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Noninvasive Assessment of Disease Progression
Abbreviations
AASD
American Association for the Study of Liver Disease
ALT
alanine aminotransferase
APRI
AST to platelet ratio index
ARFI
acoustic radiation force impulse elastography
AST
aspartate aminotransferase
AUROC
area under the receiver operating curve
BMI
body mass index
CAP
controlled attenuation parameter
CI
confidence interval
CT
computed tomography
FIB-4
fibrosis-4
GGT
γ-glutamyltranspeptidase
HA
hyaluronic acid
HDL
high-density lipoprotein
HBV
hepatitis B virus
HCV
hepatitis C virus
HR
hazard ratio
LSM
liver stiffness measurement
MRE
magnetic resonance elastography
MRI
magnetic resonance imaging
NASH
nonalcoholic steatohepatitis
NFS
nonalcoholic fatty liver disease fibrosis score
NPV
negative predictive value
PBC
primary biliary cholangitis
PSC
primary sclerosing cholangitis
PPV
positive predictive value
TIMP
tissue inhibitor of metalloproteinases
ULN
upper limit of normal
VCTE
vibration controlled elastography
Introduction
Knowledge of a patient's liver fibrosis burden is crucial for the management of chronic liver disease with major implications for treatment and prognosis. Advanced fibrosis indicates both heightened benefit from treatment and increased risk of progression to cirrhosis, which is associated with a risk of liver-related complications, hepatocellular carcinoma, and mortality.
Patient history and physical examination are insufficient for the determination of advanced fibrosis or compensated cirrhosis. The current gold standard for liver risk assessment is the liver biopsy. Although typically safe and rarely fatal, liver biopsy is always costly, demanding significant healthcare resources from space and time for a day-case procedure to a nurse and expert pathologist. Furthermore, it is an imperfect gold standard; a biopsy assesses roughly 1/50,000 of the liver and is prone to sampling error that may lead to understaging of advanced fibrosis. At the same time, patients are afraid of biopsies. Roughly half of patients offered a biopsy will refuse.
Given how critical an accurate determination of liver disease stage is for clinicians and patients alike, effective, inexpensive, and patient-preferred alternatives are needed. Accordingly, there is a major clinical role for noninvasive approaches to assess the risk of advanced fibrosis in patients with chronic liver diseases. Herein, we review the common clinically available options to assess risk in patients with liver disease.
The Value and Meaning of Fibrosis Staging and the Role of Liver Biopsies
The liver biopsy is interpreted in three clinically meaningful ways. First, it can be diagnostic, particularly when disease cannot be determined using serologic tests. Second, the biopsy often affects treatment decisions, and, third, histologic features often provide prognostic information. Patients with early-stage fibrosis are at little-to-no risk of adverse events in the short-term, while patients with advanced stage fibrosis are at increased risk of portal hypertensive decompensations, hepatocellular carcinoma, and death. As such, a significant portion of the discussion regarding treatment and prognosis for most patients with chronic liver disease relates to the staging of fibrosis.
As clinical trials for hepatitis C therapies were underway, a shared language for the description of histologic features became necessary, fostering the development of contemporary histologic scoring systems (e.g., METAVIR, metaanalysis of histologic data in viral hepatitis). In clinical practice, by contrast, the staging of fibrosis becomes binary. As opposed to absolute staging, patients need and want to know whether they are at low or high risk for hepatic complications. To that end, the critical information is based on the presence or absence of advanced fibrosis. In this sense, the patient with a low noninvasive index can be counseled in the same fashion as the patient with F0-F1 fibrosis, and vice versa.
Furthermore, the biopsy is a cross-sectional assessment of hepatic fibrosis, which is a heterogeneous process, unevenly distributed throughout the liver parenchyma. The consequences are twofold. First, whereas inexpensive noninvasive assessment of liver fibrosis can be performed cheaply and safely, longitudinal assessments by biopsy are impractical. Second, given the sampling error associated with liver biopsies, it is possible that noninvasive measures may correlate better with fibrosis burden. Indeed, when the total concentration of hepatic collagen is assessed using quantitative image analysis of biopsy specimens, noninvasive fibrosis markers perform significantly better than a standardized histologic assessment (i.e., Ishak score), even in the clinical trial setting.
The role of the liver biopsy has changed in contemporary practice, shaped by patient preferences, cost-consciousness, the ability to assess patients longitudinally, and the possibility that noninvasive markers may be more accurate than biopsy. By using noninvasive tests first, the biopsy is then used to clarify diagnoses and to assess fibrosis burden in the setting of indeterminate or conflicting biomarkers.
Approach to Noninvasive Testing
The overarching philosophy behind the noninvasive assessment of liver fibrosis is to efficiently provide the patient with a risk estimate of advanced liver disease in a form that affects clinical management. While no marker can effectively discern each stage of fibrosis as would a biopsy, this may not be important for patients with many common conditions. The key clinical considerations that risk assessment addresses are the benefits of therapy and screening for the complications of liver disease. While each disease has specific issues to consider (addressed in a later section), the goals of noninvasive risk assessment are generic.
When using noninvasive tests to avoid liver biopsy, the key is to seek concordance. There are a few reasons for this. First, it is reasonable: making clinical decisions based on tests that are proxies for histology often needs to satisfy a higher burden of test performance. Second, it is clinically expedient: one can obtain both a serologic and imaging test for advanced fibrosis in a single clinic visit. Thereafter, clinicians could immediately divide their patient population into three groups: concordant low and high risk and conflicting or intermediate results. One could choose to repeat the tests or pursue liver biopsy for the group with mixed or equivocal results, depending on how the results might change management. For patients who have a high pretest probability of advanced disease or clinicians who prefer conservative strategies, a biopsy could be considered for all patients who do not have concordant low-risk results. Third, this is also a well-studied strategy that is capable of maximizing patient outcomes. A sample application of this strategy is shown in Fig. 8-1 .
Pathophysiology of Common Serologic Tests for Liver Fibrosis
Many serologic biomarkers have been studied as surrogates for the staging of hepatic fibrosis. Most biomarkers combine multiple tests and occasionally anthropomorphic indices. The components of each test, as well as their clinical availability and cost, are detailed in Table 8-1 . These tests vary from the simple [aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio] to the complex (using proprietary or patented formulas that are performed in central processing labs). In this section we review the rationale behind each test and its components.
TABLE 8-1
Serologic Tests for Fibrosis
| Test | Send out to Lab? | Algorithm | Components | Pitfalls | Cost (2014 USD) |
|---|---|---|---|---|---|
| AST/ALT ratio | No | AST/ALT | AST, ALT | Alcohol, muscle breakdown | 1.44 |
| AST/platelet ratio index | No | (AST/ULN)/platelet count (10 9 /L) | AST, platelet count | Alcohol, muscle breakdown, extrahepatic causes of thrombocytopenia | 6.50 |
| FIB-4 | No | (Age × AST)/platelet count × √(ALT) | Age, AST, ALT, platelet count | Alcohol, muscle breakdown, extrahepatic causes of thrombocytopenia | 7.05 |
| NAFLD fibrosis score | No | –1.675 + 0.037 × age + 0.094 × BMI + 1.13 × diabetes (yes = 1, no = 0) + 0.99 × (AST/ALT ratio − 0.013) × platelet (×10 9 /L) − 0.66 × albumin (g/dL) | Age, BMI, diabetes (the presence of), AST, ALT, albumin, platelet count | Alcohol, muscle breakdown, extrahepatic causes of thrombocytopenia, malnutrition | 7.20 |
| FibroSure/FibroTest | Yes | Publicly available but only performed in reference laboratories | Age, sex, bilirubin, GGT, apoliprotein A1, haptoglobin, and α 2 -macroglobulin | Alcohol, Gilbert syndrome, renal disease, hemolysis, statin use, inherited dyslipidemia | 69.86 |
| HepaScore/FibroScore | Yes | Proprietary. Only performed in reference laboratories | α 2 -Macroglobulin, bilirubin, GGT, hyaluronic acid | Alcohol, Gilbert syndrome, renal disease, extrahepatic fibrosis | 26.02 |
| FibroMeter | Yes | Proprietary. Only performed in reference laboratories | Age, sex, platelet count, α 2 -macroglobulin, ALT, AST, GGT, INR, blood urea nitrogen | Alcohol, Gilbert syndrome, renal disease, anticoagulation | 70.50 |
| FibroSpect | Yes | Proprietary. Only performed in reference laboratories | α 2 -Macroglobulin, hyaluronic acid, tissue inhibitor of metalloproteinase | Renal disease, extrahepatic fibrosis, chronic inflammatory diseases | 56.72 |
| Enhanced liver fibrosis score | Yes | Publicly available but only performed in reference laboratories | Hyaluronic acid, tissue inhibitor of metalloproteinase, N-terminal propeptide of type III procollagen | Renal disease, extrahepatic fibrosis, chronic inflammatory diseases | 173.00 |
ALT, Alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; GGT, γ-glutamyltranspeptidase; INR, international normalized ratio.
AST/ALT Ratio
Perhaps the simplest noninvasive index of liver fibrosis is the AST/ALT ratio. Within the hepatocyte, ALT is confined to the cytosol, while AST is present in both the cytosol and mitochondria. Alcohol is a mitochondrial toxin and, furthermore, its metabolism depletes 5-pyridoxal phosphate, which is a cofactor for ALT production. Accordingly, alcohol's hepatotoxicity increases the release of AST and decreases the production of ALT. The AST/ALT ratio, therefore, is best known as a test that often distinguishes between alcoholic and nonalcoholic forms of liver disease. It has also been studied as a biomarker for cirrhosis in nonalcoholic liver diseases. There are two main reasons that these tests are of value in the noninvasive assessment of fibrosis. First, because sinusoidal liver cells facilitate the clearance of AST from serum, the impaired sinusoidal cell function seen with cirrhosis is an important cause of an elevated AST/ALT ratio. Second, both ALT and AST reflect necroinflammatory activity, which is often necessary for the formation of fibrosis.
AST/Platelet Ratio and Fibrosis-4 Indexes
The AST/platelet ratio index (APRI) and fibrosis-4 (FIB-4) index carry the basis of the AST/ALT ratio forward and add the prognostic information related to platelet count. Platelets are a sensitive marker for cirrhosis. A platelet count of less than 160 × 10 9 platelets/L has a positive likelihood ratio for the presence of cirrhosis of 6.3 (95% confidence interval [CI], 4.3-8.3). Cirrhosis decreases the platelet count in a number of ways. First, the platelet growth factor thrombopoetin is made by the liver and is deficient in patients with cirrhosis. Second, portal hypertension leads to splenic congestion and platelet sequestration. Third, gut-barrier disruption leads to systemic endotoxemia, immune activation, and formation of antiplatelet antibodies, all of which leads to platelet consumption. Accordingly, an elevated APRI is suggestive of cirrhosis by leveraging the insight that cirrhosis is associated with higher AST levels and lower platelet counts. The FIB-4 test uses an alternate algorithm based on the same physiology and adds the effect of age. The rationale for including age is sound, as it reflects a basic principle of liver injury: necroinflammation over time leads to fibrosis.
Nonalcoholic Fatty Liver Disease Fibrosis Score
The nonalcoholic fatty liver disease fibrosis score (NFS) extends observations regarding the AST/ALT ratio, platelet count, and age by adding the effect of body mass index (BMI) and diabetes. Insulin resistance is independently associated with progressive liver disease regardless of the underlying etiology. Hyperinsulinemia stimulates stellate cell activity, collagen synthesis, and connective tissue growth factor production. BMI is associated with hepatic fibrosis for two reasons. First, BMI likely reflects underlying steatosis, which is often hepatotoxic. Second, even adjusting for diabetes, BMI is still associated with fibrosis, suggesting that obesity is proinflammatory and linked to hepatic lipid peroxidation. The NFS also adds albumin, which is a serum protein produced by the liver, the levels of which decrease as liver disease advances. The NFS integrates these variables into a publicly available algorithm designed for the assessment of patients with NAFLD.
FibroMeter
FibroMeter is a noninvasive index that uses a proprietary algorithm based on elements used in other tests, including age, ALT, AST, and platelet count, and adds γ-glutamyltranspeptidase (GGT), prothrombin index, urea, and α 2 -macroglobulin (α 2 -M). GGT is a marker that is considered highly sensitive for biliary injury and therefore highlights a different component of liver injury. Owing to decreased urea synthesis by the cirrhotic liver, blood urea nitrogen has been shown in one study to be lower among patients with cirrhosis. Finally, it is well established that the prothrombin time is elevated in patients with cirrhosis.
α 2 -Macroglobulin and haptoglobin are the two components of α 2 -globin and are acute-phase reactants with variable responses to liver disease (haptoglobin is discussed in the next section). In addition, α 2 -M is a proteinase inhibitor expressed by activated hepatic stellate cells, and, as hepatic stellate cells produce collagen in the liver, it is therefore a direct marker of liver fibrosis.
FibroSure/FibroTest
FibroTest is another proprietary panel of tests that combines indirect and direct markers of liver fibrosis. This test includes haptoglobin and apoliprotein A1. Haptoglobin is negatively correlated with liver fibrosis. Hepatocyte growth factor, which is elevated in states of liver regeneration including cirrhosis, stimulates increased α 2 -M and decreased haptoglobin production. Apolipoprotein A1 is the primary component of high-density lipoproteins (HDLs) and is synthesized by the liver. For this reason, HDL levels are inversely proportional to liver fibrosis. Additionally, HDL levels may reflect ongoing liver injury in patients with NAFLD. HDL is depressed in patients with active nonalcoholic steatohepatitis (NASH) and returns to normal following resolution of NASH.
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