Physiopathology and classifying amyloidosis
Physiopathologie et classification
Amyloidosis is the manifestation of several systemic illnesses. The common characteristic that these illnesses share is the extracellular accumulation of insoluble fibrillar proteins which are deposited around the body and gradually infiltrate tissues, impairing their function. Amyloid infiltration of the heart causes the myocardium to thicken, creating the appearance of ‘hypertrophy’, leading to complications such as heart failure and conduction disorders. This is why cardiologists are usually first to diagnose amyloid cardiopathy. Unfortunately, it is often diagnosed late, after an initial diagnosis of heart failure ± LVEF or hypertensive cardiopathy. In order to improve the diagnostic process for cardiomyopathy and go beyond simple diagnostic techniques, the European Society of Cardiology (ESC) has recently reviewed how cardiomyopathies are reviewed and defined. Now, hypertrophic cardiomyopathies are simply defined as thickening of the myocardium, meaning that CMH also covers many different physio-pathological processes, from cardiomyocyte hypertrophy found in sarcomeric hypertrophic cardiomyopathy (e.g. a troponin or myosin mutation) to infiltration of the myocardium.
Classifying amyloidosis depends on the biochemical nature of the amyloid protein in the deposits. Around 20 proteins can form amyloid fibrils (fibrinogen, apo A1, etc.) The most common forms found in the heart are AL amyloids (immunoglobulins) and transthyretin (TTR) amyloids: hereditary (mutated TTR) or senile (wild type TTR).
Type of amyloidosis
Immunoglobulin light chains (Kappa or Lambda)
Heart, kidneys, liver, nervous system
Peripheral nervous system, heart
Sources, types of deposits and organs damaged in the 4 main types of amyloidosis
AL amyloidosis is mainly caused by monoclonal gammopathies (MGUS) or myeloma. Monoclonal gammopathies are very common and affect around 10% of patients aged 60. Fortunately, it is rare these gammopathies develop into amyloidosis but they are found in more than 60% of cases of amyloid cardiopathy.
Transthyretin (TTR) is a monomeric protein made in the liver. These monomers form tetramers which transport proteins (thyroid hormone, vitamin D) in the blood. This amyloidosis has two types:
Senile Transthyretin Amyloidosis: the precursor is non-mutated transthyretin (ATTRwt) and is almost exclusively found in older men. How this illness works is not yet known.
Hereditary Transthyretin Amyloidosis: this is a familial form of the illness in which transthyretin is mutated (ATTRm). The transmission is autosomal dominant. More than 100 pathogen mutations of the gene which codes for TTR have been found. The tissue deposits behave exactly like the non-mutated transthyretin. Although hereditary, a family history of the disease is only found in 50% of cases. Tissue damage varies depending on the mutation. The ATTR Val30Met mutation is the most common and has been known to manifest itself as a neuropathy in Portuguese patients aged 25-30. Some mutations (Val122Ile, Ser77Tyr, etc.) will either mainly or exclusively affect the heart. The number of amyloidosis cases amongst cardiac patients is underestimated. The Val122Ile mutation amongst patients of African origin is being discovered more and more frequently. It is thought that it is present among 3.9% of the Afro-American population. The penetrance of these mutations varies according to the genetic base and the mutation. Generally, sporadic cases occur late, usually after 50 – 60 years of age. Diagnosis is made using anatomopathological analysis which locates amyloid deposits using a transthyretin antibody. A sequencing test is used to identify the mutation in the transthyretin gene.