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S
OGDEN SURGICAL-MEDICAL SOCIETY68TH ANNUAL CONFERENCE - 2013
Norman L. Sussman, MDBaylor College of Medicine
Houston, Texas
What the LFTs are Telling YouAvoiding Common Mistakes
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OGDEN SURGICAL-MEDICAL SOCIETY68TH ANNUAL CONFERENCE - 2013
This presentation has no commercial content, promotes no commercial vendor and is not supported financially by any commercial vendor.
I receive no financial remuneration from any commercial vendor related to this presentation
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Question 1: Acute or Chronic?
Cirrhosis Platelets Imaging
Chronicity & severity Prior studies Albumin Bilirubin INR
Injury ALT/AST
Cholestasis Alk Phos GGT 5’NT Biliary imaging
U/S, MRCP, ERCP
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Question 2: Hepatocellular or Cholestatic
ALT/ULNAP/ULN
>5 = hepatocellular <2 = cholestatic
Or, just look at the fold increase of ALT and AP
Normal ALT Women < 19 IU/mL Men < 30 IU/mL
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Aspartate Aminotransferase (AST/SGOT)
Alanine Aminotransferase (ALT/SGPT)
Markers of Cell Destruction ALT is more specific to the liver
Usually higher in chronic liver injury (steady state) Viral hepatitis, AIH, NAFLD
AST may be higher than ALT Cirrhosis Alcohol (pyridoxine deficiency) Early phase of acute liver injury Other organ damage – eg rhabdomyolysis,
tumors
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Acute Liver injury Acetaminophen, Shock, IV
AmiodaroneDynamic AST/ALT Ratio
Remien et al., Hepatology 2012
Peak injury about 48 hrs AST is initially 2x ALT Differential clearance
AST – 50%/day ALT – 33%/day Equalize at about 96
hrs Bilirubin, INR, and
creatinine are key to assessing survival
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MALDModel of Acetaminophen-related Liver
Damage
Remien et al., Hepatology 2012
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Biliary Architecture - Bile Flow
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Lumen = Bile Canaliculus = Brush Border
Basolateral Aspect
Hollow Organ Liver
Epithelial Cells are Polarized
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Alkaline Phosphatase
Located on the bile canliculus Three genes
Liver/kidney/bone Intestine Placenta (man and great apes)
PI-glycan anchor (PI-g tailed proteins) GGT, 5’-nucleotidase
GGT is inducible by alcohol Access to the sinusoid (blood side of the cell) Low in patients with Wilson disease
Phospholipase Ccleavage site
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Albumin & AFP
Proteins – made by the liver AFP is the fetal analogue of albumin
Made when cells revert to a fetal phenotype – part of a coordinated switch to fetal genes Liver regeneration (eg recovery
from ALF) Inflammation (injury with
regeneration) Liver cancer
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Prealbumin
Actually Transthyretin Transports thyroxine and retinol
Used to assess nutrition 2-4 day half life Affected by inflammation
Mis-folded TTR is the most common protein in amyloid
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Bilirubin Transport
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Bilirubin
Organic anion derived from hemoglobin Measured by diazo (Van Den Bergh)
reaction Direct (conjugated) vs. indirect
Indirect – albumin-bound Direct – water soluble (urine)
Delta (albumin-bound) – clears slowly Liver disease conjugated bilirubinemia Jaundice may occur in right heart failure
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NTCP – Na TaurocholateCotransportingPolypeptide
MRP2 – MultidrugResistanceProtein 2
Y = sufate,glucuronate
Z = glycine, taurine
BSEP – Bile Salt Export Protein
OATP – Organic Anion Transport Protein
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FIC1 – PFIC1
BSEP – PFIC2ABC G5/G8 – Sitosterolemia
MDR3 – PFIC3MRP2 – Dubin-Johnson
Bile acids
Conjugated Bilirubin& other conjugates
Unknown
Phospholipids
Sterols
Canalicular Transporters & Diseases
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Coagulation FactorsLiver makes factors I, II, V, VII, IX, X
PT/INR: I, II, V, VII, X Prolonged PT/INR:
Congenital Liver failure Vitamin K deficiency Warfarin
Vitamin K dependent factors: II, VII, IX, X FV – shortest half-life and not vitamin
K dep. Vitamin K replacement
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Ammonia
Not especially useful Occasional adult with urea cycle
defect
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MELD FormulaThe Basis for Organ Allocation since
Feb 2002
6.3 + ([0.957 x log creat] + [0.378 x log bili] + [1.12 x log INR] + 0.643) x 10
Score
90 Day Mortality (%)
<10 2-810-19
6-29
20-29
50-76
30-39
62-83
>40 100
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The 2g Sodium DietSpot urine Na+>K+ predicts >78 mmol sodium excretion with 90% accuracy
2g Na+ = 88 mmole 78 mmol urinary + 10 mmol involuntary loss
Patients who excrete >78 mmol/24h can be treated with 2g dietary restriction alone
Assess excretion with 24h urinary sodium 24h creatinine excretion to test completeness
15 mg/kg for men) or 10 mg/kg for women If spot urine Na+>K+, the patient is excreting
>78 mmol Na+ (i.e. consuming >2 Na+ per day)
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Hyponatremia997 consecutive patients from 28 centers in Europe, North and South America, and Asia
for 28 days
Serum Sodium (mEq/L)
<130 131-135
>135
Heptorenal Syndrome
3.45 1.75 1 (ref)
Hepatic Encephalopathy
3.40 1.69 1 (ref)
GI bleeding 1.48 0.93 1 (ref)Bacterial Peritonitis 2.36 1.44 1 (ref)Angeli P et al. Hepatology. 2006;44:1535–1542.
Inpatients and outpatients with cirrhosis and ascites
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Hyponatremia – MELD-Na
Kim et al, NEJM 2008;359:1018-26
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Liver Failure
Portal hypertension Ascites/edema Encephalopathy Varices
Renal failure Cardiomyopathy Pulmonary Disease
Liver injury ALT & AST
Synthetic failure INR, F-V, F-VII Albumin Bilirubin
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Viral Hepatitis
Acute hepatitis panel Anti-HAV IgM, anti-HBc IgM, HBsAg, anti-
HCV The rest
HAV immunity: anti-HAV (total) Anti-HBc (total), anti- HBs Viral titers: HBV DNA, HCV RNA
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Hepatitis B
Anti-HBc IgM – current infection or flare IgG – prior infection
HBsAg: current infection Anti-HBs: immunity (titer) HBeAg and anti-HBe: stage of
disease
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Autoimmune Markers
AIH Usual: ANA, ASMA, anti-actin, LKM Unusual: SLA, ASGP, ANCA Increased IgG
PBC AMA Increased IgM
PSC: None IgG4
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Gender Female +2 HLA DR3 or DR4 +1
AP:AST (or ALT) ratio
>3<1.5
-2+2
Immune disease Thyroiditis, colitis, others
+2
-globulin or IgG above normal
>2.01.5-2.01.0-1.5
<1.0
+3+2+10
Other markers Anti-SLA, actin, LC1, pANCA
+2
ANA, SMA, or anti-LKM1 titers
>1:801:801:40
<1:40
+3+2+10
Histological features Interface hepatitisPlasmacyticRosettesNone of aboveBiliary changesOther features
+3+1+1-5-3-3
AMA Positive -4 Treatment response CompleteRelapse
+2+3
Viral markers Positive Negative
-3+3
Drugs YesNo
-4+1
Pretreatment score:Definite
diagnosis Probable diagnosis
>1510-15
Alcohol <25 g/day>60 g/day
+2-2
Post-treatment score:
Definite diagnosis Probable diagnosis
>1712-17
*Adapted from Alvarez F, Berg PA, Bianchi FB, et al. J. Hepatology 1999;31:929-938.
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AMA-Positive & AMA-Negative PBCAutoantibody AMA+ Group
(%)AMA- Group
(%)AMA 100 0ANA 20-15 71-100gp210 10-20 50p63 25 25Laminin B receptor <1 <1sp100 20-30 30-40Promyelocytic leukemia protein
22 ?
sp140 10 53SOX13 10-15 ?Centromere <5 ?Laminin B 22 14-41SMA 26-49 29Vierling JM. Clin Liver Dis. 2004; 8:177-94
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FibroTest/Fibrosure®
Five serum tests a-2 macroglbulin Haptoglobin GGT T-bilirubin Apolipoprotein A1
For a cutoff of 0.31, the negative predictive value for excluding significant fibrosis = 91%
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49 year old female
ALT 18AST 36AP 180Bili/D 12.4/10.9Alb 3.1INR 2.3WBC 18.7Hb 11.4Plate 98,0000
Admitted through the ER with jaundice, fever, chills, and RUQ pain for past three days
Pain worse when the car hit a bump
U/S: thickened gall bladder, large liver
Murphy sign during u/s
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Does this patient need a cholecystectomy?
History Gallstones – mother and
grandmother Works from home Drinks – 1-2 glasses of Scotch daily
Diagnosis – acute alcoholic hepatitis
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Summary
ALT/AST = liver injury ALT is higher in hepatitis AST his higher in acute liver injury and
cirrhosis AP/GGT/5’NT = cholestasis Wilson disease = low AP AFP is an analogue of albumin =
regeneration
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Summary
Bilirubin Direct = cholestasis & liver injury Indirect = hemolysis, Gilbert
Serum ammonia has little utility Occasional urea cycle defect
PT/INR – higher in zone 3 necrosis Severe liver injury
Hyperbilirubinemia Abnormal clotting