Download The Aminotransferases: Aspartate aminotransferase (AST

Approach to Abnormal LFT’s
By
William E. Stevens, MD
Abnormal LFT’s
Epidemiology
• 0.5% of 19,877 healthy air force recruits
have an LFT abnormality
• Alcohol, HCV, and steatosis are the most
common causes of abnormal LFT’s
• Diagnosis can be established noninvasively
in most cases
Approach to Abnormal LFT’s
• The biochemical LFT’s
AST, ALT, ALK PHOS, BILI
GGT, 5’NT, LDH
ALB, P.T.
• Abnormal LFT syndromes
Severe vs. mild elevations
Acute vs. chronic elevations
Hepatitic vs. cholestatic pattern
The Aminotransferases:
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
• Participate in gluconeogenesis; catalyzing transfer of
amino groups to a~ketoglutarate
• AST found in liver, heart and skeletal muscle, brain,
kidney, pancreas, lungs, WBC’s, and RBC’s
• ALT found primarily in liver
• Elevations occur due to hepatocyte membrane damage
• Almost all hepatobiliary diseases to some degree cause
elevation
• The higher the AST:ALT ratio, the more specific for ETOH
related liver disease
• AST:ALT >2:1 is 90% specific for ETOH injury
• AST:ALT >3:1 is 97% specific for ETOH injury
Alkaline Phosphatase
• Ubiquitous isoenzyme family found in liver, bone, placenta, kidney
intestine, WBC’s
• Slight elevations can occur normally in blood type O and B, after fatty
meals, and increase with age
• Isolated mild transient elevations are common, resolve spontaneously,
are associated with no pathology
• Abnormally low levels occur in hypothyroidism, pernicious anemia,
zinc deficiency, Wilson’s disease
• High elevations imply cholestasis due to intrahepatic, extrahepatic or
infiltrative processes
• Elevations occur due to enzyme induction and synthesis, levels may be
normal with acute biliary obstruction
Gamma Glutamyl Transpeptidase
(GGT)
• Found in liver, biliary epithelium, spleen,
pancreas, heart, lung, brain. Not found in bone
• Primarily useful in confirming hepatic origin of an
elevated alkaline phosphatase
• Induced by ETOH, anticonvulsants, coumadin, etc
• Most sensitive indicator for hepatobiliary disease
• Very nonspecific; not very useful
5’ Nucleotidase (5 NT)
• Found in liver, biliary epithelium, intestine,
brain, heart, pancreas
• Very specific for hepatobiliary disease
• Levels correlate closely with alkaline
phosphatase
• Useful in confirming hepatic origin for
elevated alkaline phosphatase
Lactate Dehydrogenase (LDH)
• Widespread, ubiquitous isoenzyme
• Elevations are due to cellular necrosis
• Massive elevations are suggestive for
ischemic necrosis
• Limited diagnostic utility
Albumin
• Liver synthesizes 10 gm/d
• Serum half life is 20 days
• Synthetic ability and serum levels decrease with
progressive liver disease
• Levels vary depending on nutritional status, volume status,
vascular integrity, catabolism, urine and stool losses
• Low levels are not specific for liver disease
Pro Time (PT)
• Liver synthesizes Factors I, II, VII, IX, X,
and degrades FDP’s
• Elevations of PT are not specific for liver
disease
• Elevations that are due to liver disease are
good indicators for severity of liver disease
Bilirubin
• Derived from catabolism of hemoglobin
• Two forms:
water soluble--conjugated--direct
water insoluble--unconjugated--indirect
• Direct bilirubin increases due to defects in hepatic bilirubin
excretion: biliary obstruction or hepatocellular disease
• Indirect bilirubin increases due to increased hemoglobin
breakdown or defects in hepatic uptake or conjugation
Evaluation of Abnormal LFT’s
• Do a history:
some liver diseases are more common in
certain ages and genders
Age
<40: Autoimmune, Wilson's Dis
>40: NASH, Hemochromatosis,
Biliary obstruction
Sex
male: Hemochromatosis, PSC
female: Autoimmune, PBC
Evaluation of Abnormal LFT’s
Do a history
• How long have they been abnormal?
• How much Alcohol?
• Any risk factors for viral hepatitis: IVDA, blood
transfusion, tattoos, intranasal cocaine, multiple sex
partners, multiple body piercing
• Autoimmune symptoms: rashes, arthralgias, myalgias,
thyroid problems, Sjogrens symptoms
• Weight changes, anorexia
• Cholestatic symptoms: RUQ pain, fever, chills, pruritus,
jaundice, dark urine, light colored stools
• Review medications, herbs, OTC medications
Evaluation of Abnormal LFT’s
Do a physical exam
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Spider angiomas
Enlarged liver and spleen
Abdominal tenderness
Findings of cirrhosis: ascites, edema,
encephalopathy, palmer erythema,
gynecomastia, testicular atrophy, caput
medusa
• Cardiac exam, heart murmurs, JVD
Abnormal LFT Syndromes
• Isolated elevation of Bilirubin
• Elevations of Alkaline Phosphatase and
Bilirubin: Cholestasis
• Massive elevations of AST / ALT
• Mild chronic elevations of AST / ALT
Approach to an
Isolated Elevation of Bilirubin
•
Elevations occur from
– Bilirubin overproduction
– Impaired bilirubin uptake, conjugation, or excretion
– First fractionate bilirubin: conjugated vs. unconjugated
•
Unconjugated hyperbilirubinemia:
– Increased bilirubin production:
• hemolysis, hematoma, dyserythropoiesis (check haptoglobin)
– Impaired bilirubin conjugation:
• Gilbert’s Syndrome: 3-7% population, increased in white males, Bili <6
• Chronic liver diseases, advanced cirrhosis, Wilson’s Disease, estrogens
• Crigler-Najjar syndrome types I and II, extremely rare
– Impaired hepatic bilirubin uptake:
• rifampin, probenicid, CHF, etc.
•
Conjugated hyperbilirubinemia:
– Dubin-Johnson Syndrome: abnormal excretion of bilirubin into bile ducts
– Rotor Syndrome: defective intrahepatic storage of bilirubin
• Both very rare; asymptomatic jaundice in 2nd decade of life
Approach to Cholestasis
Elevations of Alkaline Phosphatase and Bilirubin
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History: abdominal pain, fever, pruritis, jaundice, medications, ?IBD
If isolated Alk Phos elevation; confirm liver as source with 5’NT, GGT or Alk
Phos isoenzymes
Ultrasound
– If US is abnormal
• Biliary obstruction: CBD stones, strictures or biliary and pancreatic malignancies
• Hepatic malignancy
– If US normal
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Consider medications: steroids, erythromycins, chlorpromazine, etc.
TPN, sepsis, post-operative cholestasis, “intrahepatic cholestasis of acute illness”
PBC, PSC, Vanishing bile duct syndrome
Infiltrative diseases, steatosis/NASH, sarcoid, granulomatous liver disease
If Alk Phos is <1.5 x abnormal and US is normal, and patient is asymptomatic,
then serial follow up is reasonable
Otherwise, check AMA, consider MRCP, then Liver Biopsy or ERCP
Primary Biliary Cirrhosis
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Median age 50, Female:Male 9:1
presents with fatigue, pruritis hepatospleenomegaly
AMA+ 95%
Liver biopsy: ductopenia with inflamed damaged
intrahepatic bile ducts, granulomas, biliary cirrhosis
• Treatment: manage osteoporosis, osteomalacia, fat soluble
vitamin deficiency, pruritus, cholesterol, steatorrhea
• Ursodeoxycholic acid
Approach to Massive AST/ALT
Elevations (>2000)
• Limited differential diagnosis:
• Drugs/Toxins: Tylenol, ETOH + Tylenol, other
idiosyncratic reactions, mushrooms, herbs
• Acute Viral Hepatitis: A,B,C,D,E, HSV, Giant
Cell virus, others
• Ischemic Hepatitis: hypotension, CHF,
arrhythmias, cocaine
• CBD Stone
• Autoimmune Hepatitis
Approach to Mildly Abnormal AST /ALT:
100 Consecutive Blood Donors with Mildly Abnormal ALT
• Findings after H & P, serologies and
ultrasound:
• 48%
ETOH
• 22%
Fatty Liver
• 17%
HCV
• 4%
other
• 9%
no identifiable explanation
Mildly Abnormal LFT’s
Liver Biopsy Findings
• 81 with chronically abnormal LFT’s and negative H & P
and serologic evaluation
– 84% Hepatic steatosis or NASH
– 6% advanced fibrosis or cirrhosis
– 8% normal
• Summary
– Most etiologies are identified by history, physical, basic serologies
or ultrasound
– Most cases still with diagnostic uncertainty are due to ETOH or
Hepatic Steatosis / NASH
– Liver Biopsy aides management in ~18%
– Complication rate of liver biopsy ~1-3%
• Severe complications occur in 0.1%
Causes of Mild Chronic Elevation of
AST/ALT
• Hepatic causes:
• Nonhepatic causes:
ETOH
Medications, herbs
Hepatitis C and B
Steatosis and NASH
Autoimmune hepatitis
Hemochromatosis
Wilson’s disease
Alpha-1-antitrypsin deficiency
Celiac sprue
CHF
Thyroid and Adrenal disease
Muscle diseases and strenuous exercise
Laboratory Tests in Asymptomatic patients
with Mild Chronically Elevated AST/ALT
• Primary tests:
Repeat LFT’s
HCV antibody
HBV Surface antigen
HBV Surface antibody
HBV Core antibody
Transferrin saturation, ferritin
• Secondary tests: ANA, ASMA
Ceruloplasmin (age<40)
Alpha-1-antitrypsin phenotype
Ultrasound
Alcohol Related Liver Disease
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14 million alcoholics in U.S.
2 million in U.S. with alcohol related liver disease
>14,000 liver related deaths per year due to alcohol
prevalence is higher in men; women are more susceptible
to liver injury
• risk of liver injury increases with consumption of over 30
gm/d ETOH; only 10% who consume over 80 gm/d get
liver disease
• AST:ALT >2-3:1 GGT >2x elevated
• AST and ALT usually less than 300
Hepatic Steatosis and NASH
• Most common cause of unexplained abnormal LFT’s
• 25% ultrasounds in U.S. show “fatty liver”
• Likelihood for advanced disease increases if: age >40,
Type 2 Diabetes Mellitus, Obesity, Hyperlipidemia
• May have RUQ pain, hepatosplenomegaly
• AST=ALT (usually), levels usually <200
• Consider liver biopsy for diagnosis and staging. Liver
biopsy looks like alcoholic hepatitis
• Treatment: weight loss, improve DM and lipid control,
stop ETOH, ?ursodeoxycholic acid, ?metformin, ?Vit E
Viral Hepatitis C and B
• Hepatitis C
3-4 million in U.S
90% have “risk factors”, 30% have normal LFT’s
HCV antibody is 97% sensitive
HCV RNA PCR is confirmatory test
Treatment: PEG interferon + Ribavirin
• Hepatitis B
1 million in U.S.
Increased in homosexuals, African and Asian
immigrants, HCV risk factors
HBV S Ab+, HBV Core Ab+ = immunity, prior disease
HBV S Ag+ = presence of disease
HBV E Ag+ or HBV DNA + = active viral replication, infective
Treatment: PEG interferon, or Lamivudine, Adefovir, Entecavir
Hemochromatosis
• Primary genetic hemochromatosis; 1/200 (0.5%)
Caucasians
• Secondary hemochromatosis due to chronic hemolysis
• May have RUQ pain, arthritis, impotence, diabetes,
hepatomegaly, skin pigmentation
• Transferrin Saturation >45%, elevated Ferritin
• HFE testing: C282y, H63d mutations account for 90%;
10% Caucasians are heterozygotes
• Liver Biopsy if Age>40, abnormal LFT’s, Ferritin > 1000,
uncertain diagnosis
• Treatment: Phlebotomy every 1-2 weeks until iron
depleted; then 2-6 times per year
Medication Induced Abnormal
LFT’s
• Almost any medication can cause abnormal LFT’s
• Ask when medications were started; OTC
medications, herbal preparations
• Stop probable offending medications
• Risk/Benefit analysis if medication must be
continued. Liver Biopsy may be helpful.
Medications that Cause Elevated
LFT’s
• Antibiotics: penicillin's, mycin's, floxicin’s,
nitrofurantoin, keto and fluconazole, INH
• Antiseizure: dilantin, tegretol, valproic acid
• Statins and Niacin
• NSAID’s: diclofenac
• Sulfonylureas: glypizide
• Vitamin A
• Herbs: germander, chaparral, mahuang, gentian
• Drugs: ecstasy, cocaine, PCP, glues, solvents
Autoimmune Hepatitis
• 150,000 in U.S.; female:male, 4-6:1
• 40% have other autoimmune diseases:
thyroid, RA, UC, Sjogrens,
• ANA, ASMA + 70%
• Elevated Ig G
• Treatment: prednisone + imuran
Wilson’s Disease
• Wilson’s disease gene facilitates biliary copper excretion.
• Age of onset 6-40
• Various presentations:
Hepatic
fulminant liver failure
chronic active hepatitis
Neurologic
movement disorder
rigid dystonia
Psychiatric
neuroses, depression
• Diagnosis: low ceruloplasmin, high 24 hour urine copper,
liver biopsy, Kayser-Fleischer rings present in 95%
• Treatment: Penicillamine, Trien, Zinc
Alpha-1-Antitrypsin Deficiency
• Protease inhibitor; inhibits neutrophil elastase;
modulating inflammatory cascades
• 1/1500 Caucasians
• Abnormal phenotype causes retention of A-1-AT
in hepatocytes
• Normal: MM; most abnormal: ZZ
other variants: MZ, MS, SS, SZ
• Neonatal or childhood cholestatic hepatitis
• In adults: emphysema and cirrhosis
Asymptomatic Patients with Abnormal ALT
and Negative Serologic Evaluations
• 1124 patients with chronically elevated ALT
• 81 patients had NEGATIVE serologic evaluations
• All had Liver Biopsy. Findings:
41
fatty liver
26
NASH
4
fibrosis with fatty liver
2
cirrhosis with fatty liver
8
normal
Mild Elevations of LFT’s
Epidemiology
• 19,877 Air Force recruits
• 99 (0.5%) had ALT >55
• Only 12 (12%) had a cause identified
– HBV, HCV, Autoimmune, Gallstones
– 88% no identifiable cause identified
Hepatobiliary Syndromes
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Hepatitic pattern: elevated AST, ALT
Cholestatic pattern: elevated Alk Phos, Bili
Acute versus chronic elevations
Massive versus mild elevations