Abnormal Liver Enzymes

Patrick Northup, MD, MHS Medical Director, Liver Transplantation

Program Director, GI and Hepatology Fellowship

University of Virginia liver@virginia.edu

Case presentation

43 year old man

Needs to start statin

AST 64, ALT 72, ALP 88, TB 1.0

No new meds/herbs

One drink EtOH per day

No high risk practices or h/o transfusion

Question one

Northup: Abnormal LFTS

What would your next step be?

A. Viral hepatitis serologies, ferritin, iron studies, ANA, AMA

B. above plus RUQ ultrasound

C. Advise patient to stop EtOH and recheck LFTs in 3 months

D. Refer to hepatology

E. Schedule f/u visit with your partner next week when you are on vacation

10

Results

Northup: Abnormal LFTS

0

0.2

0.4

0.6

0.8

1

1.2

A B C D E F

Overview

• Definition of abnormal LFTs

• Abnormal AST and ALT • Less than 5x upper limits of normal

• Greater than 15x upper limits of normal

• Elevations of ALP and total bilirubin

• Initial approach to workup

• When to refer?

What are the LFTs?

ALT / AST Hepatocellular damage

TBili / ALP Cholestasis, impaired

conjugation, or biliary

obstruction

PT-INR / ALB Synthetic function

GGT / 5’-NT Cholestasis or biliary

obstruction

LDH Hepatocellular damage, not

specific for hepatic disease

What is abnormal?

You think you are here

You may be here

What is abnormal?

19,877 US Air Force recruits, 99 (0.5%) had confirmed ALT elevations

• Only 12 had identifiable liver disease

• Most people with abnormal LFTs have no identifiable liver disease

Kundratos Dig Dis Sci 1993

What is abnormal?

1033 blood donors, 186 with HCV, 40 patients treated for HCV Piton

Hepatology 1998

All tested once for level of ALT

Blood

Donors

Active

HCV

Cured

HCV

96%

27%

42%

Percent with NORMAL

LFTs

Normal ALT does not guarantee “normal” liver

What is normal?

Normal ranges at UVAHS:

Test Lower limit

normal

Upper limit

normal

T. Bili (mg/dL) 0.3 1.2

ALP (U/L) 40 150

AST (U/L) 0 35

ALT (U/L) 0 55

Hepatocellular injury

Primarily elevations of AST and or ALT

1. Mild: less than 5x ULN

2. Moderate: 5-15x ULN

3. Severe: greater than 15x ULN

Could be due to

causes from

either group

AST/ALT less than 5x ULN

Most common clinical scenario

Widest differential diagnosis

Consider non-hepatic causes

• Hemolysis

• Myopathy

• Thyroid disease

• Acute muscle injury due to strenuous exercise

AST/ALT less than 5x ULN

Chronic viral (B and C)

Acute viral (CMV, EBV)

Steatohepatitis / NAFLD

Hemochromatosis

Medications / toxins

Autoimmune hepatitis

Alpha-1 antitrypsin

Wilson’s disease

Celiac disease

Cirrhosis

There is more alcohol than you think…

AST/ALT less than 5x ULN - Meds

Augmentin

Amiodarone

Anticonvulsants

Glyburide

Niacin

Nitrofurantoin

NSAIDS

Sulfonamides

Glitazones

Herbs

Anabolic steroids

Cocaine

Ecstasy

PCP

Carbon tetrachloride

Hydrazine

Toluene

Chloroform

livertox.nih.gov

Suspected NAFLD/NASH

Suspected NAFLD/NASH

• Rule out other liver diseases (? specialist referral)

• In young you must think about Wilson’s dz and AIH

• In polypharmacy, look at meds (amiodarone, corticosteroids)

• If all negative, manage metabolic syndrome aggressively, recheck in 4-6 months

Case presentation

• 21 yo male student

• RUQ pain, nausea, “hungover”

• 12-14 beers per day for the past week

• Returned from spring break in Cancun

• TB 7.9, ALT 1089, AST 2036, ALP 199

Question two

Northup: Abnormal LFTS

Which is least likely to be the source of these findings?

1. Acute hepatitis A

2. Acetaminophen toxicity

3. Amanita toxicity

4. Acute alcoholic hepatitis

5. Acute hepatitis B

10

Results

Northup: Abnormal LFTS

0

0.2

0.4

0.6

0.8

1

1.2

AST/ALT more than 15x ULN

Much smaller differential diagnosis

More likely to have an acute symptomatic presentation

History and physical exam are key

When associated with encephalopathy and coagulopathy termed liver failure

*Alcohol alone is rarely (if ever) solely responsible for this degree of elevation

AST/ALT more than 15x ULN

• Acute viral infection (A-E, HSV)

• Medication or toxin

• Acetaminophen

• Rx meds

• Amanita

• Ischemia

• Hypotension

• Budd-Chiari

• Autoimmune hepatitis

• Acute bile duct obstruction

• Wilson’s disease (rare)

• Acute hepatic artery ligation or clot

Enzymes > 15x ULN

• Can be life threatening

• Can progress rapidly, sometimes in as little as 48 hours

• Limited differential diagnosis

• Need to assess for synthetic dysfunction

• INR

• Bilirubin

• Altered mentation

Isolated increased bilirubin

Unconjugated (indirect)

Gilbert’s syndrome (rarely >4)

Hemolysis (heart valve, vascular prosthesis)

Ineffective erythropoiesis

Hematoma resorption

TIPS shunt

Neonatal / Crigler-Najjar

Isolated increased ALP

Hepatobiliary causes Biliary obstruction

PBC / PSC

Medications

Infiltrating disease

• TB

• Sarcoid

• Fungal

Metastases

Nonhepatic Bone disease / trauma

Pregnancy

Chronic renal disease

Non-liver malignancy

CHF

Normal childhood growth

Chronic inflammation

Increased ALP and TBili

Biliary obstruction

Medications

Chronic viral hepatitis

PBC / PSC

Sepsis

TPN

Pregnancy diseases

Cirrhosis

Meds causing cholestasis

Anabolic steroids

Allopurinol

Augmentin

ACE-inhibitors

Anticonvulsants

Erythromycin

Estrogens

HIV meds

NSAIDS

TMP-sulfa

Doxy / tetracycline

Question three

Northup: Abnormal LFTS

What is your initial lab/radiology workup of abnormal liver chemistries?

A. Referral to hepatologist

B. Stop meds / EtOH repeat chemistry in 3 months

C. Repeat chemistries, HBs-Ag, HCV-Ab, Iron, TIBC, ferritin

D. above plus RUQ ultrasound

E. above plus abdominal CT

10

Results

Northup: Abnormal LFTS

0

0.2

0.4

0.6

0.8

1

1.2

Referral tohepatologist

Stop meds /EtOH repeat

chemistry in 3months

Repeatchemistries,

HBs-Ag, HCV-Ab, Iron, TIBC,

ferritin

above plusRUQ

ultrasound

above plusabdominal CT

Costs of labs / radiology

51

37

129

80

93

108

920

600

Hepatic Panel

Hepatitis ABC

HCV VL and geno

Abd U/S

Charge Medicare Reimb

Based on 2001 USD. Green Gastroenterol 2002: 1367-1384

Initial workup of abnormal enzymes

• History and physical exam can help narrow the workup

• Marked abnormalities in chemistries, signs of chronic liver disease or cirrhosis should prompt expedited workup

• Extensive workup can be exhaustive and expensive and may be unnecessary in some cases

Initial workup of abnormal enzymes

• An isolated minor abnormality (<1.5 times upper limit of normal) in an asymptomatic individual should prompt retesting in 1 to 3 months, particularly after addressing potential causes or modifiable risk factors.

• Screen for HCV if in the right age group

• Disease specific tests including auto-antibodies, copper and iron studies, alpha-fetoprotein (AFP), and other specific viral markers should only be obtained in appropriate circumstances and usually in consultation with a specialist.

Initial more detailed workup

Probably the most cost-effective and efficient initial workup for <5x normal:

• Stop EtOH/meds, recheck chem panel in 6-8 weeks

• If normal, recheck again in 6-8 weeks

• If abnormal: HBsAg, HCV-Ab, ferritin, TIBC, +/- ultrasound

• If no findings and persistent increase, then refer

Last Case

43 yo female with many years of MS. Multiple medications used for therapy

• Avonex, Copaxone distant past: poor tolerance

• Betaseron stopped 2008

• Gilenya 2011: fatigue

• Tysabri in past, restarted April 2013

Labs

• ALP 468, ALT 1039, AST 682 • Significant abdominal pain, N/V, poor po intake

Other workup

• HBV studies negative

• Hepatitis C positive

• Anti-nuclear ab positive 1:80

• RUQ U/S showed no abnormalities

• No recent acetaminophen use

What to do now?

Liver Biopsy

Summary

• Abnormal liver enzymes can be caused by many things • Less than 5x upper limits of normal is rarely an

emergency and requires a lot of detective work

• Greater than 15x upper limits of normal can be immediately life threatening

• Think about the common things, especially medications and don’t panic about a single value

• If things don’t get better or clarify themselves, call me

Questions?