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LIVER FUNCTION TEST ANDCLINICAL ASPECT
DR Nani Nordin
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Learning Objective
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Activity 1
Outline major functions of the liver.
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Functions of Liver Metabolic:Glucose metabolismStored as glycogen.
Glycogenolysis and gluconeogenesis during fasting.LipidFormation of VLDL to transport endogenous TGto adipose tissue.
Convert fatty acid from adipose tissue to ketone duringfasting.Storage of vitamin D, vitamin B12 and iron.
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Functions of the liver
Synthetic Functions Plasma protein all except Ig and complement.
Coagulation factors. Lipoprotein VLDL and HDL Primary bile acids
Deficiencies in synthetic functions occur inextensive liver dz due to large functionalreserve.
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Functions of the liver
Excretion and DetoxificationBilirubin excretion.
Amino acids.Cholesterol.Steroid hormones.Drugs-metabolized and inactivated by
enzyme of endoplasmic reticulum.Toxins- via kupffer cells.
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Activity 2
Describe bilirubin metabolism in adiagram.
Explain the difference between conjugatedand uncojugated bilirubin. What is urobilinogen?
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Bilirubin
Indirect bilirubin formed in themacrophages of thespleen and marrow.
Water insoluble Toxic- because cancross BBB
Direct bilirubin Formed in the liver:conjugated with
glucuronic acid by theenzyme UDP-glucuronyltransferase
Water soluble
U nconjugated
Together these two forms comprise the total bilirubin in the serum.
conjugated + unconjugated = total bilirubin
Conjugated
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Bilirubin Metabolism Erythrocytes are destroyed by
macrophages in the spleen and bonemarrow, releasing hemoglobin heme
The globin portion is metabolizedamino acids.
The heme is converted intounconjugated bilirubin in macrophages
of the spleen and bone marrow, boundto plasma albumin and transported tothe liver.
There it is conjugated with glucuronicacid by the enzyme UDP-glucoronyltransferase , making it water soluble for excretion in the bile.
The conjugated bilirubin in the bile isdelivered into the small intestine andexcreted as urobilinogen.
HAEM
BILIVERDIN
BILIRUBIN IX
Fe 2+
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Urobilinogen
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Activity 3
Define jaundice. Explain the pathophysiology of jaundice.
List the causes of jaundice.
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J aundice
Yellow staining of the skin and sclerae byabnormally high level of bilirubin pigment.
J aundice is clinically apparent whenbilirubin reaches about 35 mol/L.
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Pathophysiology of J aundice Occurs when bilirubin production exceed liver capacity to excrete.
Pre-hepatic-Increase rate of bilirubin productionexceeds the hepatic artery to excrete it.
Hepatic- When the normal load of bilirubincannot be conjugated and/or excreted bydamaged liver cells.
Post hepatic- Biliary flow is obstructedconjugated bilirubin cannot be excreted into theintestine and regurgitated into the systemiccirculation.
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Causes of J aundice
Prehepatic Haemolysis, ABO incompatiblity
Hepatic Congenital -Gilberts Syndrome, Crigler-Najjar Hepatic infiltration- Hepatitis(viral, autoimmune,alc,drugs) ,CirrhosisMetabolic - Haemochronatosis ,Wilsons dz ,A-1-antitrypsin deficiencyLiver malignancy- Primary ,Secondary
Post-hepatic Biliary obstructionGall stonePancreatic tumor Primary biliary cirrhosisSclerosing Cholangitis
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Activity 4
What are the roles of liver function test? Lists the parameters measured in a liver
function test. Discuss the significance of derangementof these parameters.
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THE ROLE OF LIVER FUNCTION
TESTTests of liver function are used for:
1. Screening for abnormalities in liver function
2. Documenting an abnormality3. Identifying the type and site of injury4. Prognostication and follow-up of patients
with hepatic disease
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COMPONENT OF LFT Bilirubin- conjugated and unconjugated Total protein and albumin Liver enzymes
Alanine transaminase (ALT)Aspartate transaminase (AST)Alkaline phosphatase (ALP)Gamma glutamyltransferase (GGT)
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Bilirubin Serum Total bilirubin = direct (conjugated) +indirect (unconjugated) bilirubin
Urinary bilirubin : normally there is no bilirubin in the urine, because
unconjugated bilirubin exists in the plasma attachedto albumin.
Bilirubin in urine means that there is o level of conjugated bilirubin e.g. in obstructive jaundice andhepatitis
Usually estimated by a dipstick method.
Urinary urobilinogen : o in hemolysis or if there is interference to hepaticexcretion of urobilinogen ( from enterohepatic circ .)
Its absence from urine indicate that there is completeobstruction to hepatic bilirubin excretion.
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PLASMA TOTAL PROTEINS ANDALBUMIN
The total proteins estimates both albuminand globulins
Albumin is wholly synthesized in the liver and low levels suggest severe hepatocytedysfunction
The globulin fraction, which includes the
immunoglobulins, are usually increased inchronic liver disease (e.g. chronichepatitis)
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PLASMA TRANSAMINASES
Aspartate aminotransferase (AST) andalanine aminotransferase (ALT) arepresent in large quantities in thehepatocyte.
Diseases which cause hepatocytedestruction (e.g. hepatitis) results in therelease of these enzymes.
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PLASMA ALKALINEPHOSPHATASE (ALP)
Found in the cells lining the bile passagesand on the secretory side of thehepatocyte membrane walls
o plasma levels are found in obstructivejaundice.
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PLASMA GGT
Located on the hepatocyte membrane andis increased in cholestasis
Its activity is also increased (enzymeinduction) by a number of drugs andtoxins (e.g. alcohol, phenytoin sodium)
Thus, high plasma GGT levels do notalways indicate liver disease.
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Activity 5
Define acute liver injury and chronic liver injury.
Lists the causes acute and chronic liver injury. Discuss the biochemical findings in acuteand chronic hepatitis
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Acute Liver Injury
Acute hepatic injury refers to hepatocytedamage that occurs abruptly and over ashort period of time.
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Chronic Liver Injury Chronic hepatic injury refers to continuing hepatocyte damage for
more than 6 months. It is defined pathologically by ongoing hepatic necrosis and
inflammation in the liver, often accompanied by fibrosis. Chronic hepatocyte injury is usually recognized by slight elevation of
aminotransferases (usually less than 4 times the upper referencelimit), although activities may be intermittently elevated and, in asmall percentage of cases, persistently within reference limits.
Persistence of increased ALT for more than 6 months after an episodeof acute hepatitis OR
Elevation of ALT (without another explanation) on more than oneoccasion over a period of 6 months. A shorter time may beappropriate in patients with risk factors for chronic viral hepatitis,genetic causes of hepatic injury, or autoimmune liver injury; or in thepresence of clinical signs or symptoms of liver disease. (IIB).
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Causes of acute liver injury
Hepatitis-viral (hepatitis virus, CMV, EBV,alcohol
Toxic injury Ischaemic injury Wilsons disease
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Causes of chronic liver injury Hepatitis virus
Non-alcoholic steatohepatitis
Hemochromatosis
Wilsons Disease
Autoimmune hepatitis
Primary biliary cirrhosis
Sclerosing cholangitis
Alpha-1-antitrypsin deficiency
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Acute hepatitis Chronic hepatitis
Definition Acute inflammation of the liver.May be caused by viral , drugs,toxic agents
Chronic inflammatoryreaction of the liver of morethan 6 months
Clinical presentation andphysical findings
Hx of anorexia, nauseatenderness or discomfort over the liver Fever, + jaundice, enlargedtender liver
Lab. findings Biochemical findings arepredominantly those of cellmembrane damage: ALT>ASTPlasma transaminases are veryhigh at the onset of symptomsThere may be superimposed
cholestatic picture~jaundice,pale stools and dark urineComplete lab recovery:
Hepatitis A: 9 weeksHepatitis B: 16weeks may becomechronic
Persistently abnormalserum transaminases
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Activity 6Liver pathology can be classified according
to theLFTs results as:
Hepatocellular
Cholestatic (obstructive) Mixed hepatocellular and cholestatic
Give examples of diseases in therespective category
Explain the expected LFT derangement inhepatocellular and cholestatic liver injury.
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Category Hemolytic/Iron overload
Hepatocellular O bstructive
ALT Normal o Normal or o
AST Normal o Normal or oALP/GGT Normal o or Normal o o o
CONJU GATEDBILIRU BIN
Normal o o
UN CONJU GATEDBILIRU BIN
o o Normal
URO BILINO GE N IN THE UR IN E
o o or Normal q
R epresentativediseases
Haemolytic anemias,thalassemia major
Multiple transfusion
Acute hepatitis,cirrhosis,
Drug toxicityReye syndrome
Obstruction:intrahepatic,
extrahepaticSpace-occupying
lesionsDrugs
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Hepatocellular destruction
Damage to cells release of intracellular enzymes o plasma levels of AST & ALT(up to 10x). (Normal ALT
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Cholestasis Defines as obstruction to bile outflow occurring
anywhere between the secretory surface of thehepatocyte and the junction of the bile ducts with theduodenum.
The characteristic features are jaundice and a highplasma ALP level, usually greater than 3x normal
The plasma bilirubin is mainly conjugated (backflow). Plasma ALT may be normal or mildly o
If obstruction persist hepatocellular destruction may besignificant and very high plasma levels of ALTs will occur Plasma GGT is always o .
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Obstructive jaundice
IntrahepaticIntrahepatic : hepatitis, tumour, cholangitis,drugs
Extrahepatic jaundiceExtrahepatic jaundice : cholelithiasis,tumor, biliary stricture, biliary atresia
SpaceSpace- -occupying lesionoccupying lesion : tumor, cysts,granuloma, abscess
DrugsDrugs CirrhosisCirrhosis : alcoholic, biliary, cryptogenic,Wilsons disease, haemachromatosis.
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It is important to distinguish hepatocellular jaundice fromextrahepatic obstructive jaundice, because the latter isan indication for exploratory surgery. The biochemicalfindings are similar but one useful laboratory test is the
measurement of alkaline phosphatase (ALP).alkaline phosphatase (ALP). ALP may come from the liver, bone, intestine and
placenta. Serum ALP may be 3xo in obstructive jaundice, while
90% of patients with hepatocellular jaundice have valuesless than that.
Patients with hepatocellular jaundice also tend to havemarked elevation of serum LD, ALT, AST and GGT
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Activity 7
List common drugs that can cause liver disease.
Briefly explain the mechanism of liver damage by acetaminophen.
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Activity 8
3 metabolic conditions that can cause liver injury include: Wilsons disease
Haemochromatosis1-antitrypsin deficiencyheBriefly describe these 3 conditions and
state relevant laboratory investigationsrequired for the diagnosis.
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Metabolic liver diseaseDisease Presentation Diagnosis and Laboratory findings
EE 11--antitrypsinantitrypsindeficiencydeficiency
Pulmonary emphysema inchildhoodHepatitis in neonatesCirrhosis in children andyoung adults
Dz is confirmed demostrating a lowplasma E 1-antitrypsin and byidentifying the phenotype
WilsonsWilsons
Disease:Disease:RecessivelyinheritedCaused byimpaired hepaticincorporation of
copper intocaeruloplasmin
Present at 10-30 years due
to excessive deposition of copper in the liver and brain
Acute hepatitis or Parkinson-likeextrapyrimidal symptoms.
Kayser-fleischer ring isfound
Low plasma copper and
ceruloplasminIncreased urinary copper excretionLiver biopsy: increased copper
content
HemochromatosisHemochromatosis: Recessivelyinherited
Onset usually after age 50Arthropathy, cardiomegaly,
hepoatomegaly, skinpigmentation,
Mild abnormal LFTsElevated plasma iron>50% saturation of the transferrin
Liver biopsy: excess iron in the liver
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Case 1
A 24-year-old known intravenous drug user presented with jaundice and RHC pain
since 1 week.On the day prior to the development of jaundice he noted that his urine was dark.
His liver function tests were as follows.
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Referenceinterval
Albumin 35g/L 30-50
Bilirubin 250mol/L 1-20
AST 1420 U/L
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What do these results suggest? J ustify Why was her urine dark?
What further investigations required topredict severity of the liver disease?
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1) What do these results suggest? J ustify.Acute liver injury most likely acute hepatitis.J ustification:From history 1 week indicate acute problem.
Very high in transaminases (ASTx30, ALTx45)compared to increase in ALP (2-7X)- indicateshepatocellular damage.
Painful RHC suggests inflammation.Most likely diagnosis is acute hepatitis.Need to further confirmed with hepatitis screening.
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2) Why is her urine dark?Dark coloured urine is due to the presence of conjugated bilirubin and
increase in urobilinogen.Conjugated bilirubin is water soluble and a small molecule, thus it can
be filtered by the glomeruli.The presence of bilirubin in the urine indicates increase plasma levels
of conjugated form.95% of bilirubin normally present in the plasma is uncojugated .
Therefore , a positive urine bilirubin is always pathological and maybe the earliest indication of hepatitis.
Urinary urobilinogen are raised when increased amounts of bilirubinenters the gut (haemolysis) or ifthere is impaired re-excretion of theurobilinogen arriving via enterohepatic circuation (liver damage).Colourless urobilinogen can be oxidized into a coloured pigment,urobilin.
Urine urobilinogen often detected in a normal person.The presence of urine urobilinogen is not useful in the diagnosis of iver diseaseunless it present in high amount.
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3) What further investigations required topredict severity of the liver disease?
Prothrombin time (PT)Most important prognostic factor of hepaticinjury.Prolonged PT of > 4 secs above upper
refrence limit indicates severe liver injury.
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Case 2
A 48-year-old, with a 20 year history of alcoholism was admitted for management of
alcohol withdrawal. Physical examinationrevealed slightly yellow sclera and anenlarged, hard, non-tender liver. He had been
well previously and was not on medication.His liver function tests were as follows.
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Ref Range
Total protein 65g/L 60-80
Albumin 26g/L 30-50ALP 500 U/L 30-120
ALT 64U/L
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1) What is the possible diagnosis. J ustify.2) Explain elevated GGT.
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1) What is the possible diagnosis. J ustify.Low albumin indicates chronic liver
disease.Mild increase in liver enzymes with predominant increasein ALPx16 ,ALTx2 indicate predominance obstructivelesion/ cholestatic jaundice.
Ddx -Biliary obstruction
- Drug reaction- Liver cirrhosisBilirubin level is usually higher in biliary obstruction. In this
case bilirubin only increase by 2X.Most likely diagnosis is liver cirrhosis due to alcohol
consumption.
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2) Explain elevated GGT.Increase GGT is due to enzyme induction
eg alcohol .It also indicates damage to the hepatobiliarytract.
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Case 3
A 40 year-old-female complain of epigastricpain radiated to the back associated with
jaundice. Urine was dark and stool was pale.Her LFT were as followed.
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Ref Range
Total protein 78g/L 60-85
Albumin 39g/L 30-50ALP 620 U/L 30-120
ALT 55 U/L
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1) What is the possible diagnosis? J ustify2) What further investigation required?
3) Explain the pale stool.
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1) What is the possible diagnosis? J ustifySignificant increase in ALP (X20) and
GGT suggest cholestatic liver injury.This result in a very high bilirubin level.
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2) What further investigation required?Ultrasound of biliary tract and gall bladder
to look for presents of stone, dilated ducts,thickness of GB wall.ERCP
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3) Explain the pale stool.Brown pigment in the stool is due the
presence of stercobilin.Stercobilin is formed by the oxidation of
urobilinogen in the colon by the gut flora.In biliary obstruction, lack of conjugated
bilirubin excreted to the gut to beconverted to urobilinogen, hence palestool.