RAMZI SHAWAHNA

LIVER FUNCTION TEST

Liver: Is the largest solid organ Has large reserve capacity Is capable of regeneration

Function:

Metabolism: fat, protein, drugs, hormones Filtration: bacteria, endotoxins, viruses, antigens, byproducts of coagulation Storage: fluids, vitamins, minerals

LIVER

LIVER DYSFUNCTION DIAGNOSIS

The diagnosis of liver disease depends on a combination of patient history, physical examination, laboratory testing, biopsy and sometimes imaging studies such as ultrasound scans.

LIVER FUNCTION TESTS A misnomer

elevated aminotransferases/alkaline phosphatase are only markers of liver injury, not liver dysfunction

These can be affected by extrahepatic factors nutritional state hemolysis antibiotic use

Poor sensitivity and specificity for liver disease

HISTORY Systemic symptoms Family Hx

Hemochromatosis, Wilson’s Disease, alpha1 antitrypsin deficiency

Gilbert’s syndrome, Dubin-Johnson Syndrome, Rotor’s syndrome

Alcoholism Drug abuse

HISTORY

Occupational exposuresChemicals (vinyl choloride,

dimethylformamide, 2-Nitropropane, Trichloroethylene)

Other co-morbid illnessesAutoimmune diseases, IBD, Diabetes Mellitus

MedicationsPrescriptionHerbals, Vitamins

MEDICATIONS CAUSING ELEVATION OF AMINOTRANSFERASES

Acetaminophen

Amoxicillin-clavulanic acid

NSAIDS

Phenytoin

Valproate

GENERAL CATEGORIES OF TESTS

variety of tasks, no single testnot very sensitive (cirrhosis)or specific (non-hepatic factors)

THREE CATEGORIES Markers of Liver Injury/Necrosis Markers of Cholestatic Liver Disease Markers of Liver Function

COMMON SERUM LIVER CHEMISTRY TESTS

Normal values

ALT (SGPT) AND AST (SGOT) LEVELS

AST and ALT are markers of hepatocellular injury

Participate in gluconeogenesis, transfer of amino groups from aspartate or alanine to ketoglutaric acid to form oxaloacetete or pyruvate.

AST present in cytosol and mitochondria in liver, cardiac muscle, skeletal muscle, kidney, brain, pancreas, lungs, WBC and RBC.

ALT a cytosolic enzyme, highest concentration in the liver

ALT considered a “liver specific” enzyme

THREE CATEGORIES Markers of Liver Injury/Necrosis Markers of Cholestatic Liver Disease Markers of Liver Function

ALKALINE PHOSPHATASE

•Present in nearly all tissues - isoenzymes

•Localised in the microvilli of the bile canalicus in the liver

•Also present in bone, intestine, placenta, kidney and WBCs

•Elevation may be physiological or pathological

•Normal adult serum AP is from liver and boneIntestine contributes about 15%

ALKALINE PHOSPHATASE Catalyze the hydrolysis of a large number

of organic phosphate esters, optimally at an alkaline pH.

Liver - synthesized in the bile duct epithelial cells

Bone - osteoblastic activity Kidneys Intestine Placenta- levels may double late in

pregnancy

ELEVATION OF SERUM ALKALINE PHOSPHATASE Isolated Associated with hyperbilirubinemia

(cholestatic disorders) May be sole abnormality in many cholestatic

or infiltrative diseases To be interpreted in the clinical setting of

history and physical examination if sole abnormality

GGT Catalyzes the transfer of the γ-

glutamyl group from γ-glutamyl peptides (glutathione) to other peptides and L-amino acids.

Elevated in liver, biliary, or pancreatic disease.

Very sensitive for detecting hepatobiliary disease, but poor specificity

Used primarily to confirm hepatic origin of elevated ALP

BILIRUBIN

Product of hemoglobin breakdown 2 Forms

Unconjugated (indirect)- insoluble↑ in hemolysis, Gilbert syndrome, meds

Conjugated (direct)- soluble↑ in obstruction, cholestasis, cirrhosis, hepatitis, primary biliary cirrhosis, etc.

No elevation until loss of > 50% capacity

UNCONJUGATED HYPERBILIRUBINEMIA >80% of total bilirubin is indirect Liver function is otherwise normal Increased bilirubin production

hemolysis - seldom > 5 mg/dL ineffective erythropoeisis blood transfusion resorption of hematomas

UNCONJUGATED HYPERBILIRUBINEMIA Decreased hepatocellular uptake

drugs (e.g., rifampin) Gilbert's syndrome?

Decreased conjugationGilbert's syndrome Crigler-Najjar syndromePhysiologic jaundice of the newborn

CONJUGATED HYPERBILIRUBINEMIA Hepatocellular dysfunction Biliary obstruction + Urobilinogen

unconjugated bilirubin is tightly bound to albumin and not excreted renally

marker of hepatobiliary disease

ALBUMIN

Synthesized exclusively by the liver 20 day half life - levels usually preserved

acutely Synthesis regulated by nutritional

states, osmotic pressure, systemic inflammation, and hormones

Hypoalbuminemia most common in patients with chronic liver disorders (ie cirrhosis) due to decreased synthesis

Not specific for liver disease

PROTHROMBIN TIME Factor 1 - fibrinogen Factor II- prothrombin Factor V - proaccelerin; labile factor Factor VII - stable factor Factor IX - Christmas factor Factor X - Stuart Prower factor Factor XII and XIII - prekallikrein and high

molecular weight kinogen

PROTHROMBIN TIME Parenchymal liver disease

Poor utilization of vitamin K Hypovitaminosis K

Prolonged obstructive JaundiceSteatorrheaDietary DeficiencyAntibiotics (alter gut flora)

Differentiate by giving IV Vitamin Knormalization or 30% improvement within 24

hrs surmises good parenchymal function

BILIRUBIN METABOLISM

Pre-hepatic Hepatic Post-hepatic

BILIRUBIN METABOLISM: PRE-HEPATIC

Bilirubin is formed in macrophages of the reticuloendothelial system. The initial substrate is predominantly hemaglobin.

Heme group biliverdin bilirubin Bilirubin is insoluble in water and so must be carried

by albumin within plasma. Bilirubin circulates in the blood before uptake by the

liver. Pre-hepatic jaundice = if bilirubin is not taken up by

the liver or if it is produced in excess, unconjugated bilirubin is deposited in extra-hepatic tissues.

BILIRUBIN METABOLISM: HEPATIC

Bilirubin is taken up into hepatocytes and bound to intracellular proteins.

Bilirubin + UDP glucuronic acid = bilirubin diglucuronide > bilirubin monoglucuronide > UDP

The glucuronide conjugated form of bilirubin is water soluble and is excreted into bile. Excretion occurs into the bile canaliculus by carrier-mediated transport.

Hepatic jaundice = disorders of bilirubin uptake or conjugation

BILIRUBIN METABOLISM: POST-HEPATIC

Glucuronide-conjugated bilirubin in bile may be degraded to urobilinogen or partially reabsorbed into plasma.

Urobilinogen pathway: may be reabsorbed by the gut and returned to the

liver converted to urobilin reabsorbed into plasma for excretion by kidneys

Conjugated bilirubin pathway: May be acted upon by bacterial enzymes within the

gut to form the bile pigment stercobilinogen. Stercobilinogen may be reabsorbed into plasma for recycling to the liver or for excretion by the kidney, or, it may be oxidized to stercobilin.

Obstructive jaundice = failure of bilirubin to reach the gut, resulting in a reduction in pigment within the stool

UNCONJUGATED HYPERBILIRUBINEMIA

Increased Bilirubin Production Extravascular hemolysis Extravasation of blood into tissues Intravascular hemolysis Errors in production of red blood cells

Impaired Hepatic Bilirubin Uptake CHF Portosystemic shunts Drug inhibition: rifampin, probenecid

Impaired Bilirubin Conjugation Gilbert’s disease Crigler-Najarr syndrome Neonatal jaundice (this is physiologic) Hyperthyroidism Estrogens Liver diseases (chronic hepatitis, cirrhosis, Wilson’s)

CONJUGATED HYPERBILIRUBINEMIA

Intrahepatic Cholestasis (impaired excretion) Hepatitis (viral, alcoholic, and non-alcoholic) Primary biliary cirrhosis or end-stage liver dz Sepsis and hypoperfusion states Pregnancy Infiltrative disease: TB, amyloid, sarcoid,

lymphoma Drugs/toxins i.e. chlorpromazine, arsenic Post-op patient or post-organ transplantation Hepatic crisis in sickle cell disease