2 Approach To Elevated LFT

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
Disclosures
• Consultant for Gilead Pharmaceuticals
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
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
Why is identification of patients with abnormal
liver enzymes important?
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
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
Currently at the peak of the HCV
epidemic2
Hepatitis C surpassed HIV as a cause of
virus-related death in 2006
Incidence of Hepatitis C 8
http://www.cdc.gov/hepatitis/statistics/
Second Culprit on the Loose…
Insulin Resistance
Diabetes is an important risk factor
for progression of fibrosis11,12
Obesity Epidemic
• Coincides with the rise in NAFLD
Rising Prevalence of NAFLD 10
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
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
Over time, there has been an increase
in mortality from liver disease2
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
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
Why are LFT’s ordered?
• Routine check-up
• Drug monitoring
• Symptoms
• Screen for liver disease

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

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%)
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
c
Bilirubin increase of <5 x upper reference limit
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
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
Clinical Case #2
63 year old female with a history of obesity, hypertension,
diabetes who presents for evaluation of elevated liver enzymes.
ALT 64Platelet Count 110

AST 53INR 1.1
AP 90
TB 1.0
Physical Exam: Evidence of spider angiomas and palmar

erythema
Clinical Case #2
• Ultrasound splenomegaly, steatosis
• ANA normal
• ASMA normal
• Ferritin 500
• Iron/TIBC 24
• A1AT Normal
• HBsAg Negative
• Hepatitis C antibody positive
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
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
INTRAHEPATIC
Drugs Anabolic steroids, estrogens, ACE-I,
antimicrobials, NSAIDS, allopurinol,
antiepileptics, hydralazine, procainamide,
quinidine, phenylbutazone
Primary biliary Predominantly middle-aged women with EXTRAHEPATIC
cirrhosis median age of 50 years old, 95% of patients INTRINSIC
have +AMA Immune-mediated Autoimmune pancreatitis, Primary
Primary sclerosing Strongly associated with IBD, commonly in duct injury sclerosing cholangitis
cholangitis younger men, diagnosed by ERCP/MRCP Malignancy Ampullary cancer, cholangiocarcinoma
Granulomatous liver Sarcoidosis, TB, fungal infections, Infections AIDS cholangiopathy, CMV,
disease brucellosis, Q fever, schistosomiasis cryptosporidiosis, microsporidosis,
Viral hepatitis EBV, CMV,Hepatitis A, B, C, E parasitic infections
Genetic conditions Benign recurrent intrahepatic cholestasis EXTRINSIC
type 1,2 Malignancy Gallbladder cancer, metastases, portal
Malignancy HCC, metastatic disease, paraneoplastic adenopathy, pancreatic cancer
syndrome Mirizzi syndrome Compression of common hepatic duct by
Infiltrative liver Amyloidosis, lymphoma stone in neck of gallbladder
disease Pancreatitis Also includes pancreatic pseudocyst
Intrahepatic
cholestasis of
pregnancy
Total parent
nutrition
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
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
Real LFT’s
• Bilirubin
• PT/INR
• Albumin
Bilirubin Metabolism
Type Cause
Unconjugated Hemolysis
hyperbilirubinemia
Gilbert’s syndrome
Hematoma reabsorption
Ineffective erythropoiesis
Conjugated Bile duct obstruction
hyperbilirubinemia
Hepatitis
Cirrhosis
Autoimmune cholestatic diseases (PBC, PSC)
Total parenteral nutrition
Drug toxins
Vanishing bile duct syndrome
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
Clinical Case #4
• RUQ US Dilated common bile duct to 20 mm,
gallstones without evidence of cholecystitis
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
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
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
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
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
References
1. Younossi ZM, Stepanova M, Afendy M, et al. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from
1988 to 2008. Clin Gastroenterol Hepatol. 2011 Jun;9(6):524-530.
2. Udompap P, Kim D, Kim WR. Current and Future Burden of Chronic Nonmalignant Liver Disease. Clin Gastroenterol Hepatol. 2015 Nov;13(12):2031-41.
Epub 2015 Aug 17.
3. Hultcrantz R, Glaumann H, Lindberg G, Nilsson LH. Liver investigation in 149 asymptomatic patients with moderately elevated activities of serum
aminotransferases. Scand J Gastroenterol 1986; 21:109–113.
4. Ioanou GN, Boyko EJ, Lee SP. The prevalence and predictors of elevated serum aminotransferase activity in the United States in 1999-2002. Am J
Gastroenterol 2006; 101:76–82.
5. Chou R et al. Agency for Healthcare Research and Quality; 2012.
6. Chak E et al. Liver Int. 2011 Sep;31(8):1090-101.
7. Lavanchy D. Liver Int. 2009 Jan;29 Suppl 1:74-81.
8. Puoti C, Castellacci R, Montagnese F et al. Histological and virological features and follow-up of hepatitis C virus carriers with normal aminotransferase
levels: the Italian prospective study of the asymptomatic C carriers (ISACC). J Hepatol 2002; 37: 117–123.
9. Ly KN et al. Ann Intern Med. 2012;156:271-8.
10. Lazo M, Hernaez R, Eberhardt MS, et al. Prevalence of nonalcoholic fatty liver disease in the United States: the Third National Health and Nutrition
Examination Survey, 1988-1994. Am J Epidemiol. 2013 Jul 1;178(1):38-45.
11. L.A. Adams, S. Sanderson, K.D. Lindor, P. Angulo. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with
sequential liver biopsies. J Hepatol, 42 (2005), pp. 132–138.
12. McPherson S, Hardy T, Henderson E, et al. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications
for prognosis and clinical management. J Hepatol. 2015 May;62(5):1148-55.
13. Heron M. Natl Vital Stat Rep.2012;61:1–96.
14. Scaglione S et al. J Clin Gastroenterol. 2014 Oct 8.
15. Chou R et al. Agency for Healthcare Research and Quality; 2012.
16. Kundrotas LW; Clement DJ. Serum alanine aminotransferase (ALT) elevation in asymptomatic US Air Force basic trainee blood donors. Dig Dis Sci 1993;
38:2145-2150
17. Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol. 2003
May;98(5):960–7.
18. Liangpunsakul S, Chalasani N. Unexplained Elevations in Alanine Aminotransferase in Individuals with the Metabolic Syndrome: Results from the Third
National Health and Nutrition Survey (NHANES III). The American Journal of the Medical Sciences [Internet]. 2005;329(3).

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Approach to Elevated LFT’s

Miguel H. Malespin M.D.

• Review interpretation of abnormal liver enzymes

• Develop an approach to managing elevated liver

• Elevated liver transaminase levels are found in

• Approximately 9% of patients with elevated

•Nearly ½ of persons with chronic HCV are

• Rates of hepatic decompensation and

• “Burned out cirrhosis”

• The term liver function tests are actually a

• Screen for liver disease

• Does this appear to be acute or chronic?

• If chronic, do findings exist that are

• Serum glutamic oxaloacetic transaminase (SGOT)

• Serum glutamic pyruvic transaminases (SGPT)

• AST or ALT <31 IU/L for women

• Some of the most common identifiable causes

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

Total bilirubin 3.5 ALT 5344

ALT 64Platelet Count 110

Physical Exam: Evidence of spider angiomas and palmar

• Obtain baseline labs to evaluate for

• In chronic liver disease, hepatic synthesis of

– In chronic liver diseases, prolonged prothrombin time is a

– In acute liver diseases, it is a more reliable indicator of

• We are currently at the peak of HCV prevalence and

• Cirrhosis is the greatest risk factor for hepatocellular

• The initial step is determination of an acute,

• Upon establishment of chronicity, the role of

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