Summary. In order to estimate the function of the pineal gland, the sympathetic nervous system and the adrenal medulla in patients with familial amyloid.
doumo2@ J Neural Transm (1987) 69:97-103
IV~mm/~l'ranmn~sion 9 by Springer-Verlag 1987
Disturbed Function of the Pineal Gland in Familial Amyloid Polyneuropathy S. Higa 1, T. Suzuki 1, S. Sakoda 1, S. K i s h i m o t o 1, Y. Takaba 2, A. Nakajima 3, and S.P. Markey 4 1 Third Department of Internal Medicine, Osaka University Hospital, Japan 2 Arao City Hospital and 3 Nakajima Medical Clinic, Arao City, Kumamoto Prefecture, Japan 4 Laboratory of Clinical Science, National Institute of Mental Health, U.S.A. With 3 Figures Received June 9, 1986; revised September 10, 1986
Summary In order to estimate the function of the pineal gland, the sympathetic nervous system and the adrenal medulla in patients with familial amyloid polyneuropathy relative to healthy subjects, we have quantified urinary 6hydroxymelatonin, normetanephrine and metanephrine. Urinary 6-hydroxymelatonin level correlated with neither of two O-methylated catecholamine levels in healthy subjects. The excretion of both 6-hydroxymelatonin and metanephrine were reduced in the patient group as compared with the control group, and the normal daily rhythm of 6-hydroxymelatonin was undetectable in the most of the patients. This finding indicates that the function of the pineal gland is disturbed in familial amyloid polyneuropathy. Key words: Pineal gland, familial amyloid polyneuropathy, 6-hydroxymelatonin, metanephrine, normetanephrine. Introduction In type 1 familial amyloid polyneuropathy (FAP), various clinical manifestations including orthostatic hypotension, alternation of diarrhea and constipation, dyshydrosis, sexual impotence in man, and bladder distrubance suggest the wide involvement of the autonomic nervous system (Araki et al., 1968). We have, however, never
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seen any description about the involvement of the pineal gland which is also innervated by a peripheral sympathetic nerve from the superior cervical ganglion. Recently, urinary 6-hydroxymelatonin ( 6 0 H M e l ) , a main metabolite of melatonin, has been shown a useful index for the activity of the pineal gland (Tetsuo et aL, 1981 b). On the other hand, urinary free normetanephrine (NM) and metanephrine (M) are supposed to reflect well the functional state of the general sympathetic nervous system and the adrenal medulla, respectively (Higa et aL, 1985). By measuring 6 0 H M e l and O-methylated catecholamines in the same urine, we estimated the function of the sympatho-pineal system in conjunction with that of the general sympathetic nervous system and the adrenal medulla in FAP.
Subjects and Methods We have investigated 23 members of 4 families afflicted with FAP in Arao (Sakoda et aL, 1983); 8 patients (3 male and 5 female; age range 35 to 47 years) and 15 asymptomatic subjects (7 male and 8 female; age range 14 to 61 years), of whom three were wives of patients. The diagnosis of FAP was based on clinical manifestations, family history and microscopic examination of the sural nerve biopsy. No patient had any clinical sign of hepatic insufficiency. The severity of the clinical stage was classified into stage 1 (mild), stage 2 (moderate) and stage 3 (advanced) as described by Suzuki et al. (1979). Urine collection was fractionated in three sequential 8-hour portions a day (7 a. m. to 3 p. m., 3 p. m. to 11 p. m. and 11 p. m. to 7 a. m.) over two consecutive days in August and October with no dietary or activity restriction. Although, in a few inpatients, urine collections have been completed by using indwelling catheters, three fractions from two other patients were deficient because of urinary incontinence in the night. Immediately after collection, urine was frozen until assayed for 60HMel, NM and M. Gas chromatography-mass spectrometry methods were used for determination of 6 0 H M e l (Tetsuo et aL, 1981 a) and O-methylated catecholamines (Higa et aL, 1980).
Results The excretion of 6 0 H M e l , N M and M in the asymptomatic group was 7.1 ___4.4, 19.4 ___8.3 and 20.0 ___9.3/1g/day (mean + S.D.), respectively. Two subjects who were at risk for FAP had exceptionally low levels of 6 0 H M e l excretion (0.2 and 0.6/.tg/day, Fig. 1 a). In the control group, the excretion of 6 O H M e l did not bear any positive
Disturbed Function of the Pineal Gland in Familial Amyloid Polyneuropathy 99
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correlation with that of NM (r=0.16, Fig. 1 a) or M (r=O.03, Fig. 1 b), in contrast to a close relationship between NM and M (r = 0.87, p < 0.01, Fig. 1 c). The similar tendency was confirmed also in patient group in which only the correlation between the excretion of NM and M (r = 0.76, p < 0.05) but not 6 0 H M e l and NM (r = 0.70, p > 0.05) or M (r = 0.51, p > 0.05) was significant. The excretion of 6 0 H M e l , NM and M in all patients with FAP were 2.3 + 3 . 7 , 12.6 + 9.8 and 10.7 + 7.1/~g/day (mean + S.D.), respectively. Only the values for 6 0 H M e l and M in the patient group are significantly lower than those in the asymptomatic group (p < 0.01). Subjects with FAP excreted less NM than controls but only a trend was noted (p > 0.05). All three metabolites had a tendency to decline in parallel with the severity of the disease (Fig. 2). The normal circadian rhythm of urinary 6 0 H M e l was blunted in patients with FAP (Fig. 3), except for one stage 1 case who also had a high value in daily output (10.7/~g/day in stage 1, Fig. 2).
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Disturbed Function of the Pineal Gland in Familial Amyloid Polyneuropathy 101
Discussion
In human studies, close relationships have been described between plasma free NM and plasma norepinephrine (Kobayashi et aL, 1980), urinary free NM and urinary norepinephrine, urinary free M and urinary epinephrine (Higa et aL, 1985), and urinary conjugated 6 0 H M e l and plasma melatonin (Markey et al., 1985). Furthermore, the excretion rates of 6 0 H M e l (Tetsuo et aL, 1981 b), free NM and M (Higa et aL, 1985) decrease in patients with autonomic nervous failure. Thus, it may be concluded that urinary levels of these three metaholites rather reflect the production of their precursors than alterations of degradation rates. The synthesis and release of melatonin have been known to be stimulated by the light-darkness cycle (Cardinali, 1981; Tetsuo et aL, 1980), while both norepinephrine and epinephrine are released under the physical, psychological and metabolic stress (Christensen and Videbaek, 1974; Axelrod and Resine, 1984). This different condition for the production of the precursors may result in the dissociation between the exretion of 6 0 H M e l and two O-methylated catecholamines in the present study. On the other hand, in the FAP patient group, the excretion of both 6 0 H M e l and M was reduced, especially in the advanced stage of FAP. In this context, Tetsuo, M. et al. reported the decreased 6 0 H M e l output in idiopathic orthostatic hypotension, a peripheral type of autonomic neuropathy, and attributed it to the disturbed function of the peripheral sympathetic nerve (Tetsuo et aL, 1981 b). A similar disturbance of the peripheral nerves occurs in FAP, as suggested by the deficit of the noradrenergic nerves as seen histochemically (Ikeda et aL, 1983), and the low levels of plasma norepinephrine (Suzuki et aL, 1981) and the decreased excretion of urinary norepinephrine which was significant only in nine stage 3 cases (Suzuki et aL, 1979). We could not find any significant difference in NM output between the symptomatic and asymptomatic groups, probably due to the relatively large number of patients in stage 1 and 2 (7 of 8 patients). However, under the same conditions, we have observed statistically lower excretion of 6 0 H M e l and M in the FAP patient group. A possible explanation for this would be infiltration of amyloid into the pineal gland, which is reasonable because the neuro-endocrine organs outside of the blood-brain-barrier are preferentially involved with amyloid deposition as well as the autonomic nervous system (Shirabe et aL, 1969). This would suggest that the dysfunction of the pineal gland might precede other clinical manifestations. In fact, during preparation of this communication, one asymptomatic subject described as an
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outlier with low output (0.6/ag/day in Fig. 1) has proceeded to develop FAP. Although it is uncertain whether the main pathological change resides in the pineal gland or the sympathetic nerve innervating it, our data indicates that the function of the pineal gland as well as that of the adrenal medulla is disturbed in FAP.
Acknowledgement This work has been supported in part by grants for Specific Diseases from the Ministry of Health and Welfare, Japan.
References Araki S, Mawatari S, Ohta M, Nakajima A, Kuroiwa Y (1968) Polyneuritic amyloidosis in a Japanese family. Arch Neurol 18:593-602 Axelrod J, Resine TD (1984) Stress hormones: their interaction and regulation. Science 224:452-459 Cardinali DP (1981) Melatonin: a mammalian pineal hormone. Endocrin Rev 2:327-346 Christensen NJ, VidebaekJ (1974) Plasma catecholamines and carbohydrate metabolism in patients with acute myocardial infarction. J Clin Invest 54:278-286 Higa S, Suzuki T, Sakoda S, Azuma T, Kishimoto M, Markey SP (1985) Urinary free normetanephrine in orthostatic hypotension. Autonom Nerv Syst 22:331-337 (in Japanese with English abstract) Higa S, Suzuki T, Sakoda S, et al. (1980) A new method for determination of free normetanephrine and metanephrine in urine by selected ion monitoring. Proc Jpn Soc Mass Spectrom 5:165-168 (in Japanese with English abstract) Ikeda S, Oguchi K, Kobayashi S, Tsukahara S, Yanagisawa N (1983) Histochemical study of rectal aminergic nerves in type 1 familial amyloid polyneuropathy. Neurology 33:1055-1058 Kobayashi K, DeQuattro V, Bornheimer J, Kolloch R, Miano L (1980) Plasma normetanephrine: a biochemical marker of sympathetic nerve function in man. Life Sci 26:1821-1826 Markey SP, Higa S, Shih H, Danforth DN, Tamarkin L (1985) The correlation between human plasma melatonin levels and 6-hydroxymelatonin excretion. Clin Chim Acta 150:221-225 Sakoda S, Suzuki T, Higa S et al. (1983) Genetic studies of familial amyloid polyneuropathy in the Arao district ofJapan: I. The genealogical survey. Clin Genet 24:334-338
Disturbed Function of the Pineal Gland in FamilialAmyloid Polyneuropathy 103 Shirabe T, Hashimoto M, Araki S, Mawatari S, Kuroiwa Y (1969) Two autopsy cases of familial polyneuropatic amyloidosis. Adv Neurol Sci (Tokyo) 13:206-215 Suzuki T, Higa S, Sakoda Set al. (1981) Orthostatic hypotension in familial amyloid polyneuropathy: Treatment with DL-threo-3,4-dihydroxyphenylserine. Neurology (New York) 31:1323-1326 Suzuki T, Tsuge T, Higa S e t al. (1979) Catecholamine metabolism in familial amyloid polyneuropathy. Clin Genet 16:117-124 Tetsuo M, Markey SP, Kopin IJ (1980) Measurement of 6-hydroxymelatonin in human urine and its diurnal variations. Life Sci 27:105-109 Tetsuo M, Markey SP, Colburn RW, Kopin IJ (1981) Quantitative analysis of 6-hydroxymelatonin in human urine by gas chromatography-negative chemical ionization mass spectrometry. Anal Biochem 110:208-212 Tetsuo M, Polinsky RJ, Markey SP, Kopin IJ (1981) Urinary 6-hydroxymelatonin excretion in patients with orthostatic hypotension. J Clin Endocrinal Metab 53:607-610 Authors' address: Dr. S. Higa, Third Department of Internal Medicine, Osaka University Hospital, 1 chome Fukushima-ku, Osaka 553, Japan.
