Interpretation of abnormal liver function tests. Dr Rania Bakry, MD

Interpretation of abnormal

liver function tests

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

 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

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

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

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

Medications causing elevation of aminotransferases

Acetaminophen

Amoxicillin-clavulanic acid HMGCoA reductase inhbtrs INH

NSAIDS Phenytoin Valproate Many others

Herbs and toxins

•Herbs/alt. medicines •Illicit drugs

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

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, CCl

₄



Ischemic hepatitis

Suggested algorithm for evaluating raised transaminases

(Annals of Internal Medicine, 2002)

Other enzyme tests for hepatocellular necrosis 

Glutamate dehydrogenase



Isocitrate dehydrogenase



Lactate dehydrogenase



Sorbitol dehydrogenase

More useful as marker for •Hemolysis,

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

 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,

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

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

 AP elevation upto 3 times ULN

 > 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

•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

Suggested algorithm for evaluating a raised s.alkaline phosphatase

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

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

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.

RE cell plasma hepatocyte

HEME UCB UCB

+ albumin UCB+ligandin BMG BDG bile urobilinogen stercobilinogen

Bilirubin

UDP-glucoronyltransferase

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

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



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  Hepatitis

 Cirrhosis

 Medications/Toxins

 Primary biliary cirrhosis  Primary sclerosing

cholangitis

 Sepsis

 Total parenteral nutrition

 Intrahepatic cholestasis

of pregnancy

 Benign recurrent

cholestasis

 Vanishing bile duct

syndromes

 Dubin-Johnson syndrome  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

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

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

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

14_{C - aminopyrine breath test}

Antipyrine clearance

Galactose elimination capacity 13_{C - 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

misnomer

• Does not effectively assess actual function • not always specific for the liver

• limited information regarding presence or

severity of complication

Liver Function 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

What tests to do before referral?

Consider the following;

•Screen for viral hepatitis

•Antinuclear antibodies

•Ceruloplasmin in pts < 40 yrs

•Iron studies - S ferritin, transferrin saturation •US of the hepatobiliary system

•IgM anti HAV •HBsAg

•Anti HCV