Evaluation of Abnormal Liver Function Tests

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Evaluation of Abnormal Liver Function Tests

• TUMS
• Imam Khomeini Rasoul Hospitals
• Dr. Nader Roushan
• Gastroenterologist
• Pardise hemmat 4.11.91
• 2/90

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Approach to px with jaundice
/EUS
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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 17 h
• ALT more specific to liver, v. low
  concentrations in kidney and skeletal muscles.
• In liver totally cytosolic.
• Half-life 47 h

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• 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

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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

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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

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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)

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Patterns of liver enzyme alteration

• Acute hepatitis transaminase gt 10x ULN
• Cholestatic
• Mild rise in ALT

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Acute hepatitis (ALTgt10xULN)

• Viral
• Ischaemic
• Toxins
• Autoimmune
• Early phase of acute obstruction

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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

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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

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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)

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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)

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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 LFTs monthly
• 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 studies transferrin saturation ferritin
• Autoantibodies immunoglobulins
• Consider caeruloplasmin
• Alpha-1- antitrypsin
• Coeliac serology
• TFTs, lipids/glucose
• Consider liver biopsy esp if ALT gt 100)

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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

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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

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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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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

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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
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LIVER BIOPSY FOR SERONEGATIVE ALT lt 2X NORMAL

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

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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

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Non-Alcoholic Fatty Liver Disease
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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
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NAFLD - Classification and Causes

• PRIMARY
• Increased insulin resistance syndrome
• Diabetes mellitus (type II)
• Obesity
• Hyperlipidemia

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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

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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)

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Prevalence of NAFLD / NASHHigh 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 obese
  subjects 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 in asymptomatic
  individuals
• ALT 2-5x normal
• Bilirubin rarely raised
• RUQ discomfort, fatigue and malaise in some
  patients

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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

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NASH - Natural History 10 year retrospective
follow up studyn 98 11 Liver Related deaths
in types 3 and 480 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 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

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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
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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 gt 2x normal
• AST gt ALT
• At least moderate central obesity
• NIDDM or Impaired glucose tolerance
• Hypertension
• Hypertriglyceridaemia
• Day, Gut 2002505585-588

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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

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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

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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 cryptogenic
  cirrhosis
• 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 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

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Liver bx?W/U -
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