liver function test and clinical aspect sctl (1)

8/7/2019 LIVER FUNCTION TEST AND CLINICAL ASPECT sctl (1)

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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.

liver function test and clinical aspect sctl (1)

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