Aetiology

Systemic amyloidosis is characterised by considerable aetiological heterogeneity, but clinical manifestations of the different amyloidoses may overlap.[19]

Immunoglobulin light chain (AL) amyloidosis

Aetiology is unknown; however, AL amyloidosis is associated with a clonal plasma cell dyscrasia, and is closely related to multiple myeloma. Less than 0.5% of patients diagnosed with AL amyloidosis will progress to overt multiple myeloma.[20]

Patients with AL amyloidosis and co-existing multiple myeloma have a poor prognosis (median overall survival <16 months).[21]

Secondary (AA) amyloidosis (non-familial)

Inflammatory polyarthropathies account for 60% of cases; conditions include rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, and ankylosing spondylitis.[16] The risk of developing AA amyloidosis from chronic inflammatory arthritides is decreasing, possibly due to advances in treatment for chronic inflammatory diseases.[15][16][17]

Inflammatory bowel disease (specifically Crohn's disease), bronchiectasis, tuberculosis, subcutaneous injection of illicit drugs, decubitus ulcers, chronic urinary tract infections, and osteomyelitis can result in AA amyloidosis.[16] Castleman's disease is a non-cancerous lymphoproliferative disorder, where the plasma cell variant can cause AA amyloidosis.[22][23]

The likelihood of developing AA amyloidosis in the absence of one of these non-familial inflammatory disorders is extremely small.

Familial periodic fever syndromes leading to AA amyloidosis

Familial Mediterranean fever, tumour necrosis factor (TNF) receptor-associated periodic fever syndromes (TRAPS), cryopyrin-associated periodic syndromes (CAPS; e.g., Muckle-Wells syndrome), and mevalonate kinase deficiency (formerly known as hyper-IgD syndrome) have been implicated.[24][25][26][27]​​​​

The likelihood of developing AA amyloidosis in the absence of one of these familial inflammatory disorders is extremely small.

Hereditary (familial) amyloidosis

Aetiology of hereditary (familial) amyloidosis includes mutations of:[3]

  • Transthyretin (TTR), leading to progressive cardiomyopathy or progressive neuropathy or both

  • Fibrinogen A alpha-chain, mainly leading to renal involvement

  • Apolipoprotein A, mainly leading to renal involvement

  • Lysozyme, mainly leading to renal involvement

A monoclonal gammopathy may be present in patients with hereditary amyloidosis, which can lead to a misdiagnosis of AL amyloidosis.[28][29] Clinical awareness, a careful family history, and laboratory/pathological evaluation (including genetic testing) are essential to avoid a misdiagnosis of AL amyloidosis in this setting.[30]

Leukocyte chemotactic factor 2 (LECT2) amyloidosis

LECT2 amyloidosis mainly affects the kidney.[3] It is common among certain ethnicities (e.g., Egyptian, Indian, Pakistani, Hispanic).[31][32][33] Aetiology is unknown; genetics may have a role but pathogenic mutations have not been identified.​[32][33]​​​​​[34]

Pathophysiology

Amyloidosis comprises a group of disorders that contribute to tissue damage, and organ dysfunction, through the deposition of amyloid proteins.

Immunoglobulin light chain (AL) amyloidosis

  • AL amyloidosis is caused by clonal plasma cells that produce abnormal immunoglobulin light chains that are inherently prone to misfolding from a native alpha-helical state into an insoluble beta-pleated sheet configuration.[35]

  • The development of amyloidosis is linked both to the quantity of light chain that is produced, as well as a qualitative thermodynamic tendency for the light chain fragment to misfold into the amyloid configuration.[36][37]

  • The kidney and the heart are the primary target organs in AL amyloidosis. The liver and nerves can also be targeted.

  • Significant differences in gene usage are found in AL amyloidosis.[38] Patients with AL clones derived from 6aV lambda VI germline gene usage are more likely to present with dominant renal involvement. Those with clones derived from 1c, 2a2, and 3r V lambda genes are more likely to present with cardiac and multisystem disease.[39]

  • Renal involvement is reported in approximately 55% of patients with AL amyloidosis.[40] The light chains interact with mesangial cells, which catabolise them into fragments that form amyloid fibrils.[41] Amyloid fibrils deposit extracellularly in the mesangium and capillary loops, resulting in disruption of the glomerular basement membrane.[41]

  • Cardiac involvement is reported in 55% to 76% of patients with AL amyloidosis, and is the main cause of death in these patients.[42][43][44]​ Amyloid fibrils deposit extracellularly within the myocardium, which disrupts myocardial contractility and relaxation, and electrical conductance.[45][46]​ Cardiac amyloidosis resembles idiopathic restrictive cardiomyopathy, but ventricular long axis function is depressed in all patients with cardiac amyloidosis compared with only 36% of patients with idiopathic restrictive cardiomyopathy.[47]

  • Liver involvement is reported in approximately 15% of patients with AL amyloidosis.[48] Approximately 10% of patients have palpable hepatomegaly (>5 cm below the right costal margin).[16][49]

  • Nerve involvement is reported in 10% of patients with AL amyloidosis.[48] Amyloid deposits in the vasa nervorum result in clinical findings similar to ischaemic neuropathy and lead to a mixed axonal demyelinating picture. Carpal tunnel syndrome occurs in approximately 50% of patients.[50] The presence of autonomic neuropathy (e.g., signs of erectile dysfunction, orthostatic hypotension, gastrointestinal dysfunction, or urinary dysfunction) is an important clue.[51]

Secondary (AA) amyloidosis (non-familial) and familial periodic fever syndromes

  • AA amyloidosis results from impaired proteolysis of the acute phase reactant, serum amyloid A protein (SAA). N-terminal fragments of SAA, termed amyloid A, are deposited as fibrils in tissue and organs, causing organ damage. Amyloid A is common to AA amyloidosis (non-familial) and familial periodic fever syndromes.

  • AA amyloidosis most commonly affects the kidney and less commonly the gastrointestinal tract and thyroid.[52][53]​​ The most common late sequela of sustained production of AA amyloid is dialysis-dependent renal failure.

  • Long-term survivors of AA amyloidosis (non-familial) can develop cardiac amyloidosis, but with a frequency much lower than that seen in AL amyloidosis and familial periodic fever syndromes.

Hereditary (familial) amyloidosis

  • Most forms of hereditary amyloidosis are a consequence of misfolding of an inherited mutant transthyretin (TTR) molecule.

  • Rarer forms of hereditary amyloidosis are due to mutations of apolipoprotein A1, apolipoprotein A2, fibrinogen, gelsolin, and lysozyme.

  • Hereditary TTR amyloidosis usually presents as cardiomyopathy and/or neuropathy (peripheral and autonomic).[54][55]

Wild-type transthyretin (ATTRwt) amyloidosis

  • Occurs in the elderly and is sometimes referred to as senile systemic amyloidosis or senile cardiac amyloidosis.[54]

  • Amyloid deposition occurs predominantly in the heart. Up to 20% of patients may have mild peripheral neuropathy.[56]

Leukocyte chemotactic factor 2 (LECT2) amyloidosis

  • Caused by abnormal LECT2 protein.[57] 

  • Amyloid deposition occurs mainly in the kidney.[3]​[33]​ Other organs may be involved (e.g., liver)

Classification

Types of amyloidosis[3]​​

  • Localised

  • Systemic

    • Derived from immunoglobulin light chains (referred to as AL amyloidosis or primary systemic amyloidosis)

    • Derived from amyloid A protein (referred to as AA amyloidosis or secondary amyloidosis)

    • Derived from other proteins (e.g., leukocyte chemotactic factor 2 [LECT2])

  • Familial periodic fever syndromes causing AA amyloidosis

    • Familial Mediterranean fever

    • Tumour necrosis factor (TNF) receptor-associated periodic fever syndromes (TRAPS)

    • Cryopyrin-associated periodic syndromes (CAPS; e.g., Muckle-Wells syndrome)

    • Mevalonate kinase deficiency (formerly known as hyper-IgD syndrome)

  • Hereditary (familial) amyloidosis

    • Hereditary transthyretin (TTR) amyloidosis (referred to as variant or ATTRv amyloidosis)

      • Neuropathy

      • Cardiomyopathy

    • Fibrinogen amyloidosis

    • Apolipoprotein amyloidosis

    • Gelsolin amyloidosis

    • Lysozyme amyloidosis

  • Wild-type TTR amyloidosis (referred to as ATTRwt amyloidosis)

  • Dialysis-related amyloidosis (beta-2 microglobulin amyloidosis)

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