Chronic liver disease represents an important and growing cause of morbidity and mortality in the United States, affecting 360 per 100,000 persons, and ranking as the 12th leading cause of overall mortality, at the cost of greater than $2 billion per year.1–2 The end stage of chronic liver disease is cirrhosis and the most frequent and lethal complications are secondary to the development of portal hypertension, including variceal hemorrhage, portosystemic encephalopathy, ascites, spontaneous bacterial peritonitis, and the hepatorenal syndrome.3 In most cases, the progression of liver disease toward cirrhosis occurs in successive stages of liver fibrosis, but the complications are always initiated by portal hypertension, which is typically determined by measuring the hepatic venous pressure gradient (HVPG).
Although liver biopsy remains the primary tool for staging liver fibrosis in chronic hepatitis C virus (HCV) infection and other chronic liver disorders, it is limited by sampling error and both inter and intraobserver variability in interpretation. Furthermore, progression and regression of fibrosis cannot be accurately quantified by liver biopsy. Moreover, liver biopsy may be also associated with such complications as abdominal pain, hypotension, hemobilia, and intraperitoneal hemorrhage, which has an associated mortality rate of up to 0.5%.4 Accordingly, the need for routine liver biopsy prior to antiviral therapy for HCV has been questioned.5 The ideal liver diagnostic test would be simple, non-invasive, inexpensive, widely accessible, reliable in measurement and interpretation, and provide clinically relevant information about liver fibrosis and portal hypertension. Direct measurement of HVPG has been demonstrated to be the best predictor of complications stemming from cirrhosis and portal hypertension, and may be useful in assessing response to antiviral therapy for HCV.6–7 Unfortunately, HVPG also cannot be applied in clinical practice because it is invasive, costly, and requires technical expertise found only in large tertiary care centers. It is not surprising that there has been a rapidly growing interest in developing novel non-invasive approaches to assessing liver fibrosis and portal hypertension.
Most of this attention has been directed toward serum markers that represent indirect or direct markers for liver fibrosis. Indirect markers such as APRI, FIB-4, Fibrotest, and the Forns index represent simple, easily calculated scores that reflect changes in liver function but do not directly measure fibrosis. Direct biomarkers signal changes in turnover of extracellular matrix (ECM) proteins by matrix metalloproteinases (MMPs), which are synthesized by hepatic stellate cells and inhibited by tissue inhibitors of metalloproteinases (TIMPs). Direct measurement of these proteins (i.e., hyaluronic acid, TIMPs) or in combination with indirect markers (i.e., Fibrospect) may more accurately reflect ongoing fibrosis. Although these tests appear to be sensitive to the detection of advanced fibrosis, they are not as reliable in detecting or distinguishing among lesser degrees of fibrosis, and existing studies have been performed in small, selected populations, and therefore require further validation.8–11
In contrast, transient elastography represents a novel ultrasound-based technology in which the tip of an ultrasonic transducer probe is placed between two intercostal spaces at the level of the right lobe, and transmits a vibration of low amplitude and frequency to the liver, inducing an elastic shear wave that propagates through liver tissue. Pulse-echo ultrasound permits measurement of wave velocity, as expressed in kilopascals, which corresponds directly with liver stiffness. As liver stiffness is measured across the liver within an area of 1 × 2 cm, this appears to reflect a larger sample of the liver parenchyma than liver biopsy.12 Accordingly, increasing data from multiple centers suggest that transient elastography accurately estimates liver fibrosis across a wide range of chronic liver disorders, including chronic HCV infection.13–20 In the largest study, Ganne-Carrie et al. assessed the diagnostic accuracy of transient elastography in diagnosing cirrhosis among 1007 patients with chronic liver disease, and reported optimal receiver operator curve (ROC) characteristics at a liver stiffness cutoff of 14.6 kPa. At this threshold, liver stiffness measurement demonstrated an area under the curve (AUROC) of 0.95, with positive and negative predictive values of 74% and 96%, respectively, suggesting greater accuracy in excluding cirrhosis than in its diagnosis.15
In this issue of HEPATOLOGY, Vizzutti et al.21 aimed to evaluate the role of transient elastography in predicting clinically significant portal hypertension, as measured by the HVPG and endoscopic evidence for varices. Sixty-one consecutive patients with clinical or histopathologic evidence of cirrhosis underwent transient elastography after an overnight fast, followed immediately by direct measurement of HVPG in the hepatic hemodynamic laboratory. Among individuals without prior histologic examination, a transjugular liver biopsy specimen was obtained. Subjects proceeded to undergo an upper endoscopy the following day, with a laboratory profile obtained within one week of study enrollment. Within this cohort, a positive correlation between HVPG and liver stiffness measurement (LSM) was observed (r = 0.81). The sensitivity and specificity of LSM in diagnosing clinically significant portal hypertension, as defined by HVPG ≥10 mm Hg, was 97% and 92%, respectively, using a cutoff threshold of ≥13.6 kPa. The negative predictive value and sensitivity of LSM in predicting severe portal hypertension (HVPG ≥12 mm Hg) was also favorable at 91% and 94%, respectively. However, similarly to the HVPG, its ability to predict and distinguish between grades of esophageal varices was poor, suggesting a plateau effect in which further increases in liver stiffness are not reflected in the development of late complications of portal hypertension.
The major strengths of this paper include: (1) use of liver biopsy standard in all patients; (2) technical expertise of LSM operator, as reflected by the high success rate of measurements exceeding 90%; (3) the use of unselected, consecutive patients; (4) blinding of expert pathologist to LSM results; (5) the use of appropriate statistical methods; and (6) the absence of financial conflict of interest, as this study was funded by institutional and foundation grants. The major limitations of this study include: (1) small sample size; (2) the failure to assess intraobserver and interobserver variability with the absence of a second LSM operator; (3) the absence of blinding of the LSM operator to clinical data; (4) low LSM acquisition with a success rate of only 60%, although this is acceptable and similar to previous studies; and (5) the exclusion of patients with overt complications of cirrhosis, thus limiting the authors' ability to elucidate the limitations of this technique in predicting clinically significant portal hypertension. Surprisingly, 19 patients in this study had Child B or C cirrhosis in the absence of clinical decompensation.
This paper represents the first study to evaluate the correlation between LSM and clinically significant portal hypertension as reflected by both direct HVPG measurement and the identification of esophageal varices on upper gastrointestinal endoscopy. Previous studies have evaluated the correlation between LSM and either HVPG measurement or esophageal varices. Kazemi et al. evaluated the ability of LSM to predict the presence of large esophageal varices in patients with known cirrhosis.22 In this cohort of 165 patients, the AUROC of LSM for large varices grade 2 or larger was 0.83, and LSM <19 kPa had a 93% NPV for the presence of large varices, suggesting a potential role for LSM in selecting patients for endoscopic screening. This finding was not corroborated in this study by Vizzutti et al., which suggested that LSM was quite poor in predicting and grading esophageal varices, with a NPV of only 66%. Carrion et al. evaluated the role of LSM in diagnosing advanced fibrosis and portal hypertension among patients with post-transplant recurrence of HCV infection.23 In this cohort of 124 patients, the authors reported excellent correlation between LSM and mild (F0-F1) and significant (F2-F4) fibrosis, as well as a close correlation between LSM and HVPG (r = 0.84), with a NPV of 94% for diagnosis of portal hypertension, defined by HVPG ≥6 mm Hg, suggesting a role for LSM in assessing the severity of post-transplant recurrence of HCV infection.
Although LSM appears to be a reliable surrogate for liver biopsy in identifying mild or advanced fibrosis, the pathophysiological basis for its correlation with portal hypertension remains poorly defined. In individuals with cirrhosis, portal hypertension develops initially as the result of an increase in intrahepatic resistance to portal blood flow due to profound morphologic changes characterized by fibrosis and regenerative nodules compressing the sinusoids, which lead to vascular obliteration, activation of hepatic stellate cells, and vasoconstriction due in large part to intrahepatic nitric oxide deficiency and enhanced vasoconstrictor activity. With the development of portosystemic collaterals, portal hypertension is maintained by an increase in portal blood inflow mainly due to nitric oxide–mediated splanchnic vasodilatation.24–26 Although transient elastography may reflect a progressive rise in portal pressure, due mainly to an increase in intrahepatic vascular resistance from the accumulation of fibrillar extracellular matrix, it cannot measure the complex hemodynamic changes characteristic of late portal hypertension. This is confirmed by the findings of Vizzutti et al., who reported a much stronger correlation between HVPG and LSM at HVPG <10 mm Hg when compared with HVPG >10 mm Hg. Accordingly, it is unlikely to be useful in monitoring the hemodynamic response to drug therapy, the effects of which are mediated primarily by alterations in splanchnic blood flow.
To this date, direct HVPG measurement remains the gold standard for the diagnosis and staging of portal hypertension. It represents an excellent predictor of clinical decompensation, and is the only reliable predictor of a hemodynamic response to pharmacologic therapy. It will be of great interest to learn from future studies how LSM responds to various anti-portal hypertensive agents, recognizing the differential effects these agents may have on decreasing intrahepatic resistance or reducing splanchnic blood flow. While decreases or increases in portal pressure induced by anatomical changes should be reflected in LSM, it will not likely be sensitive to changes in portal pressure due to functional vascular changes.
Although the use of noninvasive modalities such as LSM is attractive, additional validation studies evaluating its diagnostic accuracy in a representative American population are needed prior to regulatory approval and wide application to clinical practice. Of note, the mean body mass index (BMI) in this study was 23, and patients with BMI ≥35 kg/m2 were excluded, which contrasts with the higher mean BMIs reported in large U.S. registration trials for HCV therapy.27, 28 As technical failure of LSM is significantly more common in patients with BMI ≥28 kg/m2, LSM may be relevant for only a subset of individuals.29
The enthusiasm for new approaches to assessing liver fibrosis and portal hypertension will continue to grow as additional imaging techniques (e.g., magnetic resonance elastography), and gene analysis and proteomic technologies evolve. LSM represents one of several noninvasive tools that appear to be useful in diagnosing and staging liver fibrosis in selected patients, although the data supporting its role in evaluating the consequences of portal hypertension remain unconvincing. Additional data in carefully designed studies will help define its appropriate role in clinical practice.