Transthyretin-Related Amyloidosis Treatment & Management

Updated: Jul 22, 2020
  • Author: Jefferson R Roberts, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Treatment

Approach Considerations

Transthyretin-related amyloidosis (ATTR) involves many organs and systems, so an interdisciplinary approach is essential for the management of comorbidities. Patisiran and inotersen are approved by the US Food and Drug Administration (FDA) for treatment of polyneuropathy caused by hereditary transthyretin-related amyloidosis (hATTR) in adults, and tafamidis is approved for transthyretin-mediated amyloid cardiomyopathy (ATTR-CM). Several other medications are under investigation, but liver transplantation remains the gold standard for therapy. Ideally, patients should be referred while early in stage I for liver transplantation—or possibly multi-organ transplantation, depending on heart and/or kidney involvement.

Close follow-up of asymptomatic carriers of ATTR gene mutations has been recommended to facilitate early recognition of ATTR onset and intervention with disease-modifying therapy. [37] A Japanese group has suggested annual routine assessments and in-depth assessments every 3-5 years, with the frequency of these increased as required. [38]

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Medical Care

The US Food and Drug Administration (FDA) has approved patisiran (Onpattro) and inotersen (Tegsedi) for treatment of polyneuropathy caused by hATTR in adults. Tafamidis (Vyndamax) and tafamidis meglumine (Vyndaqel) are FDA approved for transthyretin-mediated amyloid cardiomyopathy (ATTR-CM). [5]  Tolcapone has Orphan Drug designation for treatment of ATTR. Diflunisal and revusiran remain under investigation.

Patisiran

Patisiran utilizes RNA interference, a cellular process in which small interfering RNAs (siRNAs) control gene expression by mediating the cleavage of specific messenger RNAs (mRNAs). [39]  Patisiran comprises siRNAs that are specific for TTR mRNA, formulated in lipid nanoparticles. Administration is via intravenous infusion every 3 weeks.

Approval was based on the APOLLO clinical trial, in which patients taking patisiran (n=148) showed significantly improved scores on the Neuropathy Impairment Score+7 and Norfolk Quality of Life Questionnaire–Diabetic Neuropathy (QOL-DN) at 18 months, compared with those taking placebo (n=77) (P <  0.001). [40] Continuing follow-up (for up to 9 years in some cases) suggests that long-term tafamidis treatment may confer a survival benefit. [41]

Inotersen

Inotersen was approved by the FDA in October 2018. Like patisiran, it is indicated for polyneuropathy of hATTR in adults; unlike patisiran, inotersen is given as a once-weekly subcutaneous injection that the patient or caregiver can administer. It is an antisense oligonucleotide that causes degradation of mutant and wild-type transthyretin mRNA by binding TTR mRNA. This action results in reduced TTR protein levels in serum and tissue.

Approval was based on an international, randomized, double-blind, placebo-controlled phase III trial (NEURO-TTR) in which patients with stage 1 or 2 hATTR with polyneuropathy (n=172) were randomly assigned in a 2:1 ratio to receive weekly inotersen or placebo. Scores on the mNIS+7 and the QOL-DN showed improvement in those receiving inotersen (P <  0.001). [42]

An ongoing open-label extension study in 135 patients who had completed NEURO-TTR found that after 39 cumulative months of treatment, inotersen slowed disease progression and reduced deterioration of quality of life in patients with hATTR polyneuropathy. Long-term disease stabilization was better with early versus delayed initation of treatment with inotersen. Routine platelet and renal safety monitoring proved effective, due to the adverse effect profile of potential thrombocytopenia and glomerulonephritis. [42, 43]  

Tafamidis

Tafamidis and tafamidis meglumine were approved by the FDA in May 2019 for treatment of ATTR-CM. [44] Both agents selectively bind to transthyretin tetramer to prevent the transthyretin transport protein destabilization and amyloid formation that causes ATTR-CM; however, the two agents are not substitutable on a per-mg basis.

Tafamidis, or 2-(3,5-dichloro-phenyl)-benzoxazole-6-carboxylic acid, selectively binds to TTR with negative cooperativity and kinetically stabilizes wild-type native TTR and mutant TTR. Therefore, tafamidis has the potential to halt the amyloidogenic cascade initiated by TTR tetramer dissociation, monomer misfolding, and aggregation. [45]  Early intervention with tafamidis led to minimal disease progression over 5.5 years in patients with mild ATTR-FAP. [46]

Tafamidis has been found to be an effective therapy, with an acceptable adverse effect profile, for patients with heart faiure related to thyretin amyloid cardiomyopathy. A phase 3 trial involving 441 patients with transthyretin amyloid cardiomyopathy over 30 months comparing 80 mg tafamidis, 20 mg tafamidis, and placebo, found reductions in all cause mortality and cardiovascular-related hospitalizations when taking tafamidis. Compared with placebo, tafamidis was found to reduce the decline of functional capacity and quality of life. [47]

A tafamidis trial in patients with stage I neuropathic ATTR (mobilization without need for support) failed to achieve statistical significance for its primary endpoints of neurological deterioration and quality of life. However, because all measured endpoints indicated that the drug decreased the rate of disease progression, tafamidis was approved by the European Medical Agency in 2011 for patients in stage I of neuropathic ATTR. [48] Since 2011, tafamidis has been approved for use in Japan, Mexico, and Argentina, where it is used as a first-line treatment option for patients with early-stage ATTR–familial amyloid polyneuropathy (FAP).

Tolcapone

Tolcapone is FDA approved for treatment of Parkinson disease and has Orphan Drug designation for treatment of ATTR. Tolcapone occupies the T4-binding sites located at the TTR dimer-dimer interface and prevents amyloidogenesis by stabilizing the tetramer in vivo in mice and humans. [49]  An added benefit is that it also inhibits TTR cytotoxicity. It has been shown that tolcapone docks better than tafamidis in wild type–TTR.

Diflunisal

Diflunisal is a nonsteroidal anti-inflammatory drug that is FDA approved for treatment of arthritis. At a dosage of 250 mg twice daily, diflunisal successfully complexes to the thyroxine binding site and kinetically stabilizes circulating TTR tetramers, inhibiting release of the TTR monomer required for amyloidogenesis. In a randomized, placebo-controlled trial in patients with stage I-II ATTR–familial amyloid polyneuropathy (FAP), diflunisal improved quality of life scores and reduced progression of neurological impairment compared with placebo. Its use for this indication remains off-label. [50, 51]

Treatment of cardiac involvement

Management of identified ATTR-CM should involve early consideration of tafamidis or tafamidis meglumine, as earlier administration may slow the progressive disease process. [47] Diuretic agents must be used with caution. Although diuretics are commonly prescribed for patients with heart failure, their use in amyloidosis is complicated. Due to the restrictive effect of the disease, ventricular compliance is poor and end-diastolic volumes are low. Patients often require a higher filling pressure to distend the stiffened heart, and diuretic therapy reduces preload, which can further reduce stroke volume and systolic blood pressure. [25]

Beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) are poorly tolerated in cardiac amyloidosis and should be avoided. Digoxin binds to amyloid fibrils and can lead to locally high levels; it also must be used with caution. [25]

Given the high incidence of sudden death in patients with ATTR-CM, it is prudent to consider prophylactic placement of an implantable cardioverter defibrillator (ICD). [25]

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Surgical Care

Liver transplantation

Prior to 1990, no therapy for TTR-FAP was available. Liver transplantation was first performed for FAP in 1990, and as of December 31, 2017 a total of 2236 liver transplants had been reported to the Familial Amyloid Polyneuropathy World Transplant Registry (FAPWTR). [52] Transplantation replaces the main source of variant TTR with a source of normal-sequence TTR, sometimes leading to gradual fibril reabsorption and disease stabilization, especially of neurologic complications. Liver transplantation seems to halt progression of sensory, motor, and autonomic neuropathy. Ideally, the transplantation should be performed as early in the disease course as possible, before significant neurologic disability has been incurred. [53]

Cardiac, leptomeningeal, gastrointestinal, or ocular involvement often progresses despite transplantation. Atrial fibrillation (AF) is a risk factor for ischemic central nervous system complications observed after liver transplantation. [18]

Overall 20-year survival after transplantation, all mutations included, was 55.3%. The expected mortality rate decreased on average by approximately 4% per year between 1990 and 2010. Improved survival in TTR Val30Met patients was most pronounced during the first 5-year period, whereas non–TTR Val30Met patient survival improved throughout the 20-year period. The natural history of the disease has a 10-15 year prognosis. [53]

Combination heart and liver or liver and kidney transplantation has been performed in select patients, with variable success, and an 18.1% rate of postoperative cardiac complications has been shown with heart transplantations. Patients undergoing combined transplantation were generally older than those only being treated with liver transplantation for TTR amyloidosis and more likely carrying a non-TTR Val30Met mutation. [53]

Carpal tunnel release

Involvement of the carpal ligament is observed not only in ATTR but also, most commonly, in patients undergoing dialysis and in patients with light chain amyloidosis (AL). Treatment is surgical release.

At the time of carpal tunnel release, a biopsy should be performed if a definitive diagnosis has not been established previously so that both Congo red staining and immunostaining can be performed. Why the carpal ligament, or indeed any organ, is a favored location for amyloid deposition is not known.

Vitrectomy

Vitrectomy is useful in patients with vitreous involvement. TTR is known to be produced locally by retinal pigment epithelial and ciliary pigment epithelium cells. The progression of ocular disease after liver transplantation suggests that continued intra-ocular TTR production is relevant in this context. In a review of 513 cases, no differences were found in ocular tests between patients who received liver transplants and nontransplanted patients. [54]

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Diet

There is no specific diet for ATTR. A small observational study of 24 men with wt-ATTR cardiomyopathy demonstrated that consumption of green tea extract for 1 year may potentially inhibit amyloid fibril formation in the heart. [55] Patients with associated heart disease can also benefit from a low-sodium diet, and may wish to review American Heart Association recommendations on reducing dietary sodium.

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Consultations

Once the diagnosis of ATTR has been made, a multi-disciplinary approach with the following consultations is advised:

  • Rheumatology
  • Cardiology
  • Neurology
  • Nephrology
  • Ophthalmology
  • Gastroenterology
  • General Surgery
  • Genetic Counseling
  • Physical therapy
  • Nutrition

 

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Activity

Since polyneuropathy (FAP) is a major constellation of symptoms in ATTR, a loss of function is a trigger for liver transplantation. Early involvement of physical therapy to detect subtle changes in function would be helpful.

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Prevention

There are no known primary preventive measures. Once the diagnosis has been made, medical and surgical treatments serve as secondary prevention, and supportive care for complications serve as tertiary prevention.

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Long-Term Monitoring

For cardiac follow-up, monitor New York Heart Association (NYHA) class and electrocardiographic (ECG) changes in order to mitigate symptoms and determine the need for ICD placement and possibly accompanying heart transplantation in select cases if liver transplantation is indicated. Early detection of cardiac abnormalities is important; the prophylactic implantation of pacemakers was found to prevent 25% of major cardiac events in TTR-FAP patients followed up over an average of 4 years. [56]

For ATTR-FAP, liver transplantation should be considered while the patient is still in stage I FAP.

Nephrologic follow-up involves monitoring for microalbuminuria and possibly nephrotic-range proteinuria, as patients may progress to end-stage renal disease .

Ophthalmological monitoring recommendations, which are the same for liver transplant recipients and non-transplanted patients, set out the following schedule for eye examinations [54] :

  • Starting at the time of genetic diagnosis and, thereafter, repeated every 2 years in asymptomatic carriers and annually in symptomatic patients
  • Annually after discovery of abnormal conjunctival vessels
  • Every 6 months for lacrimal dysfunction, amyloid deposition of the iris, and amyloid deposition of the anterior capsule of the lens
  • Every 3 months for scalloped iris, glaucoma, vitreous amyloidosis, retinal angiopathy

Routine laboratory monitoring following diagnosis is based on medications and treatment course, as well as organ system involvement.

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