ARCH GASTROENTEROHEPATOLOGY 2001; 20 ( No 1 – 2 ):
Review article
R.Ješić, M.Krstić, D.Tomić, A.Pavlović, T.Cvejić, V.Bulat, T.Aleksić, R.Šarenac,Đ. Ćulafić
Clinic for Gastroenterology and Hepatology, Institute of Digestive Diseases, Clinical Center of Serbia, Belgrade.
( accepted April 10th, 2001 )
Address correspondence to: Professor Dr Rada Ješić
Institute of Digestive Diseases
Clinical Center of Serbia
Koste Todorovića 6
YU-11000 Belgrade, Yugoslavia
Abnormal liver function tests ( LFT ) are commonly the first indicator of liver diseases. Normal or slightly abnormal LFT do not rule out numerous liver diseases, even including the advanced cirrhosis.
Morphologically and functionally liver parenchyma is a dynamic structure. Hepatocytes represent for about 90% of liver cell mass. The damage of hepatocytes is associated with the alterations of their organelles, and morphological change result in changes of various biochemical functions of the liver. Complex cellular integrating processes depending upon the adequate blood supply (flow), functional parenchyma integrity, and efficient drainage capacity of bile ducts and hepatic veins define hepatic function. This indicates that mechanisms for maintaining the hepatocyte function are very complex. Therefore it is apparent that one test may not reflect (measure) the global hepatic function(s).
For didactic reasons, all liver LFT are divided into three groups: standard (analytic), clearance, and dynamic tests.
The term “liver function tests” ( LFT ) implies standard tests for measurement of synthetic liver function (serum albumins), excretory function (bilirubin) and inflammatory activity of hepatocytes (serum aminotransferases). The utility of these tests in monitoring the immediate liver function is rather low. Likewise, many of these usual laboratory tests other than alanine aminotransferases and bile acids are not specific for hepatic function, and may reflect extrahepatic pathological processes (1).
On the contrary, numerous liver disorders such as inactive cirrhosis manifested by reduced hepatic function may be associated with normal serum bilirubin level as well as aspartate (AST) or alanine aminotransferase (ALT), AF, albumin or GGT.
In other words, these so-called LFT provide information on integrity of hepatocytes (ALT and AST) and biliary system (AF, GGT).
With the exception of serum albumins and prothrombin time (PT), other tests fail to furnish information on hepatic function, that is, they are not sufficiently reliable in monitoring the immediate liver function (1,2).
Some of these tests, if used separately, may provide multiple false-negative findings. Using the battery of “liver function tests” ( LFT ) the number of false-negative findings is reduced to minimum (3).
As it is already mentioned, the majority of regular “liver function tests” ( LFT ) are relatively non-specific, providing limited - indirect informations, reflecting hepatic function in earlier time period, and their values are influenced by other extrahepatic factors. They are used separately or combined with scoring systems such as Child-Pugh score. Moreover, the value of these tests is limited regarding the disease aetiology and morphological changes.
Liver biopsy remains the golden standard in detecting and defining the aetiology of variety of liver disease. Recently, the interest for “real-time” LFT has been increasingly growing.
The predominant functions of the liver are the clearance of endo- and xenobiotics, their metabolism and excretion, and the synthesis of biologically important compounds such as clotting factors and albumin (4).
Generally, two approaches have been used to assess liver function. One approach is measure liver synthetic capacity, which is determined by substrate administration and monitoring of synthesis products in liver. Another approach is monitor hepatic clearance function. They depends upon organ perfusion, transfer of solutes from blood to hepatocytes, as well as upon volume, number and enzymatic composition of hepatic cells. If the substance is primarily retained in liver, total body clearance follows hepatic clearance. In the other words, hepatic clearance depends upon hepatic perfusion and extracts, and both may be modified due to liver disease. The key determinant which allows hepatic extraction is a functional portion of hepatocytes and blood-hepatic exchange. This is significantly reduced with collagenation of Disse˘s spaces which occurs in cirrhosis. Therefore, all LFT reflect hepatic perfusion, functional capacity and blood-hepatic exchange (3,5,6).
Certain liver tests such as indocyanine green, sorbitol and galactose clearance tests depend mainly upon hepatic perfusion, and some other similar ones such as galactose-eliminating capacity and aminopyrine demethylation primarily depend on functional capacity of liver. The metabolism of these substances occurs in microsomal mono-oxygenase system of liver, depending on numerous hepatic enzymes. The main process proceeds with the participation of cytochrome P-450 system. It is quite clear that the reduced hepatic function may be reflected by decreased metabolism of many endo- and xenobiotics. Imperfection of these tests which measure hepatocyte microsomal function(s) is caused by environmental factors, diet, smoking and parallel drugs administration whicn may induce or inhibit mono-oxygenase enzyme system regardless the presence or absence of liver disease (7).
The function of liver gradually decreases with aging with simultaneous reduction of liver volume. This must be considered when liver function tests are interpreted. It is not surprising that many patients with established cirrhosis have also normal quantitative LFT.
The clinical benefitof quantitative measurement of hepatic function is as follows: to define the residual liver function, to follow-up the course of the disease and prognosis in patients with acute liver diseases and cirrhosis, to anticipate the surgical risk and postoperative course in patients with reduced residual function and finally to determine an optimal time for liver transplantation (7,8).
The evaluation of metabolic and excretory capacity of liver is carried out by regular “quantitative” clearance LFT. Exogenous, non-toxic substances (stains, sugar, drugs) orally or parenterally given are used. They are metabolized exclusively in liver and may be detected in blood, saliva and expired air. The most common is antipyrine clearance test showing a good correlation with the degree of liver damage expressed through Child˘s classification. Its disadvantage is that it correlates poorly with “in vitro” loading of hepatic microsomal capacity of liver, while its metabolism is influenced by the age, diet, alcohol consumption, smoking and toxic substances. Aminopyrine breath test may be useful as prognostic factor for patients with alcoholic hepatitis and cirrhosis of liver as well as prior to surgical intervention. Its shortcoming is low sensitivity to detect hepatic dysfunction in cholestasis or extrahepatic biliary obstruction. Coffeine clearance test is beneficial in severe liver lesions, and is almost useless in a moderate liver damage. The transformation of galactose into glucose after galactose loading depends upon the degree of functional ability of hepatocytes. Plasma galactose level reflects hepatic functional mass and hepatic blood flow (8,9). Reduced galactose tolerance appears only in severe hepatocyte damage. The test is abnormal in acute and chronic liver diseases as well as in metastatic hepatic neoplasms, but it is not atypical in obstructive jaundice. According to some authors, galactose-eliminating test is more accurate than Mayo index for optimal timing of liver transplantation, then for evaluation of new pharmacological therapeutical modalities in this disease as well as in expecting the lethal outcome of patients with primary biliary cirrhosis (10). Galactose-eliminating capacity (GEC) is used as prognostic index for patients with fulminating hepatic insufficiency, and in these patients GEC < 13 mmol/min/kg indicates that transplantation of liver is required. In patients with cirrhosis, but not in those with steatosis, GEC correlates significantly with the majority of most commonly used liver tests, because it reflects quite well the cytosol function of liver. Galactose breath test (GBT) may be used for monitoring of liver cytosol function.
Surgical interventions in patients with chronic liver diseases are associated with the increased risk. In these patients maximal ratio of indocyanine green (ICG) elimination combined with volumetric measurement of residual liver function serves to verify the surgical risk.
With a great progress of liver transplantation, the need for more adequate tests for donor selection has been increasing constantly as well as for the improvement of diagnosis in posttransplantation hepatic dysfunction. Appropriate donor function tests are still lacking. MEGX formation after intravenous lidocaine depends upon the activity hepatic cytochrome P-450 3A4 isoenzyme that catalyzes oxidative N-deethylation lidocaine. In potential donors MEGX determination may be a useful test for their selection for liver transplantation (11,12). Graft survival is considerably prolonged when donor˘s MEGX test is > 90mg/L.
This test, after seven days of transplantation, shows significant correlation with a number of rejection episodes. It serves to monitor the donor, s liver function and the condition of transplant candidate(s ). It is also beneficial for perioperative evaluation in patients with focal lesions, especially those with cirrhosis of liver, as well as in those with functional hepatic disease (11).
MEGX test has high sensitivity (82%) and specificity (80%) in distinguishing chronic hepatitis from cirrhosis in comparison to standard liver tests (12,13,14).
In spite of all new array of liver function tests, the precise and acurate measurement of functional hepatic reserve is still controversial. There is no ideal test for its determination; such test would require a test substance with exclusively hepatic elimination and excretion, and minimal interreaction with concomitant drugs and other metabolites.
MEGX test appeared to be an attractive alternative to earlier methods in evaluatiing hepatic functional reserve. More studies to define MEGX test prognostic value in cirrhotic patients are necessary. It is also important to continuue with further investigations to determine the influence of portosystemic shunt and hepatic dysfunction on lidocaine metabolism and MEGX test. Moreover, it is necessary to devise any accurate, non-invasive test (method) to detect the substances in various liver compartments, namely, to create a pharmacokinetic model matching the kinetics of test substance.
The existing commercially available tests are invasive and cannot determine the biliary substance concentration.
Various complex models have been applied to control hepatic function. One recent model is the combination of dynamic test and CT imaging. Being the sampling method, it has several advantages in relation to present available dynamic tests. It has been designed for this imaging-based testing to enable independent monitoring of parenchymal and biliary fractions in maintaining normal function of liver, as well as control of functional integrity in different liver segments (15).
The conventional liver tests reflect the entire capacity of liver, but fail to reveal it in the isolated segments. In vivo studies should evaluate if this method is clinically applicable and valuable.
“Redox tolerance test” of recent date is used for monitoring of hepatic functional reserve and prognosis of patients with obstructive jaundice, before and after percutaneous transhepatic biliary drainage (16).
In summary, quantitative liver function tests are not screening tests for detection of liver diseases. They are more complex to perform and more expensive than conventional biochemical tests, but superior in monitoring of degree of liver dysfunction.
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