LIVER-FUNCTION.pdf

CLINICAL CHEMISTRY 2 LECTURE/ LIVER FUNCTION Located under diaphragm Hepatic duct connects liver to gall bladder ANATOMY OF LIVER 1.2 to 1.5 kg in healthy individual Chief...

CLINICAL CHEMISTRY 2 LECTURE/ LIVER FUNCTION Located under diaphragm Hepatic duct connects liver to gall bladder ANATOMY OF LIVER 1.2 to 1.5 kg in healthy individual Chief metabolic organ in the body Divided into 2 lobes by falciform ligament (right lobe 6 times larger than left) Blood (1500mL/min) Portal vein Nutrient rich blood Bringing absorbed material from the GIT 75% total blood supply BLOOD SUPPLY TO GI tract liver (nutrient rich) THE LIVER Hepatic artery Providing oxygen rich blood need for metabolic processes 25% total blood supply to the liver heart liver (oxygen-rich) MICROSCOPIC ANATOMY OF LIVER Microscopic unit, functional unit of liver LOBULES Responsible for all metabolic and excretory functions TWO MAJOR CELL TYPES KUPFFER Macrophage CELLS Active phagocytes capable of engulfing bacteria HEPATOCYTES 80% of the organ Radiate outward from the central vein Responsible for regenerative of the liver. BIOCHEMICAL FUNCTION OF LIVER Synthesis of protein-enzymes (capability to create starch or CHO), clotting factors (hemostasis), lipoproteins Metabolism of cholesterol into bile acids. Normal liver produces 12 grams of albumin daily. TPAG- most important liver function test. (Total Protein Albumin Globulin) Glycogen SYNTHETIC - storage form of CHO is synthesized by liver. FUNCTION - stimulated by glucagon and series of enzyme reactions - available if the body needed a quick accessible source of biochemical energy Plasma proteins – Major synthetic function – Albumin – most dominant Thyroid hormones and Steroid hormone - Requires transport proteins which are made by liver. - ALBUMIN- THE MOST ABUNDANT PROTEIN SAPLAD, JOHNA MAY C. 1  CLINICAL CHEMISTRY 2 LECTURE/ LIVER FUNCTION Biochemical Function Description Key Highlights The liver processes and excretes endogenous (e.g., - Major role in processing heme waste Excretion/Secretion bilirubin) and exogenous substances into bile or (bilirubin). urine. Bile, composed of bile acids, pigments, - Produces ~3 L of bile daily. cholesterol, and other substances, is produced at - Bilirubin gives stool its brown color. approximately 3 L/day, with 1 L excreted. Bilirubin is the principal pigment. The liver metabolizes carbohydrates, lipids, and - Maintains stable glucose levels. proteins. It regulates blood glucose levels through - Major site for lipid metabolism (70% of Metabolism glycogenesis (storage) and glycogenolysis cholesterol produced here). (breakdown). Lipid metabolism involves the - Synthesizes most proteins except synthesis of triglycerides and cholesterol, primarily immunoglobulins. produced by the liver. ▪ The body has two mechanisms for - Acts as a gatekeeper for substances detoxification of foreign materials (drugs absorbed in the GI tract. Detoxification and and poisons) and metabolic products - Prevents harmful substances from entering Drug Metabolism (bilirubin and ammonia). systemic circulation. ▪ Reversible binding to inactivate compounds or - Essential for drug detoxification. chemical modification for excretion - Involves complex enzymatic processes ▪ The most important mechanism is the (CYP450). drug-metabolizing system of the liver. - Modifies drugs for easier elimination from ▪ This system is responsible for the the body. detoxification of many drugs through oxidation, reduction, hydrolysis, hydroxylation, carboxylation, and demethylation. ▪ Many of these take place in the liver microsomes via the cytochrome P-450 isoenzymes BILE Made up of bile acids or salts, bile pigment, cholesterol and other substances extracted from blood 3L per day 1L excretes STORAGE ALL fat and water-soluble vitamins Glycogen TESTS MEASURING THE HEPATIC SYNTHETIC FUNCTION WHAT DOES LIVER DETOXIFY? Useful for quantitating the severity of hepatic function FOREIGN MATERIALS Provides useful indices for assessing severity of liver disease - DRUGS Serum Albumin - POISONS Vitamin K (II, VII, IX, X) – 1972 METABOLIC PRODUCTS TPAG = (TOTAL PROTEIN, ALBUMIN, GLOBULIN) - BILIRUBIN - AMMONIA SAPLAD, JOHNA MAY C. 2 CLINICAL CHEMISTRY 2 LECTURE/ LIVER FUNCTION MEASURING CONJUGATION and EXCRETION FUNCTION BILIRUBIN DELTA BILIRUBIN JAUNDICE BILIRUBIN End product of hemoglobin metabolism Principal pigment of bile BILIRUBIN METABOLISM PRE-HEPATIC Type: Unconjugated hyperbilirubinemia Cause: Increased bilirubin production prior to liver metabolism Common cause: Hemolytic anemia (increased red blood cell destruction) Bilirubin levels: Rarely exceed 5 mg/dL due to liver's ability to handle the overload Bilirubin type: Unconjugated bilirubin, not water soluble, bound to albumin Urine bilirubin: Not present in urine due to lack of kidney filtration RBC HEMOGLOBIN HEME (IRON PORPHYRIN+GLOBIN (PROTEIN) BILIVERDIN B1 UNCONJUGATED INDIRECT HEPATIC Type: Can be conjugated or unconjugated hyperbilirubinemia, depending on the underlying cause. Cause: Primary problem resides within the liver itself, affecting bilirubin metabolism or transport. Common cause: Varies depending on the specific liver disease (e.g., viral hepatitis, cirrhosis, drug-induced liver injury). Bilirubin levels: Vary depending on the underlying cause; can be elevated for both conjugated and unconjugated bilirubin. Bilirubin type: Can be both conjugated and unconjugated, depending on the specific liver disease. Urine bilirubin: May or may not be present in urine, depending on the type of bilirubin and the severity of the liver disease. RBC LIVER =BILIRUBIN MONOGLUCORONIDE B2 CONJUGATED DIRECT BILE POST - HEPATIC Type: Conjugated hyperbilirubinemia Cause: Biliary obstructive disease Common cause: Gallstones or tumors Bilirubin levels: Elevated conjugated bilirubin levels Bilirubin type: Conjugated bilirubin Urine bilirubin: May be present in urine due to backup of bile into the bloodstream and subsequent filtration by the kidneys. BILE INTESTINE UROBILINOGEN UROBILIN (URINE) STERCOBILINOGEN STERCOBILIN (STOOL) SAPLAD, JOHNA MAY C. 3  CLINICAL CHEMISTRY 2 LECTURE/ LIVER FUNCTION COMPARISON OF BILIRUBIN FRACTION BILIRUBIN 1 BILIRUBIN 2 UNCONJUGATED CONJUGATED WATER SOLUBLE WATER SOLUBLE NON-POLAR POLAR INDIRECT DIRECT HEMOBILIRUBIN CHOLEBILIRUBIN SLOW REACTING ONE MINUTE/PROMPT BILIRUBIN PRE-HEPATIC BILIRUBIN POST- HEPATIC HEMOLYSIS OBSTRUCTIVE VALUES OF BILIRUBIN IN SOME DISEASES BILIRUBIN 1 BILIRUBIN 2 GILBERT’S SYNDROME BILIARY OBSTRUCTION (GALL STONES) CRIGLER-NAJJAR SYNDROME PANCREATIC CANCER HEMOLYTIC ANEMIA DUBIN-JOHNSON SYNDROME HEPATOCELLULAR DISEASE BILIARY ATRESIA LUCEY-DRISCOLL SYNDROME HEPATOCELLULAR DISE ASE G6PD DEFICIENCY CONVENTIONAL IS CONJUGATED BILIRUBIN 0.0-0.2 mg/dL 0-3 umol/L UNCONJUGATED BILIRUBIN 02-0.8 mg/dL 3-14 umol/L TOTAL BILIRUBIN 0.2-1.0 mg/dL 3-17 umol/L SAPLAD, JOHNA MAY C. 4  CLINICAL CHEMISTRY 2 LECTURE/ LIVER FUNCTION SPECIMEN COLLECTION AND STORAGE SPECIMEN OF CHOICE: DIAZOTIZED SULFANILIC ACID: Serum Serum and Plasma SERUM: Addition of alcohols precipitate proteins causing interference Preferred for Evelyn-Malloy FASTING SAMPLE IS PREFERABLE Lipemia will increase measured bilirubin concentration No hemolyzed sample Decrease reaction with diazotized sulfanilic acid Photosensitive Decrease of 30-50% per hour SPECIMEN CONSIDERTION/PRESERVATION Serum and Plasma separated from: RED CELLS ROOM TEMPERATURE (4 C) 2 DAYS -20 C Indefinite Methods Evelyn-Malloy Jendrassik and Grof JAUNDICE Icterus or hyperbilirubinemia Yellow discoloration of the skin, sclera and mucous Kernicterus - B1 crosses the myelin rich structure of brain - 20 mg/dL UNCONJUGATED HYPERBILIRUBINEMIA B1 = Increased PRE-HEPATIC Too much destruction of RBC B2 = Normal JAUNDICE Acute and chronic hemolytic anemia Total bilirubin = Increased Exceed 5.0 mg/dL Urobilinogen = Normal POST HEPATIC Failure of bile to flow to the intestine B1 = Normal JAUNDICE Impaired bilirubin excretion due to gall stones/ B2 = Increased cholelithiasis Total bilirubin = Increased Urobilinogen = Normal/Decreased NO. 1 MARKER FOR OBSTRUCTIVE JAUNDICE Urine bilirubin = Positive (ALP) ALKALINE PHOSPATASE ALP = Positive HEPATOCELLULAR Hepatocyte injury caused by viruses, alcohol and B1 = Increased COMBINED parasites B2 = Increased JAUNDICE Cirrhosis, viral hepatitis (A E) Total bilirubin = Increased Urobilinogen = Decreased Urine bilirubin = Positive SAPLAD, JOHNA MAY C. 5  CLINICAL CHEMISTRY 2 LECTURE/ LIVER FUNCTION Bilirubin Transport Deficit Impaired Cellular uptake of Bilirubin GILBERT’S SYNDROME Increased B1 Total bilirubin - 1.5 to 3.0 mg/dL - 4.5 mg/dL (sometimes) CRIGLER-NAJJAR SYNDROME Conjugation deficit Deficiency of enzyme glucoronyl transferase (UDGT) Increased B1 Phototherapy = infants TYPE OF CRIGLER-NAJJAR TYPE 1 TYPE 2 SYNDROME COMPLETE DEFICIENCY OF ENZYME PARTIAL DEFICIENCY OF UDGPT GLUCORYL TRANSFERASE SMALL AMOUNT OF B2 IS PRODUCED TOTAL OF ABSENCE OF B2 PRODUCTION GREATER DANGER OF KERNICTERUS BILE IS COLORLESS UDGPT (URIDINE DIPHOSPHATE GLUCORONOSYLTRANSFERASE) Bilirubin excretion deficit DUBIN-JOHNSON SYNDROME Blockage of excretion of bilirubin AND Increased B2 and Total bilirubin ROTOR SYNDROME Intense dark pigmentation of liver - Accumulation of lipofuscin pigment Conjugation inhibitor LUCEY-DRISCOLL SYNDROME Unconjugated hyperbilirubinemia due to circulating inhibitor of bilirubin conjugation Increased B1 TEST FOR DETOXIFICATION FUNCTION (ENZYME TEST AND AMMONIA TEST) ENZYME TEST Injury to liver caused by cytolysis and necrosis - Liberation of various enzymes Used to assess the extent of liver damage Differentiate hepatocellular from obstructive Indication of cell injury ALP, aminotransferases, 5’ -nucleotidase, GGT, OCT, LAP, LDH SAPLAD, JOHNA MAY C. 6  CLINICAL CHEMISTRY 2 LECTURE/ LIVER FUNCTION AMMONIA Arises from deamination of amino acids Marker for detoxification Least NPN ONLY NPN not a KIDNEY Test but a LIVER TEST Liver disease NH3 Urea Used to diagnose hepatic failure/ hepatic coma Neurotoxic Associated with encephalopathy Lowers GABA Increased: Cirrhosis and Hepatitis, Reye’s syndrome Normal Value: 19-60 ug/dl LIVER FUNCTION ALTERATION DURING DISEASE CIRRHOSIS DRUG AND ALCOHOL RELATED DISORDERS TUMORS HEPATITIS REYE’S SYNDROME CIRRHOSIS Scar in tissue Patient has prolonged survival Can’t be reversed but treatment can Scars but w/ poor prognosis stop or delay further progression - Blocks the flow of blood Other causes of cirrhosis Treatment depends or cause of through the organ - Chronic Hepatitis B, C, D cirrhosis - Prevents the liver from - Autoimmune hepatitis Alcohol cirrhosis – Stop drinking functioning properly - Inherited disorders alcohol Rarely no signs and symptoms a1-antitrypsin deficiency Hepatitis related cirrhosis If liver deteriorates Wilson’s disease - Interferon for viral hepatitis Fatigue Hemochromatosis - Corticosteroids for autoimmune Nausea, Galactosemia hepatitis Unintended weight loss Nonalcoholic steatohepatitis Jaundice Blocked bile ducts, drugs, toxins Bleeding from GIT and infections Intense itching and swelling in legs and abdomen TUMORS PRIMARY LIVER CANCER METASTATIC LIVER CANCER (malignant) (benign) Begins in liver cells Tumors from other parts spread (colon, lung, and breast cancer) More common Hepatocellular carcinoma Hepatocellular adenoma Bile duct obstruction hemangiomas (HEPATOCELLULAR ADENOMA) – Occurring (Hemangiomas)- masses of blood vessels with no etiology exclusively in females of child-bearing SAPLAD, JOHNA MAY C. 7 CLINICAL CHEMISTRY 2 LECTURE/ LIVER FUNCTION DRUG and ALCOHOL RELATED DISORDERS Due to adverse effects of drugs Paracetamol (Acetaminophen) Ethanol - Small amount very mild, transient and unnoticed injury to the liver. - Alcoholic cirrhosis (prolonged consumption) - AST, ALT, GGT, ALP SYNTHESIS Albumin synthesis Bile production Cholesterol Metabolism Detoxification of Drugs and Alcohol Excretion Factors for clotting Glycogen storage Hormone production SAPLAD, JOHNA MAY C. 8