A range of clinical disorders occur because of proteins, misfolded, binding together to form so-called amyloid (“starch-like”) fibrils that subsequently deposit and impact organ function. Devoid of the structural, supportive, or motility function of most fibrous proteins, amyloid is the abnormal, extracellular, insoluble, proteinaceous deposits in organs and tissues, protein deposits that remain resistant to degradation. Unlike other fibrous proteins, amyloid protein does not commonly have any functional role; but rather, deposited as if the extracellular matrix were some wasteland for fibrous proteins gone wrong. Diseases as varied as Alzheimer’s, the spongiform encephalopathies, and type II diabetes mellitus, all involve amyloid protein in their pathophysiology, an amyloid characteristically misfolded into a cross-β sheet conformation. Each amyloid disease type is characterised by a specific protein or peptide aggregate. More than 20 plasma proteins that can form amyloid have been identified and treatment is amyloid-disease specific to the exact protein causing the disorder, the two most common types of disordered proteins conferring, respectively, light chain (AL) and transthyretin (ATTR), amyloidosis.
A misnomer, the name amyloid was based on deposits seen from crude iodine-staining techniques used on liver autopsy specimens identified by German botanist, Matthias Schleiden, and later by the German pathologist, Rudolf Virchow, in the mid-19th century; staining believed indicative of a carbohydrate nature to amyloid’s moieties. But by 1927, it had become established that examination under polarised light after Congo-red staining, revealed a characteristic apple-green birefringence reflecting amyloid’s fibrillar (i.e. fibrous protein) nature, a fibrillary nature subsequently confirmed under transmission electron microscopy. X-ray diffraction then revealed the characteristic cross-β structure to amyloid protein. In 1982, the American neurologist and biochemist, Stanley Prusiner, put forward his putative ‘prion’ hypothesis: an infectious protein particle capable of causing the fatal neurodegenerative scrapie of sheep; an amyloidogenic protein that, unlike other amyloid forming proteins, was infective and which he termed a “prion.” Later, Bovine spongiform encephalopathy (BSE) in cows, and variant Creutzfeldt-Jacob disease (vCJD) in humans, confirmed the transmissibility of prions from species to species. Amyloid formation is believed to be important to the pathogenesis of the prion diseases.1
With silk-like tensile strength (equivalent to steel), the amyloid fibrils are extremely stable and resistant to degradation. While their stability and insolubility means they are useful forms for bio-nanotechnology, these properties also render amyloid destructive and confer to them the ability to accumulate in tissues. Less certain, however, is whether amyloid is a causative agent in disease pathogenesis or a secondary event.1 Systemic amyloidosis is more commonly seen than isolated localised deposits of the protein. AL or light-chain (previously “primary”) amyloidosis is among the more common and more severe, although still relatively uncommon, affecting some 10 per million per year.
Light-chain Amyloidosis (AL)
Light chains are antibody fragments, derived from a clonal population of plasma cells (mature B lymphocytes) in the bone marrow. This small clonal population together gradually make and accumulate abundant antibody light-chain and, in its abundance, this light-chain disseminates through blood plasma cells, and the protein misfolds and binds together, forming pathological amyloid fibrils that deposits in organs, most commonly the heart and kidneys but also GIT (tongue, stomach, large intestine), liver, nerves, and skin. Amyloid light chains can be either kappa or lambda light chains. In AL amyloidosis, the light chain proteins are misshapen and produced in excess. Because AL amyloidosis is associated with the overproduction of plasma cell proteins, it is linked to multiple myeloma. Given that some 70% of patients already have more than one organ involved at the time of diagnosis, patients with AL amyloidosis often present with cardiac dysfunction, nephrotic syndrome, neuropathy, low blood pressure, and gastrointestinal symptoms.
AL amyloidosis is the most common type of systemic amyloidosis in developed countries.
Clinical Presentation of AL amyloidosis is protean, because of the wide number of tissues or organs that may be affected, a variable presentation that may account for delayed diagnosis:
- most commonly asthenia and dyspnoea (poorly specific)
- renal manifestations the most frequent (affecting 2/3 at presentation):
- heavy proteinuria, with nephrotic syndrome and impaired renal function in half of the patients.
- heart involvement (affecting > 50% of patients):
- restrictive cardiopathy, the most serious complication
Systemic AL amyloidosis should be distinguished from other diseases related to deposition of monoclonal LC, and from other forms of systemic amyloidosis, e.g. due to deposition of transthyretin (TTR), a thyroxine and vitamin-A transporter synthesised in the liver.. In TTR amyloidosis, either an age (senile), wild-type, or an autosomal dominant inherited amino-acid substitution result in fibrillogenesis; whereby TTR dissociates into intermediates that misassemble into amyloid fibrils and deposit in end-organs, most notably the heart.. While AL amyloidosis is treated with chemotherapy and transplant, TTR cardiac amyloidosis is treated with targeted therapy such as tafamidis.3 NTLA-2001 is an in vivo gene-editing therapeutic agent that is designed to inactivate the TTR gene in liver cells to prevent the production of misfolded transthyretin (TTR) protein, thereby reducing the concentration of TTR in serum.
References
- Rambaran, Roma N, and Louise C Serpell. “Amyloid fibrils: abnormal protein assembly.” Prion vol. 2,3 (2008): 112-7. doi:10.4161/pri.2.3.7488.
- Desport E, Bridoux F, Sirac C, Delbes S, Bender S, Fernandez B, Quellard N, Lacombe C, Goujon JM, Lavergne D, Abraham J, Touchard G, Fermand JP, Jaccard A; Centre national de référence pour l’amylose AL et les autres maladies par dépôts d’immunoglobulines monoclonales. “Al amyloidosis.” Orphanet J Rare Dis. 2012 Aug 21;7:54. doi: 10.1186/1750-1172-7-54.
- Al Hamed, R., Bazarbachi, A.H., Bazarbachi, A. et al. “Comprehensive Review of AL amyloidosis: some practical recommendations.” Blood Cancer J. 11, 97 (2021). https://doi.org/10.1038/s41408-021-00486-4.
