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. Author manuscript; available in PMC: 2015 Sep 9.
Published in final edited form as: Appl Radiol. 2013 Apr 4;42(4):5–12.

MR Elastography of Liver Disease: State of the Art

Jun Chen, Meng Yin, Kevin J Glaser, Jayant A Talwalkar, Richard L Ehman
PMCID: PMC4564016  NIHMSID: NIHMS718906  PMID: 26366024

Hepatic fibrosis is a common result of different chronic liver diseases caused by viral infections, alcohol abuse, nonalcoholic fatty liver disease (NAFLD), autoimmune disease and metabolic/genetic disorders. Hepatic fibrosis is a dynamic process which can, in some cases, be reversible with effective treatment (1, 2). Otherwise, it can progress to more advanced stages including cirrhosis where liver function is impaired and severe complications can occur such as variceal bleeding, ascites, portal hypertension, hepatocellular carcinoma and death (3). In 2009, chronic liver disease and cirrhosis were responsible for 143,000 hospitalizations, 11,000 in-hospital deaths (7.7% death rate), and 6.7 billion dollars of hospital charges in total (4).

Accurately detecting and staging fibrosis is important in the management of chronic liver disease for initiating treatment and monitoring its effects on the liver. Chronic viral hepatitis C (HCV) infection is a significant cause of hepatic disease and its treatment may depend on the presence of substantial fibrosis (5, 6).

It is well known that liver biopsy is the current reference method for the detection and staging of fibrosis. However, it is an invasive method and can cause undesired complications including bleeding (1.7%) (7) and death (0.01-1%) (7-9). The accuracy of liver biopsy is affected by sampling errors (20-33% of patients can have fibrosis stage misclassified by 1 category) (10, 11), and intra- and inter-operator inconsistency (Kappa coefficient 0.62 – 0.89, where 1 means perfect agreement) (11, 12). Furthermore, this approach is not well accepted by patients and physicians alike (13).

Conventional noninvasive imaging techniques (ultrasound, computed-tomography, MRI) can visualize the morphologic changes of liver due to fibrosis and cirrhosis. However, the sensitivity and accuracy of these modalities are low for detecting earlier stages of fibrosis and thus are not suitable for staging liver fibrosis over its entire spectrum (14). Over the last several years, new noninvasive methods of assessing liver fibrosis have been developed and investigated, including serum tests, diffusion-weighted MR imaging (DWI), contrast enhanced MR imaging (CE-MRI), ultrasound based transient elastography (UTE) and MR elastography (MRE). Accumulated data showed that the AUROC (area under receiver operating characteristic curve) values are between 77%-91% for serum tests (15-20), 88% for DWI (21), and 83% for CE-MRI (22) to detect the presence of liver fibrosis due to different disease causes. As one of the two existing methods of measuring liver stiffness, UTE has higher AUROC values (0.79-0.98) (23-25), yet it is less accurate for detecting early fibrosis stages and has a high technical failure rate in certain patient subsets (ascites, narrow intercostals space, obesity) (26-28). The other method of measuring liver stiffness, MR elastography (MRE) is the most accurate (AUROC = 92% - 100%) method for detecting and staging liver fibrosis to date, especially in early stages of fibrosis because of its capability of measuring cross-sectional areas of hepatic parenchyma, and the technique is not affected by the ascites and obesity (3, 21, 26, 27, 29-31). In one study, MRE even detected necroinflammation before the onset of fibrosis in patients with NAFLD (32). The detection of early stage fibrosis is of clinical significance as treatments for liver disease are thought to be more effective when compared to later stages of fibrosis. Given its technical advantages and high diagnostic accuracy, this article reviews the application of MR elastography to address clinical questions involving HCV, NAFLD, and methotrexate (MTX) exposure.

Hepatic MR Elastography

MR elastography is a technology for characterizing the biomechanical properties (e.g., stiffness) of tissues in vivo. It uses MR phase-contrast techniques to acquire images of wave propagation in tissue which are produced by an external source of mechanical vibration. The images of wave propagation are interpreted and processed by inversion algorithms which result in a tissue stiffness map called an elastogram from which the tissue stiffness is measured (33). MRE exams of normal livers have visibly shorter wavelengths in the wave images and lower liver stiffness values in the elastograms, which means normal livers are soft. Fibrotic and cirrhotic livers have longer wavelengths and higher liver stiffness values, which means diseased livers are hard (3, 21, 26, 27, 29-31). This is consistent with the experience of palpation by clinicians in which the fingers are used to subjectively examine and feel the stiffness of the liver. Details of the MRE technique and scan parameters can be found in the literature (3, 30, 31). A typical MRE procedure is summarized here. As shown in Figure 1, a patient lies on the scanner table in a supine position and a drum-like acoustic passive driver is positioned against the body wall, close to the liver, and secured by an elastic belt (not shown in the figure for a clear view) wrapped around the body. The passive driver is connected to an acoustic speaker system located outside the scanner room via a flexible polyvinylchloride (PVC) tube which provides a programmed external mechanical vibration. The acoustic speaker produces vibrations at audible frequencies (typically 40-80Hz) which are transmitted to the passive driver through the tube. A gradient-echo MRE imaging sequence is used to acquire images of the wave propagation within the liver. Subsequently, elastograms are calculated using a direct inversion of the differential equations describing the wave propagation (34). In addition to the liver, MRE has been adapted for use in other organs like the brain, breast, muscle, heart, kidney, spleen and lung with promising results observed to date for these applications (35-47).

Figure 1.

Figure 1

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Diagram of the MR Elastography driver system setup for a clinical whole-body MRI scanner. 1: patient table, 2: patient, 3: passive MRE driver, 4: MRI scanner bore, 5: flexible tube, 6: active MRE driver (acoustic speaker).

Diagnostic accuracy of MRE for detecting fibrosis in chronic liver disease

Hepatic fibrosis is an accumulation of the extracellular matrix that results from hepatic stellate cell transdifferentiation to myofibroblasts trigged by necroinflammation of hepatocytes. The necroinflammation is a wound-healing response to liver cell injury which may be due to different causes of liver disease (48). Accumulated data have shown that liver stiffness measured by MRE is highly correlated with and increases with fibrosis stage identified by liver histology (3, 21, 26, 27, 29-31). In some cases, an early increase of liver stiffness was found even before the onset of fibrosis due to liver cell injury (32, 49-53). One possible explanation of the strong relationship between liver disease and liver stiffness could be that early liver cell injury leads to changes in the extracellular matrix that increase the stiffness of hepatic tissue, which through a process known as mechanotransduction promotes the activation of stellate cells and the subsequent development of fibrosis (32, 49, 50), which in turn increases the liver stiffness as well. The persistent elevation in stiffness of the mechanical environment is then felt to accelerate the fibrosis progression to more advanced stages. To date, the data have shown that in chronic liver diseases with different causes, MRE has high diagnostic accuracy (AUROC = 92% - 100%) for detecting and staging hepatic fibrosis, as seen in Table 1. Within our institution, we use a liver stiffness value of 2.93 kPa as the threshold for detecting nonfibrotic liver tissue, where an abnormal liver stiffness is greater than 2.93 kPa. The diagnostic accuracy, sensitivity, specificity, positive and negative predictive values of this cut-off value are no less than 97% (3).

Table 1.

Diagnostic accuracy of MRE for detecting different stages of hepatic fibrosis in patients with chronic liver disease

Causes Number of subjects (N) Fibrosis stage MRE liver stiffness (kPa) Sens (%) Spec (%) NPV (%) PPV (%) AU ROC (%) Ref
Virus, alcohol, NASH, antitrypsin deficiency, drug toxicity, unknown. 96 >= F1a 2.42 85 91 64 97 96 Huwart 2008 (57)
>= F2a 2.49 100 91 100 93 99
Virus, alcohol, NASH, autoimmune disease, antitrypsin deficiency, primary biliary cirrhosis, unknown. 88 >= F1a 2.4 83 100 67 100 96 Huwart 2007 (30)
>= F2a 2.5 98 100 97 100 100
Healthy (N=35), HCV, NASH, autoimmune disease, primary biliary cirrhosis, alcoholic. 48 >= F1b 2.93 98 99 97 99 99 Yin 2007 (3)
>= F2b 4.89 86 85 NA NA 92
Healthy (N=16), virus, NASH, autoimmune disease, primary biliary cirrhosis, toxin, unknown. 74 >= F1c 2.90* 75 94 NA NA 92 Asbach 2010 (59)
>= F2c 3.19* 77 97 NA NA 93
Virus, alcohol, NASH, NAFLD, autoimmune disease, primary sclerosing cholangitis, unknown. 76 >= F1b 5.02 77 100 72 100 92 Wang 2011 (21)
>= F2b 5.37 91 97 93 97 98
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Note - Biopsy criteria

a

METAVIR

b

Brunt for NASH and alcoholic hepatitis and METAVIR for others

c

generalized method.

*

real part of liver stiffness. Sens = Sensitivity; Spec = Specificity; NPV = Negative Predictive Value; PPV = Positive Predictive Value; AUROC = Area Under Receiver Operating Characteristic Curve; NA = not available.

Reproducibility and Consistency

Several groups have shown that hepatic MR elastography has excellent reproducibility and inter-operator consistency. The coefficient of variation between hepatic stiffness measurments conducted on different days among the same individuals ranged between 7% - 12% (54-56), while the intra-class correlation coefficient for hepatic stiffness measured by two different operators was 97%-99% (100% means exactly the same reading) (57, 58).

Chronic Hepatitis C Virus

Approximately 150,000 patients were newly diagnosed with chronic liver disease in the USA adult population each year during 1999-2001 with two thirds of individuals affected by hepatitis C (60). Determining the presence and degree of liver fibrosis is important for planning treatment in patients with chronic hepatitis C viral infection (5, 6). Serum tests are routinely performed to assess the liver damage due to HCV, but they have low specificity for identifying disease severity. Therefore, liver biopsy is the only reference method to confirm and stage fibrosis in HCV patients. Utilizing multiple parameters from serum tests and clinic risk factors in a model could improve the diagnostic accuracy. A study used a model including four readily available characteristics, platelet count, presence of spider nevi, AST and gender to predict the presence of cirrhosis in HCV patients. The AUROC for this model was 0.94 for the training set and 0.93 for the validation patient group (61). However, a model of using combined data from serum tests and clinical information needs further validation because of the different patient demographics between training patient group and the tested patients. For example, the AUROC value of using such a model dropped from 0.84 in training patient group to 0.77 in validation patient group for detecting significant fibrosis (stages F2-F4) in HCV patients (16). A combined data review from 4 studies showed that ultrasound-based transient elastography (UTE) had an AUROC of 0.83 to detect significant fibrosis (F2-F4) in HCV-related patient, but was less accurate for earlier stages for earlier stages of fibrosis (62). Chronic liver disease patients with other causes of liver disease have been evaluated by MRE in different studies with excellent diagnostic accuracies for detecting clinically significant hepatic fibrosis as seen in Table 1. In one MRE study of subjects with HCV (METAVIR F2–F4) and healthy volunteers, the mean liver stiffness was significantly greater in patients with HCV than healthy volunteers, and the correlation between liver stiffness and fibrosis stage confirmed by liver biopsy was 0.89 (54). Here we show two MRE scan examples of HCV patients with and without biopsy proved fibrosis.

Figure 2 (a) and (b) shows an MRI/MRE exam of a 47-year-old male patient with untreated HCV. The patient had normal T2-weighted images, and the hepatic stiffness measured on the elastogram was 2.1 ± 0.3 kPa (nonfibrotic value < 2.93). Liver biopsy was done 40 days before the MRI/MRE exam, and found grade 2 of 3 necroinflammation and stage 0 of 4 fibrosis.

Figure 2.

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MRI/MRE exams of two patients with chronic HCV infection. Upper row: a 47-year-old male, (a) T2-weighted image revealed no abnormality, (b) Elastogram demonstrated a mean hepatic stiffness of 2.1 kPa, which is well within the normal range of less than 2.9 kPa. Liver biopsy demonstrated no fibrosis. Bottom row: a 68-year-old male, (c) T2-weighted image demonstrated no abnormality, with smooth liver margins. (d) Elastogram demonstrated elevated hepatic stiffness, averaging 4.5 kPa. Liver biopsy demonstrated stage 3 fibrosis.

Figure 2 (c) and (d) shows an MRI/MRE exam of a 68-year-old male patient with known HCV. The patient had smooth liver margins on the T2-weighted images, and the hepatic stiffness was 4.5 ± 0.3 kPa (nonfibrotic value < 2.93); Liver biopsy was done 18 days after the MRI/MRE scan, and found grade 2 of 3 necroinflammation and stage 3 of 4 fibrosis.

Nonalcoholic Steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) is an increasingly prevalent clinical syndrome associated with obesity and type-2 diabetes mellitus, which is estimated to affect one third of the general adult population in the USA (63-67). The spectrum of NAFLD ranges from simple steatosis to necroinflammation and fibrosis. Simple steatosis is thought to have a benign long-term prognosis. In contrast, up to 25% of patients may progress from simple steatosis to nonalcoholic steatohepatitis (NASH) which is characterized by necroinflammation and/or varying degrees of fibrosis (63, 65, 68). Studies to date estimate that early-stage NASH has a probability of 18-39% to progress to more advanced stages of hepatic fibrosis and cirrhosis within 8 years from initial detection (69-73). It is anticipated that NASH-induced cirrhosis will also become the most common indication for liver transplantation in the future (65). Therefore, early liver biopsy has been suggested in all NAFLD patients to stratify this disease so that earlier interventions and more aggressive treatment can be applied to reduce overall mortality (73). Due to the invasive nature of liver biopsies, however, other noninvasive methods have been evaluated for the diagnosis and serial assessment of NASH including novel serological and imaging tests. Serum markers for detecting NAFLD have reasonably good accuracy (AUROC = 77% - 91%) for detecting advanced fibrosis (15-20) but are poor at diagnosing milder degrees of fibrosis and necro-inflammation. Plasma pentraxin 3 (PTX3) and cytokeratin 18 (CK18) fragments have shown improved accuracy for detecting NASH (AUROC = 75% - 83%), yet further validation of these approaches is still required (74-77). UTE has a high accuracy (AUROC = 79% - 0.98%) for detecting fibrosis in NASH patients (23-25). However, UTE scans in patients with NAFLD showed unreliable measurements in 14% of patients due to obesity and decreased diagnostic accuracy (28, 78). In addition, UTE was not sensitive in identifying steatohepatitis without fibrosis in patients with NAFLD (25). In contrast, an independent study using MRE detected a significant increase in liver stiffness due to necroinflammation prior to the onset of fibrosis in NASH patients compared to patients with simple steatosis. MRE had a sensitivity of 94% and a specificity of 73% using a threshold of 2.74 kPa to discern NASH from simple steatosis (AUROC = 0.93) (32). Here we demonstrate 3 MRE scans of fatty liver disease patients with simple steatosis alone, necroinflammation but no fibrosis, and fibrosis.

Figure 3 (a) and (b) shows an MRI/MRE exam of a 62-year-old female patient with known NAFLD, BMI = 40.7 kg/m2. This patient had normal appearance on the T2-weighted images, and the mean (± SD) hepatic stiffness measured on the elastogram was 2.05 ± 0.28 kPa (nonfibrotic value < 2.93). Liver biopsy was done one day after the MRI/MRE exam and found grade 0 of 3 necroinflammation, stage 0 of 4 fibrosis.

Figure 3.

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MRI/MRE exams of three NFALD patients. Upper row: a 62-year-old female patient with obesity (BMI 41) and clinical evidence of fatty liver disease, (a) T2 weighted images demonstrated no abnormality, (b) Elastogram demonstrated normal mean hepatic stiffness of 2.1 kPa. Liver biopsy demonstrated no necroinflammation and no fibrosis. Middle row: a 44-year-old male patient with obesity (BMI 39) and clinical evidence of fatty liver disease, (c) T2-weighted image demonstrated a normal hepatic contour, (d) Elastogram demonstrated increased hepatic stiffness, averaging 4.48 kPa. Liver biopsy demonstrated grade 1 necroinflammation and no fibrosis. Bottom row: a 60-year-old female patient with obesity (BMI 31) and clinical evidence of fatty liver disease, (e) T2-weighted images revealed hepatic nodularity, (f) Elastogram demonstrated markedly elevated hepatic stiffness, averaging 10.2 kPa. Hepatic biopsy demonstrated grade 2 necroinflammation and stage 4 fibrosis.

Figure 3 (c) and (d) shows an MRI/MRE exam of a 44-year-old male patient with NASH and abnormal liver serum tests, BMI = 38.8 kg/m2. This patient had normal contour and appearance on the T2-weighted images, and the mean (± SD) hepatic stiffness measured on the elastogram was 4.38 ± 0.39 kPa (nonfibrotic value < 2.93). Liver biopsy was done 13 days after the MRI/MRE exam, and found grade 1 of 3 necroinflammation, stage 0 of 4 fibrosis.

Figure 3 (e) and (f) shows an MRI/MRE exam of a 60-year-old female patient with NASH, BMI = 31.4 kg/m2. This patient had small regenerative nodules in the T2-weighted images, and the mean (± SD) hepatic stiffness measured on the elastogram was 10.24 ± 0.9 kPa (nonfibrotic value < 2.93). Liver biopsy was done 21 days after the MRI/MRE exam, and found grade 2 of 3 necroinflammation, stage 4 of 4 fibrosis.

Obese patients undergoing bariatric surgery

Bariatric surgery has been shown to be a very effective treatment for medically-complicated obesity. In turn, patients undergoing bariatric surgery who are also affected by NAFLD and NASH have experienced improvements in liver histology following significant weight loss. One study showed that in 116 patients who had necroinflammatory activity on a presurgical liver biopsy, 108 had complete regression after the surgery. In 12 patients who had fibrosis at the first biopsy, 10 had complete remission and 2 had improvement. In all patients, the BMI decreased from 55.2 ± 8.3 to 30.5 ± 6.6 kg/m2 (79).

Here is an example of follow-up MRE scans of a NASH patients with obesity after the bariatric surgery in our institution, which shows a potential of using MRE to evaluate the treatment of NASH. A 33-year-old female obese patient with a BMI of 47.2 kg/m2 underwent bariatric surgery on 03/07/2005. Liver biopsy done on the same day found grade 1 of 3 necroinflammation and stage 3 of 4 fibrosis. No further liver biopsy was performed. A clinical liver MRI scan including MRE was performed on 4/27/2007 and a second exam was performed on 7/10/2008. At the first MRI/MRE visit, the patient had a BMI of 40 kg/m2, mean (± SD) liver stiffness of 3.67 ± 0.1 kPa (nonfibrotic value < 2.93), and mild increased T2 signal in the periportal tracts suggestive of inflammation. At the second visit, the patient had a BMI of 33 kg/m2, mean (± SD) liver stiffness of 2.32 ± 0.33kPa (nonfibrotic value < 2.93) and the increased T2 signal in the periportal tract was no longer evident. The decreased liver stiffness was consistent with the improvement of this patient's condition (Figure 4).

Figure 4.

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Liver stiffness and BMI decreased after bariatric surgery for a 33-year-old female obese patient.

Methotrexate use

Methotrexate (MTX) is the most frequently prescribed drug for rheumatoid arthritis (RA) because of its efficacy, low cost and safety (80). Generally speaking, MTX is tolerated well by most patients yet its potential for hepatotoxicity and liver fibrosis has remained an ongoing concern for clinicians. It is uncertain whether the risk for liver fibrosis is increased with cumulative doses of MTX. In 1994, American College of Rheumatology (ACR) developed guidelines for laboratory monitoring of liver enzyme tests, and suggested further evaluation including liver biopsy based on the frequency (5 of 9) of abnormal aspartate aminotransferase (AST) values during one year (81). In a recent study using liver stiffness measurement by MRE as a surrogate measure of liver fibrosis, it was demonstrated that neither the total MTX dose nor the duration of MTX treatment was associated with mean hepatic stiffness in 65 RA patients who underwent MRE scans (unpublished data). Here are two MRE scan examples of two RA patients with MTX use for the disease control, which shows a potential of MRE to detect liver fibrosis due to the drug toxicity.

Figure 5 (a) and (b) shows an MRI/MRE exam of a 70-year-old female RA patient with 24 years of MTX use, the total MTX dose was 18468 mg, BMI = 24.1 kg/m2. This patient had mean (± SD) hepatic stiffness measured as 2.07 ± 0.30 kPa (nonfibrotic value < 2.93), and had 0/4 abnormal AST tests done during 2 years prior to the MRI/MRE exam. This patient continued to use MTX for the treatment of RA.

Figure 5.

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MRI/MRE exams of two patients with rheumatoid arthritis. Upper row: a 70-year-old female treated for 24 years with methotrexate, (a) conventional T1 weighted MR imaging of the liver revealed no abnormality, (b) Elastography demonstrated normal hepatic stiffness of 2.1 kPa. This patient continued to receive methotrexate therapy. Bottom row: a 66-year-old male treated for 4 years with methotrexate, (c) conventional T1 weighted MR imaging revealed no abnormality, (d) Elastography demonstrated mildy elevated hepatic stiffness of 3.1 kPa. Liver biopsy demonstrated mild periportal fibrosis.

Figure 5 (c) and (d) shows an MRI/MRE exam of a 66-year-old male RA patient with 4 years of MTX use, the total MTX dose was 3680 mg, BMI = 37.3 kg/m2. The mean (± SD) hepatic stiffness measured on the elastogram was 3.13 ± 0.40 kPa (nonfibrotic value < 2.93). Liver biopsy was ordered due to the abnormal liver stiffness by the GI doctor and the biopsy found mild fatty change with mild portal fibrosis. This patient had 0/10 abnormal AST tests done during 2 years prior to the MRI/MRE exam thus liver fibrosis would not have been suspected or found without the MRE scan.

Comparison with ultrasound-based transient elastography

Both MRE and UTE noninvasively measure liver stiffness, but MRE can more accurately measure liver stiffness because it captures two dimensional cross-sectional images, while UTE may have sampling errors due to its one-dimensional nature like liver biopsy. UTE also has technical limitations when measuring liver stiffness in patients with obesity, ascites and narrow intercostal spaces (26-28); UTE scans in patients with NAFLD showed unreliable measurements in 14% patients due to obesity and decreased diagnostic accuracy (28, 78). Recently, extra large probes have been developed to address the technical limitations of UTE for imaging obese patients, but these still require further verification. MRE is not limited by these factors, yet the approach also has its own technical limitations including claustrophobia, typical contraindications for MRI regarding magnetically susceptible implants, and low liver signal related to increased hepatic iron from hemochromatosis or advanced chronic liver disease (3, 57). However, continued developments in MRE technology indicate that patients with low liver signal can potentially undergo liver stiffness assessment using short echo time and spin-echo MRE sequences (82).

In the case of characterizing liver tumors, MRE is the only technique capable of noninvasively measuring tumor stiffness because it reports cross-sectional stiffness information about the liver and the tumors inside it. Tumor assessment is currently not possible with UTE because the fixed acoustic window of UTE cannot specifically target tumors which can occur at any location in the liver.

Conclusions

Based on growing evidence in the scientific literature, quantitative elasticity imaging is being increasingly recognized by the hepatology community as a useful diagnostic tool for noninvasively assessing chronic liver disease. MRE technology has moved from the laboratory to the clinic and is increasingly available as an FDA-approved option for MRI systems. Over the past 4 years, over 1700 patients have undergone hepatic MRE exams as a part of clinical practice at our institution. Similar experience is accumulating at many other centers around the world. For many patients, MRE is emerging as an effective, more comfortable, and less expensive diagnostic alternative to biopsy for assessing hepatic fibrosis.

Acknowledgment

NIH RO1 Grant EB 001981 and EB 10393

Footnotes

Conflict of interest/author disclaimer

JC, MY, KJG, RLE and the Mayo Clinic have patent rights and a financial interest related to the subject of this manuscript. JAT does not have conflict of interest. All research described here conducted under the oversight the Mayo Clinic Office of Conflict of Interest Review Board.

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