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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    Acute hepatitis (ALT>10xULN)

    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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    Acute hepatitis (ALT>10xULN)

    Ischaemic- sepsis, hypotension

    ?most common cause in-patients

    Often extremely high >50x

    Decrease rapidly

    LDH raised 80%

    Rarely jaundiced

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    Acute hepatitis (ALT>10xULN)

    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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    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

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    Acute hepatitis (ALT>10xULN)

    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)