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.
CAN NONINVASIVE TESTS DETECT HEPATIC FIBROSIS?
Cirrhosis (stage 4 fibrosis) results in nodular transformation of the liver and impedance of portal blood flow, setting the stage for portal hypertension and its sequelae. Knowing whether cirrhosis is present is important in subsequent management.
In advanced cases, cirrhosis is associated with typical clinical manifestations and laboratory and radiographic findings. In such cases, needle biopsy will add little. However, in most cases, particularly early in the course, clinical, laboratory, and radiologic correlates of cirrhosis are absent. In one study of patients with hepatitis C, 27% had cirrhosis, but in only a small number would cirrhosis have been apparent from clinical signs and laboratory and imaging studies.6
Since a major contemporary role for liver biopsy is in assessing the degree of fibrosis, it is reasonable to ask if newer noninvasive means are available to estimate hepatic fibrosis. The remainder of this review focuses on assessing our increasing ability to stage the degree of fibrosis (including the presence or absence of cirrhosis) by noninvasive means.
Clinical features point to cirrhosis, but not earlier fibrosis
Clinical manifestations help point to the diagnosis of cirrhosis but not to earlier stages of fibrosis.
For example, if a patient is known to have liver disease, the findings of ascites, splenomegaly, or asterixis mean that cirrhosis is highly probable. Similarly, hypersplenism (splenomegaly with a decrease in circulating blood cells but a normal to hyperactive bone marrow) in a patient with liver test abnormalities almost always represents portal hypertension due to cirrhosis, although other, nonhepatic causes are possible, such as congestive heart failure and constrictive pericarditis.
These features generally emerge late in the course of cirrhosis. The absence of such stigmata certainly does not preclude the presence of cirrhosis. Thus, these clinical signs have a high positive predictive value but a low negative predictive value, making them insufficient by themselves to diagnose or stage liver disease.
Laboratory tests are of limited value in assessing the degree of fibrosis
Standard liver tests are of limited value in assessing the degree of fibrosis.
Usual laboratory tests. At one end of the spectrum, anemia, thrombocytopenia, and leukopenia in the presence of liver disease correlate with cirrhosis. At the other end, a serum ferritin concentration of less than 1,000 mg/mL in a patient with hemochromatosis and no confounding features such as hepatitis C, HIV infection, or heavy alcohol use strongly predicts that the patient does not have significant hepatic fibrosis.8
Bilirubin elevation is a late finding in cirrhosis, but in cholestatic diseases bilirubin may be elevated before cirrhosis occurs.
Albumin is made exclusively in the liver, and its concentration falls as liver function worsens with progressive cirrhosis.
The prothrombin time increases as the liver loses its ability to synthesize clotting factors in cirrhosis. Coagulopathy correlates with the degree of liver disease.
Hyponatremia due to impaired ability to excrete free water is seen in patients with cirrhosis and ascites.
In summary, the usual laboratory tests related to liver disease are imprecise and, when abnormal, often indicate not just the presence of cirrhosis, but impending or actual decompensation.
Newer serologic markers, alone or in combination, have been proposed as aids in determining the degree of fibrosis or cirrhosis in the liver. Direct markers of fibrosis measure the turnover or metabolism of extracellular matrix. Indirect markers of fibrosis reflect alterations in hepatic function (see below).
Parkes et al9 reviewed 10 different panels of serum markers of hepatic fibrosis in chronic hepatitis C. Only 35% of patients had fibrosis adequately ruled in or ruled out by these panels, and the stage of fibrosis could not be adequately determined.
These serologic markers have not been validated in other chronic liver diseases or in liver disease due to multiple causes. Thus, although they show promise for use by the general internist, they need to be validated in patients with disease and in normal reference populations before they are ready for “prime time.”
Direct serologic markers of fibrosis
Direct serologic markers of fibrosis include those associated with matrix deposition—eg, procollagen type III amino-terminal peptide (P3NP), type I and IV collagens, laminin, hyaluronic acid, and chondrex.
P3NP is the most widely studied marker of hepatic fibrosis. It is elevated in both acute and chronic liver diseases; serum levels reflect the histologic stage of hepatic fibrosis in various chronic liver diseases, including alcoholic, viral, and primary biliary cirrhosis.10–12 Successful treatment of autoimmune hepatitis has been shown to lead to reductions of P3NP levels.13
Other direct markers of fibrosis are those associated with matrix degradation, ie, matrix metalloproteinases 2 and 3 (MMP-2, MMP-3) and tissue inhibitors of metalloproteinases 1 and 2 (TIMP-1, TIMP-2). Levels of MMP-2 proenzymes and active enzymes are increased in liver disease, but studies are inconsistent in correlating serum levels of MMP-2 to the degree of hepatic fibrosis.14,15 These tests are not commercially available, and the components are not readily available in most clinical laboratories.
