Zusammenfassung
In einer Starvationsuntersuchung wurde im Tierexperiment die Mangelernährung entsprechend einer Anorexia nervosa simuliert. Ratten im Alter von 11 bis 13 Wochen erhielten eine hypokalorische Diät in einer Standardzusammensetzung oder eine hypokalorische cholinreduzierte Diät. Die Dauer der Gewichtsreduktion betrug 12 bis 20 Wochen, das Ausmaß der Gewichtsreduktion lag zwischen 30 % bis 40 % vom Ausgangsgewicht. Bei einem Teil der Tiere erfolgte anschließend eine Wiederauffütterung (6 bis 12 Wochen) mit Standardnahrung oder cholinangereichert ad libitum. Untersucht wurden Blutparameter und die Membranfluiditäten im ZNS. Unter Gewichtsreduktion fand sich eine signifikante Abnahme vom Gesamteiweiß und der Triglyzeride (Z = -3,53 bzw. -3,42; p < 0,001) und eine Zunahme der Fluidität (Z = -2,83; p < 0,01). Nach langandauernder Gewichtsreduktion und anschließender Wiederauffütterung lag eine katabole Stoffwechsellage mit einem signifikant erhöhten Harnstoff/Kreatinin-Quotienten vor. Die cholinangereicherte Wiederauffütterung führte zu einer Normalisierung der Blutparameter und der Membranfluidität im ZNS. Bei Cholinanreicherung stieg das Gesamteiweiß signifikant (Z = -2,03; p < 0,01). Außerdem fanden wir eine negative Korrelation zwischen dem Gesamteiweiß und dem Harnstoff/Kreatinin-Quotienten (rS = -0,47; p < 0,001; n = 64), möglicherweise infolge eines verringerten Proteinkatabolismus oder eines erhöhten Proteinanabolismus. Darüber hinaus korrelierten Gesamteiweiß und Kreatinin mit den Membranfluiditäten des ZNS (rS = 0,65 bzw. 0,58 mit p < 0,001), so dass diese Parameter als potenzielle Prädiktoren für die Zellfunktion im mangelernährten Gehirn und zur Verlaufsuntersuchung einer Anorexie diskutiert werden können. Wir stellen die Hypothese auf, dass Cholinanreicherung der Nahrung zur Stabilität zerebraler Membranen beiträgt und den Verlauf der Stoffwechselveränderungen bei Anorexia nervosa günstig beeinflusst.
Abstract
Malnutrition in anorexia nervosa was simulated in an animal starvation study. Female rats aged 11 to 13 weeks received a hypocaloric standard diet or a hypocaloric choline reduced diet. Weight reduction lasted for 12 to 20 weeks and was between 30 % to 40 % of initial weight. Several animals were refed after weight reduction up to 6 to 12 weeks with a standard or a choline enriched diet ad libitum. Serum parameters and membrane fluidity of the CNS were measured after weight reduction or after refeeding. Weight reduction leads to a significant decrease of serum protein, triglycerides (Z = -3,53 resp. -3,42; p < 0,001) and an increase of membrane fluidity in the CNS (Z = -2,83; p < 0,001). Long-term diet with marked weight reduction and following refeeding causes a catabole metabolic situation with significant increase of urea/creatinine-ratio. Choline enriched refeeding after diet results in normalization of serum parameters and membrane fluidity of the CNS. Choline enrichment leads to a significant increase of serum protein (Z = -2,03; p < 0,01). Besides we found a negative correlation between serum protein and urea/creatinine-ratio (rS = -0,47; p < 0,001; n = 64). This is possibly caused by a reduced protein catabolism or an increased protein anabolism. Furthermore membrane fluidity in the CNS correlates with serum protein (rS = 0,65; p < 0,001; n = 41) and with serum creatinine levels (rS = 0,58; p < 0,001; n = 42). We conclude that these serum parameters are potential predictors for cell function in the starved brain and consequently for the course of anorexia nervosa. We furthermore hypothesize that choline enriched nutrition after starvation improves the stabilization of cerebral membranes and the metabolic situation in anorexia nervosa.
Schlüsselwörter
Anorexia nervosa - Cholin - Serumparameter - Fluidität
Key words
anorexia nervosa - choline - serum parameter - fluidity
Literatur
1
Blusztajn J K.
Choline, a vital amine.
Science.
1998;
281
794-795
2
Zeisel S H, Blusztajn J K.
Choline and human nutrition.
Annu Rev Nutr.
1994;
14
269-296
3
Los D A.
Murata N. Membrane fluidity and its roles in the perception of environmental signals.
Biochimica et Biophysica Acta.
2004;
1666
142-157
4
Holman R T, Adams C E, Nelson R A, Grater S JE, Jaskiewicz J A, Johnson S B, Erdman J W.
Patients with anorexia nervosa demonstrate deficiencies of selected essential fatty acids, compensatory changes in nonessential fatty acids and decreased fluidity of plasma lipids.
J Nutr.
1995;
125
901-907
5
Lejoyeux M, Bouvard M P, Viret J, Daveloose D, Adès J, Dugas M.
Modifications of erythrocyte membrane fluidity from patients with anorexia nervosa before and after refeeding.
Psychiatry Research.
1996;
59
255-258
6
Gaggiotti G, Taus M, Spazzafumo L, Tesei M, La Rocca R, Mozzanti L.
Modifications of functional and physico-chemical properties of rat ileal plasma membranes.
Biochemistry and Molecular Biology International.
1995;
35
851-854
7
Albi E, Tomassoni M L, Viola-Magni M.
Effect of lipid composition on rat liver nuclear membrane fluidity.
Cell Biochemistry and Function.
1997;
15
181-190
8
Winocour P D, Bryszewska M, Watala C, Rand M L, Epand R M, Kinlough-Rathbone R L, Packham M A, Mustard F.
Reduced membrane fluidity in platelets from diabetic patients.
Diabetes.
1990;
39
241-244
9
Winocour P D, Watala C, Kinlough-Rathbone R L.
Membrane fluidity is related to the extent of glycation of proteins, but not to alterations in the cholesterol to phospholipids molar ratio in isolated platelet membranes from diabetic and control subjects.
Thrombosis and Haemostasis.
1992;
67
567-571
10
Hirsch M J, Growdon J H, Wurtman R J.
Relations between dietary choline or lecithin intake serum levels, and various metabolic indices.
Metabolism.
1978;
27
953-960
11
Zeisel S H.
Dietary influences on neurotransmission.
Adv Pediatr.
1986;
33
23-48
12
Blusztajn J K, Liscovitch M, Mauron C. et al .
Phosphatidylcholine as a precursor of choline for acetylcholine synthesis.
J Neural Transm Suppl.
1987;
24
247-259
13
Fischer L M, Scearce J A, Mar M-H, Patel J R, Blanchard R T, Macintosh B A, Busby M G, Zeisel S H.
Ad libitum choline intake in healthy individuals meets or exceeds the proposed adequate intake level.
J Nutr.
2005;
135
826-829
14 Institute of Medicine and National Academy of Sciences USA .Dietary Reference Intakes for Folate, Thiamin, Riboflavin, Niacin, Vitamin B12, Panthothenic Acid, Biotin, and Cholin. Washington DC, National Academy Press 1998
15
Yates A A, Schlicker S A, Suitor C W.
Dietary reference intake: the new basis for recommendations for calcium and related nutrients, B vitamins, and choline.
J Am Diet Assoc.
1998;
98
699-706
16 Zeisel S H. Choline: Essential for Brain Development and Function. In: Advances in Pediatrics. Mosby Year Book Europe LTD. 1997 44: 263-295
17
Lombardi B.
Effects of choline deficiency on rat hepatocytes.
Fed Proc.
1971;
30
139-142
18
Da Costa K-A, Cochary E F, Blusztajn J K, Garner S C, Zeisel S H.
Accumulation of 1,2-sn-diradylglycerol with increased membrane-associated protein kinase C may be the mechanism for spontaneous hepatocarcinogenesis in choline deficient rats.
J Biol Chem.
1993;
268
2100-2105
19
Michael U F, Cookson S L, Chavez R, Pardo V.
Renal function in the choline deficient rat.
Proc Soc Exp Biol Med.
1975;
150
672-676
20
Caniggia A.
Effect of choline on hemopoiesis.
Haematologica.
1950;
34
625-627
21
Chang C H, Jensen L S.
Inefficacy of carnitine as a substitute for choline for normal reproduction in japanese quail.
Poult Sci.
1975;
54
1718-1720
22
Blusztajn J K, Wurtman R.
Choline and cholinergic neurons.
Science.
1983;
221
614-620
23
Wurtman R J.
Nutrients affecting brain composition and behavior.
Integr Psychiatry.
1987;
5
226-257
24
Blusztajn J K, Holbrook P G, Lakher M, Liscovitch M, Maire J C, Mauron C, Richardson U I, Tacconi M, Wurtman R J.
“Autocannibalism” of membrane choline-phospholipids: physiology and pathology.
Psychopharmacol Bull.
1986;
22
781-786
25
Zeisel S H, Da Costa K-A, Franklin P D, Alexander E A, Lamont J T, Sheard N F, Beiser A.
Choline, an essential nutrient for humans.
FASEB J.
1991;
5
2093-2098
26
Schlemmer H-P, Möckel R, Marcus A, Hentschel F, Göpel C, Becker G, Köpke J, Gückel F, Schmidt M H, Georgi M.
Proton magnetic resonance spectroscopy in acute, juvenile anorexia nervosa.
Psychiatry Research Neuroimaging.
1998;
82
171-179
27
Möckel R, Schlemmer H-P, Gückel F, Göpel C, Becker G, Köpke J, Hentschel F, Schmidt M H, Georgi M.
1 H-MR-Spektroskopie bei Anorexia nervosa: Reversible zerebrale Metabolitenveränderungen.
Fortschritte Röntgenstrahlen.
1999;
170
371-377
28 Wöckel L, Schweinhardt P, Bertsch T, Kühl S, Koch S, Komorowski G v., Wiegand G, Schweer D, Fassbender K, Schmidt M H. The influence of cholesterol and phospholipid-content on membrane fluidity in the CNS of starved rats. New York: 9th International Conference of the AED Abstractband 2000: S: 46
29
Da Costa K-A, Gaffney C E, Fischer L M, Zeisel S H.
Choline deficiency in mice and humans is associated with increased plasma homocysteine concentration after a methionine load.
Am J Clin Nutr.
2005;
81
440-444
30
Frieling H, Römer K, Röschke B, Bönsch D, Wilhelm J, Fiszer R, de Zwaan M, Jacoby G E, Kornhuber J, Bleich S.
Homocysteine plasma levels are elevated in females with anorexia nervosa.
J Neural Transm.
2005;
112
979-985
31
Moyano D, Vilaseca M A, Artuch R, Valls C, Lambruschini N.
Plasma total-homocysteine in anorexia nervosa.
Eur J Clin Nutr.
1998;
52
172-175
32
Bleich S, Bandelow B, Javaheripour K, Müller A, Degner D, Wilhelm J, Havemann-Reinecke U, Sperling W, Rüther E, Kornhuber J.
Hyperhomocysteinemia as a new risk factor for brain shrinkage in patients with alcoholism.
Neurosci Lett.
2003;
335
179-182
33
Bleich S, Carl M, Bayerlein K, Reulbach U, Biermann T, Hillemacher T, Bönisch D, Kornhuber J.
Evidence of elevated homocysteine levels in alcoholism. The Franconian Alcoholism Research Studies (FARS).
Alcohol Clin Exp Res.
2005;
29
334-336
34
Bottiglieri T, Laundy M, Crellin R, Toone B K, Carney M W, Reynolds E H.
Homocysteine, folate, methylation, and monoamine metabolism in depression.
J Neurol Neurosurg Psychiatry.
2000;
69
228-232
35
Homocysteine Studies Collaboration .
Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis.
JAMA.
2002;
288
2015-2022
36
Seshadri S, Beiser A, Selhub J, Jacques P F, Rosenberg I H, D’Agostino R B, Wilson P W, Wolf P A.
Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease.
N Engl J Med.
2002;
346
476-483
37
Olthof M R, Brink E J, Katan M B, Verhoef P.
Choline supplemented as phosphatidylcholine decreases fasting and postmethionine-loading plasma homocysteine concentrations in healthy men.
Am J Clin Nutr.
2005;
82
111-117
38
Olthof M R, Vliet T van, Verhoef P, Zock P L, Katan M B.
Effect of homocystein-lowering nutrients on blood lipids: results from randomised placebo-controlled studies in healthy humans.
PloS Medicine.
2005;
2
446-456
39
Aperia A, Broberger O, Fohlin L.
Renal function in anorexia nervosa.
Acta Paediatr Scand.
1978;
67
219-224
40
Beumont P V, Russell J D, Touyz S W.
Treatment of anorexia nervosa.
The Lancet.
1993;
341
1635-1640
41
Brotman A W, Rigotti N, Herzog D B.
Medical complications of eating disorders: outpatient evaluation and management.
Comprehensive Psychiatry.
1985;
26
258-272
42
Evrard F, Pinto da Cunha M, Lambert M, Devuyst O.
Impaired osmoregulation in anorexia nervosa: a case-control study.
Nephrol Dial Transplant.
2004;
19
3034-3039
43
Fichter M M, Pirke K M.
Metabolic changes in anorexia nervosa and their diagnostic relevance.
Nervenarzt.
1982;
53
635-643
44
Herpertz-Dahlmann B, Remschmidt H.
Haematologic changes associated with weight loss in anorexia nervosa.
Monatsschrift Kinderheilkunde.
1988;
136
739-744
45
Kennedy A, Kohn M, Lammi A, Clarke S.
Iron status and haematological changes in adolescent female inpatients with anorexia nervosa.
J Paediatr Child Health.
2004;
40
430-432
46
Lambert M, Hubert C, Depresseux G, Vande Berg B, Thissen J-P, Deuxchaisnes C N, Devogelaer J-P.
Hematological changes in anorexia nervosa are correlated with total body fat mass depletion.
Int J Eat Disord.
1997;
21
329-334
47
Miller K K, Grinspoon S K, Ciampa J, Hier J, Herzog D, Klibanski A.
Medical findings in outpatients with anorexia nervosa.
Archives of Internal Medicine.
2005;
165
561-566
48
Rock C L, Curran-Celentano J.
Nutritional disorder of anorexia nervosa: a review.
Int J Eat Disord.
1994;
15
187-203
49
Silverman J A.
Anorexia nervosa. Clinical and metabolic observations.
Int J Eat Disord.
1983;
2
159-166
50
Turner M SJ, Shapiro C M.
The biochemistry of anorexia nervosa.
Int J Eat Disord.
1992;
12
179-193
51
Warren M P, Vande Wiele R L.
Clinical and metabolic features of anorexia nervosa.
American Journal of Obstetrics and Gynecology.
1973;
117
435-449
52
Wöckel L, Bertsch T, Koch S, Gretz N, Poustka F, Schmidt M H.
The influence of choline reduced and choline enriched diet on serum parameters and membrane fluidity in the CNS. 10th Annual Meeting of the EDRS, Amsterdam.
Abstractband.
2004;
10
165
53 Wöckel L, Bertsch T, Koch S, Gretz N, Poustka F, Schmidt M H. Cholin - Ein mögliches Supplement in der Behandlung der Anorexie?. Heidelberg: 29. Kongress der DGKJP, Abstractband 2005: S: 250
54
McCay C, Crowell M, Maynard L.
The effect of retarded growth upon length of life and upon ulimate size.
J Nutr.
1935;
10
63-69
55
Göpel C, Schmidt M H, Klein M.
Are they starving their brains away? Cerebral changes in acute anorexia nervosa - approach by an animal model. 8th New York International Conference on Eating Disorders.
Abstractband.
1998;
8
24
56
Thabrew M I.
Liver microsomal membrane lipid composition in marasmic-kwashiorkor.
Life Sciences.
1983;
32
671-675
57
Cazzola R, Rondanelli M, Russo-Volpe S, Ferrari E, Cestaro B.
Decreased membrane fluidity and altered susceptibility to peroxidation and lipid composition in overweight and obese female erythrocytes.
J Lipid Res.
2004;
45
1846-1851
58
Žák A, Vecka M, Tvrzická E, Hrubý M, Novák F, Papežová H, Lubanda H, Veselá L, Staňková B.
Composition of plasma fatty acids and non-cholesterol sterols in anorexia nervosa.
Physiol Res.
2005;
54
443-451
59
Da Costa K-A, Badea M, Fischer L M, Zeisel S H.
Elevated serum creatine phosphokinase in choline-deficient humans: mechanistic studies in C2C12 mouse myoblasts.
Am J Clin Nutr.
2004;
80
163-170
60
Wurtman R J, Hirsch M J, Growdon J.
Lecithin consumption raises serum-free-choline levels.
Lancet.
1977;
2
68-69
61
Wurtman R J, Regan M, Ulus I, Yu L.
Effect of oral CDP-choline on plasma choline and uridine levels in humans.
Biochemical Pharmacology.
2000;
60
989-992
62
López G, Coviella I, Agut J, Ortiz A, Wurtman R J.
Effects of orally administered cytidine 5’-diphosphate choline on brain phospholipid content.
J Nutr Biochem.
1992;
3
313-315
63
Buchman A L, Dubin M, Jenden D. et al .
Lecithin increases plasma free choline and decreases hepatic steatosis in long-term TPN patients.
Gastroenterology.
1992;
102
1363-1370
64
Sheard N F, Tyak J A, Bistrian B R. et al .
Plasma choline concentrations in humans fed parenterally.
Am J Clin Nutr.
1986;
43
219-224
65
Buchman A L, Dubin M, Moukarzel A A. et al .
Choline deficiency: a cause of hepatic steatosis during parenteral nutrition that can be reversed with intravenous choline supplementation.
Hepatology.
1995;
22
1399-1403
66
Yao Z, Vance D E.
Head group specifity in the requirement of phosphatidylcholine biosynthesis for very low density lipoprotein secretion from cultured hepatocytes.
J Biol Chem.
1989;
264
11 373-11 380
67
Goshal A K, Ahluwalia M, Farber E.
The rapid induction of liver cell death in rats fed a choline-deficiency methionine-low diet.
Am J Physiol.
1983;
113
309-314
68
Di Pascoli L, Lion A, Milazzo D, Caregaro L.
Acute liver damage in anorexia nervosa.
Int J Eat Disord.
2004;
36
114-117
69
Yaryura-Tobias J A, Pinto A, Neziroglu F.
Anorexia nervosa, diabetes mellitus, brain atrophy and fatty liver.
Int J Eat Disord.
2001;
30
350-353
70
Furuta S, Ozawa Y, Maejima K, Tashiro H, Kitahora T, Hasegawa K, Kuroda S, Ikuta N.
Anorexia nervosa with severe liver dysfunction and subsequent critical complications.
Internal Medicine.
1999;
38
575-579
71
Buchman A L, Ament M E, Sohel M, Dubin M, Jenden D J, Roch M, Pownall H, Farley W, Awal M, Ahn C.
Choline deficiency causes reversible hepatic abnormalities in patients receiving parenteral nutrition: proof of a human choline requirement: a placebo-controlled trial.
J of Parenteral and Enteral Nutrition.
2001;
25
260-268
72
Dodson W L, Sachan D S.
Choline supplementation reduces urinary carnitine excretion in humans.
Am J Clin Nutr.
1996;
63
904-910
73
Case T, Lemieux S, Kennedy S H, Lewis G F.
Elevated plasma lipids in patients with binge eating disorders are found only in those who are anorectic.
Int J Eat Disord.
1999;
25
187-193
74
Mira M, Steward P M, Vizzard J, Abraham S.
Biochemical abnormalities in anorexia nervosa and bulimia.
Annals of Clinical Biochemistry.
1987;
24
29-35
75
Umeki S.
Biochemical abnormalities of the serum in anorexia nervosa.
The Journal of Nervous and Mental Disease.
1988;
176
503-506
76
Weinbrenner T, Züger M, Jacoby G E, Herpertz S, Liedtke R, Sudhop T, Gouni-Berthold I, Axelson M, Berthold H K.
Lipoprotein metabolism in patients with anorexia nervosa: a case-control study investigating the mechanisms leading to hypercholesterolaemia.
British Journal of Nutrition.
2004;
91
959-969
77
Marcus A, Blanz B, Lehmkuhl G, Rothenberger A, Eisert H-G.
Somatische Befunde bei Kindern und Jugendlichen mit Anorexia nervosa.
Acta Paedopsychiatrica.
1989;
52
1-11
78
Mickley D, Greenfeld D, Quinlan D M, Roloff P, Zwas F.
Abnormal liver enzymes in outpatients with eating disorders.
Int J Eat Disord.
1996;
20
325-329
79
Milner M R, McAnarney E R, Klish W J.
Metabolic abnormalities in adolescent patients with anorexia nervosa.
Journal of Adolescent Health Care.
1985;
6
191-195
80
Ozawa Y, Shimizu T, Shishiba Y.
Elevation of serum aminotransferase as a sign of multiorgan-disorders in severely emaciated anorexia nervosa.
Internal Medicine.
1998;
37
32-39
81
Rivera-Nieves J, Kozaiwa K, Rees Parrish C, Iezzoni J, Berg C L.
Marked transaminase elevation in anorexia nervosa.
Digestive Diseases and Sciences.
2000;
45
1959-1963
82
Nova E, Lopez-Vidriero I, Varela P, Toro O, Casas J, Marcos A.
Indicators of nutritional status in restricting-type anorexia nervosa patients: 1-year follow-up study.
Clinical Nutrition.
2004;
23
1353-1359
83
Feillet F, Feillet-Coudray C, Bard J-M, Parra H-J, Favre E, Kabuth B, Fruchart J-C, Vidailhet M.
Plasma cholesterol and endogenous cholesterol synthesis during refeeding in anorexia nervosa.
Clinica Chimica Acta.
2000;
294
45-56
84
Gower B A, Weinsier R L, Jordan J M, Hunter G R, Desmond R.
Effects of weight loss on changes in insulin sensitivity and lipid concentrations in premenopausal African American and white women.
Am J Clin Nutr.
2002;
76
923-927
85
Phinney S D, Tang A B, Waggoner C R, Tezanos-Pinto R G, Davis P A.
The transient hypercholesterolemia of major weight loss.
Am J Clin Nutr.
1991;
53
1404-1410
86
Lewis G F, Ralevski E, Neitzert C S, Uffelman K D, Steiner G, Kennedy S H.
Lipids and lipoproteins in anorexia nervosa before and after partial weight restoration.
Endocrinology and Metabolism Clinics of North America.
1994;
1
109-115
87
Halmi K A, Fry M.
Serum lipids in anorexia nervosa.
Biological Psychiatry.
1974;
8
159-167
88
Swenne I.
The significance of routine laboratory analyses in the assessment of teenage girls with eating disorders and weight loss.
Eating and Weight Disorders.
2004;
9
269-278
89
Halmi K A, Falk J R.
Common physiological changes in anorexia nervosa.
Int J Eat Disord.
1981;
1
16-27
90
Marinella M A.
Refeeding syndrome.
Am J Phys Med Rehabil.
2004;
83
65-68
91
Castro J, Deulofeu R, Gila A, Puig J, Toro J.
Persistence of nutritional deficiences after short-term weight recovery in adolescents with anorexia nervosa.
The International Journal of Eating Disorders.
2004;
35
169-178
92
Ogata E S, Foung S KH, Holliday M A.
The effects of starvation and refeeding on muscle protein synthesis and catabolism in the young rat.
J Nutr.
1978;
108
759-765
93
Herzog W, Deter H-C, Fiehn W, Petzold E.
Medical findings and predictors of long-term physical outcome in anorexia nervosa: a prospective, 12-year follow-up study.
Psychological Medicine.
1997;
27
269-279
94
Deter H-C, Schellberg D, Köpp W, Friedrich H C, Herzog W.
Predictability of a favorable outcome in anorexia nervosa.
European Psychiatry.
2005;
20
165-172
95
Zeisel S H, Mar M-H, Howe J C, Holden J M.
Concentrations of choline-containing compounds and betaine in common foods.
J Nutr.
2003;
133
1302-1307
Dr. Lars Wöckel
Klinik für Psychiatrie und Psychotherapie des Kindes- und Jugendalters der Universitätsklinik Frankfurt/Main
Deutschordenstr. 50
60528 Frankfurt/Main
eMail: woeckel@em.uni-frankfurt.de