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ORIGINAL ARTICLE
Ahead of print publication  

Noninvasive assessment of liver fibrosis by magnetic resonance elastography in patients with rheumatic disease on long-term methotrexate treatment


1 Department of Rheumatology, Yashoda Hospitals, Secunderabad, Telangana, India
2 Department of Radiology, Yashoda Hospitals, Secunderabad, Telangana, India

Date of Submission18-Aug-2021
Date of Acceptance04-Dec-2021
Date of Web Publication21-Apr-2022

Correspondence Address:
Arindam Nandy Roy,
Department of Rheumatology, Yashoda Hospitals, Secunderabad - 500 003, Telangana
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_186_21

  Abstract 


Background: Long-term methotrexate (MTX) use is associated with hepatic fibrosis in patients with rheumatic diseases. Liver biopsy (invasive conventional diagnostic procedure for hepatic fibrosis) is associated with sampling errors and procedural risks. Magnetic resonance elastography (MRE) is a novel, reliable, and noninvasive imaging technique with excellent diagnostic accuracy for staging hepatic fibrosis and cirrhosis. Till date, studies are scarce on its use in staging MTX-induced liver fibrosis and cirrhosis. The aim of this study is to assess the usefulness of MRE in detecting and quantifying liver fibrosis and to compare these with biochemical parameters in patients with rheumatic diseases on long-term MTX therapy.
Methods: Patients with different rheumatic diseases, aged ≥18 years and on MTX treatment for >5 years were included in the study. Their medical records were reviewed, and data regarding demographics, diagnosis, disease duration, MTX dosage and duration were collected. On the day of MRE examination, series of biochemical parameters were conducted in patients. Predefined cutoff MRE values were used for staging liver fibrosis.
Results: A total of 48 subjects diagnosed with different rheumatic diseases on long-term MTX were recruited in the study, and majority of them were female (n = 41). The mean age and body mass index of the patients were 53.56 ± 8.36 years and 28.08 ± 4.43, respectively. Around 37.5% (n = 18) of the patients had abnormal aspartate transaminase (AST)-to-platelet count ratio index (APRI) score. The mean MRE value of the study group was 2.83 ± 0.90 kPa. Around 45.83% (n = 22) of the patients had normal liver stiffness values (<2.5) whereas stages F0 (2.5–2.9 kPa), F1 (2.9–3.5 kPa), F2 (3.5–4.0 kPa), F3 (4.0–5.0 kPa), and F4 (>5.0 kPa) were observed in 12.5% (n = 6), 18.75% (n = 9), 10.42% (n = 5), 10.42% (n = 5), and 2.08% (n = 1) of the patients, respectively. MRE values did not correlate with disease duration and cumulative dose of MTX. However, a positive correlation was observed between MRE and liver biochemical parameters (AST: Alanine transaminase [ALT] ratio, ALT, platelet count, APRI, albumin, and mean liver size; P > 0.05).
Conclusion: Considering the risk for complications with liver biopsy, MRE provides a reliable, highly accurate, noninvasive assessment of hepatic fibrosis in patients with rheumatic diseases receiving long-term MTX therapy.

Keywords: Liver biopsy, liver cirrhosis, magnetic resonance imaging, rheumatic diseases



How to cite this URL:
Roy AN, Darapureddy AK, Kumar YA. Noninvasive assessment of liver fibrosis by magnetic resonance elastography in patients with rheumatic disease on long-term methotrexate treatment. Indian J Rheumatol [Epub ahead of print] [cited 2022 Oct 1]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=343636




  Introduction Top


Methotrexate (MTX) is an essential disease-modifying antirheumatic drug (DMARD) used in treating rheumatic diseases including rheumatoid arthritis (RA) owing to its efficacy and low cost.[1],[2] Its long-term use has been associated with hepatotoxicity and hepatic fibrosis that are major adverse events of the treatment.[2],[3] Liver biopsy is an invasive conventional diagnostic procedure for hepatic fibrosis, which is reported to be associated with sampling errors and procedural risks with a significant morbidity and mortality rate of 1% and 0.01%–0.1%, respectively.[4],[5],[6],[7] Serum biomarkers proved effective in the diagnosis of advanced liver fibrosis and cirrhosis stages but are ineffective in differentiating early stages of fibrosis. Given these factors, recently, a combination of serological and noninvasive magnetic resonance imaging (MRI)-based elastography methods is gaining prominence for predicting stages of liver fibrosis and cirrhosis with higher diagnostic sensitivity and specificity.[8],[9]

Magnetic resonance elastography (MRE) is an MRI-based technique used for measuring the mechanical properties of tissues in vivo. Popular clinical application of MRE has been in diagnosing different stages of liver fibrosis. MRE has been well validated in several previous studies, and is widely used for quantitatively imaging increased stiffness in hepatic parenchyma during conditions such as chronic liver diseases, by analyzing the propagation of shear waves through the liver.[9],[10],[11] This technique provides quantitative maps of liver tissue indicative of stiffness over larger regions. MRE is less operator dependent than ultrasound-based techniques.[9] Until date, studies describing the use of MRE in MTX-induced liver fibrosis and cirrhosis are scarce.

With this background, we aimed to evaluate the diagnostic accuracy of MRE in staging MTX induced liver fibrosis and cirrhosis, and compare these findings with different liver biochemical parameters.


  Methods Top


Study settings

This was a cross-sectional study conducted from April 2018 to August 2020 in the Department of Rheumatology at Yashoda Hospitals, Secunderabad.

Ethics statement

The study was conducted with the approval of the Institutional Ethics Committee of Yashoda Hospitals, Secunderabad (IEC Approval no: RTS/CR/PP-08/2020 Date of Approval: 18th December 2020). All patients provided written informed consent. This study was conducted by adhering to the Declaration of Helsinki ethics principles, International Council for Harmonization-Good Clinical Practices (GCP) guidelines, Indian Council of Medical Research, and the Indian GCP guidelines.

Inclusion and exclusion criteria

Patients with different rheumatic diseases, satisfying criteria of the American College of Rheumatology/European League against Rheumatism, aged 18 years or above and on MTX treatment for >5 years were included in the study. Patient medical information such as demographics, diagnosis, disease duration, MTX dosage, and duration was retrieved from their medical records.

Patients with underlying chronic liver disease together with hepatitis B or C, hemochromatosis, alpha-1-antitrypsin deficiency, auto immune hepatitis, history of alcohol use while receiving MTX therapy, treatment with drugs that might induce liver fibrosis, patients with contraindications that may interfere with MRE examination, and pregnant women were excluded.

Liver function tests

On the day of MRE examination, serum biochemical markers of liver function (serum albumin, aspartate transaminase [AST], and alanine transaminase [ALT]), liver size, and two combination biomarkers, i.e., AST: ALT ratio and AST-to-platelet ratio index (APRI), were measured and calculated for each patient as described previously.[12],[13] AST: ALT ratio is approximately 0.8 in normal subjects.[14],[15] A ratio ≥1 has great value in distinguishing cirrhotic from noncirrhotic patients in nonalcoholic liver disease.[14],[16],[17] According to a meta-analysis study on predicting significant fibrosis, an APRI cutoff of 0.7 was 77% sensitive and 72% specific, whereas for cirrhosis, a cutoff of 1.0 was 76% sensitive and 72% specific in patients with chronic hepatitis C.[18] The APRI score was calculated by the formula, APRI = 100× ([AST/top normal AST]/[platelets/1000]) as described previously.[15]

Magnetic resonance elastography imaging

The principle of MRE is briefly described as follows. It is a technology that combines MRI imaging with low-frequency shear waves (range, 20–200 Hz) to create a visual elastogram that shows stiffness of liver tissues. Shear waves propagate more rapidly in stiffer tissue compared to softer tissue. If low-frequency mechanical shear waves generated with a special acoustic driver system are transmitted continuously, the speed of propagation is reflected in the wavelength, and as tissue stiffness intensifies, the wavelength becomes longer. Micron-level displacements associated with wave propagation in the tissue will be imaged using a modified phase-contrast MRI motion-encoding gradients.

MRE was performed on a 3-T MR unit (Magnetom Skyra, Siemens Medical Solutions, Erlangen, Germany) using resoundant active and passive drivers that are connected through a plastic tube. During MRI, low-frequency acoustic pressure waves at 60 Hz generated by an active driver (located away from the magnetic field of the MR imaging unit) were transmitted via a passive pneumatic driver to patient's right upper abdomen. Multiple two-dimensional gradient echo sequences along with cyclic motion encoding gradients were performed. The requisite total acquisition time for the attainment of MRE data was approximately 30 s. Quantitative MR elastograms depicting liver stiffness were generated by processing the propagating shear wave images using a local frequency estimation inversion algorithm as described elsewhere.[19] The degree of liver stiffness was typically calculated by drawing regions of interest in the elastograms. Staging of liver stiffness was carried out as previously described.[20] Normal liver tissue has stiffness values <3 kPa and hepatic fibrosis can be diagnosed using MRE with high sensitivity and specificity if stiffness values are above this. Liver stiffness increases gradually with histological stage of fibrosis (stage F1 to F4).

Liver iron estimation is studied by MRI relaxation time(T).Iron shortens T1, T2 and T2* relaxation times measured by MRI.The reciprocals of T2 and T2*, known as R2 and R2*, are directly proportional to iron estimation. Increases systematically with hepatic iron overload.[21] In this study, LIC was measured as described by Obrzut et al.[22] In brief, LIC was estimated by assessing the R2* relaxation rates of liver tissue using MRI. Images for measuring the LIC were obtained using the IDEAL-IQ technique.

Hepatic triglyceride content (fat) was measured using magnetic resonance spectroscopy as described by Szczepaniak et al.[23]

Statistical analysis

Categorical variables are presented as frequency and their percentages. Continuous variables are presented as mean ± standard deviation. A logistic regression was performed to identify the correlation between various clinicobiochemical parameters and MRE values. Statistical significance was considered at P < 0.05. Statistical analysis was conducted using statistical software package, version 9.4 SAS Institute Inc., Cary, NC, USA.


  Results Top


Demographics and baseline characteristics of study population

The study recruited 48 subjects who were diagnosed with different rheumatic diseases, RA (41) peripheral spondyloarthritis (SpA) (3), psoriatic arthritis (PsA) (3), and systemic lupus erythematosus (1), and majority of the subjects were female (n = 41). The mean age and body mass index (BMI) of the subjects were 53.56 ± 8.36 years and 28.08 ± 4.43, respectively. The mean duration (months) of rheumatic disease in these patients was 97.23 ± 30.55, and all patients received MTX therapy with a mean cumulative dose (mg) of 5268.13 ± 2315.61 for a mean period of 89.48 ± 30.11 months [Table 1].
Table 1: Demographic, clinical, and biochemical parameters of patients (n=48)

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Aspartate transaminase-to-platelet count ratio index and aspartate transaminase/alanine transaminase

In our study cohort, patients were divided into different groups based on the APRI cutoff scores that have clinical significance in predicting different stages of liver fibrosis. The mean APRI score of the study group was 0.31 ± 0.15. The APRI scores and fibrosis stages were described in [Table 2]. The mean AST: ALT ratio in rheumatic disease patients was elevated (1.17 ± 0.40) [Table 1].
Table 2: Fibrosis based on aspartate aminotransferase-to-platelet count ratio index score

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Liver magnetic resonance elastography

The mean MRE value of the study group was 2.83 ± 0.90 kPa. Around 45.83% (n = 22) of the patients had normal liver stiffness values (<2.5) whereas stages F0 (2.5–2.9 kPa), F1 (2.9–3.5 kPa), F2 (3.5–4.0 kPa), F3 (4.0–5.0 kPa), and F4 (>5.0 kPa) were observed in 12.5% (n = 6), 18.75% (n = 9), 10.42% (n = 5), 10.42% (n = 5), and 2.08% (n = 1) of the patients, respectively [Table 3].
Table 3: Liver fibrosis stages based on magnetic resonance elastography

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Correlation between magnetic resonance elastography findings and clinical and biochemical parameters

Various MRE findings were analyzed with logistic regression analysis for their association with clinical and biochemical parameters [Table 4]. A positive correlation was found between MRE and biomarkers of liver fibrosis (AST: ALT ratio, ALT, platelet count, APRI, albumin, and mean liver size), however, no statistical significance was observed between them. A negative correlation (statistically insignificant) was observed with age, gender, disease diagnosis, MTX duration, AST, and liver fat signal fraction. No correlation was observed with BMI, disease duration, and MTX cumulative dose.
Table 4: Correlation between magnetic resonance elastography findings and clinical and biochemical parameters

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Magnetic resonance elastography findings of patients with clinically significant fibrosis (≥F2)

The MRE findings and biochemical parameters of 11 patients with significant fibrosis are summarized in [Table 5]. Mean liver stiffness values increased with stages of fibrosis. Five patients (history of RA [n = 4] and peripheral SpA [n = 1]) had fibrotic stage F2 with MRE value ranging between 3.8 and 3.95 kPa. Another five patients with history of two different rheumatic diseases (RA, n = 3, and PsA, n = 2) had MRE values ranging between 4.2 and 4.6 kPa indicative of fibrotic stage F3. One patient with a history of systemic lupus erythematous had high MRE value of 5.05 kPa that was indicative of fibrotic stage F4/cirrhosis.
Table 5: Key findings of patients having clinically significant fibrosis

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  Discussion Top


Hepatic fibrosis has been considered to be a major safety concern with long-term usage of MTX therapy.[24] Several risk factors such as diabetes, obesity, alcoholism, and nonalcoholic fatty liver disease (NAFLD) have been attributed for MTX-induced hepatotoxicity.[25] Thus, in patients who have been on long-term MTX therapy, periodic assessment of liver function is advised.

Till date, biopsy is considered standard for liver fibrosis. However, the procedure is associated with sampling errors, intra- and inter-observer variability and poor repeatability. Furthermore, it may lead to death also.[9] Hence, noninvasive method like MRE with benefits of assessing the entire liver is gaining prominence.

With growing clinical experience, MRE is an emerging noninvasive technique for assessing hepatic fibrosis and is especially suitable as an alternative to liver biopsy due to its high reproducibility.[26] MRE employs propagating mechanical shear waves (range: 20–200 Hz) to probe stiffness in tissues. These shear waves propagate more rapidly in stiffer liver tissue compared to soft tissue and thus the speed of propagation of wavelength is directly proportional to the tissue stiffness. For evaluating the liver, a continuous acoustic vibration at 60 Hz is transmitted to the abdomen that is safe and well tolerated.[9]

MRE is significantly more accurate in diagnosing fibrosis in obese patients, as it is not influenced by BMI, ascites, or body habitus, all of which may limit the application of ultrasound-based quantitative elastography techniques.[27],[28] There are limited studies that compare MRE with acoustic radiation force impulse (ARFI). However, in some previous studies, MRE demonstrated a higher technical success rate and diagnostic accuracy compared to Fibroscan and ARFI.[11],[27] The accuracy of ARFI is poor for diagnosing fibrosis at lower dichotomization cut points and hence MRE is recommended.[29]

This is the first study to be carried out in Indian settings that use MRE for assessing liver fibrosis in patients with rheumatic diseases receiving long-term MTX therapy. Our study results demonstrate that MRE could be an effective, noninvasive option for staging hepatic fibrosis. Of the 48 subjects diagnosed with different rheumatic diseases, 54.16% (n = 26) of the patients had MRE values indicative of different stages of liver fibrosis (stage F0: 12.5%; F1: 18.75%; F2 and F3 10.42% each, and stage F4: 2.08%). Among them, specifically 11 (22.91%) patients had clinically significant fibrosis with high values of mean liver stiffness (3.5–4.6), and out of them, one patient had cirrhosis (F4) with a mean liver stiffness value of 5.05. Liver stiffness values measured by MRE in our study were similar to that reported in previous studies, and could also be able to differentiate fibrosis from cirrhosis.[30] The mean AST: ALT ratio was 1.17 ± 0.40, which was higher and abnormal in our study cohort. Several previous studies have reported elevated ALT/AST levels in rheumatic disease patients who were undergoing MTX therapy.[31],[32]

In our study, MRE values did not correlate with the MTX duration and the cumulative dose. In line with our observations, in one previous study, neither cumulative MTX dose nor treatment duration correlated with mean liver stiffness values.[33] Although statistically insignificant, a positive correlation was observed between MRE findings and biomarkers of liver fibrosis (AST: ALT ratio, ALT, platelet count, APRI, albumin, and mean liver size). In previous studies, fibrotic stages measured by MRE showed a positive correlation with APRI as observed in this study.[30],[34],[35] In a Phase II clinical trial conducted on patients with nonalcoholic steatohepatitis, MRE-based hepatic imaging results significantly correlated with histological features assessed cross-sectionally and longitudinally. Liver stiffness measured by MRE significantly correlated with fibrosis assessed by biopsy.[36] In a retrospective study, Lumongga and Anggraeni demonstrated a positive correlation between AST/ALT ratio and stage of histologic liver fibrosis in patients with chronic hepatitis.[37] In a previous study, Loaeza-del-Castillo et al. demonstrated a positive correlation between APRI score and stages of liver fibrosis (based on liver biopsy) in patients with chronic hepatitis C infection and NAFLD.[38] Hence, the combined use of both serum biomarkers and MRE is advantageous in detecting liver fibrosis or cirrhosis noninvasively in patients on long-term MTX therapy, and it is possible to minimize the usage of liver biopsy as it is associated with significant morbidity.

Study limitations

One of the limitations of this study is the lack of liver biopsy to correlate with our MRE findings. This study was a single-center-based retrospective analysis consisting relatively small sample size. Despite having considerable advantages compared to other techniques, MRE has multiple limitations. MRE is relatively costlier than the ultrasound-based elastographic techniques. MRE is typically a breath-hold technique and hence it requires respiratory co-operation by patients in order to optimize imaging. This technique is not suitable for patients who have claustrophobia or for those unable to lie down motionless for a short period. Furthermore, availability of MRE worldwide is very limited for its use in routine practice. Performing MRE in patients with diseases such as hemochromatosis or hemosiderosis is difficult due to hepatic iron overload and in those patients MRI signals may be too low.


  Conclusion Top


MRE is a reliable, noninvasive imaging technique with excellent diagnostic accuracy for detecting hepatic fibrosis and cirrhosis. It is safer and potentially less affected by sampling errors than biopsy. MRE was able to differentiate the different stages of fibrosis from cirrhosis even in patients with normal liver parameters. Neither cumulative dose nor MTX duration correlated with MRE findings. Many of these patients had biochemical abnormalities (AST: ALT ratio and APRI). Combined use of biochemical liver function tests and MRE is advantageous in detecting liver fibrosis or cirrhosis in patients on long-term MTX therapy, thus avoiding liver biopsy. Further investigation with MRE in a larger patient population of rheumatic diseases is warranted to validate our study findings. Furthermore, correlation with MRE vis-a-vis dose dependence needs further studies with high-volume data.

Acknowledgment

The authors would like to thank the CBCC Global Research for providing medical writing support in development of this manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

 
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