Assessment of Liver Fibrosis: Palpate, Poke or Pulse? * #

Liver fibrosis is the cardinal feature of cumulative injury from chronic liver disease and is responsible for most of the terminal clinical features. Assessing fibrosis accurately is vital to the management of patients with chronic liver disease. Quantifying the extent of liver fibrosis is an important factor in the decision to recommend treatment, to assess treatment response and to decide upon when to begin screening for liver cancer and varices. Historically, advanced fibrosis or cirrhosis was diagnosed on clinical grounds by examining the patient for stigmata of chronic liver disease and palpating a shrunken, firm, nodular liver. This is a relatively insensitive manner to diagnose cirrhosis and certainly less so for minor degrees of fibrosis. The advent of liver biopsy allowed the earlier stages of fibrosis to be diagnosed, which facilitated institution of early therapy to prevent disease progression. Thus, for the past 6 decades a liver biopsy has been the accepted gold standard for assessing fibrosis. However, liver biopsy is not without drawbacks. It has low patient acceptance because it is invasive and associated with some discomfort and risk to the patient.1 Moreover, sampling error of at least 24% is reported usually because of specimen fragmentation or inadequate length.2-4 Interpretation of the biopsy is also subject to diagnostic inconsistencies due to inter- and intra-observer error.5, 6 As such, there has been a flurry of interest in developing new, noninvasive modalities to assess fibrosis such as biochemical markers, biomarkers, and new imaging techniques. These approaches have included surrogate markers of fibrosis consisting of readily available biochemical tests such as the Forns index,7 AST to platelet ratio index (APRI),8 and the commercially available FibroTest.9 Newer advances such as serum protein glycomics10 and proteomics11 may also have a role in fibrosis assessment, especially when used in conjunction with existing methods such as the FibroTest. APRI, AST to platelet ratio; kPa, kilopascals; ROC, receiver operating characteristic; ALT, alanine aminotransferase; HCV, hepatitis C virus; ULN, upper limit of normal; NASH, nonalcoholic steatohepatitis; NAFLD, nonalcoholic fatty liver disease; BMI, body mass index. The latest technological advance in fibrosis assessment is the Fibroscan, a specially adapted ultrasound machine that uses the principle of one-dimensional transient elastography to measure liver stiffness.12 A special probe is used to both generate and measure the velocity of a low amplitude, low frequency vibration that is transmitted from the skin to the liver tissue. Pulse–echo ultrasound is used to measure the velocity of the shear wave through the liver tissue. The velocity of the shear wave is directly proportional to the stiffness of the tissue and thus indirectly measures extent of fibrosis: the stiffer the tissue the faster the shear wave. The machine reports a value in kilopascals (kPa), which can then be extrapolated to a fibrosis score. Preliminary studies have shown the Fibroscan to be a useful device for assessing fibrosis. Two initial studies in patients with chronic hepatitis C, including all stages of fibrosis, reported good accuracy for predicting Metavir stage F2 to F4 with ROC values ranging from 0.79 (F2) to 0.97 (F4).13, 14 However, there was considerable overlap in the range of liver stiffness measurements among metavir stages which may have been related to liver biopsy issues such as small sample size (median biopsy length in both studies ranged from 17 to 18 mm), and differences in degree of necroinflammation and steatosis. Fibroscan performed better in separating cirrhosis (F4) from lesser degrees of fibrosis and in samples with longer biopsies. In this issue of HEPATOLOGY, Colletta and colleagues from Italy report upon the correlation of the Fibroscan and FibroTest with liver biopsy results in a cohort of patients with chronic hepatitis C with persistently normal serum alanine aminotransferase (ALT) levels.15 Forty untreated HCV RNA–positive patients with well-documented ALT levels less than 1.2 × upper limit of normal (ULN) underwent two liver biopsies separated by a median interval of 78.5 months. All patients were tested once by Fibroscan and FibroTest within a period of 9 months after the second biopsy. Significant fibrosis defined as Metavir stage F2 was present in 1 patient (2.5%) at initial liver biopsy and in 14 patients (35%) at second biopsy. Fibrosis progressed by one or more stages in approximately half of the patients. Only 1 patient had regression in fibrosis stage. Using the previously reported cutoffs of 8.7 and 9.6 kPa for Metavir fibrosis stages 2 and 3 respectively, the agreement between Fibroscan and liver biopsy assessment of fibrosis was perfect with a weighted kappa of 1.0. In contrast, the concordance between FibroTest and liver biopsy was poor with a weighted kappa of −0.041. Excess alcohol consumption (>20 g/day) and high viral load (>8 × 106 copies /mL) were identified by logistic multivariate regression to predict fibrosis progression in this cohort. Two results from this study were quite striking. First was the high rate of liver fibrosis progression in patients with persistently normal ALT levels and the second was the remarkable capability of ultrasound elastography to distinguish the full spectrum of histopathological fibrosis stages. Both findings are in stark contrast to previously published data regarding the natural history of hepatitis C fibrosis accumulation with minimal transaminase activity16, 17 and with the ability of Fibroscan to clearly separate distinct fibrosis stages.13, 14, 18 The perfect agreement between liver biopsy and Fibroscan raises the possibility that Fibroscan is influenced by similar errors inherent to liver biopsy such as the effect of subcapsular fibrosis or that both sample predominantly the right lobe of the liver. Alternatively, if the factors that contribute to errors of liver biopsy presumably differ from those of Fibroscan then it would suggest that the sample size of the study was not large enough to discern this difference. If the ultrasound elastographic findings of this study are indeed verified, would this herald the end of the liver biopsy for fibrosis assessment? Although certainly promising, it may be premature to jump to that conclusion. A liver biopsy provides other useful information in addition to fibrosis determination. It is used to diagnose, grade and stage disease.19 Fibroscan was developed as a means to stage disease. It is unable to determine the cause of a liver disease or to distinguish subtle diagnostic differences such as nonalcoholic steatohepatitis (NASH) from nonalcoholic fatty liver disease (NAFLD), diagnose rejection or graft versus host disease. Nor can Fibroscan grade disease activity (amount of necroinflammation or severity of injury) as in NASH or primary biliary cirrhosis. Thus, it will not replace ALT but might supplant liver biopsy to assess progression of disease toward cirrhosis. As with any new diagnostic test, considerable assessment and validation is needed prior to introduction into general clinical practice. Preclinical evaluation should address issues such as inter and intra-observer test concordance and precision. An appropriate evaluation would be prospective and blinded in design and include the full spectrum of patients (different ages, races, body mass indices [BMIs]), variety of chronic liver diseases such as viral hepatitis, NASH, cholestatic and metabolic diseases along with accurate pathologic evaluations (liver biopsies of adequate size to stage fibrosis) using reasonable clinical endpoints such as progression of fibrosis by one point. The test should also be validated using other well-studied scoring systems such as Ishak.20 In this way, the generated cutoff values determined from such a study would place ultrasound elastography on solid ground for use in practice. Currently, elastographic study results are derived mostly from selected patients with chronic hepatitis C. Even with appropriate evaluation of the test dynamics, additional issues still need to be tackled in order to broadly apply this technology. Several technical limitations preclude the use of ultrasound elastography in approximately 5% to 8% of patients.13, 14, 21 The principal reason for this failure is obesity. A much higher failure rate would be expected in the United States given the higher BMI of the general population.22 However, this challenge is being addressed with further developments in ultrasonic probe technology. Additional limitations include a narrow intercostal space and ascites. However, ascites is typically indicative of decompensated cirrhosis and an elastographic measurement is unlikely to alter the overall clinical management. The quality of the liver parenchyma and intrahepatic structures may also potentially affect the physics of elastography. Large vascular structures in the acquisition window have the potential for yielding false measurement readings. Similarly, although necroinflammation and steatosis were reported not to influence liver stiffness measurements this needs to be assessed in larger cohorts with different patterns of fibrosis (portal versus central) and more severe grades of steatosis. Transient elastography is an appealing test to evaluate fibrosis because it can be performed rapidly, painlessly, with relative ease and is expected to have high patient acceptance. It would appear that Fibroscan has certain advantages over other diagnostic indices or predictive models based on laboratory tests in that it is completely noninvasive, provides a more direct measure of fibrosis, should not be affected by other disease states, and should theoretically be applicable to all chronic liver diseases. But, what does the future hold for this technology? Perhaps the best application of Fibroscan may be to monitor patients longitudinally after a baseline biopsy is performed or to postpone a biopsy until a certain threshold liver stiffness measurement is obtained. Furthermore, diagnostic accuracy might be improved by combining Fibroscan with other noninvasive modalities.14 This could obviate the need for liver biopsies in a number of cases. A recent study suggested that Fibroscan might be useful for predicting clinical complications of end-stage liver disease. Foucher and colleagues correlated the elastographic measurements with clinical complications of cirrhosis.21 They reported that the cutoff values of 27.5, 37.5, 49.1, 53.7, and 62.7 kPa based on ROC curves had a negative predictive value of >90% for the diagnosis of grade 2-3 esophageal varices, Child-Turcotte-Pugh B or C cirrhosis, past history of ascites, hepatocellular carcinoma and bleeding esophageal varices, respectively. Whether or not ultrasound elastography can be extended to risk stratify or screen for cirrhotic liver complications will need to be assessed in future long-term longitudinal studies. Lastly, ultrasound elastography may find a niche in monitoring response to treatment. Thus in clinical trials with blinded results, in specific diseases with well defined endpoints (such as long-term therapy of chronic hepatitis B) it would be important to determine whether Fibroscan can document response as well as or better than serial liver biopsies. For this reason Fibroscan should be incorporated now into studies of long-term therapy so that its efficacy can be evaluated. Ultrasound elastography represents a significant step forward in attempting to overcome some of the deficiencies associated with needle liver biopsy. Ultimately, however, elastography is still limited by its sampling size, as it is only 100 times larger than liver biopsy and the fact that its diagnostic accuracy is linked to an imperfect gold standard, the liver biopsy. Therefore future research should continue to be pursued in the field of fibrosis assessment. Ideally, efforts should focus on imaging modalities that would provide a more global impression of fibrosis, on genetic markers that would allow risk stratification given the recent studies that have suggested a role for genetic polymorphisms in fibrosis progression,23, 24 and on diagnostic markers that correlate dynamically with extracellular matrix formation. As antifibrotic therapies are brought forward to the clinical arena there will be an even greater need to assess fibrosis as a means of monitoring treatment effectiveness. The liver biopsy will still have a role to play in the diagnosis, grading, and assessment of chronic liver disease. However, completely noninvasive assessment of liver fibrosis may be only a pulse away.