Interpretation of liver function Tests (lfts)

Liver Function Tests

Liver function tests can be used to:

· Screen for liver infections, such as hepatitis

· Monitor the progression of a disease, such as viral or alcoholic hepatitis, and determine how well a treatment is working

· Measure the severity of a disease, particularly scarring of the liver (cirrhosis)

· Monitor possible side effects of medications

Tests Based on Detoxification and Excretory Functions

Serum Bilirubin Breakdown product of the porphyrin ring of heme-containing proteins.Total bilirubin found in the blood in two fractions: conjugated and unconjugated

Raised conjugated bilirubin is seen in obstruction of the hepatobiliary system or in parenchymal liver disease, such as hepatitis from any cause or advanced cirrhosis.

Unconjugated Bilirubin – Insoluble in water – Bound to albumin in blood – Elevation is rarely due to liver disease – Elevation- prompt a work up for hemolysis. The most likely cause of an isolated raised unconjugated bilirubin, once haemolysis has been excluded, is Gilbert’s syndrome - an inherited metabolic disorder characterised by impaired conjugation.

Conjugated Bilirubin – Water soluble – Almost always implies liver or biliary tract disease (cholestasis!). – Rate limiting step in bilirubin metabolism is the transport of conjugated bilirubin into bile canaliculi – Elevation maybe seen in any type of liver disease.

Blood Ammonia produced during normal protein metabolism and by intestinal bacteria. Liver plays a role in the detoxification of ammonia by converting it to urea, which is excreted in the kidneys. Blood ammonia is used for detecting encephalopathy or for monitoring hepatic enzyme functions. Elevated arterial ammonia levels correlates with outcome in hepatic failure.

Enzymes that Reflect Hepatocyte Damage / Cytolysis

Aminotransferases

1. Aspartate transaminase (AST). An increase in AST levels may indicate liver damage or disease or muscle damage.Found primarily in the liver, cardiac muscle, skeletal muscle, kidneys, brain, pancreas, leukocytes, and erythrocytes.

2. Alanine transaminase (ALT) is an enzyme that helps metabolize alanine, an amino acid; found primarily in the liver.

Liver cell membrane damage -> increased permability-> enzymes are released into the blood in great amounts. Striking elevations during viral hepatitis, ischemic liver injury (prolonged hypotension or acute failure), and toxin/drug induced liver injury

Acute hepatocellular disorders: ALT higher or equal of AST

AST:ALT ration >3:1 highly suggestive of alcoholic liver disease

Enzymes that reflect Cholestasis

1) Alkaline Phosphatase (ALP), 2) 5’-nucleotidase, 3) Y- glutamyl transpeptidase ( GGT).

Alkaline Phosphatase and 5’-nucleotidase found in or near the bile canalicular membrane of hepatocytes, GGT located in ER and in bile duct epithelial cells, more diffuse localization, therefore elevation reflects a less specificity for cholestasis.

Serum Alkaline Phosphatase is an enzyme in the liver, bile ducts and bone. Higher-than-normal levels of ALP may indicate liver damage or disease, such as a blocked bile duct (cholestatic disorders), or certain bone diseases.

Gamma-glutamyltransferase. Abundant in the liver and also present in the intestines, kidneys, pancreas, and prostate, but not in bone, GGT can be useful in determining whether elevated ALP is of bone or liver origin. Levels of GGT may be elevated by not liver-relatedfactors, including obesity, excess alcohol consumption, and certain drugs. In spite of this low specificity, GGT is one of the best predictors of mortality in liver disease.

 

Tests that measure biosynthesic function of the liver

Serum Albumin synthesized exclusively by hepatocytes, levels <3g/dL suggest a chronic liver disease. Not a good indicator of acute liver disease due to slow turnover. Hypoalbuminemia is not specific for liver disease, it may occur in protein malnutrition, protein losing enteropathies, sepsis, systemic inflammatory disorders, nephrotic syndrome, and some chronic infections.

 

Serum Globulin. Group of proteins made up of gamma globulins (Ig) produced by B lymphocytes and alpha and beta globulins produced in the hepatocytes. Gamma globulins are increased in chronic liver disease, such as chronic hepatitis and cirrhosis.

- Polyclonal increases of IgG are common in autoimmune hepatitis.

- Increase IgM levels are common in primary biliary cirrhosisdue to increased synthesis of antibodies.

- Increase IgA levels occur in alcoholic liver disease.

Coagulation Factors except F8, are made exclusively in the hepatocytes. Measurement is single best acute measure of hepatic function. When there is significant parenchymal liver damage (usually >70% loss of synthetic function), clotting factors production is reduced, which may be demonstrated by prolonged 1) PT or 2)international normalized ratio (INR).

Prothrombin time (PT) is the time it takes your blood to clot. Increased PT may indicate liver damage but can also be elevated if you're taking certain blood-thinning drugs, such as warfarin.

Marked PT elevation > poor prognostic sign in hepatitis, cirrhosis and other liver diseases.

!The accuracy of the PT is known to be very system-dependent.

The international normalized ratio (INR) is calculated from a PT result and is used to monitor how well anticoagulant warfarin is working to prevent thrombosis. The INR is the ratio of a patient's prothrombin time to a normal (control) sample and was devised to standardize the results.

Prolonged PT or INR can, therefore, indicate acute or chronic liver dysfunction, but can also be caused by vitamin K deficiency in fat malabsorption and chronic cholestasis.

Step 1 – Assess ALT and ALP

Is ALT and/or ALP raised?

If the ALT is raised, decide if this is a more than a 10-fold rise (↑↑) or a less than a 10-fold rise (↑)

If the ALP is raised, decide if this is a more than a 3-fold rise (↑↑) or a less than a 3-fold rise (↑)

 

Step 6- What to do next

Once the pattern of LFT derangement has been established, it is crucial to determine the cause.

Common causes of acute hepatocellular injury include:

- Poisoning (paracetamol overdose)

- Infection (Hepatitis A and B)

- Liver ischaemia

 

Common causes of chronic hepatocellular injury include:

- Alcoholic fatty liver disease

- Non-alcoholic fatty liver disease

- Chronic infection (Hepatitis B or C)

- Primary biliary cirrhosis

- Less common causes of chronic hepatocellular injury include:

- alpha-1 antitrypsin deficiency

- Wilson’s disease

- Haemochromatosis

Liver Function Tests

Liver function tests can be used to:

· Screen for liver infections, such as hepatitis

· Monitor the progression of a disease, such as viral or alcoholic hepatitis, and determine how well a treatment is working

· Measure the severity of a disease, particularly scarring of the liver (cirrhosis)

· Monitor possible side effects of medications

Tests Based on Detoxification and Excretory Functions

Serum Bilirubin Breakdown product of the porphyrin ring of heme-containing proteins.Total bilirubin found in the blood in two fractions: conjugated and unconjugated

Raised conjugated bilirubin is seen in obstruction of the hepatobiliary system or in parenchymal liver disease, such as hepatitis from any cause or advanced cirrhosis.

Unconjugated Bilirubin – Insoluble in water – Bound to albumin in blood – Elevation is rarely due to liver disease – Elevation- prompt a work up for hemolysis. The most likely cause of an isolated raised unconjugated bilirubin, once haemolysis has been excluded, is Gilbert’s syndrome - an inherited metabolic disorder characterised by impaired conjugation.

Conjugated Bilirubin – Water soluble – Almost always implies liver or biliary tract disease (cholestasis!). – Rate limiting step in bilirubin metabolism is the transport of conjugated bilirubin into bile canaliculi – Elevation maybe seen in any type of liver disease.

Blood Ammonia produced during normal protein metabolism and by intestinal bacteria. Liver plays a role in the detoxification of ammonia by converting it to urea, which is excreted in the kidneys. Blood ammonia is used for detecting encephalopathy or for monitoring hepatic enzyme functions. Elevated arterial ammonia levels correlates with outcome in hepatic failure.

Enzymes that Reflect Hepatocyte Damage / Cytolysis

Aminotransferases

1. Aspartate transaminase (AST). An increase in AST levels may indicate liver damage or disease or muscle damage.Found primarily in the liver, cardiac muscle, skeletal muscle, kidneys, brain, pancreas, leukocytes, and erythrocytes.

2. Alanine transaminase (ALT) is an enzyme that helps metabolize alanine, an amino acid; found primarily in the liver.

Liver cell membrane damage -> increased permability-> enzymes are released into the blood in great amounts. Striking elevations during viral hepatitis, ischemic liver injury (prolonged hypotension or acute failure), and toxin/drug induced liver injury

Acute hepatocellular disorders: ALT higher or equal of AST

AST:ALT ration >3:1 highly suggestive of alcoholic liver disease

Enzymes that reflect Cholestasis

1) Alkaline Phosphatase (ALP), 2) 5’-nucleotidase, 3) Y- glutamyl transpeptidase ( GGT).

Alkaline Phosphatase and 5’-nucleotidase found in or near the bile canalicular membrane of hepatocytes, GGT located in ER and in bile duct epithelial cells, more diffuse localization, therefore elevation reflects a less specificity for cholestasis.

Serum Alkaline Phosphatase is an enzyme in the liver, bile ducts and bone. Higher-than-normal levels of ALP may indicate liver damage or disease, such as a blocked bile duct (cholestatic disorders), or certain bone diseases.

Gamma-glutamyltransferase. Abundant in the liver and also present in the intestines, kidneys, pancreas, and prostate, but not in bone, GGT can be useful in determining whether elevated ALP is of bone or liver origin. Levels of GGT may be elevated by not liver-relatedfactors, including obesity, excess alcohol consumption, and certain drugs. In spite of this low specificity, GGT is one of the best predictors of mortality in liver disease.

 

Tests that measure biosynthesic function of the liver

Serum Albumin synthesized exclusively by hepatocytes, levels <3g/dL suggest a chronic liver disease. Not a good indicator of acute liver disease due to slow turnover. Hypoalbuminemia is not specific for liver disease, it may occur in protein malnutrition, protein losing enteropathies, sepsis, systemic inflammatory disorders, nephrotic syndrome, and some chronic infections.

 

Serum Globulin. Group of proteins made up of gamma globulins (Ig) produced by B lymphocytes and alpha and beta globulins produced in the hepatocytes. Gamma globulins are increased in chronic liver disease, such as chronic hepatitis and cirrhosis.

- Polyclonal increases of IgG are common in autoimmune hepatitis.

- Increase IgM levels are common in primary biliary cirrhosisdue to increased synthesis of antibodies.

- Increase IgA levels occur in alcoholic liver disease.

Coagulation Factors except F8, are made exclusively in the hepatocytes. Measurement is single best acute measure of hepatic function. When there is significant parenchymal liver damage (usually >70% loss of synthetic function), clotting factors production is reduced, which may be demonstrated by prolonged 1) PT or 2)international normalized ratio (INR).

Prothrombin time (PT) is the time it takes your blood to clot. Increased PT may indicate liver damage but can also be elevated if you're taking certain blood-thinning drugs, such as warfarin.

Marked PT elevation > poor prognostic sign in hepatitis, cirrhosis and other liver diseases.

!The accuracy of the PT is known to be very system-dependent.

The international normalized ratio (INR) is calculated from a PT result and is used to monitor how well anticoagulant warfarin is working to prevent thrombosis. The INR is the ratio of a patient's prothrombin time to a normal (control) sample and was devised to standardize the results.

Prolonged PT or INR can, therefore, indicate acute or chronic liver dysfunction, but can also be caused by vitamin K deficiency in fat malabsorption and chronic cholestasis.

INTERPRETATION OF LIVER FUNCTION TESTS (LFTS)

LFTs are ordered for two primary reasons:

- To confirm clinical suspicion of potential liver injury or disease

- To distinguish between hepatocellular injury (hepatic jaundice) & cholestasis (post-hepatic or obstructive jaundice)

A. ALT (Alanine transaminase = 3-40 iu/l), AST (Aspartate aminotransferase = 3-30 iu/l), ALP (Alkaline phosphatase= 30-100 umol/l) and GGT (Gamma-Glutamyltransferase = 8-60 u/l) are used to distinguish between hepatocellular damage and cholestasis.

B. Bilirubin (reference ranges = 8-20,5umol/l), albumin (35-50 g/l) and PT (protrombine time = 10-14 s/1) are used to assess the liver’s synthetic function.

Step 1 – Assess ALT and ALP

Is ALT and/or ALP raised?

If the ALT is raised, decide if this is a more than a 10-fold rise (↑↑) or a less than a 10-fold rise (↑)

If the ALP is raised, decide if this is a more than a 3-fold rise (↑↑) or a less than a 3-fold rise (↑)