Autoimmune Hepatitis: Management in special

Populations

Michael A Heneghan, MD, MMedSc, FRCPI.

Institute of Liver Studies,

King’s College Hospital, London.

Special Populations

Pregnancy

Elderly

Cirrhosis

Ethnic populations

Amenorrhoea

• Prevalence • 60% on transplant waiting list

• 20% if cholestatic liver disease

• Problem of selection bias and reporting

Mass et al. Transplantation 1996

Age and Presentation

Gronbaek et al. J Hepatol 2014 Van Gerven Scand J Gastro 2014;49:1245-54

AIH may present in Pregnancy: Standard Induction Regimens

• Prednis(ol)one

• 0.5-1 mg/kg/day with reducing doses to maintainance of 5-7.5 mg/day

• Budesonide

• 9 mg/day with reducing doses to maintainance of 3 mg/day

• Restrict to patients who are non-cirrhotic

Addition of Azathioprine 1 mg/kg/day when bilirubin < 100 and following measurement of TPMP levels.

EASL Clinical Practice Guidelines: 2015

Normal Pregnancy

• Palmar erythema

• Spider naevi (60%)

• Increased blood volume and cardiac ouput

• Small oesophageal varices present in up to 50%

• Compression of IVC and azygous flow

• Decreased gallbladder motility

• lithogenicity of bile ( cholesterol synthesis)

Summary of biochemical changes

Parameter Alteration from non

pregnant state

Albumin/Total protein Decreased

Urea/Uric Acid/PCV Decreased

Alk phos Increase

(Bone/placenta)

Fibrinogen/Chol/Trigl Increased

Bilirubin Increased

Bile acids/AST/ALT/GGT No change

Alpha feto protein HCC/Spina bifida

Definitions • Low birth weight was defined as <2500 g.

• Small for gestational age (SGA) birth • Birth weight <2 SD below the mean for gestational age

according to the reference curve of estimated foetal growth.

• Gestational age at birth categorized into: • very preterm (<32 weeks),

• moderately preterm (32–36 weeks)

• term (37–44 weeks).

Swedish Patient Register (PAR) 2006-2011

Variable AIH N = 171 Non-AIH N = 576 642

Induction therapy 66 (38.6%) 3882 (0.7%)

No induction therapy 105 (61.4%) 572 760 (99.3%)

Maintenance therapy 68 (39.8%) 843 (0.1%)

No maintenance therapy 103 (60.2%) 575 799 (99.9%)

No treatment 82 (48.0%) 572 305 (99.2%)

Treatment 89 (52.0%) 4337 (0.8%)

Stokkeland et al Liver International 2015 In press

Swedish Patient Register (PAR) 2006-2011

Variable AIH N = 171 Non-AIH N = 576 642

Prednisolone 61 (35.7%) 3762 (0.7%)

Budesonide 8 (4.7%) 181 (0.0%)

Azathioprine 52 (30.4%) 641 (0.1%)

No azathioprine 119 (69.6%) 576 001 (99.9%)

Mercaptopurine 2 (1.2%) 52 (0.0%)

Tacrolimus 12 (7.0%) 37 (0.0%)

Cyclosporine 3 (1.8%) 84 (0.0%)

Mycophenolate 0 (0.0%) 10 (0.0%)

Methotrexate 0 (0.0%) 67 (0.0%)

Stokkeland et al Liver International 2015 In press

Pregnancy and birth outcomes for all women with AIH and population controls in Sweden

AIH N = 171 (%)

Non-AIH N = 576 642 (%)

Crude RR Adjusted RRa

Gestational diabetes

8 (4.7%) 6475 (1.1%) 4.17 (2.12–8.20)

4.35 (2.21–8.57)

Pre-eclampsia 5 (2.9%) 15 744 (2.7%) 1.07 (0.45–2.54)

0.99 (0.41–2.36)

Gestational hypertension

4 (2.3%) 6112 (1.1%) 2.21 (0.84–5.82)

2.23 (0.85–5.88)

Caesarean section

31 (18.1%) 96 622 (16.8%) 1.08 (0.79–1.49)

0.89 (0.62–1.29)

Apgar score at 5 min

7–10 166 (97.1%) 565 605 (98.1%)

Ref = 1 Ref = 1

Low birth weight (<2500 g)

17 (9.9%) 18 844 (3.3%) 3.04 (1.94–4.78)

2.51 (1.51–4.19)

Stokkeland et al Liver International 2015 In press

Immune tolerance in Pregnancy

H

L

0

5 0

1 0 0

1 5 0

2 0 0

2 5 0

2 0 1 3 2 0 1 4 2 0 1 5 2 0 1 6

A s p a r t a t e T r a n s a m i n a s e

IU

/L

L i c e n c e , K a t a r z y n a

A s p a r t a t e T r a n s a m i n a s e ( I U / L )

H

L

2 5

3 0

3 5

4 0

4 5

5 0

5 5

2 0 1 3 2 0 1 4 2 0 1 5 2 0 1 6

G l o b u l i n

g/

L

L i c e n c e , K a t a r z y n a

G l o b u l i n ( g / L )

Remission in pregnancy followed by post delivery flare

Immune Tolerance in Pregnancy Lessons from Multiple Sclerosis

• Classically attributed to shift to Th2 dominance

• Increased level of sex hormones

• Immunoregulatory factors in pregnancy include • tolerance-promoting signaling molecules

• pregnancy-specific serum proteins • HLA-G, CD200, Fas-ligand,

• alpha-fetoprotein, and indoleamine 2,3-dioxygenase.

• Finnish MS and Pregnancy Study Group (5000 genes) • Down regulation of HLA G region after delivery in MS

Rouass Friese et al. PNAS 2007

Other immunological findings in pregnancy and MS activity

• Increased CD56bright NK cells in late pregnancy • (Same prevalence is seen following interferon beta and

daclizumab treatment)

• Increased Tregs prevalence

• All reversed in the postpartum situation

• ? mechanisms for keeping autoreactive T cells in check are enhanced during pregnancy.

• CD56 bright NK cell population • HLA-G-positive and CD4+CD25high regulatory T cells.

• Mechanism is lost immediately after the delivery.

Airas L. Acta Neurol Scand. 2015

Pregnancy in AIH 1982-2009 81 self-reported in 51women

Live birth

rate

Termination Miscarriage Gestation

<37 weeks

Gestational

flare

Post-partum

flare

Any Flare

Prednisolone

monotherapy 20/27 (74%) 3/27 (11%) 4/27 (15%) 37 (28-40) 2/20 (10%) 7/20 (35%) 8/20 (40%)

Azathioprine

+/-

prednisolone

21/32 (65%) 6/32 (19%) 4/32 (13%) 38 (32-39) 0/32 (0%) 7/32 (21%) 7/32 (21%)

Any therapy

(prednisolone

, tacrolimus,

azathioprine)

42/61 (68%) 10/61 (16%) 8/61 (13%) 38 (28-40) 2/61 (3%) 15/61 (24%) 16/61 *

(26%)

No Therapy 17/20 (85%) 2/20 (10%) 0/20 (0%) 38 (27-39) 3/20 (15%) 8/20 (40%) 10/20 *

(50%)

Westbrook et al. J Autoimmunity 2012

Foetal outcomes

Live Birth rate Prematurity

<37 weeks

SCBU

Cirrhosis vs. no Cirrhosis

(n=33) (n=48)

19/33 vs. 40/48

p=0.02

5/19 vs. 7/40

p=0.43

4/19 vs. 2/40

p=0.07

Maternal disease remission > 1year

(n=52) vs.

no remission (n=29)

38/52 vs. 21/29

p=0.95

8/38 vs. 4/21

p=0.99

3/38 vs. 3/21

p=0.65

Therapy (n=61) vs. no therapy (n=20)

42/61 vs. 17/20

p=0.25

6/42 vs. 6/17

p=0.07

5/42 vs. 1/17

p=0.66

AIH gestational flare (n=5) vs. no

gestational flare (n=76)

4/5 vs. 55/76

p=0.99

2/4 vs. 10/55

p=0.18

2/4 vs. 4/55

p=0.047

Westbrook et al. J Autoimmunity 2012

Maternal outcomes Patient Cirrhosis Maternal complication Peak AST Foetal Outcome Maternal Outcome

1 No Died 28 weeks gestation 24 Died Death: sudden death at 25 weeks for

pulmonary hypertension secondary

to thromoembolism

2 Yes Post-partum flare with encephalopathy –

transplanted

217 Alive / healthy Death: 14-months post-partum, from poor

compliance on chronic rejection

3 Yes Post partum flare – very difficult to

control. Significant jaundice mild

ascites.

643 Alive / healthy Transplanted: 3 years post –partum

4 a

4 b

Yes

Yes

Post partum flare with decompensation

(ascites)

Ascites at 10 weeks, unable to control

therefore Termination of pregnancy

647

151

Born 28 weeks –

SCBU, Alive

healthy

NA

Transplanted: 3 years post partum of

second child

5 No Severe flare at 24 weeks, decompensated

with ascites

200 Baby delivered at 28

weeks –

cerebral palsy

Alive

Remains stable on immunosupression

6 Yes Variceal bleed at 31 weeks, controlled

endoscopically

30 Alive healthy, 34

weeks

Death: 7 months post partum secondary to

uncontrollable variceal bleed.

7 Yes Severe Post Partum Haemorrhage Born 32 weeks

needed SCBU

Death: Variceal bleed 1 year post partum,

refused blood transfusion

8 Yes Uneventful pregnancy 28 Healthy Deterioration 12 months post partum, died

whilst having LT assessment

Autoantibodies may affect outcome

• 42 pregnancies in 22 AIH patients

• 26% rate of adverse pregnancy outcomes

• Medical explanation elucidated in 4 of 11

• 7 unexplained adverse outcomes • associated with antibodies to SLA/LP (odds ratio 51; p < 0.003)

• and Ro/SSA (odds ratio 27; p < 0.02). Of 35 live births,

• 30 children developed normally over a mean observation period of nearly 5 yr.

• Eleven of these had been exposed to azathioprine in utero.

• The rate of serious maternal complications was 9% and a high rate (52%) of postpartum flares was noted.

Schramm et al. Am J Gastro 2006

US FDA: Categories of Safety

• A Controlled studies show no risk

• B No evidence of risk in humans • Animal findings may show risk (but humans no) Or if no

human studies, animal studies neg

• C Risk cannot be ruled out • Human studies lacking and animal studies are positive for risk

or lacking

• D Positive evidence of risk • Investigational or post-marketing data show risk

• X Contra-indicated

Alternative therapy in AIH: Considerations for Pregnancy

• Mycophenolate

• Tacrolimus • Levels of 5-8

• Cyclosporine • Levels 100-150

• Sirolimus

• Side effect profile

• Age

• Renal Impairment

• Diabetes

• Compliance

• Cytopaenia

• Combinations acceptable

Categorisation of commonly used immunosuppressants

• Prednis(ol)one Class B

• Ciclosporine Class C

• Tacrolimus Class C

• Azathioprine Class D

• Mycophenolate Class D

• Sirolimus Class C

• Monoclonals Class C

Heneghan et al. J Hepatol 2008

Summary of pregnancy outcomes with MMF

• 13 newborns exposed to MMF

• Microtia (12) with auditory canal atresia (9)

• Cleft lip and palate (6)

• Micrognathia (4); hypertelorism (4); ocular coloboma (3);

• Short fingers (2) and hypoplastic nails (2)

• Cardiac defects (Aortic arch or conotruncal defects)

• (EMFO tetrada: Ear, Mouth, Fingers, Ocular/Organ malformation)

Merlob et al. Reprod Toxicol 2009 Anderka et al. Am J Med Genet 2009

Microtia

Micrognathia

Abnormal Physiology in Cirrhosis

• Men

• Testosterone

• LH and FSH

• Blunting of Pituitary responses

• Oestrogens

• Prolactin

• Women

• LH and FSH

• Oestrogens

• Blunting of Pituitary responses

Ongoing alcohol use in ESLD also impacts in men and Women

Van Thiel et al. Hepatology 1981

62 Pregnancies in 29 Women with cirrhosis

• Cirrhosis on biopsy 41/62 (66%)

• Radiology and lab parameters 21/62 (34%).

• Median age at conception was 29 years (range 16-40 years).

• Three patients conceived using IVF

• 21/62 (34%) of pregnancies were unplanned.

• 2 twin pregnancies,(women who had not undergone IVF.

AIH

Alc

Viral

Bil Atr

Genetic

Vascular

Other

Westbrook et al Clin Gastro Hepatol 2011

Demographics at Conception

• Median MELD 7 (range 6-17),

• Median Meld-Na 9 (6-17),

• Median UKELD 44 (range 36-53)

• Median CP score was 5 (5-8).

• 11 pregnancies occurred in 8 women who had a previous decompensation

• 3 encephalopathy,

• 5 ascites

• 3 variceal bleed

Childs A

Childs B

Missing

Westbrook et al Clin Gastro Hepatol 2011

62 Conceptions in Cirrhosis

Westbrook et al Clin Gastro Hepatol 2011

Prognostic Scoring and Foetal Outcome

MELD MELD-Na UKELD CP

Live birth v

miscarriage

or still birth

7(6-15) v 7(6-16)

P=0.88

8(6-15) v 9(8-17)

p=0.45

43(36-50) v 44(40-51)

P=0.45

5(5-8) v 6(5-8)

p=0.29

Live birth v

termination

7(6-15) v 8(6-15)

p=0.64

9(6-14) v 9(7-17)

p=0.28

43(36-50) v 45(37-51)

p=0.46

6(5-8) v 6(5-8)

p=0.24

Gestational week

<37 v > 37

8(6-15) v 6(6-15)

p=0.01

11(6-15) v 9(6-13)

p=0.01

47 (41-50) v 42(39-47)

P=0.01

7(5-7) v 7(5-8)

p=0.02

Caesarean v

vaginal

delivery

7(6-15) v 6(6-15)

p=0.31

9(7-15) v 8(6-13)

p=0.91

43 (36-50) v 42 (20-48)

P=0.29

6(5-8) v 6(5-7)

p=0.86

Neonatal ICU v

ward

10(7-15) v 6(6-15)

p=0.02

7(6-14) vs. 9(6-15)

p= 0.28

48(42-50) v 42(36-48)

P=0.02

7(5-8) v 6(5-7)

p=0.08

Westbrook et al Clin Gastro Hepatol 2011

Maternal Deaths

Age at

conception

MELD UKELD Live birth Significant pregnancy

related complication

Interval from birth

to death (months)

Transplanted

16 7 43 Yes Yes 16 Yes – 2/12

post partum

34 15 47 Yes No 28 No

33 14 47 Yes Yes 6 No

25 10 48 Yes Yes At delivery No

Westbrook et al Clin Gastro Hepatol 2011

Predicting outcome at conception in Cirrhotic patients who become pregnant

• UKELD Score

(48,(43-48) v 43, (36-51), p=0.02)

• MELD score

(10,(7-14) v 7,(6-17), p=0.01)

• Associated with an increased risk a significant liver related adverse event for the mother.

• Child Pugh score

(7, (5-8) vs. 5, (5-8) p=0.2).

1 - Specificity

1.0 0.8 0.6 0.4 0.2 0.0

Se

nsit

ivit

y

1.0

0.8

0.6

0.4

0.2

0.0

UKELD MELD

ROC Curve

AU ROC

MELD = 0.798 (95% CI 0.661 – 0.935)

UKELD = 0.801 (95% CI 0.950 – 0.953)

Westbrook et al Clin Gastro Hepatol 2011

Platelet count as a predictor of varices on endoscopy in the 2nd trimester

• 3 patients had variceal bleed

• All had varices prior to conception

• 1 had prior bleed

• MELD (p=0.06) and UKELD (p=0.08) associated with a trend towards variceal bleeding.

• Women with varices on screening endoscopy more likely to deliver by cesarean when compared with women without (13/18 vs. 4/15, p=0.02).

• No patient with varices had significant bleeding following CS from the presence of abdominal wall varices.

Westbrook et al Clin Gastro Hepatol 2011

Breastfeeding

Azathioprine treatment during lactation

AP&T 2008;28:1209-13.

Plasma concentration of 6MP Concentration of 6MP in Milk

Absolute number of children with various infectious diseases. n = 15 in each group; AZA =

children breastfed by mothers under maintenance AZA treatment, no AZA = children breastfed

by mothers without maintenance AZA treatment; median observation period in AZA = 3.3 years,

in no AZA = 4.7 years.

Sieglinde Angelberger et al. J Crohns Colitis 2011;5:95-100

© 2010 European Crohn's and Colitis Organisation

Absolute number of children hospitalised due to infections. n = 15 in each group; AZA = children

breastfed by mothers under maintenance AZA. Treatment, no AZA = children breastfed by

mothers without maintenance AZA. Treatment; median observation period in AZA = 3.3 years, in

no AZA = 4.7 years.

Sieglinde Angelberger et al. J Crohns Colitis 2011;5:95-100

© 2010 European Crohn's and Colitis Organisation

Considerations of Age and Cirrhosis and Ethnicity in AIH

Feld et al. Hepatology 2005

Age and Prevalence of Symptoms

Prevalence of Cirrhosis or advanced fibrosis at

diagnosis according to age

Ngu et al. Hepatol 2013:57:2399-2406

Presence of Cirrhosis at baseline and

Survival

Feld et al. Hepatology 2005

Survival According to Age and features

associated with Death/Tx

Incomplete

normalization of

ALT at 6 months.

Low albumin at

diagnosis

Age at presentation

≤20 years

>60 years

Ngu et al. Hepatol 2013:57:2399-2406

Risk factors for HCC development in AIH

Features At

Presentation

Hazard Ratio (CI) p

Jaundice

Variceal Bleed

Cirrhotic

0.26 (0.052-1.32)

8.41 (1.75-40.47)

8.01 (1.64-39.07)

0.105

0.008

0.001

Yeoman et al. Hepatology 2008

10.9/1000 yrs follow-up

6.2% of all patients

12.3% of cirrhotic

Male = Female

After 9yrs of cirrhosis

Mortality & risk of malignancy in AILD

Ngu et al Hepatology 2012;56:622-629.

AIH in non-Caucasian populations

Publication

Country

No of Patients Ethnicity Clinical

Observations

Zolfino 2003

UK

12 6 African

5 Asian

↓ Responsiveness

↑ Transplant

Falalla 2010

Saudi Arabia

33 Middle East ↓ Responsiveness

↑ Cirrhosis

Choudhuri 2005

India

38 Indian ↑ Cirrhosis

All type 1 AIH

Toda 1997

Japan

317 Japanese ↑ Responsiveness

↓ Cirrhosis

Peng 2014

Northern China

83 Chinese 50% Definite AIH

Minuk 2008

Canada

33 First Nation ↑ Fibrosis

↑ Inflammation

Take Home Messages

Pregnancy possible

Considerations around Immunosuppression

Considerations around cirrhosis

Counselling pre-conception

Cirrhosis as a special population

Age

Ethnicity

Screening

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