Transthyretin-Related Amyloidosis (ATTR) is a progressive and often underdiagnosed condition characterized by the deposition of misfolded transthyretin (TTR) protein in various tissues, leading to a range of clinical manifestations. TTR is a transport protein primarily synthesized in the liver, which carries thyroid hormones and retinol-binding protein in the bloodstream. ATTR can be classified primarily into two forms: hereditary (hATTR) and wild-type (wtATTR), with the former caused by genetic mutations in the TTR gene and the latter resulting from age-related deposition of the normal protein. The hereditary form is often associated with specific mutations, such as V30M, that lead to the unstable conformation of the TTR protein, while wild-type amyloidosis frequently presents in older adults, particularly males, without a known familial history. The accumulation of amyloid fibrils in organs like the heart, kidneys, liver, nervous system, and gastrointestinal tract results in a diverse array of symptoms. Cardiac involvement is common and may manifest as heart failure, arrhythmias, or restrictive cardiomyopathy, leading to significant morbidity and mortality. Patients may also present with neuropathy, where the autonomic and peripheral nerves are affected, producing symptoms such as pain, tingling, and numbness in the extremities, or gastrointestinal symptoms like diarrhea, constipation, and malabsorption due to enteric neuropathy. Given the multifaceted clinical picture, diagnosis can be challenging and often requires a combination of clinical evaluation, imaging studies, and histopathological examination. The gold standard for diagnosis involves tissue biopsy showing amyloid deposits, which can be confirmed through techniques such as Congo red staining or mass spectrometry. Other diagnostic tools include cardiac imaging, such as echocardiography or cardiac MRI, which can reveal characteristic patterns like thickened myocardium. Laboratory tests may also assist in the diagnosis, including serum TTR levels, and genetic testing for familial cases. The management of ATTR has evolved significantly in recent years, transitioning from supportive care to disease-modifying therapies. The emergence of TTR stabilizers, such as tafamidis and diflunisal, has been a game-changer in preserving functional capacity and improving outcomes in patients with both hereditary and wild-type forms of the disease. Additionally, neural therapies like inotersen and patisiran, which are designed to reduce TTR production, have demonstrated efficacy in improving neuropathic symptoms and enhancing patient quality of life. Multidisciplinary approaches encompassing cardiology, neurology, and genetics are essential for the comprehensive management of ATTR, underlining the importance of early diagnosis and intervention. As awareness of ATTR grows within the medical community, efforts are being made to improve recognition of this rare but life-altering condition, as timely diagnosis and appropriate treatment can significantly alter the disease course and patient prognosis, ultimately leading to improved quality of life for individuals affected by this complex disorder.
