GASTROENTEROLOGY 1984;86:1421-7 Nonalcoholic Cirrhosis Associated With Neuropsychological Dysfunction in the Absence of Overt Evidence of Hepatic Encephalopathy RALPH E. TARTER, ANDREA M. HEGEDUS, DAVID H. VAN THIEL, ROBERT R. SCHADE, JUDITH S. GA VALER, and THOMAS E. STARZL Departments of Psychiatry, Medicine, and Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania Although much is known about the neuropsycholog­ Moreover. they have been shown to be better at ical functioning of cirrhotic individuals with Laen­ detecting subtle cerebral pathology than are routine nec's (alcohol associated) cirrhosis, little is known clinical neurological examinations. skull x-rays. and about the neuropsychological functioning of indi­ cerebral angiograms (4), Previous neuropsychologi­ viduals with nonalcoholic cirrhosis. In the present cal investigations that have implicated cerebral dys­ investigation, we have determined that individuals function in patients with cirrhosis have been limited suffering from chronic nonalcoholic cirrhosis, de­ by the fact that they either (a) studied a small spite the absence of clinical signs of hepatic enceph­ number of subjects, (b) tested a limited range of alopathy, are impaired on neuropsychological tests psychological processes, (c) evaluated patients who that measure visuopractic capacity, visual scan­ were receiving medication. or (d) only examined ning. and perceptual-motor speed. In contrast, intel­ patients who had undergone surgical interventions lectual, language, memory, attentional, motor, and or had a history of alcoholism; factors that. in and of learning abilities are intact. In comparison with a themselves. might have been responsible for impair­ chronically ill control group of patients suffering ments that were detected (1.2.5-9). from Crohn's disease, individuals with advanced Inasmuch as emotional stability and neuropsycho­ nonalcoholic cirrhosis exhibit less emotional distur­ logical competency (e.g .. communication ability, bance, but are more impaired in their daily activi­ perceptual-motor coordination. problem-solving ties. These findings indicate that individuals with skills) are basic requirements for successful every­ nonalcoholic cirrhosis, even in the absence of overt day living. a comprehensive neuropsychiatric evalu­ clinical signs of encephalopathy, manifest neuro­ ation. which would increase our understanding of psychological impairments and experience signifi­ the effects of hepatic disease on such functional cant disruption in the routines of everyday living. capacities. would be important in patient manage­ ment decisions. The information accrued from such For the latent or subclinical condition of hepatic testing would be particularly valuable in assisting encephalopathy in particular. neuropsychological the physician making decisions in areas in which the testing procedures (psychometric measures) have vocational. social. and psychiatric aspects of the been found to be more sensitive indicators of the disease might be considered important. disorder than is the electroencephalogram (1-3). Methods Received June 9, 1983. Accepted January 11. 1984. Address requests for reprints to: Ralph E. Tarter, Ph.D., 3811 Subjects O'Hara Street, Pittsburgh, Pennsylvania 15213. Thirty biopsy-confirmed cases of chronic nonalco­ This work was supported in part by grants from the National Institutes of Health (#R01 AM32556-01). the Gastroenterological holic cirrhosis comprised the experimental group. The Medical Research Foundation of Southwestern Pennsylvania, and group consisted of 18 patients with primary biliary cirrho­ the Hunt Foundation. sis and 12 patients with postnecrotic cirrhosis. All mem­ © 1984 by the American Gastroenterological Association bers of the group were inpatients at Presbyterian Universi- 0016-5085/84/53.00 1422 T:\RTER ET AL. GASTROENTEROLOGY 'Vol .16. Nc;. 6 Table 1. Scores of the Nonalcoholic Cirrhosis Subjects on Selected Laboratory Parameters Documenting Liver Disease Nonalcoholic cirrhosis subjects Laboratory test Normal values -x SD Alanine transaminase <37 IUIL 343.60 IU/L 928.07 Asparate transaminase <34 IUIL 218.80 lUlL 598.36 Alkaline phosphatase <100 IUIL 802.36 lUlL 812.82 Bilirubin. total 0.3-1.5 mgldl 10.61 mgldl 10.72 Bilirubin. direct <0.4 mgldl 7.74 mgldl 8.81 Albumin 3.5-5.0 gldl 3.31 gldl 0.63 Globulin 1.3-1.7 gldl 3.25 gldl 0.99 Prothrombin time 10.8-12.8 s 13.23 s 2.40 Indocyanine green serum <0 mglml at 20 min 48.86 mglml 31.34 (level at 20 min") Fasting ammonia level 9.0-41.0/JomlL 38.70/JomlL 14.39 " 0.5 mglkg given i.v. at time zero. ty Hospital in Pittsburgh, Pennsylvania. The group had a The neuropsychological battery was designed to meet mean age and education level of 40.93 (s = 8.60) and 13.73 three criteria: replicability, comprehensiveness. and valid­ (s = 2.53) yr. respectively. None of the patients had a ity. The tests that were selected have been demonstrated history of alcohol or drug abuse. neurological injury or previously to identify impairments in patients with vari­ disease, or psychiatric disorder. In addition, none of the ous form~ of cirrhosis (1,2,5-9). In order to yield a more subjects have had shunt surgery, nor did any of them comprehensive profile of intellectual. attentional. memo­ exhibit overt clinical signs of hepatic encephalopathy. ry. language. learning. perceptual-motor. and spatial pro­ Chronicity of their illness, estimated from the time of the cesses. it also was necessary to extend the range of func­ first diagnosis to the time of this evaluation, was 3.81 yr. tions that had been measured by previous investigations. Table 1 presents the results of the various laboratory The specific tests used to evaluate these neuropsychologi­ parameters that quantify the severity of the hepatic dys­ cal processes are listed in Table 2 in Results. Only tests function present in these subjects. that have been validated to detect cerebral dysfunction A chronic-illness control group consisting of 10 patients were included in the test battery (10.11). suffering from Crohn's disease was studied also. They Administration of the test battery required -2.5 h. In were selected as the comparison group because they had a order to circumvent any possible confounding effects of chronic medical illness, often received the same medica­ fatigue that may affect the test performance. the testing was tions. and were treated by the same physicians as the conducted over two individual 75-min sessions separated patients with cirrhosis. Moreover, this group of subjects by a day of rest. Subjects completed the following three also controls for any nonspecific effects that a chronic questionnaires between the two test days: Minnesota Mul­ illness has on neuropsychiatric functioning. Most of the tiphasic Personality Inventory (MMPIJ,* the Sixteen Per­ patients in the control group, on at least one occassion. sonality Factors Questionnaire (16PF)/ and the Sickness had been treated as an inpatient, but were under medical Impact Profile (SIP). * care on an outpatient basis at the time of the evaluation. The tests were scored according to standardized proce­ Moreover. none of the subjects in the Crohn's disease dures. The neuropsychological battery listed in Table 2 control group had a history or biochemical evidence of contains separate verbal (Peabody Picture Vocabulary liver disease, alcohol or drug abuse. or neurological dis­ Test) and nonverbal (Raven's Progressive Matrices) mea­ ease or had been treated for a psychiatric disorder. They sures of intelligence quotient (lQ). The attention and had a mean age of 39.30 (s = 11.82) yr and an educational concentration test scores indicate the longest sequence of level of 14.90 (s = 2.88) yr. Their mean disease chronicity digits that the person could recall accurately. immediately was 5.29 yr. None of these factors differed from those after their presentation. The mental control score is a present in the liver disease study group. No member of combined index of speed and accuracy in counting back­ either group was taking medications (e.g., steroids, neuro­ wards. reciting the alphabet. and performing serial addi­ leptics) that are known to impair cognitive capacity. tions. An index of nine is the maximum score on this test. The learning and memory tests of the Weschler Memory Scale were scored according to standard procedures for the immediate recall components. and the same" criteria were Procedures and Analyses Once a specific hepatic diagnosis was established • The Minnesota Multiphasic Personality Inventory is a clini­ cally standardized quantitative test of psychopathology and per­ using clinical. biochemical. and serologic data. and con­ sonality disturbance. T The Sixteen Personality Factors Question­ firmed by liver biopsy, the liver disease patients were naire is a standardized quantitative measure of normal personality administered a battery of neuropsychological. psychiatric. functioning across 16 different dimensions. *. The Sickness Impact and psychosocial measures. The neuropsychiatric exami­ Profile is a quantitative and validated health status assessment nation was conducted without the tester's awaren'ess of the scale that measures the percentage of impairment due to an illness medical diagnosis. on behavioral functioning and social adjustment. _ ... _._-_•.. ---------- June 1984 ENCEPHALOPATHY IN NONALCOHOLIC CIRRHOTICS 1423 used for scoring the subject's performance upon delayed Test measures comprehension capacity. The test score recall; Le., 30 min later. The logical