ORIGINAL PAPERS

Co-occurrence of Gilbert's

syndrome and psychosisA. S. Mahdi and M. S. Elameer

Idiopathic unconjugated hyperbilirubinaemia (Gilbert's

syndrome) ¡sa common benign disorder that, whenseen in association with psychiatric illnesses, oftenleads to the inappropriate withholding of psychotropicmedication. We describe three cases with Gilbert'ssyndrome and psychosis in which diagnosis of Gilbert's

syndrome was delayed. This led to unnecessaryinvestigations, further relapses and increasedadmissions to hospital. We emphasise the need forpsychiatrists to be more aware of this benign condition.

Hereditary gluconosyl transferase deficiency(Gilbert's syndrome) was originally reported byGilbert & Lereboullet (1901). Since then therehas been increasing recognition of this benignchronic disorder. It is relatively common, theincidence in the general population being reported as about 3-7% (Blanckaert & Fevery,1990), and mainly affects males between 20 and40 years of age (Taylor, 1984).

It is characterised by mild persistent unconjugated hyperbilirubinaemia, the patient oftenbeing unaware of the condition until it isdetected by physical examination or routinelaboratory testing. Patients with Gilbert's syndrome are found to have partial deficiency ofgluconosyl transferase, which is important forremoval of bilirubin by the liver through conjugation with glucotonic acid. This deficiencycauses an increase in the level of unconjugatedbilirubin (indirect) in comparison with conjugated (direct) bilirubin. The jaundice can fluctuate and may exacerbate following prolongedfasting, fever, infection, excess exertion oralcohol ingestion.

Diagnosis is mainly by exclusion, but shouldbe suspected in a patient with:

(a) total serum bilirubin in the range 21-51/miol/l (1.2-3mg/dl) rarely exceeding86/zmol/l (5mg/dl) and mostly of theunconjugated type (found following prolonged fasting or calorie depletion,300cal/day for two days);

(b) no systemic symptoms:(c) no overt or clinically recognised haemo

lysis;(d) normal test of routine liver function.

Diagnosis is confirmed by reduced calorie intakeor nicotinic acid provocation or bilirubin analysiswith thin layer Chromatographie methods(Davidson et al, 1975; Seig et al, 1986).Gilbert's syndrome was reported in one case ofmanic-like psychosis and in another case ofbipolar affective disorder (Loyd et al, 1982;Cohen & Cohen. 1992). Durst et al (1993)described four cases of Gilbert's syndrome andconcurrent psychiatric illnesses (schizoid personality disorder, endogenous depression andtwo cases of paranoid psychosis) where administration of psychotropic medication was undertaken and produced no adverse effects onhepatic function. They emphasised that psycho-tropic medication should be used wheneverneeded. Muller et al (1991) studied the bilirubinplasma concentration of 892 patients withpsychiatric illness and found that 11% hadraised levels. The levels were significantly higherin patients with schizophrenia (25.4%) than inthose with other diagnoses (6.1-9.3%). Theyindicated that their findings were independentof drug usage and suggested a relationshipbetween hyperbilirubinaemia and psychosis.Some hypotheses for the relationship were apossible genetic disposition for Gilbert's syndrome, increased vulnerability of red cell membranes or the role of oestrogen in schizophrenia.

We describe the clinical presentation of threepsychiatric patients with Gilbert's syndrome,and the difficulties in their management thatresulted.

Case number 1Mr R.J. is a 37-year-old male with a history ofschizotypal personality disorder. He has hadseveral admissions to hospital, resulting fromhis withdrawn, uncommunicative and depressedbehaviour and self-neglect. He was first found tohave hyperbilirubinaemia (see Table 1) while hewas being treated with 70 mg lofepramine twicedaily. He was referred to a consultant physicianfor a second opinion, where various investigations were done, including abdominal ultrasound, hepatitis screen, alpha antitrypsinlevel, serum copper and caeruloplasmin. It was

566 Psychiatric Bulletin (1998). 22, 566-568

ORIGINAL PAPERS

concluded that he was suffering from liverdamage secondary to antldepressant medication,and we were advised not to prescribe anyantidepressants or drugs from the phenothiazinegroup. Avery clear notification was placed on thefront of his case notes advising that psychotro-pics should be avoided due to multiple allergy.

He was almost medication free for nearly fouryears, during which he was admitted three timesand treated unsuccessfully with electroconvul-sive therapy. His serum bilirubin remainedelevated even when he was off medication. Itwas felt that a small dose of flupenthixolinjection 20 mg every two weeks might bebeneficial. It was noticed that there was nofurther evidence of liver damage while he wason such medication. Unfortunately, the patientand his parents were reluctant to continue onmedication, worrying that he was sensitive todrugs. On his last admission he presented withodd beliefs and behaviour and a history ofdiscontinuation of his medication three monthspreviously. The question of using psychotropicmedication was raised again by the nursing staffin view of the notification in his case notes. Hewas again referred to the consultant physicianwho confirmed Gilbert's syndrome after measurement of total serum bilirubin before andafter 24-hour fasting. The patient and parentswere reassured about the benign nature ofGilbert's syndrome and the safety of the use ofpsychotropic medication. He was prescribedtrifluoperazine 5mg twice daily and he showeda very good response.

Case number 2Mr L.D. is a 26-year-old male diagnosed withparanoid schizophrenia at the age of 22, when hewas prescribed 50 mg chlorpromazine threetimes daily. At follow-up he was noticed to bejaundiced and liver function tests showed totalserum bilirubin 42/<mol/l direct less than14//mol/l (Table 1). Referral to a consultantphysician resulted in a suggested diagnosis ofGilbert's syndrome and a recommendation thatneuroleptic medication should be kept low andalternative psychiatric therapy used if possible.Chlorpromazine medication was discontinued

Table 1. Liver function tests

and the patient showed a deterioration in hismental condition. He was referred again to agastroenterologist who confirmed a diagnosis ofGilbert's syndrome and reassured us about theuse of psychotropic medication. Medication wasrestarted and the patient and his father reassured that the condition was benign and medication safe and necessary.

Case number 3Miss N.D. is a 30-year-old female who wasdiagnosed as having bipolar affective disorderat the age of 23. At that time she showed a goodresponse to haloperidol 5mg daily, but after afew weeks of treatment she was noticed to havemild jaundice which was associated with diarrhoea, nausea and vomiting. Liver function testsshowed high serum bilirubin, total serum bilirubin 23/imol/l, direct less than 11/imol/1(Table 1) and because of this her medicationwas stopped. After a few months she wasadmitted to hospital with a relapse of hercondition when she presented with delusionsand hypomanic features. She was prescribedchlorpromazine 25 mg four times daily. Herroutine blood test showed that the serumbilirubin was shown to be raised. Other liverfunction tests were normal. She was referred tothe consultant physician who suggested a diagnosis of Gilbert's syndrome and again this wasconfirmed by estimation of total serum bilirubinbefore and after 24-hour fasting. Taking theadvice of the consultant physician, neurolepticswere prescribed whenever needed.

CommentAll three patients described in our study werediagnosed as having Gilbert's syndrome, mainlyby estimation of total serum bilirubin before andafter 24-hour fasting and persistent high level ofindirect type bilirubin, while other liver functiontests were normal.The failure to diagnose Gilbert's syndrome at anearly stage led to our patients having unnecessaryand expensive investigations and inappropriatewithdrawal of medication. The use of psycho-tropic medication is necessary in most cases of

Casenumber123Normal

levels'Bilirubin

(total)(/imol/l)2742232-17Bilirubindirect(¿imol/l)<11<14<110-10Alenineaminotransferase(u/l)2217190-40ALK(u/l)1151448590-280GT(u/l)8121911-50Urea(mmol/l)5.62.73.21.7-6.0Creatinin(/¿mol/l)94855653-115

l. Normal level values from Biochemistry Laboratories at West Wales General Hospital (further details available fromthe author upon request).

Co-occurrence of Gilbert's syndrome and psychosis 567

ORIGINAL PAPERS

psychosis and unnecessary discontinuation inour cases led to relapses and further difficultiesin management. Reintroduction of psychotropicmedication decreased the incidences of relapsesand confirmed the safety of neuroleptics inGilbert's syndrome as suggested by others(Cohen & Cohen, 1992: Durst et al. 1993).

Psychiatric illnesses are regarded as complexdisorders: disorders which show evidence of geneeffect but do not show clear Mendelian patternsof inheritance. Comorbidity of such illneses withother genetic disorders might be of help inunderstanding their psychopathology. A hypothetical explanation for the higher incidenceof hyperbilirubinaemia and schizophrenia, geneticpredisposition, was emphasised by Muller et cd(1991). Further reporting of similar cases to thepresent study may emphasise the significantcomorbidity of Gilbert's syndrome and mentaldisorder which will need further clarification.

ReferencesDAVIDSON,A. R., ROJAS-BEUNO.A.. THOMPSON.R. P. H., et cd

(1975) Reduced caloric intake of nicotinlc acidprovocation tests in the diagnosis of Gilbert'ssyndrome. Brilish Medical Journal, ii. 480.

BLANCKAERT.N. & FEVERY.J. (1990) Physiology and patho-physiology of bilirubin metabolism. In Hepatology: ATextbook ojLiver Disease (eds T. Zakim & T. D. Boyer),pp. 254-285. Philadelphia. PA: W. B. Saunders.

COHEN. L. S. & COHEN. D. E. (1992) Lithium inducedhyperbilimbinaemia in an adolescent. Journal ofClinical Psychopharmacology. 11. 274-275.

DURST.R.. JAUTINSKY-RUBIN.K.. DOREViTCH.A., et al (1993)Idiopathic unconjugated hyperbilirubinaemia (Gilbert'ssyndrome) and concurrent psychotropic drugadministration. P/iarmacopsycnialry. 26. 49-52.

GILBERT.A. & LEREBOULLET.P. (1901) La cholemie simplefamiliale. Semaine Médicale.2l. 241-245.

LoYD.D. W..TSUANG. M. T. & BENGE.J. W. (1982) A study ofa family with Leopard syndrome. Journal of ClinicalPsychiatry. 43. 113-116.

MULLER.N.. SCHILLER.P. & ACKENHEIL.M. (1991) Coincidence of schizophrenia and hyperbilirubinaemia.Pharmacopsychiafry. 24. 225-228.

SEIG. A.. STICH, A.. RAEDSCH.R.. et al (1986) Gilbert'ssyndrome: diagnosis by typical serum bilirubin pattern.Clinical Chimica Acta. 154, 41-48.

TAYLOR. S. (1984) Gilbert's syndrome as a cause ofpostoperative jaundice. Anaesthesia. 39. 1222-1224.

*A. S. Mahdi, Senior House Officer in Psychiatry,and M. S. Elameer, Consultant Psychiatrist, StDavid's Hospital. Carmarthen. Carmarthenshire.SA31 3HB

'Correspondence

Butterflies, fractals and psychiatrySteven Reid

In this paper concepts related to the field of non-lineardynamics and chaos theory are discussed, and theirrelevance to psychiatry is considered.

'In all chaos there is a cosmos, in all disorder a secretorder' (Jung. 1954)

For many, chaos theory is a new branch ofscience that appears to involve 'the butterflyeffect' and 'fractals', but which is little understood and has no obvious relevance to psychiatry. The purpose of this paper is to unravela number of unfamiliar concepts, and describesome of the influences this emergent mathematical theory has had upon medicine and morespecifically, psychiatry.

Previously the application of basic sciences toclinical medicine has relied upon linear, deterministic processes which were relatively easilyunderstood and predictable. Classical determinism as propounded by Laplace, viewed theuniverse as a gigantic, intricate clockworkmachine in which all events were predictableand the magnitude of any evoked response wasproportionate to the size of its stimulus.However, there are physical systems which areseemingly non-linear and highly unpredictablesuch as turbulence in liquids (e.g. blood flowin the heart) and cerebral electrical activity. Inthese situations small changes can result inlarge and unanticipated effects. Since the 1960s,scientists from a variety of backgrounds havebeen attempting to provide models for this

568 Psychiatric Bulletin (1998). 22. 568-570