LIVER FUNCTION TESTSLIVER FUNCTION TESTS

Liver FunctionsLiver Functions

• General Metabolic Function:General Metabolic Function:– Glucose to GlycogenGlucose to Glycogen

– GlycogenolysisGlycogenolysis

– GluconeogensisGluconeogensis

– Carbon skeletons of fatty acids transported to adipose Carbon skeletons of fatty acids transported to adipose tissue as very low-density lipoprotein (VLDL)tissue as very low-density lipoprotein (VLDL)

– Fatty acids reaching the liver from fat stores may be Fatty acids reaching the liver from fat stores may be metabolized in the tricarboxylic acid cycle, converted to metabolized in the tricarboxylic acid cycle, converted to ketones or incorporated into triglycerides ketones or incorporated into triglycerides

Liver FunctionsLiver Functions

• Synthetic functions:Synthetic functions:

– Plasma proteinsPlasma proteins

– Most coagulation factors, Including fibrinogen, factor Most coagulation factors, Including fibrinogen, factor II (prothrombin), V, VII, IX, X, XI, XII, and XIIIII (prothrombin), V, VII, IX, X, XI, XII, and XIII

– Primary bile acidsPrimary bile acids

– Lipoproteins: VLDL, HDL Lipoproteins: VLDL, HDL

Liver FunctionsLiver Functions

• Excretion and Detoxification:Excretion and Detoxification:– CholesterolCholesterol

• UnchangedUnchanged• Bile acidsBile acids

– Amino AcidsAmino Acids• Deamination, amino group and the ammonia produced by Deamination, amino group and the ammonia produced by

intestinal bacterial action converted to ureaintestinal bacterial action converted to urea

– Steroid Hormones: Metabolized and inactivated by Steroid Hormones: Metabolized and inactivated by conjugation with glucuronate and sulphate conjugation with glucuronate and sulphate

– Many drugs which are metabolized and inactivated by Many drugs which are metabolized and inactivated by enzymes of the endoplasmic reticulum systemenzymes of the endoplasmic reticulum system

– Toxins: the reticuloendothelial Kupffer cells in the Toxins: the reticuloendothelial Kupffer cells in the hepatic sinusoids are well placed to extract toxic hepatic sinusoids are well placed to extract toxic substances substances

• Efficient excretion of the end products of metabolism and Efficient excretion of the end products of metabolism and of bilirubin depends on:of bilirubin depends on:

– Normally functioning liver cellsNormally functioning liver cells

– Normal blood flow through the liverNormal blood flow through the liver

– Patent biliary ductsPatent biliary ducts

Liver Function TestsLiver Function Tests

• Are groups of Clinical Biochemistry Laboratory Blood Assays Are groups of Clinical Biochemistry Laboratory Blood Assays Designed to Give Information About The State of a Patient’s Designed to Give Information About The State of a Patient’s LiverLiver

• Most Liver Diseases Cause Only Mild Symptoms Initially, But It Most Liver Diseases Cause Only Mild Symptoms Initially, But It Is Vital That These Diseases be Detected EarlyIs Vital That These Diseases be Detected Early

• This Testing Performed on a Patient’s Serum or Plasma This Testing Performed on a Patient’s Serum or Plasma Samples Obtained by PhlebotomySamples Obtained by Phlebotomy

• Some of These Tests Are Associated with Functionality, Some Some of These Tests Are Associated with Functionality, Some With Cellular Integrity and Some With Conditions Linked to With Cellular Integrity and Some With Conditions Linked to The Biliary TractThe Biliary Tract

• Liver function tests are used to aid in diagnosing, differential Liver function tests are used to aid in diagnosing, differential diagnosis, evaluating severity, monitoring therapy and assessing diagnosis, evaluating severity, monitoring therapy and assessing the prognosis of the liver disease and dysfunctionthe prognosis of the liver disease and dysfunction

Liver Function TestsLiver Function Tests

– Total bilirubin (TBIL): Bilirubin is a breakdown product of heme. The Total bilirubin (TBIL): Bilirubin is a breakdown product of heme. The liver is responsible for clearing the blood of bilirubin (2-14 liver is responsible for clearing the blood of bilirubin (2-14 µmole/L). Total µmole/L). Total bilirubin might be increased by the following drugs:bilirubin might be increased by the following drugs:

• Anabolic SteroidsAnabolic Steroids• AntibioticsAntibiotics• AntimalarialsAntimalarials• Ascorbic AcidAscorbic Acid• DiabineseDiabinese• CodeineCodeine• DiureticsDiuretics• EpinephrineEpinephrine• Oral contraceptivesOral contraceptives• Vitamin AVitamin A

– Direct bilirubin: elevated in bile duct obstruction by gallstones or cancer Direct bilirubin: elevated in bile duct obstruction by gallstones or cancer should be suspected (0-4 should be suspected (0-4 µmole/L).µmole/L).

– Alanine transaminase (ALT): is an enzyme necessary for energy Alanine transaminase (ALT): is an enzyme necessary for energy production. It is present in a number of tissues including the liver production. It is present in a number of tissues including the liver (hepatocytes), heart and skeletal muscles it (hepatocytes), heart and skeletal muscles it rises dramatically in rises dramatically in acute liver damage, such as viral hepatitis or paracetamol overdoseacute liver damage, such as viral hepatitis or paracetamol overdose (5-40 IU/L). Drugs that may increase ALT levels:(5-40 IU/L). Drugs that may increase ALT levels:

• AcetaminophenAcetaminophen• AmpicillineAmpicilline• CodeineCodeine• DicumaroleDicumarole• IndomethacineIndomethacine• MethotrexateMethotrexate• Oral contraceptivesOral contraceptives• TetracyclinesTetracyclines• VerapamilVerapamil

– Aspartate transaminase (AST): Aspartate transaminase (AST): enzyme involves in energy enzyme involves in energy production.production. it is raised in acute liver damage, but is also present in it is raised in acute liver damage, but is also present in red cells, cardiac and skeletal muscle, and is therefore not specific red cells, cardiac and skeletal muscle, and is therefore not specific to the liver (10-40 IU/L).to the liver (10-40 IU/L).

• ALT in conjuction with AST helps to distinguish between heart ALT in conjuction with AST helps to distinguish between heart damage and liver tissue damagedamage and liver tissue damage

– Alkaline phosphatase (ALP): It maily comes from liver, Alkaline phosphatase (ALP): It maily comes from liver, bone and placenta. In the liver it is in the cells lining the bone and placenta. In the liver it is in the cells lining the biliary ducts. ALP levels in plasma will rise with large biliary ducts. ALP levels in plasma will rise with large bile duct obstruction, intrahepatic cholestasis or bile duct obstruction, intrahepatic cholestasis or infiltrative diseases of the liver (30-120 IU/L).infiltrative diseases of the liver (30-120 IU/L).

– Gamma glutamyl transpeptidase (GGT): Although Gamma glutamyl transpeptidase (GGT): Although reasonably specific to the liver and a more sensitive reasonably specific to the liver and a more sensitive marker for cholestatic damage than ALP, it may be marker for cholestatic damage than ALP, it may be elevated with even minor, sub-clinical levels of liver elevated with even minor, sub-clinical levels of liver dysfunction. It is raised in alcohol toxicity acute and dysfunction. It is raised in alcohol toxicity acute and chronic (2-30 IU/L). Drugs that may cause increased chronic (2-30 IU/L). Drugs that may cause increased GGT levels:GGT levels:

• AlcoholAlcohol• PhenytoinPhenytoin• PhenobarbitalPhenobarbital

– GGT level is compared with ALP level to distinguish between GGT level is compared with ALP level to distinguish between skeletal disease and liver diseaseskeletal disease and liver disease

• Lactate Dehydrogenase (LDH): is an Lactate Dehydrogenase (LDH): is an enzyme found in many body tissues, enzyme found in many body tissues, including liver. Elevated levels of LDH may including liver. Elevated levels of LDH may indicate liver damageindicate liver damage

• Coagulation Tests (prothrombin time, PT): Coagulation Tests (prothrombin time, PT): It is not a sensitive measure of liver functionIt is not a sensitive measure of liver function

• Albumin (Alb): it is made specifically by the Albumin (Alb): it is made specifically by the liver, Its levels are decreased in chronic liver, Its levels are decreased in chronic liver diseases such as cirrhosis (3.2-5.4 g/L).liver diseases such as cirrhosis (3.2-5.4 g/L).

– Ammonia: a breakdown product of protein that Ammonia: a breakdown product of protein that is normally converted into urea by the liver. is normally converted into urea by the liver. Analysis of blood ammonia aids in the diagnosis Analysis of blood ammonia aids in the diagnosis of sever liver diseases and helps to monitor the of sever liver diseases and helps to monitor the course of these diseases. Increasing ammonia course of these diseases. Increasing ammonia signals end-stage liver disease and a high risk of signals end-stage liver disease and a high risk of hepatic coma (10-70 µg/dl). Drugs that may hepatic coma (10-70 µg/dl). Drugs that may cause increased levels of ammonia are:cause increased levels of ammonia are:• AlcoholAlcohol• BarbituratesBarbiturates• NarcoticsNarcotics• DiureticsDiuretics

• 5’Nucleotidase (5’NTD): is specific for cholestasis or 5’Nucleotidase (5’NTD): is specific for cholestasis or damage to the intra or extrahepatic biliary systemdamage to the intra or extrahepatic biliary system

• Serum GlucoseSerum Glucose

• CholesterolCholesterol

• Serological Tests: to demonstrate antibodiesSerological Tests: to demonstrate antibodies

• DNA tests: hepatitis and other virusesDNA tests: hepatitis and other viruses

• Tests for antimitochondrial antibodiesTests for antimitochondrial antibodies

• Test for transthyretin (prealbumin)Test for transthyretin (prealbumin)

• Protein ElectrophoresisProtein Electrophoresis

• Bile AcidsBile Acids

• Alpha-fetoproteinAlpha-fetoprotein

• Carcinoembryonic antigenCarcinoembryonic antigen

• Total proteinTotal protein

• FibronogenFibronogen

• Serum Protein Electrophoresis:Serum Protein Electrophoresis:– Abnormal in both necrotic and obstructive liver Abnormal in both necrotic and obstructive liver

diseasesdiseases

– In the acute stages of hepatitis, the albumin will be low In the acute stages of hepatitis, the albumin will be low and the gamma globulin fraction will be elevated. The and the gamma globulin fraction will be elevated. The alpha-1 globulin and alpha-2 globulin fractions will be alpha-1 globulin and alpha-2 globulin fractions will be elevatedelevated

– In biliary cirrhosis the beta globulin may be elevated In biliary cirrhosis the beta globulin may be elevated owing to an increase in beta lipoproteinowing to an increase in beta lipoprotein

– In hepatic cirrhosis the albumin will be greatly In hepatic cirrhosis the albumin will be greatly decreaseddecreased

• Liver function tests performed individually do not give the Liver function tests performed individually do not give the physician very much information, but used in combination physician very much information, but used in combination with a careful history, physical examination and imaging with a careful history, physical examination and imaging studies, they contribute to making an accurate diagnosis of studies, they contribute to making an accurate diagnosis of the specific liver disorderthe specific liver disorder

• Differentiation of acute and chronic forms of Differentiation of acute and chronic forms of hepatocellular injury is aided by examining the ratio of hepatocellular injury is aided by examining the ratio of ALT to AST, called the DeRitis ratio. In acute hepatitis, ALT to AST, called the DeRitis ratio. In acute hepatitis, Reye’s syndrome and infectious mononucleosis the ALT Reye’s syndrome and infectious mononucleosis the ALT predominates. However, in alcoholic liver disease, chronic predominates. However, in alcoholic liver disease, chronic hepatitis and cirrhosis, the AST predominates hepatitis and cirrhosis, the AST predominates

• The most prevalent liver disease is viral hepatitis. Tests for The most prevalent liver disease is viral hepatitis. Tests for this condition include a variety of antigen and antibody this condition include a variety of antigen and antibody markers and nucleic acid tests.markers and nucleic acid tests.

• Acute viral hepatitis is associated initially with 20 to 100 Acute viral hepatitis is associated initially with 20 to 100 fold increases in transaminases and is followed shortly by fold increases in transaminases and is followed shortly by bilirubin elevation. Such patients should be tested for bilirubin elevation. Such patients should be tested for hepatitis B surface antigen (HbsAg) and IgM antibodies to hepatitis B surface antigen (HbsAg) and IgM antibodies to hepatitis B core antigen (anti-HBc IgM) and anti-hepatitis hepatitis B core antigen (anti-HBc IgM) and anti-hepatitis C virus (anti-HVC) to identify these causes. In addition to C virus (anti-HVC) to identify these causes. In addition to hepatitis A-E, viral hepatitis may be caused by Epstein-hepatitis A-E, viral hepatitis may be caused by Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections Barr virus (EBV) and cytomegalovirus (CMV) infections of the liver. Tests for these viruses such as the infectious of the liver. Tests for these viruses such as the infectious mononucleosis antibody test, anti-viral capsid antigen test mononucleosis antibody test, anti-viral capsid antigen test (anti-VCA), and anti-CMV tests are useful in diagnosing (anti-VCA), and anti-CMV tests are useful in diagnosing these infection these infection

• ALT values are significantly increased in cases of hepatitis and ALT values are significantly increased in cases of hepatitis and moderately increased in cirrhosis, liver tumors, obstructive moderately increased in cirrhosis, liver tumors, obstructive jaundicejaundice

• AST values are increased in liver damage, hepatitisAST values are increased in liver damage, hepatitis

• ALP values are increased in diseases that impair bile formation ALP values are increased in diseases that impair bile formation (cholestasis)(cholestasis)

• GGT values are elevated in hepatitis, cirrhosis, liver tumors or GGT values are elevated in hepatitis, cirrhosis, liver tumors or metastasis, toxic injury to the liver mainly by alcoholmetastasis, toxic injury to the liver mainly by alcohol

• LDH levels are elevated in viral hepatitisLDH levels are elevated in viral hepatitis

• Bilirubin levels: increased indirect or total bilirubin levels in Bilirubin levels: increased indirect or total bilirubin levels in hemolytic disease and transfusion reaction. Increased direct hemolytic disease and transfusion reaction. Increased direct bilirubin levels can be diagnostic of bile duct obstruction, bilirubin levels can be diagnostic of bile duct obstruction, gallstones, cirrhosis, or hepatitis gallstones, cirrhosis, or hepatitis

Glycogen Storage diseasesGlycogen Storage diseasesGSDsGSDs

Glycogen Storage Disease Type-IGlycogen Storage Disease Type-I

• Von Gierke’s disease, is the most common of the glycogen Von Gierke’s disease, is the most common of the glycogen storage diseasestorage disease

• It is a genetic disease results from deficiency of the glucose-It is a genetic disease results from deficiency of the glucose-6-phosphatase6-phosphatase

• Glucose-6-phosphatase is an enzyme located on the inner Glucose-6-phosphatase is an enzyme located on the inner membrane of the endoplasmic reticulummembrane of the endoplasmic reticulum

• The catalytic unit is associated with a calcium binding The catalytic unit is associated with a calcium binding protein, and three transporter proteins (T1,T2,T3) that protein, and three transporter proteins (T1,T2,T3) that facilitate movement of glucose-6-phosphate, phosphate and facilitate movement of glucose-6-phosphate, phosphate and glucose respectively, into and out of the enzymeglucose respectively, into and out of the enzyme

• The ability of the liver to produce free glucose from The ability of the liver to produce free glucose from glycogen and from gluconeogenesis is impairedglycogen and from gluconeogenesis is impaired

• Affects Liver, Kidney and IntestineAffects Liver, Kidney and Intestine

Types of GSD-I and molecular BiologyTypes of GSD-I and molecular Biology

• The most common forms of GSD-I areThe most common forms of GSD-I are

– GSD-Ia (80%) and GSD-Ib (20%)GSD-Ia (80%) and GSD-Ib (20%)

– GSD-Ia; an autosomal recessive disease results from GSD-Ia; an autosomal recessive disease results from mutations of mutations of G6PC,G6PC, the gene for glucose-6-phosphatase the gene for glucose-6-phosphatase

– GSD-Ib results from mutations of the gene for T1, the GSD-Ib results from mutations of the gene for T1, the G6P transporter.G6P transporter.

– The metabolic charateristics of both GSD-Ia and -Ib are The metabolic charateristics of both GSD-Ia and -Ib are quite similar quite similar

– Prenatal diagnosis: fetal liver biopsy, DNA analysis Prenatal diagnosis: fetal liver biopsy, DNA analysis using chorionic villus samplingusing chorionic villus sampling

Metabolic effects of G6P deficiency Metabolic effects of G6P deficiency

• Hypoglycemia: fastingHypoglycemia: fasting– Chronic hypoglycemia produces secondary metabolic adaptationsChronic hypoglycemia produces secondary metabolic adaptations

• Low insulin levelsLow insulin levels• High glucagon levelsHigh glucagon levels• High cortisol levelsHigh cortisol levels

• Lactic acidosis: Lactic acidosis: – Arises from impairment of gluconeogenesisArises from impairment of gluconeogenesis– Accumulation of G6P inhibits conversion of lactate to pyruvateAccumulation of G6P inhibits conversion of lactate to pyruvate– Uric acid, ketoacids and free fatty acids increase the anion gapUric acid, ketoacids and free fatty acids increase the anion gap

• Hypertriglyceridemia: resulting from increased triglyceride production Hypertriglyceridemia: resulting from increased triglyceride production caused by chronically low insulin levelscaused by chronically low insulin levels

• Hyperuricemia: Hyperuricemia: – Results from a combination of increased generation and decreased Results from a combination of increased generation and decreased

excretion of uric acid, which is generated when increased amount of G6P excretion of uric acid, which is generated when increased amount of G6P are metabolized via the pentose phosphate pathwayare metabolized via the pentose phosphate pathway

– Purine degradationPurine degradation– Diminished urinary excretion , uric acid competes with lactic acid for Diminished urinary excretion , uric acid competes with lactic acid for

renal excretion and lactic acid is high renal excretion and lactic acid is high

• Hepatomegaly and Liver problem: due to accumulation of glycogenHepatomegaly and Liver problem: due to accumulation of glycogen– Liver enzymes and bilirubin are usually normalLiver enzymes and bilirubin are usually normal

– Risk of developing liver tumors Risk of developing liver tumors

• Growth failure: due toGrowth failure: due to– Chronically low insulin levelsChronically low insulin levels

– Persistent acidosisPersistent acidosis

– Chronic elevation of catabolic hormonesChronic elevation of catabolic hormones

– Calories insufficiencyCalories insufficiency

– MalabsorptionMalabsorption

• Kidney effect:Kidney effect:– They are enlarged due to accumulation of glycogenThey are enlarged due to accumulation of glycogen

– Uric acid nephropathyUric acid nephropathy

– Chronic glomerular damage similar to diabetic nephropathy lead to renal Chronic glomerular damage similar to diabetic nephropathy lead to renal failurefailure

• Others; mild malabsorption, infection risk, bleeding, developmental Others; mild malabsorption, infection risk, bleeding, developmental delaydelay

Glycogen Storage Disease Type-IIGlycogen Storage Disease Type-II

• Pompe’s Disease, Lysosomal alpha(1-4)-glucosidase deficiencyPompe’s Disease, Lysosomal alpha(1-4)-glucosidase deficiency

• Inborn lysosomal enzyme defectInborn lysosomal enzyme defect

• Affects Liver, Heart, MuscleAffects Liver, Heart, Muscle

• Excessive glycogen concentrations found in abnormal vacoules in the Excessive glycogen concentrations found in abnormal vacoules in the cytosolcytosol

• Normal blood sugar levelsNormal blood sugar levels

• Massive cardiomegalyMassive cardiomegaly

• Normal glycogen structureNormal glycogen structure

• Early death usually occurs from heart failureEarly death usually occurs from heart failure

Glycogen Storage Disease Type IIIGlycogen Storage Disease Type III

• Cori’s disease, genetic disorder characterized by a Cori’s disease, genetic disorder characterized by a deficiency in glycogen debranching enzymes (amylo-1,6 deficiency in glycogen debranching enzymes (amylo-1,6 glucosidase)glucosidase)

• Inherited as autosomal recessiveInherited as autosomal recessive

• Abnormal glycogen deposits in the liver, muscle and some Abnormal glycogen deposits in the liver, muscle and some cases the heartcases the heart

• Divided into four classes:Divided into four classes:

– GSD IIIa; muscle and liver involvementGSD IIIa; muscle and liver involvement

– GSD IIIb; liver involvement onlyGSD IIIb; liver involvement only

– GSD IIIc and GSD IIId; are rare phenotypes GSD IIIc and GSD IIId; are rare phenotypes

• The disease usually presents during infancy with:The disease usually presents during infancy with:– HypoglycemiaHypoglycemia

– Failure to thriveFailure to thrive

– HepatomegalyHepatomegaly

– HypotoniaHypotonia

– CardiomyopathyCardiomyopathy

– CirrhosisCirrhosis

Glycogen Storage Disease Type IVGlycogen Storage Disease Type IV

• Anderson’s disease, is a very rare hereditary metabolic Anderson’s disease, is a very rare hereditary metabolic disorderdisorder

• It is due to the absence of the glycogen branching enzyme It is due to the absence of the glycogen branching enzyme (amylo-1,4-1,6 transglucosidase) which is critical in the (amylo-1,4-1,6 transglucosidase) which is critical in the production of glycogenproduction of glycogen

• Production of a very long un-branched glucose chains Production of a very long un-branched glucose chains (amylopectin), insoluble leads to glycogen precipitation in (amylopectin), insoluble leads to glycogen precipitation in the liver and the heartthe liver and the heart

• Liver failure Liver failure

Glycogen Storage Disease Type VIGlycogen Storage Disease Type VI

• Hers’s diseaseHers’s disease

• Caused by a deficiency in liver glycogen phosphorylaseCaused by a deficiency in liver glycogen phosphorylase

• Presented with;Presented with;

– HepatomegalyHepatomegaly

– Growth retardationGrowth retardation

– Mild hypoglycemiaMild hypoglycemia

– HyperlipidemiaHyperlipidemia

– Hyperketosis Hyperketosis