LIVER FUNCTION TESTS

1. LIVER FUNCTION TESTS

2. Liver Functions • General Metabolic Function: • Glucose to Glycogen • Glycogenolysis • Gluconeogensis • Carbon skeletons of fatty acids transported to adipose tissue as very low-density lipoprotein (VLDL) • Fatty acids reaching the liver from fat stores may be metabolized in the tricarboxylic acid cycle, converted to ketones or incorporated into triglycerides

3. Liver Functions • Synthetic functions: • Plasma proteins • Most coagulation factors, Including fibrinogen, factor II (prothrombin), V, VII, IX, X, XI, XII, and XIII • Primary bile acids • Lipoproteins: VLDL, HDL

4. Liver Functions • Excretion and Detoxification: • Cholesterol • Unchanged • Bile acids • Amino Acids • Deamination, amino group and the ammonia produced by intestinal bacterial action converted to urea • Steroid Hormones: Metabolized and inactivated by conjugation with glucuronate and sulphate • Many drugs which are metabolized and inactivated by enzymes of the endoplasmic reticulum system • Toxins: the reticuloendothelial Kupffer cells in the hepatic sinusoids are well placed to extract toxic substances

5. Efficient excretion of the end products of metabolism and of bilirubin depends on: • Normally functioning liver cells • Normal blood flow through the liver • Patent biliary ducts

6. Liver Function Tests • Are groups of Clinical Biochemistry Laboratory Blood Assays Designed to Give Information About The State of a Patient’s Liver • Most Liver Diseases Cause Only Mild Symptoms Initially, But It Is Vital That These Diseases be Detected Early • This Testing Performed on a Patient’s Serum or Plasma Samples Obtained by Phlebotomy • Some of These Tests Are Associated with Functionality, Some With Cellular Integrity and Some With Conditions Linked to The Biliary Tract • Liver function tests are used to aid in diagnosing, differential diagnosis, evaluating severity, monitoring therapy and assessing the prognosis of the liver disease and dysfunction

7. Liver Function Tests • Total bilirubin (TBIL): Bilirubin is a breakdown product of heme. The liver is responsible for clearing the blood of bilirubin (2-14 µmole/L). Total bilirubin might be increased by the following drugs: • Anabolic Steroids • Antibiotics • Antimalarials • Ascorbic Acid • Diabinese • Codeine • Diuretics • Epinephrine • Oral contraceptives • Vitamin A • Direct bilirubin: elevated in bile duct obstruction by gallstones or cancer should be suspected (0-4 µmole/L).

8. Alanine transaminase (ALT): is an enzyme necessary for energy production. It is present in a number of tissues including the liver (hepatocytes), heart and skeletal muscles it rises dramatically in acute liver damage, such as viral hepatitis or paracetamol overdose (5-40 IU/L). Drugs that may increase ALT levels: • Acetaminophen • Ampicilline • Codeine • Dicumarole • Indomethacine • Methotrexate • Oral contraceptives • Tetracyclines • Verapamil • Aspartate transaminase (AST): enzyme involves in energy production. it is raised in acute liver damage, but is also present in red cells, cardiac and skeletal muscle, and is therefore not specific to the liver (10-40 IU/L). • ALT in conjuction with AST helps to distinguish between heart damage and liver tissue damage

9. Alkaline phosphatase (ALP): It maily comes from liver, bone and placenta. In the liver it is in the cells lining the biliary ducts. ALP levels in plasma will rise with large bile duct obstruction, intrahepatic cholestasis or infiltrative diseases of the liver (30-120 IU/L). • Gamma glutamyl transpeptidase (GGT): Although reasonably specific to the liver and a more sensitive marker for cholestatic damage than ALP, it may be elevated with even minor, sub-clinical levels of liver dysfunction. It is raised in alcohol toxicity acute and chronic (2-30 IU/L). Drugs that may cause increased GGT levels: • Alcohol • Phenytoin • Phenobarbital • GGT level is compared with ALP level to distinguish between skeletal disease and liver disease

10. Lactate Dehydrogenase (LDH): is an enzyme found in many body tissues, including liver. Elevated levels of LDH may indicate liver damage • Coagulation Tests (prothrombin time, PT): It is not a sensitive measure of liver function • Albumin (Alb): it is made specifically by the liver, Its levels are decreased in chronic liver diseases such as cirrhosis (3.2-5.4 g/L).

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

12. 5’Nucleotidase (5’NTD): is specific for cholestasis or damage to the intra or extrahepatic biliary system • Serum Glucose • Cholesterol • Serological Tests: to demonstrate antibodies • DNA tests: hepatitis and other viruses • Tests for antimitochondrial antibodies • Test for transthyretin (prealbumin)

13. Protein Electrophoresis • Bile Acids • Alpha-fetoprotein • Carcinoembryonic antigen • Total protein • Fibronogen

14. Serum Protein Electrophoresis: • Abnormal in both necrotic and obstructive liver diseases • In the acute stages of hepatitis, the albumin will be low and the gamma globulin fraction will be elevated. The alpha-1 globulin and alpha-2 globulin fractions will be elevated • In biliary cirrhosis the beta globulin may be elevated owing to an increase in beta lipoprotein • In hepatic cirrhosis the albumin will be greatly decreased

15. Liver function tests performed individually do not give the physician very much information, but used in combination with a careful history, physical examination and imaging studies, they contribute to making an accurate diagnosis of the specific liver disorder • Differentiation of acute and chronic forms of hepatocellular injury is aided by examining the ratio of ALT to AST, called the DeRitis ratio. In acute hepatitis, Reye’s syndrome and infectious mononucleosis the ALT predominates. However, in alcoholic liver disease, chronic hepatitis and cirrhosis, the AST predominates

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

17. ALT values are significantly increased in cases of hepatitis and moderately increased in cirrhosis, liver tumors, obstructive jaundice • AST values are increased in liver damage, hepatitis • ALP values are increased in diseases that impair bile formation (cholestasis) • GGT values are elevated in hepatitis, cirrhosis, liver tumors or metastasis, toxic injury to the liver mainly by alcohol • LDH levels are elevated in viral hepatitis • Bilirubin levels: increased indirect or total bilirubin levels in hemolytic disease and transfusion reaction. Increased direct bilirubin levels can be diagnostic of bile duct obstruction, gallstones, cirrhosis, or hepatitis

18. Glycogen Storage diseasesGSDs

22. Glycogen Storage Disease Type-I • Von Gierke’s disease, is the most common of the glycogen storage disease • It is a genetic disease results from deficiency of the glucose-6-phosphatase • Glucose-6-phosphatase is an enzyme located on the inner membrane of the endoplasmic reticulum • The catalytic unit is associated with a calcium binding protein, and three transporter proteins (T1,T2,T3) that facilitate movement of glucose-6-phosphate, phosphate and glucose respectively, into and out of the enzyme • The ability of the liver to produce free glucose from glycogen and from gluconeogenesis is impaired • Affects Liver, Kidney and Intestine

23. Types of GSD-I and molecular Biology • The most common forms of GSD-I are • GSD-Ia (80%) and GSD-Ib (20%) • GSD-Ia; an autosomal recessive disease results from mutations of G6PC, the gene for glucose-6-phosphatase • GSD-Ib results from mutations of the gene for T1, the G6P transporter. • The metabolic charateristics of both GSD-Ia and -Ib are quite similar • Prenatal diagnosis: fetal liver biopsy, DNA analysis using chorionic villus sampling

24. Metabolic effects of G6P deficiency • Hypoglycemia: fasting • Chronic hypoglycemia produces secondary metabolic adaptations • Low insulin levels • High glucagon levels • High cortisol levels • Lactic acidosis: • Arises from impairment of gluconeogenesis • Accumulation of G6P inhibits conversion of lactate to pyruvate • Uric acid, ketoacids and free fatty acids increase the anion gap • Hypertriglyceridemia: resulting from increased triglyceride production caused by chronically low insulin levels • Hyperuricemia: • Results from a combination of increased generation and decreased excretion of uric acid, which is generated when increased amount of G6P are metabolized via the pentose phosphate pathway • Purine degradation • Diminished urinary excretion , uric acid competes with lactic acid for renal excretion and lactic acid is high

25. Hepatomegaly and Liver problem: due to accumulation of glycogen • Liver enzymes and bilirubin are usually normal • Risk of developing liver tumors • Growth failure: due to • Chronically low insulin levels • Persistent acidosis • Chronic elevation of catabolic hormones • Calories insufficiency • Malabsorption • Kidney effect: • They are enlarged due to accumulation of glycogen • Uric acid nephropathy • Chronic glomerular damage similar to diabetic nephropathy lead to renal failure • Others; mild malabsorption, infection risk, bleeding, developmental delay

26. Glycogen Storage Disease Type-II • Pompe’s Disease, Lysosomal alpha(1-4)-glucosidase deficiency • Inborn lysosomal enzyme defect • Affects Liver, Heart, Muscle • Excessive glycogen concentrations found in abnormal vacoules in the cytosol • Normal blood sugar levels • Massive cardiomegaly • Normal glycogen structure • Early death usually occurs from heart failure

27. Glycogen Storage Disease Type III • Cori’s disease, genetic disorder characterized by a deficiency in glycogen debranching enzymes (amylo-1,6 glucosidase) • Inherited as autosomal recessive • Abnormal glycogen deposits in the liver, muscle and some cases the heart

28. Divided into four classes: • GSD IIIa; muscle and liver involvement • GSD IIIb; liver involvement only • GSD IIIc and GSD IIId; are rare phenotypes • The disease usually presents during infancy with: • Hypoglycemia • Failure to thrive • Hepatomegaly • Hypotonia • Cardiomyopathy • Cirrhosis

29. Glycogen Storage Disease Type IV • Anderson’s disease, is a very rare hereditary metabolic disorder • It is due to the absence of the glycogen branching enzyme (amylo-1,4-1,6 transglucosidase) which is critical in the production of glycogen • Production of a very long un-branched glucose chains (amylopectin), insoluble leads to glycogen precipitation in the liver and the heart • Liver failure

30. Glycogen Storage Disease Type VI • Hers’s disease • Caused by a deficiency in liver glycogen phosphorylase • Presented with; • Hepatomegaly • Growth retardation • Mild hypoglycemia • Hyperlipidemia • Hyperketosis