Pemeriksaan Fungsi Hati .: Prof. Dr. Adi Koesoema Aman SPPK (KH)

PEMERIKSAAN FUNGSI
HATI .
Prof. Dr. Adi Koesoema Aman SpPK(KH)

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
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
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
 Tests of the biosynthetic capacity of the liver
Eg. S albumin, prothrombin time
 Tests to detect fibrosis in the liver

Eg. Type 4 collagen, Fibrotest etc
 Tests for chronic inflammation or altered

immunoregulation
Immunoglobulins and specific antibodies
Schiff’s diseases of the liver, 2007

Common serum liver chemistry tests
Normal values
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 - Wilson’s dis, hemochromatosis, autoimmune diseases
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
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
Medications causing elevation of aminotransferases
Acetaminophen
Amoxicillin-clavulanic acid
HMGCoA reductase inhbtrs Herbs and toxins
INH •Herbs/alt. medicines
NSAIDS •Illicit drugs
Phenytoin •Toxins
Valproate
Many others
ALD
 Reliable history
 Ratio of SGOT to SGPT is at least 2:1
 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 2:1 or more,
highly suggestive of alcohol abuse
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 < 1:1 in the absence of
cirrhosis
 Values < 250 IU usually
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
DD of severe elevations of ALT,
AST (> 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
Suggested algorithm for evaluating raised transaminases
PMJ 2003
What is “Normal”?
(Annals of Internal Medicine, 2002)

Other enzyme tests for hepatocellular
necrosis
 Glutamate dehydrogenase
 Isocitrate dehydrogenase
 Lactate dehydrogenase
More useful as marker for
•Hemolysis,
•Myocardial infarction
 Sorbitol dehydrogenase
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
 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
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
When SAP elevation is detected
Repeat the test
Confirm the hepatic origin
•Serum gammaglutamyl transferase
•5´-Nucleotidase
•AP isoenzymes
If medications suspected, discontinue them and repeat test

Persistently elevated SAP - evaluate for
•Cholestatic liver disease
•Infiltrative liver disease
•Biliary obstruction
 AP elevation upto 3 times ULN
•Nonspecific
•Occurs in all types of liver disorders
•Viral hepatitis
•Cirrhosis
•Infiltrative diseases of the liver
•CHF etc
 > 3 times ULN

•Cholestatic disorders Extrahepatic
Intrahepatic
•Infiltrative disorders
•Mets
•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 ( > 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
Suggested algorithm for evaluating a
raised s.alkaline phosphatase
PMJ 2003
Gammaglutamyl transferase
(γ-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 2:1 or more suggestive of ALD
 Medications can cause mild rise
 Normal range 0 to 30 IU/L
Causes of raised serum
gammaglutamyl transferase (SGGT)
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
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 > 50% capacity
Bilirubin
UDP-glucoronyltransferase
RE cell plasma hepatocyte

HEME UCB UCB UCB+ligandin
+ BMG
albumin BDG
bile
urobilinogen stercobilinogen
Isolated unconjugated
hyperbilirubinemia
 IDB fraction > 85% of total bilirubin
1. Increased production
• hemolysis
• ineffective erythropoiesis : folate, IDA
• drugs : rifampicin
• resolution of hematoma
2. Defects in hepatic uptake/conjugation
• Gilbert’s syndrome
• Crigler-Najjar syndrome
Gilbert’s 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
Conjugated hyperbilirubinemia
 DB > 50% of total bilirubin

 can’t differentiate obstruction and
parenchymal disease
 Delta fraction
• CB tightly bound to albumin
• tendency of hyperbilirubinemia to resolve
more slowly than other biochemical tests
Conjugated hyperbilirubinemia
 Bile duct obstruction  Intrahepatic cholestasis

 Hepatitis of pregnancy
 Cirrhosis  Benign recurrent
 Medications/Toxins cholestasis
 Primary biliary cirrhosis  Vanishing bile duct
 Primary sclerosing syndromes
cholangitis
 Sepsis  Dubin-Johnson syndrome
 Total parenteral nutrition  Rotor syndrome
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
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
Prothrombin time
prolonged :
• vitamin K deficiency (malnutrition,
malabsorption, antibiotics)
• massive transfusion
• congenital disease
• liver disease
• warfarin
• DIC
Prothrombin time
 in vit K deficiency, vit K 10 mg SC decreases
prolonged PT >30% 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

Modified Child-Turcotte-Pugh score for grading
severity of liver disease
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
Take home message
 initial evaluation : assess in clinical

context
 classified in 3 groups
1.synthetic function : albumin, clotting
time
2.cholestasis : bilirubin, ALP, GGT
3.hepatocyte injury : AST, ALT
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

When to refer for a specialist opinion?
 Unexplained liver abnormalities > 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
What tests to do before referral?
Consider the following;
•Screen for viral hepatitis

•IgM anti HAV
•HBsAg
•Anti HCV
•Antinuclear antibodies
•Ceruloplasmin in pts < 40 yrs
•Iron studies - S ferritin, transferrin saturation
•US of the hepatobiliary system
PMJ 2003

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PEMERIKSAAN FUNGSI

Prof. Dr. Adi Koesoema Aman SpPK(KH)

 Tests to detect injury to hepatocytes

 Tests to detect fibrosis in the liver

 Tests for chronic inflammation or altered

Schiff’s diseases of the liver, 2007

 Mild AST, ALT elevation (less than 5

 Wide range of liver diseases

(Annals of Internal Medicine, 2002)

•Present in nearly all tissues - isoenzymes

If medications suspected, discontinue them and repeat test

 > 3 times ULN

RE cell plasma hepatocyte

 benign, unconjugated hyperbilirubinemia

 DB > 50% of total bilirubin

 Bile duct obstruction  Intrahepatic cholestasis

 depends on nutrition, hormonal factors,

• Not a reliable indicator of acute liver disease

 The liver synthesizes coagulation factors except

 INR (international normalised ratio)

ISI - international sensitivity index

 initial evaluation : assess in clinical

Liver Chemistry Tests

 Unexplained liver abnormalities > 1.5 times

•Screen for viral hepatitis

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