New Perspectives for the Treatment of Transthyretin Amyloidosis
di Sophia Palma
Amyloidosis secondary to the accumulation of Transthyretin (TTR) it is a complex, rare and systemic disease, that is, it has consequences at the level of the whole organism. The main organs involved are the heart, peripheral nerves, more rarely the central nervous system and the kidneys.
The pathology is determined, in fact, by the accumulation of TTR, a protein produced by the liver necessary for the transport of thyroid hormones into the circulation. For reasons still unclear, this shatters into single filaments, "fibrils", Which re-aggregate changing shape and slowly deposit in the organs, between cell and cell, with a progressive damage of the same. In the heart this accumulation determines, as the main manifestation, a Cardiomyopathy that resembles hypertrophic Cardiomyopathy, as the amyloid "fibrils" are deposited between the cardiomyocytes, that is the contractile cells of the heart, and gradually, over the years, increase in thickness of the walls. They can cause defects in electrical impulse conduction and contractile dysfunction itself up to heart failure, as well as various arrhythmias (eg atrial and even ventricular fibrillation). In men, having a "Carpal Tunnel Syndrome" can be one of the early clinical manifestations, and in this case the recommendation is to have periodic cardiological checks to detect any subsequent heart involvement.
In Tuscany, except for some areas of the Tuscan-Romagnolo Apennines, patients with TTR amyloidosis mostly have a Transtyretin that does not derive from a genetic mutation: in these cases the disease occurs at a very advanced age, mostly in men over 80, for reasons that are still unclear. However, Amyloidosis can also have genetic causes: more than one hundred mutations have been identified in the TTR gene that encodes Transthyretin, involved in the genesis of the disease. In the event that the disease is caused by a genetic mutation, the disease is transmitted with a 50% probability from the affected parent to the children, or in a way called autosomal dominant; therefore, close relatives, siblings and children are advised to carry out a genetic test in their turn to arrive at the diagnosis early and therefore to evaluate possible preventive therapies, available today.
The diagnosis, however, is complex and very often comes late both for the great variability of clinical manifestations and for the rarity of the disease itself, and a late diagnosis, unfortunately, is very dangerous for the patient because current therapies are more effective if started. early.
The therapy
Until a few years ago, therapeutic options were limited; the therapy was mainly based on symptom control and constant monitoring of the patient's state of health, because there were no specific therapies available that could slow or block the progression of the disease. The cardiologist prescribed antiscompensating drugs, diuretics, pressure control drugs and a few others, in order to affect the patient's perceived well-being but without being able to really affect the progression of the disease. One option in the past was a liver (and heart, if necessary) transplant.
For some time, however, medical research has been looking for new drugs capable of treating patients with amyloidosis. Very often rare diseases lack drugs, called in this context "orphan drugs", specific for their treatment. It is essential to invest in research to encourage companies operating in this sector in order to give a cure to patients suffering from rare diseases. In the case of Amyloidosis, after numerous clinical studies in various centers (in which the Careggi Cardiomyopathies Unit also participated) and many funds invested in the United States, in October 2021 a new drug was also approved by AIFA, the Tafamidis. This drug is a stabilizer of Transtyretin, that is, it binds to the protein in the blood and makes it much more difficult to break down: this slows down the progression of the disease due to the lower formation of amyloid fibrils. Tafamidis has been defined as revolutionary in the treatment of TTR amyloidosis precisely because of its ability to prevent the disease from worsening. It has been shown that it is able to lower the risk of death from cardiovascular causes, to decrease hospitalizations and also to bring about an improvement in the well-being perceived by the patient.
The possibility of prescribing this drug, despite the regular approval by AIFA, remains limited to multidisciplinary reference centers, with doctors experienced in amyloidosis, using specific therapeutic plans. Although Tafamidis is not the only specific therapy for amyloidosis currently available.
Another drug is the Patisiran, recently approved in the United States, which is giving excellent therapeutic results and is based on a new technology ("RNA interference"). It works by blocking the synthesis of Transtyretin, and is so innovative that it has earned its researchers the Nobel Prize.
CARDIAC AMYLOIDOSIS SIMULATES A HYPERTROPHIC CARDIOMYOPATHY: WHEN TO DISTINGUISH IT
In a study conducted a few years ago in patients diagnosed with Hypertrophic Cardiomyopathy, referred to the Cardiomyopathies Unit of AOU Careggi and to the Cardiomyopathies Center of the Auxologico Institute, the percentage of patients who were instead affected by cardiac amyloidosis, of genetic or non-genetic origin, increased with their age, up to over 20 percent in patients over 70 years of age. However, even in younger patients it could be identified: distinguishing it is very important for the possibility of using new drugs, whose effectiveness increases if cardiac amyloidosis is identified and treated early.