Transthyretin (TTR) is a transport protein produced mainly in the liver and secreted into the bloodstream. Its name reflects its primary jobs: it transports thyroid hormones and retinol (vitamin A) throughout the body. This protein circulates in the blood and the cerebrospinal fluid, ensuring these substances reach various tissues and organs. The choroid plexus, a structure in the brain, is responsible for secreting TTR into the cerebrospinal fluid. TTR’s presence and function are highly conserved across vertebrate species, indicating its biological importance.
The Normal Function of Transthyretin
One of transthyretin’s main jobs is to carry thyroxine, a hormone that regulates metabolism. TTR is the primary carrier of this hormone within the cerebrospinal fluid, ensuring the central nervous system has an adequate supply. It also transports retinol (vitamin A) by binding to another protein called retinol-binding protein (RBP). The protein’s effectiveness stems from its stable structure, which exists as a “tetramer,” a complex made of four identical subunits joined together. This four-part structure is exceptionally stable and creates a central channel where thyroxine can bind for transport.
Transthyretin Misfolding and Amyloidosis
The disease process, transthyretin amyloidosis (ATTR), begins when the stable TTR tetramer becomes unstable. This causes the four-part complex to dissociate into its individual monomers, which is the starting point for the disease. Once separate, the monomers are prone to misfolding into an abnormal, unstable shape that causes them to become “sticky.”
They then aggregate with other misfolded monomers, assembling into larger, insoluble structures called amyloid fibrils. These rope-like protein deposits are resistant to being cleared by the body’s natural processes. The accumulation of these amyloid fibrils in tissues and organs, such as the heart and nerves, disrupts their normal function and leads to organ damage.
Types of Transthyretin Amyloidosis
Transthyretin amyloidosis is categorized into two main types based on the cause of the protein’s instability. The first is the hereditary form, variant ATTR (ATTRv), which is caused by a mutation in the TTR gene passed down through families. Over 140 known mutations can affect the protein’s stability, causing it to misfold more readily. ATTRv affects both men and women, and symptoms can appear as early as a person’s 30s or 40s, though onset varies by mutation. The pattern of organ involvement also differs, as some mutations predominantly affect the peripheral nerves (polyneuropathy), while others primarily target the heart (cardiomyopathy).
The second form is wild-type ATTR (ATTRwt), which is not caused by a genetic mutation. In this type, the normal transthyretin protein misfolds and forms amyloid deposits, a process strongly associated with aging. The TTR protein can become unstable in older individuals for reasons not yet fully understood. ATTRwt primarily affects the heart and is a recognized cause of heart failure in older adults, particularly in men over 60.
Diagnosis and Management
Diagnosing ATTR amyloidosis requires specific tests to confirm the presence of amyloid deposits and determine the type. A tissue biopsy is a common diagnostic tool, where a small sample is taken from an affected area, such as abdominal fat or the salivary gland. The tissue is stained with Congo red, a dye that binds to amyloid fibrils and gives off a characteristic apple-green color when viewed under polarized light. For suspected cardiac involvement, a non-invasive pyrophosphate (PYP) scan can be effective. This scan uses a radioactive tracer that accumulates in TTR amyloid deposits in the heart, allowing for a diagnosis without a heart biopsy. Once amyloid is confirmed, genetic testing is performed to distinguish between the hereditary (ATTRv) and wild-type (ATTRwt) forms.
The management of ATTR amyloidosis has advanced, with therapies aimed at halting the progression of the disease. Treatments are grouped by their mechanism of action. One strategy involves using “stabilizers,” medications that bind to the TTR tetramer to prevent it from breaking apart. Drugs like tafamidis and acoramidis work by locking the four subunits together, slowing the amyloid-forming process.
Another therapeutic approach uses “silencers.” These genetic therapies, such as patisiran and inotersen, reduce the liver’s production of the TTR protein. By lowering the amount of circulating TTR, there is less protein available to misfold and form new amyloid deposits. These treatments have shown effectiveness, particularly for the polyneuropathy associated with hereditary ATTR.
Alongside these therapies, supportive care is a large part of management. This involves treatments aimed at managing symptoms in organs already affected by amyloid. For patients with cardiomyopathy, this may include management of heart failure symptoms with specific medications, and for those with polyneuropathy, it can involve treatments for nerve pain and other neurological issues.