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Initial Approach
history and physical examination algorithm approach useful mainly when no clinical clues
history patients symptoms risk factors for liver disease concomitant conditions medications occupational exposure to hepatotoxins physical examination body habitus splenomegaly ascites cutaneous stigmata of chronic liver disease
Albumin
depend on nutrition, volume status, vascular integrity, catabolism, hormone, loss in stool and urine not specific for liver disease T1/2 19-21 D
not reliable indicator of acute liver disease
Hypoalbuminemia
globulin 1.decrease synthesis -protein malnutrition -chronic liver disease -chronic inflammation 2.increase loss -PLE -NS 3.increase Vd (ascites, overhydration) 4.increase turnover (catabolic state, steroid) chol/TG Hb
Globulin
produced by stimulated B lymphocyte elevation in chronic liver disease chronic inflammation and malignant disease
40 2 PE : T 37 C, markedly pale, no jaundice, koilonychia, glossitis, coarse hair, no sign of chronic liver disease, liver and spleen not palpated LFT : TB 1 mg/dl [0.3-1 mg/dl] DB 0.2 mg/dl [0.1-0.3 mg/dl] AST 35 U/L [0-35 U/L] ALT 35 U/L [0-35 U/L] ALP 100 U/L [30-120 U/L] alb 1.8 g/dl [3.5-5.5 g/dl] glob 2 g/dl [1.5-3.5 g/dL] chol 80 mg/dl [<200] LFT
Case 1
40 2 PE : T 37 C, not pale, no jaundice, no sign of chronic liver disease, liver and spleen not palpated LFT : TB 1 mg/dl [0.3-1 mg/dl] DB 0.2 mg/dl [0.1-0.3 mg/dl] AST 35 U/L [0-35 U/L] ALT 35 U/L [0-35 U/L] ALP 100 U/L [30-120 U/L] alb 1.8 g/dl [3.5-5.5 g/dl] glob 2 g/dl [1.5-3.5 g/dL] chol 250 mg/dl [<200] LFT
Case 2
40 2 PE : T 37.8 C, mildly pale, no jaundice no sign of chronic liver disease, liver and spleen not palpated, shifting dullness + LFT : TB 1 mg/dl [0.3-1 mg/dl] DB 0.2 mg/dl [0.1-0.3 mg/dl] AST 35 U/L [0-35 U/L] ALT 35 U/L [0-35 U/L] ALP 100 U/L [30-120 U/L] alb 1.8 g/dl [3.5-5.5 g/dl] glob 4.5 g/dl [1.5-3.5 g/dL] chol 100 mg/dl [<200] LFT
Case 3
40 2 PE : T 37 C, mildly pale, no jaundice, spider nevi, palmar erythrema, liver and spleen not palpated, shifting dullness + LFT : TB 1 mg/dl [0.3-1 mg/dl] DB 0.2 mg/dl [0.1-0.3 mg/dl] AST 35 U/L [0-35 U/L] ALT 35 U/L [0-35 U/L] ALP 100 U/L [30-120 U/L] alb 1.8 g/dl [3.5-5.5 g/dl] glob 4.5 g/dl [1.5-3.5 g/dL] chol 100 mg/dl [<200] LFT
Case 4
Prothrombin time
liver synthesize coagulation factor except FVIII most present in excess, clotting abnormal occur only when substantial impairment in ability of liver to synthesis PT : FI, II, V, VII, IX and X T1/2 FVII 6 hrs. (shortest) prognosis : acute, chronic hepatocellular disease
Prothrombin time
prolonged : vitamin K deficiency (malnutrition, malabsorption, antibiotics) massive transfusion congenital disease liver disease warfarin DIC
Prothrombin time
in vit K deficiency, vit K 10 mg SC decrease prolong PT >30% within 24 hrs. INR : no advantage over PT
AST catalyze transfer amino groups to form pyruvate cytosol (20%) and mitochondria (80%) T1/2 17 hr. (cytosol) 87 hr. (mitochondria) liver, cardiac muscle, skeletal muscle, kidneys, brain, pancreas, lungs, leucocytes, and RBC
ALT catalyze transfer amino groups to form oxaloacetate cytosol T1/2 47 hr. low concentration in other tissues
AST, ALT
level of transminase elevation predominant AST elevation rate of transaminase declination
AST/ALT ratio
< 1 : majority of liver disease >2
extrahepatic source alcoholic hepatitis ischemic and toxin acute Wilsons disease : hemolysis cirrhosis
AST/ALT ratio
90 80 70
60
50
40
30
20
10
alcoholic
chronic hepatitis
obstructive jaundice
viral hepatitis
Macro AST
Common medication
Acetaminophen overdose Statins NSAIDs Antibiotics Antiepileptics Antituberculosis drugs Herbal remedies, alternative medications and substance abuse
Case 5
40 LFT : TB 1 mg/dl [0.3-1 mg/dl] DB 0.2 mg/dl [0.1-0.3 mg/dl] AST 75 U/L [0-35 U/L] ALT 90 U/L [0-35 U/L] ALP 100 U/L [30-120 U/L] alb 4 g/dl [3.5-5.5 g/dl] glob 3 g/dl [1.5-3.5 g/dL] LFT management
Case 5.1
40 , BW 90 kg, Height 160 cm., truncal obesity LFT :TB 1 mg/dl [0.3-1 mg/dl] DB 0.2 mg/dl [0.1-0.3 mg/dl] AST 75 U/L [0-35 U/L] ALT 90 U/L [0-35 U/L] ALP 100 U/L [30-120 U/L] alb 4 g/dl [3.5-5.5 g/dl] glob 3 g/dl [1.5-3.5 g/dL] management
Diagnostic approach in mild elevations of the serum AST and ALT elevated ALT and AST < 5X history and PE, discontinue hepatotoxic medications confirm abnormality if an error is suspected liver chemistries, PT, albumin, CBC, hepatitis A, B and C serologies, Fe, TIBC, Ferritin
negative positive
lifestyle modification
discontinue alcohol and hepatotoxic drug, weight loss, diabetes control
abnormal
observe
Case 5.1
40 , BW 90 kg, Height 160 cm., truncal obesity LFT :TB 1 mg/dl [0.3-1 mg/dl] DB 0.2 mg/dl [0.1-0.3 mg/dl] AST 75 U/L [0-35 U/L] ALT 90 U/L [0-35 U/L] ALP 100 U/L [30-120 U/L] alb 4 g/dl [3.5-5.5 g/dl] glob 3 g/dl [1.5-3.5 g/dL] viral profile-negative
NAFLD/NASH
NAFLD = macrovesicular steatosis with mild or without inflammation, no fibrosis NASH = NAFLD + inflammation/ ballooning/fibrosis alcohol <70 g/D in women, <140 g/D in men 2 hits hypothesis
hyperinsulinemia increased FFA in liver steatosis hepatocyte necrosis and inflammation
NAFLD/NASH
asymptomatic, vague RUQ pain, fatigue, malaise hepatomegaly, splenomegaly, spider angiomata, palmar erythema, ascites AST, ALT 2-4x, AST/ALT<1 1/3 ALP slightly elevated
NAFLD/NASH
U/S bright liver CT-lower density than spleen MRI-bright on T1W biopsy (gold standard) : macrovesicular steatosis, parenchymal inflammation, hepatocyte necrosis, ballooning hepatocyte degeneration
NAFLD/NASH
weight reduction, exercise, control DM and dyslipidemia orlistat, sibutramine, Bariatric surgery avoidance of toxins : drugs, alcohol insulin sensitizing agents
thiazolidinediones metformin
Case 5.2
40 IVDU LFT :TB 1 mg/dl [0.3-1 mg/dl] DB 0.2 mg/dl [0.1-0.3 mg/dl] AST 75 U/L [0-35 U/L] ALT 90 U/L [0-35 U/L] ALP 100 U/L [30-120 U/L] alb 4 g/dl [3.5-5.5 g/dl] glob 3 g/dl [1.5-3.5 g/dL] investigation
Case 5.2
40 IVDU LFT :TB 1 mg/dl [0.3-1 mg/dl] DB 0.2 mg/dl [0.1-0.3 mg/dl] AST 75 U/L [0-35 U/L] ALT 90 U/L [0-35 U/L] ALP 100 U/L [30-120 U/L] alb 4 g/dl [3.5-5.5 g/dl] glob 3 g/dl [1.5-3.5 g/dL] HBsAg positive antiHCV negative
Case 6
40 LFT :TB 1 mg/dl [0.3-1 mg/dl] DB 0.2 mg/dl [0.1-0.3 mg/dl] AST 280 U/L [0-35 U/L] ALT 250 U/L [0-35 U/L] ALP 100 U/L [30-120 U/L] alb 4 g/dl [3.5-5.5 g/dl] glob 3 g/dl [1.5-3.5 g/dL] LFT management
Alcoholic hepatitis
appropriate history of alcoholic consumption, serologic exclusion of other liver disease 40-80 g/D, 20-40 g/D 10-12 yrs. characteristic pattern
AST rarely exceeds 300 IU/dl AST/ALT >1 in 92%, >2 in 70%
pyridoxine deficiency alcohol induces release of mitochondrial AST
GGT/ALP >2.5
Case 6
40 20
LFT :TB 1 mg/dl [0.3-1 mg/dl] DB 0.2 mg/dl [0.1-0.3 mg/dl] AST 280 U/L [0-35 U/L] ALT 250 U/L [0-35 U/L] ALP 100 U/L [30-120 U/L] alb 4 g/dl [3.5-5.5 g/dl] glob 3 g/dl [1.5-3.5 g/dL] LFT management
Alcoholic hepatitis
Rx abstinence alcohol drinking severe alcoholic hepatitis (DF >32)
[DF = 4.6 x (PT-control) + serum bilirubin] glucocorticoid (no GI bleeding and active infection) improve survival, not reduce HRS pentoxyfilline reduce HRS
AST predominate : medication/toxin, ischemic >75 times : ischemic, toxic, viral (less common)
Case 7
40 underlying disease AF, HT CHF LFT :TB 2 mg/dl [0.3-1 mg/dl] DB 1 mg/dl [0.1-0.3 mg/dl] AST 2500 U/L [0-35 U/L] ALT 2200 U/L [0-35 U/L] ALP 180 U/L [30-120 U/L] alb 4 g/dl [3.5-5.5 g/dl] glob 3 g/dl [1.5-3.5 g/dL] LFT, DDx management
Ischemic hepatitis
Ischemic hepatitis
sudden and massive (>2000) elevation of liver enzyme, tend to decrease rapidly and return normal within 1 wk. mild and transient elevation of bilirubin (80% < 2 mg/dl) and ALP extreme elevation LDH (>5000), ALT/LDH < 1.5 rare acute liver failure Rx and prognosis underlying disease
Ischemic hepatitis
Case 8
40 RUQ pain 12 LFT :TB 2 mg/dl [0.3-1 mg/dl] DB 1.5 mg/dl [0.1-0.3 mg/dl] AST 1200 U/L [0-35 U/L] ALT 1400 U/L [0-35 U/L] ALP 180 U/L [30-120 U/L] alb 4 g/dl [3.5-5.5 g/dl] glob 3 g/dl [1.5-3.5 g/dL] LFT, DDx management
Case 8
40 RUQ pain 12 LFT :TB 2 mg/dl [0.3-1 mg/dl] DB 1.5 mg/dl [0.1-0.3 mg/dl] AST 1000 U/L [0-35 U/L] ALT 1300 U/L [0-35 U/L] ALP 180 U/L [30-120 U/L] alb 4 g/dl [3.5-5.5 g/dl] glob 3 g/dl [1.5-3.5 g/dL] U/S : bile duct dilatation with gall stone F/U LFT 72 hr. AST 300 U/L, ALT 600 U/L
LDH
non specific rhabdomyolysis, MI, hemolysis, stroke, renal infarction, acute or chronic liver disease use in
ischemic hepatitis : transient, massive elevation malignant infiltration of liver : sustained elevation with ALP
Bilirubin
UDP-glucoronyltransferase
urobilinogen
stercobilinogen
Bilirubin
Direct bilirubin : reacted directly with reagent Indirect bilirubin : require addition of alcohol for color development Unconjugated bilirubin = indirect form Conjugated bilirubin = bilirubin mono and di-glucoronides
Diagnostic approach in elevated serum bilirubin elevated bilirubin History and PE unconjugated bilirubin normal ALP, ALT, AST conjugated bilirubin
ineffective erythropoiesis : folate, IDA drug : rifampicin, ribavirin, probenecid resolution of hematoma Gilberts syndrome Crigler-Najjar syndrome
Case 9
30 LFT :TB 3 mg/dl [0.3-1 mg/dl] DB 0.2 mg/dl [0.1-0.3 mg/dl] AST 30 U/L [0-35 U/L] ALT 30 U/L [0-35 U/L] ALP 100 U/L [30-120 U/L] alb 4 g/dl [3.5-5.5 g/dl] glob 3 g/dl [1.5-3.5 g/dL] LFT, DDx management
Gilberts syndrome
benign, unconjugated hyperbilirubinemia with otherwise normal liver chemistries up to 5% of normal population polymorphism in TATA box of gene encoding bilirubin UDP-GT impair ability to conjugate bilirubin prominent in fasting state, systemic illnesses, hemolysis, some medications
Gilberts syndrome
Dx :
asymptomatic, healthy mild unconjugated hyperbilirubinemia (<4 mg/dl) with otherwise normal liver chemistries test exclusion medications and hemolysis
Case 10
30 3 PE : T 38 C, markedly pale, mild jaundice, no sign of chronic liver disease, liver and spleen not palpated LFT : TB 5.4 mg/dl [0.3-1 mg/dl] DB 0.8 mg/dl [0.1-0.3 mg/dl] AST 120 U/L [0-35 U/L] ALT 45 U/L [0-35 U/L] ALP 110 U/L [30-120 U/L] alb 3.6 g/dl [3.5-5.5 g/dl] glob 3.6 g/dl [1.5-3.5 g/dL] LFT DDx management
Indirect Hyperbilirubinemia
Bilirubin hemolysis Gilberts syndrome 5 mg/dl 5 mg/dl AST, ALT increase AST normal Alb N N Glob N N PT N N
Diagnostic approach in elevated serum bilirubin elevated bilirubin History and PE unconjugated bilirubin normal ALP, ALT, AST conjugated bilirubin
Conjugated hyperbilirubinemia
DB > 50% of total bilirubin cant differentiate obstruction and parenchymal disease Delta fraction
CB tightly bound to albumin tendency of hyperbilirubinemia to resolve more slowly than other biochemical tests
Conjugated hyperbilirubinemia
Bile duct obstruction Hepatitis Cirrhosis Medications/Toxins Primary biliary cirrhosis Primary sclerosing cholangitis Sepsis Total parenteral nutrition Intrahepatic cholestasis of pregnancy Benign recurrent cholestasis Vanishing bile duct syndromes Dubin-Johnson syndrome Rotor syndrome
Diagnostic approach in elevated serum bilirubin elevated bilirubin History and PE unconjugated bilirubin normal ALP, ALT, AST conjugated bilirubin normal ALP, ALT, AST abnormal ALP, ALT, AST
Rotors syndrome Dubin-Johnson syndrome
Diagnostic approach in elevated serum bilirubin elevated bilirubin History and PE unconjugated bilirubin normal ALP, ALT, AST conjugated bilirubin normal ALP, ALT, AST abnormal ALP, ALT, AST AST, ALT ALP Dubin-Johnson syndrome predominate predominate / /
Rotors syndrome as elevated ALT evaluation U/S
present
absent
ERCP
Case 11
30 3 PE : T 37 C, not pale, mild jaundice, no sign of chronic liver disease, liver and spleen not palpated LFT : TB 6.2 mg/dl [0.3-1 mg/dl] DB 4.8 mg/dl [0.1-0.3 mg/dl] AST 100 U/L [0-35 U/L] ALT 120 U/L [0-35 U/L] ALP 520 U/L [30-120 U/L] alb 3.6 g/dl [3.5-5.5 g/dl] glob 3.6 g/dl [1.5-3.5 g/dL] LFT management
Alkaline phosphatase
family of isoenzyme catalyze hydrolysis of No. of P esters at alkaline pH require Zn for activity present in nearly all tissues (liver, bone, intestinal, placenta, kidney) liver ALP
isoenzyme, 5-nucleotidase, GGT
Alkaline phosphatase
Physiologic >60 yr. child and adolescent pregnancy blood group O post meal (fatty meal) Pathologic intrahepatic extrahepatic
Alkaline phosphatase
Intrahepatic
viral alcohol drug pregnancy PBC PSC TPN sepsis vanishing bile duct syndrome benign recurrent cholestasis benign post-op. cholestasis paraneoplastic syndrome venoocclusive disease GVHD
Extrahepatic
intraluminal obstruction : gall stones, ascariasis, hemobilia disease of BD : PSC, choledochal cyst, cholangioCA, AIDS cholangiopathy external compression : LN, GB CA, Mirizzis syndrome, CA pancreas, ampullar adenoma
Alkaline phosphatase
in biliary obstruction
induction of ALP synthesis 2 to enhanced translation of mRNA ALP levels, may not rise until 1-2 days T1/2 1 wk, take several days for levels to normalise after resolution
Alkaline phosphatase
initial evaluation : determine hepatic or nonhepatic origin, concomitant elevation of other serum LFT level not a reliable indicator of severity of underlying liver disease degree not help to distinguish intrahepatic and extrahepatic
Infiltrative diseases
modest (up to 3x) rise in aminotransferase, and up to 20x rise in ALP, bilirubin N-5x
TB Fungal infection HCC Lymphoma Metastatic malignancy Amyloidosis Sarcoidosis Other granulomatous diseases
Alkaline phosphatase
ALP > 1000 : malignant biliary obstruction, sepsis, AIDS with systemic infection decrease : hypothyroidism, pernicious anemia, Zn deficiency, congenital, Wilsons disease, severe hepatic insufficiency
Diagnostic approach in elevated serum alkaline phosphatase elevated ALP History and PE normal bilirubin, ALT, AST GGT or 5nucleotidase
negative positive
yes
no
not hepatobiliary
no duct dilatation
ERCP
AMA
negative
observation
> 6 months
40 LFT : TB 1 mg/dl [0.3-1 mg/dl] DB 0.2 mg/dl [0.1-0.3 mg/dl] AST 35 U/L [0-35 U/L] ALT 35 U/L [0-35 U/L] ALP 320 U/L [30-120 U/L] alb 1.8 g/dl [3.5-5.5 g/dl] glob 2 g/dl [1.5-3.5 g/dL] LFT
Case 12
-glutamyltransferase (GGT)
catalyzed transfer of -glutamyl groups of peptides to other amino acid abundant in liver, kidney, pancreas, intestine, and prostate, spleen, heart, brain but not in bone T1/2
7-10 days 28 days in alcohol-associated liver injury
-glutamyltransferase (GGT)
increase
alcohol drug anticonvulsant (CBZ, phenytoin, and barbiturate), warfarin, OC almost all type of liver diseases COPD, renal failure, DM, hyperthyroidism, RA, AMI, pancreatic disease
40 LFT : TB 1 mg/dl [0.3-1 mg/dl] DB 0.2 mg/dl [0.1-0.3 mg/dl] AST 35 U/L [0-35 U/L] ALT 35 U/L [0-35 U/L] ALP 320 U/L [30-120 U/L] alb 1.8 g/dl [3.5-5.5 g/dl] glob 2 g/dl [1.5-3.5 g/dL] GGT 86 [0-50] LFT
Case 12
Summary
Hepatocellular necrosis toxin/ ischemia AST/ALT ALP Bilirubin PT albumin 50-100X 1-3X 1-5X viral 5-50X 1-3X 1-30X alcohol 2-5X 1-10X 1-30X Biliary obstruction complete 1-5X 2-20X 1-30X partial 1-5X 2-10X 1-5X 1-3X 1-20X 1-5X normal normal Infiltration
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