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The human body is made up of various organs and one of the most important homeostatic organs is the liver. However, despite its very active role, is mostly underemphasised and although most of its functions are not as regulatory as the brain, the liver is involved in important processes. These include biochemical, excretory and synthetic functions, therefore, to detect deviations in its function, several tests must be carried out. These test are referred to as ”Liver function tests”. They provide clues on the liver function and help to evaluate the level or amount of liver damage. Hence, they are used in the diagnosis of liver disease. And since early diagnosis and therapeutic intervention plays a large role in the treatment of liver diseases, liver function tests are important.
Liver function tests
The liver is the largest visceral organ in the body. It weighs about 1.3kg (3lb) in an adult (patho book ref). It has about 500 individual functions. To ensure that the liver continues to carry out these functions, there are several tests which are carried out on the liver when investigating a patient with liver disease. These tests are carried out on the bllod, each of them checking the amounts or levels of various constituents in the blood. Liver function tests include tests depict cholestasis (alkaline phosphatase, gamma glutamyl transpeptidase), tests reflecting the synthetic function of the liver tests (albumin and prothrombin time),tests portraying excretion (bilirubin, alkaline phosphatase and gamma glutamyl transpeptidase) and tests monitoring the amount of cell damage or liver injury (Aspartate aminotransferase and alanine aminotransferase).
This is a yellow compound or pigment formed by the breakdown of haemoglobin. This originates from the breakdown of worn out, old or damaged red blood cells. The senescent blood cells are taken up and destroyed macrophages (Kupffer cells) of the phagocytic system (which are located primarily in the spleen and in the liver. During the breakdown of haemoglobin into heme and globin, the globin is further degraded to form new proteins and the heme part forms bilverdin. In the Kupffer cells, the bilverdin is converted to bilirubin by the use of enzymes. The bilirubin is then released into the plasma where it binds to albumin and becomes an unconjugated bilirubin.
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The unconjugated or free bilirubin enters the hepatocytes and after mixing with glucuronic acid, it becomes a conjugated bilirubin. This conjugated bilirubin is water soluble and hence, soluble in bile, therefore if the outflow of bile is interrupted, conjugated bilirubin will affect the colour of the urine, it becomes darker. Conjugated bilirubin enters into the small intestines through the bile ducts and there, it is deconjugated into urobilinogen by bacteria. The urobilinogin formed could either be reabsorbed into circulation by the hepatic portal vein into the liver to be re-excreted into the bile or excreted in faeces. This process is known as the enterohepatic circulation. The urobilinogen excreted in faeces or urine is oxidized to urobilin which is responsible for the colour of faeces.
There are two tests which are carried out for bilirubin. They are direct-reacting (which is carried out for conjugated bilirubin) and indirect-reacting (which is carried out for unconjugated bilirubin). Various conditions can lead to an elevation in the amount of bilirubin in the blood, such as blockage of the bile ducts, excess production of bilirubin, reduced conjugation, reduced secretion and reduced uptake by the liver. Increased levels of indirect bilirubin are usually caused by liver cell disorder. An example is in hepatitis where the damaged biliary excretion leads to the presence of excess faecal urobilinogen in the urine. This gives the urine a darker colour and can be used as an indication of early cell injury. And an increase of direct bilirubin characteristically results from an obstruction which could either be located within or outside the liver (e.g. a blockage in the bile ducts or gallstones). When the bile duct is obstructed, the concentration of urinary urobilinogen reduces because the stoppage in the excretion of bile into the gut does not lead to synthesis of the faecal urobilinogen.
Albumin is a major protein which is synthesised by the liver cells and secreted into the blood. The capacity of the synthetic function of the liver can be measured with the use of albumin. The serum albumin test, therefore, is carried out in order to measure the amount of protein in the serum. Albumin has a comparatively long half life of twenty one days, therefore, liver damage must persist (be long term) before reduced levels of serum can be noticed. Inability to maintain the serum levels between the reference value of 35- 50 g/L leads to a low reading of albumin, referred to as hypoalbuminaemia, which signifies impending liver failure. Apart from liver failure, there are other conditions which can result in low serum albumin. Examples include urinary loss, hypercatabolism and also severe malnutrition.
Alkaline phosphatase is an isoenzyme which is present in the liver canalicular plasma membrane of hepatocytes, in the placenta, intestine and in the bone for bone building. The normal amount of alkaline phosphates is less 100 IU/L. Increase in alkaline phosphatase is mostly due to increase in enzyme production in areas close to an obstruction and also due to the molecular weight of the biliary isoenzyme. This can be detected with the used of serum electrophoresis. Increase in alkaline phosphatase can be caused by disorders such as cholestasis within the liver (intrahepatic) or outside the live (extrahepatic), space occupying lesions (such as abscesses, cysts and tumours) and hepatitis. During pregnancy, the isoenzyme located in the placenta is released and the isoenzyme in the bone is also released in children and adolescents during growth. These are known as physiological increases in serum alkaline phosphatase. In disorders such as rickets, the serum alkaline phosphatase level is increased. This type of increase is called a pathological increase. And although bilirubin levels increase alongside alkaline phosphatase levels, sometimes the bilirubin value can remain normal regardless of an increased alkaline phosphatase level.
Gamma Glutamyl transpeptidase
Gamma-glutamyltraferse, gGT, is a glycoprotein which is found in many tissues such as the prostate, liver, intestine, pancreas, and kidneys. It has a normal range which is <50IU/L. Unlike alkaline phosphatase, gGT is more liver-specific. gGt is higher in men than in women and infants and neonates have high levels up until 1yr. Although it can be used in testing for cholestasis because its level rises in cholestasis alongside ALP, it is more sensitive in indicating alcohol and drug (e.g. Phenytoin) intake. The increase of both ALP and gGT can be interpreted with the knowledge that in cholestasis ALP is usually higher than gGT while in an alcoholic disease, gGT is more than ALP. Some other conditions which could result in increased gGT levels include: myocardial infarction, uncomplicated diabetes mellitus and acute pancreatitis. Paracetamol and phenobarbitone are drugs that could also lead to increased levels of g-glutamyl transpeptidase. Anorexia Nervosa and obesity could serve as non hepatic causes for the increased amounts of the enzyme
Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST)
Alanine Aminotransferase and Aspartate aminotransferase are is one of the key enzymes which are used to indicate hepatocellular necrosis. They are primarily found in the liver, the cystol of hepatocytes(ALT) and in the mitochondria (AST). The transfer of the alpha amino acid of aspartate and alanine to alpha keto group and ketoglutaric acid respectively is catalysed by ALT. ALT and AST have a normal range of < 40IU/L . When the value is >20 times (1000U/L), it is considered severe and the raised ALT level can lead to severe viral hepatitis , circulatory shock and drug or toxin induced necrosis. The levels of AST and ALT are reasonably increased (2 – 30 times) in hepatitis (e.g. alcoholic hepatitis). An increased level of AST normally indicates acute abnormality of liver, heart and/or skeletal muscles.
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