Transcript Evaluation of Abnormal Liver Function Tests

Evaluation of Abnormal Liver
Function Tests
Dr Chris Hovell
Consultant Gastroenterologist
Dorset County Hospital
LFT’s

Markers of hepatocellular damage

Cholestasis

Liver synthetic function
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


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 LFT’s become
abnormal then investigate
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
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
Patterns of liver enzyme alteration

Hepatic vs cholestatic

Magnitude of enzyme alteration (ALT >10x vs
minor abnormalities)

Rate of change

Nature of the course of the abnormality (mild
fluctuation vs progressive increase)
Patterns of liver enzyme alteration

Acute hepatitis –transaminase > 10x ULN

Cholestatic

Mild rise in ALT
Acute hepatitis (ALT>10xULN)





Viral
Ischaemic
Toxins
Autoimmune
Early phase of acute obstruction
Acute hepatitis (ALT>10xULN)





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
Acute hepatitis (ALT>10xULN)






Ischaemic- sepsis, hypotension
?most common cause in-patients
Often extremely high >50x
Decrease rapidly
LDH raised 80%
Rarely jaundiced
Acute hepatitis (ALT>10xULN)






Toxins - paracetamol (up to 50% of all cases of
Acute Liver Failure)
Ecstasy ( 2nd most common cause in the young
<35)
Any drug
herbal remedies
Alcohol – almost never, AST <7xULN in 98%
AST/ALT ratio > 1 in 92%, >2 in 70%
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
Acute hepatitis (ALT>10xULN)

Early phase- extrahepatic obstruction/cholangitis
 Usually have history of pain
 USS – dilated CBD ? ERCP or lap chole
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 investigationdilated ducts
Ca pancreas, CBD stones, cholangioca or liver
mets
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
“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”
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)
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)
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
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 > 100)
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.
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
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%.
Prevalence of Inherited Liver Diseases
Homozygote
Frequency
Gene
Frequency
Heterozygote
Frequency
Haemochromatosis 1:400
1:20
1:10
α1AT 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
Disease
Leggett et al Brit J. Haem. 1990
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
Clinical Manifestations of
haemochromatosis

Skin pigmentation
 Liver disease
 Diabetes mellitus
 Arthropathy
 Impotence
 Fatigue
 Cardiomegaly
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
Liver biopsy Findings in
Abnormal 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
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
Other Liver biopsy Findings in
Abnormal LFTs Skelly et al. J Hepatol 2001










Cryptogenic hepatitis
Drug induced
Alcoholic liver disease
Autoimmune hepatitis
PBC
PSC
Granulomatous disease
Haemochromatosis
Amyloid
Glycogen storage disease
9%
7.6%
2.8%
1.9%
1.4%
1.1%
1.75%
1%
0.3%
0.31%
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
LIVER BIOPSY FOR
SERONEGATIVE ALT < 2X
NORMAL





N = 249, mean age 58, etoh < 25 units per
week, 9% diabetes, 24% BMI > 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
LIVER BIOPSY FOR
SERONEGATIVE ALT < 2X
NORMAL
Of those with NAFLD:

56% had simple steatosis

44% inflammation and/or fibrosis
Risk of Severe Fibrotic Disease associated with:

BMI >27

Gamma GT > 2x normal
Ryder et al BASL 2003
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
Non-Alcoholic Fatty Liver
Disease
The spectrum of
Nonalcoholic Fatty Liver Disease
Type 1
Fat alone
Type 2
Fat + inflammation
Type 3
Fat + ballooning degeneration
Type 4
bodies
Fat + fibrosis and/or Mallory
Only types 3 and 4 have been definitively
shown to progress to advanced liver disease
and can be classified as NASH
NAFLD - Classification and Causes
PRIMARY
Increased insulin resistance syndrome
Diabetes mellitus (type II)
Obesity
Hyperlipidemia
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
Wilson’s disease
Salicylates
Malnutrition
IBD
HIV infection
Prevalence of NAFLD and
NASH

No good data - histological diagnosis

Car Crash post mortem study - 24%
NAFL, 2.4% NASH - Hilden et al 1977 (n=503)

USS - 16.4- 23% NAFL (Italy, and Japan)
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)
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
NAFLD - Clinical Features

Mostly an incidental finding in
asymptomatic individuals
 ALT 2-5x normal
 AST:ALT < 1 except in severe injury
 ALP, GGT 2-3x normal <50%
 Bilirubin rarely raised
 RUQ discomfort, fatigue and malaise in
some patients
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
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
.
28
30
25
%
Developing
Cirrhosis
21
%
20
15
10
5
3.4
0
Matteoni et al 1999
0
1
2
3
NAFL Types
4
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 liverrelated morbidity or mortality (liver failure +
HCC) over short period

Adams et al Gastroenterology 2005
NASH - RISK FACTORS FOR
FIBROSIS AND CIRRHOSIS
Independent risk factors in several studies:









Age >45
ALT > 2x normal
AST/ALT ratio > 1
Obesity, particularly truncal
Type 2 diabetes
Insulin Resistance
Hyperlipdaemia (trigycerides > 1.7)
Hypertension
Iron overload
NB: Studies are in selected groups; may not apply to all patien
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 > 2x normal
AST > ALT
At least moderate central obesity
NIDDM or Impaired glucose tolerance
Hypertension
Hypertriglyceridaemia
Day, Gut 2002;50:5585-588
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
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
NASH
DRUG TREATMENT

No completed RCTs to date
 CLOFIBRAT
– No improvement in LFTs or histology over 1
year in NASH (n=16)

Laurin et al 1996
Gemfobrozil
– One randomized study, improved LFTs after 4
weeks (n=46) Basaranoglu et al 1999
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
NASH - DRUG TREATMENT 3
ANTIOXIDANTS

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

NASH - DRUG TREATMENT 4
Insulin 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
Management of NAFLD
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
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
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
NO CLINICAL SIGNS
PERSISTENT ABNORMAL
LFTs > 6/12
NO CLINICAL SIGNS
ALT >3x normal
High risk LFT profile
IF ABNORMAL
TREAT
MEASURE:
TG
Chol.
AST/ALT Ratio
TFTs
BP
Fasting Blood Sugar
Calculate BM1
RE-EVALUATE DIAGNOSIS
AND BIOPSY
CONFIRM
TREATMENT
EFFECTIVE
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
RETURN TO NORMAL OR IMPROVE
MONITOR
GUIDANCE NOTES
PREDICTIVE OF PATHOLOGY
VS NORMAL:
OTHER GROUPS WITH HIGH RISK
PATHOLOGY:
•ALT > 2 x Normal
•AST: ALT >1
•Age > 50
• Low Platelet Count
•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 > 2 x Normal
AST > ALT
Moderate Central Obesity
BM1 > 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.