Noninvasive tests for liver disease, fibrosis, and cirrhosis: Is liver biopsy obsolete?
ABSTRACTLiver biopsy has been used to diagnose chronic liver disease and to assess the degree of hepatic inflammation and fibrosis. However, it is an invasive test with many possible complications and the potential for sampling error. Noninvasive tests are increasingly precise in identifying the cause of many cases of liver disease and even the amount of liver injury (fibrosis). This review discusses the role of noninvasive tests to diagnose liver disease and to assess hepatic fibrosis and cirrhosis.
KEY POINTS
- Liver biopsy remains an important tool in the evaluation and management of liver disease.
- The role of liver biopsy for diagnosis of chronic liver disease has diminished, owing to accurate blood tests and imaging studies.
- Noninvasive tests for assessing the degree of hepatic fibrosis are showing more promise and may further reduce the need for liver biopsy. Elastography, in particular, shows promise in measuring hepatic fibrosis.
- Liver biopsy is still needed if laboratory testing and imaging studies are inconclusive.
Indirect serologic markers of fibrosis
Some indirect markers are readily available:
The AST:ALT ratio. The normal ratio of aspartate aminotransferase (AST) to alanine aminotransferase (ALT) is approximately 0.8. A ratio greater than 1.0 provides evidence of cirrhosis. However, findings have been inconsistent.
The AST:platelet ratio index (APRI), a commonly used index, is calculated by the following formula:
In studies of hepatitis C and hepatitis C-HIV, the APRI has shown a sensitivity of 37% to 80% and a specificity of 45% to 98%, depending on the cutoff value and whether a diagnosis of severe fibrosis or cirrhosis was being tested.16–19 These sensitivities and specificities are disappointing and do not provide information equal to that provided by needle liver biopsy in most patients with chronic liver disease.
The combination of prothrombin, gamma glutamyl, and apolipoprotein AI levels (PGA index) has been validated in patients with many types of chronic liver disease, and its accuracy for detecting cirrhosis is highest (66%–72%) in patients with alcoholic liver disease.20,21
FibroIndex uses the platelet count, AST level, and gamma globulin level to detect significant fibrosis in chronic hepatitis C, but its accuracy has yet to be validated.22
The FIB-4 index is based on four independent predictors of fibrosis, ie, age, the platelet count, AST level, and ALT level. It has shown good accuracy for detecting advanced fibrosis in two studies in patients with hepatitis C.23,24
Fibrometer (based on the platelet count; the prothrombin index; the levels of AST, alfa-2 macroglobulin, hyaluronate, and blood urea nitrogen; and age) predicted fibrosis well in chronic viral hepatitis.25,26
Fibrotest and Fibrosure are proprietary commercial tests available in many laboratories. They employ a mathematical formula to predict fibrosis (characterized as mild, significant, or indeterminate) using the levels of alpha-2 macroglobulin, alpha-2 globulin, gamma globulin, apolipoprotein A1, gamma glutamyl transferase, and total bilirubin. For detecting significant fibrosis, these tests are reported to have a sensitivity of about 75% and a specificity of 85%.27–29
ActiTest incorporates the ALT level into the Fibrotest to reflect liver fibrosis and necro-inflammatory activity.
A meta-analysis showed that Fibrotest and ActiTest could be reliable alternatives to liver biopsy in patients with chronic hepatitis C.30 The area under the receiver operator characteristic curve for the diagnosis of significant fibrosis ranged from 0.73 to 0.87; for the diagnosis of significant histologic activity it ranged from 0.75 to 0.86. Fibrotest had a negative predictive value for excluding significant fibrosis of 91% with a cutoff of 0.31. ActiTest’s negative predictive value for excluding significant necrosis was 85% with a cutoff of 0.36. None of these serum tests have become part of standard of practice for diagnosing fibrosis or cirrhosis.
The Sequential Algorithm for Fibrosis Evaluation (SAFE) combines the APRI and Fibrotest-Fibrosure tests in a sequential fashion to test for fibrosis and cirrhosis. In a large multicenter study31 validating this algorithm to detect significant fibrosis (stage F2 or greater by the F0–F4 METAVIR scoring system32), 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%.
Another algorithm was developed to simultaneously detect significant fibrosis and cirrhosis. It had a 97.4% accuracy, but 64% of patients still required a liver biopsy.31
SAFE algorithms have the potential to reduce the number of needle biopsies needed to assess the degree of hepatic fibrosis.
CONVENTIONAL IMAGING STUDIES ARE NOT SENSITIVE FOR FIBROSIS
Standard imaging studies often show findings of cirrhosis but are not particularly sensitive, with a low negative predictive value.
Ultrasonography can show a small, nodular liver in advanced cirrhosis, but surface nodularity or increased echogenicity can be seen in hepatic steatosis as well as in cirrhosis. In one study,33 ultrasonography identified diffuse parenchymal disease but could not reliably distinguish fat from fibrosis or diagnose cirrhosis.
Often, in cirrhosis, the right lobe of the liver is atrophied and the caudate or left lobes are hypertrophied. Efforts to use the ratio of the widths of the lobes to diagnose cirrhosis have shown varying performance characterstics.34,35
One study of the splenic artery pulsatility index has shown this to be an accurate predictor of cirrhosis.36
Computed tomography provides information similar to that of ultrasonography, and it can identify complications of cirrhosis, including portal hypertension and ascites. On the other hand, it costs more and it exposes the patient to radiation and contrast media.
