1. macrophages: RBC destruction, heme degradation, & bilirubin synthesis 2. liver: bilirubin uptake, bilirubin conjugation (UDP-glucuronyl transferase), secretion into bile 3. intestine: bacterial degradation, urobilinogen absorption, stercobilin excretion 4. kidney: urobilinogen uptake; urobilin excretion (pigments the urine)

Liver Function Tests Flashcards by Kyra Porter

liver - major metabolic functions

*nutrient processing (amino acid synthesis, glycogen synthesis and storage, etc)
*lipid metabolism
*vitamin & mineral storage
*plasma protein synthesis (albumin, clotting factors [INR])
*bile secretion
*detoxification

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important hepatic enzymes that we measure using liver function tests

*AST
*ALT
*alkaline phosphatase
*GGT

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alanine-amino transferase (ALT)

*transaminase that regulates amino acid homeostasis by catalyzing the transfer of an amino group between alanine and pyruvate
*location: mainly hepatocytes
*important role in gluconeogenesis
*requires pyridoxal-PO4 (vitamin B6) as cofactor

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aspartate-amino transferase (AST)

*transaminase that regulates amino acid homeostasis by catalyzing the transfer of an amino group between aspartate and glutamate
*location: hepatocytes (also muscle, heart, intestine)

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normal ratio of AST:ALT

AST:ALT < 1 (except in alcoholic hepatitis)

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impact of hepatocyte injury on AST and ALT levels

*hepatocyte injury (by viruses, toxins, or hypoxia) releases AST and ALT into plasma
*finding elevated levels of AST and ALT indicates that the hepatocytes are “sick”

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alkaline phosphatase (ALP)

*location: canalicular membrane, bile duct epithelium
*assists with phosphate reabsorption and detoxification of lipopolysaccharides
*also present in BONE, intestine, and kidney
*plays role in BILE FORMATION AND SECRETION

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gamma-glutamyl transpeptidase (GGT)

*location: canalicular membrane, bile duct epithelium
*not present in other tissues (but harder to assay than alkaline phosphatase)

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impact of bile duct obstruction on alkaline phosphatase levels

*bile duct obstruction increases ALP synthesis and release into plasma

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important plasma proteins measured in liver function tests

*albumin
*clotting factors

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albumin

*hepatic synthesis (most abundant plasma protein)
*slow turnover: half-life = 20 days (level affected by nutrition, hydration, acute inflammation, renal disease)
*limited utility in assessing acute liver injury

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clotting factors

*hepatic synthesis (except factor VIII and vonW factor)
*note - synthesis of II, VII, X, require vitamin K
*rapid turnover: half-life = 6-60 hours
*INR measures collective function of I, II, V, VII, X
*useful to assess acute liver injury, MELD score

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what does INR measure

*collective function of clotting factors: I, II, V, VII, and X
*useful to assess acute liver injury

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bilirubin synthesis

macrophages: RBC destruction, heme degradation, & bilirubin synthesis
liver: bilirubin uptake, bilirubin conjugation (UDP-glucuronyl transferase), secretion into bile
intestine: bacterial degradation, urobilinogen absorption, stercobilin excretion
kidney: urobilinogen uptake; urobilin excretion (pigments the urine)

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causes of elevated unconjugated (indirect) bilirubin

*hemolytic anemia (increased red cell destruction)
*decreased UDP glucuronyl transferase activity (Crigler-Najjar & Gilbert’s syndromes; neonatal jaundice)

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causes of elevated conjugated (direct) bilirubin

*hepatocyte bilirubin transporter dysfunction (Dubin-Johnson and Rotor syndromes)

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causes of elevated conjugated + unconjugated bilirubin (total bili)

*hepatocyte injury or dysfunction
*bile duct obstruction

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causes of elevated ALT & AST

*hepatocyte cell injury or necrosis

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causes of elevated alkaline phosphatase

*bile duct obstruction
*cholestasis (pathophysiological cessation of bile flow)

hemolytic anemias - pathophysiology

*decreased RBC lifespan; increased RBC destruction -> overwhelms the transport capacity of OATP
*extra-vascular and/or intra-vascular
*causes: autoimmune, mechanical, vasculitis, infections, toxins, drugs, hemoglobinopathies, leukemias

hemolytic anemias - clinical findings

*schistocytes
*nucleated RBCs
*RBC agglutination

hemolytic anemias - lab findings

*total bilirubin: mildly elevated
*direct bilirubin: NORMAL
*urine: bilirubin (-); INCREASED UROBILINOGEN
*plasma: increased LDH; decreased haptoglobin
*CBC: increased reticulocytes; increased RDW

hemolytic anemias - clinical course

*can be indolent or fulminant
*severe cases: hemoglobinuria, CHF, ARDS, shock, renal failure

Gilbert’s syndrome - pathophysiology

*decreased activity of UDP-glucuronyl transferase (activity ~25% of normal)
*dominant or recessive inheritance of UGT1A1 gene SNPs
*very common

Gilbert's syndrome - clinical findings

faint "lemon yellow" scleral icterus

Gilbert's syndrome - lab findings

*total bilirubin: mildly elevated *direct bilirubin: NORMAL *urine bilirubin: NEGATIVE *plasma: ALT, AST, AP normal

Gilbert's syndrome - clinical course

*first noticed in teens/young adults *increased bilirubin found on routine labs *transient mild jaundice with fasting, stress, exercise, illnesses *without established Dx, patients may be rejected for insurance

Crigler-Najjar Syndrome - pathophysiology

*serious impairment of UDP-glucuronyl transferase activity *type I: absent UDP-GT activity *type II: ~10% UDP-GT activity *recessive UGT1A1 gene SNPs *very rare

Crigler-Najjar Syndrome - lab findings

*type I: total bilirubin = extremely elevated *type II: total bilirubin = elevated *direct bilirubin & LFTs NORMAL note - the elevated total bili is due to elevated unconjugated (indirect) bilirubin (because it is not getting conjugated effectively)

Crigler-Najjar Syndrome - clinical course

*type I: jaundiced at birth; pale stool; severe risk of kernicterus with acute and chronic neurological damage *type II: jaundice may appear later after birth; lower risk of kernicterus

Crigler-Najjar Syndrome - treatment

*type I: phototherapy, exchange transfusions; liver transplantation *type II: phototherapy, phenobarbital (induces P450 enzymes, including UDP-GT

physiologic jaundice of newborn - pathophysiology

delayed onset of UDP-glucuronyl transferase activity

physiologic jaundice of newborn - lab findings

*total bilirubin = elevated *direct bilirubin & LFTs normal

physiologic jaundice of newborn - clinical course

*benign if bili < 20 *if > 20, kernicterus

physiologic jaundice of newborn - treatment

phototherapy

how does phototherapy affect neonatal jaundice

*makes unconjugated bilirubin water-soluble (without the need to be conjugated)

Dubin-Johnson syndrome - pathophysiology

*defective canalicular MRP2 *recessive inheritance *bilirubin is conjugated but not excreted

Dubin-Johnson syndrome - lab findings

*total bilirubin: mildly elevated *most bilirubin is conjugated (direct) *urine bilirubin: positive *plasma: ALT, AST, AP normal *normal urine coproporphyrin *abnormal copro-I/III ratio = 4:1

Dubin-Johnson syndrome - clinical course

*liver has BLACK PIGMENTATION *hyperechoic appearance on ultrasound *gallbladder not visualized on HIDA or OCG

Dubin-Johnson syndrome - treatment

*benign condition (no treatment)

Rotor syndrome - pathophysiology

*defective sinusoidal OATP *bilirubin is conjugated but not excreted

Rotor syndrome - lab findings

*total bilirubin: mildly elevated *most bilirubin is conjugated (direct) *urine bilirubin: positive *plasma: ALT, AST, AP normal *increased urine coproporphyrin *copro-I/III ratio = 1:4

Rotor syndrome - clinical course

*normal liver appearance *normal radiological gallbladder visualization note - contrast these to the findings in Dubin-Johnson (where the liver is black)

Rotor syndrome - treatment

benign condition (no treatment)

what are the "LFTs"

*liver function tests: -total bilirubin -ALT -AST -alkaline phosphatase -INR

physical exam findings indicative of liver disease

*scleral icterus *hepatomegaly *spider hemangioma *palmar erythema *gynecomastia *abdominal distension, shifting dullness, fluid wave *peripheral edema *signs of CHF *ecchymoses *asterixis *caput medusa *corneal rings

imaging for evaluation of liver disease

*start with RUQ ultrasound!