Amyloidosis is a group of conditions characterized by the buildup of abnormal protein deposits, called amyloid fibrils, in organs and tissues. These deposits can interfere with normal organ function, leading to various symptoms and potential organ failure. Transthyretin (ATTR) amyloidosis is a specific type where the transthyretin protein misfolds, forming these harmful deposits. This progressive disorder can affect multiple organ systems and significantly impact health.
What is Transthyretin Amyloidosis
Transthyretin (TTR) is a protein primarily produced in the liver, also found in the brain and eye. It transports thyroid hormone and vitamin A. TTR typically exists as a stable structure of four identical protein subunits, known as a tetramer.
In ATTR amyloidosis, this normally stable TTR protein becomes unstable, dissociates into individual subunits, and misfolds. These misfolded proteins then aggregate and form insoluble amyloid fibrils that deposit in various tissues. The disease manifests in two primary forms: hereditary ATTR (hATTR) amyloidosis and wild-type ATTR (wtATTR) amyloidosis.
Hereditary ATTR amyloidosis is a genetic condition caused by inherited mutations in the TTR gene. Over 120 different mutations have been identified, influencing disease onset, symptoms, and progression. Common mutations include V30M (prevalent in European/Japanese populations, often leading to nerve-related symptoms) and V122I (frequently seen in African Americans, commonly associated with cardiac involvement). This form can manifest at varying ages.
Wild-type ATTR amyloidosis, conversely, is not caused by a genetic mutation but arises from age-related instability of the normal TTR protein. It primarily affects older adults, particularly men over 60. This form is increasingly recognized as more common than previously thought, often causing symptoms mistaken for other age-related conditions.
How ATTR Amyloidosis Impacts the Body
Misfolded transthyretin amyloid fibrils deposit in multiple organ systems, causing varied symptoms depending on the specific organs involved. The heart and nerves are among the most commonly affected areas. Amyloid accumulation stiffens and damages tissues, impairing their normal function.
Cardiac involvement, known as ATTR cardiomyopathy (ATTR-CM), occurs when amyloid deposits build up in the heart muscle. This stiffens the heart walls, preventing proper blood filling and leading to restrictive cardiomyopathy. Symptoms often resemble heart failure, including shortness of breath, swelling in the legs, ankles, or abdomen, and fatigue. Irregular heart rhythms, such as atrial fibrillation, can also occur.
Nerve damage, or neuropathy, is another common manifestation, particularly in hATTR amyloidosis. Amyloid deposits can affect peripheral nerves, leading to sensory and motor issues such as numbness, tingling, pain, or weakness. Carpal tunnel syndrome can be an early sign. Autonomic nerves, which control involuntary bodily functions, can also be impacted, resulting in digestive issues like alternating diarrhea and constipation, nausea, early satiety, and unintentional weight loss. Other autonomic symptoms include dizziness upon standing and sexual dysfunction.
Beyond the heart and nerves, ATTR amyloidosis can affect other body parts. Kidney involvement may lead to protein in the urine and, in some cases, kidney dysfunction. Ocular manifestations, such as vitreous opacities, can also occur. Less common areas include the gastrointestinal tract and ligaments, which can manifest as lumbar spinal stenosis or biceps tendon rupture.
Identifying ATTR Amyloidosis
Diagnosing ATTR amyloidosis is challenging because its symptoms are varied and can mimic those of more common conditions. Clinical suspicion often arises when a combination of symptoms is present, especially if they affect multiple organ systems or if there is a family history. The diagnostic process typically involves specialized tests.
Non-invasive cardiac imaging plays a significant role in identifying ATTR-CM. Echocardiography can reveal thickening and stiffening of the heart muscle, while cardiac magnetic resonance imaging (MRI) provides detailed images of amyloid infiltration patterns. A key diagnostic tool for cardiac ATTR is Technetium-99m pyrophosphate (PYP) scintigraphy, a nuclear imaging scan. This scan involves injecting a radioactive tracer that binds to amyloid deposits in the heart, showing increased uptake in ATTR-CM, and can often differentiate it from other types of cardiac amyloidosis, potentially avoiding a heart biopsy.
While PYP scintigraphy is highly specific for cardiac ATTR, tissue biopsy remains a method for confirming amyloid deposits in other organs. A small tissue sample (e.g., fat pad, rectum) is stained with Congo red dye, revealing characteristic apple-green birefringence under polarized light. For cardiac ATTR, if a PYP scan is positive and AL amyloidosis has been ruled out through blood and urine tests, a biopsy may not be necessary.
Genetic testing is crucial for diagnosing hATTR amyloidosis and differentiating it from wtATTR. This involves a blood test to identify specific mutations in the TTR gene, which informs disease progression and treatment decisions. Blood and urine tests also assess organ function and rule out other forms of amyloidosis, particularly AL amyloidosis, which requires different management.
Current Approaches to ATTR Amyloidosis Treatment
Treatment strategies for ATTR amyloidosis focus on slowing disease progression, managing symptoms from organ damage, and targeting underlying protein misfolding. Recent advancements offer therapies beyond symptomatic relief. A multidisciplinary approach, involving specialists like cardiologists, neurologists, and nephrologists, is often employed.
Disease-modifying therapies interfere with amyloid fibril formation. TTR stabilizers bind to the TTR protein, preventing its dissociation into unstable, misfolding subunits. Tafamidis, an FDA-approved TTR stabilizer, reduces cardiovascular mortality and hospitalizations in ATTR cardiomyopathy patients. Diflunisal, a nonsteroidal anti-inflammatory drug, also stabilizes TTR, though off-label and requiring careful monitoring due to potential side effects.
Another category of disease-modifying therapies includes gene silencers, such as RNA interference (RNAi) therapies and antisense oligonucleotides (ASOs). These treatments, including patisiran, vutrisiran, inotersen, and eplontersen, work by reducing TTR protein production in the liver, decreasing misfolded protein available for amyloid deposits. Patisiran, vutrisiran, inotersen, and eplontersen are approved for polyneuropathy in hATTR amyloidosis; vutrisiran also has an expanded indication for ATTR-CM.
Symptomatic management is equally important to improve quality of life. For cardiac involvement, diuretics manage fluid retention and shortness of breath, while pacemakers address conduction abnormalities. For neuropathy, pain medications like gabapentin or pregabalin may be prescribed to alleviate nerve pain. Organ transplants (liver, heart) were historically more common for hATTR patients but are now considered in more specific cases due to newer disease-modifying therapies.