What is Amyloidosis?

The term 'amyloid' was coined in 1854 by Rudolf Virchow, who mistakenly believed the deposits were starch-like due to their reaction with iodine. Modern definition is based on the characteristic fibrillar structure and Congo red positivity under polarized light — displaying apple-green birefringence. The International Society of Amyloidosis (ISA) uses a standardized nomenclature system: prefix 'A' followed by letters identifying the precursor protein.

Amyloidosis is based on a fundamental biological process: the misfolding of normally soluble proteins into insoluble fibrillar aggregates. This pathological transformation begins with destabilization of the natural protein structure, followed by conformational change from the physiological alpha-helix to the pathological beta-sheet configuration. Amyloid formation proceeds via a nucleation-elongation cascade, where small oligomeric seeds serve as nucleation centers for further fibril growth. The resulting fibrils have extraordinary stability and resistance to physiological degradation, leading to progressive accumulation in the extracellular space of various tissues.

AL amyloidosis is caused by deposition of misfolded immunoglobulin light chains produced by clonal plasma cells. Lambda chains are more frequently involved (approx. 80% of cases). The disease is often associated with hematological conditions including multiple myeloma, Waldenström macroglobulinemia, and chronic lymphocytic leukemia, but can occur in MGUS. AL amyloidosis is characterized by rapid progression and early multi-organ involvement. The heart is affected in 50–70% of cases, making it one of the most aggressive forms of cardiac amyloidosis. Renal manifestations frequently present as nephrotic syndrome.

ATTR amyloidosis is caused by deposition of misfolded transthyretin (TTR), a protein mainly synthesized in the liver that physiologically transports thyroxine and retinol. It exists in two variants:

ATTRwt (Wild-type): Caused by age-related destabilization of normal TTR without an underlying gene mutation. Affects primarily older men, manifesting mainly as cardiac amyloidosis. Prevalence is much higher than previously assumed — up to 25% in patients over 80.

ATTRv (Hereditary): Based on mutations in the TTR gene — more than 120 pathogenic variants identified. In Germany, prevalence estimated at 1:100,000. Follows an autosomal-dominant inheritance with variable penetrance. Clinically manifests primarily as progressive polyneuropathy, with cardiac manifestations in some variants.

AA amyloidosis arises from deposition of serum amyloid A (SAA) fragments, an acute-phase protein elevated in chronic inflammatory processes. Typically secondary to rheumatoid arthritis, inflammatory bowel disease, or chronic infections. Incidence: 1–2 per million, declining in developed countries due to improved treatment of inflammatory diseases. The kidney is most commonly affected; cardiac involvement is rare.

Beyond the main forms exist various rare systemic amyloidoses: AH (heavy chain immunoglobulin), ABeta2M (dialysis-associated), AApoAI, AGel (gelsolin), AFib (fibrinogen). Localized forms include Abeta amyloidosis in Alzheimer's disease, AIAPP in Type 2 diabetes, and ACal in medullary thyroid carcinoma — each restricted to specific organs.

The systemic nature of amyloidosis leads to characteristic multi-organ involvement:

The natural course of amyloidosis is progressive and leads to significant morbidity and mortality. Cardiac involvement is the most important prognostic factor. The 5-year mortality of cardiac amyloidosis is estimated at approximately 60%. In AL amyloidosis with cardiac involvement, the prognosis is particularly poor — up to 50% mortality per year after the first cardiac decompensation. These prognoses underscore the critical importance of early diagnosis and specific therapy.