Systemic AA amyloidosis: epidemiology, diagnosis, and management

Figures & data

Table 1 Classification of the main types of systemic amyloidosis

Denomination	Clinical syndrome	Amyloidogenic protein
AL	Monoclonal gammopathy	Immunoglobulins/light chains
AA	Sustained, chronic inflammation	Serum amyloid A protein
AF	Familial polyneuropathy, familial cardiomyopathy, familial nephropathy	Mutant transthyretin, A1-apolipoprotein, gelsolin, fibrinogen, lysozyme, etc
ATTRwt	Senile restrictive cardiomyopathy	Wild-type transthyretin
AH	Dialysis-related	ß2-microglobulin

Abbreviations: AL, amyloid light-chain; AA, amyloid A; AF, familial amyloidosis; ATTRwt, transthyretin-related amyloidosis, wild-type; AH, amyloid A hereditary.

Table 2 Distribution of underlying diseases causing amyloidosis in six Spanish series

	Real de Asúa et al (2013)^Citation13	García-Morán et al (1992)^Citation14	González-García et al (1986)^Citation15	De La Sierra et al (1985)^Citation16	Martínez-Vea et al (1983)^Citation17	Castilla et al (1977)^Citation18
Sample size	n=54	n=69	n=44	n=60	n=37	n=29
Age at diagnosis (years)	64±13	48±15	47±18	57±13	49±16	52
AL amyloidosis	24 (44%)	19 (28%)	12 (27%)	19 (32%)	12 (32%)	6 (21%)
Multiple myeloma	5 (21%)	7 (37%)	3 (25%)	7 (37%)	–	0
AA amyloidosis	30 (56%)	49 (71%)	32 (73%)	38 (63%)	25 (68%)	21 (72%)
Rheumatoid arthritis	9 (30%)	10 (20%)	6 (19%)	12 (32%)	2 (8%)	4 (19%)
Ankylosing spondylitis	4 (13%)	1 (2%)	1 (3%)	8 (21%)	5 (20%)	–
Chronic infections	3 (10%)	29 (59%)	14 (44%)	16 (42%)	12 (50%)	13 (62%)
Inflammatory bowel disease	2 (7%)	–	–	–	1 (3%)	–
Autoinflammatory diseases	2 (7%)	5 (10%)	2 (6%)	–	–	–
Psoriasis	2 (7%)	–	–	4 (11%)	1 (3%)	–
Tumors	2 (7%)	1 (2%)	2 (6%)	1 (3%)	1 (3%)	4 (19%)
Other illnesses	2 (7%)	3 (7%)	4 (12%)	1 (3%)	3 (12%)	–
No final diagnosis	4 (13%)	–	3 (9%)	–	–	–

Note: Reproduced with permission from Real de Asúa D, Costa R, Contreras MM, Gutiérrez Á, Filigghedu MT, Armas M. Clinical characteristics of the patients with systemic amyloidosis in 2000–2010. Rev Clin Esp. 2013;213(4):186–193. Copyright ©2013 Elsevier.¹³

Abbreviations: AL, amyloid light-chain amyloidosis; AA, amyloid A.

Figure 1 Diagnostic algorithm in patients with suspected amyloidosis.

Note: Copyright © 2005. John Wiley and Sons. Reproduced from Gertz MA, Comenzo R, Falk RH, et al. Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, April 18–22, 2004. Am J Hematol. 2005;79(4):319–328.²⁷
Abbreviations: ECG, electrocardiogram; EMG, electromyogram; MRI, magnetic resonance imaging; NT-proBNP, N-terminal probrain natriuretic peptide.

Table 3 Criteria for organ involvement in AL amyloidosis

Organ	Test	Criteria
Kidney	24-hour urine	Proteinuria ≥0.5 g/24 h, predominantly albumin
Heart	ECG	Voltage <5 mm in all limb leads (indirect criterion)
	NT-proBNP	Normal values practically exclude myocardial involvement
	Echocardiogram	Mean wall thickness >12 mm; no other cardiac cause
		Combination of ECG ventricular hypertrophy and low voltage on ECG strongly suggests myocardial involvement
	Cardiac MRI	Delay in subendocardial gadolinium enhancement
Liver	Alkaline phosphatase	Value >1.5× upper limit of normal
	Imaging studies	Hepatomegaly >15 cm in the absence of heart failure
Gastrointestinal tract	Direct biopsy	Histological
Nerve	Clinical	Symmetric lower extremity sensorimotor peripheral neuropathy
	EMG
	Autonomic function tests	Severe orthostatic hypotension
		Intestinal dysmotility (gastric emptying disorder, pseudo-obstruction, voiding dysfunction)
Lung	Imaging studies	Diffuse bilateral interstitial pattern
	Direct biopsy	Histological
Skin and soft tissue	Clinical	Macroglossia, jaw claudication, skin lesions
	EMG	Carpal tunnel syndrome
	Direct biopsy	Histological

Note: Only criteria marked in bold are considered major criteria for the diagnosis of organ involvement in AL amyloidosis.

Notes: Copyright © 2005. John Wiley and Sons. Adapted from Gertz MA, Comenzo R, Falk RH, et al. Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, April 18–22, 2004. Am J Hematol. 2005;79(4):319–328.²⁷

Abbreviations: AL, amyloid light-chain amyloidosis; ECG, electrocardiogram; NT-proBNP, N-terminal probrain natriuretic peptide; MRI, magnetic resonance imaging; EMG, electromyography.

Table 4 Useful treatments for systemic AA amyloidosis

Treatments targeting underlying predisposing disease

• Neoplasm: chemotherapy; surgery

• Infectious diseases: antibiotic therapy

• Autoimmune diseases: methotrexate; leflunomide; chlorambucil; tacrolimus; infliximab; etanercept; abatacept; colchicine; anakinra; canakinumab

Treatments targeting amyloidosis: tocilizumab; dimethyl-sulfoxide; eprodisate; heparins; statins

Supportive treatment

• Orthostatic hypotension: fludrocortisone; midodrine

• Malabsorptive syndromes and gastrointestinal dysautonomia: antibiotic therapy; corticosteroid pulses; and combination treatment with octreotide

Novel therapeutic options: anti-SAP antibodies (CPHPC); antisense complementary oligonucleotides; and phagocytic depletion with clodronate

Abbreviations: AA, amyloid A; SAP, serum amyloid P component; CPHPC, R-1-[6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid.

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