Resolved Psychosis after Liver Transplantation in a Patient with Wilson’s Disease

Orazio Sorbello 1, *, Daniela Riccio 1, Margherita Sini 1, Mauro Carta 2, Luigi Demelia 1
1 Reparto di Gastroenterologia Azienda Ospedaliero Universitaria , Cagliari, Italy
2 Clinica Psichiatrica, Università di Cagliari, Italy

Article Metrics

CrossRef Citations:
Total Statistics:

Full-Text HTML Views: 1031
Abstract HTML Views: 851
PDF Downloads: 230
Total Views/Downloads: 2112
Unique Statistics:

Full-Text HTML Views: 546
Abstract HTML Views: 518
PDF Downloads: 166
Total Views/Downloads: 1230

© Sorbello et al.; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

* Address correspondence to this author at the SS 554 bivio per Sestu Azienda Ospedaliero –Universitaria Cagliari Department of Gastroenterology 09130 Cagliari, Italy; Tel: +39- 070-51096100; Fax: 070 51096100; E-mail:


A psychiatric involvement is frequently present in Wilson’s disease. Psychiatric symptoms are sometimes the first and only manifestation of Wilson’s disease. More often a psychiatric involvement is present beside a neurologic or hepatic disease.

We describe the case of a 18 years-old male patient who shows a clinic and laboratoristic pattern of cirrhosis and an history of subchronic hallucinatory psychosis, behavioral symptoms and mood disturbances with depressed mood. He hadn’t familiar history of liver or psychiatric disease. Laboratory and imaging tests confirmed the diagnosis of Wilson’s disease with psichiatric involvement. After liver transplantation copper metabolism and liver function normalised and we noticed no recurrency of the psichiatric illness. Very few cases of psychiatric improvement after orthotopic liver transplantation (OLT) has been described until now.

Keywords: Copper metabolism, genetic liver disease, OLT, psychosis, psychiatric illness, Wilson’s disease.


Wilson’s disease (WD), or hepatolenticular degeneration [1], is an autosomal recessive disorder caused by the mutation of the ATPase7B gene [2]. The role of the ATPase7B is the ATP-dependent escretion of copper into the biliary system [3]. The effect of copper accumulation in the liver leads to acute liver failure, chronic hepatitis or liver cirrhosis [4], while the overload of copper can generate both neurological and psychiatric involvement [5].

Accumulation of copper in the cytoplasm of hepatocytes results in cellular necrosis and leakage of copper into the plasma. The excess copper then collects in extrahepatic tissues, including the basal ganglia and the limbus of the cornea. ATP7B transports copper into the secretory pathway of the cell for incorporation into the cuproenzymes and excretion from the cell. An increase in the intracellular copper level causes ATP7B to move to a cytoplasmic vesicular compartment. As the copper is concentrated into vesicles for excretion from the cell, the cytosolic copper concentration decreases, and ATP7B returns to the trans-Golgi network. The movement of ATP7B appears to involve amino acid sequences in its carboxyl terminus. The copper concentration is higher in brains of people with Wilson disease than in other people or animals with diseases of copper overload. Wilson himself referred to a “mental change”, whose “importance should not be understimate” [1]. From 30% to 100% of symptomatic patients with WD suffer from psychiatric symptoms. From 10% to 20% of patients present psychiatric disorders from 1 to 5 years before the diagnosis of WD and one third of this patients receive psychiatric treatment, including hospitalization [6]. The most frequent psychiatric symptoms in WD are personality changes such as irritability and low threshold to anger, depression sometimes leading to suicidal ideation and attempts, deteriorating academic and work performance that is present in almost all neurologically affected patients [7]. Anxiety, behavioral abnormalities, cognitive impairment have also been described [8]. Psychiatric symptoms in WD usually showed a limited response to neuroleptic medication or other psychiatric drugs [9]. In other cases psychiatric symptoms improved after penicillamine treatment [5, 10, 11]. The improvement was noticed after 1 or 2 years of treatment [5]. Few cases of psychiatric WD who underwent OLT have been described: in one case behavioural and personality disorders were completely unaffected after transplantation [20]. We describe the case of a 18-year-old patient with complete normalization of copper and ceruloplasmine levels and efficacy of OLT on psychiatric abnormalities.


A 18-year-old boy was referred to Our Institute in February, 1992. Few months before he suffered from severe asthenia, fever (38-39° C), vomiting, diarrhea and pain referred to right hypochondrium. Examination showed gynaecomastia, pitting oedema and hepatosplenomegaly.

During hospitalization he had hallucination and phoneme. No neurological deficit was noted.

Laboratory investigations showed platelets 45.000/mm3, aspartate aminotransferase (AST) 106 IU/L, alanine aminotransferase (ALT) 107 IU/L, γ-glutamyl-tranferase (GGT) 131 IU/L, International Normalised Ratio 1.4, PChE 2165 U/l. Hepatitis virus serology, TORCH, Monotest, Widal-Wright, Weil-Felix, Tine test, alpha1-antitrypsin assay and autoimmunity tests were negative. Serum ceruloplasmin level was 16 mg/dl, serum copper concentration 45 mcg/dl, urinary copper concentration/24 h after 600 mg of D-penicillamine [12] 303 mcg/24h.

Ultrasound scanning showed a cirrhotic liver with diffusely disomogeneous ultrasonografic structure, splenomegaly with omogeneous ultrasound structure.

EGDS revealed oesophageal varices (F3).

Liver biopsy detected architectural abnormalities with chronic hepatitis with high grading and bridging fibrosis; the staging was III-IV sec. Desmet [13]. Liver copper content was 255 mcg/g dry weight.

The values of the copper balance and liver biopsy were diagnostic of Wilson’s disease.

A psychiatric consultation was arranged and was found a Psychotic Disorder Due To Wilson’s Disease (American Psychiatric Association. DSM IV TR ed.APA Washington DC 1994). The clinical picture presented auditory, somatic and formed visual allucinations (as “zoopsias”) and persecutory delusions. Insomnia, asthenia, anorexia, depressed mood and social isolation were associated.

In order to evaluate the involvement of the CNS the patient underwent slit lamp examination, that was negative for the presence of Kayser-Fleisher’s ring. Magnetic resonance imaging (MRI) brain scan was normal. The clinical picture, results of laboratory examination and liver copper content however suggested Wilson’s disease.

The patient reached endstage liver disease and required a transplant; therefore d-penicillamine treatment was not attempted.


The patient underwent OLT in July 1993 (“S.Giovanni Battista” Hospital, Torino) and after operation we observed a sudden improvement of liver function and copper escretion. Laboratory investigations demonstrated platelets 284.000/mm3, aspartate aminotransferase (AST) 27 U.I./l, alanine aminotransferase (ALT) 21 U.I./l, International Normalised Ratio 1.3 INR, PChE 8660 U/l. Serum ceruloplasmin level rised to 39 mg/dl, serum copper concentration 89.47 mcg/dl, basal urinary copper (17.4 μg/24 h); only urinary copper concentration/24 h after challenge of D-penicillamine was still high (360 mcg/24h) Moreover the transplant resolved any psychiatric disfunction. We observe this regression until now, twelve years after the transplantion.

After the operation MRI brain scan was still normal and Kayser-Fleisher’s ring was absent again. Evoked potentials (somatosensory, visual and brainstem auditory EPs: SEP, VEP, BAEP) proved normal.

Finally, in february 2009, 99mTc-ECD-SPECT (single photon emission tomography) revealed an abnormal distribution of the drug in the brain, with deficient perfusion of left temporal lobe and normal perfusion in the basal ganglia.


Wilson’s disease is a genetic disorder due to the mutation of the ATPase7B, that represents the sole mechanism of copper excretion. Mutated ATPase7B fails the incorporation of copper in ceruloplasmin that results in the decrease of the holoceruloplasmine synthesis with low ceruloplasmin serum level in affected patients. Progressive copper accumulation in the liver causes an oxidative damage that leads to acute or chronic hepatitis, asymptomatic cirrhosis or acute liver failure [14]. In young adults neuropsychiatric symptoms predominate and are associated, in 90% of cases, with Kayser-Fleisher’s ring [15].

Psychiatric symptoms are often the first and unique manifestation of the disease, particularly in adolescents and young-adults; this can bring to futile psychiatric treatments [16] and delay the diagnosis from 1 to 5 years [4].

More frequently psychiatric disease is associated with hepatic and/or neurologic involvement.

The most frequent psychiatric symptom is depression [7]. Depression seems to be correlated with alterations of serotoninergic trasmission in the thalamus-hypotalami and midbrain-pons region, in particular with low density of the presynaptic serotonin transporter (SERT) [5]. This alterations could be related also with psychotic symptoms; in fact it is well known that in schizophrenic psychosis there is an alteration of serotoninergic transmission [17].

Emotional lability, lack of appropriate emotions, personality changes, increased or reduced sexual interest, cognitive impairment, schizofrenia, nervous anorexia [18] and catatonia [19] have also been described [4].

Our patient suffered from severe liver disease (cirrhosis Child Pugh B7) with severe psichiatric involvement. The patient didn’t suffer from neurologic symptoms; neurological examination and MRI brain scan were normal.

The treatment of WD consist of copper-chelating agents such as penicillamine [20]. Zinc sulphate or acetate inhibit intestinal copper absorption and had produced succesfull results in patient with neurologic disease [21]. Zinc sulphate therapy is more indicate than penicillamine therapy because penicillamine can determine a massive dismission of copper into circulation with acute worsening of clinic conditions.

On the other hand it is not yet clear which is the best therapy in patients with psychiatric involvement. In such cases penicillamine or zinc sulphate has been usefull for psychiatric symptoms [22], without any employment of neuroleptic medications [4]. In other cases psychiatric drugs determined a decline of psychiatric situation [23].

In this case the patient didn’t assume any medical therapy because he presented the indication for a sudden liver tranplantation for decompensated cirrhosis accompanying the psychiatric illness. The sole risolutive therapy for WD is liver transplantation that normalises liver function and correct the metabolic defect of copper escretion [24].

After transplantation we observed the normalisation of liver function, of copper metabolism and of psychiatric symptoms. Only urinary copper concentration/24h after penicillamine challenge was elevated. We suppose high value of urinary copper escretion indicate a persistent copper overload in extrahepatic tissues. In considering high postoperative urinary copper leves, we suggest not to discontinuate medical therapy after OLT.

In the post-operative the patient underwent again brain MRI, ECD-SPECT and evoked potentials (EPs) for neurological evaluation. MRI brain scan and EPs were normal, while the SPECT showed an asimmetric distribution of the drug. Several studies demonstrate that ECD-SPECT is the most sensitive neuroimagine procedure in the monitoring of the disease, also in patients without neurological symptoms. In one study there was a particular frequency (86%) of diffused or focal decrease of ECD uptake [25]. Also in our patient we observed a deficit of perfusion in the left temporal lobe, though MRI and EPs were normal.

In the late postoperative (twelve years after the operation) liver functional values were stil normal and no more psychiatric abnormalities were observed.

As an hypothesys, we suppose that our patient didn’t have relapses because he underwent liver trasplant in an early fase of the psychiatric disease: infact MRI before the transplant showed normal images. Unfortunately in 1994 we didn’t dispose of the SPECT. If confirmed in other studies this hypothesis could suggest the importance of early treatment.

Literature offers scarse and discordant data regarding the curative effects of OLT under psychiatric aspects. It has been described both the curative effect of the transplant on neuropsichiatric symptoms [26] and the severe worsening of psychiatric illness [27]. In conclusion from our study emerge some prospectives of resolution also of psychiatric disease accompained by late-postoperative persistent improvement, especially in case of early treatment.


[1] Wilson SAK. Progessive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver Brain 1912; 34: 295-507.
[2] Terada K, Schilsky ML, Miura N, Sugiyama T. ATP7B (WND) protein Int J Biochem Cell Biol 1998; 30(10): 1063-7.
[3] Petrukhin K, Lutsenko S, Chernov I, Ross BM, Kaplan JH, Gilliam TC. Characterization of the Wilson disease gene encoding a P-type copper transporting ATPase: genomic organization, alternative splicing, and structure/function predictions Hum Mol Genet 1994; 3(9): 1647-56.
[4] Gill HH, Shankaran K, Desai HG. Wilson's disease: varied hepatic presentations Indian J Gastroenterol 1994; 13(3): 95-8.
[5] Loudianos G, Gitlin JD. Wilson’s Disease Semin Liver Dis 2000; 20(3): 353-64.
[6] Akil M, Brewer GJ. Psychiatric and behavioral abnormalities in Wilson's disease Adv Neurol 1995; 65: 171-8.
[7] Eggers B, Hermann W, Barthel H, Sabri O, Wagner A, Hesse S. The degree of depression in Hamilton rating scale is correlated with the density of presynaptic serotonin transporters in 23 patients with Wilson's disease J Neurol 2003; 250(5): 576-80.
[8] Rathbun JK. Neuropsychological aspects of Wilson’s disease Int J Neurosci 1996; 85(3-4): 221-9.
[9] Walter G, Lyndon B. Depression in hepatolenticular degeneration (Wilson’s disease) Aust N Z J Psychiatry 1997; 31(6): 880-2.
[10] McDonald LV, Lake CR. Psychosis in an adolescent patient with Wilson's disease: effects of chelation therapy Psychosom Med 1995; 57(2): 202-4.
[11] Keller R, Bergamasco B. Psychiatric symptoms as late onset of Wilson’s disease: neurological findings, clinical features and treatment Ital Neurol Sci 1999; 20(1): 49-54.
[12] Demelia L, Curreli N, Murru A. Diagnostic value of 24/ hr urinary copper exctrection after penicillamine challenge in the adult Wilson’s disease patients Hepatology 2004; 40: 570A.
[13] Desmet VJ, Gerber MA, Hoofnagle JH, Manns M, Scheuer PJ. Classification of chronic hepatitis: diagnosis, grading and staging Hepatology 1994; 19: 1513-20.
[14] Gill HH, Shankaran K, Desai HG. Wilson's disease: varied hepatic presentations Indian J Gastroenterol 1994; 13(3): 95-8.
[15] Steinl P, Ferenci P, Dienes HP, et al. Wilson’s disease in patients presenting with liver disease: a diagnostic challenge Gastroenterology 1997; 113: 212-8.
[16] Stiller P, Kassubek J, Schönfeldt-Lecuona C, Connemann BJ. Wilson’s disease in Psychiatric patients, Letters to the Editor Psychiatr and Clin Neurosci 2002; 56: 649.
[17] Lyne J, Kelly BD, O’Connor WT. Schizophrenia: a review of neurofarmacology Ir J Med Sci 2004; 173(3): 155-9.
[18] Gwirtsman HE, Prager J, Henkin R. Case report of anorexia nervosa associated with Wilson's disease Int J Eat Disord 1993; 13(2): 241-4.
[19] Davis EJ, Borde M. Wilson's disease and catatonia Br J Psychiatry 1993; 162: 256-9.
[20] Walshe JM. Penicillamine, a new oral therapy for Wilson’s disease Am J Med 1956; 21: 487-95.
[21] Huang CC, Chu NS. Wilson’s disease:resolution of MRI lesions following long term zinc therapy Acta Neurol Scand 1996; 93: 215-18.
[22] Walter G, Lyndon B. Depression in hepatolenticular degeneration (Wilson’s disease) Aust N Z J Psychiatry 1997; 31(6): 880-2.
[23] Keller R. Psychiatric symptoms as late onset of Wilson’s disease: neuroradiologocal findings, clinical features and treatment Ital J Neurol Sci 1999; 20(1): 49-54.
[24] DuBois RS, Giles G, Rodgerson DO, et al. Orthotopic liver transplantation for Wilson’s disease Lancet 1971; 1: 505-8.
[25] Giagheddu M, Tamburini G, Piga M, et al. Comparison of MRI, EEG, EPs and ECD-SPECT in Wilson's disease Acta Neurol Scand 2001; 103(2): 71-81.
[26] Schilsky ML, Scheinberg IH, Sternlieb I. Liver transplantation for Wilson's disease: indications and outcome Hepatology 1994; 19(3): 583-7.
[27] Kassam N, Witt N, Kneteman N, Bain VG. Liver transplantation for neuropsychiatric Wilson disease Can J Gastroenterol 1998; 12(1): 65-8.