Proton MR spectroscopic measurement of neurometabolites in hepatic encephalopathy during oral lactulose therapy.
OBJECTIVE
MR imaging and MR spectroscopy are increasingly being used to determine response to pharmacologic therapy. Hepatic encephalopathy (HE) is characterized by abnormal cerebral metabolites, yet the response to lactulose and other anti-HE measures is still primarily determined by using arbitrary categorical clinical rating scales, rather than MR spectroscopy. The purpose of this study was to determine whether MR spectroscopy could demonstrate relevant neurometabolic changes associated with lactulose therapy and thereby provide further support for the use of MR spectroscopy in clinical trials.


METHODS
Ten control subjects and 23 patients with grades I to III HE were studied by proton MR spectroscopy with imaging parameters of 2000/26 (TR/TE). Metabolic ratios were calculated for myo-inositol (mI)/creatine (Cre), choline (Cho)/Cre, (glutamine + glutamate) (Glx)/Cre, N-acetylaspartate (NAA)/Cre, and (Cho + mI)/Glx. A time series design trial was used in which eight patients with HE were compared before and after lactulose therapy (60 mL by mouth three times per day).


RESULTS
Relative to control subjects, HE was characterized by 43%, 64%, and 5% reductions, respectively, in mI/Cre, (Cho + mI)/Glx, and Cho/Cre. In comparison, Glx/Cre was increased by 75% and NAA/Cre was not changed. Therapy with lactulose was associated with increases of 29%, 37%, and 7%, respectively, in mI/Cre, (Cho + mI)/Glx, and Cho/Cre, as well as respective decreases of 15% and 42%, respectively, in Glx/Cre and HE grade. NAA/Cre did not change with lactulose therapy.


CONCLUSIONS
MR spectroscopy detects neurometabolic changes associated with pharmacologic therapy for HE. The metabolic ratios ml/Cre and (Cho + mI)/Glx are the most sensitive measures of lactulose effect. These data support the expanded use of MR spectroscopy as an adjunctive technique in pharmaceutical development and clinical trials for HE.
Haseler
L J
LJ
Center for Noninvasive Diagnosis, University of New Mexico School of Medicine, Albuquerque, USA.
Sibbitt
W L
WL
Mojtahedzadeh
H N
HN
Reddy
S
S
Agarwal
V P
VP
McCarthy
D M
DM
D000284:Administration, Oral; D000328:Adult; D001921:Brain / Q000378:metabolism*; D002794:Choline / Q000378:metabolism; D003401:Creatine / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006501:Hepatic Encephalopathy / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D007792:Lactulose / Q000627:therapeutic use*; D009682:Magnetic Resonance Spectroscopy; D008875:Middle Aged; D012016:Reference Values
D005973:Glutamine; D018698:Glutamic Acid; D007792:Lactulose; D003401:Creatine; D002794:Choline