Amyloidosis

A group of disorders characterised by extracellular deposition of misfolded protein in an abnormal beta pleated sheet configuration, forming insoluble fibrils that disrupt tissue architecture and function, classified by the precursor protein involved rather than by clinical presentation alone, since the precursor determines prognosis and treatment entirely.

Classification by precursor protein

• AL amyloidosis (immunoglobulin light chain) arises from a clonal plasma cell dyscrasia producing free light chains that misfold and deposit systemically, frequently in the heart, kidneys, liver, peripheral nerves and soft tissue, and carries the worst prognosis of the common forms if untreated.

• AA amyloidosis (serum amyloid A) results from chronic inflammatory or infective states (rheumatoid arthritis, inflammatory bowel disease, chronic infection, familial Mediterranean fever) driving sustained elevation of the acute phase reactant serum amyloid A, with a predilection for renal deposition.

• ATTR amyloidosis (transthyretin) occurs in hereditary form from a mutated transthyretin gene, or in wild type form (previously termed senile systemic amyloidosis) from age related misfolding of normal transthyretin, with a strong predilection for cardiac and, in the hereditary form, peripheral and autonomic nerve involvement.

• Other rarer forms include dialysis related (beta 2 microglobulin) amyloidosis and localised amyloid deposits confined to a single organ without systemic disease.

• Cardiac involvement produces restrictive cardiomyopathy with heart failure symptoms (dyspnoea, oedema, fatigue) often out of proportion to apparent left ventricular function on standard assessment, with a low voltage electrocardiogram despite increased wall thickness on echocardiography, a striking and diagnostically important discordance.

• Renal involvement causes proteinuria, often in the nephrotic range, progressing to renal impairment.

• Peripheral and autonomic neuropathy, particularly prominent in ATTR amyloidosis, presents with sensory symptoms, carpal tunnel syndrome (frequently bilateral and an important early clue, sometimes preceding systemic diagnosis by years), orthostatic hypotension, gastrointestinal dysmotility and erectile dysfunction.

• Macroglossia, periorbital purpura (classically after minor trauma such as coughing or straining, "raccoon eyes"), and hepatosplenomegaly are more specific though less common findings, particularly in AL amyloidosis.

• Bleeding tendency from acquired factor X deficiency (factor X binds to amyloid fibrils) and vascular fragility occurs in AL disease.

• Soft tissue and musculoskeletal involvement includes shoulder pad sign, macroglossia and submandibular gland enlargement.

Symptoms of the underlying plasma cell dyscrasia (AL) or chronic inflammatory disease (AA) accompany the amyloid related features.

• Tissue biopsy with Congo red staining showing apple green birefringence under polarised light is the definitive diagnostic test, with the biopsy site chosen for accessibility (abdominal fat pad aspirate and rectal biopsy have reasonable sensitivity for systemic AL and AA disease, with organ specific biopsy where these are negative and suspicion remains high).

• Typing of the amyloid subtype is essential once histology confirms amyloid, since AL, AA and ATTR are treated entirely differently: mass spectrometry based proteomic analysis of the biopsy is the most accurate typing method, with immunohistochemistry as an alternative where mass spectrometry is unavailable.

• Serum and urine protein electrophoresis with immunofixation, and serum free light chain assay, identify the underlying clonal plasma cell process in suspected AL amyloidosis and are essential before assuming an alternative diagnosis.

• Bone marrow examination with plasma cell quantification and cytogenetics in confirmed AL amyloidosis, staged in parallel with the myeloma diagnostic pathway.

• Genetic testing for transthyretin mutations distinguishes hereditary from wild type ATTR amyloidosis, with important implications for family screening and, in some countries, organ transplantation eligibility.

• Cardiac assessment with echocardiography (increased wall thickness with a granular sparkling myocardial appearance), cardiac magnetic resonance imaging (characteristic late gadolinium enhancement pattern), and cardiac biomarkers (troponin, natriuretic peptides) for staging and prognosis.

• Technetium pyrophosphate bone scintigraphy is a highly specific, non invasive test for cardiac ATTR amyloidosis, and in the appropriate clinical context with a negative monoclonal protein screen can obviate the need for endomyocardial biopsy.

• AL amyloidosis is treated as a plasma cell dyscrasia, with chemotherapy directed at eliminating the clonal light chain production.

  Bortezomib based regimens (commonly with cyclophosphamide and dexamethasone) are standard first line therapy, with daratumumab increasingly incorporated into frontline regimens given significant efficacy.

  Autologous stem cell transplantation is considered in eligible patients with adequate organ function.

  Organ support (diuretics for cardiac involvement, used cautiously given the sensitivity of the restrictive physiology to volume changes) runs concurrently.

• AA amyloidosis is managed by aggressive treatment of the underlying inflammatory or infective driver to suppress serum amyloid A production, which can halt progression and allow partial regression of deposits: biologic therapy targeting the underlying inflammatory disease (tumour necrosis factor inhibitorsmanaging further organ support and monitoring for progression to end stage renal disease, which remains the dominant long term complication even with inflammation controlled.

• ATTR amyloidosis management differs by cause. Tafamidis, a transthyretin stabiliser, is approved for ATTR cardiomyopathy (both hereditary and wild type) and slows progression when started before advanced heart failure. Patisiran and inotersen, RNA interference and antisense therapies respectively that suppress hepatic transthyretin production, are used for hereditary ATTR polyneuropathy.

  Liver transplantation, historically the mainstay for hereditary ATTR (removing the source of mutant protein production), is now reserved for selected cases given the efficacy of pharmacological silencing therapy. Combined heart and liver transplantation is considered in advanced hereditary disease with cardiac involvement.

Symptomatic management across all subtypes includes diuretics titrated cautiously for cardiac involvement, management of orthostatic hypotension and autonomic dysfunction, anticoagulation consideration given high atrial thrombus risk from restrictive physiology and atrial mechanical dysfunction even in sinus rhythm, and dietary sodium restriction.

Genetic counselling and family screening for relatives of patients with hereditary ATTR amyloidosis, given autosomal dominant inheritance with variable penetrance.

Long term multidisciplinary follow up (haematology, cardiology, nephrology, neurology) given the multisystem nature of disease and the need for coordinated organ surveillance throughout treatment.