This document provides an overview on evaluating and managing elevated liver enzymes. It discusses the prevalence of liver disease in the US and the importance of identifying abnormal liver enzymes. The document reviews how to interpret different liver enzymes and develop a differential diagnosis for acute vs chronic conditions. Clinical cases are presented to demonstrate how to investigate the underlying cause of elevated enzymes. The conclusion emphasizes that stable elevated enzymes do not exist and screening is important given rising rates of HCV and NASH.

1. Approach to Elevated LFT’s
Miguel H. Malespin M.D.
Assistant Professor, Department of Medicine
Medical Director, Hepatology
Department of Medicine, Division of
Gastroenterology and Hepatology

2. Disclosures
• Consultant for Gilead Pharmaceuticals

3. Learning Objectives
• Describe the prevalence of liver disease within the
United States
• Review interpretation of abnormal liver enzymes
• Develop an approach to managing elevated liver
enzymes

4. Critical Role of Primary Care
• Elevated liver transaminase levels are found in
up to 8.9% of patients seen in primary care
clinics 1,2
• Approximately 9% of patients with elevated
liver enzymes are asymptomatic 3,4

5. Why is identification of patients with abnormal
liver enzymes important?

6. Peak of the Hepatitis C Epidemic
• Prevalence of HCV within the United States is
~1.6% 5
– Making it the most common bloodborne
pathogen in the United States
– Estimated 4 and 7 million persons 6,7

7. Rising Prevalence of Elevated Liver
Enzymes
• Nearly ½ of persons with chronic HCV are
unidentified
– Normal liver enzymes are found in 25–30% of
chronic HCV carriers 8
– Institution of screening for baby boomers born
between 1945-1965

8. Currently at the peak of the HCV
epidemic2

9. Hepatitis C surpassed HIV as a cause of
virus-related death in 2006

10. Incidence of Hepatitis C8
http://www.cdc.gov/hepatitis/statistics/

11. Second Culprit on the Loose…

12. Insulin Resistance

13. Diabetes is an important risk factor
for progression of fibrosis11,12

14. Obesity Epidemic
• Coincides with the rise in NAFLD

15. Rising Prevalence of NAFLD10

17. Epidemiology Related to Cirrhosis
• Prevalence of cirrhosis in the United States is
estimated to be ~0.27 percent of the
population
– 633,323 Adults 13
• Nearly 2 million deaths annually are
attributable to CLD and cirrhosis 14
– 12th leading cause of death

18. Epidemiology of Cirrhosis
• Total number of persons with cirrhosis is
estimated to peak at 1 million in 202015
• Rates of hepatic decompensation and
hepatocellular carcinoma are expected to
increase for another 10 to 13 years15

19. Over time, there has been an increase
in mortality from liver disease2

20. Normal transaminases do not exclude the
presence of chronic liver disease
• Fluctuation in transaminase levels occur
– Particularly in patients with chronic HBV, HCV, and
NASH
• “Burned out cirrhosis”
• Poor sensitivity/specificity
– 19,877 asymptomatic US Airforce basic trainees, 99
were found to have abnormal ALT elevation, 12 were
positive for liver disease 16

21. What are LFT’s?
• Serologic measurements ordered to evaluate for
liver disease
• The term liver function tests are actually a
misnomer
– Serum aminotransferases (ALT/AST) reflect
inflammation
– Alkaline Phosphatase (AP) reflects biliary injury
– Bilirubin, albumin, and PT/INR more accurately reflect
hepatic function

22. Why are LFT’s ordered?
• Routine check-up
• Drug monitoring
• Symptoms
• Screen for liver disease

23. General Approach
• What is the liver trying to tell me?
• Does this appear to be acute or chronic?
• If chronic, do findings exist that are
concerning for advanced fibrosis/cirrhosis

24. Elevated Aminotransferases
• Good indicators of hepatocellular injury
• Serum glutamic oxaloacetic transaminase (SGOT)
– AST is located in the cytosol and mitochondria
– Also present in striated muscle, the kidney, brain,
pancreas, lung, leukocytes, and erythrocytes
• Serum glutamic pyruvic transaminases (SGPT)
– ALT lies in the cytosol
– More specific indicator of liver injury

25. Normal Values
• AST <37 IU/L or ALT <40 IU/L for men
• AST or ALT <31 IU/L for women

26. Elevated Aminotranferases
• Elevated aminotransferase levels are present
in 7.9% of the population when sampling
asymptomatic individuals 17
• Some of the most common identifiable causes
include: 18
– alcohol use (13.5%)
– hepatitis C (7.0%)
– hemochromatosis (3.4%)
– hepatitis B (0.9%)
– combination of causes (6.1%)

27. Moderate-marked elevation in aminotransferases Mild elevation in aminotransferases
Ischemic injury a, c Nonalcoholic fatty liver disease
Toxic injury a, c Alcoholic hepatitis
Acute viral hepatitis a, b, d Pharmacology
Acute biliary obstruction a, d, e Chronic viral hepatitis (B, C)
Alcoholic hepatitis a, d, e Hereditary hemochromatosis
Autoimmune hepatitis
Wilson’s disease
α-1-antitripsin deficiency
Celiac disease
Extrahepatic causes
Table 1. Causes of elevated aminotransferases.
a Aminotransferase level increase of 5-10 x upper limit of normal
b Aminotransferase level increase of >10 x upper limit of normal
cBilirubin increase of <5 x upper reference limit

28. Elevated
aminotransferases
Extrahepatic
Chronic, mild
elevations
(<5xULN)
Acute, moderate-
severe elevations
(5-10xULN,
>10xULN)
Exposure
(alcohol, drugs)

29. Acute, moderate-
severe elevations
(5-10xULN,
>10xULN)
Ischemic injury
if hypotensive
Acute viral
anti-HAV IgM, HBsAg,
HBcAg IgM/HCV PCR
Autoimmune
ANA, ASMA
(anti-LKM)
Acetaminophen
toxicity
acetaminophen levels
Liver biopsy if
still unclear

30. Clinical Case #1
• 45 year old male with a history of alcohol
abuse and chronic back pain for which he
takes 3 Norco tablets a day presents with
jaundice, nausea, malaise and abdominal
pain.
Total bilirubin 3.5 ALT 5344
Direct bilirubin 2.7 AST 3923
Alkaline phosphatase 240 INR 1.3

31. Acute, moderate-
severe elevations
(5-10xULN,
>10xULN)
Ischemic injury
if hypotensive
Acute viral
anti-HAV IgM, HBsAg,
HBcAg IgM/HCV PCR
Autoimmune
ANA, ASMA
(anti-LKM)
Acetaminophen
toxicity
acetaminophen levels
Liver biopsy if
still unclear

32. Clinical Case #1
• RUQ US: normal liver contour
• Acetaminophen level: <1
• ANA: Normal
• ASMA: Normal
• Hepatitis B surface antigen Positive
• Hepatitis B core IgM Positive

33. Chronic, mild elevations
(<5xULN)
Hereditary
hemochromatosis
ferritin, Fe, TIBC
(HFE mutation)
Alpha-1 antitrypsin
deficiency
A1AT levels
Chronic viral
HBsAg, anti-HCV
Autoimmune
ANA, ASMA,
anti-LKM
Wilson's disease
ceruloplasmin
NAFLD
no serum test

34. Clinical Case #2
63 year old female with a history of obesity, hypertension,
diabetes who presents for evaluation of elevated liver
enzymes.
ALT 64 Platelet Count 110
AST 53 INR 1.1
AP 90
TB 1.0
Physical Exam: Evidence of spider angiomas and palmar
erythema

35. Chronic, mild elevations
(<5xULN)
Hereditary
hemochromatosis
ferritin, Fe, TIBC
(HFE mutation)
Alpha-1 antitrypsin
deficiency
A1AT levels
Chronic viral
HBsAg, anti-HCV
Autoimmune
ANA, ASMA,
anti-LKM
Wilson's disease
ceruloplasmin
NAFLD
no serum test

36. • Ultrasound splenomegaly, steatosis
• ANA normal
• ASMA normal
• Ferritin 500
• Iron/TIBC 24
• A1AT Normal
• HBsAg Negative
• Hepatitis C antibody positive
Clinical Case #2

37. Extrahepatic
Biliary
obstruction
Ultrasound, CT
Celiac
anti-tTG
Rhabdomylosis
CK
Thyroid disease
TSH

38. General Approach
• Obtain baseline right upper quadrant
ultrasound to evaluate for liver lesions,
hepatic morphology, thrombus, splenomegaly
• Obtain baseline labs to evaluate for
acute/chronic liver disease
• Referral to GI/Hepatology

39. Alkaline Phosphatase/Gamma-
glutamyl Transferase (GGT)
• ALP
– Produced predominantly in the liver and bone
– Can be found in renal, intestinal, placental tissue, or within
leukocytes
• GGT/ALP Fractionation
– It has a high sensitivity for hepatobiliary disease
– Elevated GGT levels also occur in alcohol-related liver
disease
– Most useful when elevated alkaline phosphatase levels
occur with otherwise normal liver enzymes and bilirubin
levels

40. INTRAHEPATIC
Drugs Anabolic steroids, estrogens, ACE-I,
antimicrobials, NSAIDS, allopurinol,
antiepileptics, hydralazine, procainamide,
quinidine, phenylbutazone
Primary biliary
cirrhosis
Predominantly middle-aged women with
median age of 50 years old, 95% of patients
have +AMA
Primary sclerosing
cholangitis
Strongly associated with IBD, commonly in
younger men, diagnosed by ERCP/MRCP
Granulomatous liver
disease
Sarcoidosis, TB, fungal infections, brucellosis,
Q fever, schistosomiasis
Viral hepatitis EBV, CMV,Hepatitis A, B, C, E
Genetic conditions Benign recurrent intrahepatic cholestasis
type 1,2
Malignancy HCC, metastatic disease, paraneoplastic
syndrome
Infiltrative liver
disease
Amyloidosis, lymphoma
Intrahepatic
cholestasis of
pregnancy
Total parent nutrition
Graft-Versus-Host
EXTRAHEPATIC
INTRINSIC
Immune-mediated
duct injury
Autoimmune pancreatitis, Primary
sclerosing cholangitis
Malignancy Ampullary cancer, cholangiocarcinoma
Infections AIDS cholangiopathy, CMV,
cryptosporidiosis, microsporidosis,
parasitic infections
EXTRINSIC
Malignancy Gallbladder cancer, metastases, portal
adenopathy, pancreatic cancer
Mirizzi syndrome Compression of common hepatic duct by
stone in neck of gallbladder
Pancreatitis Also includes pancreatic pseudocyst

41. Elevated ALP
Biliary pain
RUQ
ultrasound
Asymptomatic
Isolated
elevated
ALP
GGT normal
Bone, renal,
cardiac,
endocrine
etiologies or
malignancies
GGT high
Biliary obstruction or
extraheaptic malignancies
ultrasound
Medications/Alcohol
Hepatitis B, C
HBsAg, anti-HCV
PBC
AMA
PSC
MRCP, ERCP
Autoimmune cholangitis
IgG4
Concurrent
elevated
AST, ALT
Hepatocellular
injury
Cholestasis
If etiology still unclear, consider
MRCP, ERCP, EUS, or liver
biopsy

42. Clinical Case #3
• 45 year old female presents for evaluation of
elevated liver enzymes. She denies abdominal
pain.
ALT 45
AST 39
ALP 650
TB .9
INR .8

43. Elevated ALP
Biliary pain
RUQ
ultrasound
Asymptomatic
Isolated
elevated
ALP
GGT normal
Bone, renal,
cardiac,
endocrine
etiologies or
malignancies
GGT high
Biliary obstruction or
extraheaptic malignancies
ultrasound
Medications/Alcohol
Hepatitis B, C
HBsAg, anti-HCV
PBC
AMA
PSC
MRCP, ERCP
Autoimmune cholangitis
IgG4
Concurrent
elevated
AST, ALT
Hepatocellular
injury
Cholestasis
If etiology still unclear, consider
MRCP, ERCP, EUS, or liver
biopsy

44. Clinical Case #3
• Denies medication or recent antibiotic use
• Denies alcohol use
• RUQ US negative
• Hep b sAg negative
• HCV Ab negative
• ANA/ASMA negative
• AMA positive

46. Real LFT’s
• Bilirubin
• PT/INR
• Albumin

47. Bilirubin Metabolism

48. Type Cause
Unconjugated
hyperbilirubinemia
Hemolysis
Gilbert’s syndrome
Hematoma reabsorption
Ineffective erythropoiesis
Conjugated
hyperbilirubinemia
Bile duct obstruction
Hepatitis
Cirrhosis
Autoimmune cholestatic diseases (PBC, PSC)
Total parenteral nutrition
Drug toxins
Vanishing bile duct syndrome

49. Elevated bilirubin
Isolated bilirubin
<15% direct
Hemolysis
LDH, haptoglobin, peripheral
smear
Drugs
Gilbert's or Crigler-Najjar
syndrome
>15% direct
Dubin-Johnson or
Rotor's syndrome
Elevated AST/ALT
+/- ALP
Hepatocellular and
cholestatic causes

50. Clinical Case #4
• 33 year old female with a BMI 32 presents to
clinic for evaluation of jaundice and right
upper quadrant pain.
ALT 55
AST 49
AP 233
TB 3.5

51. Elevated bilirubin
Isolated bilirubin
<15% direct
Hemolysis
LDH, haptoglobin, peripheral
smear
Drugs
Gilbert's or Crigler-Najjar
syndrome
>15% direct
Dubin-Johnson or
Rotor's syndrome
Elevated AST/ALT
+/- ALP
Hepatocellular and
cholestatic causes

52. Clinical Case #4
• RUQ US Dilated common bile duct to 20 mm,
gallstones without evidence of cholecystitis

53. Albumin
• Exclusively made by in the liver and accounts
for 75% of the plasma colloid pressure.
• In chronic liver disease, hepatic synthesis of
albumin is impaired
– Not specific to liver diseases

54. Prothrombin Time
• Measurement of the rate at which prothrombin is
converted to thrombin
– The extrinsic pathway depends on the activity of clotting
factors II, V, VII, and X—all of which are synthesized in the
liver
• Therefore, prothrombin time is a reflection of liver dysfunction
– In chronic liver diseases, prolonged prothrombin time is a
sign of advanced liver disease
– In acute liver diseases, it is a more reliable indicator of
immediate synthetic function given it’s shorter half life

55. Conclusion
• Stable elevated liver enzymes DO NOT exist
• We are currently at the peak of HCV
prevalence and there is a concomitant rise in
the prevalence of NASH
– Screen patients born between 1945-1965
• Cirrhosis is the greatest risk factor for
hepatocellular carcinoma and hepatic
decompensation

56. Conclusion
• Interpretation of laboratory values in patients
with abnormalities in liver panel testing is
critical to developing a differential diagnosis
and initiation an adequate work-up
• The initial step is determination of an acute,
chronic, or acute-on-chronic process

57. Conclusion
• Acquisition of histology can be used to
confirm a suspected diagnosis, rule out
hepatic disease, and stage the degree of
fibrosis
• Upon establishment of chronicity, the role of
the practitioner is to establish the severity of
hepatic dysfunction, potential for reversibility,
and the need for escalation of care

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