Faculty Peer Reviewed
You are asked to see a 45 year-old male with a medical history significant for untreated hepatitis C (HCV RNA 5,000,000 copies/mL, genotype 1a). He presents complaining of worsening fatigue and weakness for several months. Labs are remarkable for mildly elevated transaminases, low albumin, and an elevated INR. The patient is very worried because he has heard that hepatitis C can cause liver cancer and asks you if there is a non-invasive screening test for liver cancer. You suspect that the patient has cirrhosis. Acknowledging that the development of cirrhosis is the primary risk factor for development of hepatocellular carcinoma (HCC) in patients with HCV, you plan to look up the data examining whether a liver biopsy is necessary to assess the degree of fibrosis/cirrhosis or whether non-invasive methodologies are available.
Currently, liver biopsy remains the gold standard for staging the extent of fibrosis/cirrhosis in patients with chronic liver disease; however, there is active research examining a number of serologic markers and imaging procedures that may obviate the need for liver biopsy. This article will focus on the imaging modalities currently being investigated for diagnosis of liver fibrosis.
Fibrosis is the final common pathway for almost all forms of chronic liver disease. Fibrosis results from the accumulation of collagen and proteoglycans in the extracellular matrix in response to repetitive liver injury . There are multiple staging systems for fibrosis; the most commonly is the Metavir classification (figure 1) . Staining for collagen is performed on biopsies using trichrome stain. The scoring system reflects the natural history of fibrosis development. Initially, fibrous connective tissue surrounds the portal triads (stage 1). Stage 2 fibrosis is characterized by extension of the collagen fibers into the periportal space, while fibrous connective linking neighboring portal triads and extending to central veins is considered, stage 3 disease. Finally, cirrhosis (stage 4) is when most portal areas are connected by fibrous tissue and hepatocyte clusters are completely surrounded by fibrous tissue forming cirrhotic nodules . The detection of hepatic fibrosis has important clinical implications for the management of chronic liver disease. For example, the presence of clinically significant hepatic fibrosis (histologic grade greater than or equal to 2) influences the timing of antiviral treatment for patients with chronic hepatitis B or C . Similarly, patients with nonalcoholic fatty liver disease who are found to have fibrosis will need closer monitoring and follow-up for the development of cirrhosis  and more aggressive counseling for weight loss and lipid control. Furthermore, the presence of cirrhosis will require initiation of screening for HCC as well as gastroesophageal varices.
Figure 1: Metavir classification for the stage of liver disease
No scarring 0
Minimal scarring 1
Scarring has occurred and extends outside the areas in the liver that contain blood vessels 2
Bridging fibrosis is spreading and connecting to other areas that contain fibrosis 3
Cirrhosis or advanced scarring of the liver 4
While liver biopsy remains the gold standard method for diagnosing hepatic fibrosis, it is an invasive test with many possible complications. The most common complication is pain (84%), but other, more serious, complications may occur, including: hemorrhage (intraperitoneal or intrathoracic); puncture of the gallbladder, colon, or pleura; accidental biopsy of the kidney or pancreas; and creation of an arteriovenous fistula in the liver . The mortality rate from the procedure is estimated to range from 0.01% to 0.1%, with bleeding accounting for the largest percentage of deaths . Sampling error also remains a major limitation for liver biopsy and it is difficult to overcome; only 1/50,000 of the liver is analyzed by a standard biopsy. Further, pathologic examination of a liver biopsy is subject to interobserver and intra-observer variability. Given the potential complications and the diagnostic limitations of a liver biopsy, there is a pressing need for more accurate and non-invasive tools for the diagnosis and assessment of liver fibrosis.
Conventional cross-sectional imaging studies (CT and MRI), and to a lesser extent abdominal ultrasound, are very useful in the diagnosis of advanced cirrhosis. The cirrhotic liver develops characteristic changes in morphology that include increased surface nodularity, enlargement of the gallbladder fossa, atrophy of the right lobe, and relative increase in size of the caudate lobe . However, these imaging studies have lower sensitivity for earlier stages of disease and are not suitable for staging liver fibrosis over its entire spectrum. Newer techniques must be capable of detecting hepatic fibrosis at an early stage.
Ultrasound elastography is a promising new technique for the detection of hepatic fibrosis. Elastography refers to a method for estimating liver stiffness; it can currently be performed with either US or MR imaging. In US elastography, a device creates a mild-amplitude, low-frequency shear wave which travels through the liver. The shear wave is then detected by pulse-echo US . The wave travels faster through denser tissue, allowing the radiologist to estimate the tissue density and thus, indirectly, the degree of hepatic fibrosis. This technique has several advantages: it is non-invasive, low-cost, can be repeated at intervals relatively easily, and can assess a larger portion of the liver parenchyma than does liver biopsy. A meta-analysis of nine studies  showed that US elastography had a sensitivity of 87% (95% CI 84%-90%) and a specificity of 91% (95% CI 89%-92%) for a diagnosis of cirrhosis. More impressive though, was that in seven of the nine studies, US elastography diagnosed stage II to IV fibrosis with 70% sensitivity (95% CI 67%-73%) and an 84% specificity (95% CI 80%-88%), suggesting that this method can reliably identify liver disease during its earlier stages. Limitations of US elastography, as with all US techniques, include its operator-dependent nature and its reduced effectiveness in obese patients. In addition, other conditions apart from fibrosis can result in increased liver stiffness, including heart failure, acute inflammation and portal hypertension, so results have to be interpreted with caution .
MR imaging offers several distinct modalities for the detection of hepatic fibrosis. These include: double contrast-enhanced MR imaging, diffusion-weighted imaging, perfusion imaging, and MR elastography . Administration of a gadolinium-based contrast agent, improves the visibility of fibrosis. Preferential accumulation of contrast in the extracellular fluid, where collagen is deposited, allows fibrotic areas to be more readily detected on MR imaging. Double contrast-enhanced MRI involves the administration of gadolinium and another contrast agent called superparamagnetic iron oxide (SPIO). SPIO is a reticuloendothelial system-specific contrast agent and after intravenous administration, approximately 80% of it is taken up by the liver . As a result, liver parenchyma has low signal intensity on MR imaging. Fibrotic areas, however, accumulate less iron oxide, due largely to a reduced Kupffer cell (a reticuloendothelial cell) density, and will appear as high-signal-intensity reticulations . Individually, gadolinium and SPIO are of limited efficacy. In combination, however, they are synergistic and demonstrate fibrosis with higher clarity than either agent alone. In a study by Aguirre et. al. , the sensitivity and specificity for the detection of grade 3 or higher fibrosis exceeded 90% with this MR modality. Limitations of this method include: high cost; the need for high-quality images free of motion (requiring prolonged breath-holds by patients); and some minor adverse reactions associated with the contrast agents, the most common of which was back pain (10%) . Further, the sensitivity at lower stages of fibrosis is significantly reduced.
Diffusion-weighted imaging (DWI) measures the ability of water protons to diffuse in a particular tissue. This is expressed as the apparent diffusion coefficient (ADC), which increases as the molecular diffusion of water increases . As collagen accumulates in a fibrotic liver, the free diffusion of water molecules is restricted, thus the ADC corresponding to these areas is lower than that seen in normal hepatic parenchyma; therefore, by measuring the ADC in different sections of the liver, one can theoretically identify the fibrotic areas. The challenging aspects of this technique, including confounding factors that can contribute to altered ADC and technical imaging parameters, render DWI in need of further refinement before adoption for large-scale use. MR perfusion imaging is another technique being applied to the detection of liver fibrosis. It takes advantage of physiologic changes that occur as fibrosis progresses: decreased portal venous blood flow, increased hepatic arterial blood flow, and formation of intrahepatic shunts . This technique is sensitive to microscopic level of blood flow and measures the rate at which blood is delivered to the tissues. In one study , for example, researchers reported significant perfusion differences between patients with and without advanced fibrosis. Patients with advanced fibrosis had increased absolute arterial blood flow and an increased arterial fraction. This imaging technique is still in its infancy and it is limited by many of the same features as DWI.
Finally, MR elastography (MRE) is a new technique that possibly holds the most promise for becoming a clinically useful tool in the near future for the diagnosis of hepatic fibrosis. As in US elastography, a mechanical wave is propagated through the liver and measurement of its velocity allows for quantification of liver stiffness. The greater the liver stiffness (fibrosis), the faster the wave propagation. In a study by Yin et al. which examined the performance of this technique in 50 patients with various forms of chronic liver disease and 35 healthy volunteers, the authors found that with a cutoff mean liver stiffness value of 2.93 kPa, MRE had a sensitivity of 98% and a specificity of 99% for differentiating any stage of fibrosis from normal liver tissue . The advantages of MR elastography, compared to US, include sampling of the entire liver, insensitivity to body habitus, and that it is operator-independent. Standard contraindications to MRI, confounding contributors to liver stiffness and high cost are some of the limitations of this technique.
In addition to the imaging techniques described above, a number of researchers are examining he use of serologic markers that can identify the presence of hepatic fibosis or cirrhosis with a simple blood test. Markers that estimate the turnover or metabolism of extracellular matrix may serve this purpose as direct markers of fibrosis. These include procollagen type III amino-terminal peptide (P3NP), and matrix metalloproteinases 2. There are also several indirect markers of fibrosis. The Sequential Algorithm for Fibrosis Evaluation (SAFE) combines two such markers, the APRI and Fibrotest-Fibrosure tests, which are used in a sequential fashion to test for fibrosis and cirrhosis. The AST: platelet ratio index (APRI), is calculated by the following formula: (AST/upper limit of normal for AST) x100/ platelet count x 10 9 /L). Fibrotest and Fibrosure are commercial tests that use a mathematical formula to predict fibrosis using the levels of alpha-2- macroglobulin, alpha-2 globulin and other proteins . In a large multicenter study that studied the ability of the SAFE to detect significant fibrosis, its accuracy was 90.1%, the area under the receiver operating characteristic curve was 0.89 (95% CI 0.87-0.90), and it reduced the number of liver biopsies needed by 46.5%. When the algorithm was used to detect cirrhosis, its accuracy was 92.5%, the area under the curve was 0.92 (95% CI 0.89-0.94), and it reduced the number of liver biopsies needed by 81.5% .
Currently liver biopsy remains the only validated, reproducible test capable of determining the extent of liver damage. However, the eventual adoption of a non-invasive test for detection and staging of fibrosis is inevitable as active research on many such imaging and serologic tests are close to fruition.
Dr. Becky Naoulou is a a 3rd year resident at NYU Langone Medical Center
Peer reviewed by Michael Poles, MD, Section Editor, Clinical Correlations
Image courtesy of Wikimedia Commons
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