excretory, synthetic or detoxifying mechanisms

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The liver carries out several important functions that involve excretory, synthetic or detoxifying mechanisms. However, only a few can be quantified by levels of product travelling within the bloodstream. Liver function tests (LFTs) check the levels of various proteins and enzymes in the bloodstream that are produced by liver cells or when they are damaged. Patients with suspected liver disease routinely have LFTs carried out as specific patterns can tell a doctor the likely prognosis of liver disease so that further tests can then be carried out if required. LFTs can also show how serious liver damage is so that efficient monitoring and response to drugs and treatment can be arranged.

There are only a few LFTs that actually measure total liver function and therefore the term ‘LFTs' is actually a misnomer. Aminotransferase and alkaline phosphatase enzymatic levels are useful in detecting the level of damage that has occurred to liver cells and to obstruction by bile (that is synthesised by liver cells to enable digestion of fats). Individual tests themselves do not provide an overall picture of liver function; it is the collective data of values measured that can foresee the possibility of liver disease, potential causes and also severity of disease. Other laboratory tests can also aid in monitoring the level of liver function and response to treatment.

A blood test is required before LFTs can be performed. Some laboratories insist that the patient be in a fasting state before samples are collected while others do not require such preparations. Different laboratories may also have varying cut-off values due to following different methods and guidelines.

The Tests

Total protein imitates the synthetic functions of the liver and should be between 63-80 g/L.

Albumin is only produced by liver cells and therefore its value illustrates synthetic liver function. As albumin remains in the bloodstream for quite some time, dramatic variations often reflect chronic liver disease. Normal albumin values range between 35-50 g/L. Other conditions such as malnutrition and kidney damage result in low levels of albumin in the peripheral circulation due to low protein intake or loss of albumin into urine respectively. As a result, peripheral oedema symptoms can be recognised due to decreased level of salts and proteins in the bloodstream.

Bilirubin produced from breakdown of red blood cells is detoxified by the liver and excreted into bile. High levels of bilirubin can cause jaundice but is not necessarily due to liver abnormalities; other conditions can also increase breakdown of red cells such as blood transfusions. Total plasma bilirubin value should normally be less than 20 µmol/L.

Alkaline Phosphatase is generally found in bile tracts in the liver and its levels usually correlate to the degree of biliary obstruction. However, as different types of alkaline phosphatases are found in other parts of the body as well, elevated levels could point to disease outside the liver, such as a cancerous tumour. Normal levels of alkaline phosphatase range between 35 and 50 g/L.

Gamma Glutamyl Transpeptidase (GGT) is another enzyme present in liver and bile duct cells. Diseases that result in obstruction of bile flow will more than likely result in elevated GGT levels. Alcohol abuse, anticoagulants such as warfarin and epileptic drugs can also increase GGT levels. Long-term chronic alcohol abuse can also play a role in raising GGT levels but other underlying conditions can also result in elevations. Normal individuals usually have GGT levels less than 60 U/L.

Alanine and Aspartate are aminotransferases that are markers of liver damage occurring as a result of disorders such as viral hepatitis. The liver, kidneys, cardiac and skeletal muscles are just a few parts of the body that contain Aspartate Amino Transferase (AST) whilst Alanine Amino Transferase (ALT) is found primarily in the liver itself. As blood normally contains low levels of these enzymes, elevations could point to damage to liver cells.

Even though virtually any type of liver cell injury can raise the level of aminotransferase, the increase does not necessarily reflect the seriousness of liver damage. Normal values for AST and ALT are 42U/L and <36 U/L respectively.

Ammonia is produced from protein metabolism in the large intestine. Detoxification of ammonia is carried out within the liver through conversion to urea. Ammonia measurements can not only provide information on the degree of liver function, but also the existence of a condition where ammonia toxicity can impair brain function (known as encephalopathy) causing symptoms such as confusion and tremors. However, blood ammonia levels compare poorly with symptoms and so measurements have their limitations. Normal values vary widely between laboratories due to differing techniques followed.

LFTs do have various limitations and hence is the reason why doctors interpret the results in conjunction with a patient's medical history and signs/symptoms seen at presentation. Also, like many other tests and investigations, reliable results may not be enough. For example, LFT results may actual be normal for a patient with severe liver disease and other patients may have results that do not seem ‘normal', possibly due to variations in the mean in populations, but actually be normal for that person. Another reason why LFTs are not used as standalone procedures is because most of the time the exact type of disease cannot be deduced. However they do provide clues to the likely type of disease allowing further tests and investigations to be carried out to confirm or rule out predictions.

Another limitation of LFTs is that a range of drugs and other medical circumstances/underlying conditions can interfere with results causing abnormal values to be produced. Therefore tests need to be repeated, and if inconclusive, then different investigations need to be carried out instead.

Alcohol Abuse

Possible markers of alcoholism include GGT and the transaminases AST and ALT. Other markers include carbohydrate-deficient transferrin (CDT) and haemoglobin-associated acetaldehyde (HAA).

GGT is found in the plasma membrane of various tissues including the liver. Excessive drinking of alcohol over long periods of time will result in elevated levels of GGT. However, high levels of drinking over short periods of time generally will not. The rise in GGT due to chronic alcoholism has not yet been solved. Nonetheless it has been postulated that GGT increase may be due to alcohol triggering hepatic microsomal production. Another theory suggests alcohol damages liver cells causing release of GGT from hepatocytes. The sensitivity of liver GGT measurements for diagnostic use of alcoholism varies between 39-87% (Titcomb, et al., 2001). Another aspect to consider is that other substances can also alter GGT levels in the liver. Compounds such as phenytoin, phenobarbitone and NSAIDs can all increase GGT levels. Furthermore non-alcoholic related liver disease such as heart and kidney diseases are just a few types of conditions that can also alter GGT levels. As a result the diagnostic use of GGT as a marker of alcoholism is balanced, as it can point towards alcohol abuse but further tests may need to be carried out, including interviewing the patient to assess their character.

AST and ALT are liver cell enzymes that are both released into circulation when organ damage or destruction occurs. Like GGT, both the transaminases are found in a selection of other tissues, especially AST. As a result increased ALT level commonly provides a more realistic marker of liver breakdown. Characteristic causes of liver disease include alcoholic or non-alcoholic steatosis and hepatitis B or C. Drug-induced hepatitis infections cause greater rises in AST and ALT than alcohol abuse. Furthermore liver disease due to alcoholism can be detected by contrasting levels of AST and ALT. It has been found that higher elevations of AST compared to ALT point towards alcohol abuse. The ratio of AST to ALT is used diagnostically to confirm or rule out alcoholism. A ratio greater than two is a marker of alcoholic liver disease. In conclusion GGT, AST and ALT measurements analysed together can give indications of alcohol abuse. Elevations in GGT and AST together are strong pointers of alcoholism. In addition, if alkaline phosphatase levels have doubled also then further tests need to be done to check for hepatitis.

Drug Abuse/Toxicity

A range of drugs (medicinal or otherwise) and several disease states can cause elevations in liver enzymes and therefore it is very difficult to predict drug use.

Rises in ALT over AST are found in diseases which cause liver deterioration and incorporate viral hepatitis and drug abuse. This is in comparison to alcoholic liver disease where AST levels are much higher than ALT levels.

GGT elevation alone may also be a possible marker of drug abuse, but due to the contraindications mentioned previously, this is only suggestive and not a fact.

Rises in alkaline phosphatase and GGT exceeding AST and ALT levels can also be a result of intra-hepatic drug toxicity leading to bile obstructivity or cholestasis.

In conclusion, the determination of drug abuse through the use of LFTs is unpredictable and maybe of confined use as it does not provide a quantitative picture and therefore is used only for qualitative purposes. LFTs are good for differential diagnostic use but should be repeated as necessary with special attention to ALT level fluctuations. This is because ALT is a good forecaster of liver disease advancement. However, sooner or later, a liver biopsy will need to be done as this is the only certain pointer of liver destruction.