Transthyretin-Related Amyloidosis Treatment & Management

Updated: Jan 26, 2017
  • 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, an interdisciplinary approach is essential for the management of co-morbidities. Several 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 transplantaiton, depending on heart or kidney involvement.

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Medical Care

The US Food and Drug Administration (FDA) has not approved any medical treatments for ATTR. However, tafamidis, diflunisal, patisiran, revusiran, and tolcapone have been under investigation.

Tafamidis

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. [24]  Early intervention with tafamidis led to minimal disease progression over 5.5 years in patients with mild ATTR-FAP. [50]

The 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. [25] 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).

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-FAP, diflunisal improved quality of life scores and reduced progression of neurological impairment compared with placebo. Its use for this indication remains off-label. [26, 27]

Patisiran and Revusiran

Patisiran (ALN-TTR02) and revusiran (ALN-TTRsc) utilize RNA interference, a cellular process in which small interfering RNAs (siRNAs) control gene expression by mediating the cleavage of specific messenger RNAs (mRNAs). [48]

Patisiran comprises siRNAs that are specific for TTR mRNA, formulated in lipid nanoparticles. A phase I ascending-dose study in healthy volunteers demonstrated rapid, dose-dependent, and durable knockdown of serum TTR with patisiran. [28]  A phase II study demonstrated that patisiran was generally well tolerated and effective in reducing both mutant and wild-type TTR levels in patients with FAP. The 0.3 mg/kg three times weekly dosing schedule is under investigation in the phase III APOLLO trial. [28]  A randomized, double-blind, placebo-controlled, phase III trial of patisiran has been initiated. [48]

Revusiran is administered subcutaneously and consists of a TTR-targeting siRNA conjugated to a triantennary N-acetylgalactosamine (GalNAc) ligand that binds to asialoglycoprotein receptor expressed on hepatocytes. A phase II study of revusiran (5 or 7.5 mg/kg daily for five days, then weekly for 5 weeks), serum TTR levels were reduced by 90%. [48] The ENDEAVOUR study, a phase III randomized, double-blind, placebo-controlled trial of revusiran 500 mg once daily for 5 days then weekly for 18 months, is ongoing. Results are expected to be reported in early 2018.

Tolcapone

Tolcapone is FDA approved for treatment of Parkinson disease. Tolcapone occupies the T4-binding sites located at the TTR dimer-dimer interface and prevents amyloidoenesis by stabilizing the teramer in vivo in mice and humans. [47]  In addition, an added benefit is it also inhibits TTR cytotoxicity. It has been shown that tolcapone docks better than tafamidis in wt-TTR. It has been entered into clinical trials (NCT02191826, EudraCT number: 2014-001586-27) and could be in the market in a relatively short time.  

Treatment of cardiac involvement

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 nature 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. [19]

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. [19]

Given the high incidence of sudden death in patients with TTR cardiac amyloidosis, it is prudent to consider prophylactic placement of an implantable cardioverter defibrillator (ICD). [19]

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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 to date more than 2100 liver transplants have been reported to the Familial Amyloid Polyneuropathy World Transplant Registry (FAPWTR). [29] 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. [30]

Cardiac, leptomeningeal, gastrointestinal, or ocular involvement often progresses despite transplantation.

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. [30]

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 transplant for TTR amyloidosis and more likely carrying a non-TTRVal30Met mutation. [30]

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. [31]

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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. [46] 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 transplant 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. [38]

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 [31] :

  • 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

 

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