Liver biopsy is currently considered the gold standard for assessing hepatic fibrosis or cirrhosis. However, it is an invasive procedure, with rare but potentially life-threatening complications.1 In addition, the accuracy of liver biopsy in assessing fibrosis has limitations because of well-known sampling errors and interobserver variability.2–6 Transient elastography [FibroScan (FS)] is a rapid, noninvasive, and reproducible method for measuring liver stiffness.7 FS examination can be performed in about 95% of patients but is problematic in those with ascites or a body mass index above 28 kg/m2.8 A strong association of liver stiffness measured by FS and the degree of liver fibrosis could be demonstrated in patients with chronic hepatitis.9–12 On the basis of these studies, cutoff values for liver stiffness have been defined. A cutoff value of about 12.5 kPa is considered to be optimal for discrimination of liver fibrosis from liver cirrhosis in patients with chronic hepatitis C virus infection.10 Liver stiffness increases during alanine aminotransferase (ALT) flares in patients with chronic viral hepatitis.13 All published data are derived from patients with chronic hepatitis of different etiologies, but nothing is known about the value of liver stiffness determination in patients with acute liver damage. Differentiation of patients with acute liver damage in a previously healthy liver from those with preexisting chronic liver disease such as cirrhosis may become important for therapeutic strategies. The aim of the present study was to determine if the measurement of liver stiffness by FS in patients presenting with acute liver damage can reliably detect preexisting cirrhosis.
Transient elastography [FibroScan (FS)] is a rapid, noninvasive, and reproducible method for measuring liver stiffness, which correlates with the degree of liver fibrosis in patients with chronic hepatitis. Whether FS is useful in the detection of preexisting liver fibrosis/cirrhosis in patients presenting with acute liver damage is unclear. Patients with acute liver damage of different etiologies were analyzed. Liver stiffness was measured during the acute phase of the liver damage and followed up to the end of the acute phase. A total of 20 patients were included in the study. In 15 of the 20 patients, initial liver stiffness values measured by FS during the acute phase of the liver damage were suggestive of liver cirrhosis. However, none of these 15 patients showed any signs of liver cirrhosis in the physical examination, ultrasound examination, or liver histology [performed in 11 of 15 (73%) patients]. A significant difference was observed in the initial bilirubin levels (5.8 ± 6.5 mg/dL versus 15.7 ± 11.8 mg/dL; P = 0.042) and age (32.4 ± 17.5 years versus 49.7 ± 15.8 years; P = 0.042) between patients with liver stiffness below or above 12.5 kPa. Six patients with initially high liver stiffness were followed up to abatement of the acute hepatitic phase; in all of them, liver stiffness values decreased to values below the cutoff value for liver cirrhosis. Conclusion: Transient elastography frequently yields pathologically high values in patients with acute liver damage and is unsuitable for detecting cirrhosis/fibrosis in these patients. (HEPATOLOGY 2007.)
Patients and Methods
Twenty patients presenting with acute hepatitis at the Hepatology Unit of the University Hospital Düsseldorf (Düsseldorf, Germany) from August 2005 to June 2007 were analyzed. The determination of the etiology of the acute liver disease was made with standard criteria. Toxic hepatitis was due to intake of nitrofurantoin, efavirenz, amphetamine, prophylthiouracil, sirolimus, flumatid, lamictal, and opipramol. All patients underwent an ultrasound examination. At the time of diagnosis of acute hepatitis, liver stiffness was measured by FS. Liver biopsy was performed with the Menghini technique with a 1.6-mm-diameter needle. Patients who did not undergo liver biopsy were followed up until the acute hepatitis resolved. Liver stiffness was measured at least twice in each patient.
Liver Stiffness Measured by FS.
Details of the technical background and examination procedure have been described previously.7 The tip of the probe transducer was placed on the skin between the rib bones and the level of the right lobe of the liver. The measurement depth was between 25 and 65 mm below the skin surface. Ten measurements were performed with success rates of at least 60%. The results were expressed in kilopascals. The median value was taken as representative.
Liver Histology and Quantification of Liver Fibrosis.
Liver biopsy specimens were fixed in formalin and embedded in paraffin. Liver fibrosis was evaluated semiquantitatively according to the METAVIR scoring system. Fibrosis was staged on a 0-4 scale as follows: F0 = no fibrosis; F1 = portal fibrosis without portal septa; F2 = portal fibrosis with few septa; F3 = numerous septa without cirrhosis; and F4 = cirrhosis.
Ultrasound examination was performed after patients had fasted for at least 6 hours. Liver cirrhosis was suspected when two of the following criteria were present: (1) nodular aspect of the liver surface, (2) portal vein diameter > 12 mm, (3) collateral circulation, and (4) hypertrophy of segment 4 (quadrate lobe).14
Data were entered into SPSS, version 11.0 (SPSS, Inc., Munich, Germany). A χ2 or Fisher's exact test (F test) was used for the comparison of categorical variables, and a Mann-Whitney test was used for the comparison of continuous variables. The significance level was set at 0.05, and all P values were two-tailed. All statistical analyses were performed with SPSS.
A total of 20 patients (male/female, 11/9) with acute hepatitis were seen during the study period. Patients' characteristics and etiology of the acute liver damage are shown in Table 1. The mean age was 45 ± 18 years. Initial serum ALT activities ranged from 151 to 5382 units/L (mean: 1355 ± 1217 units/L). All patients underwent abdominal sonography. None of the patients had criteria for liver cirrhosis in the ultrasound examination; however, it is uncertain whether sonographic cirrhosis criteria can be applied to patients with acute liver damage. Liver stiffness was measured at least twice during the acute hepatitic phase by FS in all patients. Initial liver stiffness values ranged from 4.4 to 72 kPa (Table 1). The mean success rate of measurements was 89% (range: 60-100%). Fifteen patients (75%) showed during the acute phase of the liver damage liver stiffness values above 12.5 kPa, that is, values suggestive of liver cirrhosis. Liver biopsy was performed in 11 (73%) of these 15 patients (that is, patients 1, 10-16, and 18-20). None of these patients showed a higher stage of fibrosis than F2 in the liver biopsy. Stages of fibrosis and initial liver stiffness measured by FS of the patients are shown in Table 1.
|Patient||Sex||Age (Years)||Etiology of Acute Hepatitis||Liver Biopsy Performed||Stage of Fibrosis (METAVIR)||ALT (IU/L)||Bilirubin (mg/dL)||AP (IU/L)||Initial Liver Stiffness (kPa)|
Liver stiffness was followed up until the acute liver damage resolved in six patients with an initial liver stiffness above 12.5 kPa (patients 3, 4, 5, 10, 13, and 19). In all these patients, liver stiffness returned to values below the threshold suggestive of cirrhosis (Table 2). In patients (10, 13, and 19) in which a liver biopsy was taken during the acute hepatitic phase, the liver stiffness values found after resolution of the acute liver damage corresponded well to the histological degree of fibrosis (Tables 1 and 2). The development of liver stiffness values, ALT, and bilirubin during resolution of acute hepatitis in patient 10 is shown in Fig. 1.
|Patient||Acute Phase||After Resolution of the Acute Hepatitic Phase|
|Initial Liver Stiffness (kPa)||ALT (Units/mL)||Liver Stiffness (kPa)||ALT (Units/mL)|
In a total of 78 measurements, liver stiffness did not correlate with serum ALT activities (P = 0.074; r = 0.257) or bilirubin levels (P = 0.339; r = −0.148). Also, after the division of the patients according to the etiology of their acute liver damage, no significant correlations between liver stiffness and ALT or bilirubin levels could be observed. However, in 7 of 8 patients with acute toxic hepatitis, initial liver stiffness values were above 12.5 kPa, whereas only 5 of the 9 patients presenting with acute viral hepatitis A and B showed initial liver stiffness values suggestive of cirrhosis. This difference between toxic and viral liver damage, however, was statistically not significant (P = 0.29). The absolute liver stiffness values also did not differ between these groups (32.9 ± 21.5 kPa versus 20.9 ± 19.7 kPa; P = 0.2).
In order to identify parameters that may influence the liver stiffness during the acute liver damage phase, all patients were divided according to their initial measured liver stiffness. The first group included all patients with a liver stiffness below 12.5 kPa (that is, patients 2, 7, 8, 9, and 17). The second group included all other patients. A significant difference was observed in the initial bilirubin levels (5.8 ± 6.5 mg/dL versus 15.7 ± 11.8 mg/dL; P = 0.042) and age (32.4 ± 17.5 years versus 49.7 ± 15.8 years; P = 0.042) between both groups. Other factors such as BMI (20.9 ± 2.9 kg/m2 versus 24.8 ± 5.1 kg/m2; P = 0.055) and initial ALT (1351 ± 687 IU/mL versus 1357 ± 1369 IU/mL; P = 0.80) did not differ between these groups.
A good correlation between the grade of liver fibrosis and liver stiffness measured by FS has been demonstrated for patients with chronic hepatitis of different etiologies (hepatitis C virus, hepatitis B virus, alcohol, and human immunodeficiency virus/hepatitis C virus coinfection).11, 15 A cutoff value of 12.5 kPa has been described for discrimination of liver cirrhosis from liver fibrosis in patients with chronic hepatitis C.10 In our own study group comprising 147 patients with chronic hepatitis of various etiologies, a similar cutoff value of 13 kPa was determined.9
In the present study, we analyzed 20 patients with acute liver damage of different etiologies. All patients underwent liver stiffness measurements by FS during the acute phase of the liver damage. An initial liver stiffness above 12.5 kPa, which is otherwise suggestive of liver cirrhosis, was measured in 15 patients (75%). However, none of the patients showed any signs of liver cirrhosis by the physical or ultrasound examination. Liver biopsy was performed in 11 of the 15 patients with an initial liver stiffness above the cutoff value, and none of them revealed a liver fibrosis stage above F2. Patients with chronic hepatitis and liver fibrosis up to F2 were reported to exhibit liver stiffness values below 9.5 kPa.10 Thus, a discrepancy between the liver stiffness found during the acute phase of liver damage and the fibrosis grade in the liver biopsy was found. Six patients with an initial liver stiffness above 12.5 kPa were followed up until catabasis of the acute hepatitis. Parallel to the decrement of the ALT, as a marker for the inflammation, liver stiffness returned to values below the cirrhosis threshold. Liver cirrhosis was excluded in 14 of the 15 patients with an initial liver stiffness higher than 12.5 kPa by at least three methods in each patient: (1) physical examination, (2) ultrasound, and (3) liver biopsy or measurement of liver stiffness after the acute phase of the hepatitis. One patient (patient 6) with an initial liver stiffness above 12.5 kPa did not undergo liver biopsy or was followed up until ALT normalized.
The data in the present study show that liver stiffness measurements by FS in patients with acute liver damage overestimate the real stage of fibrosis and may erroneously suggest the presence of liver cirrhosis. The reasons underlying the high stiffness in acute toxic liver damage are unknown but could be related to hepatocyte swelling, cholestasis, or infiltrates of inflammatory cells in the acutely inflamed liver. A significant difference in the initial bilirubin level was observed between patients with an initial liver stiffness below and above 12.5 kPa. This may indicate that the intrahepatic cholestasis may influence the initial measured liver stiffness.
FS examination has been repeatedly shown to be a rapid, noninvasive, and reliable method for assessment of fibrosis/cirrhosis in patients with chronic hepatitis.7–11, 14 However, as shown in the present study, in patients with acute liver damage, liver stiffness assessment is unreliable for diagnosing underlying fibrosis or cirrhosis. About 75% of the patients with acute liver damage exhibited liver stiffness values of an order of magnitude that would otherwise predict the presence of cirrhosis in patients with chronic hepatitis. Thus, FS results need to be interpreted with caution in patients with acute liver damage, and high values of liver stiffness do not predict the simultaneous presence of cirrhosis in these patients. This may become therapeutically relevant when the question has to be answered of whether a patient suffers from acute liver damage in a previously healthy liver or from an acute exacerbation of a chronic liver injury.