Bijzet, Johan

Hazenberg, Bouke P. C.

Limburg, Pieter C.

Marrink, Jan

Nakazato, Masamitsu

Smit Sibinga, Cees Th.

van Rijswijk, Martin H.

English

University of Groningen

   University of GroningenThe Effect of Plasma Exchange on Serum Levels of TTR Met-30 in a Patient with FAP Type IHazenberg, Bouke P. C.; Marrink, Jan; Nakazato, Masamitsu; Limburg, Pieter C.; SmitSibinga, Cees Th.; Bijzet, Johan; van Rijswijk, Martin H.Published in:Familial amyloidotic polyneuropathyIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:1990Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Hazenberg, B. P. C., Marrink, J., Nakazato, M., Limburg, P. C., Smit Sibinga, C. T., Bijzet, J., & vanRijswijk, M. H. (1990). The Effect of Plasma Exchange on Serum Levels of TTR Met-30 in a Patient withFAP Type I: Influence of the Acute-Phase Response. In P. Pinho e Costa, A. Falcão de Freitas, & M. J. M.Saraiva (Eds.), Familial amyloidotic polyneuropathy: and other related transthyretin disorders (pp. 371-374). (Archivos de medicina; Vol. 3, No. special issue). Arquivos de Medicina.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 20-11-2022Hazenberg BPC et al Effect of Plasma Exchange on Serum Levels of TTR THE E F F E C T OF PLASMA EXCHANGE ON SERUM L E V E L S OF TTR Met 30 IN A PATIËNT WITH FAP T Y P E I Influence of the Acute-Phase Response B o u K E P. C . HAZENBERG*, JAN MARRINK*, MASAMITSU NAKAZATO**, PiETER C . LIMBURG*, C E E S T H . SMIT SIBINGA***, JOHAN BUZET*, MARTIN H . VAN RUSWUK* Summary: A 53-year-old man, member of a Dutch family with familial amyloidotic polyneu-ropathy (FAP) type I , was treated with plasma ex-change for 6 months to investigate the effect of this treatment on the clinical symptoms and se-rum levels of T T R Met 30. Plasma exchange was usually well tolerated. No further deterioration of the neuropathy could be demonstrated after these 6 months. The crea-tinine clearance worsened slightly from 18 to 15 ml/min. The T T R Met 30 levels feil from mean 80 before to mean 51 mgA directly after the plasma exchanges (N=l l ) . T T R Met 30 levels as per-centage of total T T R feil from mean 21 to mean 14%. Sometimes the T T R Met 30 levels did not return to the starting levels after plasma ex-change, but showed a further decrease. Analysis of these data revealed a relationship to periods with an active acute-phase response. T T R Met 30 levels became even undetectable (<5.6 mg/1) dur-ing three periods with the most impressive acute-phase response (CRP >100mg/l). This phenome-non was not observed for total T T R levels. INTRODUCTION In familial amyloidotic polyneuropathy (FAP) type I a variant transthyretin (TTR Met 30) * - Department of Medicine, State University, Oostersin-gel 59, 9713 EZ Groningen, The Netherlands. ** - Third Department of Medicine, Miyazaki Medical College, 5200 Kihara, Kiyotake, Miyazaki 889-16, Japan. *** - Red Cross Bloedbank Groningen-Drenthe, PO Box 1191, 9701 BD Groningen, The Netherlands. is deposited in the form of amyloid fibrils. No curative therapy for this disease has been des-cribed until now. Recently some reports about possible bene-fits of plasma exchange therapy have been pub-lished (1-4). However, the underlying hypothesis differs among the various authors. Some authors expect a restoration of a deficiency in the serum of a factor called amyloid degrading activity (ADA) by the plasma exchange giving back normal donor plasma (1). Others tried to remove T T R and replace with albumin expecting to lower the circulating precursor of amyloid (2). We think the most rational approach is that of some other authors (3,4). They used the plasma exchange to remove as much TTR Met 30 as possible and return normal donor plasma so giving back nor-mal TTR. We adopted this view and performed plasma exchange therapy during 6 months in a 53-year-old male patiënt, member of a Dutch family with FAP type I (5,6). Our objective was to stop or retard further deterioration of the renal function and the neuropathy and to observe the effect of this therapy on the levels of total T T R and T T R Met 30 in the serum. Case history (A) IV.35 A man acquired diarrhoea and fecal inconti-nence at age 44. The foUowing years he experi-enced lower limb neuropathy, impotence and non-painful pretibial ulcers. Biopsy of the rectum at the age of 48 showed amyloid deposition when stained with Congo red and viewed under a po-larization microscope. Renal tunction gradually worsened to a creatinine clearance of about 20 ml/min and proteinuria of 1-2 g/24h was ob-served. 371 Familial Amyloidotic Polyneuropathy Arquivos de Medicina, Vol. 3, Spec. Issue M A T E R I A L A N D M E T H O D S Plasma exchange protocol The plasma exchange procedure was per-formed using the Haemonetics plasmapheresis apparatus. Each run on this apparatus permitted the removal of an average of 500 ml of blood, its centrifugation and the return of the packed red cells to the patiënt together with infusion of 250 ml of cryodepleted plasma. In each procedure about 1 to 1.5 times the plasma volume of the patiënt was exchanged (an average of 2 liters) in 4 runs. Because of an estimated half-Ufe of T T R of about 2.5 days in the circulation (7), the fre-quency of the first 6 runs was two times per week. After these three weeks a maintenance frequency was chosen of once per fortnight during the rest of the six months. Clinical evaluation Renal function was measured by creatinine clearance and proteinuria. The neuropathy was evaluated by an EMG and nerve conduction stu-dies. E C G and echocardiography were per-formed to evaluate the possible involvement of the heart. An ophthalmologist screened this pa-tiënt for possible ocular involvement. After six months of plasma exchange therapy the patiënt was reevaluated to see whether differences were detectable. Quantification of plasma proteins Albumin levels were measured by nephe-lometry. The serum levels of total T T R (pre-albumin) were established by means of an en-zyme-linked immunosorbent assay (ELIS A) per-formed according to our own design (6). The level of T T R Met 30 in serum and plasma was measured by means of a radioimmunoassay spe-cific for the FAP-nonapeptide of the variant T T R molecule as described by Nakazato et al (8). CRP was measured by E L I S A as described (9). R E S U L T S Clinical evaluation and complications The creatinine clearance before the start of therapy was 18ml/min and the proteinuria 1.7 g/ 24h. In this period the patiënt experienced renal failure as a result of urinary obstruction by renal calculi. After the management of this problem the renal function retumed to a creatinine clearance of 15 ml/min after 6 months and proteinuria of 1.4 g/24h. Ophthalmologic, neurologie and cardio-logie evaluation did not reveal differences com-pared to the begiiming of this treatment. Complications due to this therapy were infre-quently observed. Despite the orthostatic hypo-tension, plasma exchange was well tolerated. The first plasma exchange procedure was accompa-nied by fever, chills and impressive signs of hypocalcemia just after the first run had taken place. This hypocalcemia was thought to be the result of a combination of malabsorption, renal insufficiency and the return of plasma mixed with citrate (to prevent coagulation) . Except for the hypocalcemia no other cause for the acute-phase response could be detected. From that moment on, careful monitoring of the serum calcium was performed and this phenomenon could be pre-vented by giving calcium intravenously at the start of each procedure. Unfortunately this patiënt experienced an ac-cidental fracture of his right hip and surgery (dy-namic hip screw) was performed. Fracture heal-ing and wound healing were retarded. Other familiar problems like urinary infections, fluid balance problems because of the diarrhoea and colostoma were frequently observed in this pe-riod. Effect of plasma exchange on TTR Met 30 serum levels The immediate effect of the 11 procedures is shown in figure 1. The mean T T R Met 30 serum level feil from 80 before to 51 mgA directly 372 Hazenberg BPC et al Effect of Plasma Exchange on Serum Levels of TTR 200 T T R Met30 (mg/1) T T R Met30 (% of total T T R ) 50 40 100 R 30 20 10 U before after before after 0 Fig. 1 - TTR Met 30 before and after plasma exchange therapy (N= 11). Plasma levels in mg/1 and as percentage of total TTR. T T R plasma exchange 700 Albumin n 3 5 20 40 - © - A l b u m i n (g/l) 60 80 100 120 140 days - Total T T R (mg/I) - B - T T R Met30 (mg/1) 160 Fig. 2 - Longitudinal effect of plasma exchange therapy on total TTR, albumin and TTR Met 30 plasma levels. (In case of plasma exchange, the levels at the beginning of each procedure have been used.) 373 Familial Amyloidotic Polyneuropathy Arquivos de Medicina, Vol. 3, Spec. Issue afterwards. T T R Met 30 levels as percentage of total T T R feil from mean 21 to mean 14%. Figure 2 shows the serum levels of T T R Met 30, total T T R and albumin during 4 months of plasma exchange therapy. Total T T R and albu-min show a comparable pattem, while T T R Met 30 levels behave quite differently. At three differ-ent periods T T R Met 30 was undetectable (<5.6 mg/1) while total T T R and albumin levels at the same moment were rather high. Closer examina-tion of the clinical situation of the patiënt in these periods revealed episodes of acute-phase re-sponses like the above mentioned problem during the first plasma exchange procedure, urinary infections, an accidental fracture of the right collum femoris followed by surgery and prob-lems with wound healing. The three periods with-out a detectable T T R Met 30 level were charac-terized by a CRP level of > 100 mg/1. D I S C U S S I O N No clear clinical effects of the 6 months plasma exchange therapy could be demonstrated in our patiënt. However, a further deterioration of either nephropathy or neuropathy was not ob-served. We did not expect improvement of func-tion and we know from literature that a slow-down of the process is hard to observe and takes more time than this short period (3). The mean T T R Met 30 plasma levels feil down about 33% immediately after the proce-dure. More impressive fluctuations were not re-lated to the plasma exchange procedures but to periods of inflammation, accompanied by high CRP plasma levels (>100 mgA). It is not clear whether this dramatic fall of T T R Met 30 levels may indicate either a diminished production (accompanied by an accelerated catabolism) or enhanced amyloid deposition. Because of the diverse implications of these proposed mecha-nisms this finding warrants further elucidation. R E F E R E N C E S 1 - ROSENTHAL CJ, KULA RW, SOLOMON N et al: Plasma exchange in the treatment of patients with systemic amyloidosis. In Amyloidosis. Glenner GG, Osserman EF, Benditt EP et al, eds.. Plenum Press, New York, 629-637, 1986. 2 - UITTY RJ, DONAT JR, ROZDILSKY B et al: Familial oculoleptomeningeal amyloidosis. Report of a new family with unusual features. Arch Neurol 45: 1118-1122, 1988. 3 - COUTINHO P, MACEDO E, ESTACIO A et al: Periodic plasma exchanges in the treatment of familial amyloid polyneuropathy: Preliminary results. In Amy-loid and Amyloidosis. Isobe T, Araki S, Uchino F et al, eds.. Plenum Press, New York, 845-849, 1988. 4 - IKEGAWA S, TANASE S, MORINO Y et al: Evalu-ation of serum variant prealbumin levels, and its behav-iour after plasma exchange for familial amyloidotic polyneuropathy (type 1). In Amyloid and Amyloidosis. Isobe T, Araki S, Uchino F et al, eds.. Plenum Press, New York, 839-844, 1988. 5 - SCHOLTEN JH: Familiaire, hereditaire amyloidose. Folia Med Neeri 10: 10-16, 1967. 6 - HAZENBERG BPC, MARRINK J, NAKAZATO M et al: Two Dutch families with FAP type I. Clinical data and biochemical characterization of the TTR variant. Arquivos de Medicina, Vol 3, Spec Issue (this volume). 7 - VAHLQUIST A, PETERSON PA, WIBELL L: Me-tabolism of the vitamin A transporting protein complex. I - Tumover studies in normal persons and in patients with chronic renal failure. Eur J Clin Invest 3; 352-362, 1973. 8 - NAKAZATO M, KURIHARA T, MATSUKURA S et al: Diagnostic radioimmunoassay for amyloidotic polyneuropathy before clinical onset. J Clin Invest 77: 1699-1703,1986. 9 - HAZENBERG BPC, LIMBURG PC, BIJZET J et al: SAA versus CRP serum levels in different inflamma-tory conditions, studied by ELISA using polyclonal anti-AA and monoclonal anti-SAA antibodies. In Amyloid and Amyloidosis. Isobe T, Araki S, Uchino F et al, eds.. Plenum Press, New York, 229-233, 1988. 374 

The Effect of Plasma Exchange on Serum Levels of TTR Met-30 in a Patient with FAP Type I:Influence of the Acute-Phase Response

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The Effect of Plasma Exchange on Serum Levels of TTR Met-30 in a Patient with FAP Type I:Influence of the Acute-Phase Response

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