In this report, we show a clear histopathologic finding that peripheral nerves regenerated in a patient with familial amyloid polyneuropathy after liver transplantation.

Case Report

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A 31-year-old woman with a 3-year history of type I familial amyloid polyneuropathy had undergone living-related partial liver transplantation, as reported elsewhere [8, 9]. Liver transplantation from a cadaveric donor is not performed in Japan because the Japanese do not believe that brain death constitutes death. The patient had a mutant transthyretin gene with a valine to methionine substitution at position 30 (³⁰Met transthyretin). The donor was the patient's healthy 33-year-old sister. After surgery, the patient's autonomic neurologic dysfunction (bowel and bladder dysfunction and orthostatic hypotension) and neuropathic symptoms in the lower limbs gradually disappeared. In addition, ³⁰Met transthyretin in serum almost disappeared [8]. One year after transplantation, the patient returned to her previous activities. Three years after transplantation, she has no residual symptoms ascribed to familial amyloid polyneuropathy. A series of motor and sensory nerve conduction studies on the right tibial nerve showed slight improvement after transplantation: Motor nerve conduction was 43.0 m/s before and 41.0 m/s 3 years after transplantation; sensory nerve conduction was 38.0 m/s before and 48.0 m/s 3 years after transplantation (normal values: motor nerve conduction, 40 m/s; sensory nerve conduction, 35 m/s).

Methods

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Biopsy was done on the left sural nerve before liver transplantation and on the right sural nerve 3 years after transplantation. Formalin-fixed and paraffin-embedded sections were stained with alkaline Congo red, and the characteristic apple-green birefringence of amyloid was identified under a polarizing microscope. So that we could study myelinated fiber lesions, the specimens were fixed in 3% glutaraldehyde in 0.1 mole of cacodylate buffer at a pH of 7.4, postfixed in 1% osmium tetroxide in the same buffer, and embedded in epoxy resin. Transverse sections of 1-µm thickness were cut, stained with 1% toluidine blue, and examined by light microscopy. The diameter of the myelinated fiber and the density of the fiber per square millimeter of the endoneurial area were estimated from photographs enlarged to a final magnification of x1000. From these results, histograms of diameter frequency were constructed.

Results

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Before transplantation, amyloid deposits were seen in the epineurium, perineurium, and endoneurium of the left sural nerve; a nodular pattern of amyloid deposits in the endoneurium predominated. A generalized, severe reduction in the density of nerve fibers was seen in each fascicle (Figure 1, left; Figure 2). After transplantation, a similar pattern of amyloid deposits was seen in the right sural nerve but the size of these deposits seemed stable (Figure 1, middle inset). The density of myelinated fibers was much higher after transplantation than before transplantation. In particular, the number of small myelinated fibers was much higher after transplantation than before transplantation (Figure 1, middle and right; Figure 2).

View larger version (0K): [in this window] [in a new window]   Figure 1. Histopathologic and morphometric findings in the biopsy specimens obtained from the sural nerves. Left. Sural nerve before transplantation. Diffuse fiber loss is seen. Arrowheads indicate a nodular deposit of amyloid. (Original magnification, x140.) Middle. Sural nerve after transplantation. Depleted areas of myelinated fibers are less extensive than areas in the left sural nerve. Inset reveals amyloid deposits in the endoneurium after staining with Congo red. (Original magnification, x140.) Right. The area framed in the middle panel at higher magnification. Many small myelinated fibers are present; the arrow indicates a cluster of these fibers. All sections were embedded in epoxy resin and stained with toluidine blue. (Original magnification, x400.) Bars = 50 µm.

View larger version (0K): [in this window] [in a new window]   Figure 2. Diameter-frequency histogram of myelinated fibers in the sural nerves before transplantation (black bars) and after transplantation (white bars).

Discussion

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Before 1990, no effective treatment was available for the many intolerable symptoms of familial amyloid polyneuropathy. In 1990, physicians used liver transplantation to treat patients with this disease. Since the success of this surgery was reported [4], more than 150 patients with familial amyloid polyneuropathy throughout the world have had this treatment [10]. Follow-up studies [6, 9, 11-13], conducted over a 5-year period after transplantation, have shown early disappearance of variant transthyretins from serum and no further disease progression. In some patients, neurologic symptoms have improved and autonomic neuropathy was alleviated sooner than was peripheral somatic neuropathy. Quality of life has improved in patients who successfully recovered from surgery [14]. Most postoperative deaths occurred in patients with advanced disease [7, 9, 12].

The clinical evidence has led to a consensus that liver transplantation is a promising treatment for familial amyloid polyneuropathy. The need for early transplantation in less symptomatic patients is now emphasized. However, little objective evidence has documented the regression of amyloid deposits or the recovery of peripheral nerves. Studies of scintigraphy done by using radiolabeled serum amyloid P component have shown a significant decrease in whole-body uptake of this tracer after liver transplantation; this finding indicates that amyloid-laden lesions regressed [6]. Results on autonomic function tests improved in a patient with familial amyloid polyneuropathy who survived 8 months after liver transplantation [15].

Type I familial amyloid polyneuropathy with variant ³⁰Met transthyretin usually features distal to proximal symmetrical involvement of peripheral nerves that starts in the legs [1]. A primary neuropathic process in this disorder is axonal degeneration caused by local amyloid deposits [16]. It is well known that the pathologic feature of sural nerve biopsy specimens is selective loss of unmyelinated and small myelinated fibers in the early stage of disease [17]. In our patient, clinical improvement was accompanied by a change in the population of myelinated fibers in the left and right sural nerves. The diffuse pattern of nerve fiber loss in the biopsy specimen of the left sural nerve obtained before liver transplantation coincided with the findings of sural nerves seen in patients with advanced type I familial amyloid polyneuropathy. The biopsy specimen obtained from the right sural nerve 3 years after transplantation revealed a substantial increase in the number of myelinated fibers and many small myelinated fibers. Because patients in whom type I familial amyloid polyneuropathy has a progressively deteriorating course seldom have well-preserved small myelinated fibers in the biopsy specimens obtained from the sural nerves [16], our findings indicate that myelinated fibers regenerate in the peripheral nerves after liver transplantation. Moreover, the reduction of amyloid mass seems to occur in the proximal portions of the long extremity nerves. This report provides valuable histopathologic evidence of the usefulness of liver transplantation as therapy for familial amyloid polyneuropathy.

Dr. Yanagisawa: National Institute for Longevity Sciences and National Chuubu Hospital, Obu 474, Aichi, Japan.

Dr. Matsunami: Department of Surgery, Matsunami General Hospital, Hashiba 501-61, Gifu, Japan.

Drs. Hashikura, Ikegami, and Kawasaki: Department of Surgery, Shinshu University School of Medicine, Matsumoto 390, Japan.