Chronic Liver Disease Cerebral Abnormalities in Patients With Cirrhosis Detected by Proton Magnetic Resonance Spectroscopy and Magnetic Resonance Imaging ANGELA GEISSLER, 1 GUNTRAM LOCK, 2 RU ¨ DIGER FRU ¨ ND, 1 PAUL HELD, 1 STEPHAN HOLLERBACH, 2 TILO ANDUS, 2 JU ¨ RGEN SCHO ¨ LMERICH, 2 STEFAN FEUERBACH, 1 AND AXEL HOLSTEGE 2 functions, thereby defining subclinical hepatic encephalopa- Hepatic encephalopathy is a common problem in cir- thy. 1 Neuropsychiatric testing is biased by education, intelli- rhosis. The pathogenesis of this complication of ad- gence, compliance, age, and learning effects. 2 Because early vanced liver disease still remains unclear. Magnetic res- diagnosis and treatment of subclinical hepatic encephalopa- onance spectroscopy was used to assess prospectively thy have been suggested to be critical for the preservation of cerebral metabolism in 51 patients with histologically cerebral function, 3 efforts have been made to apply other, proven cirrhosis (Child-Pugh classes A, B, and C, 18, 18, more objective and reliable methods in the diagnosis of he- and 15, respectively) and 36 healthy volunteers. Ac- patic encephalopathy. cording to the results of psychometric tests, overt he- Using proton magnetic resonance spectroscopy (MRS), typ- patic encephalopathy, subclinical encephalopathy, and ical cerebral metabolite patterns have been found in clinical no encephalopathy were found in 14, 21, and 16 patients, or subclinical hepatic encephalopathy. 2,4 The predominant respectively. Myoinositol/creatine ratios in gray (.36 { findings are a decreased myoinositol/creatine (Myo/Cr) ratio, 4 .17) and white (.35 { .22) matter voxel were reduced sig- decreased of choline/creatine (Cho/Cr) ratio, 4 and increased nificantly (P õ .0001) in cirrhotic patients compared glutamine/glutamate/creatine (Glx/Cr) ratio 4,5 in the brain. with healthy volunteers (gray matter, .51 { .11; white Alterations of cerebral metabolism measured by MRS re- matter, .64 { .16). In addition, patients showed a signifi- turned to normal in most patients after liver transplanta- cant reduction (P Å .024) in white matter choline/cre- tion, 6-8 demonstrating that they are related to liver disease. atine ratio (.77 { .27) compared with controls (.92 { .25), In magnetic resonance imaging (MRI), the presence of and glutamine/glutamate level was elevated in cirrhotic signal hyperintense basal ganglia in T1-weighted images ap- patients compared with controls (gray matter, P õ .0001; pears closely related to severe liver disease with both portal- white matter, P Å .036). Changes in cerebral myoinositol systemic shunting 9 and hepatic encephalopathy. 10-14 How- and glutamine/glutamate levels correlated significantly ever, the latter finding has been questioned recently. 15 with the severity of hepatic encephalopathy (P õ .0001). Pomier Layrargues et al. 16 and Krieger et al. 17 have demon- However, these metabolic alterations were also detected strated recently that the concentration of manganese, a para- in patients without hepatic encephalopathy (normal magnetic substance, is elevated in bright basal ganglia. psychometric test results). N-acetyl aspartate/creatine The aim of the present study was to evaluate prospectively ratios did not differ between patients and controls. Mag- cerebral metabolism and morphological abnormalities in 51 netic resonance imaging detected bright basal ganglia in clinically well-defined patients with histologically proven cir- 37 patients, which correlated significantly with portal- rhosis with or without signs of hepatic encephalopathy using systemic shunting and elevation of glutamine/gluta- MRS and MRI. mate, but not with the degree of hepatic encephalopa- thy. In conclusion, magnetic resonance imaging and PATIENTS AND METHODS spectroscopy showed that alterations of cerebral metab- olism are common in patients with cirrhosis, even with- Patients and Volunteers. Fifty-one patients with proven cirrho- out evidence of clinical or subclinical hepatic encepha- sis, 35 male and 16 female, aged 51 { 11 years (mean { SD) and 53 lopathy. (HEPATOLOGY 1997; 25:48-54.) { 12 years, respectively, were prospectively included in the study. Patients with neurological disorders, diabetes mellitus, or renal fail- ure were not enrolled in this study. Thirty-five patients had alcoholic cirrhosis, 8 patients had posthepatitic cirrhosis, and 3 had hemochro- In patients with cirrhosis, hepatic encephalopathy is a com- matosis; the other 5 had cirrhosis caused by Wilson’s disease (n Å mon complication. Although the clinical diagnosis of severe 2), primary biliary cirrhosis (n Å 2), and portal malformation (n Å portal-systemic encephalopathy is easily made, minor neuro- 1). Severity of liver disease was staged according to the Child-Pugh psychiatric alterations are difficult to detect. Psychometric classification: 18 patients were classified as having Child A disease, tests have been used to detect subtle neuropsychiatric dys- 18 as Child B, and 15 as Child C. In each patient a thorough clinical examination, psychometric testing, MRI, and MRS were performed within 24 hours. Gastroscopy was performed in all but two patients to assess the presence of esophageal varices. All patients were exam- Abbreviations: MRS, magnetic resonance spectroscopy; Myo/Cr, myoinositol/creatine; ined by abdominal ultrasound. Cho/Cr, choline/creatine; Glx/Cr, glutamine/glutamate/creatine; MRI, magnetic resonance Thirty-six healthy volunteers (21 male, 15 female; aged 37 { 16 imaging; TR, repetition time; TE, echo time; NAA/Cr, N-acetyl aspartate/creatine. years and 39 { 17 years, respectively) served as controls. From the Departments of 1 Radiology and 2 Internal Medicine I, University of Regensburg, Informed consent was obtained from all patients and volunteers. Regensburg, Germany. This study is in agreement with the 1975 Declaration of Helsinki. Received February 12, 1996; accepted September 25, 1996. This article is dedicated to Prof. Wolfgang Gerok, on the occasion of his 70th birthday. Methods Address reprint requests to: Angela Geissler, M.D., Department of Radiology, University of Regensburg, 93042 Regensburg, Germany. Clinical and Laboratory Evaluations. All patients were examined Copyright  1997 by the American Association for the Study of Liver Diseases. 0270-9139/97/2501-0009$3.00/0 using a standardized protocol including patient history, clinical ex- 48 AID Hepa 0027 / 5P1B$$$521 12-16-96 18:05:39 hpta WBS: Hepatology