The liver in pregnancy

The liver in pregnancy:
hypertransaminasemia and beyond
Filomena Morisco
Università Federico II di Napoli
Filomena Morisco
Università Federico II di Napoli
La sottoscritta dichiara di non aver avuto negli ultimi 12
mesi conflitto d’interesse in relazione a questa
presentazione
e
che la presentazione non contiene discussione
di farmaci in studio o ad uso off-label
Physiological changes in pregnancy
Hemodinamic
Biochemical
Joshi D et al. Lancet 2010; 375: 594–605
Mufti AR et al Clin Liver Dis. 2012
Hay JE Hepatology 2008
3-5% of all pregnancies are
complicated by abnormal liver tests
These should be further investigated because
improve maternal and fetal outcome , with resultant
decreased morbidity and mortality
Classification of liver diseases in pregnancy
1. Pregnancy-related
2. Pregnancy-unrelated
- pre-existing
- coincindent with pregnancy
Pregnancy and liver diseases
Flow-Chart in Hipertransaminasemia
Hepatocellular Pattern
Cholestatic Pattern
Virus, AutoAc, Alchol, Drugs
Virus, AutoAc, Alchol, Drugs
Ultrasonography
Ultrasonography
If negative
pregnancy-related liver diseases
should be suspected
Pregnancy-related liver diseases
Trimester
Hypermesis
gravidarum
Intrahepatic
cholestasis of
pregnancy
Pre-eclampsia
and eclampsia
HELLP
Acute fatty liver
of pregnancy
Risk factors
Clinical features
0.3-2
↑ BMI, psychiatric
illness, diabetes,
multiple
pregnancies
intractable vomiting,
resulting in dehydration,
ketosis, and weight loss (≥5%)
0.1-1.5
contraceptive pill
and family history
Pruritus,
Ittero, diarrhoea and
steatorrhea
2,3
5-10
age (<16 or >45),
primiparity,
hypertension, family
history
Right upper abdominal pain,
headache, nausea-vomiting
2,3
5-10
(of women with
pre-eclampsia)
advanced maternal
age, multiparity,
white ethnic origin
Right upper abdominal pain,
nausea-vomiting, hypertension
and proteinuria in 85%
0.014-0.006
twin pregnancies,
nulliparity
varie from nausea and
abdominal pain to hepatic
encephalopathy and jaundice
1,2
1,2,3
2,3
Frequency
(%)
Pregnancy-related liver diseases
Pathogenesis
Maternal
complications
Fetal
complications
-
-
abnormal biliary transport
low risk
risk of chronic placental
insufficiency, prematutity.
Fetal distress
20-40%
defective placentation
hypertensive crises, renal
disfunction, edema,
liver damage
increased perinatal
morbidity and mortality
HELLP
Hemolytic anemia with
microangiopathic smear
Hemolytic anemia,
increased liver enzymes,
low platelets, DIC.
Mortality 1-25%
Perinatal infant
mortality 6-11%
Acute fatty liver of
pregnancy
abnormality in
mitochondrial b-oxidation
liver failure
prompt delivery
Hypermesis
gravidarum
Intrahepatic
cholestasis of
pregnancy
Pre-eclampsia
and eclampsia
abnormal gastric motility,
hormonal factors,
changes in the ANS
is essential
Characteristic timings and diagnostic laboratory features
of liver diseases related to pregnancy
Trimester
Diagnostics
HG
1,2
↑ bilirubin (x4), ↑ ALT/AST (x2-4)
ICP
1,2,3
↑ bilirubin (x6), ↑ ALT/AST (x6), ↑ bile acids
Pre-eclampsia
2,3
↑ bilirubin (x2-5), ↑ ALT/AST (x10-50), ↓ platelets
HELLP
2,3
↑ ALT/AST (x10-20), ↑ LDH, ↑ uric acid, ↓ platelets
AFLP
2,3
↑ bilirubin (x6-8), ↑ ALT/AST (x5-10, rarely >20)
HG: hypermesis gravidarum;
ICP; intrahepatic cholestasis of pregnancy;
AFLP: acute fatty liver of pregnancy
Lancet 2010; 375: 594–605
Pregnancy-unrelated liver diseases
Pre-existing liver diseases
1. Cirrhosis and portal hypertension, non cirrhotic portal hypertension
2. Hepatitis B and C
3. Autoimmune and cholestatic liver diseases
4. Metabolic diseases
5. OLTx
CIRROSI E GRAVIDANZA
Le gravidanze in pazienti con cirrosi sono rare.
Cirrosi avanzata: frequenti amenorrea, infertilità (20-66%) ed
aborti spontanei.
Non sembrano esistere il letteratura dati epidemiologici sulla ‘fertilita’ nelle
donne cirrotiche.
Lancet 2010; 375: 594–605
Schramm C, et al. Am J Gastroenterol 2006
Tiribelli C et al. Annals of Hepatology 2006
Pregnancy in liver cirrhosis with and without portal hypertension
References
Titles
Year of pubblication
Burslem R
Liver cirrhosis and pregnancy
1952
Whelton MJ
Pregnancy in patients with hepatic cirrhosis. Management
and outcome
1968
Borhanmanesh F
Pregnancy in patients with cirrhosis of the liver
1970
Steven MM
Pregnancy and liver disease
1981
Britton RC
Pregnancy and esophageal varices
1982
Pajor A
Pregnancy in liver cirrhosis. Assessment of maternal and fetal
risks in 11 patients and review of the management
1994
Aggarwal N
Pregnancy and cirrhosis
1999
Tan J
Pregnancy and cirrhosis
2008
Peitsidou P
Exacerbation of liver cirrhosis in pregnancy: a complex
emerging clinical situation
2008
Murthy SK
Impact of cirrhosis and liver trasplant on
during labor and delivery
2009
Shaheen AA
The outcomes of pregnancy in patients with cirrhosis :
a population-based study
maternal health
2010
Cirrhosis etiology in patients with pregnancy
339 pazienti osservate
alcoholic liver disease
CBP
24%
31%
HCV
HBV
7%
4%
autoimmune hepatitis
16%
18%
other
Shaheen, Liver International 2010
OUTCOME
CIRRHOSIS
NO CIRRHOSIS
( n= 339)
( n= 6625)
P-VALUE
UNADIUSTED OR
Unadjusted prevalence of pregnancy outcomes according to the presence of cirrhosis
(95% CI)
Obstetric outcomes (%)
Antepartum admission
33,6
10,8
0,0001
4.21 (3.32–5.34)
Caesarean delivery
41,8
28,3
0,0001
1.82 (1.39–2.39)
Assisted delivery
42,2
56,8
0,0001
0.56 (0.42–0.73)
Normal delivery
16,0
14,9
0,63
1.09 (0.76–1.57)
Multiple gestations
2,2
2,6
1
0.85 (0.35–2.09)
Premature rupture of membranes
6,2
5,0
0,44
1.26 (0.72–2.18)
Placenta previa
0,0
1,0
0,28
Placental abruption
7,1
1,7
0,0001
4.41 (2.55–7.60)
5,9
2,1
0,0001
2.88 (1.78–4.67)
38,7
10,3
0,0001
5.51 (4.16–7.30)
Intrauterine growth restriction
5,3
2,1
0,003
2.70 (1.47–4.96)
Fetal distress
6,2
4,7
0,34
1.34 (0.77–2.32)
Congenital anomaly
0,4
0,5
1
0.82 (0.11–6.03)
48,9
17,2
0,0001
4.62 (3.52–6.05)
Death
1,8
0,0
0,0001
Antepartum uterovaginal haemorrhage
6,8
1,5
0,0001
4.95 (3.10–7.91)
Postpartum uterovaginal haemorrhage
13,3
3,0
0,0001
5.00 (3.31–7.55)
Blood trasfusion
9,7
0,8
0,0001
13.63 (8.68–21.40)
Peripartum infection
2,1
1,4
0,34
1.51 (0.70–3.29)
14,5
9,4
0,003
1.63 (1.19–2.23)
6,8
3,9
0,02
1.78 (1.15–2.78)
0,03
0,0
1
Gestational diabetes
6,5
6,0
0,64
Venous thromboembolism
0,0
0,2
1
–
Fetal complications (%)
Death
Preterm
Any fetal complication
Maternal complications (%)
Hypertension during pregnancy
Preeclampsia
Eclampsia
Any maternal complication
–
–
1.10 (0.70–1.71)
–
50,7
24,2
0,0001
3.22 (2.59–4.02)
(Abdel
Aziz M, et al, Liver
International
J 2010)
(Abdel Aziz M. Shaheenet al, Liver International 2010)
Shaheen, Liver International 2010
No data available in Italian or European population
QUESTIONARIO: CIRROSI E GRAVIDANZA
1. Nella tua esperienza clinica ha mai osservato pazienti cirrotiche gravide?
Si
No
Se si, quante negli ultimi tre anni: N_
2. Quale era l’eziologia della cirrosi in tali casi?
Virale
N__
HBV___
Alcolica
N__
Autoimmune
N__
Dismetabolica
N__
HCV__
HDV___
3. Su specifica richiesta di una paziente cirrotica di intraprendere un gravidanza, cosa consigli ?
Di non affrontare una gravidanza in qualunque caso.
Dipende dallo stadio della cirrosi e/o dalla presenza di ipertensione portale. In
particolare :
Grado CHILD per sconsigliare la gravidanza……
Grado IP : presenza di varici ( grado ) __
gastropatia congestizia __
4. Nella tua esperienza hai avuto delle complicanze in questo tipo di pazienti?
Se si quale/i: ……
QUESTIONARIO: CIRROSI E GRAVIDANZA
18 risposte
QUESTIONARIO: CIRROSI E GRAVIDANZA
1. Nella tua esperienza clinica ha mai osservato pazienti
cirrotiche gravide ?
1.Si
2.No
Se si, quante negli ultimi tre anni: ……
No pazient : 8/18
Si : 10/18
For a total of 37 patients
2. Quale era l’eziologia della cirrosi in tali casi?
37 pazients
Viral hepatitis
The course of most hepatitis infections is unaltered during pregnancy
There is no evidence of increased risk of abnormal liver function
tests and pregnancy complications in women with well compensated
chronic viral liver disease
S. Sookoian. Annals of Hepatology 2006
It is possible to observe an increase in viral load and ALT in the later
stages of pregnancy and also a flare after delivery.
Paternoster DM, et al. Am J Gastroenterol 2001
Sangfelt P,et al. Scand J Infect Dis 2004
HCV and HBV positive mothers with excess weight gain also had a greater
risk of gestational diabetes.
Infants of HCV-positive mothers were more likely to be low birthweight and to
require neonatal intensive care unit.
Pergam S.A. et al. Obstetrics 2008
Lao T.T. J. Hepatol 2007
x
Alcohol
Stato dell’arte
Alcol and pregnacy
Increased incidence of fetal
malformations, miscarriage and /
or preterm births.
(It is not known whether this is
due to a direct effect of alcohol or
alcohol-related disorders such as
cirrhosis of the liver)
E.L. ABEL Alcohol & Alcoholism 1997
Alcohol liver disease
and pregnancy
No data available
NASH and pregnancy
AIH
Pregnancy course
HAI clinical course
► fetal mortality 19%
perinatal mortality 4%
► biochemical remission after
►preterm birth 17-20% vs 6%
► cytolytic flare during the
of the general population
conception in 73%
pregnancy from 4 to 33%
(21% by the 12th week);
► In 10-80% of cases flare up
Floreani A. et al, APT 2006
after delivery! Close monitoring!
Schramm C, et al. Am J Gastroenterol 2006
Heneghan MA, et al. Gut 2001
Heneghan MA, et al. J of Autoimmunity 2012
► maternal mortality and/or
OLT 9-11%
FDA classification
AZATHIOPRINE
D
PREDNISOLONE
C
UDCA
B
Primary Biliary Cirrhosis
Pregnancy course
► No fetal and maternal complication
PBC clinical course
► Biochemical remission during the
pregancy
► AMA fell within the normal
range
► Flare up after delivery:
Intensive Follow-up
Poupon R at al. Journal of Hepatology 2005
3. Su specifica richiesta di una paziente cirrotica di
gravidanza, cosa consigli ?
intraprendere una
1. Di non affrontare una gravidanza in qualunque caso.
2. Dipende dallo stadio della cirrosi e/o dalla presenza di ipertensione
portale. In particolare :
Grado CHILD per sconsigliare la gravidanza……
Grado IP : presenza di varici (grado)……..
gastropatia congestizia ………
altro ………………………………
77.7%
22.2%
Grado CHILD per sconsigliare la gravidanza:
28.5%
71.4%
Grado IP presenza di varici e gastropatia congestizia
35.7%
35.7%
21.4%
50%
35.7%
14.5%
State of the art
If cirrhosis is well compensated , pregnancy
usually, continues without complication for the
mother and the baby
Tiribelli C et al. Annals of Hepatology 2006
Stato dell’arte :
Decompensated cirrhosis
Very few cases of pregnancies in women with
advanced cirrhosis
Risk of maternal-fetal complications in 30-50%
of cases
-Perinatal mortality 11-18%
- Miscarriages, premature births and/or stillbirths:
15-20%
Lopez-Mendez E et al. Ann Hepatol 2006
Ipertensione portale con cirrosi
L’IP peggiora per l’incremento del volume e del flusso ematico e può
peggiorare anche per l’incremento delle resistenze vascolari venose
(compressione dell’utero sulla cava inferiore)
Complicanze materne severe quali:
insufficienza epatica acuta (morbilità 24%, mortalità 1/3 delle pazienti
entro 48h): OLT
emorragie digestiva (morbilità dal 20% al 75%, mortalità circa 20%
Rischio maggiore : sanguinamento da varici esofagee (20%45%). Più frequente durante il 2° trimestre ed il parto.
Si Raccomanda EGDs alle donne cirrotiche che hanno
programmato una gravidanza
Garcia-Tsao G. Portal hypertension. Curr Opin Gastroenterol 2006
Bosch J, et al. J Hepatol 2000
Incidenza di sanguinamento da varici
in donne gravide con ipertensione portale
Diagnosis
Pts
Cirrhosis
13
Cirrhosis
9
9
3
33
Borhanmanesh
Cirrhosis
92
117
24
21
Cheng
Cirrhosis
53*
83
13
16
Britton
22
32
14
44
Cheng
38
77
25
33
Britton
Non-cirrhotic
portal
Pregnancies Bleeding
n.
n. %
16
1
6
Author
Whelton
Hypertension
Non-cirrhotic
portal
hypertension
* included 20 without oesophageal varices
Scleroterapia endoscopica in gravidanza
Reporter
n
Salema BJ 1988
Augustine P 1989
1
2
3
29
32
22
2
2
1
4
22
1
5
6
7
8
9
10
11
12
30
21
24
25
20
24
37
38
4
1
2
1
2
2
1
1
Kochhar R 1990
Potzi P 1991
Pauzner D 1991
Iwase H 1994
age parity disease
LC
EHPH
ST
therapy
profilaxis
emergency
emergency
+ profilaxis
ST
emergency
+ profilaxis
EHPVO emergency
NCPF
profilaxis
NCPF
profilaxis
EHPVO emergency
ST
emergency
ST
profilaxis
LC
emergency
NCPF
profilaxis
times patient
baby
6
-
A
A
A
A
A
A
-
A
A
7
5
9
5
5
2
3
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
Ipertensione portale in gravidanza
bendaggio profilattico
Può essere indicato in caso di varici ad alto rischio
(non ci sono evidenze sufficienti)
propanololo
Può essere impiegato ma può dare significativi eventi
avversi (ritardo di crescita del feto, bradicardia del feto,
ipoglicemia).
terlipressina
Impiegata in casi aneddotici (rischio di ridotta
perfusione della placenta e distacco placentare).
TIPS
Indicato in caso estremi (radiazioni sul feto)
Mufti AR et al Clin Liver Dis. 2012
Hay JE Hepatology 2008
4. Nella tua esperienza hai avuto delle complicanze in
questo tipo di pazienti?
Se si quale/i: …….
7 episodi
37 pazienti
18,8%
Complicanze
82,8%
-
Calcolosi della via biliare
Distacco precoce placenta
3 emorragie digestive
Trombosi portale
Scompenso
Cirrhosis and pregnancy
The management of complications arising
during pregnancy is similar to that of
general population of cirrhotic patients
The optimal management of mother and fetus requires the
collaboration of the gynecologist,
gastroenterologist, nutritionist and surgeon