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Current applications of elastometry and Fibro- and ActiTest for diagnostics of hepatic fibrosis
Ch.S. Pavlov, D.V. Glushenkov, V.T. Ivashkin V.Kh.Vasilenko Hospital of Propaedeutics of Internal Medicine, Gastroenterology, and Hepatology, I.M.Sechenov Moscow Medical Academy Russian Journal of Gastroenterology, Hepatology, and Coloproctology (RJGHC)
Diagnostics and treatment of chronic diffuse hepatic diseases is one of the main problems of modern hepatology. Development of sequential stages of fibrosis culminating in cirrhosis and hepatic cancer is the major pathway fro progression of these diseases and this essentially determines unfavorable life-threatening prognosis and short time of survival of these type of patients [5,13,17].
Hepatic fibrosis is universal pathological process resulting from liver damage; it is characterized by excessive deposition of extracellular matrix due to elevated synthesis of its components and reduced rate of their decomposition (Fig. 1). Development of fibrosis is accompanied with accumulation and deposition of collagen types I, III, and IV, laminin, fibronectin, glucosaminoglycans, proteoglycans, elastin, etc. in the spaces of Disse thus resulting in formation of connective tissue membrane within the walls of intralobular venous capillaries.
Closure of functional intercellular cavities (which normally are the areas of metabolic exchange between hepatocytes and the blood coming through the portal vein) is known in the literature as sinusoidal capillarization. Alterations in transport between the blood coming in through the portal vein and hepatocytes leads to development of hypoxia and involvement of hepatocytes in fibrogenesis. Active contraction of presinusoidal astrocytes and expansion of the Disse spaces filled with collagen fibers blocks the blood flow coming through the portal vein to increase the pressure in the portal vein forming portal hypertension syndrome including portocaval anastomoses. Further progression of these lesions subsequently induces reorganization of hepatic architecture and causes development of cirrhosis [13,15,17,18,22].
Early diagnostics and accurate determination of the stage of fibrosis should enable timely prescription of appropriate therapy to lower the rate of progression of fibrosis to stop development of cirrhosis and hepatic cancer [13,15,17].
In patients with chronic viral hepatitis (CVH), hepatic fibrosis should be extensively investigated due to the following reasons.
1. Severe fibrosis influences efficacy of the treatment regimen and detection of fibrosis might require increased duration of therapy and increase in doses of the drugs [3,4,8,14,34,40].
Fig. 1. Pathogenesis of hepatic fibrosis
2. Diagnosis of particular stage and risk of progression of fibrosis in patients which develop adverse effects during therapy significantly contributes to determination of subsequent medical tactics and can decide whether the prescribed treatment can be continued [8,14,21,29,34,40].
3. Detection of hepatic fibrosis concomitant to steatohepatitis in patients with non-alcoholic steatohepatitis can dictate the necessity for certain drug therapy [11,27].
4. Reversal of fibrosis during treatment is the main criterion for efficacy of drug therapy and is actively studied in clinical trials of new medications [13,17,34,40].
5. Patients with severe fibrosis are included in the group of high risk of development of complications such as cirrhosis and hepatic cancer [6,15,17,23].
Liver biopsy
Current development of clinical medicine and hepatology in particular is characterized by gradual distancing from traditional morphometric method of investigation of hepatic tissue which was established during the past decades and which was the main way to accumulate any medical knowledge. The morphometric method is widely available and is safe; the examination is performed dynamically to evaluate progression of the lesions and treatment efficacy; morphological evaluation enables to locate and estimate extent of fibrosis [15,16,23,29].
However, expansion of liver biopsy application to the practice of specialized divisions is limited by a number of problems including lack of regulatory documents describing the manipulations, lack of qualified morphologists who can objectively describe and quantify the morphological signs, and invasiveness of the procedure and potential risk of complications directly associated with experience of physician who is actually performing the biopsy of the liver [16,18,23].
Some patients refuse the liver biopsy because of being afraid. Up to one third of patients refuse the biopsy due to possible pain at the site of biopsy and adverse effects of anesthesia and this slows down the decision to start anti-viral therapy and extend the presence of the patients in a hospital [34,40]. Another important problem is morphometric interpretation of changes in the hepatic tissue. The suggested systems of semi-quantitative evaluation of an index of histological activity (IHA) and stage of fibrosis in patients with CVH are far from perfect (Table 1).
The goal of the system of semi-quantitative evaluation is to systematize the signs of necroinflammatory reaction and extent of hepatic fibrosis. The main negative feature of these systems is lack of clear separators between criteria used to evaluate fibrosis and expression of necroinflammatory reaction (IHA) which often results in unclear estimation of the results [16,18,26,44].
Thus, all these considerations have led to introduction of noninvasive methods of diagnostics of hepatic fibrosis in clinical practice.
Noninvasive evaluation of hepatic fibrosis
Significant advantages of modern methods of noninvasive diagnostics versus liver biopsy include simple application, low cost, abundance of information in each stage of fibrosis, possibility to follow up the dynamics of the process, convenient use for screening of the patients of risk groups, and ambulatory conditions of the procedure; this is paramount importance to diagnose the early stages of the disease and to timely administration of the treatment for prevention of further progression of fibrosis [1,7,25,31,47].
During the recent years, noninvasive methods of diagnostics of fibrosis and actively developing into several directions.
* Serum markers of fibrosis:
1. Mediators of fibrogenesis and components of extracellular matrix determined in the serum (collagen types I, III, and IV, hyaluronic acid, laminin and its fragments, YKL-40, metalloproteinases, tissue inhibitors of metalloproteinases, cytokines, etc.). Low specificity towards hepatic fibrogenesis in the main disadvantage of these methods since these parameters can be indicative of any similar process in another tissue (pulmonary and pancreatic fibrosis, etc.) [30].
2. Indirect data. A number of panels of biochemical markers (AST, ALT, AP, GGTP, total bilirubin, etc.) and acute phase proteins (alpha2-macroglobulin, haptoglobin, ferritin, etc.) are suggested to evaluate the activity of hepatic fibrogenesis.
Discriminant functions derived on the basis of changes in these parameters correspond to activity of inflammatory process in the tissue and to lesions in synthetic activity of the liver and thus are indirectly indicative of the stage of fibrosis [2-4,25,27,42].
Table 1
Comparison of systems for semiquantitative evaluation of hepatic fibrosis
|
Points
|
R.G.Knodell, 1981
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P.J.Scheuer, 1991
|
K.G.Ishak, 1994
|
K.P.Batts, 1995
|
METAVIR, 1994
|
|
0
|
Absence of fibrosis
|
Absence of fibrosis
|
Absence of fibrosis
|
Absence of fibrosis
|
Absence of fibrosis
|
|
1
|
Fibrous expansion of portal ducts
|
Expanded fibrous portal tracts
|
Fibrous widening of portal tracts with or without short fibrous septa
|
-
|
Star-like widening of portal tracts without formation of septa
|
|
2
|
Expansion of portal ducts + portoportal septa
|
Periportal or portoportal septa, liver architecture normal
|
Fibrous widening of the majority of portal tracts with or without short fibrous septa
|
Portal fibrosis
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Widening of portal tracts with singular portoportal septa
|
|
3
|
Bridging fibrosis, portoportal or portocentral septa
|
Fibrosis with lesions of liver architecture but without clear cirrhosis
|
Fibrous widening of the majority of portal tracts with singular bridging portoportal septa
|
Periportal fibrosis, fibrosis of septa
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Multiple portocentral septa without cirrhosis
|
|
4
|
Cirrhosis
|
Probable or evident cirrhosis
|
Fibrous widening of the majority of portal tracts with clear bridging portoportal and portocentral septa
|
Cirrhosis
|
Cirrhosis
|
|
5
|
-
|
-
|
Multiple bridging septa with singular knots (incomplete cirrhosis)
|
-
|
-
|
|
6
|
-
|
-
|
Probable or evident cirrhosis
|
-
|
-
|
*Methods of visualization
1. Elastometry of the liver enables detection of hepatic fibrosis by generating vibration impulses followed by computer analysis to monitor changes in elastic properties of the tissue and rate of progression of the disease. Clinical experience of liver hardening evaluated by palpation was the theoretical basis for development of elastometry application to diagnose severe fibrosis or cirrhosis [20,24,28,32,33,35,46].
2. Doppler studies of hepatic vessels. Hemodynamics of hepatic blood flow is changed gradually with occurrence of blood flow obstacles and outgrowth of fibrous membranes along sinusoids.
3. Ultrasound B-regimen study, computer tomography, and magnetic resonance tomography can be hardly used to evaluate the stage of fibrosis due to lack of evaluation criteria at early stage of the disease.
Our data on the use of Fibroscan apparatus and fibro- and acti-test for noninvasive diagnostics of hepatic fibrosis in patients with chronic hepatitis B (CHB) and chronic hepatitis C (CHV) are presented below; the data were obtained at V.Kh.Vasilenko Hospital of Propaedeutics of Internal Medicine, Gastroenterology, and Hepatology, I.M.Sechenov Moscow Medical Academy.
Hepatic elastometry with Fibroscan apparatus
General characteristics of Fibroscan apparatus
Fibroscan apparatus (Echosens, France) is an ultrasound transforming detector with oscillation source of medium amplitude and low frequency (Fig. 2).
Fig. 2. Fibroscan apparatus
The oscillations generated by the apparatus are transferred to the tested liver tissue and create elastic waves which modulate reflected ultrasound. Rate of spreading of the elastic waves is determined by elasticity of hepatic tissue. Total volume of tested tissue is 6 cm3 on average which greatly exceeds the volume of biopsy [33,46].
Fig. 3. Procedure of the test
Procedure of the test
The Fibroscan apparatus test is performed on a patient positioned on his back and the right hand is drawn aside as far as possible. Transducer of the sensor is positioned to sixth-eighth intercostal area following the median underarm line at projection of the right lobe of the liver (Fig. 3). Precise positioning of the sensor is assisted with a window of ultrasound visualization. A region of the liver selected for the test must be free from blood vessel structures of greater than 5 mm in diameter and should be homogenous. The sensor is focused at the zone of 25-65 mm from the surface of the skin. After correct installation of the sensor, 10 reliable measurements are taken and based on their results, the software calculates the value of hepatic elasticity. The value is expressed in kilopascals (kPa). Allowed interquartile coefficient (IQR) should not exceed ¼ of the elasticity value.
Goal of the study
To investigate application of elastometry for complex evaluation of hepatic fibrosis in patients with chronic viral hepatitis in the biopsy room of V.Kh.Vasilenko Hospital of Propaedeutics of Internal Medicine, Gastroenterology, and Hepatology to conduct clinical study of the Fibroscan apparatus. The protocol of the study was filed according to the requirements for clinical trials within Russian Federation.
Specific aims of the study
1. Comparative analysis of elastometry and diagnostics of stages of fibrosis by morphometry of the tissue in patients with CHC and CHB at various stages of fibrosis.
2. Determination of factors influencing diagnostic precision of elastometry at early (F0-F1) stages of fibrosis.
3. Possible application of elastometry to evaluate dynamics of fibrosis in patients with CHC responding to combined antiviral therapy (PEG-interferon-a and Ribavirin).
Materials and methods of the study
The following parameters were determined.
1. Diagnostic accuracy of elastometry in patients with CHC and CHB at various stages of hepatic fibrosis (Fig. 4) [9,12].
Total of 50 patients were examined (34 mean and 16 women) with mean age of 35.6±10.9 years. Body mass index (BMI) mean was 24.4±4.4 kg/m2. The patients were admitted to Division of Hepatology and diagnosed with chronic hepatitis (80% HCV RNA+ and 20% HBV DNA+).
On the day of elastometry, all patients underwent hepatic biopsy by the method of Mengini. The results obtain with the Fibroscan apparatus were compared to the semiquantitative data and IHA evaluation according to Knodell and METAVIR and with parameters of clinical and biochemical activity of CH. The data were statistically evaluated with SPSS software version 14.0. The results of morphometry indicate that 12 patients (12%) had F0 stage of fibrosis, 15 patients (30%) had F1 stage, 10 (20%) patients had F2 stage, 8 (16%) patients had F3 stage, and 5 (10%) patients had F4 stage of fibrosis according to METAVIR scale.
Fig. 4. Diagnostic accuracy of elastometry in paatients with CVH
According to elastometry, mean value of hepatic elasticity was 3.5 kPa for F0, 6.5 kPa for F1, 8.3 kPa for F2, 11 kPa for F3, and 24 kPa for F4. Parameter of diagnostic accuracy was 89% for F0 fibrosis (AUROC 0.89), 88% for F1 (AUROC 0.88), 92% for F2 (AUROC 0.92), 92.5% for F3 (AUROC 0.92), and 96% for F4 (AUROC 0.96).
2. Diagnostic accuracy of elastometry in patients with CHC at early stages (F0-F1) of hepatic fibrosis [10].
Total of 25 patients were examined (15 men and 10 women from 24 to 61 years of age, mean age 35.0±12.0 years). According to HCV genotype, the patients were distributed into the following groups: 15 patients had genotype 1, 10 patients had genotypes 2 and 3. Viral load was <2 million copies/ml in 13 patients and > 2 million copies/ml in 10 patients. Mean level of ALT activity was 71±29 units/l.
On the day of elastometry, all patients underwent hepatic biopsy to determine IHA and stage of fibrosis. According to morphometry,, 10 patients (40%) had F1 stage of fibrosis and 5 patients (20%) had F0 stage of fibrosis of the METAVIR scale and mean IHA according to Knodell was 6.8±1.2 points.
According to elastometry, mean liver elasticity was 3.5±0.5 kPa for F0 and 6.5±1.5 kPa for F1. Method sensitivity for stage F1 was 66% and specificity was 83%. Analysis of the data of main clinical and morphometric parameters of liver examination in the patients indicated that the following independent factors influence diagnostic accuracy of elastometry: age of patient (>50 years old), OR 0.96 (95% CI 0.95-0.97; p<0.0001); BMI<28 kg/m2 OR 0.19 (95% CI 0.12-0.29; p<0.0001); lack of steatosis according to morphometry of liver tissue OR 1.006 (95% CI 1.002-1.009; p<0.0001).
3. Elastometry application to evaluate dynamics of hepatic fibrosis in patients with CVH treated with PEG-interferon-a and Ribavirin [19].
From November, 2006 to November 2007, we have observed 16 patients with CHC (9 men and 7 women) which had a virological response to combined antiviral therapy (PEG-interferon-a + Ribavirin). Fibroscan apparatus tests were performed prior to the beginning of treatment, in 6 months (patients with viral genotype 2 and 3) and 3 months (patients with viral genotype 1) after the end of the treatment. Mean age of the patients was 49.0±11.0 years. Six patients (38%) had viral genotype 1.
Mean value of liver elasticity before the treatment was 7.2 kPa (from 2.8 to 65.7 kPa). Initially, the patients had minimal fibrosis (<7.1 kPa) 54% (9 patients); moderate fibrosis (7.1-9.5 kPa) 20% (3 patients), expressed fibrosis (9.5-12.5 kPa) 20% (3 patients), and liver cirrhosis (>12.5 kPa) 6% (1 patient). After the end of the treatment, elasticity of the liver was decreased in 9 patients (56%; on average, down to 5.8 kPa). Mean decrease was 1.7±6.2 kPa. Redistribution of patients between fibrosis groups was noted with minimal fibrosis (<7.1 kPa) detected in 12 patients (74%); moderate fibrosis ( 7.1-9.5 kPa) was detected in 4 patients (26%); severe fibrosis (9.5-12.5 kPa) and cirrhosis (>12.5 kPa) was not detected.
Patients who had virological response to combined antiviral therapy in 6 months after termination of treatment were investigated by elastometry and had improved elastic properties of liver tissue thus indicating lowered severity of fibrosis. Hence, elastometry can be used for noninvasive diagnostics of hepatic fibrosis dynamics in patients subjected to antiviral therapy.
Discussion of results
The data illustrating diagnostic accuracy of elastometry at various stages of hepatic fibrosis are in agreement with the results of authors from other countries which suggest maximal diagnostic accuracy of elastometry for stages F3-F4 [20,33,46]. This offers and option to use the results of elastometry to make a decision to start therapy and evaluate response to therapy since it is known that severe fibrosis (>F3) negatively impacts the outcome of antiviral treatment. Low sensitivity (66%) of elastometry on fibrosis stages F0-F1 requires liver biopsy or other tests to confirm the stage of fibrosis in these patients. High specificity (83%) of elastometry on early stages of fibrosis suggests that the method can be used in patients with CHC viral genotype 1 and normal level of transaminases who might be observed in dynamics without administration of antiviral therapy.
Evaluation of extent of fibrosis with Fibro- and ActiTest
Noninvasive diagnostics of hepatic fibrosis with this method (BioPredictive, France) is aimed to timely determine the stage of fibrosis and control its development during treatment and to evaluate necroinflammatory process in hepatic tissue. Both tests are considered as alternative to liver biopsy in patients with CVH [36,37,39,43]. The methods are well known in Europe and USA. At present, the tests are used in France in over 500 private laboratories and 37 public hospitals. In the beginning, the methods were developed for patients with CHC and HCB and then were used in patients with other nosological forms of chronic liver diseases.
FibroTest includes 5 biochemical markers: alpha2-macroglobulin (AMG), haptoglobin (Hp), apolipoprotein A1 (ApoA1), gamma-glutamyl transpeptidase (GGTP), and total bilirubin. Acti-test includes the former 5 components and additional marker alanine aminotransferase (ALT).
General characterization of the components of Fibro- and ActiTest
Alpha2-macroglobulin is one of the most multifunctional blood proteins of acute phase which inhibits endopeptidases and is synthesized by the pancreas. AMG is high molecular weight glycoprotein composed of four identical subunits. In native state, AMG can bind and transport a number of cytokines (interleukins, interferons, tumor necrosis factors, stimulins, inhibins, and growth factors). Each subunit also contains a so-called trap for any proteolytic enzyme. The proteinases retain their activity while being trapped. Clearance half-time of such complex from the circulation is below 1-2 min and during this period, proteinases are still active. Thus, AMG regulates a number of functions of the body associated with blood and lymph circulation. AMG is metabolized in the liver and this metabolism activates astrocytes to stimulate fibrogenesis [42].
Haptoglobin is a plasma glycoprotein which specifically bind hemoglobin and is synthesized in the liver. Haptoglobin is considered to be the acute phase protein. Its blood level is increased due to stimulation of hepatocytes with interleukins. It is negatively associated with hepatic fibrosis [37].
Apolipoprotein A1 is synthesized by the liver and is responsible for cholesterol transport. It is included in extracellular matrix and its level is decreased at increasing stages of fibrosis [38,41].
Total bilirubin is formed during decomposition of hemoglobin in the cells of the reticuloendothelial system especially in the spleen and Kupfer cells of the liver. Increase in its level suggests hepatocellular failure.
Gamma-glutamyl transpeptidase is a sensitive but nonspecific marker of bile duct damage. Its concentration is the highest in epithelial cells of the bile ducts and is a sign of fibrosis due to lesions of the duct system of the liver [27].
Alanine aminotransferase is the most sensitive and specific indicator of hepatocellular damage (inflammation and necrosis of the cells) and is located in the cytosol of hepatocytes [27].
The data of the test are combined with the data on the age of a patient to calculate a parameter which determines stage of fibrosis and extent of CH activity with high sensitivity and accuracy (Table 2). Unified calculator for Fibro- and Acti-Test parameters is available online at www.biopredictive.com.
Table 2
Criteria for evaluation of fibro- and acti-test
|
Fibro-test
|
Evaluation of extent of fibrosis
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Acti-test
|
Evaluation of extent of CH activity
|
|
0.75-1.00
|
F4
|
-
|
-
|
|
0.73-0.74
|
F3-F4
|
0.64-1.00
|
A3
|
|
0.59-0.72
|
F3
|
0.61-0.63
|
A2-A3
|
|
0.49-0.58
|
F2
|
0.53-0.60
|
A2
|
|
0.32-0.48
|
F1-F2
|
0.37-0.52
|
A1-A2
|
|
0.28-0.31
|
F1
|
0.30-0.36
|
A1
|
|
0.22-0.27
|
F0-F1
|
0.18-0.29
|
A0-A1
|
|
0.00-0.21
|
F0
|
0.00-0.17
|
A0
|
Goal and specific aims of the study
We have examined patients with CVH (admitted to V.Kh.Vasilenko Hospital of Propaedeutics of Internal Medicine, Gastroenterology, and Hepatology, I.M.Sechenov Moscow Medical Academy) using Fibro- and Acti-Test to investigate the possibilities of the method and its applicability for complex evaluation of hepatic fibrosis and necroinflammatory activity of hepatitis. The goals included determination of diagnostic accuracy of Fibro- and Acti-Test at various stages of fibrosis according to morphological examination [4,11,12].
Materials and methods of the study
Fifty patients (33 men and 17 women) were enrolled with mean age being 35±10 years. BMI was 23.5±4.2 kg/m2. The patients were admitted to Division of Hepatology and diagnosed with chronic hepatitis (84% HCV RNA+ and 16% HBC DNA+). On the day of Fibro- and ActiTest procedures, all patients underwent hepatic biopsy by the method of Mengini. The results were compared with the data of semiquantitative IHA evaluation according to METAVIR system. Data were statistically evaluated with SPSS software version 14.0. According to morphometry, 33 patients (66%) had fibrosis stage F1, 10 patients (20%) had fibrosis stage F2, and 7 patients (14%) had their fibrosis evaluated at stage F3 according to the METAVIR scale. Mean IHA was 6.4±1.9 points.
Discussion of the results
The results of Fibro-test had 70% sensitivity (Se) and 85% specificity (Sp) for F1, 80% Se and 100% Sp for F2, 100 % Se and 100% Sp for F3, and 100% Se and 100% Sp for F4 (Fig. 5).
Fig. 5. Diagnostic accuracy of FibroTest
According to ActiTest, Se was 68% and Sp was 75% for A0, Se was 83% and Sp was 82% for A1, Se was 87% and Sp was 88% for A2, and Se was 98% and Sp was 97% for A3 (Fig. 6).
Fig. 6. Diagnostic accuracy of ActiTest
The data on diagnostic accuracy of Fibro- and ActiTest are significant in very informative and the method enables noninvasive diagnostics of extent of activity of necroinflammatory reactions and stage of hepatic fibrosis in patients with CHC and CHB. Cholestasis limits the use of the method since it results in increase in GGTP and total bilirubin (included in equation to calculate stage of fibrosis) and this negatively influences diagnostic accuracy of the method. Thus, Fibro- and Acti-Test can be considered as new and prospective development in early diagnostics of hepatic fibrosis in patients with CHC and CHB and is an alternative to transcutaneous biopsy of the liver.
Conclusion
Results of our experience with liver biopsy, use of Fibroscan apparatus (Echosens, France), and Fibro- and ActiTest for complex evaluation of hepatic fibrosis and CH activity lead to the following conclusions:
1. Liver elastometry and FibroTest can be sued for noninvasive diagnostic of hepatic fibrosis in patients with chronic viral hepatitis.
2. Results of liver elastometry and Fibro- and ActiTest are highly informative on all stages of fibrosis and this enabled to compare their diagnostic accuracy with the data of morphometric examination of the liver tissue.
3. Fibroscan use is limited is patients with BMI> 28 kg/m2 and this requires further technical improvement of the method.
4. Inability to evaluate the activity of CH limits the usefulness of elastometry as a standalone method to monitor the progress of hepatic fibrosis.
5. Short time and noninvasive type of the test enable the use of elastometry and Fibro- and ActiTest in clinical practice as methods to screen for hepatic fibrosis in patients with CVH.
6. Elastometry can be used for noninvasive diagnostic of dynamics of hepatic fibrosis in patients treated with antiviral medications.
7. Use of Fibro- and ActiTest is limited by cholestasis manifested as elevated levels of bilirubin and GGTP in patients with chronic diffuse diseases of the liver.
8. Further expansion of the list of indications for noninvasive tests can be accomplished only after comparison with the results of biopsy in patients with chronic diseases of the liver of other etiologies.
References
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