Transthyretin (TTR) is a protein found throughout the body, circulating in the plasma and cerebrospinal fluid. It was once referred to as prealbumin because it migrated faster than albumin during electrophoresis. TTR is produced primarily in the liver, with smaller amounts made in the choroid plexus of the brain and the retinal pigment epithelium in the eye. This protein plays a role in various biological processes, serving as a transporter for specific molecules within the body.
The Role of Transthyretin in the Body
Transthyretin performs two main functions in its healthy state: transporting thyroid hormones and Vitamin A. It carries thyroxine (T4), a thyroid hormone, and retinol (Vitamin A) through its association with retinol-binding protein (RBP) in the blood and cerebrospinal fluid. In the cerebrospinal fluid, TTR is the primary carrier of T4, while in plasma, it transports about 15% of the total T4.
The structure of TTR is a homotetramer, meaning it is composed of four identical subunits, each with 127 amino acids. This tetrameric structure is necessary for TTR to bind and transport thyroxine effectively.
Transthyretin Amyloidosis: An Overview
Transthyretin amyloidosis (ATTR amyloidosis) is a condition where the TTR protein misfolds and aggregates, forming insoluble deposits called amyloid fibrils. When its stable tetrameric structure becomes unstable, it can dissociate into individual subunits.
These unstable subunits then undergo conformational changes, leading to their misfolding and self-assembly into amyloid fibrils. These amyloid deposits accumulate in various tissues and organs, disrupting their normal function.
Forms of Transthyretin Amyloidosis
Transthyretin amyloidosis presents in distinct forms, primarily differentiated by their cause: hereditary and wild-type.
Hereditary ATTR Amyloidosis (hATTR)
Hereditary ATTR amyloidosis (hATTR) is an inherited disorder resulting from genetic mutations in the TTR gene. Over 120 different mutations have been identified, each influencing the age of symptom onset, organ involvement, and disease course. For example, the Val30Met (V30M) variant is common in populations of Portuguese, Swedish, and Japanese descent, while the Val122Ile (V122I) variant is observed in approximately 3% to 4% of African Americans. These genetic changes destabilize the TTR protein. The condition is inherited in an autosomal dominant pattern, meaning only one copy of the mutated gene is sufficient to cause the disease.
Wild-type ATTR Amyloidosis (wtATTR)
Wild-type ATTR amyloidosis (wtATTR), previously known as senile systemic amyloidosis, is not caused by inherited genetic mutations. This form typically affects older individuals, most commonly men over 60, with an average age of diagnosis around 75. In wtATTR, the normal TTR protein becomes unstable due to age-related factors. Although the exact prevalence is unknown, it is believed to be underdiagnosed due to symptom overlap with other common age-related conditions.
How Transthyretin Amyloidosis Affects the Body
Transthyretin amyloidosis can affect multiple organs and body systems due to the widespread deposition of amyloid fibrils. The heart is a frequently affected organ, leading to transthyretin amyloid cardiomyopathy (ATTR-CM). Amyloid deposits in the heart walls cause them to stiffen and thicken, particularly the left ventricle, which impairs the heart’s ability to fill with blood and pump it effectively. This can result in symptoms such as shortness of breath, fatigue, leg swelling, and an irregular heartbeat or palpitations, eventually progressing to heart failure.
The nervous system is another commonly impacted area, leading to polyneuropathy. Amyloid deposits in peripheral nerves can cause a loss of sensation, tingling, numbness, or pain in the hands and feet. Damage to the autonomic nervous system, which controls involuntary bodily functions, can manifest as light-headedness upon standing, bladder problems, or gastrointestinal issues. Carpal tunnel syndrome, often affecting both wrists, and lumbar spinal stenosis can also be early indicators of TTR amyloidosis due to amyloid accumulation in ligaments and soft tissues.