Evaluation of Abnormal Liver Function Tests

1
Evaluation of Abnormal Liver Function Tests

• Dr Chris Hovell
• Consultant Gastroenterologist
• Dorset County Hospital

2
LFTs

• Markers of hepatocellular damage
• Cholestasis
• Liver synthetic function

3
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

4

• 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

5
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

6
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

7
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)

8
Patterns of liver enzyme alteration

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

9
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

11
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

13
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 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
• 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 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)

22
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.

23
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 for genotype I, treatment is
  recommended for patients with moderate to severe
  hepatitis
• 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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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)

• 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 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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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
34
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

36
Non-Alcoholic Fatty Liver Disease
37
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

39
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)

41
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

43
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

45
.
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
46
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
• Prognosis in cirrhotics poor-30 developing
  liver-related morbidity or mortality (liver
  failure HCC) over short period
• Adams et al Gastroenterology 2005

47
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 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
• Exercise - patients with NAFLD have very poor
  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 1 year
  in NASH (n16) Laurin et al 1996
• Gemfobrozil
• One randomized study, improved LFTs after 4
  weeks (n46) Basaranoglu et al 1999

52
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 3ANTIOXIDANTS

• 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

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NASH - DRUG TREATMENT 4Insulin Resistance

• Metformin
• Improves sreatosis in ob/ob leptin deficient
  mouse
• Decreased Transaminases in non-diabetic subjects
  with 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 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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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
INTERVENE AND REVIEW
SCREEN FOR OCT/PD/RD DRUGS
INTERVENE AND REVIEW
SEROLOGICAL INVESTIGATIONS NEGATIVE USS NO
SPECIFIC DIAGNOSIS NO CLEAR CLINICAL (e.g. FHx A1
disease/xanthelasma/Signs CLD) ASSOCIATIONS WITH
LIVER DISEASE
ABNORMAL CLINICAL SIGNS PRESENT
RE-EVALUATE DIAGNOSIS AND BIOPSY
NO CLINICAL SIGNS PERSISTENT ABNORMAL LFTs gt 6/12
NO CLINICAL SIGNS ALT gt3x normal High risk LFT
profile
CONFIRM TREATMENT EFFECTIVE
IF ABNORMAL TREAT
MEASURE TG Chol. AST/ALT Ratio TFTs BP Fasting
Blood Sugar Calculate BM1
LIFESTYLE MODIFICATION
MONITOR EFFECTIVENESS
LFTs NOT IMPROVED
LFTs IMPROVED
RE-EVALUATE CLINICAL RISK FACTORS CONSIDER BIOPSY
AND FURTHER IMAGING SEE GUIDANCE NOTES
LFTs WORSEN OR BECOME ABNORMAL
LFTs WORSEN OR BECOME ABNORMAL
RETURN TO NORMAL OR IMPROVE
MONITOR
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GUIDANCE NOTES

• PREDICTIVE OF PATHOLOGY
• VS NORMAL
• ALT gt 2 x Normal
• AST ALT gt1
• Age gt 50
• Low Platelet Count

• OTHER GROUPS WITH HIGH RISK
• PATHOLOGY
• Raised Conjugated Bili with ? ALT
• 
  ? ALK P
• Consider BX MRCP ERCP
• Any abnormality of ALK P in addition to
• abnormality ALT/AST
• Consider BX

• PREDICTORS OF NASH AND FIBROSIS IN PRESENCE OF
  NASH
• ALT gt 2 x Normal
• AST gt ALT
• Moderate Central Obesity
• BM1 gt 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.