Gastroenterology

Gastroenterology

Volume 138, Issue 7, June 2010, Pages 2332-2340
Gastroenterology

Clinical—Liver, Pancreas, and Biliary Tract
Persistence of Cognitive Impairment After Resolution of Overt Hepatic Encephalopathy

https://doi.org/10.1053/j.gastro.2010.02.015Get rights and content

Background & Aims

In patients with cirrhosis, hepatic encephalopathy (HE) has acute but reversible as well as chronic components. We investigated the extent of residual cognitive impairment following clinical resolution of overt HE (OHE).

Methods

Cognitive function of cirrhotic patients was evaluated using psychometric tests (digit symbol, block design, and number connection [NCT-A and B]) and the inhibitory control test (ICT). Improvement (reduction) in ICT lures and first minus second halves (ΔL1–2) were used to determine learning of response inhibition. Two cross-sectional studies (A and B) compared data from stable cirrhotic patients with or without prior OHE. We then prospectively assessed cognitive performance, before and after the first episode of OHE.

Results

In study A (226 cirrhotic patients), 54 had experienced OHE, 120 had minimal HE, and 52 with no minimal HE. Despite normal mental status on lactulose after OHE, cirrhotic patients were cognitively impaired, based on results from all tests. Learning of response inhibition (ΔL1–2 ≥1) was evident in patients with minimal HE and no minimal HE but was lost after OHE. In study B (50 additional patients who developed ≥1 documented OHE episode during follow-up), the number of OHE hospitalizations correlated with severity of residual impairment, indicated by ICT lures (r = 0.5, P = .0001), digit symbol test (r = −0.39, P = .002), and number connection test-B (r = 0.33, P = .04). In the prospective study (59 cirrhotic patients without OHE), 15 developed OHE; ICT lure response worsened significantly after OHE (12 before vs 18 after, P = .0003), and learning of response inhibition was lost. The 44 patients who did not experience OHE did not have deteriorations in cognitive function in serial testing.

Conclusions

In cirrhosis, episodes of OHE are associated with persistent and cumulative deficits in working memory, response inhibition, and learning.

Section snippets

Patients and Methods

Subjects for this study included patients with an established diagnosis of hepatic cirrhosis, based on histology or clinical criteria (physical examination and laboratory and imaging findings), who were seen and evaluated in our outpatient clinics in the Medical College of Wisconsin, Virginia Commonwealth University Medical Center, and McGuire VA Medical Center. Patients with prior overt HE were included only if they were receiving appropriate treatment with lactulose and/or rifaximin, were

Results

Cross-sectional study part A: Of the 226 patients included, 54 had prior overt HE and 172 did not. Patients without prior overt HE were divided on the basis of the psychometric tests into normal and minimal HE; 52 were normal, and the remaining 120 were minimal HE. The demographic and cirrhosis details are displayed in Table 1. The 54 patients with prior overt HE were currently adherent on lactulose (defined by mini-mental score >25, corroboration of lactulose use by caregivers, and by at least

Discussion

The SONIC forms a continuum that spans the range from normal cognitive function to minimal HE to overt HE.1, 13 Both minimal and overt hepatic encephalopathy are generally considered to be fully reversible with treatment.15 However, a variety of lines of evidence suggests that the metabolic derangement caused by ammonia and other neurotoxins in cirrhosis may result in neurologic injury that can be persistent and possibly permanent.5, 16, 17, 18, 19 In autopsy series, brains of patients dying in

References (34)

  • P. Fan et al.

    Neurochemical and electrophysiological studies on the inhibitory effect of ammonium ions on synaptic transmission in slices of rat hippocampus: evidence for a postsynaptic action

    Neuroscience

    (1990)
  • J.S. Bajaj et al.

    Spectrum of neurocognitive impairment in cirrhosis: implications for the assessment of hepatic encephalopathy

    Hepatology

    (2009)
  • S. Prasad et al.

    Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy

    Hepatology

    (2007)
  • E.U. Sotil et al.

    Impact of preoperative overt hepatic encephalopathy on neurocognitive function after liver transplantation

    Liver Transpl

    (2009)
  • R.F. Butterworth et al.

    Ammonia: key factor in the pathogenesis of hepatic encephalopathy

    Neurochem Pathol

    (1987)
  • C. Rose et al.

    Is minimal hepatic encephalopathy completely reversible following liver transplantation?

    Liver Transpl

    (2004)
  • R.F. Butterworth

    Neuronal cell death in hepatic encephalopathy

    Metab Brain Dis

    (2007)
  • Cited by (248)

    View all citing articles on Scopus

    Conflicts of interest The authors disclose the following: Dr Bajaj is a consultant for and receives independent grant support from Salix and Ocera. Dr Sanyal is a consultant for Salix Pharmaceuticals. The remaining authors disclose no conflicts.

    Funding Supported in part by the American College of Gastroenterology Junior Faculty Development Award, and by clinical research center grants MO1-RR00065 and MO1-RR00058, NCRR, and NIH (awarded to J.S.B.).

    View full text