Evaluation of Abnormal Liver Function Tests

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Evaluation of Abnormal Liver Function 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
• ALT more specific to liver, v.low
  concentrations in kidney and skeletal muscles.
• In liver totally cytosolic.
• Half-life 47hrs

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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 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 become abnormal then investigate

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Markers 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

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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 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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Acute hepatitis (ALTgt10xULN)

• 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

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Acute hepatitis (ALTgt10xULN)

• Ischaemic- sepsis, hypotension
• ?most common cause in-patients
• Often extremely high gt50x
• Decrease rapidly
• LDH raised 80
• Rarely jaundiced

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Acute hepatitis (ALTgt10xULN)

• Toxins - paracetamol (up to 50 of all cases of
  Acute Liver Failure)
• Ecstasy ( 2nd most common cause in the young lt35)
• Any drug
• herbal remedies
• Alcohol almost never, AST lt7xULN in 98
• AST/ALT ratio gt 1 in 92, gt2 in 70

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Acute hepatitis (ALTgt10xULN)

• 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 (ALTgt10xULN)

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

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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 USS/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, 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

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Dear Dr Hepaticus,I have just reviewed our
patient data base and have identified 420
patients with persistently abnormal LFTs who are
otherwise well and are not known to have liver
disease. When can you see 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
• Drugs eg Abs, Nsaids, anti-epileptic,
  paracetamol, herbal remedies, Statins
• Alcohol excess
• Hepatitis C/B
• 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
• 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)

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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 3 months
• Check Hep Bsag, Hep C and ironstudies

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Investigation of Abnormal LFTs- Raised ALT / AST

• If still abnormal at 3 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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Statins

• Rare cause of acute hepatitis
• Safe with monitoring in pts with abn LFTs
• Athyros et al lancet 2010 reported 1600 greek pts
  with CVD randomly assigned to statins or usual
  care
• 437 abn lfts 227 statin and had substantial
  improvement of lfts (plt0.0001) whereas those not
  on statin had further increases
• 7 pts discontinued because ALTgt3xULN

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Hepatits 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.

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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 PCR
• Liver biopsy
• 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.

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Percentage Sustained Virological Response
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Prevalence of Inherited Liver Diseases
Leggett et al Brit 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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Clinical Manifestations of haemochromatosis

• Skin pigmentation
• Liver disease
• Diabetes mellitus
• Arthropathy
• Impotence
• Fatigue
• Cardiomegaly

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Screening Strategy for Haemochromatosis(HFE
Associated)

• Perform transferrin saturation (or UIBC)
• Ferritin high in ALD
• 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 gt 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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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
• Risk of Severe Fibrotic Disease associated with
• BMI gt27
• Gamma GT gt 2x normal

Ryder et al BASL 2003
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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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Fibroscan
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Non-invasive serum markers of fibrosis

• Combination of Hyaluronic acid, TIMP-I and P3NP
  with age

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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)
• USS - 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
• ASTALT lt 1 except in severe injury
• ALP, GGT 2-3x normal lt50
• 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
• 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

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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 0 at 5yrs 12 at 8ys
• In pts with NAFLD liver disease 3rd commonest
  cause of death vs 13th in normal popn
• 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
• BMIgt28
• 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 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
• Difficult to sustain!
• Reduce alcohol intake

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NASHDRUG TREATMENT

• Orlistat - no effect
• Metformin no proven benefit
• Bariatric surgery no RCTs (not recommended by
  cochrane)
• Pioglitazone or Vit E Sanyal NEJM 2010
• 247 pts NAFLd without DM
• Vit E (800iu) significantly improved histological
  scores/ALT but not fibrosis scores
• Current trial of combination therapies of
  atorvastatin, Vit E and C

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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
• More RCTs urgently needed

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Abnormal LFTs Key Points

• Many abnormal LFTs will return to normal
  spontaneously
• Investigation requires clinical assessment and
  should be timely and pragmatic
• Urgent referral for acute hepatitis (ALT gt10xULN)
• Early USS for cholestatic LFTs
• Mild/moderate rises ALT- check alcohol, drugs
  HepC/B, Fe
• Fatty liver-part of metabolic syndrome- treatment
  of risk factors and wt loss