Wild type ATTR amyloidosis (ORPHA:330001)
A common form of systemic amyloidosis characterized by deposition of wild type transthyretin predominantly in the heart and the soft tissues (mainly the carpal tunnel region, lumbar canal and tendons).
Epidemiology
The prevalence of wild type ATTR amyloidosis (ATTRwt amyloidosis) is estimated, on average, at 1/5,800 worldwide. In autopsy studies, fibrillar deposits of transthyretin were found in the heart of 25% of elderly people. Many recent reports evaluated the incidence of this disease in patients with heart failure and preserved ejection fraction. In this subset, the incidence could rise to 13% of cases. The disease is more frequent in males.
Clinical description
The disease onset is generally after the age of 60. The clinical picture is dominated by manifestations of cardiac failure as shortness of breath, leg swelling, fatigue, nausea and an irregular heartbeat or palpitations. Progressive renal failure may also occur during the disease history. In some cases, history of carpal tunnel syndrome or lumbar canal stenosis may precede the cardiac failure symptoms by 8-10 years.
Etiology
ATTRwt amyloidosis is caused by the dissociation of transthyretin (TTR) from tetramers to monomers, which leads to misfolding and aggregation as amyloid fibrils in the heart. Amyloid deposits can infiltrate any cardiac tissue including the conduction system, the myocardium and the vessels and it can translate in severe diastolic or systolic dysfunction.
Diagnostic methods
Suspicion of ATTRwt amyloidosis is generally raised by echocardiogram or cardiac magnetic resonance (CMR). Confirmation of diagnosis requires scintigraphy with bone radiotracers, that show increased myocardial and decreased bone uptake of the radiolabeled drug. DNA analysis is also required in order to exclude inherited forms of cardiac ATTR. In patients with a concomitant monoclonal gammopathy or an abnormal serum free light chain ratio, demonstration and typing of amyloid deposits is mandatory. Abdominal fat pad aspirate is non-invasive but has relatively low diagnostic sensitivity in ATTRwt. Endomyocardial biopsy can be considered in selected cases. The severity of the disease should be graded. The combination of cardiac biomarkers, N-terminal pro natriuretic peptide type B (NT-proBNP) and troponin, or NT-proBNP and the estimated glomerular filtration rate (eGFR), accurately predict the prognosis of this disease at the time of diagnosis.
Differential diagnosis
Differential diagnosis includes other forms of cardiac amyloidosis (light chain, AL and mutated forms of ATTRv) and other types of cardiomyopathy.
Management and treatment
Currently, the goal of treatment is to manage cardiac dysfunction in order to reduce the burden of symptoms. Treatment of heart failure based on diuretics, has a central role. The only specific approved drug for the treatment of ATTRwt is tafamidis which stabilizes TTR proteins, reduces the misfolding and accumulation of amyloid deposits in tissue, and thereby slows progression of heart failure. Many other disease specific therapeutic agents (other TTR stabilizers, TTR gene silencers and amyloid fibrils degraders) are under investigation in clinical trials.
Prognosis
Natural history of the disease is characterized by a slow but inevitable progression of heart failure. The severity of cardiac dysfunction, as assessed by cardiac biomarkers and estimated glomerular filtration rate, is the major prognostic determinant. The impact of the use of specific disease modifier drugs in the real-world setting is still under investigation but it will probably change the course of the disease in the upcoming future.

                            Last update: 
                            September 2021


                            - Expert reviewer(s): 
                            Pr Giovanni PALLADINI | EuroBloodNet*


                                * European Reference Network