The transmission of systemic transthyretin amyloidosis through domino liver transplantation, using a donor liver graft from a patient with familial amyloid neuropathy (FAP), was first described in 2005.1 This complication had not been expected, given that the onset of neurologic symptoms in cases of inherited amyloidosis typically occurs in the age range of 25 to 40 years. Accelerated deposition of amyloid in these types of liver recipients may be facilitated by the presence of amyloid fibrils in the donor liver, which act as a template for amyloidogenesis. We present a case with an unusually short latency of symptomatic onset in which therapy with diflunisal may have helped stabilize neuropathy and nephropathy while the patient waited for another liver transplant.
A man in his early 70s with end-stage cirrhosis from nonalcoholic steatohepatitis underwent a liver transplant from a donor with familial transthyretin amyloidosis. Six years later, the patient reported foot dysesthesias and muscle cramps. Sequential evaluations demonstrated moderate weakness (Medical Research Council grade 4/5) of hand intrinsic muscles and marked paresis of all muscle groups below the knees (Medical Research Council grades 2-3/5). Repeated neurological examinations demonstrated progressive and extensive loss of pain/temperature modalities in all extremities, with milder loss of vibration. There were additional symptoms of gastrointestinal and genitourinary dysautonomia. Electrophysiological studies were in keeping with an axonal sensorimotor polyneuropathy. Sural nerve biopsy revealed endoneurial perivascular eosinophilic deposits staining positive for Congo red, with typical apple green birefringence, and also staining positively with transthyretin immunohistochemistry (Figure). In gastric and duodenal biopsies, amyloid deposition was found, and liquid chromatography tandem mass spectrometry detected the peptide profile consistent with ATTR-type (transthyretin/prealbumin) amyloid deposition. Genetic testing on blood showed no evidence of transthyretin gene mutation in this liver transplant recipient.
Scale bars = 50 μm, and the arrowheads indicate the transthyretin-amyloid deposits that were revealed after staining.
Treatment with diflunisal (250 mg orally twice a day) was started 9 years after liver transplant. At 18 months, the patient’s neuropathic symptoms had plateaued and subsequently were improving compared with the rapid progression of motor and sensory deficits during the 2 years prior to therapy. Serial clinical neurological assessments also documented neurologic stabilization. At the peak of deficits 9 years after liver transplant, there was grade 2/5 weakness of ankle dorsiflexion and plantar flexion, with loss of pinprick up to the inguinal ligaments. Ten years after liver transplant, ankle dorsiflexion and plantar flexion were graded 3/5, and levels of analgesia had receded to the midthigh bilaterally. Nerve conduction amplitudes and renal function studies also stabilized during diflunisal therapy.
Since 2005, 6 cases of amyloid neuropathy following domino liver transplantation demonstrated a symptom-onset latency ranging from 7 to 9 years. Subsequently, in a larger French series of 91 patients with FAP who underwent a domino liver transplant, there were 4 nerve-biopsy–proven cases with symptomatic neuropathy, with an onset latency ranging from 6 to 9 years.2 In a Spanish series of 31 patients with FAP who underwent a domino liver transplant, 4 patients were similarly identified with conclusive electromyographic evidence of neuropathy and a positive nerve biopsy, with a similar range of latency of 6 to 9 years.3 Partial recovery of transthyretin amyloid neuropathy “acquired” through domino liver transplantation was reported in a 72-year-old patient with subsequent liver retransplantation.4 The present case suggests that diflunisal may offer stabilization and partial improvement for patients with FAP and amyloidosis secondary to domino liver transplantation. Diflunisal is a readily available nonsteroidal anti-inflammatory drug that is predicted to inhibit amyloid fibril formation by attaching to the T4 binding sites of transthyretin.5 Diflunisal demonstrated clinical efficacy in a 24-month randomized double-blind placebo-controlled trial of 130 patients with FAP. It was superior to placebo for the primary outcome of decreased progression of polyneuropathy, as well as the secondary outcome of improved quality of life questionnaire.6 Further study is required to assess the use of diflunisal early in the course of the disease to limit the progression of amyloidosis.
Corresponding Author: Pierre R. Bourque, MD, FRCPC, Division of Neurology, Department of Medicine, The Ottawa Hospital (Civic), 1053 Carling Ave, Room C 2178, Ottawa, ON K1Y 4E9, Canada (email@example.com).
Published Online: February 1, 2016. doi:10.1001/jamaneurol.2015.4715.
Conflict of Interest Disclosures: None reported.
Bourque PR, Shafi S, Jansen GH, McCurdy A, Warman Chardon J. Amyloid Neuropathy Following Domino Liver TransplantationResponse to Diflunisal. JAMA Neurol. 2016;73(4):477-478. doi:10.1001/jamaneurol.2015.4715