Abnormal LFTs and NAFLD Dr - PowerPoint Presentation

Slide1

Abnormal LFTs and NAFLD

Dr William Alazawi MA(Cantab) PhD MRCPSenior Lecturer and Consultant in HepatologyQueen Mary, University of London

Slide2

Does Liver Disease Matter?

Slide3

Mortality in England & Wales

Slide4

Liver-related mortality in under 65s

Slide5

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

Chief Medical Officer

Slide6

Population Study

How

much liver disease is out there?How much has been ‘worked up’

Slide7

Study Design

Cross sectional study using the east London GP Database690,683 adults registered in 150 coterminus GP practicesLFTs requested in 2011 and 2012

Slide8

Results

218,032 adults had LFTs tested (31.6%)31,672 (14.5%) at least 1 abnormal resultsALT or AST

Slide9

Risk of Abnormal LFTs

Multivariate analysisAlazawi et al, BJGP 2014

Slide10

LFTs - ‘something and nothing

’ ?

Slide11

‘Normal’ LFTs

Kim HC et al.

BMJ

.

2004;328(7446

):

983

142055 adults

35-59 years

8 years’ follow-

ip

Slide12

Liver ‘Function’ Tests

BilirubinUnconjugated vs conjugatedAspartate aminotransferase (AST)

Mitochondrial enzymeHeart/muscle/kidneyhepatitisAlanine aminotransferae (ALT)Liver specificAlkaline phosphatase

Bile cannalicular + sinusoidal membranes

Bone/placentaCholestasis – intra/extrahepatic

Gamma glutamyl transpeptidase (GGT)

HepatocellularCholestasis

alcohol

Slide13

Liver Tests

Pattern of Liver tests:ALT /AST = hepataticAlk Phos / γ

GT = cholestaticAST > ALT – alcoholALT > AST – eg viruses / NAFLDReverses with significant fibrosis

ALT:

Alcohol doesn’t put ALT > 500500 – 1500 – ?autoimmune hepatitis

>1500 – hepatitis viruses / drugs / ischaemia

Slide14

Total population (

e)

=690,683Total tested = 218,032

A

= Tested and normal LFTs (n= 196,360)

B= Tested, abnormal

LFTs, no diagnosis (n= 27,985)

C

D

E

NAFLD

43%

HBV/HCV

40%

ALD

10%

Other

7%

C

= Tested, abnormal LFTs and liver diagnosis recorded (n = 3,687

)

D

= Tested, normal LFTs and liver diagnosis recorded (n= 4,384

)

E

= Not tested, liver diagnosis

recorded (n=3,965)

Slide15

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

88% no liver diagnosis

Slide16

Prevalence of Liver Diagnoses

N=690,683

Alazawi et al, in press

Slide17

Liver disease and Ethnicity

Slide18

Non-Alcoholic Fatty Liver

Hepatic fat on biopsy or imagingNo other cause for fat – including alcohol

Metabolic Syndrome

Slide19

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

Slide20

Not the whole story…

Mean age 39.562% not diabetic48% not obese

East London Population Study;Alazawi et al [In submission]

Images supplied by

Dr William Alazawi, Queen Mary, University of London

Slide21

Non-Alcoholic Fatty Liver Disease

Slide22

How common is NAFLD?

Depends on population and definitionHistology – 20–51%1,2US – 17–46%3MR Spectroscopy – 31%4

ALT – 7–11%3Overall: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

. 2011 Aug;34(3):274-85;

4

Browning JD et al.

Hepatology

. 2004;40(6):1387-95;

5

Chalasani N et al.

Gastroenterology.

2012 ;142(7):1592-609

Slide23

NAFLD is associated with mortality

P=0.02

Slide24

Mortality in NAFLD

Olmsted County Cohort

420 patients over 20

yrs

(3192 p-y)

Mean follow-up 7.6

yrs

SMR 1.34

Adams

et al

2005

Slide25

Increased CV Disease

Systolic BPFasting blood glucoseTotal cholesterol & triglyceridesInsulin resistanceDecreased adiponectinRaised LDL cholesterol

Yu et al 2008

Francanzani et al 2008

Fallo et al 2008

Sung et al 2008

Slide26

Increased risk of HCC

Chaldwell & Park, 2009

Slide27

NAFLD and Liver Cancer

Dyson et al 2013 J Hepatol

23% of NAFLD are non-cirrhotic

34.8%

Newcastle MDM data

Slide28

Non-Alcoholic Fatty Liver Disease

FAT

INFLAMMATION

Slide29

NASH is not benign

NASH liver mortality OR 5.71 (2.31-14.13)1NASH + 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

3

Ekstedt 2015

Slide30

NASH vs

FatRetrospective series - biopsies from 1980sN=118 NAFLD

Söderberg C et al.

Hepatology

. 2010;51(2):595-602

Slide31

The Prevalence of NASH

Brooke Medical Center

Williams et al, 2011

12.2%

Slide32

Progression of NAFLD

30% of population has NAFLD

10% of NAFLD develop NASH

25% of NASH develop cirrhosis

10 - 25% of cirrhosis develop HCC

Siegel & Zhu 2009

Slide33

Does SS Progress to NASH?

9-20% NASH progress to cirrhosis1-3SS stable over timeOlmsted 420 cohort; 7.6 yr follow upNo SS deaths

35% NASH died3

1

Harrison 2003

2

Ong 2003

3

Adams 2005

Slide34

Risk Factors for NASH

Age / Male Gender ? / Hispanic ethnicityDietFructose Corn Syrup / CoffeeMicrobiomeFirmicutes - ?ethanol-producingGenetics

PNPLA3, TM6SF2steatosis and fibrosisMetabolic syndromeObesityDiabetesHyperlipidaemia

Slide35

Symptoms of NAFLD

AsymptomaticFatigue – as much as PBC

Severe impairment of QOL RUQ painAssociations include

OSA and hypothyroidism

Slide36

Diagnosis of NALFD

Abnormal LFTsExclude viral / EtOH / AI / HC / Drugs

U/S suggests fatty infiltrateOther causes of fatty liver:SurgeryTPNPCOS (FSH / LH & testosterone)Lipodystrophy

Drugs –

Tamoxifen / methotrexate /

amiodarone / HAART

Slide37

Slide38

Liver Biopsy

30 % pain / 0.3-0.6% bleeding

Pathologist - dependent10-30% false negative for cirrhosis

PROs

CONsStaging

Invasive

GradingCost

DiagnosisSampling

Co-Pathology

Reluctance

Static

information

Slide39

Non-Invasive Tests of Fibrosis

Blood TestsElastographyIdeally:AccurateAvailableStage and GradeValid (numbers and aetiologies)

Slide40

Non-Invasive Tests of Fibrosis

Blood TestsElastographyIdeally:AccurateAvailableStage and GradeValid (numbers and aetiologies)

Slide41

Gressner et al, 2009

Slide42

Slide43

Assessing risk of fibrosis

NAFLD-FSAge / BMI / DM / AST:ALT / Plt / AlbuminAPRI

AST / PltFIB-4Age / AST / ALT / PltBARDBMI / DM /

AST:ALT

Slide44

NAFLD fibrosis score

733 patients480 training, 253 validationRochester / Newcastle / Sydney / Italy90% Caucasian

BMI 32.2DM / IFG – 69%NPV 88%60% of patients could avoid biopsyPPV 78%

25% of patients ‘indeterminate

’

Slide45

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

Slide46

Management of NAFLD?

Follow-up metabolic syndrome:Correct hyperlipidaemiaDietStatins – monitor change from baseline

Glitazones – not soundly proven; use if indicated for hyperlipidaemia Other CV risk factorsHypertensionSmoking cessation

Insulin Resistance

Slide47

Exercise

Low/moderate intensity (n=141)

9x more likely to exercise >1hr/week150 mins / week or increase by >60mins improvement in ALTMetabolic indices (HOMA-IR)Independent of weight loss

St George et al, 2009

Slide48

Weight loss improves NAS

Musso et al, 2009

Slide49

Thiazolidinediones

Stimulate nuclear PPAR-γInduce insulin sensitising genesReduce IRPromote favourable lipid profilePromote weight gain

Slide50

Pioglitazone

Placebo-controlledN=55Hypocaloric dietImproved inflammation

No change in histology

Belfort et al 2007

NEJM

Slide51

Rosiglitazone – FLIRT

Ratziu et al 2008

Gastroenterology

Slide52

Pioglitazone vs Vit E vs placebo

N=247 – NASH2 point reduction in NAS43% Vitamin E19% Placebo (pioglitazone not sig different)Improved inflammatory componentsNo improvement in fibrosis (no worsening)Pioglitazone assoc with weight gain but improved IR

Sanyal

et

al 2012

Slide53

Obeticholic acid

Farnesoid X nuclear receptorDownregulate SREBP1cIncrease SIRT1 Reduces fat and fibrosis in animal modelsImprove hepatic insulin sensitivityDecrease steatosis

Inhibit lipogenesisCause regression of atherosclerosisAnti-fibrotic

Slide54

FLINT study

Phase IIb double blind placebo controlled multicentre RCT Non-cirrhotic NASH patientsHistologyN=28353% diabetesPrimary outcomeImprovement in NAS by at least 2 points

No worsening of fibrosis

Slide55

Neuschwander-Tetri et al, Lancet 2014

Slide56

Change in liver enzymes and weight

Slide57

Ongoing work at Barts Health

Clinical trialsLOXL2CenicrivirocObservational studiesImmune and inflammatory responseDiabetes & NAFLD

Basic science studiesMechanisms of diseaseTherapeutic targets

Slide58

A

bnormal liver function tests

and/

or ultrasound

showing

fatty liver

Screen

Positive or uncertain

Behaviour

/ lifestyle advice

Alcohol

Exercise

Diet

Cardiovascular risk factors

Negative

or

M

etabolic Risk:

I / H risk

Likely

NAFLD:

Calculate NAFLD

F

ibrosis Score

*

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

.

§

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

Abnormalities resolve

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

Abnormalities persist

Slide59

Barts Health Liver

Network:ConsultantsClinical nurse specialistsRegistrars & Clinical fellowsPharmacistsAdministrators

Slide60

Primary Care & Commissioning

A pathway for abnormal LFTs?Avoid unnecessary repetition of testsOne-stop clinics?Risk stratificationAccess to behaviour and lifestyle services

Slide61

A

bnormal liver function tests

and/

or ultrasound

showing

fatty liver

Screen

Positive or uncertain

Behaviour

/ lifestyle advice

Alcohol

Exercise

Diet

Cardiovascular risk factors

Negative

or

M

etabolic Risk:

I / H risk

Likely

NAFLD:

Calculate NAFLD

F

ibrosis Score

*

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

.

§

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

Diagnostic Liver Clinic

Bart’s Health

Hepatology

Starts April

2015

Diagnosis and Advice

§

Abnormalities resolve

Low

risk

Follow

-up in Primary

Care

Annual review

AUDIT-C Positive

Brief Intervention

Repeat tests in 3 months

Management in Primary Care

Referra

l

Abnormalities persist

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

Slide62

We are keen to do more

william.alazawi@bartshealth.nhs.uk