostatic malignancy? SpoilerProstatic venous plexus Has a connection with the valveless vertebral veins, which may be a passage of spread of malignancy. Prostate symptoms can be classified as storage or voiding symptoms, give two examples of each. Storage SpoilerFrequency Nocturia Urgency Incontinence Voiding SpoilerTerminal dribbling Slow stream Slow to start voiding What is an important part of the examination of a male patient with storage or voiding symptoms? How may we distinguish between benign or malignant pathology? SpoilerDigital rectal examination. May feel a smooth enlargement suggestive of benign disease, or a craggy, hard mass, which would suggest malignant disease. What tumour marker is used to help diagnose and monitor prostate cancer, and what are its limitations? SpoilerProstate-specific antigen (PSA) Not specific to malignancy – can also be raised in BPH, prostatitis, and after instrumentation (e.g. catheterisation, DRE) Lacks sensitivity and specificity, so used alongside DRE and biopsy rather than as a standalone diagnostic test Give two options for the pharmacological management of benign prostatic hyperplasia. Spoiler5-alpha reductase inhibitors – e.g. Finasteride. Anticholinergic agents – e.g. Tolterodine Alpha blockers can also be used. Give two risk factors for prostate cancer. SpoilerEthnicity – more common in people of black ethnicity. Age – people aged over 50 are much more likely to have prostate malignancy.