Approach to Elevated Liver Enzymes

Approach to Elevated Liver Enzymes
Kevork M Peltekian
Division of Digestive Care & Endoscopy
@LiverSensible
Things We Are Going To Go Over Late
This Afternoon on Saturday
• Overview
– What are liver enzymes? Is there a problem if they are
elevated? What if they are normal – does that mean there
is no liver disease?
• Case Management and Investigation
– Is isolated hyperbilirubinemia a case of Gilbert’s
Syndrome?
– What do I do with a patient who has elevated alkaline
phosphatase but normal bilirubin
– What are the treatable risk factors that cause elevated ALT
and/or AST?
• Questions
Markers of Hepatocellular Damage
(Transaminases)
AST (SGOT)
• Source: liver, heart skeletal
muscle, kidneys, brain, RBCs
• In liver 20% activity is
cytosolic and 80%
mitochondrial
• Clearance performed by
sinusoidal cells, half-life
17hrs
ALT (SGPT)
• Source: more specific to
liver, but low concentrations
in kidney and skeletal
muscles
• In liver totally cytosolic.
• Half-life 47hrs
Gamma-GT
• Source: hepatocytes and biliary epithelial cells,
pancreas, renal tubules and intestine
• Very sensitive but non-specific
• Raised in ANY liver disease whether hepatocellular or
cholestatic - usefulness limited
• Confirm hepatic source for a raised ALP
• Induced by alcohol, medications or herbal therapies
• Isolated increase does not require any further
evaluation, suggest watch and repeat 3/12 only if
other enzymes become abnormal then investigate
Markers of Cholestasis
(Alkaline Phosphatase)
• Source: liver and bone (and also placenta, kidneys,
intestines or WBC)
• Hepatic ALP present on surface of bile duct epithelia
and accumulating bile salts increase its release from
cell surface. Takes time for induction of enzyme
levels so may not be first enzyme to rise and half-life
is 1 week.
• Bone-specific ALP isoenzymes, 5-NT or gamma GT
may be necessary to evaluate the origin of ALP
Markers of Liver Dysfunction or Portal
Hypertension
Bilirubin (D), Albumin, and
INR (Prothrombin Time)
• Useful indicators of liver
synthetic function
• In primary care when
associated with liver disease
abnormalities should raise
concern
Platelet counts and MCV
• Thrombocytopenia is a
sensitive indicator of
advanced liver fibrosis or
portal hypertension
• Macrocytosis often reflect
bone marrow toxicity from
alcohol and other drugs in
patients with normal folate
and vitamin B12 levels
Isolated Indirect Hyperbilirubinemia
• Product of hemoglobin
breakdown
• Unconjugated (indirect)insoluble
– Hemolysis: check Hgb,
MCV, RDW, and
Reticulocyte count
• Refer to hematology
– Gilbert’s syndrome:
• Reassure patient;
• 3-7% population
Elevated Alkaline Phosphatase
• A 47 year old female from Pictou County
presents with complaints of itching, dry
mouth, and RUQ abdominal pain. She also
notices some pigmentation changes on her
eyelids. Her medical history includes frequent
UTI’s and osteopenia.
• You obtain the following labs: AST=55, ALT=75,
Alkaline Phosphatase=350, GGT=110, CBC
normal
Elevated Serum Alkaline Phosphatase
Rule out physiological cause such as pregnancy, post prandrial
DETERMINE THE SOURCE BY CHECKING GGT
Normal
Increased
Bone origin
Hepatobiliary
origin
Elevated ALP Hepatobiliary Origin
Ultrasound of Abdomen
Hepatic or
Pancreatic Lesions
Dilated Bile
Ducts
Normal
Refer to HPB
Specialist
Further
Imaging
Assess Degree of ALP
Elevation and Medication List
Refer to Liver
Specialist
Elevated Alkaline Phosphatase
AMA(+) Primary Biliary Cirrhosis
Xanthomata
Fat Soluble
Vitamin Deficiency
Osteopenia
Hyperlipidemia
Urinary Tract
Infections
Gallstones
Steatorrhea
Renal Tubular
Acidosis
Malignancy
Heathcote EJ. Hepatology 2000;31:1005-1013.
Kaplan MM. N Engl J Med 1996;335:1570-1580.
Prevalence of Elevated ALT/AST in US
NHANES 1999-2002
• If defined as
– AST <37 or ALT <40
– No hepatitis C or alcohol use
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ALT elevated – 7.3%
AST elevated – 3.6%
Either elevated – 8.1%
Prevalence of elevated liver tests was 2x
higher compared to NHANES 1988-1994
Ioannou GN, et al. Am J Gastroenterol 2006;101:76-82
Is ALT a Sensitive Marker of Liver
Disease?
• Hepatitis C viremia
– Historical normal values (up to 40 U/L)
• Sensitivity 55%, specificity 97%
– Updated normal values (males 30 U/L, females 19 U/L)
• Sensitivity 76%, specificity 89%
• Detection of fibrosis in NAFLD
– 43% of normal ALT patients had fibrosis
– 38% of elevated ALT patients had fibrosis
Prati D, et al. Ann Intern Med 2001;137:1-9, Mofrad P, et al. Hepatology 2003;37:1286-1292
Is ALT a Good Predictor of Liver
Damage?
n=46
Grading
16
15
14
13
12
11
10
9
8
7
6
5
4
3
2
1
0
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Normal ALT
Puoty et al. Hepatology 1997;28:1393-11398
n=52
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Hepatitis C Infection
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Abnormal ALT
Let Me Put Serum ALT in Perspective
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We don’t know what a normal level is
It lacks sensitivity for common liver diseases
Elevations may be seen in normal people
Degree of elevation does not correlate with
severity of liver disease
Should we Ignore Elevated ALT levels?
Risk of death according to ALT level
142,055 Korean subjects applying for life insurance, ages 35-59
Kim H, et al. BMJ 2004;328:983
Case Presentation
 49 y/o female comes to establish care after moving
to your area
 Pertinent history
Hypertension
Obesity
Fibromyalgia
 ROS
Weight gain of 45 pounds over the last year
Diffuse arthralgias and myalgias
No history of liver disease, denies alcohol use
Prior physician had a “concern” about lupus
Case Presentation
• Medications
– Gabapentin,
– duloxetine,
– lisinopril,
– acetaminophen/hydrocodone PRN
• Exam
– BMI 39, BP 145/90
– No significant findings on exam
Selected Laboratory data
One year ago
Current Labs
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AST – 75
ALT – 105
AP – 98
T. bilirubin – 0.4
Albumin 4.2
Total protein – 6.5
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AST 50
ALT – 80
AP – 105
T. bilirubin – 0.5
Albumin 4.0
Total protein – 6.9
ANA (+) 1:160
Initial Step
Exclude common treatable liver
diseases
• Chronic viral hepatitis
– HBsAG, anti-HCV
• Hemochromatosis
• Serum iron, TIBC and ferritin
Our Patient’s Results
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HBsAg (-)
Anti-HCV (-)
Iron 59
TIBC 350
Transferin saturation 17%
Ferritin 650 ng/ml
Our Patient’s Results
Iron 59
TIBC 350
Transferrin
saturation 17%
Ferritin 650 ng/ml
Could this be Hemochromatosis?
– Common – 1/400 whites,
penetrance of ~30%
– Presents with mild (<4x ULN)
transaminase elevations
– End-organ damage in middle age
– Best screening test – transferrin
saturation >45%
• Elevated ferritin may indicate
inflammation
– Genetic testing available to
establish the diagnosis
• C282Y homozygote
Adams PC, Barton JC. Lancet 2007;370:1855-60
Our Patient’s Results
AST – 75
ALT – 105
AP – 98
T. bilirubin – 0.4
Albumin 4.2
Total protein – 6.5
ANA (+) 1:160
IgG level - normal
Could this be Autoimmune
Hepatitis?
– Treatable, fatal if untreated
– Typical presentation
• Significant ALT elevation (>5x
ULN)
• Elevated total protein, gamma
globulin, IgG levels
• Increased bilirubin is common
– Autoimmune markers
• ANA (+) in ~ 67%
• F-actin Smooth Muscle antibody
(+) in ~87%
– Liver biopsy with typical but
not diagnostic findings
Krawitt EL. NEJM 2006;354-366
Our Patient’s Results
AST – 75
ALT – 105
AP – 98
T. bilirubin – 0.4
Albumin 4.2
Total protein – 6.5
Could this be alcoholic liver
disease?
• History unreliable
• Alcoholics usually do not
develop liver disease
– Don’t assume alcohol use is
the cause of elevated
transaminases
• Typical liver enzyme pattern
– AST:ALT ratio >2 or 3
– Levels usually <200 U/dl
• Diagnosis
– Exclude other causes of liver
disease
Levitsky J, Mailliard ME. Sem Liv Dis 2004;24:233-247
Our Patient’s Results
AST – 75
ALT – 105
AP – 98
T. bilirubin – 0.4
Albumin 4.2
Total protein – 6.5
What about Celiac Disease?
• Affects 1% of the US
population
• Elevated liver enzymes
– Most common hepatic
presentation of celiac disease
– 40% adults and 54% of
children with Celiac disease
• Up to 9% of patients with
unexplained elevated liver
enzymes have celiac disease
• Diagnostic testing
– TTG IgA antibodies
Rubio-Tapia A, Murray JA. Hepatology 2007;46:1650-1658
Our Patient’s
Results
AST – 75
ALT – 105
AP – 98
T. bilirubin – 0.4
Albumin 4.2
Cholesterol - 295
LDL – 175
HDL – 32
Triglycerides – 350
FBS – 99 mg/dL
The Metabolic Syndrome
1. Abdominal obesity
√
2. Hypertension
√
3. Elevated triglycerides
√
4. Low HDL√
5. Fasting BS >100 mg/dL
Driven by insulin resistance
HOMA: Glucose x insulin / 405 – if > 2 indicates
insulin resistance
Cusi K. Clin Liv Dis 2009;13:545-563
Diagnosing NAFLD
• Exclude other causes of liver disease
• Identify the typical phenotype
– Metabolic syndrome criteria
• Be aware that ultrasound may lead to an incorrect
diagnosis in 10% to 30% of cases
– A “bright liver” may indicate fibrosis, not fat
– A normal liver may have up to 30% fat
• Recognize common confounding variables
– ANA is positive in up to 30%
– Elevated ferritin is common in NAFLD
Vuppalanchi R, Chalasani N. Hepatology 2009;49:306-317
Rules for Detecting Hepatotoxicity
• ALT elevation
– <3x ULN no action needed
– >3x ULN deserves close attention
– >5x ULN discontinue the medication
• Hy’s Law
– ALT + bilirubin elevation with normal alkaline
phosphatase = disaster!
Black M, et al. Gastroenterology 1975;69:289-302
Reuben A, Hepatology 2004;39:574-578
Case Presentation
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A liver biopsy was not done
Atorvastatin was prescribed
Vitamin E as d-tocopherol 800 IU daily
Weight loss program
– Lost 45 pounds over 16 months
• Cardiac evaluation revealed no premature
atherosclerosis
• Liver enzymes normalized
My 6 LFT’s
Liver-related Favourite Titbits
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HBsAg
HCV Antibody
Fe Saturation
BMI
Alcohol Intake
Medication and Herbal
Therapy
@LiverSensible

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