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OGDEN SURGICAL-MEDICAL SOCIETY68TH ANNUAL CONFERENCE - 2013

Norman L. Sussman, MDBaylor College of Medicine

Houston, Texas

What the LFTs are Telling YouAvoiding Common Mistakes

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.

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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

Question 2: Hepatocellular or Cholestatic

ALT/ULNAP/ULN

>5 = hepatocellular <2 = cholestaticOr, just look at the fold increase of ALT and

AP Normal ALT

Women < 19 IU/mL Men < 30 IU/mL

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

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

MALDModel of Acetaminophen-related Liver

Damage

Remien et al., Hepatology 2012

Biliary Architecture - Bile Flow

Lumen = Bile Canaliculus = Brush Border

Basolateral Aspect

Hollow Organ Liver

Epithelial Cells are Polarized

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

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

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

Bilirubin Transport

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

NTCP – Na TaurocholateCotransportingPolypeptide

MRP2 – MultidrugResistanceProtein 2

Y = sufate,glucuronate

Z = glycine, taurine

BSEP – Bile Salt Export Protein

OATP – Organic Anion Transport Protein

FIC1 – PFIC1

BSEP – PFIC2ABC G5/G8 – Sitosterolemia

MDR3 – PFIC3

MRP2 – Dubin-Johnson

Bile acids

Conjugated Bilirubin& other conjugates

Unknown

Phospholipids

Sterols

Canalicular Transporters & Diseases

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

Ammonia

Not especially useful Occasional adult with urea cycle

defect

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

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)

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

Hyponatremia – MELD-Na

Kim et al, NEJM 2008;359:1018-26

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

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

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

Autoimmune Markers

AIH Usual: ANA, ASMA, anti-actin, LKM Unusual: SLA, ASGP, ANCA Increased IgG

PBC AMA Increased IgM

PSC: None IgG4

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.

AMA-Positive & AMA-Negative PBC

Autoantibody AMA+ Group (%)

AMA- Group (%)

AMA 100 0

ANA 20-15 71-100

gp210 10-20 50

p63 25 25

Laminin B receptor <1 <1

sp100 20-30 30-40

Promyelocytic leukemia protein

22 ?

sp140 10 53

SOX13 10-15 ?

Centromere <5 ?

Laminin B 22 14-41

SMA 26-49 29Vierling JM. Clin Liver Dis. 2004; 8:177-94

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%

49 year old female

ALT 18

AST 36

AP 180

Bili/D 12.4/10.9

Alb 3.1

INR 2.3

WBC 18.7

Hb 11.4

Plate 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

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

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

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