investigating general liver disease/transaminitis

Investigating general liver

disease/transaminitis

Emmanuel A. Tsochatzis

Senior Clinical Lecturer and Consultant Hepatologist

UCL Institute of Liver and Digestive Health

Royal Free Hospital Institute for Liver and Digestive Health

BHIVA Autumn Conference

London 14 October 2016

Talk outline

Causes of transaminitis

How to investigate

NAFLD

Who needs referral to the hepatologist

Treatment

Liver disease in HIV infected patients

• Viral hepatitis

• Alcohol

• Drug toxicity

• NAFLD

• Infection

• Cancer/lymphoma

The dark ages

Diagnosis No of patients

Granulomatous hepatitis (M.avium, other acid-fast bacilli)

191 (37%)

Other infections (CMV, P.carinii, Candida)

14 (3%)

Neoplasia (lymphoma, HCC)

19 (4%)

Viral hepatitis/cirrhosis 91 (18%)

Alcoholic hepatitis 15 (3%)

Nonspecific findings 179 (36%)

501 biopsies

Main indications:

1) Abnormal LFTs

2) FUO

3) Hepatomegaly

Poles JAIDS 1996

The developing world

Diagnosis Number of patients

Drug-induced liver injuries 127 (42%)

Granulomatous inflammation 86 (29%)

Viral hepatitis 66 (22%)

NAFLD/NASH 58 (19%)

Alcohol 16 (5%)

301 biopsies (2000-2013)

South Africa

Mean CD4 count 127 Sonderup Hepatology 2015

The developed world

Ingiliz Hepatology 2009

Diagnosis Number of patients

Steatosis 18 (60%)

Steatohepatitis 16 (53%)

Any fibrosis 19 (63%)

Advanced fibrosis (F3-F4) 4 (13%)

30 patients with chronic unexplained transaminases

• Retrospective analysis 2002-2015

• Patients with viral hepatitis co-infection excluded

• Demographics, indication for biopsy, stage of HIV

related disease documented.

• Steatosis, fibrosis and inflammation were recorded

• Definitive diagnoses were noted

Royal Free Hospital experience

Lever EASL 2015

Results

• A total of 143 biopsies were performed on a cohort

consisting of 4456 HIV positive individuals (2.8%)

• 75% males, mean age 49.6 years at biopsy

• Mean time between HIV diagnosis and biopsy was

8.1 years (range 0.1 years to 29 years)

• Abnormal LFTs main biopsy indication (70%)

Steatosis/inflammation

None

31%

Mild

26%

Moderate

14%

Severe

5%

Inadequate

sample

3%

Not

commented

21%

Steatosis (n=143)

Minimal

19%

Mild

33%

Moderate

10%

Marked

3%

None

22%

Not

documented

9%

Inadequate

sample

4%

Inflammation

(n=143)

69% had some degree of steatosis 43% at least minimal inflammation

Fibrosis and other diagnoses

None

65%

Mild

8%

Moderate

6%

Severe

2%

Cirrhosis

3%

Other

0%

Inadequate

sample

8%

Not

commented

on

8%

Fibrosis (n=143)

Cholestasis

11%

Granulomas

27%

Lymphoma

22%

Other

neoplasm

5%

AIH

8%

Drug

reaction

16%

Tuberculosis

11%

Other Diagnoses on

Liver Biopsy (n=37)

Some fibrosis in 20%, no fibrosis in 65%

Liver test abnormalities in patients

with HIV mono-infection

• Cross-sectional audit of consecutive HIV mono-infected patients

• Patients with persistently elevated LFTs in at least two

measurements six months apart

• 156/2398 (6.5%) persistently elevated transaminases

Lombardi EASL 2016, manuscript submitted

Abnormal LFTs in HIV mono-infection

• 97% on cART treatment

• US in 42%, of which 71% had steatosis

• APRI <0.5 n=81 (51.9%), >1.5 n=5 (3.2%)

• FIB4>1.45 in 33%, >3.25 in 4%

• TE only in 19 patients

• Liver biopsy NASH 13/20 patients, 1 with cirrhosis

Lombardi EASL 2016, manuscript submitted

A look for DDI hepatopathy

Refused bx

(n=5)

Normal Liver

(n=4)

Sampling frame

(n=376)

HBV/HCV co-infection

(84) or known DDI

related liver disease

(n=2) excluded

Bhagani S 2016

How to investigate transaminitis

• Drug history

• Alcohol history

• CD4 count

• Viral hepatitis markers

• Ferritin, transferrin saturation

• ANA, SMA, LKM, immunoglobulins

• Caeruloplasmin, a1-antithrypsin

• Liver ultrasound

• Non-invasive fibrosis assessment

(Fibroscan)

• Metabolic host-mediated (intrinsic and idiosyncratic)

• Hypersensitivity (early occurrence)

• Mitochondrial toxicity (prolonged exposure)

• Didanosine/stavudine more consistently associated

with advanced fibrosis

Drug toxicity

Soriano 2008; Blanco 2011; Mendeni 2011

What is NAFLD ?

Steatosis

Steatosis/inflammation Fibrosis Cirrhosis

Steatosis NASH Cirrhosis

• Non-Alcoholic Fatty Liver Disease

• Wide disease range from simple steatosis to cirrhosis

12-40% 15%

Non alcoholic fatty liver disease (NAFLD)

• Prevalence 20-25% of the general population

• Estimated 40-60% in patients with HIV

• 2-7% has steatohepatitis (NASH)

• Hepatic manifestation of metabolic syndrome

• >50% of secondary care referrals due to NAFLD

Kotronen, Arterioscler Thromb Vasc Biol 2008

NAFLD: Potential consequences

Epidemiology

Growing prevalence of obesity

Finucane Lancet 2011

Increasing prevalence of MS in HIV

33,347 patients – MS from 8.7% to 44.1% in 7 years

Worm AIDS 2010

Obesity in HIV patients

Crum-Cianflone 2010

MS more prevalent in HIV than controls

Bonfanti 2007

NASH in HIV patients

1. HAART treatment

NRTIs, thymidine analogues (IR), didanosine

(mitochondrial toxicity)

2. Lipodystrophy

3. HIV virus

Mitochondrial damage, lipid levels


HAART

virus proteins

The Journal of Endocrinology and Metabolism 2003

Mitochondrial toxicity

Lipids level changes

Insulin resistance


Lipids level changes

Insulin resistance

NAFLD/NASH

NAFLD in HIV mono-infection


Ingiliz Hepatology 2009

No evidence of mitochondrial DNA depletion

Evidence of mitochondrial toxicity

No relation to the type of cART used

NAFLD in HIV patients

• 225 mono-infected patients, NAFLD in 83

• Mean BMI 23.8 kg/m2

Guaraldi Clin Infect Disease 2008

Variable 95% CI P

ALT/AST ratio 4.59 (2.09–10.08) <0.001

Male sex 2.49 (1.07–5.81) <0.001

Cumulative NRTI 1.12 (1.03–1.22) <0.001

Waist circumference 1.07 (1.03–1.11) <0.001


• 128 consecutive HIV mono-infected patients

• Mean BMI 24.5 kg/m2

• 55% NAFLD on US

• 18% Fibroscan >7.4 Kpa

• Age and MS independent predictors of >7.4 KPa

Lombardi, Digestive Liver Diseases 2016

APRI>1.5 in 8.3% of 432 patients

T2DM and detectable HIV viraemia independent predictors

Cohort also included patients who used alcohol


DallaPiazza BMC Infect Dis 2008

Prognosis – hepatology referrals

Natural history of NAFLD

P=NS P=0.01

Simple steatosis NASH

Ekstedt, Hepatology 2006

129 patients

Mean follow-up 13.7 years

Natural history of NASH

Ekstedt Hepatology 2015

• Age (mitochondrial dysfunction)

• All metabolic syndrome components

- Obesity/increased WC

- T2DM

- Hypertension

- Dyslipidaemia

• Smoking

Factors associated with progression

NASH and mortality

• CVS main cause of death

• Liver disease only 3d cause of mortality

Ekstedt, Hepatology 2006

Soderberg, Hepatology 2010

NAFLD – referral pathways

• High prevalence, low severity

• No liver-specific treatment

• How to select patients for referral?

• Non-invasive fibrosis assessment

Simple non-invasive clinical scores for F>2

• FIB4

Age, ALT, AST, PLT

• NAFLD fibrosis score

Age, BMI, hyperglycemia, AST/ALT, PLT, albumin

Angulo Hepatology 2007 Shah Clin Gastroenterol Hepatol 2009

Calculation of simple NITs

FIB-4: http://gihep.com/?page_id=9

NAFLD fibrosis score: http://nafldscore.com

Liver calculator Free application for smartphones

Risk classification according to simple NITs

60%

35%

5%

Low risk for >F2 Indeterminate risk for >F2 High risk for >F2

FIB4<1.3 1.3<FIB4<3.25 FIB4>3.25

NITs and prognosis

• NITs initially developed as surrogate markers

of fibrosis with a view to replace LB

• Increasingly used to assess prognosis

Cumulative liver related events

Diagnosis of NAFLD

(Negative Liver Screen & USS Fatty liver)

High risk for >F2 Low risk for >F2

Referral

Hepatology

Management in HIV clinic

Non-invasive fibrosis tests (one or two tiers as needed)

Summary se and sp of NIT for NAFLD

TN/(TN+FN)

FIB-4

(n=100)

High risk n=5

TP=2 FP=3

Low risk n=71

FN=1 TN=70

Indeterminates n=24

F3/4=2, F0-2=22

Fibroscan Refer n=11

TP=4, FP=7

High risk n=6

TP=2 FP=4

Low risk n=20

FN=0 TN=20

Referral rate 11%

F3/4 referred 76%

Fibroscan 24

Cost/100 pts £4520

FIB-4

(n=100)

High risk n=5

TP=2 FP=3

Low risk n=71

FN=1 TN=70

Indeterminates n=24

F3/4=2, F0-2=22

Fibrotest Refer n=13

TP=4, FP=9

High risk n=8

TP=2 FP=6

Low risk n=16

FN=0 TN=16

Referral rate 13%

F3/4 referred 78%

Fibrotest 24

Cost/100 pts £4950

FIB-4

(n=100)

High risk n=5

TP=2 FP=3

Low risk n=71

FN=1 TN=70

Indeterminates n=24

F3/4=2, F0-2=22

ELF Refer n=9

TP=4, FP=5

High risk n=4

TP=2 FP=2

Low risk n=26

FN=0 TN=26

Referral rate 9%

F3/4

referred

76%

ELF 24

Cost/100 pts £3660/

5290

Natural history of NAFLD

Adams, Gastro 2005

77%

87%

420 patients

Mean follow up 7.6 years

0

200

400

600

800

1000

1200

1400

1600

March 2012-Feb 2013 March 2013 - Feb 2014 March 2014 – Feb 2015

601

837

1437

Ne

w E

lect

ron

ic c

od

es

for

NA

FLD

Annual new primary care electronic codes for NAFLD in

Camden and Islington London Boroughs

Annual new cases of NAFLD in C&I *population of Camden and Islington = 400,000

Post-pathway Pre-pathway Srivastava 2015

Initial impact of pathway *after evaluation of 40% of post pathway data at Royal Free London

Post-pathway Pre-pathway

Composite

consultant

judgment

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Pre-pathway (2012-2013) Non NAFLD pathway 2014-2015 NAFLD pathway (excluding normal

LFT's)

F fibrosis

F fibrosis

Srivastava 2015

Treatment

Who should be treated?

Simple steatosis:

Lifestyle advice, CVS factors

NASH, F0-F1 fibrosis:

Lifestyle advice, CVS factors, clinical trials

NASH, significant fibrosis:

Liver-specific interventions, clinical trials

Potential treatment targets

• Lifestyle changes

• Antioxidant factors

• Insulin resistance

• Fibrosis

Weight loss and NASH

Vila-Gomez Gastro 2015

293 patients

Dietary intervention

52 weeks

Statins in liver disease

437 patients with abnormal LFTs

LFT improvement

Less CVS events

Athyros Lancet 2010

PIVENS

Pioglitazone, Vitamin E or placebo

4334

19

0

20

40

60

80

100

NAS score

Vit E Pioglitazone Placebo

44 4131

0

20

40

60

80

100

Fibrosis

Vit E Pioglitazone Placebo

P=NS P=0.001

P=0.04

Sanyal NEJM 2010

287 non-diabetic patients

2 years of treatment

Vitamin E: current evidence

• Effective in two RCTs (PIVENS, TONIC)

BUT:

– Increased mortality in doses >400 IU/day

– Increased risk of prostate cancer

FXR nuclear receptor

Lipid metabolism

Reduces lipogenesis (SREBP1c)

Increases fatty acid oxidation

Liver

Reduces inflammation (NF-kB)

Antifibrotic

Carbohydrate metabolism

Improves insulin sensitivity

Reduces neoglucogenesis

Obeticholic acid

• Farnesoid X receptor agonist

• Non-cirrhotic NASH

• Double blind, phase II, placebo controlled trial

• 25 mg OCA (n=141), placebo (n=142) 72 weeks

• Primary endpoint = 2 point improvement in NAS with no

worsening of fibrosis

• Improvement in histology (50 OCA, 23 placebo)

• Increase in LDL

Neuschwander-Tetri Lancet 2014

FLINT - histological data

Feature OCA Placebo Relative Risk P value

Number of patients 102 98

Decrease of NAS score by

points with no worsening of fibrosis

50(45%) 23(21%) 1.9 (1.3-2.8) 0.0002

Improvement in Fibrosis 36(35%) 19(19%) 1.8(1.1-2.7) 0.004

Improvement in Ballooning 47(46%) 30(31%) 1.5(1.0-2.1) 0.03

Improvement in lobular

inflammation

54(53%) 34(35%) 1.6(1.1-2.2) 0.006

Improvement in Steatosis 62(61%) 37(38%) 1.7(1.2-2.3) 0.001

LEAN – liraglutide vs. placebo

Feature Liraglutide

(n=23)

Placebo

(n=22)

P

NASH regression 9 (39%) 2 (9%) <0.05

NAS score -1.3 -0.8 NS

Improvement in fibrosis 6 (26%) 3 (14%) NS

Improvement in ballooning 14 (61%) 7 (32%) NS

Improvement in steatosis 19 (83%) 10 (45%) <0.05

Improvement in lobular

inflammation

11 (48%) 12 (55%) NS

Armstrong Lancet 2015

Treatment of metabolic syndrome

components

• Obesity – exercise and diet

• T2DM– pioglitazone, metformin or liraglutide

• Hypertension – ΑΑΤ2

• Dyslipidaemia – statins

• Smoking cessation

Management of NAFLD by the HIV physician

Follow-up in HIV clinic of patients at low risk of fibrosis

-Annual LFTs

- >10% weight loss

- Treat components of metabolic syndrome

(hypertension, diabetes, hyperlipidaemia)

- In 3-5 years re-assess risk of advanced fibrosis

using non-invasive fibrosis assessment

Conclusions

• Transaminitis common in patients with HIV

• Viral hepatitis, alcohol, NAFLD, drug toxicity

• 10% of HIV patients might have NAFLD with fibrosis

• Only a minority needs hepatology referral

• Aggressive treatment of MS components

investigating general liver disease/transaminitis

Documents