Liver Function tests • Liver • The liver is the largest organ in the body. It is located below the diaphragm in the right upper quadrant of the abdominal cavity. • It extended approximately from the right 5th rib to the lower border of the rib cage. The working cells of the liver are known as hepatocytes.

• Functions of liver

• Metabolic function: • Liver actively participates in carbohydrate, lipid, protein, mineral & vitamin metabolisms.

• Excretory function: • Bile pigments, bile salts & cholesterol are excreted in bile into intestine. • Hematological function: • Liver participates in formation of blood (particularly in embryo) • Liver is also produces clotting factors like factor V, VII. • Fibrinogen involved in blood coagulation is also synthesized in liver. • It synthesize plasma proteins & destruction of erythrocytes.

• Storage function: • Glycogen, vitamins A, D & B12 & trace element iron are stored in liver.

• Protective function & detoxification: • Ammonia is detoxified to urea. • kupffer cells of liver perform phagocytosis to eliminate foreign compounds. • Liver is responsible for the metabolism of xenobiotics. is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism • Some example of liver dysfunction

• Hepatocellular disease • Cholestasis (obstruction of bile flow) • Cirrhosis • Hepatitis • Jaundice • Liver cancer • Steatosis (fatty liver)

• Genetic Disorders

– Hemochromatosis (iron storage) • Uses of Liver Function Tests (LFTs)

• Noninvasive methods for screening of liver dysfunction

• Help in identifying general types of disorder

• Assess severity and allow prediction of outcome

• Disease and treatment follow up Group I: Markers of liver dysfunction

▫ Serum bilirubin: total and conjugated ▫ Urine: bile salts and urobilinogen ▫ Total protein, serum albumin and albumin/globulin ratio ▫ Prothrombin Time

Group II: Markers of hepatocellular injury

▫ Alanine aminotransferase (ALT) ▫ Aspartate aminotransferase (AST)

Group III: Markers of cholestasis

▫ Alkaline phosphatase (ALP) ▫ g-glutamyltransferase (GGT) • Limitations

• Lack sensitivity: The liver function test (LFT) may be normal in certain liver diseases like cirrhosis, non cirrhotic portal fibrosis, congenital hepatic fibrosis, etc.

• Lack specificity : They lack specificity and are not specific for any particular disease. Serum albumin may be decreased in chronic disease and also in nephrotic syndrome. Aminotransferases (ALT) may be raised in cardiac diseases and hepatic diseases.

• Serum Bilirubin • Bilirubin is an endogenous anion derived from hemoglobin degradation from the RBC. At the end of their lifespan, red blood cells are broken down by the reticuloendothelial system, mainly in the spleen. The released haemoglobin is split into globin, which enters the general protein pool, and haem, which is converted to bilirubin after the removal of iron, which is reused. About 80 per cent of bilirubin is derived from haem within the reticuloendothelial system.

• Normal range is 0.2-0.9 mg/dl (2-15μmol/L). • ii. Direct Bilirubin: This is the water-soluble fraction. Conjugated bilirubin (direct)—formed in the liver when sugars are attached (conjugated) to bilirubin. It enters the bile and passes from the liver to the small intestines and is eventually eliminated in the stool. Normal range 0.3mg/dl (5.1 μmol/ L).

• iii. Indirect bilirubin (unconjugated): Bilirubin that is bound to a certain protein (albumin) in the blood is called unconjugated, or indirect, bilirubin. Normal range 0.2 – 0.7 mg/dL. Unconjugated bilirubin is normally all protein bound and is not water soluble and therefore cannot be excreted in the urine. Therefore, it will be metabolized by the liver and excreted from the body with Faeces. • If the plasma bilirubin level exceeds 1mg/dl, the condition is called hyperbilirubinemia. • Levels between 1 & 2 mg/dl are indicative of latent jaundice (hyperbilirubinemia without yellow staining of the tissues). • Jaundice when bilirubin level 2.9 mg/ dl (50 μmol /L). • Types of Jaundice • There are three main types of jaundice: pre-hepatic, hepatocellular, and post-hepatic. • Pre-Hepatic (hemolytic jaundice) • In pre-hepatic jaundice, there is excessive red cell breakdown which overwhelms the liver’s ability to conjugate bilirubin. This causes an unconjugated hyperbilirubinaemia. • Hepatocellular • In hepatocellular (or intrahepatic) jaundice, there is dysfunction of the hepatic cells. • This leads to both unconjugated and conjugated bilirubin in the blood, termed a ‘mixed picture’. • Post-Hepatic (obstructive jaundice) • Post-hepatic jaundice refers to obstruction of biliary drainage. The bilirubin that is not excreted will have been conjugated by the liver, hence the result is a conjugated hyperbilirubinaemia.

• Alanine aminotransferase (ALT) (SGPT): An enzyme normally present in liver and heart cells that is released into the bloodstream when the liver or heart is damaged. The blood ALT levels are elevated with liver damage (for example, from viral hepatitis) or with an insult to the heart (for example, from a heart attack). More liver-specific than AST, ALT is mainly aggregated in the cytosol of the hepatocyte. ALT activity in hepatic cells is approximately 3000 times higher than serum ALT activity. When liver injury occurs, ALT is released from injured liver cells and causes a significant elevation in serum ALT activity. • Normal range (U/L): Male: 13-35 and Female: 10-30.

• High serum levels in acute hepatitis (300-1000U/L) • Moderate elevation in alcoholic hepatitis (100-300U/L) • Minor elevation in cirrhosis, hepatitis C and non-alcoholic steato-hepatitis (NASH) (50-100U/L) • Appears in plasma many days before clinical signs appear. • A normal value does not always indicate absence of liver damage. • Obese but otherwise normal individuals may have elevated ALT levels.

• Aspartate aminotransferase (AST, SCOT) (glutamate oxaloacetate aminotransferase, GOT) is present in high concentrations in cells of cardiac and skeletal muscle, liver, kidney and erythrocytes. Damage to any of these tissues may increase plasma AST levels. (note: So drug use can elevate its level).

• Normal range: 8 – 20 U/L

• A marker of hepatocellular damage • High serum levels (less than 4 times) are observed in: Chronic hepatitis, cirrhosis and liver cancer

• Very high levels of AST (more than 10 times normal) are usually due to acute hepatitis, sometimes due to a viral infection.

• Levels of AST may also be markedly elevated (often over 100 times normal) as a result of exposure to drugs or other substances that are toxic to the liver as well as in conditions that cause decreased blood flow (ischemia) to the liver. (Toxicity is defined as serum AST or ALT concentrations greater than 1000 U/L.)

• With chronic hepatitis, AST levels are usually not as high, often less than 4 times normal, and are more likely to be normal than are ALT levels. • AST may also increase after heart attacks and with muscle injury, usually to a much greater degree than ALT. • The relative plasma activities of ALT and AST may help to indicate the type of cell damage.

• A normal AST:ALT ratio should be <1 (normal ratio ≈ 0.8 this means in normal condition ALT level is > AST). In patients with alcoholic liver disease, the AST:ALT ratio is >1 in 92% of patients, and >2 in 70%. AST:ALT scores >2 are, therefore, strongly suggestive of alcoholic liver disease and scores <1 more suggestive of NAFLD/NASH.

• Non-alcoholic Fatty Liver Disease (NAFLD) , Non-alcoholic Steatohepatitis, • Alkaline phosphatase (ALP): is an enzyme in a person's blood that helps break down proteins. The body uses ALP for a wide range of processes, and it plays a particularly important role in liver function and bone development.

• A non-specific marker of liver disease (viral hepatitis)

• Produced by bone osteoblasts (for bone calcification) • Present on hepatocyte membrane

• Normal range: 40 – 125 U/L

• Modearte elevation observed in: – Infective hepatitis, alcoholic hepatitis and hepatocellular carcinoma • High levels are observed in: Extrahepatic obstruction (obstructive jaundice) and intrahepatic cholestasis. • Very high levels are observed in: Bone diseases.

• γ-glutamyltransferase (GGT): • is an enzyme derived from the endoplasmic reticulum of the cells of the hepatobiliary tract. As this reticulum proliferates, for example in response to the prolonged intake of alcohol and of drugs such as phenobarbital and phenytoin, synthesis of the enzyme is induced and plasma GGT activity increases. Therefore, raised plasma activities do not necessarily indicate hepatocellular damage, but may reflect enzyme induction or cholestasis. • Normal range: 10 – 30U/L • Moderate elevation observed in: Infective hepatitis and prostate cancers • GGT is highly increased in alcoholics despite normal liver function tests or AST:ALT (>2). Highly sensitive to detecting alcohol abuse.

• Albumin

• is a protein made by your liver. Albumin helps keep fluid in your bloodstream so it doesn't leak into other tissues. It is also carries various substances throughout your body, including hormones, vitamins, and enzymes. Low albumin levels can indicate a problem with your liver or kidneys. • The most abundant protein synthesized by the liver • Normal serum levels: 3.5 – 5 g/dL

• Its levels decrease in all chronic liver diseases

• A low albumin can suggest liver disease or kidney disease.

• Low albumin levels can also be seen in inflammation, shock and malnutrition.

• High level happened because of dehydration, severe diarrhea, acute infections, burns, and stress from surgery or a heart attack, or eating high protein diet. • Globulin or Globulins:

• Proteins made in liver. Globulins play an important role in liver function, blood clotting, and fighting infection.

• Normal serum levels: 2.5 – 3.5g/dL

• High serum globulins are observed in chronic hepatitis and cirrhosis:

• Albumin to globulin (A/G) ratio • Normal A/G ratio: 1.2/1 – 1.5/1

• Globulin levels increase in hypoalbuminemia as a compensation. • Prothrombin is a protein produced by your liver. It is one of many factors in your blood that help it to clot appropriately.

• Prothrombin Time (PT)

• Prothrombin is a protein made by the liver. Prothrombin helps blood to clot. The "prothrombin time" (PT) is one way of measuring how long it takes blood to form a clot, and it is measured in seconds (such as 13.2 seconds). • When the PT is high, it takes longer for the blood to clot (17 seconds, for example). This usually happens because the liver is not making the right amount of blood clotting proteins, so the clotting process takes longer. A high PT usually means that there is serious liver damage or cirrhosis.

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