OGDEN SURGICAL-MEDICAL SOCIETY
68TH ANNUAL CONFERENCE - 2013
What the LFTs are Telling You
Avoiding Common Mistakes
Norman L. Sussman, MD
Baylor College of Medicine
Houston, Texas
S
OGDEN SURGICAL-MEDICAL SOCIETY
68TH 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
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/ULN
AP/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
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 Amiodarone
Dynamic AST/ALT Ratio
 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
Remien et al., Hepatology 2012
MALD
Model of Acetaminophen-related Liver Damage
Remien et al., Hepatology 2012
Biliary Architecture - Bile Flow
Epithelial Cells are Polarized
Hollow Organ
Liver
Lumen = Bile Canaliculus = Brush Border
Basolateral Aspect
Alkaline Phosphatase
 Located on the bile canliculus
Phospholipase C
 Three genes
cleavage site
 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
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
Y = sufate,
glucuronate
Z = glycine,
taurine
NTCP – Na
Taurocholate
Cotransporting
Polypeptide
MRP2 –
Multidrug
Resistance
Protein 2
BSEP –
Bile Salt
Export
Protein
OATP –
Organic
Anion
Transport
Protein
Canalicular Transporters & Diseases
Unknown
Bile acids
Sterols
Phospholipids
Conjugated Bilirubin
& other conjugates
FIC1 – PFIC1
BSEP – PFIC2
ABC G5/G8 – Sitosterolemia
MDR3 – PFIC3
MRP2 – Dubin-Johnson
Coagulation Factors
Liver 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 Formula
The 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
<10
10-19
20-29
30-39
>40
90 Day Mortality (%)
2-8
6-29
50-76
62-83
100
The 2g Sodium Diet
Spot 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)
Hyponatremia
997 consecutive patients from 28 centers in Europe, North
and South America, and Asia for 28 days
 Inpatients and outpatients with cirrhosis and ascites
Serum Sodium
(mEq/L)
Heptorenal Syndrome
Hepatic Encephalopathy
GI bleeding
Bacterial Peritonitis
<130
131-135
>135
3.45
3.40
1.48
2.36
1.75
1.69
0.93
1.44
1 (ref)
1 (ref)
1 (ref)
1 (ref)
Angeli P et al. Hepatology. 2006;44:1535–1542.
Hyponatremia – MELD-Na
Kim et al, NEJM
2008;359:1018-26
Liver Failure
 Liver injury
 ALT & AST
 Synthetic failure
 INR, F-V, F-VII
 Albumin
 Bilirubin
 Portal hypertension
 Ascites/edema
 Encephalopathy
 Varices
 Renal failure
 Cardiomyopathy
 Pulmonary Disease
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
AP:AST (or ALT)
ratio
>3
<1.5
-2
+2
-globulin or IgG
above normal
>2.0
1.5-2.0
1.0-1.5
<1.0
ANA, SMA, or antiLKM1 titers
>1:80
1:80
1:40
<1:40
DR3 or DR4
+1
Immune disease
Thyroiditis, colitis,
others
+2
+3
+2
+1
0
Other markers
Anti-SLA, actin,
LC1, pANCA
+2
+3
+2
+1
0
Histological features
Interface hepatitis
Plasmacytic
Rosettes
None of above
Biliary changes
Other features
+3
+1
+1
-5
-3
-3
Treatment response
Complete
Relapse
+2
+3
AMA
Positive
-4
Viral markers
Positive
Negative
-3
+3
Yes
No
-4
+1
Pretreatment score:
Definite diagnosis
Probable diagnosis
<25 g/day
>60 g/day
+2
-2
Post-treatment score:
Drugs
Alcohol
Definite diagnosis
Probable diagnosis
>15
10-15
>17
12-17
*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
20-30
30-40
Promyelocytic leukemia protein
22
?
sp140
10
53
10-15
?
Centromere
<5
?
Laminin B
22
14-41
26-49
29
sp100
SOX13
SMA
Vierling 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
 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
ALT
AST
AP
Bili/D
Alb
INR
WBC
Hb
Plate
18
36
180
12.4/10.9
3.1
2.3
18.7
11.4
98,0000
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