Transthyretin amyloidosis, also called ATTR amyloidosis, is a progressive and fatal disease that affects multiple organs. It comes in two versions – genetic and wild (spontaneous and not hereditary). ATTR Amyloidosis is caused by the accumulation of a genetically variant form or even the normal form of the protein, transthyretin, into amyloid fibrils. Transthyretin is primarily made within the liver. It appears that in everyone this particular protein will eventually form amyloid fibrils that can cause organ dysfunction primarily in the heart and nerves. Fortunately, this process is slow in most people and does not lead to problems over a normal life span. Unfortunately, for some individuals, this process occurs more quickly and can lead to symptoms of heart failure and nerve damage earlier in life. Most typically, these afflicted individuals have a genetic variant of the transthyretin protein which they were born with and passed down from their mother or father. This occurs more commonly in certain regions of the world; with Portugal, Sweden, and Japan being leading examples. Other areas such as the Appalachian mountain region in the United States have a higher incidence of affected people because of a common genetic variant in the population there. More patients are presenting with symptoms of heart failure who are not found to have a variant transthyretin gene. These patients have been diagnosed with wild-type ATTR. It is not yet clear why these latter individuals develop the process within their hearts despite a normal protein gene sequence. The typical patient with the latter form of ATTR is a male 80 years or more old.

The disease is being diagnosed with increasing frequency because of better diagnostic techniques now available. Currently, the only imaging modality that allows accurate diagnosis of the exact type of cardiac amyloidosis is nuclear scintigraphy using bone-avid radiotracers.

Briefly, three technetium-labeled radiotracers have been used to identify ATTR-CM: TC-99m-PYP; TC-99m-3,3-diphosphono-1,2-propanodicarboxylic acid; or TC-99m-hydroxy methylene diphosphonate. Myocardial uptake of these radiotracers is compared with adjacent bone uptake of the rib and graded to indicate that cardiac uptake is greater than rib uptake. The exact mechanism of radiotracer uptake by the myocardium is not fully understood at this time, although several hypotheses have been offered. These radiotracers confer 100% specificity for ATTR-CM when grade 2 or 3 uptake is seen in heart failure patients without monoclonal protein (which would indicate AL amyloidosis) and echocardiographic or CMR findings of amyloidosis. Therefore, cardiac scintigraphy allows a noninvasive approach to a diagnosis of ATTR-CM(cardiomyopathy).

The October 26th edition of the NEJM has a paper entitled Patisiran Treatment in Patients with Transthyretin Cardiac Amyloidosis. There is also an editorial A Step Forward in Solving Amyloidosis. The paper describes the 12-month results of administering patisiran, an RNA interference agent that inhibits the production of hepatic transthyretin. This study was a phase 3, double-blind, randomized trial. It showed that over one year, the drug was safe and that it was associated with improvement in several manifestations of ATTR amyloidosis – see figure below.

Exercise capacity improved as did symptoms. The serum transthyretin levels also fell dramatically. But as the editorial points out there was no difference in clinical outcomes between the treated and placebo groups. This lack of a beneficial clinical effect was likely the reason that the FDA failed to approve the drug for clinical use. Further study over a longer duration is needed to reveal if the drug has a beneficial therapeutic effect. As many as 25% of elderly men who develop heart failure may have ATTR amyloidosis. Patisiran will certainly carry a wallet-busting cost that will be borne by a federal government already well beyond its fiscal tether. Before prescribing it to millions of patients we need to be sure of its health benefit to a population near the end of life even without heart failure.