|Ahead of print publication
Assessment of liver fibrosis by acoustic radiation force impulse elastography in rheumatic disease patients on long-term methotrexate treatment
Arindam Nandy Roy, Gayatri Senapathy, Vijay Kumar Bongu, Yarram Ashok Kumar, Syeda Sana Fatima, Regina Lata Thadigiri
Department of Rheumatology and Radiology, Yashoda Hospital, Secunderabad, Telangana, Indiax, India
Arindam Nandy Roy,
Department of Rheumatology, Yashoda Hospitals, Secunderabad - 500 003, Telangana
Source of Support: None, Conflict of Interest: None
Background: Methotrexate treatment has been associated with liver fibrosis in patients with rheumatic disease. Liver biopsy has been the gold standard for staging liver fibrosis. Acoustic Radiation Force Impulse (ARFI) imaging is a new accurate, non-invasive method for staging liver fibrosis. Till date, no study has been conducted to evaluate the diagnostic value of ARFI in patients with rheumatic disease undergoing methotrexate treatment.
Study Objective: To assess the degree of liver fibrosis with non-invasive ARFI and to compare the findings with the biochemical parameters in rheumatic disease patients taking methotrexate for long duration.
Study Method: We reviewed the medical records of rheumatoid arthritis patients who were administered methotrexate for more than 2 years. A total of 151 patients with rheumatic disease, aged ≥ 18 years were enrolled into the study. In addition, 24 healthy subjects (controls) were recruited to compare the ARFI values with that of patients with rheumatic disease. On the day of the ARFI examination, a series of biochemical parameters were also assessed in the patient group. Pre-defined cut-off ARFI values were used to assess the stage of liver disease.
Results: The mean ARFI value in the patient group was 1.14. The mean ARFI values of different rheumatic disease patients were 1.13 (0.0), 1.26 (0.19), 1.16 (0.15), 0.945 (0.21) for Rhupus, rheumatoid arthritis, psoriatic arthritis and Sjogren's syndrome, respectively. Biochemical abnormalities (ALT/AST) were seen in 33 (21.85%) patients. Three patients had ARFI abnormalities (1: cirrhosis and 2: early stage fibrosis). There was no correlation between the ARFI values / biochemical parameters and the cumulative dose of methotrexate. However, the ARFI values correlated with the aspartate aminotransferase (AST), alanine aminotransferase (ALT) and AST to platelet ratio index. Liver fibrosis is rare in rheumatoid arthritis patients treated with a high cumulative dose of methotrexate, and is not accurately detected in patients with liver enzyme abnormalities.
Conclusion: Considering the risk and benefit ratio of liver biopsy, ARFI may be a useful non- invasive diagnostic tool for the monitoring hepatic toxicity in patients with rheumatic disease undergoing methotrexate treatment.
Keywords: Acoustic radiation force impulse imaging elastography, aspartate aminotransferase-to-platelet count ratio index, liver fibrosis, methotrexate, rheumatic diseases
|How to cite this URL:|
Roy AN, Senapathy G, Bongu VK, Kumar YA, Fatima SS, Thadigiri RL. Assessment of liver fibrosis by acoustic radiation force impulse elastography in rheumatic disease patients on long-term methotrexate treatment. Indian J Rheumatol [Epub ahead of print] [cited 2020 Apr 3]. Available from: http://www.indianjrheumatol.com/preprintarticle.asp?id=277934
| Introduction|| |
Methotrexate is a first-line drug for the treatment of several rheumatic and nonrheumatic diseases because of its cost-effectiveness in controlling disease activity and progression. Methotrexate-induced hepatotoxicity can progress as subclinical disorder. Liver biopsy is the standard invasive diagnostic procedure for staging liver fibrosis, but physicians are in a dilemma as severe complications have been reported in up to 1% of cases.
Noninvasive tests (serologic, radiologic, and their combination) attempt to predict liver fibrosis stage that would be seen histologically. While individual biomarkers of liver function have limited value, the combination of these can greatly improve their sensitivity and specificity in detecting liver fibrosis and cirrhosis. Ultrasound-based elastography (FibroScan®) is more often used nowadays to assess liver fibrosis in chronic liver disease patients and also tried for methotrexate-induced liver fibrosis in rheumatoid arthritis patients. Acoustic radiation force impulse imaging (ARFI) is a new and promising ultrasound-based elastographic technique for staging liver fibrosis. Till date, no studies have been published on the use of ARFI elastography in methotrexate-induced liver fibrosis and cirrhosis.
The objective of this study was to assess the diagnostic accuracy of ARFI in methotrexate-induced liver fibrosis and cirrhosis and to correlate with liver biomarkers and cumulative dose of methotrexate.
| Materials and Methods|| |
This was a cross-sectional study conducted from March 2016 to March 2017 in the Department of Rheumatology in Yashoda Hospital, Secunderabad.
The study was conducted with the approval of the Institutional Ethics Committee of Yashoda Hospitals, Secunderabad. Written informed consent was obtained from each patient.
One hundred fifty-one patients with different rheumatic diseases fulfilling the American College of Rheumatology/European League against Rheumatism criteria, aged ≥18 years and on methotrexate treatment for more than 2 years were included in the study. Medical records of these patients were reviewed, and data related to the demographics, diagnosis, disease duration, methotrexate dosage, and duration were collected.
Patients with underlying liver disease (hepatitis B, hepatitis C, or steatohepatitis), heavy alcoholics, diabetes mellitus, chronic renal insufficiency, congestive heart failure, obese (body mass index [BMI] >30) patients with a fatty thoracic belt, and on concomitant leflunomide treatment were excluded from the study.
Liver function tests
On the day of ARFI examination, serum biochemical markers of liver function (serum albumin, aspartate aminotransferase [AST], alanine aminotransferase [ALT], and gamma-glutamyl transferase [GGT]) were measured using VITROSR 5600 System, and a complete blood count was done by SYSMEX XN-1000 (II). Two combination biomarkers of liver function, i.e., AST-to-ALT ratio and AST to platelet count ratio index (APRI) were calculated for each patient. AST-to-ALT ratio and APRI are simple, readily available, and inexpensive tests to indirectly assess liver fibrosis. AST-to-ALT ratio is approximately 0.8 in normal subjects. A ratio ≥1 has great value in distinguishing cirrhotic from noncirrhotic patient in nonalcoholic liver disease.,,, APRI is another such test which uses the platelet count and AST and is easy to calculate. A meta-analysis of forty studies found that for 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 chronic hepatitis C patients. APRI was calculated by this formula and interpreted as shown in [Table 1].
|Table 1: Aspartate aminotransferase-to-platelet count ratio index score Interpretation|
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APRI = 100 × ([AST/Top normal AST]/[Platelets/1000])
Acoustic radiation force impulse imaging
The radiologist (second author) performed ARFI sonoelastography (Siemens Acuson S2000 US System) with a curved array US probe at 4 MHz for B-mode imaging and elastography in all patients and healthy controls after overnight fast. The right lobe of the liver was examined through the intercostal space with the patient lying in a left lateral decubitus position with the right arm in maximal abduction. The region of excitation in the liver was free of large blood vessels. A measurement depth of 2 cm below the liver capsule was chosen to standardize the examination. Every patient was asked to hold the breath for a few seconds during quiet breathing. Ten successful acquisitions were performed for each patient, and the median value with the interquartile range ≤30% was used as a representative measurement of the liver elastic modulus. The measurement was expressed in m/s, which denotes the shear-wave speed. The cutoff values for staging liver fibrosis and cirrhosis are shown in [Table 2]. Twenty-four healthy patients (controls), matched by age, gender, and BMI without any history of liver disease were recruited to compare the ARFI values.
|Table 2: Acoustic radiation force impulse imaging cutoff values for staging liver fibrosis and cirrhosis|
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Statistical analyses were conducted using IBM SPSS software IBM SPSS version 19.0 (Chicago, IL, SPSS Inc). Chi-square test was applied to identify the correlation between the biochemical and ARFI values. A statistical significance was defined as P < 0.05.
| Results|| |
Baseline characteristics of the study population
Majority of the patients were female. The average age and BMI of patients and controls were similar [Table 3]. The rheumatic disease patients studied were rheumatoid arthritis (N = 134), psoriatic arthritis (N = 12), Sjogren's syndrome (N = 4), and rhupus (N = 1).
Acoustic radiation force impulse imaging findings
The mean ARFI value was 1.14 (standard deviation [SD] 0.10) m/s in the patient group and 1.06 (SD 0.16) m/s in controls without any statistical difference between them. The mean ARFI values of different rheumatic disease patients were rheumatoid arthritis 1.26 (SD 0.19) m/s, psoriatic arthritis 1.16 (SD 0.15) m/s, rhupus 1.13 (SD 0.0) m/s, and Sjogren's syndrome 0.945 (SD 0.21) m/s, respectively. Based on the ARFI score, a significant proportion of patients (98%) did not have any sign of liver fibrosis and cirrhosis [Figure 1]. On an average, the ARFI value was <1.4 m/s over the entire range of cumulative dose of methotrexate [Figure 2]. In three patients, the ARFI values were above the cutoff level, and all three had rheumatoid arthritis. ARFI cutoff values predicted that one patient had cirrhosis (F4) and two had moderate fibrosis (F2/F3) [Table 4].
|Figure 1: Distribution of liver fibrosis/cirrhosis across the study population|
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|Figure 2: Acoustic radiation force impulse imaging value corresponding to the cumulative dose of methotrexate|
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|Table 4: Key findings of three patients who showed abnormal Acoustic Radiation Force Impulse elastography values|
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Liver function test results
The biochemical results for patient group are depicted in [Table 5]. Biochemical abnormalities (ALT or AST) were observed in 33 (21.85%) patients. Only three patients (2%) had liver enzymes two times the upper limit of normal.
Correlation of acoustic radiation force impulse imaging values with liver biochemical parameters
A significant correlation was found between ARFI and biomarkers of liver fibrosis (ALT, AST, platelet count, and APRI) [Table 6]. Parametric and Spearman's nonparametric analysis showed no statistical correlation with age, BMI, disease duration, AST/ALT ratio, albumin, GGT, and cumulative dosage of methotrexate.
|Table 6: Correlation of acoustic radiation force impulse elastography with clinical and biochemical parameters|
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| Discussion|| |
Risk of liver fibrosis with long-term usage of methotrexate is a perplexing problem, which cannot be ignored. However, the pathogenesis of chronic methotrexate hepatotoxicity cannot be explained by the drug alone. Age, gender, use of other drugs, alcoholism, obesity, diabetes mellitus, and severity of the disease are additional risk factors that predispose patients to methotrexate toxicity. Hence, a periodic review of the liver function is warranted in those who are on methotrexate treatment.
The distribution of liver fibrosis is not uniform across the whole liver, and there is a variation in stages of fibrosis between the left and right lobe; hence, liver biopsy has been associated with sampling error, as well as intra-observer and inter-observer variability. Moreover, liver biopsy has the potential to cause morbidity and mortality. Due to these limitations, noninvasive methods have emerged as an alternative for the early detection of liver damage.
In ultrasound-based liver elastography, an external force is applied to the tissue, thereby generating a shear wave. The speed of travel of this shear wave through the liver tissue corresponds to its elasticity and hence the amount of fibrosis. The first ultrasound-based elastography is transient elastography (FibroScan®) and is a well-established noninvasive method of diagnosing and staging hepatic fibrosis. ARFI imaging is a new technique where a single ultrasound transducer on a commercial ultrasound system generates acoustic radiation force in tissue and monitors the tissue displacement response., Intra-operator and inter-operator variability is minimum.
Unlike transient elastography, ARFI does not require additional transducers or other equipment; the visual control of measurement location with ARFI can avoid vascular structures, focus on the region of interest, correlate elasticity to the tissue architecture, and select the measurement depth. Meta-analyses of ARFI elastography concluded that it has excellent diagnostic accuracy (Area under the curve values 0.87 for significant fibrosis and 0.93 for cirrhosis), and similar predictive value as transient elastography for significant fibrosis and cirrhosis.
In this study, ARFI elastography was utilized for the first time to detect liver fibrosis in rheumatic disease patients using methotrexate for long-term. Of 151 patients of different rheumatic diseases, only 3 (2%) patients of rheumatoid arthritis were found to have moderate fibrosis (n = 2) and cirrhosis (n = 1). The ARFI scores did not correlate with a cumulative dose of methotrexate. Similarly, in two previous studies in rheumatoid arthritis using transient elastography (FibroScan®) 7.5% and 3.39% of patients were found to have significant liver fibrosis without any correlation to cumulative methotrexate dose.,
In our study, biochemical abnormalities (ALT or AST) were observed in 33 patients (21.85%), and 2% had more than twice the upper limit of normal. The mean AST/ALT ratio was 0.85 in our study. One of our patients having an ARFI score in the cirrhotic range (2.25 m/s) also had AST/ALT ratio of 1.02. In our study, APRI was >1 in the fibrotic and >2 in the cirrhotic patient. In one patient with abnormal ARFI value, APRI failed to reveal any sign of liver disease. Further, ARFI correlated significantly with AST (P < 0.001), ALT (P < 0.0001), APRI (P < 0.0001), and platelet count (P < 0.00249) in this study. In a study on chronic hepatitis B patients, AST/ALT ratio, APRI, and ARFI showed a significant correlation with liver biopsy. Hence, a combined use of serum biomarkers or APRI with ARFI may be used for detecting liver fibrosis and cirrhosis in most patients on long-term methotrexate therapy, thereby avoiding liver biopsy.
A major limitation of our study was a lack of liver biopsy and its correlation with the ARFI values. Our study did not consider the confounding factors such as concomitant medications (non-sterioidal anti-inflammatory drugs, steroids, and other disease-modifying antirheumatic drugs apart from leflunomide), which are likely to influence the toxicity profile of methotrexate. Obesity is a known risk factor for liver fibrosis. We could not investigate a correlation of ARFI value in obese patients taking methotrexate which was also a limiting factor in our study.
| Conclusion|| |
ARFI can be a useful imaging tool to detect liver fibrosis and cirrhosis. Liver fibrosis and cirrhosis were found to be uncommon with long-term methotrexate usage in rheumatic disease patients. The cumulative dose of methotrexate did not correlate with hepatic fibrosis as assessed by ARFI. ARFI combined with biochemical liver function tests can be a good strategy to detect liver fibrosis and cirrhosis in patients taking long-term methotrexate.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]