Pregnancy & The Liver

Michael A. Heneghan MD, MMedSc, FRCPI.

Institute of Liver Studies,

King’s College Hospital, London.

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)

Pregnancy-related liver diseases

• Hyperemesis gravidarum

• Intrahepatic cholestasis of pregnancy

• Pre-Eclampsia and eclampsia

• HELLP syndrome

• Acute fatty liver of pregnancy

Pregnancy-unrelated liver diseases

Pre-existing liver diseases

Cirrhosis and portal hypertension

Hepatitis B and C

Autoimmune liver disease

Wilson’s disease

Liver diseases co-incident with pregnancy

• Viral hepatitis

• Biliary disease

• Budd-Chiari syndrome

• Liver transplantation

• Drug-hepatotoxicity

Physiological Changes of Pregnancy

Haemoglobin (118–148 g/L) ↓ from 2nd trimester

Platelets (150–450×109/L) None

Prothrombin time (10–12 s) None

Alkaline phosphatase (42–128 IU/L) ↑ (bone & placenta)

Albumin (35–50 g/L) ↓

ALT (0–70 IU/L) None

GGT (2–35 IU/L) None

Bilirubin (0–17 μmol/L) None

Alpha-fetoprotein (0–44 μg/L) ↑

Cholesterol (3·5–5 mmol/L) ↑

Joshi et al. Lancet 2010

Diagnoses in patients with abnormal LFTs

in Pregnancy

34%

15%

11%

2%

0%

5%

25%

8%

Pre-eclam

HELLP

OCP

AFLP

Infarct

Hyperem

Sepsis

Biliary

Ch’ng et al. Gut 2002

4377 Patients

15 months

142 with abnormal LFTs

206 possible diagnoses

Timing of Liver Dysfunction

Disease Week Range

Hyperem gravidarum & abn lfts 9 (6–14)

Pre-eclamptic liver dysfunction 37 (25–40)

HELLP syndrome 36 (25–38)

Obstetric cholestasis 35 (21–39)

AFLP 38 (32–38)

Ch’ng et al. Gut 2002

Hyperemesis Gravidarum

Protracted vomiting resulting in

dehydration

ketosis

weight loss (>5% body weight)

Excessive salivation

Elevation in AST/ALT IN 50%

Rarely > 200 iu/l

Bilirubin up to 4 x normal

Acute Fatty Liver of Pregnancy

Incidence 5:100,000 maternities

Mitochondrial cytopathy

Similar pathology to

Reye’s Syndrome

Tetracycline toxicity

Valproic acid/Fialuridine

Mortality 10% for mother

10-20% for foetus

Knight et al. Gut 2008

Swansea criteria for diagnosis of acute Fatty liver of

pregnancy

Vomiting

Abdominal pain

Polydipsia/polyuria

Encephalopathy

High bilirubin (>14 μmol/L)

Hypoglycaemia (<4 mmol/L)

High uric acid (>340 μmol/L)

Leucocytosis (>11×106/L)

High AST/ALT (>42 IU/L)

High ammonia (>47 μmol/L)

Renal impairment

(creatinine >150 μmol/L)

Coagulopathy (PT >14 s or

APTT >34 s)

Microvesicular steatosis on

liver biopsy

Ascites or bright liver on

ultrasound scan

6 or more of the above in absence of other explanation

Ch’ng CL et al. Gut 2002

Knight et al. Gut 2008

Oil Red Stain

Fat in peri-central

Hepatocytes

Clinical Presentation

Microvescicular fat in affected organs

Third trimester

More common in first or twin pregnancies

AST >10 x Normal

Up to 50% of patients pre-eclampsia

Uric acid may rise prior to symptoms

Acute Fatty Liver of Pregnancy

24 Women

15/24 had AFLP or HELLP syndrome (3rd trimester)

Clinical No Age (mo) LCHAD Tri Prot Death

Liver 16 4.6 +/- 1.5 16 0 5

Heart 3 0.4 +/- 0.2 0 3 2

Nmusc 2 18 +/- 2.8 0 2 0

MOF 3 7.6 +/- 9.6 3 0 1

Ibdah et al. NEJM1999;340:1723-31

Ibdah et al. NEJM 1999:340;1723-31

Biochemical pathway of fatty acid oxidation

Management

Multi-disciplinary care

Imaging Ultrasound or CT

Biopsy can be postponed until after delivery

No resolution until delivery

If mild, may have time to observe

May rapidly progress to acute liver failure

Vaginal delivery versus Caesarian section

Liver abnormalities may persist 3-4 wks

Supplement with FFP/Plt/Cryoprecipitate

Hypertension Related liver disease of

Pregnancy Pre-eclampsia 5-10% of all pregnancies

Major cause of maternal death

Incorporates a spectrum of disease

Pre-eclampsia

Eclampsia

Hepatic Infarction

Liver Rupture

HELLP syndrome (Weinstein 1982)

Hypertension > 30mmHg (systolic)

>15 mmHg (diastolic)

or >140/90 mmHg

Proteinuria (> 300mg/24 hrs) after 20 wks gestation

Oedema (No longer necessary)

2nd and 3rd trimesters

Risks: Pre-existing hypertension

Extremes of child bearing age

First or twin pregnancies

Sibai BM, Obstet Gynaecol 2003

LFT abnormalities in BP in pregnancy

LFTs reflect severity of hypertension

24% of patients with mild hypertension

>80 of patients with severe hypertension

AST/ALT

Similar to levels in acute hepatitis

Bilirubin usually N unless haemolysis or liver rupture

ATIII correlates inversely with outcome

80% of deaths related to CNS

20% related to liver complications

Fibrin deposition in sinusoids

HELLP Syndrome

Described by Pritchard in 1954

HELLP coined by Weinstein in 1982

Pathophysiology similar to pre-eclampsia

Hemolysis due to RBC damage in vascular intima

Caucasian

> 25 yo

< 36 weeks gestation

Hx of poor pregnancy outcome

HELLP Classification Tennessee system

• AST >70 IU/L

• LDH >600 IU/L

• Platelets <100×109/L

Mississippi system

AST >40 IU/L and LDH >600 IU/L and:

• Class I: platelets <50×109/L

• Class II: platelets 50–100×109/L

• Class III: platelets 100–150×109/L

Subcapsular Haematoma in HELLP

Joshi et al. Lancet 2010

Liver Rupture and infarction in HELLP

A

B

CA: Infarction

B: Haematoma

C: Rupture

Mortality

Maternal 60%

Foetal 60%

Management

Course unpredictable

General management

Early delivery key to success

AST/ALT resolve like ischaemic hepatitis

GGT may rise for 10 days post partum

Management of HELLP

Treat as severe eclamptic

Early delivery if > 34 weeks

33% perinatal mortality in one series

19.3% still births

2-3% maternal death rate

Low dose aspirin and steroids prolonged gestation for

5.5 weeks, but perinatal mortality remained high

(28%)

54 Patients King’s ICU 1997-2008

AFLP

n=18

HELLP

n=26

Median age at presentation 31 34

Week of gestation 36 35

Pre-eclampsia (%)* 11% 100%

Platelet count (150-450

cells/µL)*

115 51

Creatinine (45-120µmol/L) 209 159

CVVHF 47% 46%

AST (10-50 IU/L)* 78 2270

Bilirubin (3-20µmol/L)* 123 53

Lactate <2mg/dl 2 1.9

INR* 1.8 1.2

P <0.01

HELLP/Hypertensive liver diseaseAFLPIschemicVODCholestasisUnclear

33%

AFLP

59%

HELLP

Westbrook et al. Am J Transpl 2010

Liver Transplantation

Patients listed for

transplantation

Patients not listed for

transplantation

P value

AST (IU/L) 3040 (3000-3739) 1141 (16-775) 0.008

Lactate (mg/dl) 7.98 (2.6-12) 2.81 (0.7-18) 0.004

Platelet count

(cells/µL)

34 (21-54) 96 (15-225) 0.009

Creatinine (mg/dL) 2.26 (1.61 - 2.53) 1.76 (0.58-4.47) 0.34

CVVH 100% 46% 0.02

Bilirubin (mg/dl) 89 (66-208) 63(0.52-19.76) 0.17

INR 1.39 (1.09-3) 1.4 (0.84-4.3) 0.48

Encephalopathy 100% 15% 0.01

Length of ITU stay

(days)

31 (3-43) 5 (1-33) 0.01

Westbrook et al, Am J Transpl 2010

Intrahepatic Cholestasis of Pregnancy

Itch with elevated bile salts

20% of all jaundice in pregnancy

Up to 1% of all pregnancies in UK/USA

Scandinavia 1-1.5%

Araucanian Indians Chile 4.7-10%

Chilean twin pregnancies 20.9%

Rarely reported in black populations

50% of women with cholestasis on OCP develop cholestasis during pregnancy

Amino phospho-lipids

Bile acids

Drugs

HEPATOCYTE

Conjugated bilirubin

Glutathione

Phosphatidylcholine

Sitosterol

Cholestrol

BILE DUCT

Cl -

Cl -

HCO3-

Bicarbonate

ChlorideCFTR (ABCC7)

AE2 (SLC4A2)

MRP2

(ABCC2)

MDR3

(ABCB4)

ABCG5/8

FIC1

(ATP 8B1)

BSEP

(ABCB11)

MDR1

(ABCB1)

PFIC 1, BRIC 1Dubin-Johnson syndrome

Cystic Fibrosis

ICP,PFIC3, Drug

Induced Cholestasis

PFIC 2, BRIC2

Joshi et al. Lancet 2010

Genetics of Intrahepatic Cholestasis

Progressive Familial Intrahepatic Cholestasis PFIC

Multiple subtypes (High & Low GGT)

Mutation in Human multidrug resistance 3 (MDR3) gene ABCB4

MDR3 P-glycoprotein a phospholipid translocator

Involved in adding phospholipid to bile

Heterozygosity associated with disease

Other factors may also be important (Oestrogens)

ABCB11 & ABCB4 represent most contributory mutn in large cohort Dixon et al. Am J Gastro 2014;109:76-84

Joshi et al. Lancet 2010

Presentation and Diagnosis

Commonest 2nd and 3rd trimesters

Itch precedes jaundice by 2 weeks

Pain rare (if present, suggests other dx)

Conjugated hyperbilirubinaemia (6 x normal)

Alk phos (5-10 x normal)

bile acids (cholic, deoxycholic, chenodeoxycholic)

AST/ALT usually normal (never more than 10 x)

Intrahepatic Cholestasis of Pregnancy

Bile accumulation in canalicular spaces

Kremer AE et al. J Hepatol 2015;62:897-904

Autotaxin activity has a high accuracy to

diagnose ICP

Autotaxin (ATX) is a lysophospholipase D

essential for angiogenesis and neuronal

development.

ATX important in cellular motility,

proliferation,

lymphocyte homing [15].

Effects of ATX mediated by formation of

lysophosphatidic acid (LPA), which may

act via one of at least six different LPA

receptors [14] and [16]. ATX levels have

been reported to be increased during

pregnancy and correlate positively with

gestational age

Management

Anti-histamines

Ursodeoxycholic acid (10-15 mg/kg/day)

Urso returns bile acids towards normal

Induces BSEP/MDR3 Transporters

Improves hepatic clearance of disulphated progesterone metabolites

Does not lithocholic acid in meconium

reduced serum taurocholic & taurodeoxycholic acid concentrations

(Prevents conjugation of Cholic Acid with Taurine & Glycine)

Dexamethasone 12mg/day for 7 days, then 3 day taper

Glantz A et al. Hepatol 2008

Tribe RM et al. Am J Gastro 2010

Geenes V et al. Eur J Obs Gyn Repr Biol 2015;189:59-63

Rifampicin in the treatment of severe ICP

14 pregnancies (54%) serum bile

acids decreased after rifampicin.

In 10 pregnancies (38%),

there was a 50% reduction in serum bile acids.

Rifampicin 300-1200 mg day after week 30

Premature birth rate up to 50%

Intra-partum foetal distress 22%

Perinatal mortality rate up to 35%

Risk of poor foetal outcome if serum bile acids

>40umol/L

Onset of Labour should not go beyond term

High risk of recurrence

Emerging data in humans and mice that increased

prevalence of metabolic phenotype in offspringGlantz et al. Hepatology 2004

Papaclevolou et al. JCI 2014

Pre-existing liver disease and Pregnancy

Pregnancy reported, but fertility low

Cirrhosis and risk of bleeding

Increased blood volume & azygous vein flow

Pressure from gravid uterus

Counterbalanced by vasodilation

Treat bleeding as in non-pregnant state

Primary prophyllaxis (banding verus beta-blockers)

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

1.00.80.60.40.20.0

Se

ns

itiv

ity

1.0

0.8

0.6

0.4

0.2

0.0

UKELDMELD

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

Acute Viral Hepatitis

Always consider Hepatitis A, B, C, E, HSV…..

Hepatitis B

Infection transmitted at time of delivery

If acute hepatitis B, 50% of infants affected

For chronic carriers in UK (Transmission rate <5%)

In endemic areas (China, Transmission rates > 80%)

Lamivudine/Entecavir FDA Class C

Tenofovir FDA Class B

Treat patients with DNA > 106 after 32 weeks

HCV and Pregnancy

Risk of transmission 0-2%

Increased risk in HIV co-infected and Geno 1 & 3

Antibodies in infant present for up to 6/12

Pregnancy not influenced by HCV

Interferon & ribavirin contra-indicated in

pregnancy but not breastfeeding

Hepatitis E Virus in Pregnancy

Water borne

Epidemic related

Increased prevalence and poor prognosis

Mortality 17.3% in pregnancy

2.1% in non-pregnancy

2.8% in men

No transmission to foetus

Conclusions: Rules of thumb regarding

jaundice in Pregnancy

Interpret LFT’s in light of physiological changes

Always consider co-existent diseases

Balance need for histology with clinical need

Delay biopsy to post-partum if possible

Ultrasound no risk

CT based on clinical need (shield foetus)

MRI (fine but avoid Gadolinium)

ERCP performed safely in pregnancy