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Similar Autonomic Nervous SystemDisorders Underlying CysticFibrosis and Pancreatic CystsAllowed CommonNeuropharmacological Therapy:Report of Four CasesFuad Lechin, MD, PhD*†‡

Bertha van der Dijs, MD*†§

Beatriz Orozco, MD†

Gerardo Hernandez-Adrian, MD†

Simon Rodríguez, MD†

Scarlet Baez, MD‡§

Departments of *Neurophysiology, †Neuropharmacology, ‡Neuroimmunology, and§Neurochemistry, Faculty of Medicine, Universidad Central de Venezuela, Caracas, Venezuela

ropharmacological therapy addressed toenhance central noradrenergic activitywas carried out by the administration ofdoxepin (noradrenaline uptakeinhibitor). Our findings are consistentwith the postulation that both syn-dromes share a common pathophysio-logical disorder, acinar secretoryoverflow, which overwhelms the pancre-atic duct drainage. Although we haveassessed and treated several patientswith these pathologies, we refer only tothese four well investigated, treated,and followed-up patients.

INTRODUCTIONOur neurochemistry laboratory investi-gated some 25,000 normal and diseasedsubjects. Circulating neurotransmittersnoradrenaline (NA), adrenaline (Ad),dopamine (DA), plasma free serotonin

KEY WO R D S : cystic fibrosis,pancreatic cy s t , central noradrenergica c t i v i t y

ABSTRACTWe discuss two cases of patients affectedby pancreatic cysts and two patientsaffected by cystic fibrosis showing simi-lar neuroautonomic profile, high adrenalsympathetic activity plus low neuralsympathetic activity, who were signifi-cantly improved with neuropharmaco-logical manipulations addressed toreverse this profile. Clinical, radiological,and neurochemical assessment showedprogressive and sustained improvementthroughout more than two years for thecystic fibrosis cases and lasted more thanfour years for the pancreatic cyst casesin the follow up of both trials. The neu-

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(f-5HT), platelet serotonin (p-5HT),tryptophan (TRP), and immunologicalparameters are routinely assessed beforeand after neuropharmacological manip-ulations1,2 and several stress tests, such asthe supine resting plus orthostasis plusexercise.3 The fact that patients affectedby cystic fibrosis and pancreatic cystspresented with several common neu-roautonomic disorders led us to go farand in-depth search for common neu-ropharmacological therapeuticapproaches. Although we have assessedmany such patients, we will refer only tothese four well investigated, treated, andfollowed patients (two with cystic fibro-sis and two with pancreatic cysts).

CASE REPORTSCase 1F.D. is a six-year-old girl who was diag-nosed as having cystic fibrosis. Hergenotype was delta-F 508/delta-F 508.She received pancreatic enzymes to con-trol her diarrhea. She came to ourInstitute on January 10, 2003. We investi-gated her exocrine pancreatic functionthroughout the secretin and starch toler-ance tests,4 confirming absolute pancre-atic insufficiency. The autonomicnervous system (ANS) investigationshowed absolute adrenal over neuralsympathetic predominance (NA/Adratio = 1.3; normal ≥ 5). Althoughplatelet serotonin (p-5HT) was elevated(813 ng/mL; 275 ± 20), free serotonin inthe plasma (f-5HT) was found to be nor-mal (2.36 ng/mL; normal ≤ 5).Tryptophane (TRP) plasma value wassignificantly reduced (5,140 ng/mL; nor-mal = 9,000-11,000 ng/mL). In addition,a deficit in respiratory function wasrevealed by the low FEV1 value (63% ofthe predicted value). Immunologicalinvestigation showed positive anti-pan-creatic (++) and antinuclear antibodies(+). All immunoglobulins were raised.Doxepin, propantheline, and clonidinewere administered to this patient and

the drug doses were adjusted to her age.Significant clinical, ANS, and immuno-logical improvements were obtainedafter the first four-week period and con-tinue up to the present (February 2005).The noradrenaline to adrenaline ratio(NA/Ad) and p-5HT returned to normalvalues; as did plasma TRP value. Anti-pancreatic and antinuclear antibodieswere not detected at the fourth four-week period. By December 2004, thepatient had grown 5.3 cm and gained 6.9kg. She continues taking pancreaticenzymes as well as her treatment.

Case 2M . M . C. is a 5-year-old boy who was diag-nosed as having cystic fibrosis in Ju l y2 0 0 2 . At his first visit to our Institute onJanuary 2, 2 0 0 4 , his height was 1.05 mand he weighed 16.6 kg. His genotypewas delta-F 508/delta-F 508. He tookpancreatic enzymes plus calcium. L a c t o s etolerance test and starch tolerance werepositive (+). ANS investigation showedadrenal over neural sympathetic predom-inance (NA/Ad = 0.9). Although both p-5HT and f-5HT were significantly raised(824.4 ng/mL and 21.2 ng/mL, r e s p e c t i v e-l y ) , tryptophan plasma values were mod-erately lowered (7,005 ng/mL).Immunological investigation showed pos-itive (+) anti-pancreatic antibodies andantigliadin IgA and IgG positive (+ inboth parameters).This patient receivedsimilar treatment to F. D. S i g n i f i c a n tincreases in body weight and height wererecorded at each of the 12 following four-week periods. His body weight increasedfrom 16.6 kg to 25.3 kg and his heightgrew from 1.07 m to 1.15 m. C i r c u l a t i n gneurotransmitters assessed at the lastvisit (February 2005) showed significantreductions of f-5HT (down to 6.2 ng/mL);at the same time, levels of p-5HTdecreased steeply (308.4 ng/mL). A sig-nificant increase of the previously lowNA/Ad ratio was observed, from 0.9 to5.4 (at orthostasis).

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Case 3A.T.B. is a 44 year-old-woman with threechildren. She visited us on June 4, 1998,with a pancreatic cyst of 4.5 cm diameterlocated between the head and the bodyof the pancreas (Figure 1). It was diag-nosed through endoscopic retrogradecholangiopancreatography (ERCP) andlaparotomy. Secretin and starch toler-ance tests were normal. ANS investiga-tion showed absolute adrenal overneural sympathetic predominance(NA/Ad ratio < 2). Both p-5HT and f-5HT values were greatly increased(923.2 ng/mL and 26.4 ng/mL, respec-tively). Plasma TRP was found very low(3,420 ng/mL). This patient received theabove-mentioned neuropharmacologicaltherapy from June 98 until the present

(February 2005), interrupted by frequenttwo-week holiday breaks. The patientremains asymptomatic and her pancreat-ic cyst is almost totally reduced (Figure1). The last p-5HT and f-5HT valueswere 316.5 and 4.6 ng/mL, respectively.

Case 4G.R.Y is a 25-year-old woman with twochildren who visited our institute on July10, 2001. She presented with a large pan-creatic cysts diagnosed by ERCP andecho. The ANS investigation revealedabsolute adrenal over neural sympathet-ic predominance (NA/Ad ratio = 1.5).Both p-5HT and f-5HT showed raisedvalues. Plasma TRP was normal.Neuroautonomic and clinical improve-ments were obtained through neu-

Figure 1. Pancreatic cyst before (A) and after (B) two years of pharmacological therapy.Significant reduction (60%-70%) was obtained. Pancreatic cyst before (C) and after (D) sevenmonths of neuropharmacological therapy: Significant reduction (50%-60%) was obtained.

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ropharmacological therapy. The cyst wasgreatly reduced (50%-60%, Figure 1).The p-5HT value dropped from 963.3 to345.4, whereas f-5HT fell from 97.4 to1.5 ng/mL. NA/Ad ratio at orthostasisrose from 0.9 to 5.4.

DISCUSSIONFour patients affected by pancreatic dis-ease, two through cystic fibrosis and twowith pancreatic cysts, presented adrenalover neural sympathetic predominancealong with raised levels of circulatingplatelet serotonin (p-5HT). This findingobliges us to consider that these diseasesshare some common pathophysiologicalmechanisms. This inference is reinforcedby the finding that both clinical andANS improvements are triggered bysimilar neuropharmacological manipula-tion addressed to reverting the Ad overNA predominance. The raised circulat-ing serotonin level found in these twotypes of pancreatic disease strongly sug-gests that enterochromaffin-cell overac-tivity is present in all.5 Further, the factthat platelet serotonin (p-5HT) was low-ered in both types of patients after clini-cal improvement, suggest that theenterochromaffin cell overactivity wasnormalized. Both the physiologic disor-ders and their clinical symptoms are cor-related with adrenal over neuralsympathetic predominance periods.6-8

This phenomenon may be associatedwith the maximal ability of the neuralsympathetic system to annul parasympa-thetic drive which is responsible forenterochromaffin cell secretion.5

Circulating serotonin arises from ente-rochromaffin cells that release 5-HT inresponse to parasympathetic drive.5Although most 5-HT is secreted into theintestinal lumen, some fraction reachesportal circulation. Serotonin that escapesto liver and lungs uptakes is trapped byplatelets.7 However, some fraction ofserotonin always remains free in theplasma (f-5HT). The normal f-5HT/p-

5HT circulating ratio is about 0.5% to1%. This ratio increases during bothplatelet aggregation9 and during anydeficit of platelet uptake.10 Plateletuptake is interfered with by both circu-lating acetylcholine10 and circulatingDA.11 The former occurs during exces-sive parasympathetic drive. The increaseof f-5HT registered in these circum-stances may be exacerbated becauseindolamine excites 5-HT3 and 5-HT4receptors located at the medullary areapostrema (outside the blood brain barri-er), which is connected to the motorvagal complex.12 This fact results in afurther increase of the peripheralparasympathetic drive discharge overthe enterochromaffin cells (Bezold-Harisch reflex). In addition, consideringthe excitatory role played by theparasympathetic system over pancreaticexocrine secretion, it is possible tounderstand the beneficial effect of neu-ropharmacological manipulationsaddressed to bridling the parasympa-thetic drive through enhancement ofneural sympathetic activity. According tothe above, it may be postulated thatpancreatic cyst formation will be favoredby factors that overwhelm the pancreat-ic duct drainage capacity by excessiveacinar cell secretion.

Several ANS and hormonal factorsare involved in pancreatic exocrinesecretion. Sympathetic nerves terminateon intrapancreatic blood vessels.13 Inaddition, inhibition of exocrine secretionmay occur in the absence of vasculareffects (alpha-receptor blockade), sug-gesting that the catecholamines may actdirectly on the secretory cells.14

Noradrenergic fibers terminate on intra-pancreatic ganglia whose stimulationabolishes vagal-induced secretion, byacting at alpha-2 adrenoceptors.13,14

These findings are supported by thecapacity of neural sympathetic enhance-ment to antagonize the hyper-parasym-

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drenaline, cortisol, growth hormone and pro-lactin plasma levels in low and high intestinaltone subjects. Neuroendocrinology.1985;40:253-261.

3. Lechin F, van der Dijs B, Orozco B, et al.Plasma neurotransmitters, blood pressure andheart during supine-resting, orthostasis andmoderate exercise in severely ill patients: Amodel of failing to cope with stress.Psychother Psychosom. 1996;65:129-136.

4. Lechin F. The Starch Tolerance Test. In:Bockus HL, ed. Gastroenterology. Volume 2.2nd ed. Philadelphia: WB Saunders;1964:chap 56.

5. Tobe T, Izumikawa F, Sano M, et al. Releasemechanisms of 5-HT in mammalian gastroin-testinal trac—especially vagal release of 5-HT. In: Fujita T, ed. Endocrine Gut-Pancreas.Amsterdam: Elsevier; 1976:371-390.

6. Robertson D, Goldberg MR, Onrot J, et al.Isolated failure of autonomic noradrenergicneurotransmission. New Engl J Med.1986;5:1494-1497.

7. Robinson RL, Culberson JL, Carmichael SW,et al. Selective CNS control of epinephrineand norepinephrine release by the adrenalmedulla. Fed Proc. 1977;36:381-387.

8. Lechin F, van der Dijs B, Lechin ME.Depression. In: Lechin F, van der Dijs B,Lechin ME, eds. Neurocircuitry andNeuroautonomic Disorders. Reviews andTherapeutic Strategies. Basel: Karger; 2002:23-27.

9. Larsson PT, Hjemdahl P, Olsson G, et al.Altered platelet function during mental stressand adrenaline infusion in humans: evidencefor an increased aggregability in vivo asmeasured by filtragometry. Clin Sci.1989;76:369-376.

10. Rausch JL, Janowsky SC, Risch SC, et al.Physostigmine effects on serotonin uptake inhuman blood platelets. Eur J Pharmacol.1985;109:91-96.

11. De Keyser J, De Waele M, Convents A, et al.Identification of D1-like dopamine receptorson human blood platelets. Life Sci.1988;42:1797-1806.

12. Reynolds DJM, Leslie RA, Grahame-SmithDG, et al. Localization of 5-HT3 receptorbinding sites in human dorsal vagal complex.Eur J Pharmacol. 1987;174:127-130.

13. Alm P, Cegrell L, Ehinger B, et al.Remarkable adrenergic nerves in theexocrine pancreas. Z Zellforsch. 1967;83:178-186.

14. Holst JJ, Schaffalitzky de Muckadell OB,Fahrenkrug J. Nervous control of pancreaticexocrine secretion in pigs. Acta PhysiolScand. 1979;105:33-51.

pathetic-induced hypersecretion under-lying pancreatic cyst formation.13-15

Considering that post-ganglionic alpha-2receptors mediate sympathetic nerveseffect, at this level, we find an explana-tion for the benefits triggered by cloni-dine (an alpha-2 agonist) in bothpancreatic cysts and pancreatitis.16-18 Wealso found that a small dose of intramus-cular injected clonidine is able to stopabruptly pancreatic secretion from theexcretory duct, in experimental dogs.16

This peripheral NA versus parasympa-thetic antagonism is consistent with theinhibitory effects exerted by LC-NAaxons ending at the dorsal motor nucle-us of the vagus located at medullaryarea.19,20

In addition, nicotine receptor antag-onists effectively block the vagal-induced pancreatic secretion. Thisfinding fits well with the beneficialeffects we obtained by the addition ofsmall doses of propantheline, a nicotine-antagonist that does not cross the bloodbrain-barrier.

Not only ANS but also hormonalmechanisms are also involved in pancre-atic exocrine secretion. The release ofboth secretin and CCK-pancreozyminare independent of the ANS influ-ence.18,21-24 However, ANS drives areable to interfere with secretory hormonerelease and/or its effects.18 For instance,alpha-adrenergic influences are able tointerfere with CCK-pancreozymineffects.18,21-24 Thus, we believe that thetherapeutic success we obtained withthis small casuistic has enough scientificsupport to attempt further neurophar-macological approaches for treatment ofthese patients.

REFERENCES1. Lechin F, van der Dijs B, Jara H, et al. Effects

of buspirone on plasma neurotransmitters inhealthy subjects. J Neural Transm.1998;105:561-573.

2. Lechin F, van der Dijs B, Jakubowicz D, et al.Effects of clonidine on blood pressure, nora-

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15. Hong SS, Magee DF. Pharmacological studiesin regulation of pancreatic secretion in pigs.Ann Surg. 1970;172:41-48.

16. Lechin F, Benshimol A, van der Dijs B.Histalog and secretin effects on serum elec-trolytes. Influence of pancreatectomy andgastrectomy. Acta Gastroenterol Latinoamer.1970;2:9-18.

17. Lechin F, van der Dijs B, Lechin ME.Neuropharmacological factors, biliary motili-ty and pancreatitis. JOP. 2002;3:152-154.

18. Lechin F, van der Dijs B, Orozco B.Cholecystokinin (CCK) and secretin and pan-creatic secretion of insulin and glucagon. DigDis Sci. 2002;47:2422-2423.

19. Barlow TE, Greenwell JR, Harper AA, et al.The effect of adrenaline and noradrenalineon the blood flow, electrical conductance andexternal secretion of the pancreas. J Physiol.(Lond) 1971;217:665-678.

20. Lechin F, van der Dijs B, Villa S, et al. Centralnervous system circuitry involved in bloodpressure regulation. In: Lechin F, van der DijsB, eds. Neurochemistry and ClinicalDisorders: Circuitry of some Psychiatric andPsychosomatic Syndromes. Boca Raton: CRCPress; 1989:121-150.

21. Lechin F, van der Dijs B, Orozco B.Gallbladder muscle dysfunction and neuroau-tonomic disorders. Gastroenterology.2002;123:1407-1408.

22. Lechin F. Adrenergic-serotonergic influenceson gallbladder motility and irritable bowelsyndrome. Am J Physiol. (Gastrointest LiverPhysiol) 1992;262:G375-G376.

23. Lechin F, van der Dijs B. Glucose tolerance,non-nutrient drink and gastrointestinal hor-mones. Gastroenterology. 1981;80:216.

24. Lechin F, van der Dijs B, Bentolila A, et al.The adrenergic influences on the gallbladderemptying. Am J Gastroenterol. 1978;69:662-668.

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