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Evaluation of Abnormal Liver Function Tests

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... Improved diabetic control Exercise Management of NAFLD NAFLD CONCLUSIONS NAFLD is common A small proportion progress to cirrhosis NASH is the commonest ... – PowerPoint PPT presentation

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Title: Evaluation of Abnormal Liver Function Tests


1
Evaluation of Abnormal Liver Function Tests
  • TUMS
  • Imam Khomeini Rasoul Hospitals
  • Dr. Nader Roushan
  • Gastroenterologist
  • Pardise hemmat 4.11.91
  • 2/90

2
Approach to px with jaundice
/EUS
3
LFTs
  • Markers of hepatocellular damage
  • Cholestasis
  • Liver synthetic function

4
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 17 h
  • ALT more specific to liver, v. low
    concentrations in kidney and skeletal muscles.
  • In liver totally cytosolic.
  • Half-life 47 h

5
  • Gamma-GT hepatocytes and biliary epithelial
    cells, pancreas, renal tubules and intestine
  • Very sensitive but Non-specific
  • Raised in ANY liver disease 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 become abnormal then investigate

6
Markers of Cholestasis
  • ALP liver and bone (placenta, kidneys,
    intestines or WBC)
  • Hepatic ALP present on surface of bile duct
    epithelia
  • 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

7
Bilirubin, Albumin and Prothrombin time (INR)
  • Useful indicators of liver synthetic function
  • when associated with liver disease? abnormalities
    should raise concern
  • Thrombocytopaenia is a sensitive indicator of
    liver fibrosis

8
Patterns of liver enzyme alteration
  • Hepatic vs cholestatic
  • Magnitude of enzyme alteration (ALT gt10x vs
    minor abnormalities)
  • Rate of change
  • Nature of the course of the abnormality (mild
    fluctuation vs progressive increase)

9
Patterns of liver enzyme alteration
  • Acute hepatitis transaminase gt 10x ULN
  • Cholestatic
  • Mild rise in ALT

10
Acute hepatitis (ALTgt10xULN)
  • Viral
  • Ischaemic
  • Toxins
  • Autoimmune
  • Early phase of acute obstruction

11
Cholestasis
  • 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 US/CT most important investigation-dilated
    ducts
  • Ca pancreas, CBD stones, cholangioca or liver
    mets

12
Cholestasis non-dilated ducts
  • Cholestatic jaundice Drugs- Antibiotics,
    NSAIDs, Hormones, ACEI
  • PBC anti- mitochondrial Ab
  • PSC MRCP
  • Chronic liver disease
  • Cholangiocarcinoma fluctuating levels
  • Primary or Metastatic cancer, lymphoma
  • Infiltrative sarcoid, inflammatory, IBD
  • Liver biopsy often required

13
COMMON CAUSES OF ABNORMAL LFTS IN THE UK
  • Transient mild abnormalities which are simply
    impossible to explain
  • Drugs eg Statins
  • Alcohol excess
  • Hepatitis C
  • Non-Alcoholic Fatty Liver Disease (NAFLD)

14
Investigation 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
  • If mild abnormalities and no risk factors or
    suggestion of serious liver disease , repeat LFTs
    after an interval (with lifestyle modification)

15
Investigation of Abnormal LFTs - 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

16
Investigation of Abnormal LFTs - 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 gt 100)

17
Liver biopsy Findings in Abnormal LFTs
  • Skelly et al
  • 354 Asymptomatic patients
  • Transaminases persistently 2X normal
  • No risk factors for liver disease
  • Alcohol intake lt 21 units/week
  • Viral and autoimmune markers negative
  • Iron studies normal
  • Skelly et al. J Hepatol 2001 35 195-294

18
Liver biopsy Findings in Abnormal LFTs Skelly 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

19
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

20
What is the Value of Liver Biopsy 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

21
LIVER BIOPSY FOR SERONEGATIVE ALT lt 2X NORMAL
  • N 249, mean age 58, etoh lt 25 units per week,
    9 diabetes, 24 BMI gt 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
22
LIVER BIOPSY FOR SERONEGATIVE ALT lt 2X NORMAL
  • Of those with NAFLD
  • 56 had simple steatosis
  • 44 inflammation and/or fibrosis

23
Ultrasound 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

24
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25
Non-Alcoholic Fatty Liver Disease
26
The spectrum of Nonalcoholic Fatty Liver Disease
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
27
NAFLD - Classification and Causes
  • PRIMARY
  • Increased insulin resistance syndrome
  • Diabetes mellitus (type II)
  • Obesity
  • Hyperlipidemia

28
NAFLD - Secondary Causes
  • Drugs 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 Wilsons disease
  • Salicylates Malnutrition
  • IBD HIV infection

29
Prevalence of NAFLD and NASH
  • No good data - histological diagnosis
  • Car Crash post mortem study - 24 NAFL, 2.4
    NASH - Hilden et al 1977 (n503)
  • US - 16.4- 23 NAFL (Italy, and Japan)

30
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)

31
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 obese
    subjects and 3 of non-obese subjects have NASH
  • Increasing prevalence in children
  • AGA, Gastroenterology 2002

32
NAFLD - Clinical Features
  • Mostly an incidental finding in asymptomatic
    individuals
  • ALT 2-5x normal
  • Bilirubin rarely raised
  • RUQ discomfort, fatigue and malaise in some
    patients

33
NASH - Natural History
  • 15-50 of NASH patients have fibrosis or
    cirrhosis at index biopsy James and Day 1998
  • NASH ? 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

34
.
NASH - Natural History 10 year retrospective
follow up study n 98 11 Liver Related deaths
in types 3 and 4 80 of those developing
cirrhosis had fibrosis at index biopsy
Developing Cirrhosis
Matteoni et al 1999
35
NASH-natural history
  • Steatosis only can progress to cirrhosis 1-2
    over 5-17yrs (Danish and Italian studies)
  • NASH fibrosis cirrhosis 12 at 8yr
  • Prognosis in cirrhotics poor-30 developing
    liver-related morbidity or mortality (liver
    failure HCC) over short period
  • Adams et al Gastroenterology 2005

36
NASH - RISK FACTORS FOR FIBROSIS AND CIRRHOSIS
  • Independent risk factors in several studies
  • Age gt45
  • ALT gt 2x normal
  • AST/ALT ratio gt 1
  • Obesity, particularly truncal
  • Type 2 diabetes
  • Insulin Resistance
  • Hyperlipdaemia (trigycerides gt 1.7)
  • Hypertension
  • Iron overload

NB Studies are in selected groups may not apply
to all patients
37
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 gt 2x normal
  • AST gt ALT
  • At least moderate central obesity
  • NIDDM or Impaired glucose tolerance
  • Hypertension
  • Hypertriglyceridaemia
  • Day, Gut 2002505585-588

38
PATHOGENESIS OF NASH Insulin 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

39
NASH - TREATMENT
  • Steady Weight Loss - logical treatmen
  • CAUTION - In some patients, inflammation and
    fibrosis increase especially with rapid wt loss (
    gastric and intestinal bypass)
  • Improved diabetic control
  • Exercise

40
Management of NAFLD
41
NAFLD CONCLUSIONS
  • NAFLD is common
  • A small proportion progress to cirrhosis
  • NASH is the commonest cause of cryptogenic
    cirrhosis
  • More information needed on prevalence,
    pathogenesis and natural history
  • RCTs urgently needed - Metfomin, antioxidants
    and UDCA

42
Abnormal 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

43
Liver bx?W/U -
44
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45
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