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Interpretation of abnormal liver function tests

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Interpretation of abnormal liver function tests Dr Selwyn Noronha Dept of Medical Gastroenterology MCH Trivandrum Bilirubin Product of hemoglobin breakdown 2 Forms ... – PowerPoint PPT presentation

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Title: Interpretation of abnormal liver function tests


1
Interpretation of abnormal liver function tests
  • Dr Selwyn Noronha
  • Dept of Medical Gastroenterology
  • MCH Trivandrum

2
Liver function tests
  • Noninvasive method of screening for the presence
    of liver dysfunction
  • Pattern of lab test abnormality allows
    recognition of general type of disorder
  • To assess the severity and occasionally allow
    prediction of outcome
  • To follow the course of the disease, evaluate
    response to treatment, and adjust treatment when
    necessary

3
Limitations
  • Lack of sensitivity (may be normal in cirrhosis
    or HCC)
  • Lack of specificity (aminotransferase levels may
    be elevated in musculoskeletal or cardiac
    disease)
  • Results suggest general category of liver
    disease, not a specific diagnosis
  • Essential to use LFT as a battery of tests and
    repeat them over time
  • Probability of liver disease is high when more
    than one test is abnormal or the findings are
    persistently abnormal on serial testing

4
General categories of tests
  • Tests of the capacity of the liver to transport
    organic anions and metabolize drugs
  • Eg. S bilirubin, s bile acids, BSP etc
  • Measures ability of the liver to clear endogenous
    or exogenous substances from the circulation
  • Tests to detect injury to hepatocytes
  • All the enzyme tests
  • Most commonly done and most useful are
    aminotransferases and alkaline phosphatase

5
  • Tests of the biosynthetic capacity of the liver
  • Tests to detect fibrosis in the liver
  • Tests for chronic inflammation or altered
    immunoregulation

Eg. S albumin, prothrombin time
Eg. Type 4 collagen, Fibrotest etc
Immunoglobulins and specific antibodies
Schiffs diseases of the liver, 2007
6
Common serum liver chemistry tests
7
Normal values
8
Initial approach to the evaluation of abnormal
liver enzyme tests
  • Asymtomatic or symptomatic
  • History and physical
  • Alcohol consumption
  • Risk factors for viral hepatitis - IV drug abuse,
    sexual promiscuity, homosexual relations,
    tattoos, nonsterile body piercing, blood and
    blood products, medications, herbal or
    alternative med., occupational exposure to toxins
  • Diabetes, obesity, hyperlipidemia
  • Family history - Wilsons dis, hemochromatosis,
    autoimmune diseases

9
Evaluation of abnormalities of ALT (SGPT) and AST
(SGOT) levels
  • AST and ALT are markers of hepatocellular injury
  • Participate in gluconeogenesis, transfer of amino
    groups from aspartate or alanine to ketoglutaric
    acid to form oxaloacetete or pyruvate.
  • AST present in cytosol and mitochondria in liver,
    cardiac muscle, skeletal muscle, kidney, brain,
    pancreas, lungs, WBC and RBC.
  • ALT a cytosolic enzyme, highest concentration in
    the liver
  • ALT considered a liver specific enzyme

10
Useful paradigm to categorize increased levels of
AST, ALT
  • Mild AST, ALT elevation (less than 5 times ULN) -
    ALT predominant or AST predominant
  • AST, ALT greater then 15 times normal
  • Elevations in the intermediate range - less
    useful for limiting the DD, caused by diseases
    from both above categories

AGA Technical review, Gastroenterology 2002
11
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12
Medications causing elevation of
aminotransferases Acetaminophen Amoxicillin-clavu
lanic acid HMGCoA reductase inhbtrs INH NSAIDS Phe
nytoin Valproate Many others
  • Herbs and toxins
  • Herbs/alt. medicines
  • Illicit drugs
  • Toxins

13
ALD
  • Reliable history
  • Ratio of SGOT to SGPT is at least 21
  • Reflects low level of activity of SGPT
  • SGOT rarely exceeds 300 IU
  • Higher values - seek additional cause of liver
    injury
  • A GGT (gammaglutamyl transferase) twice normal
    and AST/ALT ratio of 21 or more, highly
    suggestive of alcohol abuse

14
NAFLD
  • Hepatic steatosis (fatty liver) and NASH
  • Asymptomatic increase in transaminases
  • Raised BMI, Type 2 DM and hyperlipidemia
  • No evidence of clinically relevant alcohol use
  • Probably commonest cause of mild transaminase
    increases
  • AST/ALT ratio usually lt 11 in the absence of
    cirrhosis
  • Values lt 250 IU usually

15
DD of moderately elevated aminotransferases (5 to
15 times ULN)
  • Wide range of liver diseases
  • ALT, AST less useful in determining cause
  • Entire spectrum of liver diseases causing mild or
    severe aminotransferase elevation

16
DD of severe elevations of ALT, AST (gt 15 times
ULN)
  • Relatively ltd
  • Indicate marked hepatocellular injury or necrosis
  • Drug induced - acetaminophen
  • Occupational/environmental toxins - toluene, CCl4
  • Ischemic hepatitis
  • Viral hepatitis - A, B, D, E, Herpes

17
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18
Suggested algorithm for evaluating
raised transaminases
PMJ 2003
19
What is Normal?
(Annals of Internal Medicine, 2002)
20
Other enzyme tests for hepatocellular necrosis
  • Glutamate dehydrogenase
  • Isocitrate dehydrogenase
  • Lactate dehydrogenase
  • Sorbitol dehydrogenase
  • More useful as marker for
  • Hemolysis,
  • Myocardial infarction

21
Enzymes for the detection of cholestasis Alkaline
phosphatase
  • Present in nearly all tissues - isoenzymes
  • Localised in the microvilli of the bile canalicus
    in the liver
  • Also present in bone, intestine, placenta, kidney
    and wbc
  • Elevation may be physiological or pathological
  • Physiological
  • In tissues undergoing metabolic stimulation
  • Third trimester of pregnancy
  • Adolescence

22
  • Normal adult serum AP is from liver and bone
  • Intestine contributes about 15
  • Several procedures used to measure activity -
    differs in substrates used, end products
    measured, etc
  • Isoenzymes differ in reactions in various assay
    systems
  • Hence different units such as IU, KA, Bodansky

23
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24
Elevation of s. alkaline phosphatase
  • Isolated
  • Associated with hyperbilirubinemia
    (cholestatic disorders)
  • May be sole abnormality in many cholestatic or
    infiltrative diseases
  • To be interpreted in the clinical setting of
    history and physical examination if sole
    abnormality

25
When SAP elevation is detected
  • Repeat the test
  • Confirm the hepatic origin
  • If medications suspected, discontinue them and
    repeat test
  • Persistently elevated SAP - evaluate for
  • Serum gammaglutamyl transferase
  • 5-Nucleotidase
  • AP isoenzymes
  • Cholestatic liver disease
  • Infiltrative liver disease
  • Biliary obstruction

26
  • AP elevation upto 3 times ULN
  • gt 3 times ULN
  • Nonspecific
  • Occurs in all types of liver disorders
  • Viral hepatitis
  • Cirrhosis
  • Infiltrative diseases of the liver
  • CHF etc
  • Cholestatic disorders Extrahepatic

  • Intrahepatic
  • Infiltrative disorders
  • Mets

27
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29
  • USS to assess hepatic parenchyma and biliary
    system should be part of initial evaluation
  • Additional imaging of abdomen if indicated
  • CT, MRI, MRCP
  • If extrahepatic obstruction evident, ERCP or PTC
  • If no obstruction, do AMA (anti-mitochondrial
    antibody)
  • Continued presence of persistently elevated SAP (
    gt 6 months ) of unknown origin - further
    evaluation with imaging and/or biopsy
  • Potentially treatable cholestatic and
    infiltrative diseases with long asymptomatic
    periods with mild elevations of AP being the only
    finding
  • Eg PBC, PSC, Sarcoidosis etc

30
Suggested algorithm for evaluating a raised
s.alkaline phosphatase
PMJ 2003
31
Gammaglutamyl transferase (?-glutamyl
transpeptidase)
  • Found in hepatocytes and biliary epithelial cells
  • Sensitive for hepatobiliary disease but ltd by
    lack of specificity
  • With other enzyme abnormalities, raised GGT would
    support a hepatobiliary cause
  • Can confirm hepatic source for a raised AP
  • Raised GGT and raised transaminases with ratio of
    AST to ALT 21 or more suggestive of ALD
  • Medications can cause mild rise
  • Normal range 0 to 30 IU/L

32
Causes of raised serum gammaglutamyl transferase
(SGGT)
33
5-Nucleotidase
  • Normal 0.3 to 3.2 Bodansky units
  • Spectrum of abnormality similar to that of SAP
  • Specificity for hepatobiliary disease
  • May be used to confirm hepatic origin of elevated
    SAP

34
Bilirubin
  • Product of hemoglobin breakdown
  • 2 Forms
  • Unconjugated (indirect)- insoluble
  • ? in hemolysis, Gilbert syndrome, meds
  • Conjugated (direct)- soluble
  • ? in obstruction, cholestasis, cirrhosis,
    hepatitis, primary biliary cirrhosis, etc.
  • No elevation until loss of gt 50 capacity

35
Bilirubin
UDP-glucoronyltransferase
36
Isolated unconjugated hyperbilirubinemia
  • IDB fraction gt 85 of total bilirubin
  • Increased production
  • hemolysis
  • ineffective erythropoiesis folate, IDA
  • drugs rifampicin
  • resolution of hematoma
  • Defects in hepatic uptake/conjugation
  • Gilberts syndrome
  • Crigler-Najjar syndrome

37
Gilberts syndrome
  • benign, unconjugated hyperbilirubinemia with
    otherwise normal liver chemistries
  • up to 5 of normal population
  • polymorphisms of gene encoding bilirubin UDP-GT ?
    impaired ability to conjugate bilirubin
  • prominent in fasting state, systemic illnesses,
    hemolysis, some medications

38
Conjugated hyperbilirubinemia
  • DB gt 50 of total bilirubin
  • cant differentiate obstruction and parenchymal
    disease
  • Delta fraction
  • CB tightly bound to albumin
  • tendency of hyperbilirubinemia to resolve more
    slowly than other biochemical tests

39
Conjugated hyperbilirubinemia
  • Intrahepatic cholestasis of pregnancy
  • Benign recurrent cholestasis
  • Vanishing bile duct syndromes
  • Dubin-Johnson syndrome
  • Rotor syndrome
  • Bile duct obstruction
  • Hepatitis
  • Cirrhosis
  • Medications/Toxins
  • Primary biliary cirrhosis
  • Primary sclerosing cholangitis
  • Sepsis
  • Total parenteral nutrition

40
Albumin
  • depends on nutrition, hormonal factors, vascular
    integrity, catabolism, loss in stool and urine
  • not specific for liver disease
  • T1/2 19-21 days
  • Not a reliable indicator of acute liver disease
  • Levels fall in progressive disease, reflects
    synthetic fn
  • Correlates with prognosis in CLD

41
Prothrombin time
  • The liver synthesizes coagulation factors except
    FVIII
  • Most present in excess, clotting abnormality
    occurs only when substantial impairment in
    ability of liver to synthesise the CF
  • PT FI, II, V, VII, IX and X
  • T1/2 FVII 6 hrs. (shortest)
  • prognosis acute, chronic hepatocellular disease

42
Prothrombin time
  • prolonged
  • vitamin K deficiency (malnutrition,
    malabsorption, antibiotics)
  • massive transfusion
  • congenital disease
  • liver disease
  • warfarin
  • DIC

43
Prothrombin time
  • in vit K deficiency, vit K 10 mg SC decreases
    prolonged PT gt30 within 24 hrs
  • INR (international normalised ratio)
  • More often tested now
  • Standardising reports of PT
  • Avoids interlab variability
  • INR Patient PT/mean control PT ISI
  • ISI - international sensitivity index

44
Modified Child-Turcotte-Pugh score for grading
severity of liver disease
45
Quantitative tests for liver function
  • More sensitive
  • Limitations of biochemical tests
  • Expensive, ltd to research centers
  • Trials needed before wider acceptance
  • Indocyanine green clearance
  • 14C - aminopyrine breath test
  • Antipyrine clearance
  • Galactose elimination capacity
  • 13C - caffeine breath test

46
Take home message
  • initial evaluation assess in clinical context
  • classified in 3 groups
  • synthetic function albumin, clotting time
  • cholestasis bilirubin, ALP, GGT
  • hepatocyte injury AST, ALT

47
Liver Function Tests
  • misnomer
  • Does not effectively assess actual function
  • not always specific for the liver
  • limited information regarding presence or
    severity of complication

Liver Chemistry Tests
48
When to refer for a specialist opinion?
  • Unexplained liver abnormalities gt 1.5 times
    normal on 2 occasions, a minimum of 6 months
    apart
  • Unexplained liver disease with evidence of liver
    dysfunction (hypoalbuminemia, hyperbilirubinemia,
    prolonged PT or INR)
  • Known liver disease where treatment beyond
    withdrawal of the implicating agent is required

Limdi et al, Postgrad Med J 2003
49
What tests to do before referral?
  • Consider the following
  • Screen for viral hepatitis
  • Antinuclear antibodies
  • Ceruloplasmin in pts lt 40 yrs
  • Iron studies - S ferritin, transferrin saturation
  • US of the hepatobiliary system
  • IgM anti HAV
  • HBsAg
  • Anti HCV

PMJ 2003
50
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51
Thank you
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