Early diagnosis of liver cirrhosis is important. Ultrasound guided liver biopsy is the gold standard for diagnosis of liver cirrhosis. However, its invasiveness and sampling bias limit the applicability of the method. Basic imaging for the diagnosis of liver cirrhosis has developed over the last few decades, enabling early detection of morphological changes of the liver by ultrasonography (US), computed tomography, and magnetic resonance imaging (MRI). They are also accurate diagnostic methods for advanced liver cirrhosis, for which early diagnosis is difficult. There are a number of ways to compensate for this difficulty, including texture analysis to more closely identify the homogeneity of hepatic parenchyma, elastography to measure the stiffness and elasticity of the liver, and perfusion studies to determine the blood flow volume, transit time, and velocity. Amongst these methods, elastography using US and MRI was found to be slightly easier, faster, and able to provide an accurate diagnosis. Early diagnosis of liver cirrhosis US elastography is therefore a realistic alternative, but further research is still needed.
Liver cirrhosis is the end stage of chronic liver disease. It is caused by diffuse fibrosis and regenerating nodules that result from recurrent necrosis of liver cell and degeneration. It is recognized as an irreversible form of parenchymal fibrosis. Liver cirrhosis reduces hepatic function and results in multiple complications induced by nodular regeneration and portal hypertension, including ascites, variceal bleeding, and renal failure due to hepatorenal syndrome, hepatic encephalopathy, and spontaneous bacterial peritonitis. In addition, the incidence of hepatocellular carcinoma is sharply increased. Recently, early liver cirrhosis was shown to be improved by regression of collagen tissue. Regression is usually associated with the improvement of clinical status, but can vary in the degree of improvement, depending on the reversibility of liver damage. Extensive scarring with parenchymal destruction is unlikely to regress. Therefore, early diagnosis of liver cirrhosis and quantification of the proportion of fibrosis in the liver are very important in the management of chronic liver disease. Prognosis and management of chronic liver diseases hinge strongly on the amount and progression of liver fibrosis. There are a variety of causes of liver cirrhosis, with alcohol consumption, viruses, and fatty liver disease making up the majority of factors. These various etiologies induce chronic inflammation. Normal lobular architecture of the liver parenchyma is replaced by a parenchymal nodule surrounded by the fibrous tissue. Portal-central septa, connecting the portal vein and central vein, develop. As the inflammation persists, various form of fibrosis develops. The gross morphologic appearance of a cirrhotic liver is categorized by the size of the parenchymal nodules: micronodular, macronodular, or mixed. Micronodular cirrhosis is characterized by regenerative nodules of relatively uniform and small size. This pattern is seen in chronic alcoholic, hepatitis C, and biliary cirrhosis. In macronodular cirrhosis, the parenchymal nodules are larger, and more variable in size. Chronic hepatitis B is the most common cause of macronodular cirrhosis. On the other hand, liver cirrhosis is classified according to the main location of fibrosis occurrence. A portal based pattern usually results from hepatitis B and C, autoimmune hepatitis, Wilson’s disease, primary biliary cirrhosis, primary sclerosing cholangitis, recurrent pyogenic cholangitis, and hemochromatosis. Conversely, a centrizonal fibrosis pattern results from alcoholic and non-alcoholic steatohepatitis or chronic venous outflow
obstruction. There are differences in the grading and scoring of fibrosis by microscopic pathology according to the cirrhosis pattern. The METAVIR score (F0: no fibrosis, F1: portal fibrosis without bridging fibrosis, F2: portal fibrosis with few bridging fibrosis, F3: bridging fibrosis with architectural distortion, F4: cirrhosis) and the Ishak score (grades four categories of activity/necrosis, 0-4 or 0-6) are commonly used systems for grading or staging. The METAVIR score is simple, reproducible, and clinically validated, while the Ishak score is generally considered to be unnecessarily complex but preferred in many clinical trials. Pathological confirmation of microscopic specimens obtained by ultrasound-guided needle biopsy is the reference standard for fibrosis staging. However, there are several well-known limitations, including sampling errors, subjective interpretation, semiquantitativeness, invasiveness, morbidity, and mortality of the procedure.
In clinical practice, the severity of liver cirrhosis is measured by multiple serologic biomarkers and many clinical scores and panels, such as the Child-Pugh score, model for end-stage liver disease score, Fibro Test, HepaScore, FibroSpect, enhanced liver fibrosis score, and aspartate aminotransferase-to-platelet ratio index.
However, these metrics also have many limitations, since the biomarkers are not liver-specific and measurement depends highly on their clearance and excretion[8,9].
Basic imaging diagnosis of liver cirrhosis has developed over the last few decades, enabling early detection of morphological changes of the liver using ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI). These methods are accurate for diagnosis of advanced liver cirrhosis.
However, as morphological changes indicate advanced cirrhosis, there are limitations to early diagnosis of liver cirrhosis using imaging. To facilitate early diagnosis of liver cirrhosis, texture analysis and elastography to measure stiffness of the liver, and perfusion studies to determine the blood flow volume, transit time, and velocity were developed.
Shear wave elastography relies on the generation of shear waves determined by the displacement of tissues induced by the force of a focused ultrasound beam or by external pressure. The shear waves are lateral waves, with a motion perpendicular to the direction of the force that has generated them. They travel slowly (between 1 and 10m/s) and are rapidly attenuated by tissue. The propagation velocity of the shear waves correlates with the elasticity of tissue; ie, it increases with increasing stiffness of the liver parenchyma.
To correctly read the results, it should be kept in mind that elastography assesses liver elasticity that could be modified by factors other than fibrosis, such as edema, inflammation, extrahepatic cholestasis, and congestion.
In fact, these factors may lead to overestimation of the liver stiffness for a sharp enlargement of the liver, which is covered by the Glisson capsule, a poor distensible envelope.
Thus, the results obtained should always be interpreted in clinical settings. Examinations should be performed under fasting conditions because it has been demonstrated that food intake may produce false-positive results.
Elastographic Techniques Based on Shear Waves Generated by the Acoustic Beam
These techniques have the advantage of being integrated into ultrasound systems; thus, conventional sonography, which is advised every 6 to 12 months in patients with chronic liver disease, could also be performed. As of today, for the assessment of liver stiffness, these techniques are commercially available in high-end ultrasound systems made by Philips Healthcare (Bothell, WA; ElastPQ), Siemens Medical Solutions (Mountain View, CA; Virtual Touch Tissue Quantification [VTTQ]), and SuperSonic Imagine, SA (Aix-en-Provence, France; ShearWave Elastography [SWE]). These techniques generate shearwaves inside the liver by using radiation force from a focused ultrasound beam. The shear waves are generated near the region of interest in the liver parenchyma and not on the surface of the body, as happens with external vibration devices.
The ultrasound system monitors shear wave propagation using a Doppler-like ultrasound technique and measures its velocity. The shear wave velocity is displayed in meters per second or kilopascals through the Young modulus. Unlike transient elastography, the measurements are not limited by the presence of ascites because the ultrasound beam, which generates the shear waves, propagates through fluids. With the VTTQ and ElastPQ techniques, the readings of the shear wave speed are made by using a small sample box (usually 0.5 × 1 cm); thus, a quantitative estimate of liver stiffness at a single location is obtained. They have been categorized as point–shear wave elastography.27 The SWE technique is based on an ultrafast ultrasound imaging approach that allows detailed monitoring of the shear waves in a large area of liver parenchyma with real-time color-coded elasticity imaging inside a sample box, and the measurement is obtained by placing a region of interest inside the sample box. This technique is 2-dimensional elastography.
In all of the studies that have assessed the accuracy of the different devices in staging liver fibrosis, right intercostals access has been used. The patient is examined in the dorsal decubitus position with the right arm elevated above the head for optimal intercostal access in a resting respiratory position. Measurements are performed at least 1.5 to 2.0 cm beneath the Glisson capsule to avoid reverberation artifacts. In case of physical conditions affecting the signal to- noise ratio, the Philips and Siemens devices do not give any measurement. With the Supersonic Imagine device, a measurement fails when no/little signals are obtained in the sample box for all of the acquisitions.
Philips Technique (ElastPQ)
The ElastPQ technique was the most recent to enter the market; thus, only a few studies have been published so far. With this technique, liver stiffness values in healthy volunteers have been reported to be less than 4.0 kPa (1.15 m/s).39,40 Ling et al39 found that men had higher values than women (3.8 } 0.7 versus 3.5 } 0.4 kPa, or 1.13 } 0.48 versus 1.08 } 0.37 m/s) and liver stiffness was comparable with different probe positions, examiners, and age groups.
In a series that comprised 88 patients with chronic viral hepatitis and 33 healthy volunteers, the technique compared favourably with transient elastography in staging liver fibrosis, and healthy volunteers showed significantly lower values than patients with nonsignificant fibrosis.
A 55-year-old man has been infected with chronic hepatitis C for 15 years. He has had transiently elevated serum aminotransferase levels in the past but has had normal values at follow-up for 2 years. To start an antiviral treatment, he has been scheduled for liver biopsy by the referring physician. Biochemical test results obtained the day before liver biopsy are within the normal range. Shear wave elastography was performed. Value was suggestive of advanced fibrosis. Started on antivirals and doing well. Thereby SWE was helpful in avoiding invasive procedure.
Considering that liver biopsy is not a perfect reference standard, these different results could be due to a failure of liver biopsy in correctly assessing liver fibrosis and could be explained by the uneven distribution of fibrosis. In fact, histologic staging is based on a biopsy specimen that represents at most 1/50,000 of the total liver mass. In this regard, the sample size of elastographic techniques is more representative of liver tissue than a liver biopsy specimen, and the evaluation could be done in several areas of the liver parenchyma. On the other hand, even when an experienced physician performs a liver biopsy and an expert pathologist interprets the results, liver biopsy has a sampling error in diffuse liver disease staging.
2. 56 yr old female patient was diagnosed to have pulmonary tuberculosis and started on ATT. 2 weeks later she developed jaundice, she was treated by a physician as drug-induced liver disease. She had progressive jaundice hence referred for further management. SWE showed advanced fibrosis (cirrhosis). Her autoimmine profile was positive. SWE was helpful in diagnosing underlying advanced fibrosis which had already occurred due to autoimmune hepatitis.
3. 45 yr old male with chronic kidney disease was being evaluated for renal transplant, his liver enzymes were elevated, hence referred for liver biopsy. SWE was done on him which sever fibrosis F4. He was then planned foe liver and kidney transplant.
The development of new imaging modalities for diagnosing of liver cirrhosis has led to the detection and measurement of subtle changes. This has enabled early and accurate diagnosis of liver cirrhosis. Currently, elastography, used to measure the stiffness and elasticity of the liver, is more widely applied than texture analysis in diagnosis of liver cirrhosis. Results strongly correlate with hepatic fibrosis, without the need for a post-operation procedure. Although MRE has more accurate tendency, US is simple imaging tool in diagnosing cirrhosis and can be added as several additional complementary technologies. The non-inferior diagnostic capability, non-invasiveness and relative cost-effectiveness of US elastography may enable it to be one of the most useful techniques for diagnosis of liver cirrhosis.
1 Massarrat S, Fallahazad V, Kamalian N. Clinical, biochemical and imaging-verified regression of hepatitis B-induced cirrhosis. Liver Int 2004; 24: 105-109 [PMID: 15078473 DOI: 10.1111/ j.1478-3231.2004.00895.x]
2 Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009; 49: 1335-1374 [PMID: 19330875 DOI: 10.1002/hep.22759]
3 Castera L. Invasive and non-invasive methods for the assessment of fibrosis and disease progression in chronic liver disease. Best Pract Res Clin Gastroenterol 2011; 25: 291-303 [PMID: 21497746 DOI: 10.1016/j.bpg.2011.02.003]
4 Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, Denk H, Desmet V, Korb G, MacSween RN. Histological grading and staging of chronic hepatitis. J Hepatol 1995; 22: 696-699 [PMID: 7560864]
5 Maharaj B, Maharaj RJ, Leary WP, Cooppan RM, Naran AD, Pirie D, Pudifin DJ. Sampling variability and its influence on the diagnostic yield of percutaneous needle biopsy of the liver. Lancet 1986; 1: 523-525 [PMID: 2869260]
6 Seeff LB, Everson GT, Morgan TR, Curto TM, Lee WM, Ghany MG, Shiffman ML, Fontana RJ, Di Bisceglie AM, Bonkovsky HL, Dienstag JL. Complication rate of percutaneous liver biopsiesamong persons with advanced chronic liver disease in the HALT-C trial. Clin Gastroenterol Hepatol 2010; 8: 877-883 [PMID: 20362695 DOI: 10.1016/j.cgh.2010.03.025]
7 Bravo AA, Sheth SG, Chopra S. Liver biopsy. N Engl J Med 2001; 344: 495-500 [PMID: 11172192 DOI: 10.1056/nejm20010215344 0706]
8 Parkes J, Guha IN, Roderick P, Rosenberg W. Performance of serum marker panels for liver fibrosis in chronic hepatitis C. J Hepatol 2006; 44: 462-474 [PMID: 16427156 DOI: 10.1016/j.jhep.2005.10.019]
9 Grigorescu M. Noninvasive biochemical markers of liver fibrosis.J Gastrointestin Liver Dis 2006; 15: 149-159 [PMID: 16802010]
10. Sarvazyan A, Hall TJ, Urban MW, Fatemi M, Aglyamov SR, Garra BS. An overview of elastography: an emerging branch of medical imaging. Curr Med Imaging Rev 2011; 7:255–282.
11. Arena U, Vizzutti F, Corti G, et al. Acute viral hepatitis increases liver stiffness values measured by transient elastography. Hepatology2008; 47:380–384.
12. Coco B, Oliveri F, Maina AM, et al. Transient elastography: a new surrogate marker of liver fibrosis influenced by major changes of transaminases.J Viral Hepat 2007; 14:360–369.
13. Millonig G, Friedrich S, Adolf S, et al. Liver stiffness is directly influenced by central venous pressure. J Hepatol 2010; 52:206–210.
14. Millonig G, Reimann FM, Friedrich S, et al. Extrahepatic cholestasis increases liver stiffness (FibroScan) irrespective of fibrosis. Hepatology 2008; 48:1718–1723.
15. Bamber J, Cosgrove D, Dietrich CF, et al. EFSUMB guidelines and recommendations on the clinical use of ultrasound elastography, part 1: basic principles and technology. Ultraschall Med 2013; 34:169–184.
16. Ferraioli G, Tinelli C, Lissandrin R, Zicchetti M, Dal Bello B, Filice C. Performance of ElastPQR shear wave elastography technique for assessing fibrosis in chronic viral hepatitis [abstract]. J Hepatol2013; 58(suppl 1):S7.