title: White matter changes in chronic alcoholic liver disease: Hypothesized association and putative biochemical mechanisms.
abstract: Advanced liver disease has long been associated with cerebral abnormalities. These abnormalities, termed acquired hepatocerebral degeneration, are typically visualized as T1 weighted hyperintensity on MRI in the deep gray matter of the basal ganglia. Recent reports, however, have demonstrated that a subset of patients with chronic alcoholic liver disease may also develop white matter abnormalities. Thus far, the morphology of these changes is not well characterized. Previous studies have described these changes as patchy, sporadic white matter abnormalities but have not posited localization of these changes to any particular white matter tracts. This paper hypothesizes that the white matter findings associated with advanced alcoholic liver disease localize to the corticocerebellar tracts. As an initial investigation of this hypothesis, 78 patients with a diagnosis of liver cirrhosis and an MRI showing clearly abnormal T1 weighted hyperintensity in the bilateral globus pallidus, characteristic of chronic liver disease, were examined for white matter signal abnormalities in the corticocerebellar tracts using FLAIR and T2 weighted images. The corticocerebellar tracts were subdivided into two regions: periventricular white matter (consisting of the sum of the centrum-semiovale and corona radiata), and lower white matter (consisting of the corona radiata, internal capsules, middle cerebral peduncles, middle cerebellar peduncles and cerebellum). As compared to matched controls, significantly greater signal abnormalities in both the periventricular white matter and lower white matter regions of the corticocerebellar tracts were observed in patients with known liver cirrhosis and abnormal T1 W hyperintensity in the globi pallidi. This difference was most pronounced in the lower white matter region of the corticocerebellar tract, with statistical significance of p<0.0005. Furthermore, the pathophysiologic mechanism underlying these changes remains unknown. This paper hypothesizes that the etiology of white matter changes associated with advanced liver disease may resemble that of white matter findings in subacute combined degeneration secondary to vitamin B12 deficiency. Specifically, significant evidence suggests that dysfunctional methionine metabolism as well as dysregulated cytokine production secondary to B12 deficiency play a major role in the development of subacute combined degeneration. Similar dysfunction of methionine metabolism and cytokine regulation is seen in alcoholic liver disease and is hypothesized in this paper to, at least in part, lead to white matter findings associated with alcoholic liver disease.
authors.affiliation: Harvard Medical School, Boston, MA, United States. Electronic address: leith_hathout@hms.harvard.edu.
authors.forename: Leith
authors.initials: L
authors.lastname: Hathout
authors.affiliation: Department of Radiological Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA, United States; Greater Los Angeles Veterans Affairs Medical Center, Los Angeles, CA, United States.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Huang
authors.affiliation: Harvard Medical School, Boston, MA, United States.
authors.forename: Amir
authors.initials: A
authors.lastname: Zamani
authors.affiliation: Greater Los Angeles Veterans Affairs Medical Center, Los Angeles, CA, United States.
authors.forename: Craig
authors.initials: C
authors.lastname: Morioka
authors.affiliation: Department of Radiological Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA, United States; Greater Los Angeles Veterans Affairs Medical Center, Los Angeles, CA, United States.
authors.forename: Suzie
authors.initials: S
authors.lastname: El-Saden
mesh_terms: D000328:Adult; D000368:Aged; D001921:Brain / Q000473:pathology; D002908:Chronic Disease; D016207:Cytokines / Q000378:metabolism; D004487:Edema; D006787:Hospitals, Veterans; D006801:Humans; D008070:Lipopolysaccharides / Q000737:chemistry; D008103:Liver Cirrhosis / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000473:pathology*; D015141:Los Angeles; D008279:Magnetic Resonance Imaging; D008745:Methylation; D008875:Middle Aged; D015995:Prevalence; D066127:White Matter / Q000473:pathology*
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides