Acute Hepatic Encephalopathy: Diffusion-Weighted and Fluid-Attenuated Inversion Recovery Findings, and Correlation with Plasma Ammonia Level and Clinical Outcome

Discussion

Hepatic encephalopathy is, to date, a clinical diagnosis with a wide spectrum of manifestations. Etiologies include chronic hepatic failure with superimposed acute mental status changes (ACHF), medication-induced AHF (classically acetaminophen overdose), and other uncommon causes of AHF.²⁰ Because acute hepatic encephalopathy is typically a clinical diagnosis, there can be reluctance in ordering MR imaging, with CT scans usually obtained to exclude emergent phenomena such as hemorrhage, herniation, or hydrocephalus. Hence, we set out to identify characteristic regions of involvement to aid the diagnosis of acute hepatic encephalopathy and found that in most patients, the thalami, PLIC, and PVWM were involved on both DWI and FLAIR. Although no specific region was involved in all patients, in our opinion, the constellation of involved areas on FLAIR and DWI is suggestive of acute hepatic encephalopathy. These findings can appear prominent but may be reversible on DWI (though less commonly on FLAIR) and are clinically reversible, as recently described by 2 reports (totaling 3 patients).^19,21 Therefore, we opine that characteristic findings for acute hepatic encephalopathy on MR imaging should prompt a request for a PAL to solidify the diagnosis of this entity.

Also, while the clinical severity has been previously shown to correlate with PAL in ACHF, there can be overlapping and fluctuation of PALs with respect to different West Haven grades.^4–6 Hence, we set out to determine whether MR imaging, by determining MR imaging severity, is predictive of clinical outcome. Thus, we found relatively strong correlations between MR imaging severity (based on DWI and FLAIR) with PAL and of PAL with the clinical outcome. However, the correlations between MR imaging severity and clinical outcome were only moderate and were not significant at the P < .005 level when using the fairly conservative Bonferroni correction method for multiple hypothesis testing. Hence, the direct correlation between either FLAIR severity, DWI severity, or West Haven grade with the clinical outcome is not yet entirely determined. Therefore, while acute hepatic encephalopathy can be reversible, this study suggests that the MR imaging severity may predict, to some degree, the clinical outcome of patients with acute hepatic encephalopathy, but this point should be explored further by a prospective study. Most notable is that those patients having diffuse cortical involvement are more likely to have a poor outcome, though even such diffuse insults may ultimately reverse, as noted in this study and in previous case reports.^21,22

Because our study also set out to evaluate the areas of involvement and their reversibility on DWI by measuring ADC values as well, we found significantly lower ADC values on initial MR imaging in the thalami, PLIC, and PVWM relative to NAWM, but between initial and follow-up MR imaging, we found a significant difference only in the thalami. This lack of a significant difference in the PLIC and PVWM when comparing initial with follow-up MR imaging could appear contradictory. This apparent contradiction could be explained by the DWI hyperintensity noted visually in the PLIC and PVWM arising from a component of T2 bright signal intensity (T2 shinethrough phenomenon), though the significant difference in thalamic ADC suggests that the ADC values were truly decreased in that location and later normalized. However, only 5 patients underwent a repeat MR imaging, limiting statistical evaluation of this phenomenon. We note that the findings of diffuse cortical involvement improved in both patients with follow-up DWIs available, suggesting that even cases at the severe end of the spectrum acute hepatic encephalopathy can reverse.

The usefulness of FLAIR and DWI in assessing patients with hepatic encephalopathy has been illustrated in recent studies. For example, diffuse white matter hyperintensities in or around the corticospinal tracts on FLAIR or T2WI have been shown to improve posttransplantation.¹² On DWI in chronic hepatic failure, several studies have found increasing ADC values in the thalami, basal ganglia, and PVWM, which have been correlated with the degree of PAL elevation and with the severity of acute hepatic encephalopathy; these findings have been proposed to represent either chronic astrocytic swelling, increased interstitial fluid, or chronic demyelination.^13–16 In fulminant AHF or ACHF, recent studies have demonstrated lower ADC values in affected locations, suggesting intramyelinic edema, intracellular edema, acute astrocytic swelling, or oligodendroglial injury.^23–26 Accordingly, studies using diffusion tensor imaging in patients with ACHF have recently demonstrated reduced mean diffusivity in affected regions with reduced fractional anisotropy compared with controls.^24–26 Hence, we suspect that this difference in whether ADC values are increased or decreased in such involved regions would be, in part, related to the time of symptom onset, when more recent acute or early subacute lesions would demonstrate reduced ADC values due to cytotoxic effects and chronic lesions would have elevated ADC values from chronic interstitial edema or gliosis. Thus, the degree of involvement of the PLIC, thalami, and PVWM has also varied among these studies. These differences again may relate not only to the timing of MR imaging relative to symptom onset but also to the location measured (tighter white matter tracts would have lower ADC values) and possibly to the lack of visual detection of subtle findings in these regions.^{12–16,23–26}

Future studies could use diffusion tensor imaging, MR spectroscopy, or molecular imaging to provide further insight into the mechanism of injury in acute hepatic encephalopathy, particularly by focusing on the thalami, PLIC, DBS, and PVWM. Also, a prospective evaluation of patients with acute hepatic encephalopathy via FLAIR, DWI, and ADC measurements is needed to validate our findings.

The basic physiology of acute hepatic encephalopathy involves increased levels of CNS glutamine as a result of elevated CNS ammonia levels. As CNS ammonia levels increase, glutamine, a potent osmolyte, accumulates, leading to numerous consequences such as astrocyte swelling, oxidative/nitrosative damage, disruption of glucose metabolism, defective neurotransmitter synthesis (such as gamma-aminobutyric acid), and increased blood-brain barrier permeability.^7,27,28 As CNS ammonia levels rise with systemic hyperammonemia, the direct toxic effects of ammonia may take hold; thus, increasing CNS ammonia concentrations have been shown to disrupt neuronal function, and glutamine levels have been shown to correlate with the severity of hepatic encephalopathy.^27–29 These changes collectively contribute to the edema and decreased consciousness that may be seen in acute hepatic encephalopathy.^28–30

A few studies have simulated and studied the mechanism of abnormalities visualized on MR imaging and other imaging modalities in ammonia-related injury. For example, an experiment injecting rats with ammonium acetate noted ADC abnormalities in various regions, such as the thalami, caudate, putamen, and cerebellum, to name a few.¹⁸ On positron-emission tomography, increased blood flow and nitrogen-13 ammonia uptake have been noted in the thalami, lentiform nucleus, and cerebellum in acute hepatic encephalopathy.³¹ Notably, PALs have been shown to positively correlate with ADC values in the thalami, pallidi, putamen, and PVWM in patients with chronic hepatic failure.¹³ Hence, prior evidence along with our study suggests that a higher PAL predisposes to cytotoxic injury, which could be detected at an early stage with DWI. Therefore, the relatively strong significant correlations noted in this study between the PAL and the MR imaging severity/extent (based on FLAIR and DWI) as well as between the PAL and the clinical outcome would support the notion that the extent of injury is proportional to the concentration of ammonia delivered.

There are several limitations of this study, including the relatively small number of patients included and the retrospective nature. A prospective study in which patients with acute hepatic encephalopathy were scanned at regular intervals would be optimal. Also, because PALs can fluctuate relatively rapidly with treatment, a low PAL may belie severe MR imaging findings, particularly if imaging is relatively late after symptom onset or if the patient is already receiving continual ammonia-reduction therapy. Hence, we recorded the maximal PAL at ± 8 days of MR imaging, in an attempt to determine if overall higher PALs correlated with worse outcomes. Additionally, this study is limited by the use of different MR imaging scanners, preventing our use of a true control population for measuring ADC values; therefore, NAWM was used as a relative control. The use of NAWM as a reference is not optimal and is another limitation because subtle abnormalities within visually unaffected PVWM in acute hepatic encephalopathy may be detected only by using more sensitive tests, such as diffusion tensor imaging. However, early studies using diffusion tensor imaging in patients with acute hepatic encephalopathy have produced varied measurements in NAWM compared with controls.^24–26 Notably, such findings have varied as to whether visually NAWM (and which locations) was abnormal, and the results are difficult to interpret, in part because whether such measurements were correlated with abnormalities visualized on T2WI, FLAIR, or DWI as determined by a neuroradiologist was not specified.^24–26

Finally, because the PLIC may normally have mildly hyperintense signal intensity on FLAIR, T2WI, and DWI, and the DBS may also have a slightly greater intensity compared with the intensity ventrally (particularly on higher field strength magnets), we could have been predisposed to “overcalling” abnormalities in those locations and thereby generating false-positives. Therefore, a prospective study is needed that incorporates control patients, uses a single MR imaging scanner, obtains PALs at regular intervals, and implements advanced MR imaging applications such as diffusion tensor imaging, to confirm the findings of our study of affected regions on the basis of visual inspection.