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Familial amyloidotic polyneuropathy (FAP) is an autosomal-dominant inherited disease characterized by systemic deposition of amyloid fibrils in various tissues, resulting in organ dysfunction and ultimately leading to death.1 FAP is characterized by peripheral and autonomic neuropathy, cardiomyopathy, nephropathy, malnutrition, and vitreous opacities. FAP generally manifests in patients who are between the ages of 25 and 35 years, and it is ultimately fatal from progressive cardiac dysfunction, malnutrition, or other complications related to autonomic neuropathy 7 to 10 years after onset of symptoms.1, 2

Transthyretin (TTR) or prealbumin is a 127–amino acid protein predominately synthesized in the liver that functions as a transport protein for thyroxin and saturated retinol-binding protein. A mutant, amyloidogenic TTR molecule is produced in patients with FAP as a result of a single amino acid substitution.1 More than 80 point mutations in the TTR gene have been reported; however, the most common defect worldwide is Val30Met, a substitution of valine by methionine at position 30.3

Liver transplantation (LT) is the only definitive treatment for FAP and was first successfully performed for this condition in Sweden in 1990.4 The rationale for LT is to eliminate the main source of mutant TTR production, thereby arresting the progression of amyloid deposition. Since 1990, a total of 54 centers in 16 countries have performed LT for FAP.3 According to the Familial Amyloidotic Polyneuropathy World Transplant Registry,5 a total of 575 transplants have been performed in 539 patients, reaching a plateau of approximately 60 transplants for FAP per year. One- and 5-year survival rates in patients transplanted early in the course of FAP are 90 and 82%, respectively. Causes of death in patients correlate well with the causes of death in adult patients undergoing LT for chronic liver disease, with septicemia and infectious complications accounting for approximately 30% of deaths. Cardiovascular death is higher in patients with FAP (39%) vs. patients undergoing LT for chronic liver disease (9%), reflecting the inherent cardiovascular risk of patients with this disease.3

Because FAP is so slowly progressive, an innovative procedure called domino liver transplantation has been applied to these patients. The domino liver transplant procedure involves removing the liver from the patient with FAP and transplanting it into an older recipient with liver failure. Thus, patients with FAP do not remove a liver from the donor pool because their own liver is transplanted into a patient on the list. To date, 22 centers in 12 countries have reported 131 recipients of domino liver grafts with 1- and 5-year patient survival rates of 91.8 and 88.4%, respectively.3 Thus far, there have been two different reports of symptomatic FAP occurring in domino liver transplant recipients between 7 and 8 years postoperatively.6, 7

Posttransplant studies in patients with FAP show that mutant TTR levels become immeasurable in the serum.8 Reports indicate that the progression of FAP-related symptoms is halted in a large proportion of patients and that clinical manifestations improve in approximately one-third of cases.8–10 In some patients, ocular symptoms and cardiac dysfunction may continue to progress after LT.9 Successful LT is the only life-saving treatment option for patients with FAP.

SYNTHESIS OF AVAILABLE DATA

  1. Top of page
  2. SYNTHESIS OF AVAILABLE DATA
  3. PROPOSAL FOR STANDARDIZED MELD EXCEPTIONS FOR CANDIDATES WITH FAP
  4. CONFIRMATION OF AMYLOID DEPOSITION IN AN INVOLVED ORGAN
  5. ADDITIONAL GUIDELINES
  6. REFERENCES

There is sufficient evidence to justify additional priority for liver transplant candidates with FAP.

PROPOSAL FOR STANDARDIZED MELD EXCEPTIONS FOR CANDIDATES WITH FAP

  1. Top of page
  2. SYNTHESIS OF AVAILABLE DATA
  3. PROPOSAL FOR STANDARDIZED MELD EXCEPTIONS FOR CANDIDATES WITH FAP
  4. CONFIRMATION OF AMYLOID DEPOSITION IN AN INVOLVED ORGAN
  5. ADDITIONAL GUIDELINES
  6. REFERENCES

Candidates with FAP that satisfy the criteria listed below will receive an initial Model for End-Stage Liver Disease score equivalent to a 15% mortality risk at 3 months, and the Model for End-Stage Liver Disease score will be increased by a 10% mortality equivalent every 3 months.

CONFIRMATION OF AMYLOID DEPOSITION IN AN INVOLVED ORGAN

  1. Top of page
  2. SYNTHESIS OF AVAILABLE DATA
  3. PROPOSAL FOR STANDARDIZED MELD EXCEPTIONS FOR CANDIDATES WITH FAP
  4. CONFIRMATION OF AMYLOID DEPOSITION IN AN INVOLVED ORGAN
  5. ADDITIONAL GUIDELINES
  6. REFERENCES

Identification of the TTR gene mutation (Val30Met vs. non-Val30Met) by DNA analysis or mass spectrometry in a biopsy sample is considered confirmation of amyloid deposition in an involved organ.

ADDITIONAL GUIDELINES

  1. Top of page
  2. SYNTHESIS OF AVAILABLE DATA
  3. PROPOSAL FOR STANDARDIZED MELD EXCEPTIONS FOR CANDIDATES WITH FAP
  4. CONFIRMATION OF AMYLOID DEPOSITION IN AN INVOLVED ORGAN
  5. ADDITIONAL GUIDELINES
  6. REFERENCES

The candidate should be ambulatory with a modified polyneuropathy disability score <IIIb (able to ambulate with 1 crutch or less), and should have a modified body mass index >700, where modified body mass index = [(weight in kg/length in m2) × (serum albumin in g/L)].

Patients with FAP who have obvious cardiac involvement and increased left ventricular wall thickness (mean wall thickness >12 mm) should be considered for combined liver-heart transplantation or, alternatively, no transplantation at all. Because there is no agreed-on consensus in the literature regarding features that constitute significant cardiac involvement, we recommend that patients with potentially life-threatening cardiac dysrhythmia and/or cardiomyopathy with an ejection fraction <40% ± New York Heart Association class II symptoms not be considered for LT alone.4 The liver from the patient with FAP should be used for domino transplantation whenever possible into an appropriate patient awaiting LT unless the variant of FAP is one that deposits amyloid in the liver (e.g., fibrinogen alpha chain amyloidosis).

The data elements described above should be prospectively collected by the Organ Procurement Transplantation Network–United Network for Organ Sharing on exceptional case applications with a diagnosis of FAP.

REFERENCES

  1. Top of page
  2. SYNTHESIS OF AVAILABLE DATA
  3. PROPOSAL FOR STANDARDIZED MELD EXCEPTIONS FOR CANDIDATES WITH FAP
  4. CONFIRMATION OF AMYLOID DEPOSITION IN AN INVOLVED ORGAN
  5. ADDITIONAL GUIDELINES
  6. REFERENCES