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LIVER TRANSPLANTATION 13:215-218, 2007

ORIGINAL ARTICLE

Transthyretin-derived Amyloid Deposition on the Gastric Mucosa in Domino Recipients of Familial Amyloid Polyneuropathy Liver Yo-ichi Takei,1 Takahisa Gono,1 Masahide Yazaki,1 Shu-ichi Ikeda,1 Toshihiko Ikegami,2 Yasuhiko Hashikura,2 Shin-ichi Miyagawa,2 and Yoshinobu Hoshii3 1 Department of Internal Medicine (Neurology and Rheumatology) and 2Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan, and 3First Department of Pathology, Yamaguchi University School of Medicine, Ube, Japan

Familial amyloid polyneuropathy (FAP) is a form of hereditary generalized amyloidosis. Liver tissue explanted from FAP patients has normal structure and function, except for the production of amyloidogenic variant transthyretin (TTR), and domino liver transplantation (DLT) using grafts from FAP patients was first performed in 1995. FAP symptoms usually develop in genetically determined individuals after the age of 20, but it is difficult to estimate when FAP symptoms will appear in domino recipients. Concerning this problem, histological findings showing amyloid deposition have recently been obtained in a few domino recipients of FAP livers. This study investigated the presence of de novo amyloid deposition in the gastroduodenal mucosa of domino recipients transplanted at our institution. Biopsy of gastroduodenal mucosa was carried out in 5 recipients of FAP livers and TTR-derived amyloid deposits were detected in 2 patients, both of whom had undergone DLT 47 months previously. In FAP liver recipients, de novo systemic amyloid deposition may begin much sooner than previously supposed. Therefore, careful follow-up of domino recipients of FAP livers is required. Liver Transpl 13:215-218, 2007. © 2007 AASLD. Received May 24, 2006; accepted July 27, 2006.

Familial amyloid polyneuropathy (FAP) is a type of hereditary generalized amyloidosis, initially showing polyneuropathy and autonomic dysfunction with subsequent involvement of many visceral organs.1 Four areas in which this disease is known to be endemic are Portugal, Sweden, and 2 areas in Japan. The disease is caused by a mutation in the transthyretin (TTR) gene, producing a variant form of TTR as an amyloid precursor protein. Many amyloidogenic TTRs have been identified to date, and TTR with substitution of methionine for valine at position 30 is the most common variant causally related to the development of FAP.2 As TTR is produced mainly in the liver, liver transplantation for FAP patients, first performed in 1990 in Sweden,3 was shown to result in

the disappearance of Val30Met TTR from the sera of transplant recipients. According to the Familial Amyloidotic Polyneuropathy World Transplant Registry,4 more than 1,300 FAP patients in 17 countries have undergone orthotopic liver transplantation since 1990. It has been shown that liver transplantation has changed the natural courses of FAP symptoms in patients,5 emphasizing that early intervention can provide a better chance of improving patients’ conditions after transplantation. As orthotopic liver transplantation from cadaveric donors is not widely accepted in Japan, living donor liver transplantation has been employed as an alternative technique. The first liver transplantation in a Japanese FAP patient was carried out in November of 1993 using a living donor liver

Abbreviations: FAP, familial amyloid polyneuropathy; TTR,transthyretin; DLT, domino liver transplantation. Supported by a grant from the Intractable Disease Division, the Ministry of Health and Welfare, Amyloidosis Research Committee in Japan, and a grant from the Intractable Disease Division, the Ministry of Health and Welfare, Research Committee for Epochal Diagnosis and Treatment of Amyloidosis in Japan. Address reprint requests to Yo-ichi Takei, Department of Internal Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan. Telephone: 81-263-37-2673; FAX: 81-263-37-3427; E-mail: [email protected] DOI 10.1002/lt.20954 Published online in Wiley InterScience (www.interscience.wiley.com).

© 2007 American Association for the Study of Liver Diseases.

216 TAKEI ET AL.

TABLE 1. Profiles of the Domino Recipients and Donors Domino Recipient No. 1 2 3 4 5 6 7

Age

Gender

45 64 61 52 32 55 57

M F M F M M M

Domino Donor (FAP Patient)

Hepatic Diseases

Graft Survival

Age

Gender

TTR Mutation

Prognosis

⫹ LCC ⫹ LCC ⫹ LCB ⫹ LCB CTLN2 HCC ⫹ LCC HCC ⫹ LCC

70 months 22 months* 54 months 51 months 37 months 32 months 31 months

34 42 27 42 50 29 40

F M M F F M F

Val30Met Val30Met Val30Met Val30Met Val30Leu Val30Met Val30Met

Alive 70 months Alive 66 months Alive 56 months Alive 51 months Dead 13 months† Alive 32 months Dead 10 days‡

HCC HCC HCC HCC

NOTE: Modified from Stangou et al.10 Abbreviations: M, male; HCC, hepatocellular carcinoma; LCC, hepatitis C cirrhosis; F, female; Val30Met, substitution of methionine for valine at position 30; LCB, hepatitis B cirrhosis; CTLN2, adult-onset type II citrullinemia; Val30Leu, substitution of leucine for valine at position 30. *Died of hepatocellular carcinoma recurrence in the lung. †Died of congestive heart failure, ‡Died of hepatic artery and portal vein thrombosis.

graft,6 and about 50 FAP patients have since received living donor liver transplantation in Japan.7 The age of onset in FAP patients with TTR with substitution of methionine for valine at position 30 ranges from the late 20s to early 40s, and it was, therefore, expected that liver grafts explanted from FAP patients would function in recipients without formation of amyloid fibrils for long period. Domino (or sequential) liver transplantation (DLT) using grafts from FAP patients was first performed in 1995,8 and more than 400 domino transplant procedures had been carried out by the end of 2005, according to the Familial Amyloidotic Polyneuropathy World Transplant Registry. However, 2 recent reports9,10 indicated that amyloid deposition or FAP symptoms appeared in domino recipients much sooner than previously predicted. At our institution, 7 DLTs using FAP livers have been performed to date. In this study, we screened for amyloid deposits in these domino recipients and identified gastric mucosal amyloid deposits in 2 cases.

PATIENTS AND METHODS FAP Patients Seven FAP patients (3 men and 4 women, ranging in age from 27 to 50 years) underwent living donor liver transplantation at our institute between May of 2000 and August of 2003. With regard to TTR gene abnormalities, 6 patients had a mutation of Val30Met TTR, and 1 had a mutation of TTR with substitution of leucine for valine at position 30. The disease duration before the operation was 2 to 4 years.

Domino Recipients A previous report11 described these 7 domino recipients (5 men and 2 women, ranging in age from 32 to 64 years) (Table 1). The indications for DLT in 6 of them were hepatitis B or C virus-related liver cirrhosis com-

plicated by hepatocellular carcinoma, and all of these patients were excluded from standard criterion for liver transplantation (Milan criteria) from cadaveric donors. The remaining 1 patient, who had adult-onset type II citrullinemia, demonstrated rapid progression of hepatic encephalopathy, and thus urgent LT was performed using a graft from a FAP patient with Val30Leu TTR.12

Histopathological Examinations Among the 7 domino recipients, 5 underwent gastric and duodenal mucosal biopsies under endoscopic control, and serial sections from paraffin-embedded blocks were stained with alkaline Congo red. Amyloid deposits were detected by polarizing light microscopy. Areas positive for amyloid deposits were examined further using immunohistochemical staining techniques with different antibodies to human amyloid proteins.13

RESULTS Of the 7 FAP patients treated with living donor liver transplantation, 1 died of hepatic artery thrombosis 10 days after transplantation. Another patient with Val30Leu TTR died of progressive congestive heart failure 13 months postoperatively. The remaining 5 FAP patients have survived for a mean follow-up of 55 months, and all have stabilization or improvement of their FAP symptoms. DLT was uneventful in all recipients of FAP livers. One patient with multiple hepatocellular carcinoma died due to lung metastasis from the disease 22 months after DLT. None of the 6 living recipients of FAP livers showed any evidence of FAP symptoms after a mean follow-up of 46 months. Patient 6 did not undergo biopsy, because he was under medical treatment for metastatic hepatocellular carcinoma. Thus, gastroduodenal biopsy specimens obtained from only 5 recipients of

LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases

AMYLOID DEPOSITION IN DOMINO RECIPIENTS 217

TABLE 2. FAP Symptoms and Amyloid Deposition on Domino Recipients Gastroduodenal Biopsy Age at Operation

Gender

Duration After DLT

Prognosis

FAP Symptoms

1 2

45 64

M F

70 months Dead

Alive Dead (22 months*)

None NA

3 4 5 6

61 52 32 55

M F M M

54 51 37 32

months months months months

Alive Alive Alive Alive†

None None None None

7

57

M

31 months

Alive

None

No.

Biopsy Period After Operation

Amyloid Deposits

70 months Biopsy not performed 47 months 47 months 32 months Biopsy not performed 30 months

None Biopsy not performed Positive Trace None Biopsy not performed None

Abbreviations: M, male; F, female; NA, not available. *Died of hepatocellular carcinoma recurrence in the lung. †Recuperating from hepatocellular carcinoma metastasis.

FAP livers were available for this study. Amyloid deposition was detected in 2 recipients. In case 3, gastroduodenal biopsy was performed 47 months after DLT. Among the 5 specimens examined, patchy Congo-redpositive deposits were observed in 1 gastric mucosal specimen (Fig. 1A and 1B). These deposits showed typical apple-green birefringence under polarized light (Fig. 1C, arrows). Positive immunoreactivity of these amyloid deposits with an anti-human TTR antibody was also seen (Fig. 1D, arrows). In case 4, biopsy was also performed 47 months after DLT, and a tiny amyloid deposit was observed in 1 of 5 gastric mucosal specimens (Fig. 1E and 1F). In cases 1, 5, and 7, biopsies were carried out 72, 32, and 29 months after DLT, respectively, but there were no detectable amyloid deposits in these specimens.

DISCUSSION DLT using a graft from a FAP patient was first performed in Portugal in 1995.8 Since then, the Familial Amyloidotic Polyneuropathy World Transplant Registry reports that more than 400 DLTs had been performed up to November of 2005. When DLT was first proposed, it was difficult to predict when amyloid deposition would start in the recipients of FAP livers after DLT. A report from Brazil indicated there was no amyloid deposition in biopsied gut specimens from 7 recipients of FAP liver obtained an average of 6 months (4-24 months) after LT.14 However, Sousa et al. reported that nonfibrillar TTR deposition was detectable in skin biopsy specimens from domino recipients 3 years after DLT.9 Stangou et al. reported the first case of FAP symptoms developing 8 years after DLT,10 showing systemic deposition of TTR-derived amyloid. Both reports indicated that TTR-related systemic amyloidosis is induced secondarily by DLT in recipients of FAP livers and that FAP symptoms certainly have appeared in these domino recipients within 8 years after DLT. In the

Figure 1. Histopathology of the biopsied tissues shown on panels A through D. Specimens are from the duodenal mucosa of domino recipient No. 3. (A, B) Congo red staining showed amyloid deposits in mucosal tissue. A: Bar, 500 ␮m; B: bar, 100␮m. (C) Apple-green birefringence was seen under polarized light (arrows). Bar, 200␮m. (D) These deposits were positively immunolabeled with an anti-human TTR antibody (arrows). Bar, 200␮m. Panels E and F show duodenal mucosa specimens of domino recipient No. 4. (E) Congo red staining showed small amyloid deposits in mucosal tissue. Bar, 100 ␮m. (F) Birefringence was seen under polarized light. Bar, 100 ␮m.

present study, we demonstrated amyloid deposition in 2 domino recipients with posttransplant histories of less than 4 years. These 3 reports strongly suggest that

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218 TAKEI ET AL.

de novo production of variant TTR by transplanted FAP liver can lead to the formation of TTR amyloid fibrils in domino recipients soon after the operation. In individuals with a TTR gene abnormality, it takes 20 years or more for the start of amyloid deposition on their organs, and it takes several more years for FAP symptoms to develop.15 It is difficult to explain why some recipients of FAP livers develop TTR amyloidosis within short incubation periods in comparison with genetically determined FAP patients. TTR is inherently amyloidogenic, because the molecule is largely composed of ␤-sheet structure, the presence of which is a characteristic conformational finding of amyloid fibrils. Senile systemic amyloidosis mainly involving the heart is a representative disorder caused by wild-type TTR,16 and conversion of normal TTR to amyloid fibrils is presumably promoted by aging. As all domino recipients with proven amyloid deposition, including our 2 patients, were significantly older than FAP patients from endemic foci, aging and other unknown factors may have accelerated TTR-derived amyloid deposition in these recipients of FAP livers. DLT using a FAP liver graft is useful because of the shortage of available liver grafts. However, it is now evident that this unique transplantation method gives rise to the transmission of systemic TTR amyloidosis in domino recipients. There is a possibility that FAP symptoms will appear 3 or 4 years after the histological demonstration of amyloid deposition. Aspiration biopsy of abdominal fat tissue or gastroduodenal mucosal biopsy annually is useful to detect amyloid deposits at an early stage of the disease. When amyloid deposition is confirmed, it will be necessary to provide domino recipients with treatments, such as nonsteroidal anti-inflammatory drugs, that stabilize the native tetramer of TTR molecules to inhibit transthyretin amyloidogenesis and reduce the risk of the posttransplant disorder, FAP.17 Moreover, as an alternative, retransplantation might be required in these recipients.

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