Abnormal Lfts Autumn 2005

7/29/2019 Abnormal Lfts Autumn 2005

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Evaluation of Abnormal LiverFunction Tests

Dr Chris Hovell

Consultant Gastroenterologist

Dorset County Hospital


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LFTs

Markers of hepatocellular damage

Cholestasis

Liver synthetic function


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Markers of Hepatocellular damage

(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

ALTmore specific to liver, v.low concentrations inkidney and skeletal muscles.

In liver totally cytosolic.

Half-life 47hrs


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Gamma-GThepatocytes 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 LFTs becomeabnormal then investigate


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Markers of Cholestasis

ALPliver and bone (placenta, kidneys, intestines orWCC)

Hepatic ALP present on surface of bile duct epithelia andaccumulating 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


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Bilirubin, Albumin and Prothrombin time

(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


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Patterns of liver enzyme alteration

Hepatic vs cholestatic

Magnitude of enzyme alteration (ALT >10x vsminor abnormalities)

Rate of change

Nature of the course of the abnormality (mildfluctuation vs progressive increase)


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Patterns of liver enzyme alteration

Acute hepatitistransaminase > 10x ULN

Cholestatic

Mild rise in ALT


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Acute hepatitis (ALT>10xULN)

Viral

Ischaemic

Toxins

Autoimmune

Early phase of acute obstruction


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ViralHep 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 andHepBsAg, Hep C IgG or Hep C RNA


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Ischaemic- sepsis, hypotension

?most common cause in-patients

Often extremely high >50x

Decrease rapidly

LDH raised 80%

Rarely jaundiced


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Toxins - paracetamol (up to 50% of all cases of

Acute Liver Failure)

Ecstasy ( 2nd most common cause in the young2 in 70%


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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


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Early phase- extrahepatic obstruction/cholangitis

Usually have history of pain

USSdilated CBD ? ERCP or lap chole


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Cholestasis

Isolated ALP 3rd trimester, adolescents

Boneexclude 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


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Cholestasis non-dilated ducts

Cholestatic jaundiceDrugs- Antibiotics, Nsaids,Hormones, ACEI

PBCanti- mitochondrial Ab, M2 fraction, IgM

PSCassociated with IBD 70%, p-ANCA,MRCP and liver biopsy

Chronic liver disease

Cholangiocarcinomabeware fluctuating levels

Primary or Metastatic cancer, lymphoma

Infiltrativesarcoid, inflammatory-PMR, IBD

Liver biopsy often required


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Dear Dr Hepaticus,

I have just reviewed our patient database and have identified 420 patientswith persistently abnormal LFTs whoare otherwise well and are not knownto have liver disease. When can yousee them?

Yours,

Dr G Practice


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COMMON CAUSES OF

ABNORMAL LFTS IN THE UK

Transient mild abnormalities which

are simply impossible to explain

Drugseg Statins

Alcohol excess

Hepatitis C

Non-Alcoholic Fatty Liver Disease

(NAFLD)


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

History and Examination

Discontinue hepatotoxic drugs

Continue statins but monitor LFTsmonthly

Lifestyle modification (lose wt, reduce

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


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Investigation of Abnormal LFTs

- Raised ALT / AST

If still abnormal at 6 months:

Consider referral to secondary care

Hepatitis serology (B, C) Iron studiestransferrin saturation + ferritin

Autoantibodies & immunoglobulins

Consider caeruloplasmin

Alpha-1- antitrypsin

Coeliac serology

TFTs, lipids/glucose

Consider liver biopsy esp if ALT > 100)


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Hepatits C

Most asymptomatic; acute hepatitis withjaundice is uncommon

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

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

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

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


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Hepatitis C: Factors associated

with 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


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Treatment of Hepatitis C

Hep C RNA by PCRLiver biopsy for genotype I, treatment isrecommended for patients with moderate to

severe hepatitisPeg-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 aretreated with interferon and ribavirin for 12months, if responsive on viral load at 3/12.Response rate 30%-40%.


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Prevalence of Inherited Liver Diseases

Disease HomozygoteFrequency

GeneFrequency

HeterozygoteFrequency

Haemochromatosis 1:400 1:20 1:10

1AT 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 alBrit J. Haem. 1990


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Genetics of

Haemochromatosis Autosomal recessive

Mutations in HFE gene (C282Y and H63D)

Cause increased intestinal absorption of Fe

C282Y/C282Y and C282Y/H63D are

responsible for 95% of genetic

haemochromatosis


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Screening Strategy for Haemochromatosis(HFE Associated)

1.Perform transferrin saturation (or UIBC)2. If 45% - repeat fasting

3. If still 45% - perform HFE testing

4. If C282Y +/+ or C282Y/H63D +/+:

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

- Liver biopsy essential

5. If C282Y +/- :

- Counsel re:Alcohol NASH

HCV PCT

6. Venesection and family screening


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Liver biopsy Findings inAbnormal 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


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Liver biopsy Findings in AbnormalLFTs Skelly et al. J Hepatol 2001

6% Normal

26% Fibrosis

6% Cirrhosis

34% NASH (11% of which had bridgingfibrosis and 8% cirrhosis)

32% Simple Fatty Liver

18% Alteration in Management

3 Families entered into screeningprogrammes

Oth Li bi Fi di i


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Other Liver biopsy Findings in

Abnormal LFTs Skelly 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%


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LIVER BIOPSY FOR


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LIVER BIOPSY FOR

SERONEGATIVE ALT < 2X

NORMAL 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%, Autoimmune2.7%, cryptogenic hepatitis 2.5%, ALD 1.4%,metobolic 2.1%, biliary 1.8%

Ryder et al BASL 2003

LIVER BIOPSY FOR


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LIVER BIOPSY FOR

SERONEGATIVE ALT < 2X

NORMALOf 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


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Ultrasound in Liver Disease

Detects Fatty Liver

Increased echogenicity may not bespecific for fat

Unable to detect Inflammation orcirrhosis (unless advanced)

Therefore unable to discriminate betweenNASH and simple fatty liver or identifyother types of liver disease (which mayinclude fatty change)

Liver biopsy is the only way to make anaccurate diagnosis

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

biopsy

Non Alcoholic Fatty Liver


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Non-Alcoholic Fatty LiverDisease


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Type 1 Fat alone

Type 2 Fat + inflammationType 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

Nonalcoholic Fatty Liver Disease


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NAFLD - Classification and Causes

PRIMARY

Increased insulin resistance syndrome

Diabetes mellitus (type II)

ObesityHyperlipidemia


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NAFLD - Secondary CausesDrugs Surgical Procedures Miscellaneous

Corticosteroids Gastroplexy Hepatitis CSynth oestrogens Jejunoileal bypass Abetalipoproteinaemia

Amiodarone Extensive small bowel Weber-Christian

Perhexiline resection disease

Nifedipine Biliopancreatic diversion TPN with glucoseTamoxifen Environmental toxins

Tetracycline S.bowel diverticulosis

Chloroquine Wilsons disease

Salicylates MalnutritionIBD

HIVinfection


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Prevalence of NAFLD andNASH

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)


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Prevalence of NAFLD / NASH

High risk groups Severely obese subjects - 25% incidence of

NASH at laparoscopy

Type 2 diabetes - 28-55% NAFL

Hyperlipidaemia - 20-90% NAFL

Approx 60% of NAFL occurs in females

Many patients are neither obese nor diabetic(Bacon et al 1994, George et al 1998)


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Obesity 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 obesesubjects and 3% of non-obese subjects have

NASH Increasing prevalence in children

AGA, Gastroenterology 2002


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NAFLD - Clinical Features

Mostly an incidental finding inasymptomatic individuals

ALT 2-5x normal

AST:ALT < 1 except in severe injury

ALP, GGT 2-3x normal


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NASH - 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 mostcommon cause of cryptogenic cirrhosis Caldwellet al 1999, Poonwala et al 2000

In a 19 year follow up study, steatosis (alone)did not progess histologically Teli et al 1995


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.

3.4

0

21

28

0

5

10

15

20

25

30

1 2 3 4

NAFL Types

%

NASH - Natural History

10 year retrospective follow up study

n = 9811% Liver Related deaths in types 3 and 4

80% of those developing cirrhosis had fibrosis at index biopsy

%Developing

Cirrhosis

Matteoni et al 1999


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NASH-natural history

Steatosis only can progress to cirrhosis 1-2 % over

5-17yrs (Danish and Italian studies)

NASH + fibrosiscirrhosis 0% at 5yrs 12% at8ys

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


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NASH RISK FACTORS FOR

FIBROSIS 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 patie

NASH Wh Sh ld H


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NASH - Who Should Have a

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


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PATHOGENESIS OF NASHInsulin 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 TREATMENT


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NASH - TREATMENT

Steady Weight Loss - logical treatment Reduces fatty infiltration

Improves LFTs

CAUTION - In some patients,

inflammation and fibrosis increaseespecially with rapid wt loss (cf gastricand intestinal bypass)

Improved diabetic control - little histological

data

Exercise - patients with NAFLD have verypoor respiratory quotients. LFTs and RQ

improve with exercise Elias 2001


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NASHDRUG TREATMENT

No completed RCTs to date

CLOFIBRAT

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

Gemfobrozil

One randomized study, improved LFTs after 4weeks (n=46) Basaranoglu et al 1999


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NASH - 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


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NASH - DRUG TREATMENT 3

ANTIOXIDANTS

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


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NASH - DRUG TREATMENT 4

Insulin Resistance

Metformin Improves sreatosis in ob/ob leptin deficient mouse

Decreased Transaminases in non-diabetic subjectswith 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


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Management of NAFLD


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NAFLD CONCLUSIONS

NAFLD is common

A small proportion progress to cirrhosis

NASH is the commonest cause of cryptogeniccirrhosis

More information needed on prevalence,

pathogenesis and natural history RCTs urgently needed - Metfomin,

antioxidants and UDCA


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Abnormal LFTs - Conclusions

Many abnormal LFTs will return to normalspontaneously

An important minority of patients withabnormal LFTs will have importantdiagnoses, including communicable andpotentially life threatening diseases

Investigation requires clinical assessmentand should be timely and pragmatic

GUIDELINES TO IX AND BX OF PATIENTS WITH ABNORMAL LFTs AND NO CLEAR


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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 DIAGNOSIS

NO CLEAR CLINICAL (e.g. FHx A1 disease/xanthelasma/Signs CLD)

ASSOCIATIONS WITH LIVER DISEASE

RE-EVALUATE DIAGNOSIS

AND BIOPSY

ABNORMAL

CLINICAL SIGNS

PRESENT

NO CLINICAL SIGNS

PERSISTENT ABNORMAL

LFTs > 6/12

NO CLINICAL SIGNS

ALT >3x normal

High risk LFT profile

MEASURE:TG

Chol.

AST/ALT Ratio

TFTs

BP

Fasting Blood Sugar

Calculate BM1

CONFIRM

TREATMENTEFFECTIVE

LIFESTYLE MODIFICATION

LFTs NOT IMPROVED

RE-EVALUATE CLINICAL RISK

FACTORS

CONSIDER BIOPSY AND

FURTHER IMAGING

SEE GUIDANCE NOTES

LFTs IMPROVED

LFTs WORSEN OR BECOME

ABNORMALRETURN TO NORMAL OR IMPROVE

MONITOR EFFECTIVENESS

MONITOR

LFTs WORSEN OR BECOME

ABNORMAL

IF ABNORMALTREAT


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GUIDANCE NOTES

PREDICTIVE OF PATHOLOGY

VS NORMAL:

ALT > 2 x NormalAST: ALT >1

Age > 50

Low Platelet Count

OTHER GROUPS WITH HIGH RISK

PATHOLOGY:

Raised Conjugated Bili with: ALTALK 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

Abnormal Lfts Autumn 2005

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