Abnormal Liver Function. Dr William Alazawi MA(Cantab) PhD MRCP Senior Lecturer and Consultant in Hepatology Queen Mary, University of London

(1)

Abnormal Liver Function

Dr William Alazawi MA(Cantab) PhD MRCP

Senior Lecturer and Consultant in Hepatology

(2)

(3)

(4)

(5)

Does Liver Disease Matter?

“Between 2000 and 2009,

deaths from chronic liver

disease and cirrhosis in the under 65s increased by

around 20%

while they fell by the same amount in

most EU countries.

And all 3 major causes of liver disease - obesity,

undiagnosed infection, and, increasingly, harmful

drinking - are preventable.”

Dame Sally Davis

(6)

Liver ‘Function’ Tests

• Bilirubin

• Aspartate aminotransferase (AST)

• Alanine aminotransferae (ALT)

• Alkaline phosphatase

(7)

Liver ‘Function’ Tests

• Bilirubin

• Aspartate aminotransferase (AST)

• Alanine aminotransferae (ALT)

• Alkaline phosphatase

(8)

Jaundice

Pre-Hepatic

Hepatic

Post-Hepatic

www.drclark.net

Patients with jaundice should be assessed

urgently

(9)

Liver Tests

• ALT /AST = hepatatic

(10)

Population Study

• How much liver disease is out there?

• How much has been ‘worked up’

Total for 3 Boroughs n=813,700

White Indian Pakistani Bangladeshi Asian Other Black African Black Caribbean Other

(11)

Study Design

• Cross sectional study using the east London

GP Database

• 690,683 adults registered in 150 coterminus

GP practices

(12)

Results

• 218,032 adults had LFTs tested (31.6%)

• 31,672 (14.5%) at least 1 abnormal results

(13)

Risk of Abnormal LFTs

Multivariate analysis

Alazawi et al, BJGP 2014

(14)

(15)

‘Normal’ LFTs

Kim HC et al. BMJ. 2004;328(7446):983

142055 adults

35-59 years

(16)

Prevalence of Liver Diagnoses

-

2,000

4,000

6,000

Venous Thrombosis

Autoimmune

Pregnancy-related

Inherited

ALD

Hepatitis C

Acute Viral

Hepatitis B

NAFLD

N=690,683

Alazawi et al, 2014

(17)

Total Abnormal

n=31,672

Undiagnosed

n=27,895

Diagnosed

n=3,687

Undiagnosed Liver Disease in Primary

Care



_{12,687 (38%) Drugs (including statins)}



_{3,372 (11%) Excess alcohol consumption}



_{6,026 (19%) ‘Safe’ alcohol & viral tests (negative)}



_{6,300 (20%) No viral tests}

(18)

Abnormal liver function tests and/or ultrasound showing fatty liver

*A complete liver screen would additionally include testing for alpha1-antitrypsin, caeruloplasmin and alphafetoprotein. ¶_{Chronic viral}

infection should be excluded by testing for hepatitis B virus surface antigen and antibodies against hepatitis C virus. If abnormalities are acute, exclude hepatitis A and hepatitis E virus infection.

Primary Care:

Symptoms &

comorbidities

Detailed drug history

Careful family history

Alcohol review – AUDIT-C

Metabolic risk factors inc

BMI

Blood Tests

*

:

Viral hepatitis – HBV &

HCV

¶

FBC, U&E, INR, TFT

LFTs inc AST / GGT

Lipid profile

Ferritin

Autoantibodies

Immunoglobulins

Consider need for

ultrasound

Hepatology

Abnormalities resolve

AUDIT-C

Positive

Brief Intervention

Repeat tests in 3

months

All patients with clinical jaundice or bilirubin >40 should be referred urgently for assessment

Abnormalities persist

(19)

Abnormal liver function tests and/or ultrasound showing fatty liver

Screen

Positive or

uncertain

Primary Care:

Symptoms &

comorbidities

Detailed drug history

Careful family history

Alcohol review – AUDIT-C

Metabolic risk factors inc

BMI

Blood Tests

*

:

Viral hepatitis – HBV &

HCV

¶

FBC, U&E, INR, TFT

LFTs inc AST / GGT

Lipid profile

Ferritin

Autoantibodies

Immunoglobulins

Consider need for

ultrasound

Hepatology

AUDIT-C

Positive

Brief Intervention

Repeat tests in 3

months

All patients with clinical jaundice or bilirubin >40 should be referred urgently for assessment

(20)

Abnormal liver function tests and/or ultrasound showing fatty liver

Screen

Positive or

uncertain

Negative or

Metabolic Risk

NAFLD

Primary Care:

Symptoms &

comorbidities

Detailed drug history

Careful family history

Alcohol review – AUDIT-C

Metabolic risk factors inc

BMI

Blood Tests

*

:

Viral hepatitis – HBV &

HCV

¶

FBC, U&E, INR, TFT

LFTs inc AST / GGT

Lipid profile

Ferritin

Autoantibodies

Immunoglobulins

Consider need for

ultrasound

Hepatology

AUDIT-C

Positive

Brief Intervention

Repeat tests in 3

months

All patients with clinical jaundice or bilirubin >40 should be referred urgently for assessment

(21)

Non-Alcoholic Fatty Liver

Hepatic fat on biopsy or imaging

No other cause for fat – including alcohol

(22)

Independent Risk Factors for NAFLD

Explanatory Variable

Odds

Ratio

95% CI

P value

Ethnic Group

Bangladeshi

1.38

1.14

1.69

0.001 Indian

0.83

0.63

1.11

0.208 Pakistani

1.12

0.83

1.53

0.459 White (reference cat)

1.00 -

-

-African

0.53

0.42

0.66 <0.001

Caribbean

0.47

0.36

0.61 <0.001

Age (continuous)

0.998

0.994

1.003

0.470 Male

0.85

0.78

0.92 <0.001

Diabetes

2.25

2.08

2.44 <0.001

Hypertension

1.32

1.13

1.53 <0.001

Cardiovascular Disease

0.94

0.84

1.07

0.356 BMI Category

BMI underweight

0.85

0.35

2.08

0.729 BMI normal (ref)

1.00 -

-

-BMI overweight

2.90

2.40

3.51 <0.001

BMI obese

5.00

4.08

6.12 <0.001

(23)

Not the whole story…

• Mean age 39.5

• 62% not diabetic

(24)

(25)

How common is NAFLD?

• Depends on population and definition

– Histology – 20–51%

1,2

– US – 17–46%

3 – MR Spectroscopy – 31%

4 – ALT – 7–11%

3 • Overall:

– NAFLD – 20% (6.3–33%)

5

1_{Lee J et al. J Hepatol. 2007;47(2):239-44;}2_{Marcos A et al. Transplantation. 2000;69:1375–1379;}3_{Vernon G et al. Aliment Pharmacol Ther.}

(26)

NAFLD is associated with mortality

(27)

Mortality in NAFLD

(28)

Non-Alcoholic Fatty Liver Disease

(29)

NASH and liver mortality

• NASH - OR 5.71 (2.31-14.13)

1 – NASH + Fibrosis - OR 10.06 (4.35 – 22.35)

Survival of 129 / 212 patients with NASH

2

P=0.001

1

_{Musso 2011}

2

_{Ekstedt 2006}

(30)

NASH vs Fat

• Retrospective series - biopsies from 1980s

• N=118 NAFLD

(31)

NAFLD and Liver Cancer

0 20 40 60 80 100 120 140 160 180 200 ALD NAFLD HCV HBV Cirrhotic Non-Cirrhotic

Dyson et al 2013 J Hepatol

23% of NAFLD are non-cirrhotic

34.8%

(32)

The Prevalence of NASH

Brooke Medical Center

Williams et al, 2011

(33)

Progression of NAFLD

30% of

population

has NAFLD

10% of

NAFLD

develop

NASH

25% of

NASH

develop

cirrhosis

10 - 25% of

cirrhosis

develop

HCC

(34)

Does SS Progress to NASH?

• 9-20% NASH progress to cirrhosis

1-3

– SS stable over time

• Olmsted 420 cohort; 7.6 yr follow up

– No SS deaths

– 35% NASH died

3

1 _{Harrison 2003}

2 _{Ong 2003}

3 _{Adams 2005}

(35)

• Patients with >1 biopsy 1991-2011

• Median follow-up 6.6 yr

• Progressors – increase T2DM (65% vs 48%)

Does SS Progress to NASH?

0

1

2

3

4 TOTAL

0

16

4

1

2

0

23

1

6

7

3

11

2

29

2

1

7

11

3

33

3

0

2

4

9

8

23

4

0

(36)

Risk Factors for NASH

• Age / Male Gender ? / Hispanic ethnicity

• Diet

– Fructose Corn Syrup / Coffee

• Microbiome

– Firmicutes - ?ethanol-producing

• Genetics

– PNPLA3, TM6SF2

– steatosis and fibrosis

• Metabolic syndrome

– Obesity

– Diabetes

(37)

Liver Biopsy

–

30 % pain / 0.3-0.6% bleeding

Pathologist - dependent

–

10-30% false negative for cirrhosis

PROs

CONs

Staging

Invasive

Grading

Cost

Diagnosis

Sampling

Co-Pathology

Reluctance

Static information

(38)

Non-Invasive Tests of Fibrosis

• Blood Tests

• Elastography

• Ideally:

–

Accurate

–

Available

–

Stage and Grade

(39)

Non-Invasive Tests of Fibrosis

• Blood Tests

• Elastography

• Ideally:

–

Accurate

–

Available

–

Stage and Grade

(40)

(41)

Assessing risk of fibrosis

• NAFLD-FS

– Age / BMI / DM /

AST

:ALT /

Plt

/ Albumin

• APRI

– AST

/

Plt

• FIB-4

– Age /

AST

/ ALT /

Plt

• BARD

(42)

NAFLD fibrosis score

• 733 patients

– 480 training, 253 validation

– Rochester / Newcastle / Sydney / Italy

– 90% Caucasian

– BMI 32.2

– DM / IFG – 69%

• NPV 88%

– 60% of patients could avoid biopsy

• PPV 78%

(43)

Composite Scores

Angulo et al 2013 J Hepatol

Retrospective

N=320

105 months (3-317)

92% White

36% Diabetic

31% BMI>35

51% Fibrosis ¾

13% Death or OLT

(44)

Abnormal liver function tests and/or ultrasound showing fatty liver

Screen

Positive or

uncertain

Behaviour /

lifestyle advice

Alcohol

Exercise

Diet

Cardiovascular

risk factors

Negative

or

Metabolic

Risk:

I / H risk

Likely NAFLD:

Calculate

NAFLD

Fibrosis Score

infection should be excluded by testing for hepatitis B virus surface antigen and antibodies against hepatitis C virus. If abnormalities are acute, exclude hepatitis A and hepatitis E virus infection. §The Diagnostic Liver Clinic will return patients to GP with a diagnosis and advice

on future management

Primary Care:

Symptoms &

comorbidities

Detailed drug history

Careful family history

Alcohol review – AUDIT-C

Metabolic risk factors inc

BMI

Blood Tests

*

:

Viral hepatitis – HBV &

HCV

¶

FBC, U&E, INR, TFT

LFTs inc AST / GGT

Lipid profile

Ferritin

Autoantibodies

Immunoglobulins

Consider need for

ultrasound

Hepatology

Low risk

Follow-up in

Primary Care

Annual

review

AUDIT-C

Positive

Brief Intervention

Repeat tests in 3

months

All patients with clinical jaundice or bilirubin >40 should be referred urgently for assessment

(45)

Treatment in NAFLD?

• Follow-up metabolic syndrome:

– Correct hyperlipidaemia

• Diet

• Statins – monitor change from baseline

• Glitazones – not soundly proven; use if indicated for

hyperlipidaemia

– Other CV risk factors

• Hypertension

• Smoking cessation

(46)

Exercise

• Low/moderate intensity (n=141)

– 9x more likely to exercise >1hr/week

• 150 mins / week or increase by >60mins

– improvement in ALT

– Metabolic indices (HOMA-IR)

• Independent of weight loss

(47)

Weight loss improves histology

(48)

Weight loss improves histology

• 293 patients with NASH

–

40% male

–

BMI 31.3

• 52 week lifestyle

• 750kcal/day deficit

–

64% fat

–

22% fat

• Walk 200 mins / week

• 8, 16, 24, 32, 40 weeks

(49)

The NASH pipeline

(50)

Ongoing work at Barts Health

• Clinical trials

–

LOXL2

–

Cenicriviroc

–

Obeticholic acid

• Observational studies

–

Immune and inflammatory response

–

Diabetes & NAFLD

• Basic science studies

–

Mechanisms of disease

(51)

Primary Care & Commissioning

• A pathway for abnormal LFTs?

• Avoid unnecessary repetition of tests

• One-stop clinics?

–

Risk stratification

(52)

Abnormal liver function tests and/or ultrasound showing fatty liver

Screen

Positive or

uncertain

Behaviour /

lifestyle advice

Alcohol

Exercise

Diet

Cardiovascular

risk factors

Negative

or

Metabolic

Risk:

I / H risk

Likely NAFLD:

Calculate

NAFLD

Fibrosis Score

infection should be excluded by testing for hepatitis B virus surface antigen and antibodies against hepatitis C virus. If abnormalities are acute, exclude hepatitis A and hepatitis E virus infection. §The Diagnostic Liver Clinic will return patients to GP with a diagnosis and advice