ATTR Familial Amyloidosis

The clinical features of ATTR amyloidosis overlap AL amyloidosis such that the diseases cannot be reliably distinguished on clinical grounds alone. A family history makes ATTR more likely, but many patients appear to present sporadically with new mutations. Within each family disease begins at nearly the same age and symptoms usually include neuropathy and/or cardiomyopathy.  Peripheral neuropathy begins as a lower extremity sensory and motor neuropathy and progresses to the upper extremities.  Autonomic neuropathy is manifest by gastrointestinal symptoms of diarrhea with weight loss and orthostatic hypotension.

Patients with TTR Val-30-Met, the most common mutation, have normal echocardiograms but may have conduction system defects and require a pacemaker.  Patients with TTR Thr-60-Ala and several other mutations have myocardial thickening similar to that caused by AL amyloidosis, although heart failure is less common and the prognosis is better.  Vitreous opacities caused by amyloid deposits are pathognomonic of ATTR amyloidosis.

The TTR variant, Val 122 Ile, is a common allele in the black population and appears to be associated with cardiomyopathy. In a large referral population, 25 percent of black patients with amyloidosis had this TTR variant. It is likely that this disease is underdiagnosed due to a lack of physician awareness and the difficulty of distinguishing amyloid and hypertensive cardiomyopathy without an endomyocardial biopsy.

Without intervention, survival after ATTR disease onset is 5-15 years. Orthotopic liver transplantation, which removes the major source of variant TTR production and replaces it with normal TTR, is the major treatment for ATTR amyloidosis. Liver transplantation arrests disease progression and some improvement in autonomic and peripheral neuropathy can occur.  Cardiomyopathy has not improved and in some patients appears to have worsened after liver transplantation. Long-term outcome and the timing of transplantation are being evaluated. Waiting periods for organ donation are frequently long, and optimal benefit requires transplantation before severe disability occurs.