Hepatology for Surgeons
Assessment of Chronic Stable Abnormal
Liver Function Tests
Rebecca Jones
Hepatologist, Bristol Royal Infirmary
June 2004
Some Examples
• 32 yr Caucasian M with a groin abscess is noted to have abnormal LFTs which
persist after drainage of abscess:
• Bili 10, ALT 67, ALP 105, Alb 40
• 28 yr Vietnamese F is assessed for mild RUQ discomfort. She has a normal USS but
you note 2 episodes of jaundice in 4 years + current LFTs:
• Bili 8, ALT 50, ALP 98, Alb 39
• 45 yr Caucasian F with Graves disease undergoing thyroidectomy also has abnormal
LFTs:
• Bili 12, ALP 220, ALT 32, Alb 32
• 67 yr overweight M with Type 2 Diabetes undergoes cholecystectomy. At operation
you note a cirrhotic looking liver. His pre-op LFTs:
• Bili 12, ALT 83, ALP 120, Alb 38
• 45 yr M with pan-colitis undergoing elective colectomy is noted to be jaundiced pre-
op:
• Bili 97, ALP 345, ALT 45, Alb 30
Outcomes
• 32yr old man Chronic HCV
• 28yr old woman Chronic HBV
• 45yr old woman PBC
• 67yr old man NASH
• 45 yr old man PSC
Abnormal liver function tests in
Primary Care
• All patients with abnormal LFTs in 6 month period
– (defined as gGT, ALT or ALP x2 ULN)
• All records of hospital attendances and investigations
studied 12-21 months later.
• Identified 933 patients
– Follow-up data available in 873 (94%)
• 531 patients under hospital review
– 342 left
• 157 suitable for further evaluation
• Others died, left area, normal LFTs on repeat etc
Results Sherwood et al: LFTs in primary care
2001
45
40
35
30
25
%
20
15
10
5
0
AT
al
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D
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V
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C
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HF
AI
PB
HB
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NA
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Investigation of abnormal LFTs
in secondary care
• The significance of abnormal LFTs in
• outpatient referrals to hepatology service in patients with normal
serology
• Serological tests
• HCV, HBV, AIP, Ferritin, a1AT, Caeruloplasmin
• Abnormal LFTs defined as
• gGT, ALT, ALP x2 ULN for 6 months
• Exclusion criteria
• Patients with known liver disease
• patients with alcohol history of >21/14u/week, family reporting of
alcohol excess, measurable blood ETOH
%
N
0
5
10
15
20
25
30
35
40
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Clinical Diagnoses after Liver Biopsy
Skelly MM et al. J Hepatol 2001; 35:195-9
Causes of Fatty Liver Disease
• Alcohol • Nutritional
– TPN
• Insulin resistance – Severe weight loss
– Syndrome X • JI bypass
• Obesity • Gastric bypass
• Diabetes • Severe starvation
• Hypertriglyceridaemia – Refeeding syndrome
• Hypertension • Disorders of lipid
– Lipoatrophy metabolism
– Mauriac syndrome – Abetalipoproteinaemia
• Iatrogenic – Hypobetalipoproteinaemia
– Andersen’s disease
– Amiodarone, Diltiazem,
Tamoxifen, Steroids, HAART – Weber-Christian disease
• Toxic exposure
– Organic solvents
– Dimethylformamide
Prevalence of Chronic Liver Disease in
General Population: Dionysus study
Population study
•1991-1993
•2 towns in northern Italy
•6917 citizens (69%)
Data
•Dietary habits
•Alcohol history
•Detailed medical history
•Physical examination
•AST,ALT,gGT,MCV,Plts,HBV,HCV
If signs of CLD (21%)
•Further LFTs
•USS
•+/- liver biopsy
Bellentani S et al. Hepatology 1994; 20: 1442-9
Lessons from the Dionysus Study 1
Persistent signs of CLD
17.5% of general population
Signs of cirrhosis
1.1% of general population
Commonest causes of CLD
ALCOHOL 35 %
DRUGS 12 %
HCV 5%
HBV 2%
HCV,HBV,ALC 1%
OTHER 45 %
Lessons from the Dionysus Study 2
Causes of cirrhosis
HCV+ETOH 7.7%
HCV 28.2%
ETOH 25.6%
HBV+ETOH 2.6%
PBC 1.3% HBV 9.0%
Haemochromatosis 1.3%
Cryptogenic 24.4%
Lessons from the Dionysus Study 3
Prevalence & relative risk of fatty liver
100
95
90
76
80
70
60 46 Steatosis
50
40 Rel Risk
30
16
20 5.8
10 1 2.8 4.6
0
No alcohol, No alcohol, Heavy Heavy
normal BMI high BMI alcohol, alcohol, high
normal BMI BMI
• HBV, HCV + drug consumption excluded
Bellentani S et al. Ann Intern Med 2000; 132: 112-7
The Insulin Resistance Syndrome
Impaired glucose
tolerance
Type II Diabetes Hyperinsulinaemia
Insulin Clotting
Macrovascular
complications
resistance disorders
Central
Hypertension
obesity
Dyslipidaemia
Expert Committee on the Diagnosis & Classification of Diabetes Mellitus.
Diabetes Care 1997;20(7):1183–1203
Histology
• Necessary components:
– Steatosis, macro>micro,>10%, zone 3
– Mixed, mild, lobular inflammation
– Hepatocellular ballooning, zone 3
• Usually present
– Zone 3 perisunusoidal fibrosis
– Zone 1 hepatocellular glycogenated nuclei
– Lipogranulomas in lobules
– Occasional acidophil bodies/PAS-d Kupffer cells
• May be present
– Mallory’s hyaline
– Mild granular periportal hepatocellular iron
– Metamitochondria in hepatocytes
Predictors of NASH
• Age increases risk of significant disease
– 45 yrs
– BMI >31
– Type 2 diabetes
– ALT x2 Normal
– AST:ALT>1
Angulo Hepatology 1999
Ratziu Gastroenterology 2000
• In obese patients
– Raised ALT
– Hypertension
– Waist:hip ratio high
Dixon Gastroenterology 2001
Cirrhosis
• NASH with cirrhosis
• Cirrhosis with features of NASH
• Cryptogenic cirrhosis
• In cryptogenic cirrhosis a
– history of diabetes +/- obesity is present in 73%
– prevalence of diabetes +/- obesity similar to that in NASH patients
– NASH patients on average 10 years younger
Caldwell SH et al. Hepatology 1999;29: 664-669
Chronic Hepatitis B
•DNA virus
•Transmission
•Horizontal:
•IVDU, Sexual transmission
•in lower prevalence areas eg
UK, USA, N+W Europe
•Perinatal (Vertical):
•High prevalence areas eg SE
Asia + China
Schematic Representation of the HBV virus
Surface coat
(HBsAg/Ab)
Pre-core protein
Core protein (HBeAg/Ab)
(cAb IgM/IgG)
X protein
Hepatitis B serology
• HBsAg/Ab: • HBeAg/Ab:
– Serum – Serum
– 1-4 weeks after exposure. – HBV replication
– Usually gone by 6/12 – HBV DNA high
– Anti-HBs Ab develops – “High risk”
– confers immunity – Anti-HBeAb early in acute
• HBcAb:IgG/IgM infection
– Ag intracellular so not in serum – Late in chronic infection
– Ab detectable at any stage of – HBV DNA usually disappears
infection – Persistent HBV DNA and/or
– IgM usually reflects acute HBV high ALT ?mutation in pre-
core region of HBV gene
– Can increase during flares of
chronic HBV
The course of acute infection with HBV acquired in adulthood
Serology Associated with Chronic HBV
90% Perinatal infection
20-50% Infection age 1-5
5% Adult acquired
Countries with Moderate-High Risk of Chronic Hepatitis B
Treatment of Chronic HBV
• Aims:
– Seroconversion (HbeAg+)
– Suppress replication (HBeAg-)
• Current Options
– Interferon
– Lamivudine
– Adefovir
Prevention
• Taiwan data – 22 000, HCC and HBV (Beasley et al 1985)
• Childhood HBV Vaccination Significant decrease in incidence
and deaths for HCC in children following national vaccination
policy introduced in 1984 (Chang MH et al, NEJM 1997; 336: 1855-1859)
Chronic Hepatitis C Infection
RNA virus
At risk groups
•IVDU
•Clotting factors prior 1986
•Blood/organs proir 1992
•Chronic haemodialysis
•Abnormal LFTs
HCV testing
• Structure
• Nucleocapsid C
• 2 glycoproteins: envelope E1 + envelope/n-st E2/NS1
• Non-structural proteins NS2-5
• Screening test
– Enzyme-linked Immuno Assay
• Core (C22)and non-structural regions 3 (C33) +4 (C100)
• Confirmatory test
– Recombinant Immunoblot Assay
• RIBA-2
• Virological testing
– PCR: determines active viraemia
– Genotyping – determines length + success of treatment
Primary Biliary Cirrhosis
• 95% patients are female
• Rare before age 30
• 50% patients asymptomatic at diagnosis
• Pruritus + fatigue are commonest symptoms
• Inflammatory arthropathy in 40%
– Rheumatoid arthrits
– Sjogrens syndrome
– CREST
• End-stage liver disease
Examination
• Skin:
• hyperpigmentation, jaundice, xanthelasma,
scratch marks
• Abdomen:
• Hepatosplenomegaly
• Signs of chronic liver disease
Diagnosis
• ALP and gGT
• elevated, can be marked,
• of liver origin
• ALT
• usually normal, may be mildly elevated,
• not>5xULN
• Bili
• usually normal in early disease, rises in later disease,
• confers prognostic information,
• conjugated and unconjugated
• Immunoglobulins
• Raised IgM
• Anti-mitochondrial (M2) antibodies
• 95% sensitive, 98% specific
• Directed v pyruvate dehydrogenase complex
Other features
• Hyperlipidaemia (HDL)
• Auto-immune conditions
• Suspect AIH overlap syndromes when ALT also high
associated with +ANA, anti-SM ab and raised IgG on serology
• Sicca syndrome, Raynaud’s
• Thyroid disesae
• Coeliac disease
Topics not covered
• Metabolic liver disease in adults:
• Haemochromatosis, Wilson’s disease, a1Anti-
trypsin deficiency
• Drug related chronic liver disease:
• Methotrexate, amiodarone
• Chronic vascular liver disease:
• Nodular regenerative hyperplasia, Chronic Budd
Chiari Syndrome