MALIK ALQUB MD. PHD.

LIVER FUNCTION TEST

Largest solid organ, right upper quadrant (RUQ).

Large reserve capacity Capable of regeneration Function:

Metabolism: fat, CHO, protein, drugs,

hormones Filtration: bacteria, endotoxins, viruses,

antigens, byproducts of coagulation Storage: fluids, vitamins, minerals

Liver

The normal liver

The normal liver

The normal liver

Central vein

Hepatic artery

Portal vein

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

Albumin/Bili/PT can be affected by extrahepatic factors nutritional state hemolysis antibiotic use

Poor sensitivity and specificity for liver disease

“True liver tests”

Galactose clearance Caffeine Clearance Lidocaine Metabolite Formation Indocyanine Green

History Systemic symptoms Family Hx

Hemochromatosis, Wilson’s Disease, alpha1 antitrypsin deficiency

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

Sexual History Tattoos Travel history

History

Occupational exposures Chemicals (vinyl choloride,

dimethylformamide, 2-Nitropropane, Trichloroethylene)

Other co-morbid illnesses Autoimmune diseases, IBD, Diabetes Mellitus

Medications Prescription Herbals, Vitamins

Medications causing elevation of aminotransferases

Acetaminophen Amoxicillin-clavulanic acid HMGCoA reductase inhbtrs 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

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

Isolated elevated AST If ALT normal, then reflective of cardiac

or muscle disease. Marco-AST

Rare AST complexed with an immunoglobulin and

is not cleared from the blood Does not indicate serious liver disease

Drugs Acetominophen, NSAIDs, ACE-I, Niacin,

Erythromycin, Fluconazole

Useful paradigm to categorize increased levels of AST, ALT

Mild AST, ALT elevation (less than 5 times ULN) - ALT predominant or AST predominant

AST, ALT greater than 15 times normal

AGA Technical review, Gastroenterology 2002

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 wbc

•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 s. 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

Three categories

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

Bilirubin Albumin PT

Three categories

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

Bilirubin Albumin PT

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 - T.B. seldom > 5 mg/dL ineffective erythropoeisis blood transfusion resorption of hematomas

Unconjugated Hyperbilirubinemia Decreased hepatocellular uptake

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

Decreased conjugation Gilbert's syndrome Crigler-Najjar syndrome Physiologic 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

Three categories

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

Bilirubin Albumin PT

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

Three categories

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

Bilirubin Albumin PT

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 Jaundice Steatorrhea Dietary Deficiency Antibiotics (alter gut flora)

Differentiate by giving IV Vitamin K normalization or 30% improvement within 24

hrs surmises good parenchymal function

Platelets

Thrombocytopenia seen in liver is thought to be due to congestive splenomegaly Mechanism is platelet sequestration Correlation shown between spleen size and

thrombocytopenia Platelet count rarely less than 50K Bleeding associated with it uncommon Congestive splenomegaly does not

induce a significant hemostatic defect

MALIK ALQUB MD. PHD.

Jaundice

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

DDX: 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)

DDX: 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

Evaluation: History

Fever/chills, RUQ pain (cholangitis) Hepatitis risk factors Exposure to toxic substances Inherited disorders including liver diseases and

hemolytic conditions H/O blood transfusion TPN use H/O abdominal surgery HIV status Travel history Use of drugs or herbal medications Use of alcohol

Evaluation: PE Signs of end stage liver disease (cirrhosis):

ascites, splenomegaly, spider angiomata, and gynecomastia

Look for jaundice: under tongue, conjunctiva, skin

Hyperpigmentation (hemochromatosis) Kayser-Fleischer ring (Wilson’s disease) Xanthomas (primary biliary cirrhosis) Courvoisier’s sign = painless,

palpable/distended gallbladder on exam (think of CA)

Evaluation: Labs

Normal LFTs r/o hepatic injury or biliary tract disease Consider inherited disorders or hemolysis

Greater increase in Alk Phos than AST/ALT implies “cholestasis” (intrahepatic vs. obstruction) ↑Alk Phos also seen in sarcoid, TB, bone In this case, GGT is specific for biliary origin

Predominant increase in AST/ALT implies intrinsic hepatocellular disease AST/ALT ratio > 2 in alcoholic hepatitis

↓albumin or ↑PT advanced liver disease

Normal Liver

Hepatic vein

Hepatic vein

SinusoidSinusoid

Portal vein

Portal vein

LiverLiver

Splenic veinSplenic vein

Coronary veinCoronary vein

THE NORMAL LIVER OFFERS ALMOST NO RESISTANCE TO FLOW

Portal systemic collaterals

Portal systemic collaterals

Distorted sinusoidal

architectureleads to

increased resistance

Distorted sinusoidal

architectureleads to

increased resistance

Portal vein

Portal vein

Cirrhotic Liver

SplenomegalySplenomegaly

ARCHITECTURAL LIVER DISRUPTION IS THE MAIN MECHANISM THAT LEADS TO AN INCREASED INTRAHEPATIC RESISTANCE

Ascites

spider angiomata

Caput medusae

Small varicesSmall varices Large varicesLarge varicesNo varicesNo varices

7-8%/year7-8%/year 7-8%/year7-8%/year

Esophageal VaricesEsophageal Varices

Merli et al. J Hepatol 2003;38:266Merli et al. J Hepatol 2003;38:266

VARICES INCREASE IN DIAMETER PROGRESSIVELY