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To use magnetization tagged magnetic resonance imaging (MRI) (tag-MRI) to quantify cardiac induced liver strain and compare strain of cirrhotic and normal livers.
Materials and methods:
Tag-MRI was performed at 1.5T on eight subjects with no history of liver disease and 10 patients with liver cirrhosis. A breath-hold peripheral pulse-gated (PPG) conventional tag-MRI cine sequence was performed with planes to include the left lobe of the liver and the inferior wall of the heart. Commercially available software HARP (Diagnosoft, Palo Alto, CA) was used for image analysis and strain calculation. Three regions-of-interest (ROIs) were selected: segment II of the liver near the heart (A), right liver lobe far from the heart (B), and the left ventricular wall (C). The average and maximal (max) strain were measured in A, B, and C. The maximum strains were used to generate a cardiac-corrected strain gradient: (maxA-maxB)/maxC. Results were compared with Student's t-test (SPSS, Chicago, IL).
In subjects with no history of liver disease vs. cirrhotic patients, the average strain was 22% ± 7% vs. 4% ± 3% (P < 0.001), the max strain was 63% ± 15% vs. 17% ± 5% (P < 0.001), and the corrected strain gradient was 0.52 ± 0.16 vs. 0.11% ± 0.08%.
There is a significant difference in liver strain measured with tag-MRI between subjects with no history of liver disease and patients with cirrhosis.
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... Recently, intrinsic driver MRI techniques have been developed to assess liver fibrosis using cardiac motion as an intrinsic source of motion instead of an external driver (24)(25)(26). The techniques rely on analyzing the deformation of MR tags, first introduced by Zerhouni et al. (27) and Axel et al. (28). ...
... Previous techniques required multiple slice acquisitions with long breath holds. Gabor filter bank (24) and harmonic phase analysis (24,29) were used to track the deformation of the MR tags in the liver. Manually selected regions of interest below the diaphragm were used to calculate maximum and minimum strain. ...
... Previous techniques required multiple slice acquisitions with long breath holds. Gabor filter bank (24) and harmonic phase analysis (24,29) were used to track the deformation of the MR tags in the liver. Manually selected regions of interest below the diaphragm were used to calculate maximum and minimum strain. ...
... The final step is to select an ROI for measuring representative strain for each patient. 108,109 Alternatively, strain-encoded imaging gives a direct measurement of strain through a similar process that encodes strain into the signal by varying the spatial frequency of artificial tags in the image. 110 ...
... The diagnostic performance of MR strain imaging has not been assessed for staging fibrosis in its early stages. Studies have focused on differentiation between normal and cirrhotic livers 109,110 or compared liver strain in patients with cirrhosis with different Child-Pugh scores. 108 The reported diagnostic accuracy of cine-tagging for classification of Child-Pugh A or greater is in the range of 0.910-0.998 ...
Liver fibrosis is characterized by the accumulation of extracellular matrix proteins such as collagen in the liver interstitial space. All causes of chronic liver disease may lead to fibrosis and cirrhosis. The severity of liver fibrosis influences the decision to treat or the need to monitor hepatic or extrahepatic complications. The traditional reference standard for diagnosis of liver fibrosis is liver biopsy. However, this technique is invasive, associated with a risk of sampling error, and has low patient acceptance. Imaging techniques offer the potential for noninvasive diagnosis, staging, and monitoring of liver fibrosis. Recently, several of these have been implemented on ultrasound (US), computed tomography, or magnetic resonance imaging (MRI). Techniques that assess changes in liver morphology, texture, or perfusion that accompany liver fibrosis have been implemented on all three imaging modalities. Elastography, which measures changes in mechanical properties associated with liver fibrosis-such as strain, stiffness, or viscoelasticity-is available on US and MRI. Some techniques assessing liver shear stiffness have been adopted clinically, whereas others assessing strain or viscoelasticity remain investigational. Further, some techniques are only available on MRI-such as spin-lattice relaxation time in the rotating frame (T1 ρ), diffusion of water molecules, and hepatocellular function based on the uptake of a liver-specific contrast agent-remain investigational in the setting of liver fibrosis staging. In this review, we summarize the key concepts, advantages and limitations, and diagnostic performance of each technique. The use of multiparametric MRI techniques offers the potential for comprehensive assessment of chronic liver disease severity.
Level of evidence:
5 J. MAGN. RESON. IMAGING 2017;45:1276-1295.
... We do acknowledge that only one patient in our sample had significant hepatic siderosis, so further work would be required to confirm if LD measurements are definitively robust in the setting of iron-overload. Interestingly, several studies measuring cardiac-induced liver motion with magnetization-tagging have demonstrated reducing liver 'strain' with advancing liver disease [11,13,29], opposing our finding of increased normalized/absolute LD in the setting of liver disease. This may have arisen from methodological differences, and we postulate that higher LD values in liver disease may reflect greater sensitivity to increased translational motion (as a result of stiffer liver tissue), as opposed to greater elastic motion as seen in non-diseased liver (which strain methods are potentially more sensitive to). ...
... It is also worth noting that we studied a largely stable disease cohort (predominantly Child-Pugh A)-while this could account for a nonsignificantly higher patient LD, biomechanical properties of liver tissue are arguably more dependent upon the degree of fibrosis/cirrhosis severity rather than disease stability. Previous studies using magnetization-tagging based measures of liver motion for example, were still able to demonstrate significantly different measurements in similarly sized patient cohorts with predominantly stable Child-Pugh A liver disease , suggesting that LD may have lower sensitivity. ...
PurposeMR elastography and magnetization-tagging use liver stiffness (LS) measurements to diagnose fibrosis but require physical drivers, specialist sequences and post-processing. Here we evaluate non-rigid registration of dynamic two-dimensional cine MRI images to measure cardiac-induced liver deformation (LD) as a measure of LS by (i) assessing preclinical proof-of-concept, (ii) clinical reproducibility and inter-reader variability, (iii) the effects of hepatic hemodynamic changes and (iv) feasibility in patients with cirrhosis.Methods
Sprague–Dawley rats (n = 21 bile duct ligated (BDL), n = 17 sham-operated controls) and fasted patients with liver cirrhosis (n = 11) and healthy volunteers (HVs, n = 10) underwent spoiled gradient-echo short-axis cardiac cine MRI studies at 9.4 T (rodents) and 3.0 T (humans). LD measurements were obtained from intrahepatic sub-cardiac regions-of-interest close to the diaphragmatic margin. One-week reproducibility and prandial stress induced hemodynamic changes were assessed in healthy volunteers.ResultsNormalized LD was higher in BDL (1.304 ± 0.062) compared with sham-operated rats (1.058 ± 0.045, P = 0.0031). HV seven-day reproducibility Bland–Altman (BA) limits-of-agreement (LoAs) were ± 0.028 a.u. and inter-reader variability BA LoAs were ± 0.030 a.u. Post-prandial LD increases were non-significant (+ 0.0083 ± 0.0076 a.u., P = 0.3028) and uncorrelated with PV flow changes (r = 0.42, p = 0.2219). LD measurements successfully obtained from all patients were not significantly higher in cirrhotics (0.102 ± 0.0099 a.u.) compared with HVs (0.080 ± 0.0063 a.u., P = 0.0847).Conclusion
Cardiac-induced LD is a conceptually reasonable approach from preclinical studies, measurements demonstrate good reproducibility and inter-reader variability, are less likely to be affected by hepatic hemodynamic changes and are feasible in patients with cirrhosis.Grahpic Abstract
... Despite small amounts of pressure, MR was capable of capturing the resulting deformation in the liver. 21,22 This reduces the need for an external device and thus enables fast screening of patients and real-time onsite stiffness assessment. This method was used by Chung et al to detect late-stage fibrosis, ie, cirrhosis. ...
... Moreover, we introduced a novel noninvasive method to detect liver fibrosis using a new set of features extracted from tagged MR images of the liver. While the recent noninvasive methods used to assess liver stiffness consider only the peak strain or displacement at specific ROIs, 21,22 the proposed method uses the histogram of strains at all points within the liver as a feature. This results in two main advantages: ...
... Deformation and strain can then be measured through direct estimation (analysis of the Harmonic Phase (HARP) images [11,12]) or indirect estimation (tissue point tracking ) of the displacement field. The use of tagged MRI to quantify cardiacinduced strain in the liver has shown different patterns of liver motion and deformation in cirrhotic patients and healthy subjects [8,14], as well as in two cirrhotic patient groups stratified by Child-Pugh scores . Liver displacements induced by cardiac pressure range from less than 1 mm in cirrhotic patients to 5 mm for normal liver and involve a very limited part of the liver close to the bottom wall of the heart, identifiable with the second segment of the liver. ...
... The amplitude of the simulated displacements, for typical pixel sizes of real abdominal acquisitions, fell within the range of the observed liver movements in normal and cirrhotic patients (1,5 mm) [8,14,15]. In the absence of noise, displacement estimation accuracy improved as the grid tag spacing decreased and became optimal for small displacements (pixel size or less). ...
The heartbeat has been proposed as an intrinsic source of motion that can be used in combination with tagged Magnetic Resonance Imaging (MRI) to measure displacements induced in the liver as an index of liver stiffness. Optimizing a tagged MRI acquisition protocol in terms of sensitivity to these displacements, which are in the order of pixel size, is necessary to develop the method as a quantification tool for staging fibrosis. We reproduced a study of cardiac-induced strain in the liver at 3T and simulated tagged MR images with different grid tag patterns to evaluate the performance of the Harmonic Phase (HARP) image analysis method and its dependence on the parameters of tag spacing and grid angle. The Partial Volume Effect (PVE), T1 relaxation, and different levels of noise were taken into account. Four displacement fields of increasing intensity were created and applied to the tagged MR images of the liver. These fields simulated the deformation at different liver stiffnesses. An Error Index (EI) was calculated to evaluate the estimation accuracy for various parameter values. In the absence of noise, the estimation accuracy of the displacement fields increased as tag spacings decreased. EIs for each of the four displacement fields were lower at 0° and the local minima of the EI were found to correspond to multiples of pixel size. The accuracy of the estimation decreased for increasing levels of added noise; as the level increased, the improved estimation caused by decreasing the tag spacing tended to zero. The optimal tag spacing turned out to be a compromise between the smallest tag period that is a multiple of the pixel size and is achievable in a real acquisition and the tag spacing that guarantees an accurate liver displacement measure in the presence of realistic levels of noise.
... 22 By modulating the longitudinal magnetization of proton spins, tagged lines arise in MR images that provide a way to track motion of tissue over time.  Just as they are useful for diagnosing cardiac disease, biomechanical parameters estimated from MR tagging could provide potential alternative biomarkers for assisting the diagnosis of liver tumors. ...
... While HEMs were physically similar to the surrounding tissues in most cases, we observed a larger e soct value of the HEMs compared to the peripheral tissues, suggesting that HEMs were more complaint in shear than the surrounding parenchyma, analogous to fibrotic tissue.  These results add to a large body of literature using displacement and strains as biomarkers for diagnostic and treatment evaluation purposes. 33,34 Displacements from harmonic motion imaging using ultrasound are indicative of tissue stiffness and can be used to distinguish benign and malignant breast tumors. ...
Biomechanical properties can be used as biomarkers to diagnose tumors, monitor tumor development, and evaluate treatment efficacy. The purpose of this preliminary study is to characterize the biomechanical environment of two typical liver tumors, hemangiomas (HEMs) and hepatocellular carcinomas (HCCs), and to investigate the potential of using strain metrics as biomarkers for tumor diagnosis, based on a limited clinical dataset.
Magnetic resonance (MR) tagging was used to quantify the motion and deformation of the two types of liver tumors. Displacements of the tumors arising from a heartbeat were measured over one cardiac cycle. Local biomechanical conditions of the tumors were characterized by estimating two principal strains (ε1 and ε2 ) and an octahedral shear strain (εsoct ) of the tumor and its peripheral region. Biomechanical conditions of the tumors were compared with those of the arbitrarily selected regions from healthy volunteers.
We observed that the HCCs had significantly smaller strain values compared to their peripheral tissues. However, the HEMs did not have significantly different strains from those of the peripheral tissues, and were similar to healthy liver regions. The sensitivity of using ε1 , ε2 , and εsoct to diagnose HCC were all 1, while the sensitivity of using ε1 , ε2 , and εsoct to diagnose HEM were 0.67, 0.17, and 0.67, respectively.
Lagrangian strain metrics provide insight into the biomechanical conditions of certain liver tumors in the human body and may provide another perspective for tumor characterization and diagnosis.
... In a recent study, Mannelli et al (20) compared a small number of control subjects to cirrhotic patients using a similar technique and also showed statistically significant differences between groups. They also performed tagged MRI to measure cardiac-induced liver motion, but using a peripheral pulse-triggering method instead of using electrocardiogram-triggering. ...
... Such studies are yet to be conducted, but we believe that the present results are encouraging, and should be considered as a preliminary rationale for them. Comparison of ultrasound elastography with various MR elastography techniques may also be an interesting approach, possibly triggering further investigation in the liver or other deep organs, difficult to assess by manual palpation . ...
To prospectively assess the stiffness of incidentally discovered focal liver lesions (FLL) with no history of chronic liver disease or extrahepatic cancer using shearwave elastography (SWE).
Between June 2011 and May 2012, all FLL fortuitously discovered on ultrasound examination were prospectively included. For each lesion, stiffness was measured (kPa). Characterization of the lesion relied on magnetic resonance imaging (MRI) and/or contrast-enhanced ultrasound, or biopsy. Tumour stiffness was analysed using ANOVA and non-parametric Mann-Whitney tests.
105 lesions were successfully evaluated in 73 patients (61 women, 84 %) with a mean age of 44.8 (range: 20‒75). The mean stiffness was 33.3 ± 12.7 kPa for the 60 focal nodular hyperplasia (FNH), 19.7 ± 9.8 k Pa for the 17 hepatocellular adenomas (HCA), 17.1 ± 7 kPa for the 20 haemangiomas, 11.3 ± 4.3 kPa for the five focal fatty sparing, 34.1 ± 7.3 kPa for the two cholangiocarcinomas, and 19.6 kPa for one hepatocellular carcinoma (p
... In patients with early liver fibrosis, the liver parenchyma usually has a normal appearance or may exhibit only subtle, nonspecific heterogeneity on conventional MR images, though later-stage fibrotic liver develops characteristic morphologic alterations such as surface nodularity, widening of fissures, expansion of the gallbladder fossa, notching of the right lobe, atrophy of the right lobe, and relative enlargement of the lateral segments of the left lobe and caudate lobe [24,25]. A number of MR imaging techniques have been investigated to assess liver fibrosis, including T1rho imaging [22,23,, double contrast material-enhanced MR imaging , gadoxetate disodium-enhanced MRI , computer-aided analysis of hepatic contours , assessing liver strain using tagged MRI , and MR elastography [34,35]. The IVIM model assumes that each imaging voxel comprises nonexchanging intravascular and extravascular compartments. ...
This study was aimed to determine whether pure molecular-based diffusion coefficient (D) and perfusion-related diffusion parameters (perfusion fraction f, perfusion-related diffusion coefficient D*) differ in healthy livers and fibrotic livers through intra-voxel incoherent motion (IVIM) MR imaging.
17 healthy volunteers and 34 patients with histopathologically confirmed liver fibrosis patients (stage 1 = 14, stage 2 = 8, stage 3& 4 = 12, METAVIR grading) were included. Liver MR imaging was performed at 1.5-T. IVIM diffusion weighted imaging sequence was based on standard single-shot DW spin echo-planar imaging, with ten b values of 10, 20, 40, 60, 80, 100, 150, 200, 400, 800 sec/mm2 respectively. Pixel-wise realization and regions-of-interest based quantification of IVIM parameters were performed.
D, f, and D* in healthy volunteer livers and patient livers were 1.096±0.155 vs 0.917±0.152 (10-3 mm2/s, p = 0.0015), 0.164±0.021 vs 0.123±0.029 (p<0.0001), and 13.085±2.943 vs 9.423±1.737 (10-3 mm2/s, p<0.0001) respectively, all significantly lower in fibrotic livers. As the fibrosis severity progressed, D, f, and D* values decreased, with a trend significant for f and D*.
Fibrotic liver is associated with lower pure molecular diffusion, lower perfusion volume fraction, and lower perfusion-related diffusion. The decrease of f and D* in the liver is significantly associated liver fibrosis severity.
... One potential pitfall of using reduced refocusing flip angles is the increased sensitivity to motion related signal loss, particularly cardiac related motion manifested predominantly as bulk signal loss over the left lobe of the liver (16). This artifact is thought to be due to the lower flip angles leading to longer refocusing pathways, thereby creating a longer time period over which phase shifts from motion can accumulate (5,6). ...
... With b = 1,000 s/mm 2 stance current imaging modalities, e.g. transient elastography (fibroscan) and magnetic resonance (MR) elastography, and a fibrotest are being investigated for identifying and staging fibrosis  . More recently, the utility of diffusion-weighted MR imaging (MRI; DWI), an advanced MRI technique, in the detection and staging of liver fibrosis has also been evaluated. ...
... In patients with diffused liver diseases, the liver parenchyma usually has a normal appearance or may exhibit only subtle, nonspecific heterogeneity on conventional MR images. A number of MR imaging techniques have been investigated to assess early liver parenchyma fibrosis, including T 1 rho imaging , tagged MRI assessing liver strain , MR elastography [33,34] and intravoxel incoherent motion (IVIM) technique [35,36]. Our current study for the first time [22,23]; positive GlycoCEST MTR asym was observed in both rat and human before fasting, and GlycoCEST MTR asym reduced considerably after 24-hour fasting in rat. ...
To evaluate Chemical Exchange Saturation Transfer (CEST) MRI for liver imaging at 3.0-T.
Images were acquired at offsets (n = 41, increment = 0.25 ppm) from -5 to 5 ppm using a TSE sequence with a continuous rectangular saturation pulse. Amide proton transfer-weighted (APTw) and GlycoCEST signals were quantified as the asymmetric magnetization transfer ratio (MTRasym) at 3.5 ppm and the total MTRasym integrated from 0.5 to 1.5 ppm, respectively, from the corrected Z-spectrum. Reproducibility was assessed for rats and humans. Eight rats were devoid of chow for 24 hours and scanned before and after fasting. Eleven rats were scanned before and after one-time CCl4 intoxication.
For reproducibility, rat liver APTw and GlycoCEST measurements had 95 % limits of agreement of -1.49 % to 1.28 % and -0.317 % to 0.345 %. Human liver APTw and GlycoCEST measurements had 95 % limits of agreement of -0.842 % to 0.899 % and -0.344 % to 0.164 %. After 24 hours, fasting rat liver APTw and GlycoCEST signals decreased from 2.38 ± 0.86 % to 0.67 ± 1.12 % and from 0.34 ± 0.26 % to -0.18 ± 0.37 % respectively (p < 0.05). After CCl4 intoxication rat liver APTw and GlycoCEST signals decreased from 2.46 ± 0.48 % to 1.10 ± 0.77 %, and from 0.34 ± 0.23 % to -0.16 ± 0.51 % respectively (p < 0.05).
CEST liver imaging at 3.0-T showed high sensitivity for fasting as well as CCl4 intoxication.
• CEST MRI of in-vivo liver was demonstrated at clinical 3 T field strength. • After 24-hour fasting, rat liver APTw and GlycoCEST signals decreased significantly. • After CCl4 intoxication both rat liver APTw and GlycoCEST signals decreased significantly. • Good scan-rescan reproducibility of liver CEST MRI was shown in healthy volunteers.
... Conventional MR cannot detect diffused liver diseases, or the liver parenchyma exhibit only subtle, nonspecific heterogeneity. A number of MR imaging techniques have been investigated to assess early liver parenchyma fibrosis, including T 1 rho imaging [24,, tagged MRI assessing liver strain , MR elastography [33,34], and intravoxel incoherent motion (IVIM) technique [35,36]. Our current study for the first time evaluated the feasibility of CEST imaging of in vivo liver at the clinical field strength of 3 T, demonstrating the difference between over-night fast and post-meal statuses. ...
This study seeks to explore whether chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) can detect liver composition changes between after-meal and over-night-fast statuses.
Fifteen healthy volunteers were scanned on a 3.0-T human MRI scanner in the evening 1.5-2 h after dinner and in the morning after over-night (12-h) fasting. Among them, seven volunteers were scanned twice to assess the scan-rescan reproducibility. Images were acquired at offsets (n = 41, increment = 0.25 ppm) from -5 to 5 ppm using a turbo spin echo (TSE) sequence with a continuous rectangular saturation pulse. Amide proton transfer-weighted (APTw) and GlycoCEST signals were quantified with the asymmetric magnetization transfer ratio (MTRasym) at 3.5 ppm and the total MTRasym integrated from 0.5 to 1.5 ppm from the corrected Z-spectrum, respectively. To explore scan time reduction, CEST images were reconstructed using 31 offsets (with 20 % time reduction) and 21 offsets (with 40 % time reduction), respectively.
For reproducibility, GlycoCEST measurements in 41 offsets showed the smallest scan-rescan mean measurements variability, indicated by the lowest mean difference of -0.049 % (95 % limits of agreement, -0.209 to 0.111 %); for APTw, the smallest mean difference was found to be 0.112 % (95 % limits of agreement, -0.698 to 0.921 %) in 41 offsets. Compared with after-meal, both GlycoCEST measurement and APTw measurement under different offset number decreased after 12-h fasting. However, as the offsets number decreased (41 offsets vs. 31 offsets vs. 21 offsets), GlycoCEST map and APTw map became more heterogeneous and noisier.
Our results show that CEST liver imaging at 3.0 T has high sensitivity for fasting.
... Although this technique removes the necessity of purchasing an external hardware, cardiac pulsation is not contiguous and does not have the same frequency compared to wave source used in standard MRE technique. Although it is relatively new in MRE field, several authors already evaluated liver stiffness by using the heart as an internal pressure source to liver . ...
New advances in liver magnetic resonance imaging (MRI) may enable diagnosis of unseen pathologies by conventional techniques. Normal T1 (550-620ms for 1.5T and 700-850ms for 3T), T2, T2* (>20ms), T1rho (40-50ms) mapping, proton density fat fraction (PDFF) (≤5%) and stiffness (2-3kPa) values can enable differentiation of a normal liver from chronic liver and diffuse diseases. Gd-EOB-DTPA can enable assessment of liver function by using postcontrast hepatobiliary phase or T1 reduction rate (normally above 60%). T1 mapping can be important for the assessment of fibrosis, amyloidosis and copper overload. T1rho mapping is promising for the assessment of liver collagen deposition. PDFF can allow objective treatment assessment in NAFLD and NASH patients. T2 and T2* are used for iron overload determination. MR fingerprinting may enable single slice acquisition and easy implementation of multiparametric MRI and follow-up of patients. Areas covered: T1, T2, T2*, PDFF and stiffness, diffusion weighted imaging, intravoxel incoherent motion imaging (ADC, D, D* and f values) and function analysis are reviewed. Expert commentary: Multiparametric MRI can enable biopsyless diagnosis and more objective staging of diffuse liver disease, cirrhosis and predisposing diseases. A comprehensive approach is needed to understand and overcome the effects of iron, fat, fibrosis, edema, inflammation and copper on MR relaxometry values in diffuse liver disease.
... Diagnostic performance of these techniques has not yet been established, as only proofs of concepts for differentiation of normal from cirrhotic livers 119,120 have been published. Further research is required to assess the diagnostic performance of MRI cine-tagging for staging of liver fibrosis. ...
Liver fibrosis is a hallmark of chronic liver disease characterized by the excessive accumulation of extracellular matrix proteins. Although liver biopsy is the reference standard for diagnosis and staging of liver fibrosis, it has some limitations, including potential pain, sampling variability, and low patient acceptance. Hence, there has been an effort to develop noninvasive imaging techniques for diagnosis, staging, and monitoring of liver fibrosis. Many quantitative techniques have been implemented on magnetic resonance imaging (MRI) for this indication. The most widely validated technique is magnetic resonance elastography, which aims to measure viscoelastic properties of the liver and relate them to fibrosis stage. Several additional MRI methods have been developed or adapted to liver fibrosis quantification. Diffusion-weighted imaging measures the Brownian motion of water molecules which is restricted by collagen fibers. Texture analysis assesses the changes in the texture of liver parenchyma associated with fibrosis. Perfusion imaging relies on signal intensity and pharmacokinetic models to extract quantitative perfusion parameters. Hepatocellular function, which decreases with increasing fibrosis stage, can be estimated by the uptake of hepatobiliary contrast agents. Strain imaging measures liver deformation in response to physiological motion such as cardiac contraction. T1ρ quantification is an investigational technique, which measures the spin-lattice relaxation time in the rotating frame. This article will review the MRI techniques used in liver fibrosis staging, their advantages and limitations, and diagnostic performance. We will briefly discuss future directions, such as longitudinal monitoring of disease, prediction of portal hypertension, and risk stratification of hepatocellular carcinoma.
... In the heart beating process, the liver may also be accompanied by a certain degree of movement and deformation. Several research groups studied this relation and the resulting strain in the liver . In this work, we did include the effect of cardiac motion into the simulations and network training and testing. ...
Assessment of regional myocardial function at native pixel-level resolution can play a crucial role in recognizing the early signs of the decline in regional myocardial function. Extensive data processing in existing techniques limits the effective resolution and accuracy of the generated strain maps. The purpose of this study is to compute myocardial principal strain maps εp1 and εp2 from tagged MRI (tMRI) at the native image resolution using convolutional neural network (CNN) models.
For network training, validation, and testing, realistic tMRI datasets were generated and consisted of 53,606 cine images simulating the heart, the liver, blood pool, and backgrounds, including ranges of shapes, positions, motion patterns, noise, and strain. In addition, 102 in-vivo image datasets from three healthy subjects, and three Pulmonary Arterial Hypertension patients, were acquired and used to assess the network's in-vivo performance.
Four convolutional neural networks were trained for mapping input tagging patterns to corresponding ground-truth principal strains using different cost functions. Strain maps using harmonic phase analysis (HARP) were obtained with various spectral filtering settings for comparison. CNN and HARP strain maps were compared at the pixel level versus the ground-truth and versus the least-loss in-vivo maps using Pearson correlation coefficients (R) and the median error and Inter-Quartile Range (IQR) histograms.
CNN-based strain maps at a phantom resolution of 1.1mm×1.1mm and in-vivo resolution of 2.1mm×1.6mm were artifact-free with multiple fold improvement with εp1 ground-truth median error of 0.009(0.007) vs. 0.32(0.385) using HARP and εp2 ground-truth error of 0.016(0.021) vs. 0.181(0.08) using HARP. CNN-based strain maps showed substantially higher agreement with the ground-truth maps with correlation coefficients R > 0.91 for εp1 and εp2 compared to R < 0.21 and R < 0.82 for HARP-generated maps, respectively.
CNN-generated Eulerian strain mapping permits artifact-free visualization of myocardial function at the native image resolution.
... To the contrary, 2D-SWE might be more limited by factors such as operator variability compared to TE, as 2D-SWE embedded in a conventional scanner allows the choice of where to place the region of interest within the color stiffness box and whether to confirm or exclude each single measurement when determining the final value, while these choices are not available with TE  . In addition to US elastography including 2D-SWE and TE, magnetic resonance elastography (MRE) of the liver is another noninvasive method which can be used to measure the viscoelastic properties of the liver, providing a quantitative method for the diagnosis of liver fibrosis and cirrhosis as well as accurate liver fibrosis staging  . However, although the reproducibility of MRE for liver fibrosis has been reported to be even better than that of US elastography, the cost of MRE is much higher than that of SWE [41,42] . ...
To evaluate the prognostic value of liver stiffness (LS) measured using two-dimensional (2D) shear-wave elastography (SWE) in patients with hepatocellular carcinoma (HCC) treated by radiofrequency ablation (RFA).
The Institutional Review Board approved this retrospective study and informed consent was obtained from all patients. A total of 134 patients with up to 3 HCCs ≤5 cm who had undergone pre-procedural 2D-SWE prior to RFA treatment between January 2012 and December 2013 were enrolled. LS values were measured using real-time 2D-SWE before RFA on the procedural day. After a mean follow-up of 33.8 ± 9.9 months, we analyzed the overall survival after RFA using the Kaplan-Meier method and Cox proportional hazard regression model. The optimal cutoff LS value to predict overall survival was determined using the minimal p value approach.
During the follow-up period, 22 patients died, and the estimated 1- and 3-year overall survival rates were 96.4 and 85.8%, respectively. LS measured by 2D-SWE was found to be a significant predictive factor for overall survival after RFA of HCCs, as was the presence of extrahepatic metastases. As for the optimal cutoff LS value for the prediction of overall survival, it was determined to be 13.3 kPa. In our study, 71 patients had LS values ≥13.3 kPa, and the estimated 3-year overall survival was 76.8% compared to 96.3% in 63 patients with LS values <13.3 kPa. This difference was statistically significant (hazard ratio = 4.30 [1.26-14.7]; p = 0.020).
LS values measured by 2D-SWE was a significant predictive factor for overall survival after RFA for HCC.
... 3 For this reason, phase-based methods have been used to study the motion of organs other than the heart, including the brain, 4 and the liver. 5 Motion estimation has also been performed in the tongue to study speech generation. 9 Much of this previous work has been performed following similar strategies and was used in earlier cardiac work in 2D. ...
Harmonic phase analysis has been used to perform noninvasive organ motion and strain estimation using tagged magnetic resonance imaging (MRI). The filtering process, which is used to produce harmonic phase images used for tissue tracking, influences the estimation accuracy. In this work, we evaluated different filtering approaches, and propose a novel high-pass filter for volumes tagged in individual directions. Testing was done using an open benchmarking dataset and synthetic images obtained using a mechanical model. We compared estimation results from our filtering approach with results from the traditional filtering approach. Our results indicate that 1) the proposed high-pass filter outperforms the traditional filtering approach reducing error by as much as 50% and 2) the accuracy improvements are especially marked in complex deformations.
... Our objective was to evaluate liver stiffness values before and after contrast administration so that even if iron was present, its effect remained the same in both sessions. When dealing with patients suffering from iron overload, spin echo-based echo planar imaging, fast spin echo methods or T1-based tagged MRI are more reliable methods than GRE sequences as used in our study [37,38]. ...
To assess if the administration of gadoxetate disodium (Gd-EOB-DTPA) significantly affects hepatic magnetic resonance elastography (MRE) measurements in the delayed hepatobiliary phase (DHBP).
A total of 47 patients (15 females, 32 males; age range 23-78 years, mean 54.28 years) were assigned to standard hepatic magnetic resonance imaging (MRI) with application of Gd-EOB-DTPA and hepatic MRE. MRE was performed before injection of Gd-EOB-DTPA and after 40-50 min in the DHBP. Liver stiffness values were obtained before and after contrast media application and differences between pre- and post-Gd-EOB-DTPA values were evaluated using a Bland-Altman plot and the Mann-Whitney-Wilcoxon test. In addition, the data were compared with regard to the resulting fibrosis classification.
Mean hepatic stiffness for pre-Gd-EOB-DTPA measurements was 4.01 kPa and post-Gd-EOB-DTPA measurements yielded 3.95 kPa. We found a highly significant individual correlation between pre- and post-Gd-EOB-DTPA stiffness values (Pearson correlation coefficient of r = 0.95 (p < 0.001) with no significant difference between the two measurements (p =0.49)). Bland-Altman plot did not show a systematic effect for the difference between pre- and post-stiffness measurements (mean difference: 0.06 kPa, SD 0.81). Regarding the classification of fibrosis stages, the overall agreement was 87.23% and the intraclass correlation coefficient was 96.4%, indicating excellent agreement.
Administration of Gd-EOB-DTPA does not significantly influence MRE stiffness measurements of the liver in the DHBP. Therefore, MRE can be performed in the DHBP.
• MRE of the liver can reliably be performed in the delayed hepatobiliary phase. • Gd-EOB-DTPA does not significantly influence MRE stiffness measurements of the liver. • MRE performed in the delayed hepatobiliary-phase is reasonable in patients with reduced liver function.
... Liver stiffness can also be evaluated by tagged MRI, which measures liver tissue strain induced by nearby cardiac motion . Mannelli et al. demonstrated that cirrhotic patients have significantly higher liver strain than healthy controls . However, MR tagging requires substantial postprocessing, and optimal strain cutoff for different fibrosis stages is not yet clear. ...
To compare 2D gradient-recalled echo (GRE) and 2D spin-echo (SE) echo-planar imaging (EPI) MR elastography (MRE) for measurement of hepatic stiffness in adult patients with known or suspected liver disease at 3 Tesla.
Materials and methods
Three hundred and eighty-seven consecutive patients underwent MRE of the liver at 3 Tesla with 2D-GRE and 2D-SE-EPI sequences. ‘Mean liver stiffness (LS)’ calculated by averaging 3 ROIs in the right lobe, ‘Maximum LS’ calculated by an ROI in the right lobe; and ‘Freehand LS’ calculated by an ROI in the entire liver were measured by two independent readers. Inter-observer and inter-class variability in stiffness measurements were assessed. Stiffness values were correlated with degree of liver fibrosis (METAVIR scores) in 97 patients who underwent biopsy. The diagnostic performance was compared by a receiver-operating characteristic analysis.
The technical failure rate was 2.8% for 2D-SE-EPI (11/387) and 4.1% for 2D-GRE (16/387, 9 had R2* > 80 s⁻¹ indicating iron overload). There is high reproducibility for both GRE and SE-EPI variants (ICC = 0.84–0.94 for both GRE and SE-EPI MRE). The highest sensitivity, specificity, and accuracy of differentiating mild fibrosis (F0–F2) from advanced fibrosis (F3–F4) are 0.84 (GRE Freehand measurement), 0.92 (GRE Maximum stiffness measurement), and 0.88 (GRE Freehand measurement), respectively.
High intra-class correlation and intra-reader correlation are seen on measured hepatic stiffness for both 2D-GRE and 2D-SE-EPI MRE. 2D-SE-EPI has lower failure rate. Diagnostic performance of both sequences is equivalent, with highest sensitivity for 2D-GRE Freehand stiffness measurement, and highest specificity 2D-GRE Maximum stiffness measurement.
To evaluate prognostic value of hepatic stiffness (HS) measurement using MR elastography (MRE) in patients with hepatocellular carcinoma (HCC) treated by hepatic resection (HR).
We enrolled 144 patients with Barcelona Clinic Liver Cancer stage A HCCs initially treated by HR who underwent preoperative liver MRE between January 2010 and June 2013. HS values were measured using MRE. Receiver operating characteristics (ROC) and multivariate logistic regression analyses were used to determine significant predictive factors for posthepatecomy liver failure (PHLF). Overall survival (OS) was analyzed by evaluating prognostic factors using the Kaplan-Meier method and Cox proportional hazard regression model.
After HR, 43 patients (29.9 %) experienced PHLF. HS values were significant predictive factors for PHLF. In ROC analysis, the area under the curve of HS was 0.740 (P = 0.001) for PHLF. Thirty-one patients had HS values ≥ 4.02 kPa; the estimated 1, 3, 5-year survival were 90.0 %, 74.7 % and 65.4 %, respectively, versus 98.1 %, 96.5 % and 96.5 % in 113 patients with HS values < 4.02 kPa (P = 0.015). An HS value ≥ 4.02 kPa was the only significant affecting factor for OS.
HS values measured by MRE could predict PHLF development post-HR. Furthermore, an HS value ≥4.02 kPa was a significant predicting factor for poor OS post-HR.
• Hepatic stiffness value was a predictive factor for developing posthepatectomy liver failure • Hepatic stiffness value was a significant affecting factor for OS • Hepatic stiffness value ≥ 4.02 kPa was a predictive factor for poor OS.
The viscoelastic properties of the liver and spleen can be assessed with magnetic resonance elastography (MRE). Several actuators, MRI acquisition sequences and reconstruction algorithms have been proposed for this purpose. Reproducible results are obtained, especially when the examination is performed in standard conditions with the patient fasting. Accurate staging of liver fibrosis can be obtained by measuring liver stiffness or elasticity with MRE. Moreover, emerging evidence shows that assessing the tissue viscous parameters with MRE is useful for characterizing liver inflammation, non-alcoholic steatohepatitis, hepatic congestion, portal hypertension, and hepatic tumors. Further advances such as multifrequency acquisitions and compression-sensitive MRE may provide novel quantitative markers of hepatic and splenic mechanical properties that may improve the diagnosis of hepatic and splenic diseases.
To retrospectively evaluate the prognostic role of liver stiffness (LS) measurement using magnetic resonance elastography (MRE) in patients with compensated chronic liver disease (cCLD).
We enrolled 217 patients with cCLD who underwent MRE. After mean follow-up of 45.0 ± 17.6 months, cumulative incidence (CI) of hepatocellular carcinoma (HCC) occurrence, development of decompensation and overall survival (OS) were estimated using the Kaplan-Meier method. Prognostic factors were evaluated using the Cox proportional hazard regression model.
During the follow-up period, HCC occurred in 33 patients, and 1-, 3- and 5-year CIs of HCC occurrence were 3.8%, 14.8% and 18.9%, respectively. The LS value was a significant predictive factor for HCC occurrence [p < 0.001, hazard ratio (HR) = 1.59 per unit (1.25-2.03)]. Eighteen patients experienced hepatic decompensation, and 1-, 3- and 5-year CIs of decompensation were 2.8%, 7.3% and 11.3%, respectively. The LS value was also significantly associated with decompensation development [p < 0.001, HR = 2.02 per unit (1.37-2.98)]. Fourteen patients died, and 1-, 3- and 5-year OSs were 99.1%, 98.0% and 89.8%, respectively. The LS value was demonstrated to be a significant affecting factor for OS [p = 0.008, HR = 1.39 per unit (1.10-1.78)].
LS obtained from MRE was a significant predictive factor for the development of decompensation, HCC occurrence and OS in cCLD patients.
• Liver stiffness (LS) values obtained from MRE can provide prognostic information. • The LS value was a significant predictive factor for occurrence of hepatocellular carcinoma. • The LS value was significantly associated with development of hepatic decompensation. • Survival of compensated chronic liver disease patients was affected by the LS value.
To clarify the usefulness of 3.0-T MR elastography (MRE) in diagnosing the histological grades of liver fibrosis using preliminary clinical data.
Between November 2012 and March 2014, MRE was applied to all patients who underwent liver MR study at a 3.0-T clinical unit. Among them, those who had pathological evaluation of liver tissue within 3 months from MR examinations were retrospectively recruited, and the liver stiffness measured by MRE was correlated with histological results. Institutional review board approved this study, waiving informed consent.
There were 70 patients who met the inclusion criteria. Liver stiffness showed significant correlation with the pathological grades of liver fibrosis (rho = 0.89, p < 0.0001, Spearman's rank correlation). Areas under the receiver operating characteristic curve were 0.93, 0.95, 0.99 and 0.95 for fibrosis score greater than or equal to F1, F2, F3 and F4, with cut-off values of 3.13, 3.85, 4.28 and 5.38 kPa, respectively. Multivariate analysis suggested that grades of necroinflammation also affected liver stiffness, but to a significantly lesser degree as compared to fibrosis.
3.0-T clinical MRE was suggested to be sufficiently useful in assessing the grades of liver fibrosis.
• MR elastography may help clinicians assess patients with chronic liver diseases • Usefulness of 3.0-T MR elastography has rarely been reported • Measured liver stiffness correlated well with the histological grades of liver fibrosis • Measured liver stiffness was also affected by necroinflammation, but to a lesser degree • 3.0-T MRE could be a non-invasive alternative to liver biopsy.
Strain, an important biomechanical factor, occurs at different scales from molecules and cells to tissues and organs in physiological conditions. Under mechanical strain, the strength of tissues and their micro- and nanocomponents, the structure, proliferation, differentiation and apoptosis of cells and even the cytokines expressed by cells probably shift. Thus, the measurement of mechanical strain (i.e., relative displacement or deformation) is critical to understand functional changes in tissues, and to elucidate basic relationships between mechanical loading and tissue response. In the last decades, a great number of methods have been developed and applied to measure the deformations and mechanical strains in tissues comprising bone, tendon, ligament, muscle and brain as well as blood vessels. In this article, we have reviewed the mechanical strain measurement from six aspects: electro-based, light-based, ultrasound-based, magnetic resonance-based and computed tomography-based techniques, and the texture correlation-based image processing method. The review may help solving the problems of experimental and mechanical strain measurement of tissues under different measurement environments.
MR elastography is a noninvasive technique that provides high diagnostic accuracy for the staging of liver fibrosis; however, it requires external hardware and mainly assesses the right lobe.
To evaluate the diagnostic performance of MRI cine-tagging for staging fibrosis in the left liver lobe, using biopsy as the reference standard.
Institutional Review Board (IRB)-approved two-center prospective study.
Seventy-six patients with chronic liver disease who underwent an MRI cine-tagging examination and a liver biopsy within a 6-week interval.
2D-GRE multislice sequence at 3.0T with spatial modulation of the magnetization preparation sequence and peripheral pulse-wave triggering on two coronal slices chosen underneath the heart apex to capture maximal deformation with consecutive breath-holds adapted to patient cardiac frequency.
A region of interest was selected in the liver close to the heart apex. Maximal strain was evaluated with the harmonic phase (HARP) technique.
Spearman's correlation, Kruskal-Wallis test, Mann-Whitney U-test, and receiver operating characteristic (ROC) analysis were performed.
Liver strain measured on tagged images decreased with higher histological fibrosis stage (ρ = -0.68, P < 0.0001). Strain values were significantly different between all fibrosis stages (P < 0.0001), and between groups of fibrosis stages ≤F3 vs. F4 (P < 0.05). Areas under the ROC curves were 0.95 (95% confidence interval: 0.89-1.00) to distinguish fibrosis stages F0 vs. F4, 0.81 (0.70-0.92) for stages F0 vs. ≥F1, 0.84 (0.76-0.93) for stages ≤F1 vs. ≥F2, 0.86 (0.78-0.94) for stages ≤F2 vs. ≥F3, and 0.87 (0.77-0.96) for stages ≤F3 vs. F4.
MRI cine-tagging is a promising technique for measuring liver strain without additional elastography hardware. It could be used to assess the left liver lobe as a complement to current techniques assessing the right lobe.
Level of evidence:
1 Technical Efficacy: 3 J. Magn. Reson. Imaging 2019.
The effectiveness of abdominal compression for motion management in hepatobiliary-pancreatic (HPB) radiotherapy has not been systematically evaluated.
Methods & materials:
A systematic review was carried out using PubMed/Medline, Cochrane Library, Web of Science, and CINAHL databases up to 1 July 2021. No date restrictions were applied. Additional searches were carried out using the University of Manchester digital library, Google Scholar and of retrieved papers' reference lists. Studies conducted evaluating respiratory motion utilising imaging with and without abdominal compression in the same patients available in English were included. Studies conducted in healthy volunteers or majority non-HPB sites, not providing descriptive motion statistics or patient characteristics before and after compression in the same patients or published without peer-review were excluded. A narrative synthesis was employed by tabulating retrieved studies and organising chronologically by abdominal compression device type to help identify patterns in the evidence.
The inclusion criteria were met by 6 studies with a total of 152 patients. Designs were a mix of retrospective and prospective quantitative designs with chronological, non-randomised recruitment. Abdominal compression reduced craniocaudal respiratory motion in the majority of patients, although in four studies there were increases seen in at least one direction. The influence of patient comorbidities on effectiveness of compression, and/or comfort with compression was not evaluated in any study.
Abdominal compression may not be appropriate for all patients, and benefit should be weighed with potential increase in motion or discomfort in patients with small initial motion (<5 mm). Patient factors including male sex, and high body mass index (BMI) were found to impact the effectiveness of compression, however with limited evidence. High-quality studies are warranted to fully assess the clinical impact of abdominal compression on treatment outcomes and toxicity prospective in comparison to other motion management strategies.
MR elastography (MRE) is an MRI-based technique for quantitatively assessing tissue stiffness by studying shear wave propagation through tissue. The goal of this study was to test the hypothesis that hepatic MRE performed before and after a meal will result in a postprandial increase in hepatic stiffness among patients with hepatic fibrosis because of transiently increased portal pressure.
Twenty healthy volunteers and 25 patients with biopsyproven hepatic fibrosis were evaluated. Preprandial MRE measurements were performed after overnight fasting. A liquid test meal was administered, and 30 minutes later a postprandial MRE acquisition was performed. Identical imaging parameters and analysis regions of interest were used for pre- and postprandial acquisitions.
The results in the 20 subjects without liver disease showed a mean stiffness change of 0.16 ± 0.20 kPa (range, -0.12 to 0.78 kPa) or 8.08% ± 10.33% (range, -5.36% to 41.7%). The hepatic stiffness obtained in the 25 patients with hepatic fibrosis showed a statistically significant increase in postprandial liver stiffness, with mean augmentation of 0.89 ± 0.96 kPa (range, 0.17-4.15 kPa) or 21.24% ± 14.98% (range, 7.69%-63.3%).
MRE-assessed hepatic stiffness elevation in patients with chronic liver disease has two major components: a static component reflecting structural change or fibrosis and a dynamic component reflecting portal pressure that can increase after a meal. These findings will provide motivation for further studies to determine the potential value of assessing postprandial hepatic stiffness augmentation for predicting the progression of fibrotic disease and the development of portal hypertension. The technique may also provide new insights into the natural history and pathophysiology of chronic liver disease.
To investigate the diagnostic accuracy (area under the receiver operating characteristic curve [AUROC]) of magnetic resonance (MR) elastography for the early detection of nonalcoholic steatohepatitis (NASH) among patients with nonalcoholic fatty liver disease (NAFLD).
An institutional review board-approved and HIPAA-compliant retrospective study was conducted in 58 NAFLD patients. Informed consent was waived by the review board. Hepatic stiffness, relative fat fraction, inflammation grade, and fibrosis stage were assessed from MR elastography, in-phase and out-of-phase gradient-echo imaging, and liver biopsy histopathologic review, respectively. Pairwise t testing, receiver operating characteristic analysis, and partial correlation analysis were performed.
The mean hepatic stiffness for patients with simple steatosis (2.51 kPa) was less (P = .028) than that for patients with inflammation but no fibrosis (3.24 kPa). The mean hepatic stiffness for patients with inflammation but no fibrosis was less (P = .030) than that for patients with hepatic fibrosis (4.16 kPa). Liver stiffness had high accuracy (AUROC = 0.93) for discriminating patients with NASH from those with simple steatosis, with a sensitivity of 94% and a specificity 73% by using a threshold of 2.74 kPa.
In patients with NAFLD, hepatic stiffness measurements with MR elastography can help identify individuals with steatohepatitis, even before the onset of fibrosis; NAFLD patients with inflammation but no fibrosis have greater liver stiffness than those with simple steatosis and lower mean stiffness than those with fibrosis.
To preliminarily evaluate the feasibility and usefulness of MR elastography of the liver at 3 T with cine-tagging and bending energy (BE) analysis for the evaluation of hepatic fibrosis.
Twenty-two patients underwent MR elastography with four different cine-tagging grids on the liver (16- or 20-mm sagittal or coronal). Nine images serially obtained during 1-s of exhalation were analyzed to define coordinates of grid intersections. BE values were calculated using the thin-plate spline method. BE values were compared among patient groups with different fibrosis stage thresholds.
In the 22 patients, six had a fibrosis score of F0, one had F1, seven had F2, three had F3, and five had F4. Mean BE value with 16-mm sagittal grid was greater with fibrosis score F0 (1.54 ± 0.63) than with ≥F1 (0.97 ± 0.12, P = 0.013) as well as with ≤F1 (1.48 ± 0.60) than with ≥F2 (0.96 ± 0.36, P = 0.019).
Our results showed that MR elastography with 16-mm sagittal grid and BE analysis had a potential in discrimination for the patients with moderate or advanced hepatic fibrosis from those with healthy liver or slight fibrosis.
Ullrich syndrome is a recessive congenital muscular dystrophy affecting connective tissue and muscle. The molecular basis is unknown. Reverse transcription–PCR amplification performed on RNA extracted from fibroblasts or muscle of three Ullrich patients followed by heteroduplex analysis displayed heteroduplexes in one of the three genes coding for collagen type VI (COL6). In patient A, we detected a homozygous insertion of a C leading to a premature termination codon in the triple-helical domain of COL6A2 mRNA. Both healthy consanguineous parents were carriers. In patient B, we found a deletion of 28 nucleotides because of an A → G substitution at nucleotide −2 of intron 17 causing the activation of a cryptic acceptor site inside exon 18. The second mutation was an exon skipping because of a G → A substitution at nucleotide −1 of intron 23. Both mutations are present in an affected brother. The first mutation is also present in the healthy mother, whereas the second mutation is carried by their healthy father. In patient C, we found only one mutation so far—the same deletion of 28 nucleotides found in patient B. In this case, it was a de novo mutation, as it is absent in her parents. mRNA and protein analysis of patient B showed very low amounts of COL6A2 mRNA and of COL6. A near total absence of COL6 was demonstrated by immunofluorescence in fibroblasts and muscle. Our results demonstrate that Ullrich syndrome is caused by recessive mutations leading to a severe reduction of COL6.
Currently, clinical trials tend to be individually funded and applicants must include a power calculation in their grant request. However, conventional levels of statistical precision are unlikely to be obtainable prospectively if the trial is required to evaluate treatment of a rare disease. This means that clinicians treating such diseases remain in ignorance and must form their judgments solely on the basis of (potentially biased) observational studies experience, and anecdote. Since some unbiased evidence is clearly better than none, this state of affairs should not continue. However, conventional (frequentist) confidence limits are unlikely to exclude a null result, even when treatments differ substantially. Bayesian methods utilise all available data to calculate probabilities that may be extrapolated directly to clinical practice. Funding bodies should therefore fund a repertoire of small trials, which need have no predetermined end, alongside standard larger studies.
To gain insight into the function of type VI collagen, the col6a1 gene was inactivated by targeted gene disruption in the mouse. The homozygous mutants lacked collagen VI in the tissues and showed histological features of myopathy such as fiber necrosis and phagocytosis and a pronounced variation in the fiber diameter. Muscles also showed signs of stimulated regeneration of fibers. Necrotic fibers were particularly frequent in the diaphragm at all ages examined. Similar, although milder, alterations were detected in heterozygous mutant mice, indicating haploinsufficiency of the col6a1 gene function. The data led us to conclude that collagen VI is necessary for maintenance of the integrity of muscle fibers and that the col6a1 -deficient mouse can be considered an animal model of Bethlem myopathy.
Collagen VI is an extracellular matrix protein that forms a microfilamentous network in skeletal muscles and other organs. Inherited mutations in genes encoding collagen VI in humans cause two muscle diseases, Bethlem myopathy and Ullrich congenital muscular dystrophy. We previously generated collagen VI-deficient (Col6a1-/-) mice and showed that they have a muscle phenotype that strongly resembles Bethlem myopathy. The pathophysiological defects and mechanisms leading to the myopathic disorder were not known. Here we show that Col6a1-/- muscles have a loss of contractile strength associated with ultrastructural alterations of sarcoplasmic reticulum (SR) and mitochondria and spontaneous apoptosis. We found a latent mitochondrial dysfunction in myofibers of Col6a1-/- mice on incubation with the selective F1F(O)-ATPase inhibitor oligomycin, which caused mitochondrial depolarization, Ca2+ deregulation and increased apoptosis. These defects were reversible, as they could be normalized by plating Col6a1-/- myofibers on collagen VI or by addition of cyclosporin A (CsA), the inhibitor of mitochondrial permeability transition pore (PTP). Treatment of Col6a1-/- mice with CsA rescued the muscle ultrastructural defects and markedly decreased the number of apoptotic nuclei in vivo. These findings indicate that collagen VI myopathies have an unexpected mitochondrial pathogenesis that could be exploited for therapeutic intervention.
Mutations in the genes encoding collagen VI (COL6A1, COL6A2, and COL6A3) cause Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD). BM is a relatively mild dominantly inherited disorder with proximal weakness and distal joint contractures. UCMD is an autosomal recessive condition causing severe muscle weakness with proximal joint contractures and distal hyperlaxity.
We developed a method for rapid direct sequence analysis of all 107 coding exons of the COL6 genes using single condition amplification/internal primer (SCAIP) sequencing. We have sequenced all three COL6 genes from genomic DNA in 79 patients with UCMD or BM.
We found putative mutations in one of the COL6 genes in 62% of patients. This more than doubles the number of identified COL6 mutations. Most of these changes are consistent with straightforward autosomal dominant or recessive inheritance. However, some patients showed changes in more than one of the COL6 genes, and our results suggest that some UCMD patients may have dominantly acting mutations rather than recessive disease.
Our findings may explain some or all of the cases of UCMD that are unlinked to the COL6 loci under a recessive model. The large number of single nucleotide polymorphisms which we generated in the course of this work may be of importance in determining the major phenotypic variability seen in this group of disorders.
Nonsense-mediated mRNA decay (NMD) is an mRNA quality-control mechanism that degrades aberrant mRNAs containing premature translation termination codons (PTCs). The essential proteins for NMD include SMG-1, a protein kinase, and Upf1, a substrate of SMG-1 with RNA helicase activity. In this study, we evaluated the effects of NMD inhibition by siRNA-mediated knockdown of SMG-1 or Upf1 on the phenotype of Ullrich disease, an autosomal recessive congenital muscular dystrophy. The patient studied showed a homozygous frameshift mutation with a PTC in the collagen VI alpha2 gene, which encodes a truncated but partially functional protein. The patient's fibroblasts showed a nearly complete loss of the triple-helical collagen VI protein and functional defects in the extracellular matrix (ECM) due to the crucial deficiency of the collagen VI alpha2 protein. We have shown that siRNA-mediated knockdown of SMG-1 or Upf1 causes the up-regulation of the mutant triple-helical collagen VI, resulting in the formation of partially functional ECM. We suggest that the inhibition of NMD may be useful as a therapeutic approach to treat some human genetic diseases exacerbated by NMD.
Bethlem myopathy is considered a relatively mild neuromuscular disorder without significant cardiac and respiratory involvement.
To investigate cardiac and respiratory involvement in Bethlem myopathy.
University hospitals. Patients Fifty patients with Bethlem myopathy from 26 families.
Cardiac examinations, including electrocardiography and echocardiography (n = 37) and pulmonary investigations (n = 43). Holter monitoring was performed in 16 patients.
Cardiac and respiratory abnormalities.
Several cardiac abnormalities were found that were considered unrelated to the muscular disorder. Seven (16%) of 43 patients had a forced vital capacity less than 70% of the predicted value. One of 2 patients with a forced vital capacity less than 50% was also receiving respiratory support. All patients with compromised respiratory function were still ambulatory, and we found no significant correlation between the severity of arm weakness and the severity of respiratory muscle involvement.
There is no evidence of cardiac involvement in Bethlem myopathy. Respiratory failure is part of the clinical spectrum and can occur in ambulatory patients.
Ullrich congenital muscular dystrophy is a severe genetically and clinically heterogeneous muscle disorder linked to collagen VI deficiency. The pathogenesis of the disease is unknown. To assess the potential role of mitochondrial dysfunction in the onset of muscle fiber death in this form of dystrophy, we studied biopsies and myoblast cultures obtained from patients with different genetic defects of collagen VI and variable clinical presentations of the disease. We identified a latent mitochondrial dysfunction in myoblasts from patients with Ullrich congenital muscular dystrophy that matched an increased occurrence of spontaneous apoptosis. Unlike those in myoblasts from healthy donors, mitochondria in cells from patients depolarized upon addition of oligomycin and displayed ultrastructural alterations that were worsened by treatment with oligomycin. The increased apoptosis, the ultrastructural defects, and the anomalous response to oligomycin could be normalized by Ca(2+) chelators, by plating cells on collagen VI, and by treatment with cyclosporin A or with the specific cyclophilin inhibitor methylAla(3)ethylVal(4)-cyclosporin, which does not affect calcineurin activity. Here we demonstrate that mitochondrial dysfunction plays an important role in muscle cell wasting in Ullrich congenital muscular dystrophy. This study represents an essential step toward a pharmacological therapy of Ullrich congenital muscular dystrophy with cyclosporin A and methylAla(3)ethylVal(4) cyclosporin.
The randomized, controlled trial (RCT) is the "gold standard" for establishing the effect of any intervention. This approach, however, is often not feasible with rare diseases such as cutaneous T-cell lymphoma.
We review the principles of evidence-based medicine to see which are particularly pertinent to the study of rare diseases.
When an RCT is not feasible, attention is given to determining all the available prior data. Evaluation of the new data and the historic base requires attention to biases, but can allow estimation of a "true" study result.
Even when an RCT cannot be performed because of insufficient cases, utilization of evidence-based methodology can help minimize bias and maximize the truth of observed new data.
The fibrogenic evolution of chronic viral hepatitis B and C towards cirrhosis represents a key issue in clinical Hepatology whose monitoring still relies on liver biopsy and consequent histopathological staging. In the last decade, non-invasive methodologies have been proposed to predict the presence of fibrosis in chronic liver disease. Most of these methods are based on algorithms, including biochemical parameters, which have demonstrated an acceptable diagnostic accuracy towards the two extremities of the fibrogenetic process. The introduction of transient elastography has represented a further advancement in clinical Hepatology and it seems that the combination of different non-invasive methodologies will provide an improvement in the clinical management of disease progression in viral chronic hepatitis. Studies, conducted especially in chronic viral hepatitis C, suggest that transient elastography is a useful technique for the detection of severe fibrosis-cirrhosis and for the exclusion of significant fibrosis (≥F2), that could be employed as “diagnostic discriminator” for establishing clinical priorities and reducing the number of liver biopsies. This review article will focus on the clinical utility of this novel methodology for the assessment of liver fibrosis in chronic viral hepatitis and will highlight potential further advantages.
Tagged magnetic resonance imaging (MRI) has shown great promise in non-invasive analysis of heart motion. To replace implanted markers as a gold standard, however, tagged MRI must be able to track a sparse set of material points, so-called material markers, with high accuracy. This paper presents a new method for generating accurate motion estimates over a sparse set of material points using standard, parallel-tagged MR images. Each tracked point is located at the intersection of three tag surfaces, each of which is estimated using a thin-plate spline. The intersections are determined by an iterative alternating projections algorithm for which a proof of convergence is provided. The resulting data sets are compatible with applications developed to exploit implanted marker data. One set of these material markers from a normal human volunteer is examined in detail using several methods to visualize the markers. Numerical results that include additional studies are also discussed. Finally, an error analysis is presented using a computer-simulated left ventricle for which material markers are tracked with an RMS error of ∼0.2 mm for typical imaging parameters and noise levels.
Bethlem myopathy is a mild neuromuscular disorder with proximal muscular weakness and early flexion contractures. It is an autosomal dominant disease due to mutations in type VI collagen genes. We found a T→C substitution at the +2 position of COL6A1 intron 14 in a family, leading to skipping of exon 14 and an in-frame deletion of 18 amino acids in the triple-helical domain of the α1(VI) collagen chain. The deletion included a cysteine residue believed to be involved in the assembly of type VI collagen dimers intracellularly, prior to the protein secretion. Analysis of the affected fibroblasts showed that the shortened α1(VI) collagen chains were synthesized but not secreted by the cells and that the amount of type VI collagen microfibrils deposited by the cells was reduced. The results suggest that the clinical phenotype is due to a reduction in the level of type VI collagen in the extracellular matrix.
To demonstrate the feasibility of obtaining liver stiffness measurements with magnetic resonance elastography (MRE) at 3T in normal healthy volunteers using the same technique that has been successfully applied at 1.5 T.
The study was approved by the local ethics committee and written informed consent was obtained from all volunteers. Eleven volunteers (mean age 35 ± 9 years) with no history of gastrointestinal, hepatobiliary, or cardiovascular disease were recruited. The magnetic resonance imaging (MRI) protocol included a gradient echo-based MRE sequence using a 60 Hz pneumatic excitation. The MRE images were processed using a local frequency estimation inversion algorithm to provide quantitative stiffness maps. Adequate image quality was assessed subjectively by demonstrating the presence of visible propagating waves within the liver parenchyma underlying the driver location. Liver stiffness values were obtained using manually placed regions of interest (ROI) outlining the liver margins on the gradient echo wave images, which were then mapped onto the corresponding stiffness image. The mean stiffness values from two adjacent sections were recorded.
Eleven volunteers underwent MRE. The quality of the MRE images was adequate in all the volunteers. The mean liver stiffness for the group was 2.3 ± 0.38 kPa (ranging from 1.7-2.8 kPa).
This preliminary work using MRE at 3T in healthy volunteers demonstrates the feasibility of liver stiffness evaluation at 3T without modification of the approach used at 1.5 T. Adequate image quality and normal MRE values were obtained in all volunteers. The obtained stiffness values were in the range of those reported for healthy volunteers in previous studies at 1.5 T. There was good interobserver reproducibility in the stiffness measurements.
Magnetic resonance (MR) elastography is an emerging method for measuring the viscoelastic properties of tissues. Hepatic fibrosis, which increases the elasticity or stiffness of the liver, can be detected and staged by MR elastography. The technique has several advantages compared with transient ultrasound elastography (FibroScan): it can evaluate much larger liver volumes; it can be performed in obese patients and in those with ascites; and it can assess the full three-dimensional displacement vector, allowing a more precise analysis of viscoelastic parameters. These technical advantages mean that MR elastography is more accurate forstaging liver fibrosis than is transient ultrasound elastography. Moreover, it has been shown in animal studies using MR elastography that parameters other than fibrosis can also increase liver elasticity, including inflammation and myofibroblast activation before extracellular matrix deposition. Because of its greater accuracy-but also its higher cost-MR elastography will probably have a complementary role alongside ultrasound elastography. Nevertheless, this role should be further studied, especially in terms of response to treatment and the early detection of chronic liver diseases such as steatohepatitis.
Cirrhosis is an important and growing public health problem, affecting millions of Americans and many more people internationally. A pathological hallmark of the progression to cirrhosis is the development of liver fibrosis, so that monitoring the appearance and progression of liver fibrosis can be used to guide therapy. Here, we report a method to use magnetization-tagged magnetic resonance imaging to measure the cardiac-induced motion and deformation in the liver, as a means for noninvasively assessing liver stiffness, which is related to fibrosis. The initial results show statistically significant differences between healthy and cirrhotic subjects in the direct comparisons of the maximum displacement (mm), and the maximum (P1) and minimum (P2) two-dimensional strains, through the cardiac cycle (3.514 ± 0.793, 2.184 ± 0.611; 0.116 ± 0.043, 0.048 ± 0.011; -0.094 ± 0.020, -0.041 ± 0.015; healthy, cirrhosis, respectively; P < 0.005 for all). There are also significant differences in the displacement-normalized P1 and P2 strains (mm(-1) ) (0.030 ± 0.008, 0.017 ± 0.007; -0.024 ± 0.006, -0.013 ± 0.004; healthy, cirrhosis, respectively; P < 0.005 for all). Therefore, this noninvasive imaging-based method is a promising means to assess liver stiffness using clinically available imaging tools.
The purpose of this article is to establish the range of normal splenic stiffness in healthy volunteers using MR elastography (MRE) and to investigate any correlation with physiologic parameters and driver position.
Sixteen volunteers (mean [+/- SD] age, 37 +/- 9 years) with no history of gastrointestinal, hepatobiliary, or cardiovascular disease were recruited. The MRI protocol included T2-weighted axial and gradient-echo MRE sequences using steady-state 60-Hz excitation. Two MRE acquisitions were performed, one with the driver placed on the right side of the abdomen and the other with the driver placed on the left side. Volunteers' body mass index (BMI), arterial mean blood pressure, age, spleen volume, and liver stiffness were also determined. Two radiologists independently measured the spleen stiffness on the MRE inversion images. The correlations between spleen stiffness and BMI, arterial mean blood pressure, age, spleen volume, and liver stiffness were quantified.
Sixteen volunteers underwent MRE. With the driver placed on the right side of the abdomen, the mean splenic stiffness was 3,565 +/- 586 Pa (range, 2,353-4,442 Pa); with the driver on the left side of the abdomen, the mean splenic stiffness was significantly (p < 0.004) different (4,255 +/- 625 Pa; range, 3,194-5,581 Pa). No significant correlation was found between spleen stiffness and BMI, arterial mean blood pressure, age, spleen volume, and liver stiffness (all p > 0.05)
These preliminary results in a small number of healthy volunteers show that spleen stiffness is not significantly correlated with BMI, arterial mean blood pressure, spleen volume, or liver stiffness. A significant difference was observed using different driver positions.
To determine the clinical and molecular features of a new phenotype related to collagen VI myopathies.
We examined two patients belonging to a consanguineous family affected by myosclerosis myopathy, screened for mutations of collagen VI genes, and performed a detailed biochemical and morphologic analysis of the muscle biopsy and cultured fibroblasts.
The patients had a novel homozygous nonsense COL6A2 mutation (Q819X); the mutated messenger RNA escaped nonsense-mediated decay and was translated into a truncated alpha2(VI) chain, lacking the sole C2 domain. The truncated chain associated with the other two chains, giving rise to secreted collagen VI. Monomers containing the truncated chain were assembled into dimers, but tetramers were almost absent; secreted collagen VI was quantitatively reduced and structurally abnormal in cultured fibroblasts. Mutated collagen did not correctly localize in the basement membrane of muscle fibers and was absent in the capillary wall. Ultrastructural analysis of muscle showed an unusual combination of basement membrane thickening and duplication, and increased number of pericytes.
This familial case has the characteristic features of myosclerosis myopathy and carries a homozygous COL6A2 mutation responsible for a peculiar pattern of collagen VI defects. Our study demonstrates that myosclerosis myopathy should be considered a collagen VI disorder allelic to Ullrich congenital muscular dystrophy and Bethlem myopathy.
Three pedigrees are described in which 28 living siblings suffered from a benign myopathy. The first symptoms were observed around the fifth year of life. The proximal muscles were more involved than the distal muscles, the extensors more than the flexors. Due to a marked paresis of the extensor digitorum communis muscles 22 patients showed a flexion contracture of the interphalangeal joints of the last four fingers. In addition 20 patients showed a flexion contracture of the elbows and 12 patients had a plantar flexion contracture of the ankles. A high incidence of congenital torticollis was found. The histopathological features were non-specific and remarkably uniform and consisted of a marked variation in muslce fibre diameter and a very marked increase of fatty tissue. Light-microscopy and electronmicroscopy did not show any specific structural changes. There was normal distribution of type I and type II fibres, without type-grouping or preferential atrophy of one of the fibre types. Lobulated type I fibres were found in 6 out of 12 biopsies. Post-mortem study of one case did not show any convincing features of a neurogenic disorder. As no relationship could be found between the siblings of the 3 pedigrees as far back as the beginning of the eighteenth century, this myopathy seemed to be a new nosological entity.
A nuclear magnetic resonance imaging (MRI) method is presented for quantitatively mapping the physical response of a material
to harmonic mechanical excitation. The resulting images allow calculation of regional mechanical properties. Measurements
of shear modulus obtained with the MRI technique in gel materials correlate with independent measurements of static shear
modulus. The results indicate that displacement patterns corresponding to cyclic displacements smaller than 200 nanometers
can be measured. The findings suggest the feasibility of a medical imaging technique for delineating elasticity and other
mechanical properties of tissue.
Bethlem myopathy is an apparently rare early-onset benign autosomal dominant limb-girdle myopathy with contractures of the fingers. To determine whether this disorder is unrecognized rather than rare we used muscle computerized tomography (CT) and isokinetic muscle testing and assiduously sought contractures of the fingers in relatives of two patients with the disease. CT showed that muscle impairment was mild but more diffuse than clinically apparent and showed an unexpected progressive degeneration of lumbar paravertebral muscles. The isokinetic test showed that the quadriceps was more involved that the hamstrings. In addition we found that contractures of the last four fingers progressed centripetally with age from the distal interphalangeal joints to the wrist. As a result we proved that 15 of the 21 examined subjects had the disease, 7 of them being unaware that anything was amiss. Careful examination may reveal that Bethlem myopathy is more common than is now thought.
Muscle biopsies of four patients affected by chromosome 21-linked Bethlem myopathy were investigated by means of immunohistochemistry, with monoclonal antibodies for laminin chains, dystrophin and dystrophin associated glycoproteins. The objective of this study was to determine whether an altered molecular structure of collagen type VI, characteristic of Bethlem myopathy, could influence the expression of the protein complex linking the extracellular matrix with the subsarcolemmal cytoskeleton. Normal expression of all proteins was found except for laminin beta 1, along with an age related progressive deficiency of this protein in the muscle fibre basal lamina. This study shows that Bethlem myopathy linked to chromosome 21 is associated with a secondary decrease in laminin beta 1 expression.
This article introduces a new image processing technique for rapid analysis of tagged cardiac magnetic resonance image sequences. The method uses isolated spectral peaks in SPAMM-tagged magnetic resonance images, which contain information about cardiac motion. The inverse Fourier transform of a spectral peak is a complex image whose calculated angle is called a harmonic phase (HARP) image. It is shown how two HARP image sequences can be used to automatically and accurately track material points through time. A rapid, semiautomated procedure to calculate circumferential and radial Lagrangian strain from tracked points is described. This new computational approach permits rapid analysis and visualization of myocardial strain within 5-10 min after the scan is complete. Its performance is demonstrated on MR image sequences reflecting both normal and abnormal cardiac motion. Results from the new method are shown to compare very well with a previously validated tracking algorithm. Magn Reson Med 42:1048-1060, 1999.
We present a k-space approximation that directly relates a pulse sequence to its residual pattern of z-directed magnetization M(z), in a manner akin to the k-space approximation for small tip-angle excitation. Our approximation is particularly useful for the analysis and design of tagging sequences, in which M(z) is the important quantity-as opposed to the transverse magnetization components M(x) and M(y) considered in selective excitation. We demonstrate that our approximation provides new insights into tagging, can be used to design novel tag patterns, and, more generally, may be applied to selective presaturation sequences for purposes other than tagging.
The role of mitochondria as crucial participants in cell death programs is well established, yet the mechanisms responsible for the release of mitochondrial activators and the role of BCL2 family proteins in this process remain controversial. Here, we point out the limitations of current approaches used to monitor the physiological responses of mitochondria during cell death, the implications arising from modern views of mitochondrial structure, and briefly assess two proposed mechanisms for the release of mitochondrial proteins during apoptosis.
To investigate the molecular basis of autosomal dominant limb-girdle muscular dystrophy (AD-LGMD) in three large new families.
Genome-wide linkage was performed to show that the causative gene in all three families localized to chromosome 21q22.3 (Zmax = 10.3; theta = 0). This region contained the collagen VI alpha1 and alpha2 genes, which have been previously shown to harbor mutations causing a relatively mild congenital myopathy with contractures (Bethlem myopathy). Screening of the collagen VI alpha1 and alpha2 genes revealed novel, causative mutations in each family (COL6A1-K121R, G341D; COL6A2-D620N); two of these mutations were in novel regions of the proteins not previously associated with disease. Collagen VI is a ubiquitously expressed component of connective tissue; however, both limb-girdle muscular dystrophy and Bethlem myopathy patients show symptoms restricted to skeletal muscle. To address the muscle-specific symptoms resulting from collagen VI mutations, the authors studied three patient muscle biopsies at the molecular level (protein expression). A marked reduction of laminin beta1 protein in the myofiber basal lamina in all biopsies was found, although this protein was expressed normally in the neighboring capillary basal laminae.
The authors' studies widen the clinical spectrum of Bethlem myopathy and suggest collagen VI etiology should be investigated in dominant limb-girdle muscular dystrophy. The authors hypothesize that collagen VI mutations lead to muscle-specific defects of the basal lamina, and may explain the muscle-specific symptoms of Bethlem and limb-girdle muscular dystrophy patients with collagen VI mutations.
Ullrich congenital muscular dystrophy (UCMD) is an autosomal recessive disorder characterized by generalized muscular weakness, contractures of multiple joints, and distal hyperextensibility. Homozygous and compound heterozygous mutations of COL6A2 on chromosome 21q22 have recently been shown to cause UCMD. We performed a genomewide screening with microsatellite markers in a consanguineous family with three sibs affected with UCMD. Linkage of the disease to chromosome 2q37 was found in this family and in two others. We analyzed COL6A3, which encodes the alpha3 chain of collagen VI, and identified one homozygous mutation per family. In family I, the three sibs carried an A-->G transition in the splice-donor site of intron 29 (6930+5A-->G), leading to the skipping of exon 29, a partial reduction of collagen VI in muscle biopsy, and an intermediate phenotype. In family II, the patient had an unusual mild phenotype, despite a nonsense mutation, R465X, in exon 5. Analysis of the patient's COL6A3 transcripts showed the presence of various mRNA species-one of which lacked several exons, including the exon containing the nonsense mutation. The deleted splice variant encodes collagen molecules that have a shorter N-terminal domain but that may assemble with other chains and retain a functional role. This could explain the mild phenotype of the patient who was still ambulant at age 18 years and who showed an unusual combination of hyperlaxity and finger contractures. In family III, the patient had a nonsense mutation, R2342X, causing absence of collagen VI in muscle and fibroblasts, and a severe phenotype, as has been described in patients with UCMD. Mutations in COL6A3 are described in UCMD for the first time and illustrate the wide spectrum of phenotypes which can be caused by collagen VI deficiency.
The harmonic phase (HARP) method provides automatic and rapid analysis of tagged magnetic resonance (MR) images for quantification and visualization of myocardial strain. In this article, the development and implementation of a pulse sequence that acquires HARP images in real time are described. In this pulse sequence, a CINE sequence of images with 1-1 spatial modulation of magnetization (SPAMM) tags are acquired during each cardiac cycle, alternating between vertical and horizontal tags in successive heartbeats. An incrementing train of imaging RF flip angles is used to compensate for the decay of the harmonic peaks due to both T(1) relaxation and the applied imaging pulses. The magnitude images displaying coarse anatomy are automatically reconstructed and displayed in real time after each heartbeat. HARP strain images are generated offline at a rate of four images per second; real-time processing should be possible with faster algorithms or computers. A comparison of myocardial contractility in non-breath-hold and breath-hold experiments in normal humans is presented.
Recessive mutations in two of the three collagen VI genes, COL6A2 and COL6A3, have recently been shown to cause Ullrich congenital muscular dystrophy (UCMD), a frequently severe disorder characterized by congenital muscle weakness with joint contractures and coexisting distal joint hyperlaxity. Dominant mutations in all three collagen VI genes had previously been associated with the considerably milder Bethlem myopathy. Here we report that a de novo heterozygous deletion of the COL6A1 gene can also result in a severe phenotype of classical UCMD precluding ambulation. The internal gene deletion occurs near a minisatellite DNA sequence in intron 8 that removes 1.1 kb of genomic DNA encompassing exons 9 and 10. The resulting mutant chain contains a 33-amino acid deletion near the amino-terminus of the triple-helical domain but preserves a unique cysteine in the triple-helical domain important for dimer formation prior to secretion. Thus, dimer formation and secretion of abnormal tetramers can occur and exert a strong dominant negative effect on microfibrillar assembly, leading to a loss of normal localization of collagen VI in the basement membrane surrounding muscle fibers. Consistent with this mechanism was our analysis of a patient with a much milder phenotype, in whom we identified a previously described Bethlem myopathy heterozygous in-frame deletion of 18 amino acids somewhat downstream in the triple-helical domain, a result of exon 14 skipping in the COL6A1 gene. This deletion removes the crucial cysteine, so that dimer formation cannot occur and the abnormal molecule is not secreted, preventing the strong dominant negative effect. Our studies provide a biochemical insight into genotype-phenotype correlations in this group of disorders and establish that UCMD can be caused by dominantly acting mutations.
Patients with Ullrich's disease have generalized muscle weakness, multiple contractures of the proximal joints and hyperextensibility of the distal joints. Recently, we found a deficiency of collagen VI protein in skeletal muscle from two patients with Ullrich's disease. In this study, we investigated immunohistochemically the expression of extracellular matrix proteins and various proteins, which are markers for regenerating muscle fibers. Although we have detected the reduction of collagen VI in Ullrich's disease with the two kinds of monoclonal antibodies for the different domains of collagen VI, the remaining immunoreactive material was different between them. This might suggest the presence of incomplete collagen VI protein in the muscle fibers. Furthermore, we found that very small muscle fibers in the patients with Ullrich's disease showed marked expression of desmin, neural cell adhesion molecule and neonatal myosin heavy chain, which is a characteristic finding of regenerating fibers, however, they showed poor expression of developmental myosin heavy chain and thrombomodulin. The present findings suggest that abnormal regeneration or maturation processes are involved in the pathogenesis of dystrophic muscle changes at least in the advanced stage of Ullrich's disease.
A new study shows that mutations in Col6a, encoding collagen VI, cause muscle degeneration by affecting a distant target, the mitochondrion. The results show how elucidating the cellular consequences of genetic defects may provide unexpected perspectives into disease mechanism.
Mutations in the three collagen VI genes COL6A1, COL6A2 and COL6A3 cause Bethlem myopathy and Ullrich congenital muscular dystrophy (UCMD). UCMD, a severe disorder characterized by congenital muscle weakness, proximal joint contractures and marked distal joint hyperextensibility, has been considered a recessive condition, and homozygous or compound heterozygous mutations have been defined in COL6A2 and COL6A3. In contrast, the milder disorder Bethlem myopathy shows clear dominant inheritance and is caused by heterozygous mutations in COL6A1, COL6A2 and COL6A3. This model, where dominant mutations cause mild Bethlem myopathy and recessive mutations cause severe UCMD was recently challenged when a patient with UCMD was shown to have a heterozygous in-frame deletion in COL6A1. We have studied five patients with a clinical diagnosis of UCMD. Three patients had heterozygous in-frame deletions in the N-terminal region of the triple helical domain, one in the alpha1(VI) chain, one in alpha2(VI) and one in alpha3(VI). Collagen VI protein biosynthesis and assembly studies showed that these mutations act in a dominant negative fashion and result in severe collagen VI matrix deficiencies. One patient had recessive amino acid changes in the C2 subdomain of alpha2(VI), which prevented collagen VI assembly. No collagen VI mutations were found in the fifth patient. These data demonstrate that rather than being a rare cause of UCMD, dominant mutations are common in UCMD, now accounting for four of the 14 published cases. Mutation detection in this disorder remains critical for accurate genetic counseling of patients and their families.
Like Jekyll to Hyde, mitochondria can change from acting as the cell's powerhouses to become merciless killers. Mice lacking this mechanism develop normally, and their hearts are resistant to pathological damage.
Dominant mutations in COL6A1, COL6A2, and COL6A3, the three genes encoding collagen type VI, a ubiquitous extracellular matrix protein, are associated with Bethlem myopathy (BM) and Ullrich scleroatonic muscular dystrophy.
The authors devised a method to screen the entire coding sequence of the three genes by reverse transcriptase-PCR amplification of total RNA from skin fibroblasts and direct sequencing of the resulting 25 overlapping cDNA fragments covering 107 exons.
Four splicing and four missense mutations were identified in 16 patients with BM, six of which are novel mutations in COL6A1. Both common and private mutations are localized in the alpha1 (VI) chain between the regions corresponding to the 3' end of the NH2-globular domain and the 5' end of the triple helix, encoded by exons 3 through 14.
The clustering of the mutations in a relatively narrow area of the three collagen type VI chains in patients with Bethlem myopathy (BM) suggests that mutations in different regions could result in different phenotypes or in no phenotype at all. Moreover, the detection of mutations in only 60% of the patients suggests the existence of at least another gene associated with BM. The authors propose the direct sequencing of COL6 cDNAs as the first mutation screening analysis in BM, given the high number of exon-skipping events.
Mutations in the genes encoding collagen VI (COL6A1, COL6A2, and COL6A3) cause Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD), two conditions which were previously believed to be completely separate entities. BM is a relatively mild dominantly inherited disorder characterised by proximal weakness and distal joint contractures. UCMD was originally described as an autosomal recessive condition causing severe muscle weakness with proximal joint contractures and distal hyperlaxity. Here we review the clinical phenotypes of BM and UCMD and their diagnosis and management, and provide an overview of the current knowledge of the pathogenesis of collagen VI related disorders.
Mutations in dysferlin gene cause several types of muscular dystrophy in humans, including the limb-girdle muscular dystrophy type 2B and the distal muscular dystrophy of Miyoshi. The dysferlin gene product is a membrane-associated protein belonging to the ferlins family of proteins. The function of the dysferlin protein and the cause of deterioration and regression of muscle fibres in its absence, are incompletely known. A functional clue may be the presence of six hydrophilic domains, C2, that bind calcium and mediate the interaction of proteins with cellular membranes. Dysferlin seems to be involved in the membrane fusion or repair. Molecular diagnosis of dysferlinopathies is now possible and the types of gene alterations that have been characterized so far include missense mutations, deletions and insertions.
Pompe disease (glycogen storage disease type II, acid maltase deficiency) is a progressive metabolic myopathy caused by deficiency of the lysosomal enzyme acid alpha-glucosidase. This leads to an accumulation of glycogen in various tissues of the body, most notably in skeletal muscle. The disease has an autosomal recessive inheritance with a predicted frequency of 1 :40.000. Pompe disease is a continuous spectrum but for clinical practice different subtypes are recognized. The classic infantile form of the disease occurs in infants (shortly after birth) and is characterized by generalized hypotonia, failure to thrive, and cardiorespiratory failure. Patients usually die within the first year of life. The non-classic or late-onset form of the disease may occur at any age in childhood or adulthood. It presents predominantly as a slowly progressive proximal myopathy, with or without respiratory failure. Enzyme replacement therapy (ERT) is under study as treatment for the disease. The first results with recombinant human alpha-glucosidase are promising and a registered therapy seems near. Beneficial effects of ERT have been reported both in patients with the classic infantile form as well as in patients with the non-classic or late-onset form of the disease. The best therapeutic results are achieved when ERT is started early in the course of symptom development and before irreversible muscular damage has occurred. Detailed knowledge about the natural course of the disease becomes more and more essential to determine the indication and timing of treatment.
Elbow contracture is a common and difficult problem to manage. The purpose of this study was to determine the functional outcomes of arthroscopic capsular release in the management of elbow contractures.
A total of 22 patients (14 males, 8 females; mean age, 42 years) undergoing arthroscopic contracture release were retrospectively reviewed at a minimum follow-up of 1 year (mean, 25 months). In all, 20 patients had a capsulectomy, and 2 underwent capsulotomy. Patient-rated questionnaires (Disability of the Arm, Shoulder, and Hand questionnaire [DASH], American Shoulder and Elbow Surgeons Elbow Form [ASES-e], and Short Form-36 [SF-36]) and clinical, radiographic, and objective evaluations were used to assess outcomes. Motion and strength were measured by independent evaluators through standard goniometry and the LIDO Isokinetic System (Loredan Biomedical, West Sacramento, CA).
Mean flexion significantly improved from 122 degrees +/- 15 degrees to 141 degrees +/- 12 degrees (P < .001). Mean extension significantly improved from 38 degrees +/- 18 degrees to 19 degrees +/- 13 degrees (P < .001). Mean arc improvement was 38 degrees +/- 23 degrees (P < .001). None of the patients had instability, and no major neurovascular complications were reported. All patients had improved elbow function with a mean ASES-e score of 31 out of 36. Most patients were satisfied with their surgery, experienced minimal pain, and exhibited minimal impairment on the DASH.
Arthroscopic debridement and capsulectomy of the contracted elbow is effective. Results are comparable with those of other reports in the literature in which both arthroscopic and open methods were used.
Ullrich congenital muscular dystrophy (UCMD) is caused by recessive and dominant mutations in COL6A genes. We have analysed collagen VI expression in 14 UCMD patients. Sequencing of COL6A genes had identified homozygous and heterozygous mutations in 12 cases. Analysis of collagen VI in fibroblast cultures derived from eight of these patients showed reduced extracellular deposition in all cases and intracellular collagen VI staining in seven cases. This was observed even in cases that showed normal collagen VI labelling in skin biopsies. Collagen VI immunolabelling was reduced in all the available muscle biopsies. When comparisons were possible no correlation was seen between the extent of the reduction in the muscle and fibroblast cultures, the mode of inheritance or the severity of the clinical phenotype. Mutations affecting glycine substitutions in the conserved triple helical domain were common and all resulted in reduced collagen VI. This study expands the spectrum of collagen VI defects and shows that analysis of skin fibroblasts may be a useful technique for the detection of collagen VI abnormalities. In contrast, immunohistochemical analysis of skin biopsies may not always reveal an underlying collagen VI defect.
Progressive scoliosis with increasing pelvic obliquity in early childhood of patients with SMA type II is a common feature in this disease. Spinal surgery in muscle disorders should be carried out as soon as a progressive curve of more then 20 Celsius Cobb and a preserved FVC of 20-30% is proved. In later stages or severe forms of SMA II spinal stabilization becomes often impossible due to the respiratory insufficiency, the poor general condition and the severity of the scoliosis with marked pelvic obliquity. A special telescope rod was developed in order to enable a lengthening of this instrumentation during growth for children treated in early childhood. In 15 of 20 patients with SMA II in early childhood not satisfactory results after telescope rod implantation were observed. In spite of the telescope technique crankshaft phenomenon appeared and curve progression were observed. So then we stopped telescope rod implantation. This instrumentation could be in principle a good therapeutical tool for this indication, but its technical manufacturing has firstly to be improved decisively. For SMA II patients younger than 10 years with progressive scoliosis our therapeutic recommendation is nowadays a corset until the age of 10-12 years followed by definitive surgical correction using other multisegmental instrumentation like the Isola(R) system.