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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
http://www.kingslivercourse.org/index_2016.html