Neuropsychiatric Symptoms in Hepatitis C Patients Resemble Those of Patients With Autoimmune Liver Disease but Are Different From Those in Hepatitis B Patients

Meike Dirks; Kim Haag; Henning Pflugrad; Anita B. Tryc; Ramona Schuppner; Heiner Wedemeyer; Andrej Potthoff; Hans L. Tillmann; Kajetan Sandorski; Hans Worthmann; Xiaoqi Ding; Karin Weissenborn


J Viral Hepat. 2019;26(4):422-431. 

In This Article

Patients and Methods


One-hundred and fifty-four patients registered in the database of the hepatitis outpatient clinic at Hannover Medical School were informed about the study by letter and invited to take part, either by filling in self-report questionnaires about fatigue, mood and health-related quality of life or by attending in addition a comprehensive neurological and neuropsychological assessment. Furthermore, patients who attended the hepatitis outpatient clinic were informed by a leaflet and asked if they were interested to take part in the study. Inclusion criteria were a diagnosis of hepatitis C, hepatitis B, AIH or PBC or an overlap of AIH and PBC. Exclusion criteria were as follows: HBV/HCV co-infection, combination of AIH or PBC and virus hepatitis, other causes of liver disease besides HCV, HBV, AIH or PBC, liver cirrhosis, accompanying neurological or psychiatric diseases or diseases that might affect brain function such as HIV-co-infection, renal dysfunction, alcohol or drug abuse and medication affecting the central nervous system. Finally, 157 patients participated, but 25 had to be excluded from further analysis after a thorough evaluation of their case records because of violation of the exclusion criteria. Of the remaining 132 patients, 88 underwent the whole assessment, while 44 just filled in the self-report questionnaires. Forty-six patients were HCV infected (17 men, 5 PCR-negative), 22 had hepatitis B (14 men, 5 patients PCR-negative), 27 autoimmune hepatitis (6 men), 29 primary biliary cholangitis (4 men) and 8 an overlap syndrome (7 women). Fourteen of the 27 AIH patients were treated with low dose prednisolone (2.5-10 mg), 24 patients had azathioprine medication either as monotherapy or in addition to prednisolone. Low dose immunosuppressive therapy with prednisolone, budesonide and/or azathioprine was also used in 5 of the 29 PBC patients and 5 of 8 AIH/PBC overlap patients. Liver cirrhosis was excluded by clinical examination, ultrasound and laboratory parameters including liver enzyme levels, platelet count, INR and Fib4 score (Table 1).[14] In addition, liver biopsy results were available for 85 patients and showed none or only slight fibrosis. Patient data were compared to those of 33 healthy controls (11 men) adjusted for age and education (Table 1). The control subjects were recruited from hospital and university staff as well as friends and relatives.

All subjects gave written informed consent. The study was a priori approved by the Hannover Medical School ethics committee and performed according to the World Medical Association Declaration of Helsinki (revised in 2008).

Neurological and Neuropsychological Assessment

The patients who underwent the whole assessment (n = 88) were seen by an experienced neurologist for a neurological examination and neuropsychological testing that focused on memory and attention. The test battery comprised the subtests alertness, working memory, flexible reaction, intermodal comparison, go/no go and divided attention of the test battery for the assessment of attention (TAP) by Zimmermann and Fimm,[15] the cancelling d test of Brickenkamp,[16] the Luria list of words test[17] and the word-figure-memory test.[18] All patients (n = 132) were asked to fill in the Short-Form-36 (SF-36),[19] the Fatigue Impact Scale (FIS),[20] and the Hospital Anxiety and Depression Scale (HADS),[21] to assess health-related quality of life, fatigue, anxiety and depression.


The global null hypothesis was tested using Kruskal-Wallis test. In case of significant effects, the Mann-Whitney test was used to look for statistical differences between the groups. The percentage of pathological results in the different domains was analysed for significant group differences by use of cross-tables tests (chi square). Spearman's rank order correlation was applied for correlation analysis. Values are shown as median with interquartile range or as median and total range (age, education) where adequate. A P-value ≤ 0.05 was considered significant for all tests applied. Considering the multitude of test results, however, Bonferroni correction for multiple comparisons was applied resulting in a P-value of ≤ 0.01 for the FIS, HADS and SF-36 questionnaires, and P ≤ 0.002 for the attention and memory tests.