Evaluation of Abnormal Liver Function Tests Dr Chris Hovell Consultant Gastroenterologist Dorset...

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Evaluation of Evaluation of Abnormal Liver Abnormal Liver Function Tests Function Tests Dr Chris Hovell Consultant Gastroenterologist Dorset County Hospital

Transcript of Evaluation of Abnormal Liver Function Tests Dr Chris Hovell Consultant Gastroenterologist Dorset...

Evaluation of Abnormal Liver Evaluation of Abnormal Liver Function TestsFunction Tests

Dr Chris Hovell

Consultant Gastroenterologist

Dorset County Hospital

LFT’sLFT’s

Markers of hepatocellular damage

Cholestasis

Liver synthetic function

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

AST- liver, heart skeletal muscle, kidneys, brain, RBCs In liver 20% activity is cytosolic and 80% mitochondrial Clearance performed by sinusoidal cells, half-life 17hrs

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

In liver totally cytosolic. Half-life 47hrs

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

Very sensitive but Non-specific Raised in ANY liver discease hepatocellular or cholestatic Usefulness limited Confirm hepatic source for a raised ALP Alcohol Isolated increase does not require any further evaluation,

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

Markers of CholestasisMarkers of Cholestasis

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

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

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

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

Useful indicators of liver synthetic function

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

Thrombocytopaenia is a sensitive indicator of liver fibrosis

Patterns of liver enzyme alterationPatterns of liver enzyme alteration

Hepatic vs cholestatic

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

Rate of change

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

Patterns of liver enzyme alterationPatterns of liver enzyme alteration

Acute hepatitis –transaminase > 10x ULN

Cholestatic

Mild rise in ALT

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

Viral Ischaemic Toxins Autoimmune Early phase of acute obstruction

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

Viral – Hep A, B, C, E, CMV, EBV ALT levels usually peak before jaundice appears. Jaundice occurs in 70% Hep A, 35% acute Hep B,

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

HepBsAg, Hep C IgG or Hep C RNA

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

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

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

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

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

Any drug herbal remedies Alcohol – almost never, AST <7xULN in 98% AST/ALT ratio > 1 in 92%, >2 in 70%

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

Autoimmune Rarely presents with acute hepatitis Usually jaundiced and progressive liver failure Raised IgG and autoantibodies (anti-SM, -LKM, -

SLA) Liver biopsy Steroids and azathioprine

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

Early phase- extrahepatic obstruction/cholangitis Usually have history of pain USS – dilated CBD ? ERCP or lap chole

CholestasisCholestasis

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

isoenzymes May suggest biliary obstruction, chronic liver

disease or hepatic mass/tumour Liver USS/CT most important investigation-

dilated ducts Ca pancreas, CBD stones, cholangioca or liver

mets

Cholestasis – non-dilated ductsCholestasis – non-dilated ducts Cholestatic jaundice – Drugs- Antibiotics, Nsaids,

Hormones, ACEI PBC – anti- mitochondrial Ab, M2 fraction, IgM PSC – associated with IBD 70%, p-ANCA,

MRCP and liver biopsy Chronic liver disease Cholangiocarcinoma – beware fluctuating levels Primary or Metastatic cancer, lymphoma Infiltrative – sarcoid, inflammatory-PMR, IBD Liver biopsy often required

““Dear Dr Hepaticus,Dear Dr Hepaticus,

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

Yours, Yours,

Dr G Practice” Dr G Practice”

COMMON CAUSES OF COMMON CAUSES OF ABNORMAL LFTS IN THE UKABNORMAL LFTS IN THE UK

Transient mild abnormalities which are simply impossible to explain

Drugs – eg StatinsAlcohol excessHepatitis CNon-Alcoholic Fatty Liver Disease

(NAFLD)

Investigation of Abnormal LFTsInvestigation of Abnormal LFTs

PRINCIPLES 2.5% of population have raised LFTs Normal LFTs do not exclude liver disease Interpret LFTs in clinical context Take a careful history for risk factors, drugs (inc OTCs), alcohol,

comorbidity, autoimmunity Physical examination for liver disease Chase likely diagnosis rather than follow algorithm unless there are

no clues If mild abnormalities and no risk factors or suggestion of serious

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

Investigation of Abnormal LFTs - Investigation of Abnormal LFTs - ALT/AST 2-5x normal (100-200)ALT/AST 2-5x normal (100-200)

History and Examination Discontinue hepatotoxic drugs Continue statins but monitor LFTs

monthly Lifestyle modification (lose wt, reduce

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

Investigation of Abnormal LFTsInvestigation of Abnormal LFTs- Raised ALT / AST- Raised ALT / AST

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

Hepatits CHepatits C

Most asymptomatic; acute hepatitis with jaundice is uncommon

• 80% will have chronic / persistent infection. Of these,

• 10% will develop cirrhosis of the liver 10 years after infection

• 20-30% will develop cirrhosis of the liver 30 years after infection

• 5% will develop hepatocellular carcinoma (liver cancer) 20 years after infection.

Hepatitis C: Factors associated Hepatitis C: Factors associated with progression of liver diseasewith progression of liver disease

• The genotype of the virus -IB

• Acquiring the infection at an older age

• Alcohol misuse

• Male gender

• Co-infection with Hepatitis B or HIV

Treatment of Hepatitis CTreatment of Hepatitis C

Hep C RNA by PCRLiver biopsy for genotype I, treatment is recommended for patients with moderate to severe hepatitis Peg-interferon given by sc injection 1/ week, Ribavirin bd dose

• Patients with genotypes II and III are treated with for 6 months. Response rate 70%

• Patients with genotypes I, IV, V, and VI are treated with interferon and ribavirin for 12 months, if responsive on viral load at 3/12. Response rate 30%-40%.

Prevalence of Inherited Liver DiseasesPrevalence of Inherited Liver Diseases

Disease HomozygoteFrequency

GeneFrequency

HeterozygoteFrequency

Haemochromatosis 1:400 1:20 1:10

α1AT Deficiency 1:1600 1:40 1:20

Cystic Fibrosis 1:2500 1:50 1:25

Wilson's Disease 1:30,000 1:170 1:85

Leggett et al Brit J. Haem. 1990

Genetics of Genetics of HaemochromatosisHaemochromatosis

Autosomal recessiveMutations in HFE gene (C282Y and H63D)Cause increased intestinal absorption of Fe

C282Y/C282Y and C282Y/H63D are responsible for 95% of genetic haemochromatosis

Clinical Manifestations of Clinical Manifestations of haemochromatosishaemochromatosis

Skin pigmentationLiver diseaseDiabetes mellitusArthropathyImpotenceFatigueCardiomegaly

Screening Strategy for HaemochromatosisScreening Strategy for Haemochromatosis(HFE Associated)(HFE Associated)

1.1. Perform transferrin saturation (or UIBC)Perform transferrin saturation (or UIBC)2. If 2. If 45% - repeat fasting 45% - repeat fasting3. If still 3. If still 45% - perform HFE testing 45% - perform HFE testing4. If C282Y +/+ or C282Y/H63D +/+:4. If C282Y +/+ or C282Y/H63D +/+:

- perform serum ferritin and LFT- perform serum ferritin and LFT- if SF > 1000 and/or LFT abnormal- if SF > 1000 and/or LFT abnormal

- Liver biopsy essential- Liver biopsy essential5. If C282Y +/- : 5. If C282Y +/- : - Counsel re:- Counsel re:

AlcoholAlcohol NASH NASH HCVHCV PCT PCT

6. Venesection and family screening6. Venesection and family screening

Liver biopsy Findings in Liver biopsy Findings in Abnormal LFTsAbnormal LFTs

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

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

Liver biopsy Findings in Abnormal Liver biopsy Findings in Abnormal LFTs LFTs Skelly et al. J Hepatol 2001Skelly et al. J Hepatol 2001

6% Normal 26% Fibrosis 6% Cirrhosis 34% NASH (11% of which had bridging

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

programmes

Other Liver biopsy Findings in Other Liver biopsy Findings in Abnormal LFTs Abnormal LFTs Skelly et al. J Hepatol 2001Skelly et al. J Hepatol 2001

Cryptogenic hepatitis 9% Drug induced 7.6% Alcoholic liver disease 2.8% Autoimmune hepatitis 1.9% PBC 1.4% PSC 1.1% Granulomatous disease 1.75% Haemochromatosis 1% Amyloid 0.3% Glycogen storage disease 0.31%

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

The most accurate way to grade the severity of liver disease

Aminotransferase levels correlate poorly with histological activity

Narrows the diagnostic options, if not diagnostic

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

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

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

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

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

Ryder et al BASL 2003

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

NORMALNORMAL

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

Risk of Severe Fibrotic Disease associated with: BMI >27 Gamma GT > 2x normal

Ryder et al BASL 2003

Ultrasound in Liver DiseaseUltrasound in Liver Disease Detects Fatty Liver Increased echogenicity may not be specific for fat Unable to detect Inflammation or cirrhosis (unless

advanced)– Therefore unable to discriminate between NASH and

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

Liver biopsy is the only way to make an accurate diagnosis

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

Non-Alcoholic Fatty Liver Non-Alcoholic Fatty Liver DiseaseDisease

Type 1 Fat alone

Type 2 Fat + inflammation

Type 3 Fat + ballooning degeneration

Type 4 Fat + fibrosis and/or Mallory bodies

Only types 3 and 4 have been definitively shown to progress to advanced liver disease and can be classified as NASH

The spectrum of The spectrum of Nonalcoholic Fatty Liver DiseaseNonalcoholic Fatty Liver Disease

NAFLD - Classification and Causes NAFLD - Classification and Causes

PRIMARY

Increased insulin resistance syndrome

Diabetes mellitus (type II)

Obesity

Hyperlipidemia

NAFLD - NAFLD - Secondary CausesSecondary CausesDrugs Surgical Procedures Miscellaneous Corticosteroids Gastroplexy Hepatitis C

Synth oestrogens Jejunoileal bypass Abetalipoproteinaemia

Amiodarone Extensive small bowel Weber-Christian

Perhexiline resection disease

Nifedipine Biliopancreatic diversion TPN with glucose

Tamoxifen Environmental toxins

Tetracycline S.bowel diverticulosis

Chloroquine Wilson’s disease

Salicylates Malnutrition

IBD

HIV infection

Prevalence of NAFLD and Prevalence of NAFLD and NASHNASH

No good data - histological diagnosis

Car Crash post mortem study - 24% NAFL, 2.4% NASH - Hilden et al 1977 (n=503)

USS - 16.4- 23% NAFL (Italy, and Japan)

Prevalence of NAFLD / NASHPrevalence of NAFLD / NASHHigh risk groupsHigh risk groups

Severely obese subjects - 25% incidence of NASH at laparoscopy

Type 2 diabetes - 28-55% NAFLHyperlipidaemia - 20-90% NAFLApprox 60% of NAFL occurs in femalesMany patients are neither obese nor diabetic

(Bacon et al 1994, George et al 1998)

Obesity and Fatty liverObesity and Fatty liver

Prevalence increases with weight Up to 80% of obese individuals Up to 10-15% of normal subjects

Correspondingly, 15-20% of morbidly obese subjects and 3% of non-obese subjects have NASH

Increasing prevalence in children

AGA, Gastroenterology 2002

NAFLD - Clinical FeaturesNAFLD - Clinical Features

Mostly an incidental finding in asymptomatic individuals

ALT 2-5x normalAST:ALT < 1 except in severe injuryALP, GGT 2-3x normal <50%Bilirubin rarely raisedRUQ discomfort, fatigue and malaise in

some patients

NASH - Natural HistoryNASH - Natural History

15-50% of NASH patients have fibrosis or cirrhosis at index biopsy James and Day 1998

In Aetiological studies NASH is now the most common cause of cryptogenic cirrhosis Caldwell et al 1999, Poonwala et al 2000

In a 19 year follow up study, steatosis (alone)

did not progess histologically Teli et al 1995

..

3.40

21

28

0

5

10

15

20

25

30

1 2 3 4

NAFL Types

%NASH - Natural HistoryNASH - Natural History

10 year retrospective follow up study10 year retrospective follow up studyn = 98 n = 98

11% Liver Related deaths in types 3 and 411% Liver Related deaths in types 3 and 480% of those developing cirrhosis had fibrosis at index biopsy80% of those developing cirrhosis had fibrosis at index biopsy

%Developing

Cirrhosis

Matteoni et al 1999

NASH-natural historyNASH-natural history

Steatosis only can progress to cirrhosis 1-2 % over 5-17yrs (Danish and Italian studies)

NASH + fibrosis – cirrhosis 0% at 5yrs 12% at 8ys

Prognosis in cirrhotics poor-30% developing liver-related morbidity or mortality (liver failure + HCC) over short period

Adams et al Gastroenterology 2005

NASH - RISK FACTORS FOR NASH - RISK FACTORS FOR

FIBROSIS AND CIRRHOSISFIBROSIS AND CIRRHOSIS Independent risk factors in several studies: Age >45 ALT > 2x normal AST/ALT ratio > 1 Obesity, particularly truncal Type 2 diabetes Insulin Resistance Hyperlipdaemia (trigycerides > 1.7) Hypertension Iron overload

NB: Studies are in selected groups; may not apply to all patients

NASH - Who Should Have a NASH - Who Should Have a Liver biopsy?Liver biopsy?

To Identify Patients at Risk of Progression restrict biopsy to patients with some, if not all of:

ALT > 2x normal AST > ALT At least moderate central obesity NIDDM or Impaired glucose tolerance Hypertension Hypertriglyceridaemia

Day, Gut 2002;50:5585-588

PATHOGENESIS OF NASHPATHOGENESIS OF NASHInsulin Resistance is the First HitInsulin Resistance is the First Hit

NASH should be viewed as part of a multifactorial disease

Commonly associated with syndrome X - 85% in a retrospective study (Wilner et al 2001)

Treatment strategies may be directed at Insulin Resistance

NASH - TREATMENTNASH - TREATMENT

Steady Weight Loss - logical treatment– Reduces fatty infiltration– Improves LFTs– CAUTION - In some patients, inflammation

and fibrosis increase especially with rapid wt loss (cf gastric and intestinal bypass)

Improved diabetic control - little histological data Exercise - patients with NAFLD have very poor

respiratory quotients. LFTs and RQ improve with exercise Elias 2001

NASHNASHDRUG TREATMENT DRUG TREATMENT

No completed RCTs to date CLOFIBRAT

– No improvement in LFTs or histology over 1 year in NASH (n=16) Laurin et al 1996

Gemfobrozil– One randomized study, improved LFTs after 4

weeks (n=46) Basaranoglu et al 1999

NASH - Drug TREATMENT 2NASH - Drug TREATMENT 2

Ursodeoxycholic Acid– 3 open label studies (n = 24, 24, 31)– One randomised (vs diet alone)– Improvement in aminotransferases– 12 month study demonstrated improvement in

steatosis but not other histological features– RCT trial now underway* Laurin et al 1996, Guma et al 1997, Ceriani et al 1998

NASH - DRUG TREATMENT 3NASH - DRUG TREATMENT 3ANTIOXIDANTSANTIOXIDANTS

Betaine (methionine) – Improved LFTs, steatosis and inflammation– n = 8, 12 months therapy, Abdelmalek et al 2000

N-Acetylcysteine – Improved LFTs– n = 11, Gulbahar et al 2000

Vitamin E - Tocopherol– Improved LFTs over 4-10 months– n = 11, Lavine et al 2000

NASH - DRUG TREATMENT 4NASH - DRUG TREATMENT 4Insulin Resistance Insulin Resistance

Metformin– Improves sreatosis in ob/ob leptin deficient mouse – Decreased Transaminases in non-diabetic subjects

with NASH compared with diet alone over 4m– Reduced liver volume– n = 20, Marchesini et al 2001

– RCT planned by BASL Troglitazone

– Improved LFTs but no histological change– n = 6, 4 months, Caldwell et al 2001

Management of NAFLDManagement of NAFLD

NAFLD CONCLUSIONSNAFLD CONCLUSIONS

NAFLD is common A small proportion progress to cirrhosisNASH is the commonest cause of

cryptogenic cirrhosisMore information needed on prevalence,

pathogenesis and natural historyRCTs urgently needed - Metfomin,

antioxidants and UDCA

Abnormal LFTs - ConclusionsAbnormal LFTs - Conclusions

Many abnormal LFTs will return to normal spontaneously

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

Investigation requires clinical assessment and should be timely and pragmatic

GUIDELINES TO IX AND BX OF PATIENTS WITH ABNORMAL LFTs AND NO CLEAR DIAGNOSIS AFTER ROUTINE TESTS: WITH EMPHASIS ON FATTY LIVER AND NASH AS

UNDERLYING DIAGNOSIS

SCREEN FOR XS ALCOHOL CONSUMPTION

SCREEN FOR OCT/PD/RD DRUGS

INTERVENE AND REVIEW

INTERVENE AND REVIEW

SEROLOGICAL INVESTIGATIONS* NEGATIVEUSS NO SPECIFIC DIAGNOSISNO CLEAR CLINICAL (e.g. FHx A1 disease/xanthelasma/Signs CLD)ASSOCIATIONS WITH LIVER DISEASE

RE-EVALUATE DIAGNOSIS AND BIOPSY

ABNORMAL CLINICAL SIGNSPRESENT

NO CLINICAL SIGNSPERSISTENT ABNORMALLFTs > 6/12

NO CLINICAL SIGNSALT >3x normal

High risk LFT profile

MEASURE:TGChol.AST/ALT RatioTFTsBPFasting Blood SugarCalculate BM1

CONFIRMTREATMENTEFFECTIVE

LIFESTYLE MODIFICATION

LFTs NOT IMPROVED

RE-EVALUATE CLINICAL RISK FACTORSCONSIDER BIOPSY AND FURTHER IMAGINGSEE GUIDANCE NOTES

LFTs IMPROVED

LFTs WORSEN OR BECOME ABNORMAL

RETURN TO NORMAL OR IMPROVE

MONITOR EFFECTIVENESS

MONITOR

LFTs WORSEN OR BECOME ABNORMAL

IF ABNORMAL TREAT

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.