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Diagnosis of Hepatic Fibrosis and Cirrhosis by FibroScan, Transient Elastography, in HIV/Hepatitis C Virus-Coinfected Patients
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JAIDS Journal of Acquired Immune Deficiency Syndromes: Volume 41(2) 1 February 2006 pp 175-179
de Ledinghen, Victor MD, PhD* ; Douvin, Catherine MD ; Kettaneh, Adrien MD; Ziol, Marianne MD ; Roulot, Dominique MD, PhD; Marcellin, Patrick MD, PhD#; Dhumeaux, Daniel MD ; Beaugrand, Michel MD
From the *Service d'Hepato-Gastroenterologie, Hopital Haut Leveque, Bordeaux, France; INSERM E362 IFR 66, Universite Victor Segalen, Bordeaux, France; Service d'Hepato-Gastroenterologie, Hopital Henri-Mondor, Creteil, France; Service de Medecine Interne, Hopital Saint-Antoine, Paris, France; Laboratoire d'Anatomie-Pathologique, Hopital Jean Verdier, Bondy, France; Service d'Hepato-Gastroenterologie, Hopital Jean Verdier, Bondy, France; and #Service d'Hepato-Gastroenterologie, Hopital Beaujon, Clichy, France.
......In summary, this study highlights the diagnostic utility of liver stiffness measurement for assessing liver fibrosis and detecting cirrhosis in HIV/HCV-coinfected patients. These results suggest that liver stiffness measurement could reliably be used for first-line pretherapeutic evaluation of fibrosis in coinfected patients. Moreover, for the diagnosis of cirrhosis, liver stiffness measurement is more accurate than other noninvasive biochemical tests. If ongoing prospective studies confirm these findings, transient elastography may substantially reduce the use of liver biopsy and improve the management of HIV/HCV-coinfected patients..... In nonconcordant cases with regard to transient elastography values and METAVIR scores, transient elastography tended to overestimate fibrosis grade compared with liver biopsy..... Transient elastography does not provide any information on steatosis or inflammation, however, which are 2 major factors associated with fibrosis progression..... only 5 patients were diagnosed with grade F3 fibrosis. Therefore, we could not evaluate the performance of transient elastography for differentiating mild fibrosis (F1) from bridging fibrosis (F3). This limitation of transient elastography is clinically important, because significant fibrosis (F2F3F4 fibrosis) is an indication for HCV treatment, and other studies are needed to evaluate its performance....
BACKGROUND
Before highly active antiretroviral therapy (HAART), most deaths in HIV-infected patients were AIDS related. Since HAART has become widely available and has extended life expectancy, the management of hepatitis C virus (HCV) concurrent disease has attracted more attention. Progressive hepatic fibrosis with the development of cirrhosis is a feature of almost all chronic liver diseases. HIV coinfection accelerates the progression of HCV-related fibrosis, however, particularly in patients who routinely consume alcohol or are severely immunosuppressed.1,2 Approximately 46% of HIV-infected patients aged >40 years with chronic HCV infection have cirrhosis.3 HIV coinfection considerably reduces the survival of patients with HCV-related end-stage liver disease,4 and HCV has been implicated in up to 50% of all deaths among HIV-infected patients because of complications of cirrhosis such as liver failure, ascites, gastrointestinal bleeding, portal-systemic encephalopathy, and hepatocellular carcinoma.5-7
Liver biopsy is currently considered the gold standard for assessing hepatic fibrosis. It is an invasive and painful procedure,8 however, with rare but potentially life-threatening complications.9 In addition, the accuracy of liver biopsy in assessing fibrosis may be questioned because of sampling error and interobserver variability, and understaging is common in patients with cirrhosis.10-13 Thus, there is a need to develop and validate noninvasive tests that can accurately reflect the full spectrum of hepatic fibrosis.
Transient elastography (FibroScan; Echosens, Paris, France) is a novel, rapid, and noninvasive technique that measures liver stiffness.14 Briefly, this system is equipped with a probe consisting in an ultrasonic transducer mounted on the axis of a vibrator. A vibration of mild amplitude and low frequency is transmitted from the vibrator to the tissue by the transducer itself. This vibration induces an elastic shear wave that propagates through the tissue. In the meantime, pulse-echo ultrasonic acquisitions are performed to follow the propagation of the shear wave and measure its velocity, which is directly related to the tissue stiffness (or elastic modulus). The harder the tissue, the faster the shear wave propagates. Recent reports have shown that the FibroScan allowed accurate prediction of hepatic fibrosis in patients with chronic HCV infection.15-18 In patients with chronic hepatitis C, liver stiffness measurements ranged from 2.4 to 75.0 kilopascal (kPa).17,18 The usefulness of transient elastography in other liver diseases is still unknown, however, as well as the influence of associated conditions such as HIV infection.
The aim of this prospective study was to assess the accuracy of transient elastography for the detection of fibrosis in HIV-infected patients with chronic HCV infection and to compare its accuracy with that of other noninvasive methods.
Abstract
Background: Chronic hepatitis C in HIV-infected patients is an increasing cause of death dependent on the development of liver fibrosis, which is currently assessed by liver biopsy despite its limitations. Liver stiffness measurement, a new noninvasive method, allows the evaluation of liver fibrosis. The aim of this prospective study was to assess the accuracy of liver stiffness measurement for the detection of fibrosis and cirrhosis in HIV/hepatitis C virus (HCV)-coinfected patients and to compare its accuracy with other noninvasive methods.
Methods: We studied 72 consecutive HIV patients with chronic hepatitis C who had a simultaneous liver biopsy and liver stiffness measurement by transient elastography (FibroScan; Echosens, Paris, France) for the assessment of liver fibrosis.
Results:
Liver stiffness values ranged from 3.0 to 46.4 kilopascal. Liver stiffness was significantly correlated to fibrosis stage (Kendall τ-b = 0.48; P < 0.0001). The area under the receiver operating characteristic (AUROC) curve of liver stiffness measurement was 0.72 for F ≥ 2 and 0.97 for F = 4.
For the diagnosis of cirrhosis, AUROC curves of liver stiffness measurement were significantly higher than those for platelet count (P = 0.02), aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio (P = 0.0001), Aspartate aminotransferase-to-Platelet Ratio Index (APRI) (P = 0.01), and FIB-4 (P = 0.004).
Conclusion: Liver stiffness measurement is a promising noninvasive method for the assessment of fibrosis in HIV-infected patients with chronic HCV infection. Its use for the follow-up of these patients should be further evaluated.
DISCUSSION
As in HIV-negative patients,17,18 transient elastography accurately predicts cirrhosis. The diagnostic performance of transient elastography was good, being similar to that of transient elastography in previous reports concerning HCV-infected patients. This result was not entirely predictable, because all types of fibrosis are not taken into account in the METAVIR classification. Because perisinusoidal fibrosis and perihepatic fibrosis are not uncommon in HIV-infected patients and are caused by HIV infection, alcohol abuse, or drug toxicity, the evaluation of transient elastography was needed in HIV/HCV-coinfected patients.25 Additionally, among all noninvasive methods evaluated in this study, transient elastography offered the best diagnostic performance for cirrhosis.
The diagnostic performance of transient elastography might also have been underestimated because of the limitations of liver biopsy and the design of the METAVIR scoring system. For the diagnosis of cirrhosis, the AUROC curve of transient elastography was excellent (0.97). In nonconcordant cases with regard to transient elastography values and METAVIR scores, transient elastography tended to overestimate fibrosis grade compared with liver biopsy. Indeed, the diagnosis of cirrhosis is based on a biopsy specimen that only represents 1/50,000 of the total liver mass, and discrepancies between the histologic appearances of 2 liver samples taken simultaneously from the same patient have been documented.9 Transient elastography measures liver stiffness on a volume that can be approximated by a cylinder 1 cm in diameter and 4 cm in length, which is 500 times larger than the biopsy specimen and is thus much more representative of the entire hepatic parenchyma. Furthermore, inter- and intraobserver discrepancies of 10% to 20% (or even more) in assessing fibrosis stage have been reported, as illustrated by our results.11,19 As shown in Table 1, only 5 patients were diagnosed with grade F3 fibrosis. Therefore, we could not evaluate the performance of transient elastography for differentiating mild fibrosis (F1) from bridging fibrosis (F3). This limitation of transient elastography is clinically important, because significant fibrosis (F2F3F4 fibrosis) is an indication for HCV treatment, and other studies are needed to evaluate its performance.
To our knowledge, 2 major studies evaluating transient elastography accuracy in HCV patients have been published.17,18 For the diagnosis of cirrhosis, 2 cutoff levels were found: 12.5 and 14.5 kPa. To validate the late cutoff level from a large multicenter study, we evaluated its accuracy for the diagnosis of cirrhosis in our population. Both cutoff levels had good specificity, sensitivity, and negative predictive value in HIV/HCV-coinfected patients. Therefore, at bedside, whenever the cutoff is in the range 11.8 to 14.5 kPa, transient elastography provides a reliable prediction of cirrhosis. Indeed, the cutoff value may be different when the optimal diagnostic value is considered (maximal sum of sensitivity and specificity) or when high specificity (>90% or 95%) is required. Apparent discrepancies between the optimal cutoff values in these studies are probably not linked to the influence of HIV infection or other features related to the disease but are probably explained by the fact that, whatever the sample size, a small proportion of patients had measures in the range of 11.8 to 14.5 kPa, whereas most had measures below or above these values. One must keep in mind that liver stiffness measurement evaluates liver fibrosis and that there is no clear-cut value for the amount of fibrosis present in the liver of patients with cirrhosis versus those with extensive fibrosis without clearly nodular architecture. From a practical point of view, because of the limited number of patients with measurements in this intermediate ambiguous zone, a small variation in the cutoff value is of limited importance. The correlation of liver stiffness and fibrosis stage is not affected by steatosis and activity grade.17 Transient elastography does not provide any information on steatosis or inflammation, however, which are 2 major factors associated with fibrosis progression.
In HCV patients, many other noninvasive methods (so-called serum markers of fibrosis) have been proposed such as platelet count,20 AST/ALT ratio,22 and APRI.21 Recently, for HIV/HCV-coinfected patients, a new test (FIB-4) has been proposed.23 In our study, for the diagnosis of cirrhosis, AUROC curves of transient elastography were significantly higher than those for platelet count, AST/ALT ratio, APRI, and FIB-4. Most of these scores need values, such as transaminases or platelet counts, that could be modified by HAART, HIV infection, or denutrition. Liver stiffness measurement, by assessing the liver parenchyma directly, is not supposed to be influenced by extrahepatic conditions.
In summary, this study highlights the diagnostic utility of liver stiffness measurement for assessing liver fibrosis and detecting cirrhosis in HIV/HCV-coinfected patients. These results suggest that liver stiffness measurement could reliably be used for first-line pretherapeutic evaluation of fibrosis in coinfected patients. Moreover, for the diagnosis of cirrhosis, liver stiffness measurement is more accurate than other noninvasive biochemical tests. If ongoing prospective studies confirm these findings, transient elastography may substantially reduce the use of liver biopsy and improve the management of HIV/HCV-coinfected patients.
PATIENTS AND METHODS
Patients
Between January 2003 and January 2005, all consecutive HIV-infected patients with chronic HCV infection were prospectively included in this multicenter study. Inclusion criteria were the presence of HCV RNA and HIV antibodies in serum. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki. Patients were enrolled after written informed consent was obtained.
Liver Stiffness Measurement
Details of the technical background and examination procedure have been previously described.15,16 The tip of the probe transducer was placed on the skin between the rib bones at the level of the right lobe of the liver. Once the measurement area had been located, the operator pressed the probe button to start an acquisition. The measurement depth was between 25 and 65 mm below the skin surface. At least 5 successful measurements were performed on each patient, with a ratio of the number of successful measurements over the total number of acquisitions not lower than 30%. The results are expressed in kilopascal. The median value was kept as representative of the liver elastic modulus.
Liver Histology and Quantification of Liver Fibrosis
The liver biopsy was fixed in formalin and paraffin embedded. All biopsy specimens were analyzed by 2 experienced pathologists blinded to the clinical data and the results of transient elastography.
Liver biopsies that contained less than 10 portal tracts (except for cirrhosis) were excluded from histologic analysis. The length of each liver biopsy specimen was also established in millimeters. Fibrosis and necroinflammatory activity were staged according to the METAVIR scoring system. Fibrosis was staged on a scale from 0 to 4 as follows: F0, no fibrosis; F1, portal fibrosis without septa; F2, portal fibrosis and few septa; F3, numerous septa without cirrhosis; and F4, cirrhosis.19 Activity was graded as follows: A0, none; A1, mild; A2, moderate; and A3, severe. Steatosis was categorized by visual assessment as follows: 0, none; 1, steatosis in 1% to 10% of hepatocytes; 2, steatosis in 10% to 30% of hepatocytes; and 3, steatosis in 30% to 100% of hepatocytes.
Assessment of Noninvasive Markers for the Diagnosis of Cirrhosis
When available, assessment of different biochemical noninvasive markers for the diagnosis of cirrhosis was performed. A platelet count <140 G/L was the cutoff used for the diagnosis of cirrhosis.20 The APRI index was calculated as follows: aspartate aminotransferase (AST X upper limit of normal [ULN] X 100/platelet count [109/L]).21 A value >2 was used for the diagnosis of cirrhosis. An AST/alanine aminotransferase (ALT) ratio >1 was used for the diagnosis of cirrhosis.22 The FIB-4 score was calculated as follows: age X AST/(platelet count X √ALT).23 A value ≥3.25 was used for the diagnosis of cirrhosis.
Statistical Analysis
Kendall coefficients of correlation (τ-b) and their associated probabilities (P) evaluated the relation between histologic fibrosis scores (METAVIR) and noninvasive procedures of fibrosis, including transient elastography.
Because only a few patients had a fibrosis stage of F0, we grouped F0 and F1 categories in the consensus fibrosis stage. For fibrosis METAVIR scores of F4 versus F0123 and F234 versus F01, the diagnostic performance of transient elastography and other noninvasive methods was assessed by receiver operating characteristic (ROC) curves and compared between transient elastography and other methods. The ROC curve is a plot of sensitivity versus 1 - specificity for all possible cutoff values. The most commonly used index of accuracy is the area under the ROC (AUROC) curve, with values close to 1.0 indicating high diagnostic accuracy.
A subject is stated as being positive or negative according to whether the noninvasive marker value is greater than or less than or equal to a given cutoff value. Connected with any cutoff value is the probability of a positive test result (sensitivity) among subjects with a true result from reference and the probability of a negative result (specificity) among patients with a false result from reference.
For transient elastography, we also determined optimal cutoff values in our sample. The optimal cutoff value for F4 versus F0123 was determined at highest sensitivity with specificity forced to no less than 90%. The optimal cutoff value for F234 versus F01 was determined at highest specificity with sensitivity forced to no less than 90%. Internal validation of these cutoffs was performed by the Jackknife method.24 Statistical analyses were performed with Stata Statistical Software, release 8.2 (Stata Corporation, College Station, TX).
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