Hepatology for Surgeons

1
Hepatology for Surgeons

• Assessment of Chronic Stable Abnormal Liver
  Function Tests
• Rebecca Jones
• Hepatologist, Bristol Royal Infirmary
• June 2004

2
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

3
Outcomes

• 32yr old man Chronic HCV
• 28yr old woman Chronic HBV
• 45yr old woman PBC
• 67yr old man NASH
• 45 yr old man PSC

4
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

5
Results Sherwood et al LFTs in primary care 2001
6
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 gt21/14u/week,
  family reporting of alcohol excess, measurable
  blood ETOH

7
Clinical Diagnoses after Liver Biopsy in Patients
in 2ary care
Skelly MM et al. J Hepatol 2001 35195-9
8
Causes of Fatty Liver Disease

• Nutritional
• TPN
• Severe weight loss
• JI bypass
• Gastric bypass
• Severe starvation
• Refeeding syndrome
• Disorders of lipid metabolism
• Abetalipoproteinaemia
• Hypobetalipoproteinaemia
• Andersens disease
• Weber-Christian disease
• Toxic exposure
• Organic solvents
• Dimethylformamide

• Alcohol
• Insulin resistance
• Syndrome X
• Obesity
• Diabetes
• Hypertriglyceridaemia
• Hypertension
• Lipoatrophy
• Mauriac syndrome
• Iatrogenic
• Amiodarone, Diltiazem, Tamoxifen, Steroids, HAART

9
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
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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
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Lessons from the Dionysus Study 2
HCVETOH 7.7
HCV 28.2
ETOH 25.6
HBVETOH 2.6
PBC 1.3
HBV 9.0
Haemochromatosis 1.3
Cryptogenic 24.4
12
Lessons from the Dionysus Study 3

• HBV, HCV drug consumption excluded

Bellentani S et al. Ann Intern Med 2000 132
112-7
13
The Insulin Resistance Syndrome
Impaired glucose tolerance
Hyperinsulinaemia
Type II Diabetes
Insulin resistance
Clotting disorders
Macrovascular complications
Central obesity
Hypertension
Dyslipidaemia
Expert Committee on the Diagnosis
Classification of Diabetes Mellitus. Diabetes
Care 199720(7)11831203
14
Histology

• Necessary components
• Steatosis, macrogtmicro,gt10, 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
• Mallorys hyaline
• Mild granular periportal hepatocellular iron
• Metamitochondria in hepatocytes

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Predictors of NASH

• Age increases risk of significant disease
• 45 yrs
• BMI gt31
• Type 2 diabetes
• ALT x2 Normal
• ASTALTgt1
• Angulo Hepatology 1999
• Ratziu
  Gastroenterology 2000
• In obese patients
• Raised ALT
• Hypertension
• Waisthip ratio high
• Dixon Gastroenterology 2001

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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 199929
  664-669

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Chronic Hepatitis B

• DNA virus
• Transmission
• Horizontal
• IVDU, Sexual transmission
• in lower prevalence areas eg
• UK, USA, NW Europe
• Perinatal (Vertical)
• High prevalence areas eg SE
• Asia China

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Schematic Representation of the HBV virus
Surface coat (HBsAg/Ab)
Pre-core protein (HBeAg/Ab)
Core protein (cAb IgM/IgG)
X protein
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Hepatitis B serology

• HBsAg/Ab
• Serum
• 1-4 weeks after exposure.
• Usually gone by 6/12
• Anti-HBs Ab develops
• confers immunity
• HBcAbIgG/IgM
• Ag intracellular so not in serum
• Ab detectable at any stage of infection
• IgM usually reflects acute HBV
• Can increase during flares of chronic HBV

• HBeAg/Ab
• Serum
• HBV replication
• HBV DNA high
• High risk
• Anti-HBeAb early in acute infection
• Late in chronic infection
• HBV DNA usually disappears
• Persistent HBV DNA and/or high ALT ?mutation in
  pre-core region of HBV gene

20
The course of acute infection with HBV acquired
in adulthood
21
Serology Associated with Chronic HBV
90 Perinatal infection 20-50 Infection age
1-5 5 Adult acquired
22
Countries with Moderate-High Risk of Chronic
Hepatitis B
23
Treatment of Chronic HBV

• Aims
• Seroconversion (HbeAg)
• Suppress replication (HBeAg-)
• Current Options
• Interferon
• Lamivudine
• Adefovir

24
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)

25
Chronic Hepatitis C Infection

• RNA virus
• At risk groups
• IVDU
• Clotting factors prior 1986
• Blood/organs proir 1992
• Chronic haemodialysis
• Abnormal LFTs

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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

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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

28
Examination

• Skin
• hyperpigmentation, jaundice, xanthelasma, scratch
  marks
• Abdomen
• Hepatosplenomegaly
• Signs of chronic liver disease

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Diagnosis

• ALP and gGT
• elevated, can be marked,
• of liver origin
• ALT
• usually normal, may be mildly elevated,
• notgt5xULN
• 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

30
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, Raynauds
• Thyroid disesae
• Coeliac disease

31
Topics not covered

• Metabolic liver disease in adults
• Haemochromatosis, Wilsons disease,
  a1Anti-trypsin deficiency
• Drug related chronic liver disease
• Methotrexate, amiodarone
• Chronic vascular liver disease
• Nodular regenerative hyperplasia, Chronic Budd
  Chiari Syndrome