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Practice of FibroMax for alcoholic liver disease
Up one level
FibroTest, SteatoTest and AshTest are non-invasive diagnostic tools for alcoholic liver disease.
This article offers a review of alcoholic liver disease, its lesions and then the use of these diagnostic tests on a day-to-day basis.
Alcoholic liver disease - A brief reminder
Short history of the liver and alcohol
At the beginning of the 1950's, alcoholic liver toxicity was unknown and there was much talk about nutritional cirrhosis. The prominent role of excessive alcohol consumption in the occurrence of cirrhosis in France and the world was revealed in the middle of the 1960's. The toxicity of the hepatic metabolite of alcohol, acetaldehyde, has been demonstrated, as has its role in the occurrence of steatosis, alcoholic steatohepatitis and fibrosis.
Natural history of the disease
it is estimated that about 25% of the worldwide mortality from cirrhosis and primary liver cancer is due to the consumption of excessive alcohol. This portion is greater in the more developed countries where it totals nearly 65%. The excessive drinkers, defined as 2 glasses or more per day in women, and 3 glasses or more in men, have a risk of steatosis of about 30%, advanced fibrosis of 10% and cirrhosis of 2%. Assessment of the risk is based on the declared alcohol consumption, possibly associated with the CDT (carbohydrate deficient transferrine) assay.
Alcoholic hepatic lesions
Fibrosis
Hepatic fibrosis is a process of scarring through fibrous tissue deposit which results in the destruction of the parenchyma, with the ultimate progressive stage being cirrhosis.
The METAVIR score, initially developed to assess the stages of fibrosis in subjects with chronic viral hepatitis C and B, can also be used in patients with alcoholic liver disease. The F1 stage must be defined as a perisinusoidal fibrosis without septum since contrary to the viral hepatitises, fibrosis does not begin in the portal area but in the centrilobular region.
The METAVIR score assesses the fibrosis in alcoholic liver disease according to a 5-stage classification:
- F0 : no fibrosis
- F1 : perisinusoidal finbrosis without septa
- F2 : portal and periportal fibrosis with rare septum
- F3 : portal and periportal fibrosis with many septum
- F4 : cirrhosis
Steatosis
Hepatic steatosis is an accumulation of triglycerides in the hepatocytes.
The steatosis score is determined through the percentage of hepatocytes with cytoplasmic steatosis. It varies from 0 to 100%.
Necroinflammatory activity: alcoholic steatohepatitis (ASH)
The activity (or grade) estimates the significance of lesions of hepatocellular necrosis, polynuclear infiltrates, ballooning and the presence of Mallory bodies.
The steatohepatitis score (or acute alcoholic hepatitis) assesses the activity according to a 4-grade classification:
- H0 : no alcoholic steatohepatitis
- H1 : minimal alcoholic steatohepatitis
- H2 : moderate alcoholic steatohepatitis
- H3 : severe alcoholic steatohepatitis
The 3 BioPredictive tests for these 3 lesions
FibroTest
FibroTest measures the hepatic fibrosis stage with a blood test.
FibroTest was evaluated in relation to liver biopsy in 524 patients with alcoholic liver disease and has been used in over 350,000 patients (2008).
FibroTest retains the same diagnostic value independent of sex or transaminases.
FibroTest has the same diagnostic value for the intermediate stages and the extreme stages.
The use of FibroTest was validated for the initial diagnosis of fibrosis, but also for the 10-year prognosis of patients with alcoholic liver disease.
The French National Authority for Health (HAS) has not recommended the use of FibroTest as a first-line assessment tool for fibrosis with alcoholic liver diseases, as with hepatitis C; the reevaluation however according to the latest positive published results is scheduled in 2009.
Interpretation of the FibroTest results
The FibroTest result is provided as a score of 0 to 1, proportional to the severity of the fibrosis, with a conversion to the METAVIR system (from F0 to F4). To facilitate the visual interpretation, the result must be accompanied by a colored graph with three classes of severity:
- Green (minimal or absent)
- Orange (moderate)
- Red (significant)
The conversion of FibroTest into stages according to the three most used histological classifications (METAVIR, Knodell and Ishak) is proposed in the following grid:
| FibroTest |
METAVIR Stage of estimated fibrosis |
Knodell Stage of estimated fibrosis |
Ishak Stage of estimated fibrosis |
| 0.75-1.00 | F4 | F4 | F6 |
| 0.73-0.74 | F3-F4 | F3-F4 | F5 |
| 0.59-0.72 | F3 | F3 | F4 |
| 0.49-0.58 | F2 | F1-F3 | F3 |
| 0.32-0.48 | F1-F2 | F1-F3 | F2-F3 |
| 0.28-0.31 | F1 | F1 | F2 |
| 0.22-0.27 | F0-F1 | F0-F1 | F1 |
| 0.00-0.21 | F0 | F0 | F0 |
AshTest
Using the same blood test, AshTest measures the degree of necroinflammatory activity of alcoholic origin.
AshTest combines the markers of FibroTest-ActiTest with AST.
AshTest was validated in relation to liver biopsy in 224 subjects.
The conversion of AshTest into grades is proposed in the following grid:
| AshTest |
Estimated activity grade |
| 0.78-1.00 | H3 |
| 0.55-0.77 | H2 |
| 0.18-0.55 | H1 |
| 0.00-0.17 | H0 |
Interpretation of the AshTest results
The AshTest result is provided as a score of 0 to 1, proportional to the significance of the activity (from H0 to H3).
To facilitate the visual interpretation, the result must be accompanied by a colored graph with three classes of severity:
- Green (minimal or absent)
- Orange (moderate)
- Red (significant)
Fibromax (FibroTest + SteatoTest + AshTest) instructions for use
The use of our non-invasive tests is very simple: the physician writes a FibroMax prescription(available on the website).
The patient goes to a nearby laboratory for the ten-parameters blood test.
FibroMax combines ten serum markers with the age, sex, height and weight of the patient:
- Alpha-2-macroglobulin
- Haptoglobin
- Apolipoprotein A1
- Gamma-glutamyl transpeptidase (GGT)
- Total bilirubin
- ALT
- AST
- Total Cholesterol
- Triglycerids
- Blood sugar (fasting)
A prototype prescription is available on the website(download the prescription).
The FibroTest, SteatoTest and AshTest scores are provided together on a result sheet combining all the information. The laboratory (or the physician) connects to the BioPredictive website for calculation of the tests and prints the results sheet which is available immediately and is accompanied by an interpretation aid and precautions for use.
Precautions for use, safety
An expert system analyzes each FibroMax and its parameters in order to ensure their proper applicability. Over 95% of tests are interpretable and enable an effective diagnosis of fibrosis, steatosis and steatohepatitis. In less than 5% of cases, the expert system detects the profiles that are at risk of false positives or false negatives and clearly indicates them on the result sheet.
Applicability and safety integrated in the tests
FibroTest : 95-99%
FibroTest is applicable in 95 to 99% of cases. It has been validated for the following diseases : (available scientific publications)
- Chronic hepatitis C
- Chronic hepatitis B
- Chronic hepatitis C or B with HIV co-infection
- Alcoholic liver diseases (steatosis and steatohepatitis)
- Steatosis and non-alcoholic steatohepatitis (diabetes, overweight, hypertriglyceridemia, hypercholesterolemia, hypertension)
The test is robust and validated, including for the following specific populations:
- Subjects over the age of 65 years
- Children
- Patients with renal insufficiency and patients with renal transplanation
- Hemophiliac
- Patients with chronic inflammatory disease
- General population
The tests are not applicable in only 1 to 5% of cases:
- Acute hepatitises, e.g., acute viral hepatitis A, B, C, D, E; drug-induced hepatitis
- Extrahepatic cholestasis, e.g., pancreatic cancer, gallstones
- Severe hemolysis, e.g., some cardiac valves
- Gilbert's syndrome with high unconjugated hyperbilirubinemia
- Acute inflammatory syndrome (the blood test just needs to be postponed)
These cases are detected by our safety mechanisms and are clearly indicated on the results sheet.
Reproducibility
Only the analyses performed in pre-analytical and analytical conditions and using the automated analyzers and reagents validated by our reference center are authorized by BioPredictive.
Tracibility
Our systems are declared with the French Committee on Technologies and Freedom (CNIL) and guarantee the anonymity of the provided information. The BioPredictive information system implements a tracibility device on all of its processes, thus assuring its quality management.
Use of FibroMax in the management of alcoholic liver diseases (ALD).
The management of alcoholic liver diseases and the therapeutic decisions depend on the degree of fibrosis according to three classes of severity: green (minimal), orange (moderate) and red (significant), as well as the presence of severe alcoholic steatohepatitis.
Comparison of FibroTest and liver biopsy
Biopsy is an imperfect tool; due to sampling errors, biopsy size (5 to 30 mm) and intra- and interobservor variability, it is now agreed that biopsy presents a mean error of 30%: it is called the "imperfect Gold Standard". The "perfect Gold Standard" of the liver is utopian, it would essentially be necessary to use the entire liver to rule out any possibility of diagnostic error.
Biopsy continues to present major inconveniences: 30% of patients complain of pain, 0.6% have been noted to have severe complications and even 0.03% deaths. Its use as a first-line tool is no longer suitable, and as its repeatability is very weak, biopsy is not practical for patient monitoring.
FibroTest is a non-invasive diagnostic test (simple blood test) which is very easily reproduced and has the same relevance as a 25 mm biopsy.
There is a mean discordance of 25% observed between FibroTest and biopsy. Half of these discordances are attributable to an error of the biopsy, often too small, and the other half to FibroTest.
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In conclusion, FibroTest has the same diagnostic value as a 25 mm biopsy, while being noninvasive and easily repeatable.
Key figures of FibroTest
| 95 % | Applicability |
|---|---|
| 87,5 % | Diagnostic accuracy (percentage of true positives and true negatives compared to histology) |
| 0 % | False positives within a population of 1,000 blood donors |
| 0.84 | Diagnostic value for advanced fibrosis, estimated by the area under the curve (AUROC) |
| 0.90 | Diagnostic value for cirrhosis, estimated by the area under the curve (AUROC) |
| 0.79 | Prognostic value (death related to liver disease) of FibroTest, estimated by the area under the curve (AUROC) |
Bibliographic references
Here are several key references:
- Halfon et al, FibroTest-ActiTest as a non-invasive marker of liver fibrosis. Gastroenterol Clin Biol 2008;32:22-38
- Poynard et al, Standardization of ROC curve areas for diagnostic evaluation of liver fibrosis markers based on prevalences of fibrosis stages. Clin Chem. 2007;53:1615-1622
- Poynard et al, Methodological aspects for the interpretation of liver fibrosis non-invasive biomarkers: a 2008 update. Gastroenterol Clin Biol 2008;32:8-21
- Nguyen-Khac et al, Assessment of asymptomatic liver fibrosis in alcoholic patients using fibroscan: prospective comparison with seven non-invasive laboratory tests Aliment Pharmacol Ther. 2008;28:1188-98
- Naveau et al, Diagnostic and prognostic values of non-invasive biomarkers of fibrosis in patients with alcoholic liver disease Hepatology 2009; 49:97-105
The complete list of publications is available on the website : liste des publications.