Evaluation of Abnormal Liver Function Tests Cengiz Pata Gastroenterology Department Yeditepe...

Evaluation of Evaluation of Abnormal Liver Abnormal Liver Function TestsFunction Tests

Cengiz PataCengiz PataGastroenterology DepartmentGastroenterology Department

Yeditepe UniversityYeditepe University

LFT’sLFT’s

Markers of hepatocellular damageMarkers of hepatocellular damage

CholestasisCholestasis

Liver synthetic functionLiver synthetic function

Markers of Hepatocellular damageMarkers of Hepatocellular damage(Transaminases)(Transaminases)

ASTAST- liver, heart skeletal muscle, kidneys, brain, - liver, heart skeletal muscle, kidneys, brain, RBCsRBCs

In liver 20% activity is cytosolic and 80% In liver 20% activity is cytosolic and 80% mitochondrialmitochondrial

Clearance performed by sinusoidal cells, half-life Clearance performed by sinusoidal cells, half-life 17hrs17hrs

ALTALT –– more specific to liver, v.low concentrations in more specific to liver, v.low concentrations in kidney and skeletal muscles. kidney and skeletal muscles.

In liver totally cytosolic.In liver totally cytosolic. Half-life 47hrsHalf-life 47hrs

Gamma-GTGamma-GT – – hepatocytes and biliary epithelial hepatocytes and biliary epithelial cells, pancreas, renal tubules and intestinecells, pancreas, renal tubules and intestine

Very sensitive but Non-specificVery sensitive but Non-specific Raised in ANY liver discease hepatocellular or Raised in ANY liver discease hepatocellular or

cholestaticcholestatic Usefulness limitedUsefulness limited ?, MRCP? ?, MRCP? Confirm hepatic source for a raised ALPConfirm hepatic source for a raised ALP AlcoholAlcohol Isolated increase does not require any further Isolated increase does not require any further

evaluation, suggest watch and rpt 3/12 only if evaluation, suggest watch and rpt 3/12 only if other LFT’s become abnormal then investigateother LFT’s become abnormal then investigate

Markers of CholestasisMarkers of Cholestasis

ALPALP – liver and bone (placenta, kidneys, intestines – liver and bone (placenta, kidneys, intestines or WCC)or WCC)

Hepatic ALP present on surface of bile duct Hepatic ALP present on surface of bile duct epithelia and accumulating bile salts increase its epithelia and accumulating bile salts increase its release from cell surface. Takes time for release from cell surface. Takes time for induction of enzyme levels so may not be first induction of enzyme levels so may not be first enzyme to rise and half-life is 1 week.enzyme to rise and half-life is 1 week.

ALP isoenzymes, 5-NT or gamma GT may be ALP isoenzymes, 5-NT or gamma GT may be necessary to evaluate the origin of ALPnecessary to evaluate the origin of ALP

Bilirubin, Albumin and Bilirubin, Albumin and Prothrombin time (INR)Prothrombin time (INR)

Useful indicators of liver synthetic Useful indicators of liver synthetic functionfunction

In primary care when associated In primary care when associated with liver disease abnormalities with liver disease abnormalities should raise concernshould raise concern

ThrombocytopaeniaThrombocytopaenia is a sensitive is a sensitive indicator of liver fibrosisindicator of liver fibrosis

Patterns of liver enzyme alterationPatterns of liver enzyme alteration

Hepatic vs cholestaticHepatic vs cholestatic

Magnitude of enzyme alteration (ALT Magnitude of enzyme alteration (ALT >10x vs minor abnormalities)>10x vs minor abnormalities)

Rate of changeRate of change

Nature of the course of the abnormality Nature of the course of the abnormality (mild fluctuation vs progressive increase)(mild fluctuation vs progressive increase)

Patterns of liver enzyme alterationPatterns of liver enzyme alteration

Acute hepatitis –transaminase > 10x Acute hepatitis –transaminase > 10x ULNULN

CholestaticCholestatic

Mild rise in ALTMild rise in ALT

Acute hepatitis (ALT>10xULN)Acute hepatitis (ALT>10xULN)

ViralViral IschaemicIschaemic ToxinsToxins AutoimmuneAutoimmune Early phase of acute obstructionEarly phase of acute obstruction


ViralViral – Hep A, B, C, E, CMV, EBV – Hep A, B, C, E, CMV, EBV ALT levels usually peak before jaundice ALT levels usually peak before jaundice

appears.appears. Jaundice occurs in 70% Hep A, 35% acute Jaundice occurs in 70% Hep A, 35% acute

Hep B, 25% Hep CHep B, 25% Hep C Check for exposureCheck for exposure Check Hep A IgM, Hep B core IgM and Check Hep A IgM, Hep B core IgM and

HepBsAg, Hep C IgG or Hep C RNAHepBsAg, Hep C IgG or Hep C RNA


IschaemicIschaemic- sepsis, hypotension- sepsis, hypotension ?most common cause in-patients?most common cause in-patients Often extremely high >50x Often extremely high >50x Decrease rapidlyDecrease rapidly LDH raised 80%LDH raised 80% Rarely jaundicedRarely jaundiced


ToxinsToxins - paracetamol (up to 50% of all - paracetamol (up to 50% of all cases of Acute Liver Failure)cases of Acute Liver Failure)

Ecstasy ( 2Ecstasy ( 2ndnd most common cause in the most common cause in the young <35)young <35)

Any drug Any drug herbal remediesherbal remedies Alcohol – almost never, AST <7xULN in Alcohol – almost never, AST <7xULN in

98%98%,,AST/ALT ratio > 1 in 92%, >2 in 70%AST/ALT ratio > 1 in 92%, >2 in 70%


AutoimmuneAutoimmune Rarely presents with acute hepatitisRarely presents with acute hepatitis Usually jaundiced and progressive liver Usually jaundiced and progressive liver

failurefailure Raised IgG and autoantibodies (anti-SM, -Raised IgG and autoantibodies (anti-SM, -

LKM, -SLA)LKM, -SLA)


Early phase- Early phase- extrahepatic extrahepatic obstructionobstruction/cholangitis/cholangitis

Usually have history of painUsually have history of pain USS – dilated CBD ? ERCP or lap choleUSS – dilated CBD ? ERCP or lap chole

CholestasisCholestasis

Isolated ALP 3Isolated ALP 3rdrd trimester, adolescents trimester, adolescents Bone – exclude by raised GGT, 5-NT or Bone – exclude by raised GGT, 5-NT or

isoenzymesisoenzymes May suggest biliary obstruction, chronic May suggest biliary obstruction, chronic

liver disease or hepatic mass/tumourliver disease or hepatic mass/tumour Liver USS/CT most important Liver USS/CT most important

investigation-dilated ductsinvestigation-dilated ducts Ca pancreas, CBD stones, cholangioca or Ca pancreas, CBD stones, cholangioca or

liver metsliver mets

Cholestasis – non-dilated ductsCholestasis – non-dilated ducts

Cholestatic jaundice – Drugs- Antibiotics, Cholestatic jaundice – Drugs- Antibiotics, Nsaids, Hormones, ACEINsaids, Hormones, ACEI

PBC – anti- mitochondrial Ab, M2 fraction, PBC – anti- mitochondrial Ab, M2 fraction, IgMIgM

PSC – associated with IBD 70%, p-ANCA, PSC – associated with IBD 70%, p-ANCA, MRCP and liver biopsyMRCP and liver biopsy

Chronic liver diseaseChronic liver disease Cholangiocarcinoma – beware fluctuating Cholangiocarcinoma – beware fluctuating

levelslevels Primary or Metastatic cancer, lymphomaPrimary or Metastatic cancer, lymphoma Infiltrative – sarcoid, inflammatory-PMR, IBDInfiltrative – sarcoid, inflammatory-PMR, IBD Liver biopsy often requiredLiver biopsy often required

““Dear Dr Hepaticus,Dear Dr Hepaticus,

I have just reviewed our I have just reviewed our patient data base and have patient data base and have identified 420 patients with identified 420 patients with persistently abnormal LFTs persistently abnormal LFTs who are otherwise well and are who are otherwise well and are not known to have liver not known to have liver disease. When can you see disease. When can you see them?them?

Yours, Yours,

Dr G Practice” Dr G Practice”

COMMON CAUSES OF COMMON CAUSES OF ABNORMAL LFTS IN THE ABNORMAL LFTS IN THE

UKUK Transient mild abnormalities Transient mild abnormalities

which are simply impossible to which are simply impossible to explainexplain

Drugs – eg StatinsDrugs – eg Statins Alcohol excessAlcohol excess Hepatitis CHepatitis C Non-Alcoholic Fatty Liver Non-Alcoholic Fatty Liver

Disease (NAFLD)Disease (NAFLD)

Investigation of Abnormal Investigation of Abnormal LFTsLFTs

PRINCIPLESPRINCIPLES 2.5% of population have raised LFTs2.5% of population have raised LFTs Normal LFTs do not exclude liver diseaseNormal LFTs do not exclude liver disease Interpret LFTs in clinical contextInterpret LFTs in clinical context Take a careful history for risk factors, drugs (inc Take a careful history for risk factors, drugs (inc

OTCs), alcohol, comorbidity, autoimmunityOTCs), alcohol, comorbidity, autoimmunity Physical examination for liver diseasePhysical examination for liver disease Chase likely diagnosis rather than follow algorithm Chase likely diagnosis rather than follow algorithm

unless there are no clues unless there are no clues If mild abnormalities and no risk factors or suggestion If mild abnormalities and no risk factors or suggestion

of serious liver disease , repeat LFTs after an interval of serious liver disease , repeat LFTs after an interval (with lifestyle modification) (with lifestyle modification)

Investigation of Abnormal Investigation of Abnormal LFTs - ALT/AST 2-5x LFTs - ALT/AST 2-5x

normal (100-200)normal (100-200) History and ExaminationHistory and Examination Discontinue hepatotoxic drugsDiscontinue hepatotoxic drugs Continue statins but monitor LFTs Continue statins but monitor LFTs

monthlymonthly Lifestyle modification (lose wt, reduce Lifestyle modification (lose wt, reduce

alcohol, diabetic control)alcohol, diabetic control) Repeat LFTs at 1 month and 6 monthsRepeat LFTs at 1 month and 6 months

Investigation of Abnormal Investigation of Abnormal LFTsLFTs

- Raised ALT / AST- Raised ALT / AST If still abnormal at 6 months:If still abnormal at 6 months: Consider referral to secondary careConsider referral to secondary care Hepatitis serology (B, C)Hepatitis serology (B, C) Iron studies – transferrin saturation + ferritinIron studies – transferrin saturation + ferritin Autoantibodies & immunoglobulinsAutoantibodies & immunoglobulins Consider caeruloplasminConsider caeruloplasmin Alpha-1- antitrypsinAlpha-1- antitrypsin Coeliac serologyCoeliac serology TFTs, lipids/glucoseTFTs, lipids/glucose Consider liver biopsy esp if ALT > 100)Consider liver biopsy esp if ALT > 100)

Liver biopsy Findings Liver biopsy Findings in Abnormal LFTsin Abnormal LFTs

Skelly et al: Skelly et al: 354 Asymptomatic patients354 Asymptomatic patients Transaminases persistently 2X normalTransaminases persistently 2X normal No risk factors for liver diseaseNo risk factors for liver disease Alcohol intake < 21 units/weekAlcohol intake < 21 units/week Viral and autoimmune markers negativeViral and autoimmune markers negative Iron studies normalIron studies normal

Skelly et al. J Hepatol 2001; 35: 195-294Skelly et al. J Hepatol 2001; 35: 195-294

Liver biopsy Findings in Liver biopsy Findings in Abnormal LFTs Abnormal LFTs Skelly et al. J Hepatol Skelly et al. J Hepatol

20012001 6% Normal6% Normal 26% Fibrosis26% Fibrosis 6% Cirrhosis6% Cirrhosis 34% NASH (11% of which had 34% NASH (11% of which had

bridging fibrosis and 8% cirrhosis)bridging fibrosis and 8% cirrhosis) 32% Simple Fatty Liver32% Simple Fatty Liver 18% Alteration in Management18% Alteration in Management 3 Families entered into screening 3 Families entered into screening

programmesprogrammes

Other Liver biopsy Findings Other Liver biopsy Findings in Abnormal LFTs in Abnormal LFTs Skelly et al. J Skelly et al. J

Hepatol 2001Hepatol 2001 Cryptogenic hepatitisCryptogenic hepatitis 9%9% Drug inducedDrug induced 7.6%7.6% Alcoholic liver diseaseAlcoholic liver disease 2.8%2.8% Autoimmune hepatitisAutoimmune hepatitis 1.9%1.9% PBCPBC 1.4%1.4% PSCPSC 1.1%1.1% Granulomatous diseaseGranulomatous disease 1.75% 1.75% HaemochromatosisHaemochromatosis 1%1% Amyloid Amyloid 0.3%0.3% Glycogen storage diseaseGlycogen storage disease 0.31% 0.31%

What is the Value of Liver What is the Value of Liver Biopsy in Abnormal LFTs?Biopsy in Abnormal LFTs?

The most accurate way to grade the The most accurate way to grade the severity of liver diseaseseverity of liver disease

Aminotransferase levels correlate poorly Aminotransferase levels correlate poorly with histological activitywith histological activity

Narrows the diagnostic options, if not Narrows the diagnostic options, if not diagnosticdiagnostic

LIVER BIOPSY FOR LIVER BIOPSY FOR SERONEGATIVE ALT < 2X SERONEGATIVE ALT < 2X

NORMALNORMAL N = 249, mean age 58, etoh < 25 units N = 249, mean age 58, etoh < 25 units

per week, 9% diabetes, 24% BMI > 27per week, 9% diabetes, 24% BMI > 27 ALT 51-99 (over 6 m)ALT 51-99 (over 6 m)

72% NAFLD72% NAFLD 10% Normal histologically10% Normal histologically Others: Granulomatous liver disease 4%, Others: Granulomatous liver disease 4%,

Autoimmune 2.7%, cryptogenic hepatitis Autoimmune 2.7%, cryptogenic hepatitis 2.5%, ALD 1.4%, metobolic 2.1%, biliary 2.5%, ALD 1.4%, metobolic 2.1%, biliary 1.8% 1.8%

Ryder et al BASL 2003

LIVER BIOPSY FOR LIVER BIOPSY FOR SERONEGATIVE ALT < 2X SERONEGATIVE ALT < 2X

NORMALNORMALOf those with NAFLD:Of those with NAFLD: 56% had simple steatosis56% had simple steatosis 44% inflammation and/or fibrosis44% inflammation and/or fibrosis

Risk of Severe Fibrotic Disease associated Risk of Severe Fibrotic Disease associated with:with:

BMI >27BMI >27 Gamma GT > 2x normalGamma GT > 2x normal

Ryder et al BASL 2003

Ultrasound in Liver Ultrasound in Liver DiseaseDisease

Detects Fatty LiverDetects Fatty Liver Increased echogenicity may not be specific Increased echogenicity may not be specific

for fatfor fat Unable to detect Inflammation or cirrhosis Unable to detect Inflammation or cirrhosis

(unless advanced)(unless advanced) Therefore unable to discriminate between NASH Therefore unable to discriminate between NASH

and simple fatty liver or identify other types of and simple fatty liver or identify other types of liver disease (which may include fatty change)liver disease (which may include fatty change)

Liver biopsy is the only way to make an Liver biopsy is the only way to make an accurate diagnosisaccurate diagnosis

It may be worth treating fatty liver for 6 It may be worth treating fatty liver for 6 months before considering referral for months before considering referral for biopsy biopsy

Non-Alcoholic Fatty Liver Non-Alcoholic Fatty Liver DiseaseDisease

Abnormal LFTs - Abnormal LFTs - ConclusionsConclusions

Many abnormal LFTs will return to Many abnormal LFTs will return to normal spontaneouslynormal spontaneously

An important minority of patients with An important minority of patients with abnormal LFTs will have important abnormal LFTs will have important diagnoses, including communicable and diagnoses, including communicable and potentially life threatening diseasespotentially life threatening diseases

Investigation requires clinical Investigation requires clinical assessment and should be timely and assessment and should be timely and pragmaticpragmatic

GUIDANCE NOTES

PREDICTIVE OF PATHOLOGYVS NORMAL:

•ALT > 2 x Normal•AST: ALT >1•Age > 50• Low Platelet Count

OTHER GROUPS WITH HIGH RISK PATHOLOGY:

•Raised Conjugated Bili with: ALT ALK P• Consider: BX; MRCP; ERCP• Any abnormality of ALK P in addition to abnormality ALT/AST Consider BXPREDICTORS OF NASH AND FIBROSIS IN

PRESENCE OF NASH

• ALT > 2 x Normal• AST > ALT• Moderate Central Obesity• BM1 > 28• NIDDM/Impaired GTT• BP• TGs.

•SUGGESTED ROUTINE SEROLOGICAL INVESTIGATIONS:

•Alpha 1 AT; HAV; HBV; HCV; AIP and Igs; Fe Studies and HFE genotype; Caeruloplasmin; USS – Fatty Change or Normal echo only; Bilirubin and haemolysis studies if appropriate

- ANY ABNORMALITIES IN THESE PARAMETERS, RE-EVALUATE POTENTIAL DIAGNOSIS AND CONSIDER BIOPSY

N.B. THESE NOTES/ALGORITHMS ARE FOR GUIDANCE ONLY. THIS IS A MOVING FIELD AND DESPITE IMPROVEMENTS IN SEROLOGICAL AND RADIOLOGICAL TECHNIQUES, THERE REMAIN SMALL NUMBERS OF PATIENTS WHO HAVE SIGNIFICANT LIVER DISEASE WITH ONLY MILDLY ABNORMAL LFTs. THE ALGORITHM IS NO SUBSTITUTE FOR CAREFUL AND REPEATED CLINICAL EVALUATION AND CLINICAL VIGILANCE.

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