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Practice of FibroMax for alcoholic liver disease

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Summary
FibroMax

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.

See FibroTest in action

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

See AshTest in action

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



Applicability of
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.

Biopsy FibroTest
  • 0.6% morbidity
  • 0.03% mortality
  • no risk
  • hospitalization
  • simple blood test
  • nearby laboratory
  • sampling errors
  • size of random biopsy: from 5 to 30 mm
  • accuracy of a biochemical measurement (coefficient of variation < 5%)
  • intra- and inter-observer variability
  • excellent reproducibility, intra- and inter-laboratory
  • imperfect gold standard: risk of false positives or false negatives especially if the biopsy is too small
  • diagnostic and prognostic value equivalent to a 25 mm biopsy
  • difficult to repeat
  • very easy to repeat (blood test)
  • unfeasible by intercostal route if coagulation disorder, ascites
  • contraindicated if severe respiratory insufficiency
  • unapplicable if acute hepatitis, extrahepatic cholestasis, severe hemolysis, Gilbert's syndrome with high unconjugated hyperbilirubinemia
  • in cases of acute inflammatory syndrome, just postpone blood test
  • very unfavorable risk/benefit ratio
  • excellent risk/benefit ratio
  • enables lesions associated with fibrosis to be diagnosed, such as necroinflammatory activity, steatosis, iron overload, granulomas and other rarer lesions
  • other non-invasive BioPredictive tests enable the diagnosis of the most common lesions associated with fibrosis: necroinflammatory activity (ActiTest) and steatosis (SteatoTest).

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
0.84Diagnostic value for advanced fibrosis, estimated by the area under the curve (AUROC)
0.90Diagnostic value for cirrhosis, estimated by the area under the curve (AUROC)
0.79Prognostic value (death related to liver disease) of FibroTest, estimated by the area under the curve (AUROC)

Welcome to BioPredictive

Non-invasive liver diagnostic tests.

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BioPredictive
40 rue du Bac
75007 Paris
FRANCE

Tel : +33 1 45 44 30 64
email : contact@biopredictive.com


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