Laboratory Diagnostics in Liver Disease Flashcards
Explain the significance of increased concentration in serum of AST & ALT
Aminotransferases: AST and ALT
o Intracellular enzymes = catalyze amino group transfer from aspartic acid or alanine
Highest concentrations in liver hepatocytes and striated muscles
• Note: look at creatine phosphokinase (CPK) levels
• Elevated in rhabdomyolysis or MI but NOT in hepatic injury
Elevated levels = indicate hepatocyte injury
• But: NO correlation with degree of hepatocyte injury or prognosis
• Poor predictor of outcome in patients with chronic liver disease
AST (aspartate aminotransferase) • Mitochondria and cytosol ALT (alanine aminotransferase) • Cytosol • Present in higher quantities in liver than in other organs → more characteristic of liver/hepatocyte injury
AST/ALT ratio important
• Most cases: ration is less than 1
Except alcoholic hepatitis: ratio greater than 2 → fairly specific
• Due to depletion of pyridoxine = make less ALT
• Often ratio > 1 in cirrhosis
Explain the significance of increased concentration in serum of LDH
(lactate dehydrogenase)
o Ubiquitous cytoplasmic enzyme = poor diagnostic specificity for liver disease
Very high levels (>20x normal):
• Ischemic liver injury (shock liver)
• Drug-induced acute liver failure
Also high in hemolysis and cancer
Explain the significance of increased concentration in serum of ALP
(alkaline phosphatase)
o Catalyzes hydrolysis of phosphate esters at alkaline pH
Located in liver, bone, intestine, placenta, kidney and leukocytes
• In liver: in canalicular membrane of hepatocytes and biliary tree
Increased ALP in liver disease = cholestasis (either intra- or extra-hepatic)
• Due to increased ALP synthesis mediated by bile acids
Low ALP = zinc deficiency and Wilson’s disease complicated by fulminant hepatitis
• Because requires zinc to function
Explain the significance of increased concentration in serum of GGT
(gamma-glutamyl transpeptidase)
o Catalyzes transfer of peptide glutamuyl groups to other amino acids
Located:
• Liver: hepatobiliary tree (highest amount in cholangiocytes)
• Other: kidney, pancreas, intestine
• Absent in bone → useful to distinguish liver from bone source of high ALP
Poor specificity
Also: enzyme can be induced by alcohol or drugs (phenytoin, phenobarbital)
Explain the significance of increased concentration in serum of 5’-Nucleotidase (5’NT)
o Not routinely determined in clinical practice
o Catalyzes inorganic phosphate release from nucleotides from 5’ position of pentose ring
Location:
• Liver: canalicular plasma membranes and cholangiocytes
• Also: intestine, endocrine pancreas, other organs
But: elevated levels are of hepatobiliary origin because only type of tissue that can release 5’NT into circulation
Uses: diagnosing liver disease in pregnancy and childhood
• Here = physiological elevation of ALP (but not 5’NT)
Describe the use of PT-INR in the evaluation of common clinical conditions.
PT-INR
o Sensitive test for hepatocyte dysfunction
o Due to short ½-life of factor VII (few hours)
Not specific for hepatocyte dysfunction
• Could also be from Vit K deficiency (ex: vitamin malabsorption in cholestatic disease; DIC)
• So give Vit K parenterally → recheck PT
• If corrects to normal PT = from Vit K deficiency
Explain bilirubin formation and metabolism, and the significance of increased bilirubin values.
In macrophages: heme catabolism → hemoglobin → unconjugated bilirubin + CO2
o Unconjugated bilirubin = lipophilic; toxic to cell membranes
o Transported in plasma bound to albumin (so nontoxic)
Internalized by liver (via bilirubin transporter)
o Bound to cytosolic carrier (GST: Glutathione S-transferase)
o Brought to ER
o Conjugated with glucuronic acid = hydrophilic and nontoxic
Conjugated bilirubin excreted in bile = released in intestine
Bacterial beta-glucuronidases hydrolyze → urobilinogen and urobilin
o Urobilinogen = partially absorbed by gut → systemic circulation → excreted in urine
Increased bilirubin = see jaundice
Increase in serum conjugated bilirubin = hepatocyte or bile duct dysfunction
• Good test for excretory function
• Prognostic value in chronic liver disease (jaundice associated with mortality)
• NOT prognostic in acute liver disease
1) Hepatic:
• Reduced ability to excrete bilirubin into bile
• Conjugated bilirubin refluxes into circulation = found in urine
2) Cholestatic:
• Failure of adequate amounts of bile to reach duodenum
• Failure of canalicular secretion
• Ductular disease
• Bile duct obstruction
• Pale stools, dark urine, pruritus
• Cholestasis = get raised serum bile acids (specific for hepatobiliary disease but not routinely measured)
Unconjugated hyperbilirubinemia = hemolysis and Gilbert’s syndrome
• LDH will be increased
• Haptoglobin will be decreased
• Hemosiderin/free hemoglobin may be in urine
Compare the significance of abnormal PT-INR and albumin in the evaluation of hepatocyte synthetic function.
Liver makes all coagulation factors EXCEPT factor VIII
o VIII: make in endothelial cells
o Synthesis not affected by liver failure → useful in distinguishing impaired coagulation form liver failure vs. DIC
o In DIC: VIII is consumed
Vit K dependent: factors II, VII, IX, and X
Albumin
o Made by hepatocyte
o Half-life ~3 weeks
o May be affected by nutritional status, severe systemic inflammation (negative acute phase reactant), hypergammaglobulinemia
o In chronic liver disease and cirrhosis: low levels correlate with prognosis
Contrast the two major pathways of ammonia metabolism by hepatocytes.
Toxin from bacteria in gut → absorbed in blood
o Transported via portal vein to liver
o Converted to urea (via urea cycle) and glutamine (via glutamine synthetase)
Acute liver dysfunction and portal-systemic shunting → increased ammonia (because can’t detoxify)
Contributes to hepatic encephalopathy:
o Can travel to brain → swelling → herniation
Ammonia can also be increased after major GI hemorrhage
