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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