1. 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

2. 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

3. 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

4. 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

5. 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

6. 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

7. MALD Model of Acetaminophen-related Liver Damage
Remien et al., Hepatology 2012

11. Biliary Architecture - Bile Flow

12. Epithelial Cells are Polarized
Hollow Organ
Liver
Lumen = Bile Canaliculus = Brush Border
Basolateral Aspect

13. 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 C
cleavage site

14. 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

15. 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

16. Bilirubin Transport

17. 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

18. 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

19. Canalicular Transporters & Diseases
FIC1 – PFIC1
BSEP – PFIC2
ABC G5/G8 – Sitosterolemia
MDR3 – PFIC3
MRP2 – Dubin-Johnson
Bile acids
Conjugated Bilirubin
& other conjugates
Unknown
Phospholipids
Sterols

20. 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

21. Ammonia
Not especially useful
Occasional adult with urea cycle defect

22. 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] ) x 10
Score
90 Day Mortality (%)
<10
2-8
10-19
6-29
20-29
50-76
30-39
62-83
>40
100

23. 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)

24. 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)
<130
>135
Heptorenal Syndrome
3.45
1.75
1 (ref)
Hepatic Encephalopathy
3.40
1.69
GI bleeding
1.48
0.93
Bacterial Peritonitis
2.36
1.44
Angeli P et al. Hepatology. 2006;44:1535–1542.

25. Hyponatremia – MELD-Na
Kim et al, NEJM 2008;359:

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

27. 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

28. 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

29. Autoimmune Markers AIH Usual: ANA, ASMA, anti-actin, LKM
Unusual: SLA, ASGP, ANCA
Increased IgG
PBC
AMA
Increased IgM
PSC: None
IgG4

30. Thyroiditis, colitis, others
Gender
Female +2
HLA
DR3 or DR4 +1
AP:AST (or ALT) ratio
>3
<1.5 -2
Immune disease
Thyroiditis, colitis, others
-globulin or IgG above normal
>2.0
<1.0 +3
Other markers
Anti-SLA, actin, LC1, pANCA
ANA, SMA, or anti-LKM1 titers
>1:80
1:80
1:40
<1:40
Histological features
Interface hepatitis
Plasmacytic
Rosettes
None of above
Biliary changes
Other features -5 -3
AMA
Positive -4
Treatment response
Complete
Relapse
Viral markers
Positive Negative
Drugs
Yes No
Pretreatment score:
Definite diagnosis Probable diagnosis
>15
10-15
Alcohol
<25 g/day
>60 g/day
Post-treatment score: Definite diagnosis Probable diagnosis
>
*Adapted from Alvarez F, Berg PA, Bianchi FB, et al. J. Hepatology 1999;31:

31. AMA-Positive & AMA-Negative PBC
Autoantibody
AMA+ Group (%)
AMA- Group (%)
AMA
100
ANA
20-15
71-100
gp210
10-20 50
p63 25
Laminin B receptor
<1
sp100
20-30
30-40
Promyelocytic leukemia protein 22 ?
sp140 10 53
SOX13
10-15
Centromere
<5
Laminin B
14-41
SMA
26-49 29
Vierling JM. Clin Liver Dis. 2004; 8:177-94

32. 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%

33. 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 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

34. 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

35. 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

36. 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