Twenty‐one patients with biopsy‐confirmed liver cirrhosis (16 men, five women) aged 32–74 (50.4 ± 11.8)
years underwent magnetic resonance imaging (MRI) and 1
H MRS of the basal ganglia, white matter and frontal gray matter. In 17 patients (12 men, five women, aged 49.1 ± 12.2
N‐ammonia PET of the brain was also performed. Eighteen of the patients (13 men, five women, aged 49.3 ± 11.9
years) underwent FDG‐PET of the brain.
Fourteen patients suffered from posthepatic cirrhosis, two from primary biliary cirrhosis, one from secondary biliary cirrhosis, two from cryptogenic cirrhosis, one from haemochromatosis, and one from alcoholic cirrhosis.
Applying the criteria of Pugh et al.
the grade of liver dysfunction was scored Child A in four, Child B in nine and Child C in eight patients (13
N‐ammonia PET: Child A: 4, Child B: 7, Child C: 6; FDG‐PET: Child A: 4, Child B: 8, Child C: 6). The grading of hepatic encephalopathy was done with regard to the results of a comprehensive neurological examination and the results of the Present State Examination (PSE) Syndrome test, a battery of five neuropsychological tests, which has been recommended for the assessment of minimal hepatic encephalopathy.8,9
Those patients who presented with normal neurological examination and normal PSE‐Syndrome test results were graded hepatic encephalopathy 0, those with normal results in the physical examination but pathological PSE‐Syndrome test results as minimal hepatic encephalopathy, and those with psychomotor slowing but no disorientation as grade I hepatic encephalopathy. Nine patients had grade 0 hepatic encephalopathy, six minimal hepatic encephalopathy and six grade I hepatic encephalopathy (13
N‐ammonia PET: hepatic encephalopathy 0: 7, minimal hepatic encephalopathy: 6, hepatic encephalopathy I: 4; 18
FDG‐PET: hepatic encephalopathy 0: 8, minimal hepatic encephalopathy: 6, hepatic encephalopathy I: 4). In addition to the PSE‐Syndrome test, the cancelling d test10
was performed. Clinical and psychometric examination, MRI, MRS and PET studies were performed within 24
hours. All patients gave their written informed consent. The study was, a priori
, approved by the local ethics committee. The study protocol conformed to the ethical guidelines of the Declaration of Helsinki.
Magnetic resonance imaging/MRS
MRI and MRS were performed using a 1.5 T scanner (GE Medical Systems, Milwaukee, Wisconsin, USA). Transverse and coronal T1‐weighted images (TR 500 ms/TE 15 ms/slice thickness 5 mm/slice gap 1.5 mm) were obtained. These images were used for the co‐registration with PET studies and for the definition of regions of interest (ROI) for the MRS study. The ROI, approximately 8 cm3 in size, were placed within the basal ganglia, the parietal white matter and the frontal gray matter (fig 1). Within these ROI localised proton spectra were achieved using the STEAM/VOSY technique (TR 3000 ms/TE 18 ms/TM 14 ms/128 averages) using the PROBE/SV packet (GE Medical Systems). For quantification of the metabolite ratios (N‐acetyl‐aspartate; NAA, glutamate/glutamine, myo‐inositol, choline) relative to creatine, the spectra were transferred to a workstation for calculation of the peak area integrals.
Figure 1Location of the magnetic resonance spectroscopy voxels used in this study.
Positron emission tomography
All patients were investigated using a Siemens 951/31 ECAT tomograph in standard head position. 13
N‐ammonia PET and FDG‐PET were performed consecutively. Thirty‐one slices (plane separation 3.4 mm) were obtained simultaneously. The axial and transaxial resolution of the reconstructed image (filtered backprojection, Hann filter, cut‐off frequency 0.4, 128 × 128 matrix, pixel size 1.9 mm) was approximately 8 mm full‐width half maximum. Attenuation correction was performed with a measured transmission scan (10
minutes). After a slow bolus intravenous injection of 740 MBq 13
N‐ammonia, the data were recorded dynamically (12 × 10 s, 5 × 30 s, 2 × 120 s, 1 × 900 s frames;
23.5 minutes). Arterial blood samples were taken simultaneously. After reconstruction (including correction of the PET data for decay and attenuation) parametric images were created. Like Keiding et al.11
we applied an irreversible two tissue compartment model with three transport rate constants for kinetic analysis (the term “irreversible” refers to the fact that the tracer is, at least partly, trapped in tissue, namely the second compartment of the model).12
The model was originally developed for the quantification of ammonia studies of the heart 13
and is comparable to the model used to study cerebral glucose utilisation by FDG‐PET. It is in accord with the findings of Lockwood and colleagues14,15
on ammonia metabolism in humans. For the generation of parametric images we used a modified linearised approach16
with automatic correction of input function delay and dispersion.17
In addition, correction for ammonia metabolism was performed in accordance with the data of Rosenspire et al
Images were generated for the rate constants K1, K2, K3, Km and the fractional blood volume.19
For details of the method see Ahl et al
The cerebral metabolic rate for ammonia (CMRA
) was not calculated in this study as arterial plasma ammonia levels were not available for all patients. According to recent data of Ong et al.
however, there is a close correlation between venous and arterial plasma ammonia levels with a correlation coefficient of 0.86639 (p<0.0001). Ong et al.20
were kind enough to provide us with the linear regression equation that describes the regression between venous and arterial plasma ammonia levels in a group of 53 patients with grades 0 and 1 hepatic encephalopathy: arterial plasma ammonia level 18.74 + 0.892 ×
venous plasma ammonia level. On the basis of this equation we estimated the arterial plasma ammonia levels in our patients using their venous ammonia levels and used these data for an estimation of the metabolic rate for ammonia (estimated CMRA
Sixty minutes after the injection of 13
N‐ammonia, 370 MBq FDG were administered intravenously after a second transmission scan had been performed. The tissue activity concentration was measured dynamically over a period of 50
minutes (6 × 20 s, 3 × 60 s, 2 × 150 s, 2 × 300 s, 3 × 600 s frames; … 50
minutes). To obtain the tracer input function, 20 arterialised blood samples of 1 ml each were taken according to the dynamic measurement protocol at midframe time. Quantification of glucose metabolism was performed using the method of Patlak et al
For both glucose and ammonia metabolism, ROI were defined after co‐registration of the PET and MRI studies of each patient. ROI were defined on the respective MRI studies using a stereotactical anatomical atlas.21
Defined ROI were the thalamus, caudate nucleus, lenticular nucleus, hippocampus, cerebellum, frontomedial and frontolateral cortex, motor cortex, sensory cortex, parieto‐occipital cortex and parietal white matter. Absolute values for K1 and Km for ammonia PET and the cerebral metabolic rate of glucose were extracted as a maximum of the defined ROI. In addition, each regional value was individually normalised to global data.
For each parameter the closed test procedure was used to compare the different patient groups. Thereby, the global null hypothesis was tested using analysis of variance, and pairwise comparison was based on the t
‐test. Dependencies between MRI, MRS and PET parameters were analysed by pairwise Pearson correlations. Multiplicity within each MRS and MRI parameter with respect to the PET parameters was controlled for by the Bonferroni–Holm procedure. Furthermore, for each PET parameter as a dependent variable a stepwise multiple regression analysis with backward elimination was performed on MRI and MRS parameters by applying an exclusion limit of p>0.05. The results are described as standardised regression coefficients and the proportion of explained variance, β and R2
. All tests were performed two‐sided on the level α