1. Abstract Associations between psychiatric symptoms in patients with celiac disease have been described in the literature. We report the case of a schizophrenic patient initially suspected of Wilson disease that was diagnosed with celiac disease in our hepatology unit.
Keywords: Optical hallucinations; Gastrointestinal; Neuropathies
2. Introduction Celiac disease (CD) is an immune-mediated systemic disorder characterized by chronic inflammation induced by gluten in the small intestine, affecting about 1% of the world’s population [1]. Clinical manifestations are heterogeneous, with gastrointestinal symptoms being only one sign of a systemic disease. More than half of adult patients present with prominent non-classical extra-intestinal symptoms, such as dermatitis, high levels of aminotransferases, neuropathies and psychiatric disorders [1-5]. Symptoms can be variable and untypical, with gastrointestinal manifestations missing, making the diagnosis challenging and delaying necessary treatment, in particular if confounding factors divert diagnostic attention. This paper presents a case of a schizophrenic patient initially misdiagnosed as Wilson’s disease that was diagnosed with celiac disease in the hepatology unit.
3. Results The patient was a 19-year-old male, presenting with a variety of symptoms of known paranoid schizophrenia, including imperative voice hearing and optical hallucinations, despite ongoing pharmacological treatment. The patient had been jailed for several months for murder of a relative. Routine diagnostic testing in the context of initial manifestation of psychiatric symptoms had revealed increased transaminases (ALAT 530 U/L, ALAT 191 U/L). Further assessment showed low ceruloplasmin (0,11 g/l) and increased urine copper excretion in a primary sample (431 ug/24h). The patient was thus referred to our hepatology outpatient clinic for further evaluation of Wilson disease. At the time of presentation in our clinic, the patient’s predominant clinical signs were apathy, slowed thinking, partial memory loss, aboulia, and dysthymia. He had no signs of ataxia, dysarthria, or tremor. No current or past gastrointestinal symptoms or weight loss were reported. Family history with regards to autoimmune diseases was unsuspicious. BMI was within reference range. No Kayser-Fleischer ring was present. Medication included quetiapine and paliperidone. Clozapine and Olanzapine had been stopped several weeks before presentation. Patient characteristics are summarized in (Table 1). Laboratory testing revealed only slightly elevated transaminases compared to earlier results (AST 57 U/L, ALT 89 U/L), cholestatic parameters and liver function (INR, albumin) were normal (Table 2).
4. Discussion Our case describes a difficult diagnosis of celiac disease due to complex clinical presentations. Initial transaminase elevations led to further evaluation of liver disease. Abnormalities in copper tests with decreased serum copper and ceruloplasmin and increased urinary copper excretion was suggestive of Wilson’s disease. Only differential testing for other liver diseases led to the diagnosis of celiac disease. The patient did not show any typical manifestations of celiac disease, in particular no gastrointestinal symptoms or signs of malnutrition, apart from significant psychic disturbances. With this kind of atypical presentation, schizophrenia may be the only manifestation of the underlying disease, highlighting the variable clinical features of a systemic disease. Psychiatric symptoms in patients with celiac disease have been described in the literature [5]. In particular, associations between celiac disease and schizophrenia have been suggested in since the 1950s [9,10]. Case reports and epidemiological studies indicate a role of celiac disease in the pathogenesis of schizophrenia [11,12]. An interplay between genetic and environmental factors has been assumed, with a possible involvement of the gut-brain axis, triggered by autoimmunity and inflammation [13,14]. Epidemiological data from Taiwan and Denmark suggest an increased risk of schizophrenia in patients with celiac disease, while Swedish data found an association between celiac disease and non-schizophrenic psychosis [3,15-19]. Retrospective data from the United States found higher titers of anti-gliadin antibodies and ATA in schizophrenic patients than in the normal population, though the differences were not clinically significant [20]. Several reports of clinical improvements of schizophrenia after onset of a gluten free diet have been published, though knowledge regarding its effect and latency time to detect it remain limited [21,22]. Some reports indicate clinical improvements in non-schizophrenia neuropsychiatric symptoms after several months [12]. Observational studies of a gluten free diet on schizophrenic patients without confirmed celiac disease have given mixed results [23]. There is still insufficient data on patients with concomitant celiac disease [24]. One study has shown that decreasing levels of ATA were associated with improvement of cognitive assessment tests in patients with celiac disease [25].
Reference 1. Fasano A, Catassi C. Celiac Disease. N Engl J Med. 2012; 367(25): 2419-26.
2. Campagna G, Pesce M, Tatangelo R, Rizzuto A, La Fratta I, Grilli A. The progression ofcoeliac disease: Its neurological and psychiatric implications. Bd. 30, Nutrition Research Reviews. Cambridge University Press; 2017. S. 25-35.
3. Wijarnpreecha K, Jaruvongvanich V, Cheungpasitporn W, Ungprasert P. Associationbetween celiac disease and schizophrenia: A meta-Analysis. Eur J Gastroenterol Hepatol. 2018; 30(4): 442-6.
4. Jackson JR, Eaton WW, Cascella NG, Fasano A, Kelly DL. Neurologic and psychiatricmanifestations of celiac disease and gluten sensitivity. Psychiatr Q. 2012; 83(1): 91-102.
5. Clappison E, Hadjivassiliou M, Zis P. Psychiatric manifestations of coeliac disease, a systematic review and meta-analysis. Nutrients. 2020; 12(1): 10-5.
6. Hopper AD, Hadjivassiliou M, Hurlstone DP, Lobo AJ, McAlindon ME, Egner W, et al. What Is the Role of Serologic Testing in Celiac Disease? A Prospective, Biopsy- Confirmed Study with Economic Analysis. Clin Gastroenterol Hepatol. 2008; 6(3): 314-20.
7. Lebwohl B, Murray JA, Rubio-Tapia A, Green PHR, Ludvigsson JF. Predictors of persistent villous atrophy in coeliac disease: A population-based study. Aliment Pharmacol Ther. 2014; 39(5): 488- 95.
8. Rubio-Tapia A, Rahim MW, See JA, Lahr BD, Wu TT, Murray JA. Mucosal recovery andmortality in adults with celiac disease after treatment with a gluten-free diet. Am J Gastroenterol. 2010; 105(6): 1412-20.
9. Dohan FC. Coeliac disease and schizophrenia. Bd. 295, The Lancet. 1970; 1: 897-8.
10. Bender L. Childhood schizophrenia. Psychiatr Q. 1953; 27(1): 663- 81.
11. Kalaydjian AE, Eaton W, Cascella N, Fasano A. The gluten connection: The associationbetween schizophrenia and celiac disease. Acta Psychiatr Scand. 2006; 113(2): 82-90.
12. Oliveira-Maia AJ, Andrade I, Barahona-Corrêa JB. Case of coeliac disease presenting inthe psychiatry ward. BMJ Case Rep. 2016; 2016: bcr2016216825.
13. Severance EG, Yolken RH, Eaton WW. Autoimmune diseases, gastrointestinal disorders and the microbiome in schizophrenia: more than a gut feeling. Bd. 176,Schizophrenia Research. 2016; 176: 23- 35.
14. Jungerius BJ, Bakker SC, Monsuur AJ, Sinke RJ, Kahn RS, Wijmenga C. Is MYO9B themissing link between schizophrenia and celiac disease? Am J Med Genet Part B Neuropsychiatr Genet. 2008; 147(3): 351-5.
15. Eaton WW, Mortensen PB, Agerbo E, Byrne M, Mors O, Ewald H. Coeliac disease and schizophrenia: Population based case control study with linkage of Danish national registers. Br Med J. 2004; 328(7437): 438-9.
16. Chen SJ, Chao YL, Chen CY, Chang CM, Wu ECH, Wu CS, et al. Prevalence of autoimmune diseases in in-patients with schizophrenia: Nationwide population-basedstudy. Br J Psychiatry. 2012; 200(5): 374-80.
17. Ludvigsson JF, Osby U, Ekbom A, Montgomery SM. Coeliac disease and risk of schizophrenia and other psychosis:Ageneral population cohort study. Scand JGastroenterol. 2007; 42(2): 179-85.
18. Benros ME, Nielsen PR, Nordentoft M, Eaton WW, Dalton SO, Mortensen PB. Autoimmune diseases and severe infections as risk factors for schizophrenia: A 30-year population-based register study. Am J Psychiatry [Internet]. Dezember. 2011; 168(12): 1303-10.
19. Eaton WW, Byrne M, Ewald H, Mors O, Chen CY, Agerbo E, et al. Association of schizophrenia and autoimmune diseases: Linkage of Danish national registers. Am JPsychiatry. 2006; 163(3): 521-8.
20. Cascella NG, Kryszak D, Bhatti B, Gregory P, Kelly DL, Mc Evoy JP, et al. Prevalence of celiac disease and gluten sensitivity in the United States clinical antipsychotic trials ofintervention effectiveness study population. Schizophr Bull. 2011; 37(1): 94-100.
Nasser Semmo. Schizophrenic Patient with Drug Induced Liver Injury Initially Misdiagnosed as Wilson’s Disease with Final Diagnosis of Celiac Disease. Annals of Clinical and Medical Case Reports 2021