1. Approach to Abnormal LFT’sBy
William E. Stevens, MD

2. 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

3. 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

4. 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

5. 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

6. 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

7. Lactate Dehydrogenase (LDH)
Widespread, ubiquitous isoenzyme
Elevations are due to cellular necrosis
Massive elevations are suggestive for ischemic necrosis
Limited diagnostic utility

8. 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

9. 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

10. 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

11. 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 female: Autoimmune, PBC

12. 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

13. Evaluation of Abnormal LFT’s Do a physical exam
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

14. 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

15. 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

16. Approach to Cholestasis Elevations of Alkaline Phosphatase and Bilirubin
History: abdominal pain, fever, pruritis, jaundice, medications, ?IBD
If isolated Alk Phos elevation; confirm liver as source with 5’NT or 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
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, consider MRCP then Liver Biopsy or ERCP

17. Primary Biliary Cirrhosis
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

18. Approach to Massive AST/ALT Elevations (>2000)
Limited differential diagnosis:
Drugs/Toxins: Tylenol, ETOH + Tylenol, other idiosyncratic reactions, mushrooms, herbs
Viral Hepatitis: A,B,C,D,E, HSV, Giant Cell virus, others
Ischemic Hepatitis: hypotension, CHF, arrhythmias, cocaine
CBD Stone
Autoimmune Hepatitis

19. 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

20. 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%

21. Causes of Mild Chronic Elevation of AST/ALT
Hepatic causes: ETOH Medications, herbs Hepatitis C and B Steatosis and NASH Autoimmune hepatitis Hemochromatosis Wilson’s disease Alpha-1-antitrypsin deficiency
Nonhepatic causes: Celiac sprue CHF Thyroid and Adrenal disease Muscle diseases and strenuous exercise

22. 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

23. Alcohol Related Liver Disease
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

24. 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, hepatospleenomegaly
AST=ALT, 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

25. Viral Hepatitis C and B
Hepatitis C million in U.S % 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 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

26. 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

27. 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.

28. 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

29. 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

30. 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

31. 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

32. 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: fatty liver NASH fibrosis with fatty liver 2 cirrhosis with fatty liver 8 normal

33. 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

34. Hepatobiliary Syndromes
Hepatitic pattern: elevated AST, ALT
Cholestatic pattern: elevated Alk Phos, Bili
Acute versus chronic elevations
Massive versus mild elevations