Session 11:
The ABCs of LFTs
Learning Objectives
1. Define 3 key components of the patient history that should be further
evaluated when liver function testing reveals elevated aminotransferases.
2. Identify at least 3 laboratory tests that should be considered in a patient with an
ALT value that is 3 times the upper normal limit.
Session 11
The ABCs of LFTs
Faculty
Marc Itskowitz, MD, FACP
Associate Professor of Medicine
Temple University School of Medicine
Director of Didactic Education
Allegheny General Hospital
Pittsburgh, Pennsylvania
Dr Marc Itskowitz is director of Didactic Education at Pittsburgh’s Allegheny General Hospital (AGH), where he is also director
of the Center for Perioperative Medicine and assistant program director of the AGH–Western Pennsylvania Hospital (WPH)
Internal Medicine Residency Program. In addition, Dr Itskowitz is an associate professor of medicine at the Temple University
School of Medicine..
Dr Itskowitz earned his BA from Cornell University and received his medical degree from the Medical College of Pennsylvania,
where he was elected to the Alpha Omega Alpha Medical Honor Society. He completed his residency in internal medicine at
AGH, where he was chief resident. He currently practices internal medicine with Pittsburgh General Medicine Associates. His
clinical interests include cardiovascular risk assessment, travel medicine, and perioperative medicine, and he has lectured
frequently on these topics.
Dr Itskowitz is a fellow of the American College of Physicians and a member of the Association of Program Directors in Internal
Medicine. He is a diplomate of the American Board of Internal Medicine. Dr Itskowitz is the author of numerous journal articles
and serves on the editorial board of Emergency Medicine: Acute Medicine for the Primary Care Physician. He also is a team physician for
the Pittsburgh Pirates.
Faculty Financial Disclosure Statement
The presenting faculty reports the following:
Dr Itskowitz has no financial relationships to disclose.
Faculty Disclosures
• Dr Itskowitz has no financial relationships to disclose.
Session 11: 2:15 PM – 3:15 PM
The ABCs of LFTs
Marc Itskowitz, MD, FACP
Learning Objectives
Q1. Pre-Audience Response Question
• Define 3 key components of the patient history that should
be further evaluated when liver function testing reveals
elevated aminotransferases
Which of the following is/are TRUE?
1. Abnormal LFTs are often seen in asymptomatic patients
2. Liver damage can be present even though LFTs are
within normal limits
• Identify at least 3 laboratory tests that should be
considered in a patient with an ALT value that is 3X the
upper normal limit
3. 20% of normal patients have LFTs outside the normal
range
4. All of the above
5. 1 and 2 only
Q2. Pre-Audience Response Question
Q3. Pre-Audience Response Question
Risk factors for non-alcoholic fatty liver disease
(NAFLD) include:
Which of these findings suggest alcohol abuse?
1. AST:ALT ratio >2:1
1. Obesity
2. AST > 8 X normal
2. Diabetes
3. Pyridoxal 5-phosphate deficiency
3. Jejuno-ileal bypass surgery
4. All of the above
4. All of the above
5. 1 and 3 only
5. 1 and 2 only
1
Case 1: Debra, 48-year-old female
Case 1: Debra, 48-year-old female
• Comes to the office for routine annual checkup
• Exam:
• No current complaints
– 144/86 mm Hg, 72 regular, 14
• Past medical history:
– BMI: 36
– Hypertension
• HEENT: no icterus
– Dyslipidemia
• Lungs: clear
– Obesity
• Heart: regular, no murmurs
• No allergies
• Abdomen: soft, nontender, no organomegaly
• Medications: HCTZ, simvastatin, acetaminophen
prn joint pain
• Extremities: no edema
Debra
Question
• Labs:
Which of the following causes of abnormal LFTs should
be initially considered?
– ALT: 74 U/L (normal 9-52)
– AST: 48 U/L (normal 14-36)
– Total bilirubin: 0.3 mg/dL (normal 0.2-1.2)
1. Statin hepatotoxicity
– Total cholesterol: 202 mg/dL (normal 120-199)
2. Alcohol use
– LDL cholesterol: 112 mg/dL (normal 60-129)
3. Acetaminophen use
– HDL cholesterol: 31 mg/dL (normal >39)
4. NASH
– Triglycerides: 245 mg/dL (normal <150)
5. All of the Above
– Fasting glucose: 119 mg/dL (normal 70-99)
Prevalence of Abnormal LFTs
% of U.S. Population
Initial Evaluation of Abnormal LFTs
• Repeat the test to confirm the result
• 5% of normal patients have results outside the “normal
range”
• LFTs elevations correlate with BMI
• Normal range varies among laboratories
• Physiologic changes
– Alkaline phosphatase elevated in 3rd trimester of
pregnancy
Ioannou GN, et al. Am J Gastroenterol. 2006;101:76-82.
2
Commonly reported LFTs
Initial Evaluation of Abnormal LFTs
• Enzymes
• Physical Examination
– Aspartate transaminase or aminotransferase (AST,
SGOT)
– Muscle wasting
– Stigmata of chronic liver disease
– alanine transaminase or aminotransferase (ALT, SGPT)
Alkaline phosphatase (ALP)
• Spider nevi, palmar erythema, gynecomastia,
caput medusae
– Gamma-glutamyl transpeptidase (GGT)
– Lymphadenopathy
• Synthetic Function
– Jugular venous distension
– Albumin
– Pleural effusion
– Prothrombin time
• Bilirubin
Abnormal LFTs—Most Common Causes
in U.S.
Audience Response Question
• Fatty liver
What is the most common cause of abnormal LFTs in the
U.S. primary care population?
– Nonalcoholic fatty liver disease (NAFLD)
¾Prevalence ~30%
1. Viral hepatitis
– Nonalcoholic steatohepatitis (NASH)
2. Fatty liver
• Alcoholic liver disease
3. Statin use
• Viral hepatitis (chronic HBV and HCV)
4. Strenuous exercise
http://digestive.niddk.nih.gov/ddiseases/pubs/nash/
Causes of Chronically Elevated ALT Levels
9 Hepatic causes
9 Nonhepatic causes
– NASH
– Celiac disease
– Alcohol abuse
– Inherited disorders of
muscle metabolism
– Infectious hepatitis
– Autoimmune hepatitis
– Hemochromatosis
– Wilson’s disease
Evaluation of Chronic ALT Elevation
Step 1
¾ Review medications, herbal therapies, or
recreational drugs
¾ Screen for alcohol abuse
– Acquired muscle
diseases
¾ Obtain serology for Hepatitis B and C
¾ Screen for hemochromatosis
– Strenuous exercise
¾ Evaluate for fatty liver
– Alpha1-antitrypsin
deficiency
Pratt DS. NEJM. 2000;342 (17):1266-71.
3
Evaluation of Chronic ALT Elevation
Evaluation of Chronic ALT Elevation
Step 2
Step 3
¾ Exclude muscle disorders
¾ Consider autoimmune hepatitis
¾ Obtain thyroid function tests
¾ Consider Wilson’s disease
¾ Consider celiac disease
¾ Consider α1-antitrypsin deficiency
¾ Consider adrenal insufficiency
Evaluation of Chronic ALT Elevation
Transaminase Levels in Alcohol Abuse
• Diagnosis supported by AST:ALT of at least 2:1
Step 4
– Alcohol-related deficiency of pyridoxal 5-phosphate
¾ Obtain a liver biopsy
– Low serum activity of ALT
¾ Consider observation
• Gamma-glutamyltransferase twice normal with AST:ALT of
at least 2:1 strongly suggests diagnosis
• if ALT, AST only mildly elevated
– GGT not specific
• Rare for AST > 8 X normal value
• Rare for ALT > 5 X normal value
Pratt DS. NEJM. 2000;342(17):1266-71.
Medications and Elevated LFTs
Drug-Related Transaminase Elevations
Selected Drugs/Substances Associated With LFT Elevations
acetaminophen
omeprazole
antifungals, INH
lisinopril, losartan
glipizide
NSAIDs
allopurinol
risperidone
buproprion
SSRIs, trazodone
kava kava; germander, ephedra,
shark cartilage, senna
PCP, anabolic steroids, cocaine,
ecstasy, glues/solvents
DPH, valproate, carbamazepine
statins
Acetaminophen
• 4 Gm/day for 5-10 days caused elevated transaminases in
>50% healthy non-drinkers
• Alcohol can potentiate hepatotoxic effects
Statins
• Frequently cause elevated transaminases, but significant
hepatoxicity is rare
• Transaminase elevations usually resolve spontaneously
• May be used safely in persons with chronic liver disease
¾Almost any drug can be a cause
¾Stop medication and determine if LFTs normalize
Pratt DS. NEJM. 2000;342 (17):1266-71.
Oh RC, et al. Am Fam Phys.2011;84(9):1003-1008. Pratt DS. NEJM. 2000;342 (17):1266-71.
4
Testing for Other Causes of Abnormal
Transaminases
Autoimmune
Hepatitis
Serum Protein Electrophoresis
ANA
Anti-Smooth Muscle ABs
Liver-Kidney Microsomal ABs
Hemochromatosis
Serum Iron
TIBC
HFE Genetic Testing
Wilson’s Disease
Serum Ceruloplasmin
Ophthalmology Exam
24-hour Urine Copper Excretion
α1-Antitrypsin
Deficiency
Serum α1-Antitrypsin Level
Nonhepatic Causes of Abnormal
Transaminases
• Celiac disease
• Muscle disorders
– Inborn errors of metabolism
– Polymyositis
– Strenuous exercise
• Thyroid disorders
• Adrenal insufficiency
• Anorexia nervosa
Pratt DS. NEJM. 2000;342(17):1266-71. Oh RC, et al. Am Fam Phys. 2011;84(9):1003-1008.
Back to Debra
The Spectrum of NAFLD
• Viral serologies are negative
• Denies significant alcohol or acetaminophen use
NAFLD encompasses range of liver diseases resulting from
fatty infiltration in hepatocyte:
• Repeat LFTs after statin discontinued: unchanged
¾ Simple fatty liver with no inflammation
• Ultrasound: fatty liver
¾ 3-6% progress to steatohepatitis with inflammation
(NASH)
¾ Diagnosis: NASH
¾ Scarring (fibrosis)
¾ Cirrhosis
Oh RC, et al. Am Fam Phys. 2011;84(9):1003-1008.
NASH
Risk Factors for NAFLD
• Most strongly associated with obesity; dyslipidemia, HTN,
glucose intolerance are also risk factors
– NAFLD may be considered hepatic component of
metabolic syndrome
• Obstructive sleep apnea
• Medications (e.g., nucleoside analogs)
Mallory body
• Jejunoileal bypass
Pericellular Fibrosis
• Severe rapid weight loss
Livery biopsy is required to confirm a diagnosis or to stage
the disease
• Lipodystrophic syndromes
5
Management of NAFLD
Case 2: William, 32-year-old male
• NASH can progress to cirrhosis in some patients
• Presents to office because of abnormal LFTs on Life
Insurance physical
• Modification of risk factors, such as obesity,
hyperlipidemia, and proper diabetic control
• No current complaints
• Hepatitis A and B vaccinations
• Past Medical History: None
• Hyperlipidemia should be treated with statins
• Medications: None
• Weight loss is the only therapy with reasonable evidence
supporting benefit
• Social History: Prior history of IVDA; smokes 1 PPD;
drinks alcohol 3-4 days/ week; multiple sexual partners
in past
• Multiple other drugs have been studied, but most trials
have been too short to determine impact on important
clinical outcomes
Musso G, et al. A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease.
Hepatology. 2010;52(1):79.
William
William
• Exam:
• Labs:
– 128/76 mm Hg, 72 regular, 14
– ALT: 74 U/L (normal 9-52)
– BMI: 23
– AST: 64 U/L (normal 14-36)
• HEENT: no icterus
– Total bilirubin: 0.9 mg/dL (normal 0.2-1.2)
• Lungs: clear
– Total cholesterol: 184 mg/dL (normal 120-199)
• Heart: regular, no murmurs
– LDL cholesterol: 100 mg/dL (normal 60-129)
• Abdomen: soft, nontender, no organomegaly
– HDL cholesterol: 42 mg/dL (normal >39)
• Extremities: no edema
– Triglycerides: 133 mg/dL (normal <150)
– Fasting glucose: 101 mg/dL (normal 70-99)
Question
William
Viral hepatitis serology results:
Which of the following causes of abnormal LFTs should
be initially considered?
• Hepatitis B Surface Antigen: +
1. Hepatitis B virus
• Hepatitis B e Antigen (HBeAg): −
2. Hepatitis C virus
• Hepatitis B Surface Antibody (HBsAb): −
3. Alcohol use
• Hepatitis B e-Antibody (HBeAb): −
4. All of the above
• Hepatitis B Core Antibody (HBcAb): +
• Hepatitis C Antibody: −
6
Hepatitis B Serology
Worldwide Prevalence of Hepatitis B
HBsAg: hepatitis B surface antigen
• Marker of active infection
• Chronic HBV: HBsAg positive for at least 6 months
HBsAb: antibody to HBsAg
• Marker of immunity to hepatitis B
Anti-HB core antibody (HBcAb)
• Marker of present or past infection
HBeAg: hepatitis B “e” antigen
• Surrogate marker of high viral load
Anti-HBe: antibody to HBeAg
• Inactive carrier state
HBV DNA: active viral replication
BMJ. 2010;340:b5429.
Incidence of Acute, Symptomatic Hepatitis B by
Age Group – United States, 1990 - 2008
Hepatitis B
Reported Cases/100,000
16
<15 yrs
14
15 – 24 yrs
12
25 – 44 yrs
10
45+ yrs
8
6
4
2
0
Year
Adapted from National Notifiable Diseases Surveillance System (NNDSS)
CDC Sentinel Sites. 2001 data.
Hepatitis C Infection
Hepatitis B Virus Serology
• Risk factors
– Blood transfusions
– IVDA
– High-risk sexual behavior
– Cocaine
– Tattoos
– Body piercing
http://pathmicro.med.sc.edu/virol/hepb-cd1.gif
7
Hepatitis B Chemistry Profiles
Hepatitis C – Incidence in United States
Lai CL, et al. Lancet. 2003;362:2089-2094.
Lok AS, et al. Gastroenterology. 2001;120:1828-1853.
http://www.medscape.com/viewarticle/735146
Case 3: Steven, 21-year-old male
Hepatitis C - Diagnostic Testing
• Found to have elevated total bilirubin level with fasting
blood work
• Serologic Testing
– 92-97% sensitivity
– Total bilirubin: 1.9 mg/dL (normal 0.2-1.2)
• Serum Hepatitis C Virus RNA for confirmation
– Direct bilirubin: 0.1 mg/dL (normal 0.0-0.4)
• If positive – consider liver biopsy to assess severity
• No current symptoms
• No significant past medical history
• Medications: none
• Social History: No T/A/D abuse
Hepatocellular carcinoma in chronic HCV
Pratt DS. NEJM. 2000;342 (17):1266-71.
Question
Question
Which of the following mechanisms cause unconjugated
hyperbilirubinemia?
Which of the following regarding cholestatic liver
disease is/are TRUE?
1. Overproduction of bilirubin
1. Choledocholithiasis is the most common cause of
extrahepatic cholestasis
2. Reduced bilirubin uptake
2. Drug induced cholestasis usually is reversible after
elimination of the offending drug
3. Impaired bilirubin conjugation
4. All of the above
3. Viral hepatitis can present as cholestatic liver disease
4. All of the above
5. None of the above
8
Causes of Hyperbilirubinemia
• Unconjugated
Gilbert’s Syndrome
• Conjugated
– Gilbert’s syndrome
– Choledocholithiasis
– Heart Failure
– Cholangiocarcinoma
– Medications
– Crigler-Najjar
syndrome
• Common genetic disorder
– Primary Biliary
Cirrhosis
• 3-7% of the population
– Sclerosing
Cholangitis
– Medications
• Males > Females
– Sepsis
• Impaired conjugation of bilirubin
– AIDS cholangiopathy
– Infiltrative
diseases
– Hemolysis
– Pancreatitis
– Hyperthyroidism
– Strictures
– Cirrhosis
– Parasitic Infections
– Wilson’s disease
– Viral Hepatitis
– Alcoholic hepatitis
– Reduced UDP glucuronosyl transferase activity
• Mild hyperbilirubinemia (usually less than 3 mg/dL)
– Total Parenteral
Nutrition
– Indirect unconjugated
– Higher with illness or fasting
– Pregnancy
• No specific therapy
– End-state Liver
disease
– NASH
Diagnosis of Gilbert's Syndrome
Evaluation of Elevated Alkaline
Phosphatase Levels
• Unconjugated hyperbilirubinemia on repeated testing
• Gamma-GTP levels
• Normal complete blood count, blood smear, and
reticulocyte count and normal liver function tests (plasma
aminotransferases and alkaline phosphatase
concentrations)
– Elevated: Liver Disease
– Normal: Bone Disease
• Initial evaluation for cholestatic disease
• No changes in 12 to 18 months
– RUQ ultrasound
– AMA Abs (PBC)
• Follow up testing for cholestatic liver disease
– MRCP, ERCP, Liver biopsy
Elevated Alkaline Phosphatase Levels
• Sources
– Liver
– Bone
American Gastroenterological Association
Evaluation of Liver Chemistry Tests
– Placental
• Women in 3rd trimester of pregnancy
– Blood type O or B
• Levels may increase after fatty meal
AGA Medical Position Statement: Evaluation of Liver Chemistry Tests..
Gastroenterology. 2002;123:1364-1366.
9
AGA Recommendation: Mild Elevations of ASL or
AST (<5 X Normal)
AGA Recommendation: Elevated Bilirubin
History and Physical Examination, Liver Chemistries
History and Physical Examination*, Discontinue
hepatotoxic medications
Confirm abnormality if an error is suspected
Liver Chemistries, PT, Albumin, CBC with platelets
Hepatitis A, B and C Serologies**, Fe, TIBC, Ferritin
Negative serology, asymptomatic
patient without hepatic
decompensation
Unconjugated bilirubin
Normal Alk Phos, ALT, AST
Conjugated bilirubin
Abnormal Alk Phos, ALT, AST
Hemolysis Studies
Review Medications
RUQ ultrasound to assess
ductal dilatation
Positive serologic evaluation
present
Negative serology
Consider ultrasound, ANA, α-smooth muscle Ab,
ceruloplasmin, α1-antitrypsin
Abnormal results
Liver biopsy
Lifestyle
Modification
ERCP or
MRCP
Viral Hepatitis
Work-up
Adapted from AGA Medical Position Statement: Evaluation of Liver Chemistry Tests..
Gastroenterology. 2002;123:1364-1366.
absent
*Elevated ALT evaluation
Review medications, AMA,
ERCP or MRCP liver
biopsy
Adapted from Gastroenterology. 2002;123:1364-1366.
AGA Recommendation: Elevated Alkaline
Phosphatase
History and Physical Examination
Normal bilirubin, ALT, AST
Abnormal Liver Chemistries
γ-GGT or 5’-nucleotidase
RUQ ultrasound to assess
ductal dilatation
negative
positive
Etiology is not
hepatobiliary
RUQ ultrasound
Review
medications, AMA
No ductal
dilattion
Liver biopsy
Yes
Post
Audience Response Questions
No
ERCP
AMA
negative
Observation
Elevated alkaline
phosphatase > 6
months
*Elevated ALT evaluation
liver biopsy
ERCP or MRCP
Adapted from Gastroenterology. 2002;123:1364-1366.
Q1. Post-Audience Response Question
Q2. Post-Audience Response Question
Which of the following is/are TRUE?
Risk factors for non-alcoholic fatty liver disease
(NAFLD) include:
1. Abnormal LFTs are often seen in asymptomatic
patients
1. Obesity
2. Liver damage can be present even though LFTs are
within normal limits
2. Diabetes
3. 20% of normal patients have LFTs outside the
normal range
4. All of the above
3. Jejuno-ileal bypass surgery
5. 1 and 2 only
4. All of the above
5. 1 and 2 only
10
Q3. Post-Audience Response Question
Which of these findings suggest alcohol abuse?
Questions
?
1. AST:ALT ratio >2:1
2. AST > 8 X normal
3. Pyridoxal 5-phosphate deficiency
4. All of the above
5. 1 and 3 only
11