Liver Transplantation as a Treatment for Familial Amyloidotic Polyneuropathy

Patients

All seven patients were seen and evaluated in the Thorndike Clinical Research Center of the Boston University School of Medicine at Boston City Hospital. All had an identified mutant transthyretin and were from three families known to be affected with FAP. All patients had biopsy results that showed amyloid deposition. Liver transplant evaluation and surgery were done by the liver transplant unit at the New England Deaconess Hospital in six of the patients and at the Cleveland Clinic in one patient. Patients are still receiving several quantitative assessments including sensory and motor neurologic examinations; standard autonomic neuropathy testing as described by Ewing and colleagues [3]; cardiac status testing using electrocardiograms, echocardiograms, and Holter monitoring; ophthalmologic examinations for vitreous opacities; and a quality-of-life health status questionnaire.

Family 1 includes a sister (age 35 years) and brother (age 37 years) of Greek ancestry with the transthyretin mutation, valine 30 methionine (Val 30 Met), whose mother, maternal uncle, and grandfather died of FAP at ages 50, 37, and 40 years, respectively [4]. Clinical findings began at ages 32 and 25 years (in the sister and the brother) and included a sensory and motor neuropathy of the legs and arms, foot drop, urinary retention, orthostasis, and diarrhea. The brother had severe wasting, had cardiac conduction defects requiring a pacemaker, and was receiving total parenteral nutrition. Liver transplantations were done in March 1992 and August 1992. Eight months later, the brother died of a pacemaker failure but did not have complications from transplant surgery.

Family 2 contains a 40-year-old woman of Greek ancestry, with the transthyretin mutation Val 30 Met, whose father and paternal grandmother died of FAP at ages 44 and 60 years, respectively [4]. Clinical features were present for 5 years and were similar to those in family 1. Liver transplantation was done in July 1992.

Family 3 contains four persons of Italian ancestry with the transthyretin mutation, glutamate 42 glycine (Glu 42 Gly): a sister 40 years old, a brother 36 years old, a male cousin 35 years old, and a female cousin 42 years old. These four persons had liver transplantation in June 1992, September 1992, November 1992, and June 1992. Family history showed death due to FAP in the mother, maternal aunt, uncle, and grandfather at ages 50, 46, 40, and 41 years, respectively. All persons have a second mutation on the same transthyretin gene causing an amino acid substitution of histidine 90 asparagine (His 90 Asn) also noted in families of Portuguese and German descent who do not have FAP [5]. Clinical features in this kindred were autonomic neuropathy with diarrhea and orthostasis, cardiomyopathy, vitreous opacities, and mild peripheral neuropathy.

Results

Seven patients (35 to 42 years old) had liver transplantation ranging 2 to 11 years after the onset of symptoms of FAP. Six liver transplantations were done at the New England Deaconess Hospital, where it was noted that the operative time (median, 5.5 hours), the blood use (median, 4 units), and the intensive care unit time (3 days for one patient) were statistically less than required for transplantation in patients with chronic liver failure.

Specimens of liver tissue at the time of transplant were examined for amyloid deposition using Congo red staining. All specimens were positive with perivascular deposits graded as trace to 1+ (on a scale of 0 to 4+); more amyloid was noted in specimens from persons who had had symptoms of FAP for a long time.

Serum was collected at multiple times preoperatively and within 1 month postoperatively. Total transthyretin was quantified by an enzyme-linked immunosorbent assay. To quantify the mutant transthyretin, total transthyretin was separated from other serum proteins by a native polyacrylamide gel electrophoresis and was subjected to isoelectric focusing using a modification of a previously described protocol [6] (Figure 1). The relative proportion of normal and mutant transthyretin in each sample was quantified by densitometry (Image Quant software package, Sunnyvale, California). Preoperative transthyretin levels in all patients ranged from 153 to 373 µg/mL (normal values, 200 to 400 µg/mL); postoperative values were 248 to 458 µg/mL. All patients had slightly less mutant transthyretin than normal transthyretin before transplantation (35% to 45%). Postoperatively, sera from all patients showed only normal transthyretin.

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Figure 1. Numbers 1, 3, and 4 are from patients with transthyretin methionine 30 (Met 30), and numbers 2 and 5 are from patients with glycine 42 and asparagine 90 (Gly 42 and Asn 90). In the B lanes, normal transthyretin is the top band and mutant transthyretin is in the lower band. In the A lanes, only normal transthyretin is seen. A = after; B = before. Isoelectric focusing gels of the serum transthyretin proteins from five patients before and after liver transplantation.

Hospital stay after transplant averaged 17 days. No patient had a rejection episode requiring re-hospitalization. No objective changes in neuropathologic or cardiomyopathologic symptoms have been noted since transplantation, although several patients report a decrease in diarrhea.

Discussion

We describe the first patients who had liver transplantation as a treatment for FAP in the United States. In FAP, a mutant transthyretin protein synthesized by the liver is deposited as amyloid fibrils in various organ systems and is uniformly fatal 7 to 15 years after disease onset in middle life [1]. Treatment options with gene therapy are not expected in the near future; unlike conditions where gene therapy can be used to replace a deficient product, in FAP a need exists to eliminate a deleterious product. Liver transplantation, although a complicated and major surgical procedure, provides the first successful therapy for patients and families who have this disease.

The follow-up period for transplantation is still relatively brief (1 to 15 months) for defining neurologic improvement. However, none of the patients have had progression of their disease, a noteworthy observation in FAP. Given the optimistic surgical outlook and the bleak prognosis of FAP, transplantation should be done soon after biopsy results show amyloid deposits, thus confirming disease onset.