Brain synthetic magnetic resonance imaging and quantitative susceptibility mapping in patients with hepatitis B virus-related decompensated cirrhosis

Introduction

Damage to liver tissues caused by viruses, drugs, alcohol, or other factors is referred to as liver cirrhosis (1,2). Hepatitis B virus infection is the primary cause of liver cirrhosis in China (3,4). When cirrhosis progresses to the decompensated stage (5), it may be complicated by hepatic encephalopathy (HE).

In the decompensated stage of cirrhosis, patients experience portal hypertension and portosystemic shunt (6), in which ammonia and other harmful substances pass through the portal vein directly into the body circulation, and ultimately into the brain tissue. This interferes with the metabolism of the brain tissue, triggering cerebral edema, and thus neurological symptoms (7,8). It has been reported that the T1, T2 and proton density (PD) values of the frontal white matter and basal nuclei of patients with HE are altered (9,10), which suggests that when ammonia and other harmful substances are deposited in brain tissues, they may cause changes in the relaxation time and PD values of the corresponding tissues (11,12). Moreover, iron is critically involved in the function of the central nervous system (13). Previous studies have confirmed the presence of abnormal iron deposition in the deep nuclei and frontal white matter of patients with cirrhosis (14,15); additionally, the iron deposition in the brain tissue of patients with cirrhosis has been found to be associated with cognitive deficits (16,17).

HE is a continuous spectrum of manifestations ranging from normal cognitive function and intact consciousness to coma. The emergence of neurological symptoms severely impacts patients’ quality of life, leading to compromised driving safety and reduced work efficiency. The early diagnosis of HE is particularly crucial, yet traditional diagnostic methods are limited by their subjectivity and low sensitivity. There is thus an urgent need to establish more objective imaging techniques to achieve early and precise detection.

In recent years, synthetic magnetic resonance imaging (SyMRI) has provided rapid whole-brain quantitative analysis of relaxation time and PD (18). Meanwhile, quantitative susceptibility mapping (QSM) can detect brain iron deposition and magnetic susceptibility changes. However, research on the use of cranial SyMRI or QSM in patients with cirrhosis remains lacking. Therefore, in this study, we integrated both techniques to investigate quantitative parameter changes, with the aim of generating imaging evidence to enhance the awareness of early neurological symptoms and disease monitoring in patients with cirrhosis. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2024-2969/rc).

Methods

Study participants

Forty-one patients with HBV-related decompensated cirrhosis (cirrhosis group) who attended the Department of Infection of Xiangya Hospital of Central South University from July 2022 to December 2023 were prospectively enrolled in this study. The inclusion criteria for the cirrhosis group met the diagnostic criteria for decompensated cirrhosis in the Guidelines for the Diagnosis and Treatment of Cirrhosis of the Chinese Medical Association Division of Hepatology (19). Patients with a history of neuropsychological disorders, traumatic brain injury, brain tumors, cerebral infarction, cerebral hemorrhage, epilepsy, alcoholic encephalopathy, cardiocerebral vascular disease, or other neurological disorders were excluded. We included 40 healthy controls who were similar in age and sex to the patients, matched for educational level, and had no liver disease or liver function abnormalities, no neurologic disease or cognitive dysfunction, and no psychiatric disorders or drug effects. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, and was approved by the Clinical Medical Ethics Committee of Xiangya Hospital, Central South University (No. 2022111062). Informed consent was obtained from all individual participants.

Clinical data collection

Demographic data and laboratory test results within one month of admission or enrollment were collected from the cirrhosis group and healthy group; additionally, the clinical course and neuropsychological test results from the cirrhosis group were recorded. Neuropsychological tests were conducted in accordance with the “Guidelines for the Diagnosis and Treatment of Cirrhosis and Hepatic Encephalopathy” (20). Patients were tested with the Mini-mental State Examination (MMSE) and the Psychometric Hepatic Encephalopathy Score (PHES). The PHES test included the Number Connection Test-A (NCT-A) and the Digit Symbol Test (DST) (21).

Data acquisition

• For SyMRI data acquisition, MRI compilation (MAGIC) sequence data of brain SyMRI from all participants were acquired on a SIGNA Premier 3.0T MRI scanner and standard 48-channel head coil (GE HealthCare, Chicago, IL, USA) under the following scanning parameters: repetition time (TR) =8,402 ms, echo time (TE) =14,656 ms, acquisition matrix =320 mm × 224 mm, slice thickness =3 mm, and scanning time =6 minutes.
• Enhanced-susceptibility-weighted angiography (ESWAN) sequences of all participants were acquired on the same SIGNA Premier 3.0T MRI scanner with a standard 48-channel head coil under the following scanning parameters: TR =53.52 ms, TE =23.8 ms, acquisition matrix =320 mm × 288 mm, slice thickness =2 mm, and scanning time =8 minutes.

Data processing

Data preprocessing

(I) SyMRI images were analyzed with SyMRI post-processing software (GE HealthCare) to automatically generate T1-weighted images (T1WI), T2-weighted images (T2WI), and PD maps. For region of interest (ROI) delineation and measurement, the acquired images were processed with the SyMRI post-processing software package on a workstation (GE HealthCare). (II) The ESWAN sequence images were exported in DICOM format, and the QSM image reconstruction process, as described by Gao et al. (22) including the following components: (i) phase Laplacian of trigonometric (LoT) function construction, which included the establishment of an LoT framework for phase processing, integrated phase unwrapping, background phase removal, and single-step dipole inversion; (ii) LoT-Unet neural network architecture, which is a novel deep neural network constructed by combining LoT convolutional layers with a three-dimensional (3D) residual Unet to enable instant quantitative field mapping (iQFM) and quantitative susceptibility mapping (iQSM); (iii) training dataset preparation, in which forward-field calculations were dimulated for local fields and a model of the phase evolution process applied to generate wrapped phase data; (iv) network training, in which data slices were selected at randomly from healthy and control groups for training, and the iQSM was trained with the simulated wrapped phase as the input and susceptibility maps as labels, while the iQFM network used wrapped the phase as input and local field maps as labels; (v) dataset evaluation, in which the validation datasets were quantitatively assessed to ensure accuracy; and (vi) QSM image generation and analysis, in which the final QSM images were reconstructed and 3D Slicer software used for ROI delineation and susceptibility value extraction.

Outlining of ROIs

The ROIs were manually outlined by an experienced diagnostic neuroimaging physician, and included the bilateral frontal, parietal, and occipital white matter; bilateral caudate nuclei; putamen; globus pallidus; thalamus; substantia nigra; red nuclei; and dentate nuclei (Figures 1,2). Twenty-five cases were randomly selected from both the patient group and the control group, with repeated measurements conducted at different time points. The reliability of the measurements was evaluated via intraclass correlation coefficient (ICC) values: an ICC value below 0.40 indicated poor reliability, 0.40–0.75 indicated moderate reliability, and >0.75 indicated good reliability.

Figure 1 Schematic diagram of ROI outlined on SyMRI. (A) Bilateral frontal white matter and bilateral parietal white matter from anterior to posterior. (B) Bilateral thalamus and occipital white matter from anterior to posterior. (C) Bilateral caudate nuclei, nuclei of the putamen (lateral), and globus pallidus (medial) from anterior to posterior. (D) Bilateral substantia nigra (lateral), and red nuclei (medial). (E) Bilateral dentate nuclei. ROI, region of interest; SyMRI, synthetic magnetic resonance imaging.

Figure 2 Schematic diagram of the ROI outlined on the QSM. (A) Bilateral frontal white matter and bilateral parietal white matter in order from anterior to posterior. (B) Bilateral caudate nuclei, putamen (lateral), globus pallidus (medial), thalamus, and bilateral occipital white matter in order from anterior to posterior. (C) Bilateral substantia nigra (lateral) and red nuclei (medial). (D) Bilateral dentate nuclei. QSM, quantitative susceptibility mapping; ROI, region of interest.

Statistical analysis

Statistical analysis of all data was performed via SPSS 26.0 (IBM Corp., Armonk, NY, USA). The independent-samples t-test was used for data that conformed to a normal distribution, the Mann-Whitney test was used for data that did not conform to a normal distribution, and the chi-squared test was used to analyze the gender distribution. Analysis of covariance (ANCOVA) was applied to detect the differences between the T1 values, T2 values, PD values, and magnetic susceptibility values of the two groups. P values obtained were then corrected for multiple comparisons with the false-discovery rate (FDR) method. Pearson and Spearman correlation analyses were implemented to test the correlation between the T1 values, T2 values, PD values, and magnetic susceptibility values of the differential brain regions and the corresponding platelet counts, liver function, NCT-A completion time, DST scores, and duration of hepatitis B and cirrhosis.

Results

Clinical data and laboratory indicators

None of the patients with cirrhosis included in this study had significant neurologic symptoms. The results of MMSE test for all patients were normal (score >24). According to the Guidelines for the Diagnosis and Treatment of Cirrhosis and Hepatic Encephalopathy, there were 11 patients with cirrhosis and mild HE, while the other 30 patients did not have HE.

Compared with healthy group, the cirrhosis group had significantly higher levels of alanine aminotransferase, glutamate aminotransferase, direct bilirubin, and total bilirubin but a significantly lower platelet count, albumin content, and albumin:globulin ratio (A/G).

Analysis of SyMRI data

Compared with healthy group, the cirrhosis group had significantly lower T1, T2, and PD values in differential brain regions (P<0.05). The T1 values were lower in bilateral frontal white matter, bilateral parietal white matter, right occipital white matter (ROWM), bilateral caudate nuclei, bilateral putamen, right globus pallidus (RGP), right thalamus (RTHA), right substantia nigra (RSN), and bilateral dentate nuclei; the T2 values were lower in the bilateral putamen and bilateral thalamus; and the PD values were lower in right parietal white matter (RPWM), bilateral caudate nuclei, bilateral putamen, RTHA, and bilateral red nuclei (Table 1).

Due to there being differences in T1, T2, and PD values in some regions of patients with cirrhosis, we further tested the correlation between T1, T2, and PD values in the differential brain regions of patients with cirrhosis and their platelet counts, liver function, NCT-A completion time, DST scores, and duration of hepatitis B and cirrhosis. The results indicated that the T1, T2, and PD values of the differential brain regions of patients were correlated with platelet count and liver function (Table 2).

Analysis of QSM data

We found a tendency for increased magnetic susceptibility values in the right occipital lobe and left thalamus (LTHA) in the cirrhosis group as compared to the healthy group, but there was no significant difference after FDR correction (Table 3).

Discussion

We analyzed the T1, T2, and PD values of 10 ROIs in the brain tissue of patients with cirrhosis, including the supratentorial and infratentorial nuclei and white matter regions, and found that most of the regions in the cirrhosis group had lower T1, T2, and PD values; meanwhile, there were more brain regions with reduced T1 and PD values than there were with reduced T2 values. The ICC value (ICC =0.77) indicated good reliability between the two measurements. Therefore, it is reasonable to infer that the T1, T2, and PD values of brain tissue in patients with decompensated cirrhosis are altered before the onset of overt neurological symptoms, which also implies that the measurement of relaxation time and PD values can help to detect customarily unrecognizable brain changes (11,23).

Ammonia is an inhibitor of α-ketoglutarate dehydrogenase in the tricarboxylic acid cycle, and elevated blood ammonia in patients with cirrhosis can lead to impaired cerebral energy metabolism and ultimately brain cell edema (24,25). Cellular brain edema can lead to an increase in the T1, T2, and PD values of brain tissue (9). Paramagnetic substances such as manganese deposited in the brain of patients with cirrhosis also have the effect of shortening the relaxation time, which can also cause changes in the T1, T2, and PD values of the brain tissue (26-28). We hypothesize that the observed decrease (rather than increase) in the T1, T2, and PD values in the brain tissue of patients with cirrhosis in this study may be due to the more pronounced influence of paramagnetic substance deposition (e.g., manganese) on relaxation parameters as compared to the effects of blood ammonia. Recent studies have indicated there to be no direct correlation between observed ammonia concentrations and the severity of HE (29,30), suggesting that blood ammonia levels may exert a limited impact on cerebral metabolism and relaxation time, which aligns with our findings. Furthermore, our study demonstrated more extensive reductions in T1 and PD values across brain regions as compared to T2 value reductions, which is likely attributable to the heightened sensitivity of T1 and PD measurements to substance deposition effects.

Further comparisons in this study revealed that the decrease in T1 and PD values in the cirrhosis group as compared to the healthy group was primarily in the bilateral frontal white matter, bilateral caudate nuclei, bilateral putamen, bilateral red nuclei, bilateral dentate nuclei, the RPWM, occipital white matter, the right thalamus, and the RSN. This finding suggests that in addition to changes in the deep gray-matter nuclei in the brain of patients with cirrhosis, subtle changes in the white matter of the frontal parieto-occipital lobes also occur, with the changes in the white matter regions being predominantly in the bilateral frontal lobes. The frontal lobes are mainly associated with cognitive function (31,32), which may explain the slight cognitive impairment in patients with decompensated cirrhosis. Moreover, the results of correlation analysis showed that the decrease of T1 value in the bilateral frontal white matter was positively correlated with albumin content and A/G ratio, suggesting that the decrease in T1 value in the frontal white matter might reflect the deterioration of patients’ liver function to a certain extent. We also found that the T1 value and PD value changes of the parieto-occipital white matter, thalamus, and substantia nigra were on the right side, and perhaps the right parieto-occipital white matter, thalamus, and substantia nigra of patients with cirrhosis are more affected by the disease than are their corresponding left sides. This may be related to the handedness laterality (left-dominant vs. right-dominant patterns) or hemispheric asymmetric alterations (33-35), which need to be confirmed by more in-depth studies.

The caudate nuclei and putamen are collectively known as the neostriatum (36,37), which is mainly involved in the regulation of locomotion and is also associated with cognitive function. Lesions of the neostriatum can lead to motor and cognitive-emotional deficits (36). In this study, the decrease in T1 and PD values of the bilateral caudate nuclei and putamen might have been a manifestation of neostriatal lesions in patients with cirrhosis. Moreover, the decreased T1 and PD values of the caudate nuclei and putamen were positively correlated with platelet count. When liver function is impaired, platelet production and release will also be impaired (38,39), and so changes in platelet count, to some extent, reflect changes in liver function (40). In other words, the changes in T1 and PD values of caudate nuclei and putamen can reflect the changes in liver function to a certain extent.

The dentate nuclei are the largest and most disease-prone nuclei in the cerebellum (41), and its function involves multiple aspects of motor control and coordination. When the dentate nuclei are damaged, patients may experience inaccurate fine hand movements (42), impaired motor coordination, and discontinuous movements. In this study, we found that patients in the cirrhosis group had reduced T1 values in the dentate nuclei bilaterally, suggesting that changes in the dentate nuclei may be involved in motor dysfunction in the later stages of patients with cirrhosis.

For the QSM study, we found that the magnetic susceptibility values of the ROWM and LTHA in the cirrhosis group tended to be higher than corresponding values in the healthy group (statistical significance was not reached after FDR correction). The occipital lobe is where the visual center is located, and occipital lobe damage causes visual impairment (43). Consistent with the decreased T1 values in the ROWM of patients with cirrhosis found in the SyMRI study, the magnetic susceptibility values tended to be higher in the ROWM of the cirrhosis group in the QSM study, which may explain the altered visual function in the later stages of decompensated patients with cirrhosis. However, the brain changes may also be due to effects of HE or cirrhosis-related metabolic decompensation rather than the cause of it. The causal relationship between brain changes and patient symptoms needs to be confirmed by further studies. The thalamus is a mesolimbic structure located between the cortex and the midbrain and is involved in a variety of functions, including motor control. In contrast to the decreased T1, T2, and PD values of the right thalamus in patients with cirrhosis in the SyMRI study, there was no significant difference in the right thalamic magnetic susceptibility values of the patients with those of the healthy group in the QSM study. In contrast, the left thalamic magnetic susceptibility values tended to be higher (statistical significance was not reached after FDR correction), which is consistent with the increase in the left thalamic magnetic susceptibility values reported in a previous study (44). We can speculate that the increase in thalamic magnetic susceptibility values may—to a certain extent—be able to cause thalamic dysfunction and may also be one of the causes of motor dysfunction in the later stages of patients with cirrhosis. As for the specific site of thalamic involvement, more in-depth studies are needed to definitively locate them and to determine the causal relationship between brain changes and patient symptoms.

For the QSM study, after correcting the P values using the FDR method, we found that the difference in the magnetic susceptibility values between the two groups was not statistically significant, which may be explained as follows. First, none of the patients with cirrhosis included in this study exhibited any significant clinical symptoms, which coupled with their relatively young average age and strong individual iron regulatory capacity, resulted in there being no observable significant changes in iron levels in the corresponding brain tissues. Second, the magnetic susceptibility values might have been affected by a variety of materials, such as paramagnetic and diamagnetic substances, and the opposing effects of different substances exerted on magnetic susceptibility can offset each other, resulting in minimal discernible differences between the two groups.

Certain limitations to this study should be acknowledged. First, further subgroup analyses of patients with cirrhosis with and without HE were not performed, which might have introduced a degree of bias to the study results. Second, we did not investigate the changes in the values of brain quantitative parameters or their correlation with the patients’ clinical indicators before and after liver cirrhosis treatment. Therefore, future studies should compare the parameters in patients with cirrhosis before and after liver cirrhosis treatment to identify the changes in brain tissue in patients with cirrhosis, thus providing a more instructive imaging basis for clinical practice.

Conclusions

The measurement of T1 values, T2 values, PD values, and magnetic susceptibility values in deep gray-matter nuclei and white matter could contribute to the recognition of early neurological symptoms and the monitoring of disease progression in patients with HBV-related cirrhosis. Among these parameters, T1 and PD values may exhibit higher sensitivity than magnetic susceptibility values.

Acknowledgments

We would like to express our sincere gratitude to our supervisor and colleagues in the department for their guidance and tremendous support throughout the research and collaborative process.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2024-2969/rc

Funding: This work was supported by the Natural Science Foundation of Hunan Province (No. 2023JJ30954).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2024-2969/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, and was approved by the Clinical Medical Ethics Committee of Xiangya Hospital, Central South University (No. 2022111062). Informed consent was obtained from all individual participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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