Liver Disease in Pregnancy None UCSF Obstetrics & Gynecology - - PowerPoint PPT Presentation

10/20/2017 1

Liver Disease in Pregnancy

UCSF Obstetrics & Gynecology Update October 19th, 2017

Monika Sarkar, MD, MAS Division of GI/Hepatology

Disclosures

• None

Outline

Liver disease in pregnancy- what an OBGYN should know…

• Chronic liver disease
• Coincidental to pregnancy
• Unique to pregnancy

Case 1:

• 30 yo Asian F, G0P1 at 8 weeks gestation
• HBsAg screen is positive
• Liver tests are normal. She is not aware of

having HBV.

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What do you typically do with + HBsAg screen?

• A. Order DNA level alone
• B. Order DNA level + liver tests
• C. Order DNA level + liver tests.

Refer to GI/liver if abnormal.

• D. Order DNA level + liver tests.

Refer to GI/liver regardless of results.

Order DNA level alone Order DNA level + liver tests Order DNA level + liver te... Order DNA level + liver te...

1% 39% 50% 10%

Case 2:

• 30 yo Asian F G0P1 at 18 weeks gestation
• Prenatal HbsAg negative
• Went to ED with abdominal pain
• Liver tests elevated and told to follow-up in clinic
• Pain resolved with maalox, but liver tests

unchanged on follow-up 2 weeks later

Tbili 0.6 Alk Phos 180 ALT 75 AST 90

WHAT DO YOU DO?

albumin 3.5

Expected Changes With Pregnancy

Laboratory

AST, ALT No change Total bilirubin No change or  Alkaline phosphatase  Albumin  Alpha fetoprotein  INR No change

Bacq et al, Hepatology 1996; Prati et al, Annals of Intern Med 2002

*ALT of 19IU/ml is the upper limit of normal for women Elevations in transaminases, bilirubin, and INR are abnormal in pregnancy and should be investigated

Liver diseases in pregnancy

• 3 main categories:

– Chronic liver disease – Diseases coincidental to pregnancy – Diseases unique to pregnancy

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Liver diseases in pregnancy

• 3 main categories:

– Chronic liver disease – Diseases coincidental to pregnancy – Diseases unique to pregnancy

Chronic liver diseases For OB to consider:

• Hepatitis B
• Hepatitis C

For GI/hepatologist to consider:

• Autoimmune hepatitis
• Primary biliary

cholangitis

• Wilson’s disease
• Hemachromotosis

Hepatitis B in Pregnancy

Impact of Immigration on US HBV Prevalence

HBsAg Prevalence[2] ≥ 8% (high) 2% to 7% (intermediate) < 2% (low)

Immigration Numbers by Continent: 2000-2009[1]

~ 3.6 million Asians ~ 875,000 South Americans ~ 804,000 Africans

• 1. US Department of Homeland Security 2009. 2. Weinbaum CM, et al. MMWR Recomm Rep. 2008

Ordering and Interpreting HBV and Related Labs

Lab Test What It’s Assessing

HBsAg Active infection (chronic or acute) HBcIgM Acute infection HBcIgG Exposure (cleared or chronic infxn) HBsAb Immunity (from cleared infxn or vaccine) HBeAg/HBeAb Immune state of active HBV that guides treatment thresholds HBV DNA Level of viremia ALT HBV disease activity (liver inflammation)

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Case 1. What to order if pre-natal HBsAg screen positive

Lab Test What It’s Assessing

HBsAg Active infection (chronic or acute) HBcIgM Acute infection HBcIgG Exposure (cleared or chronic infxn) HBsAb Immunity (from cleared infxn or vaccine) HBeAg/HBeAb Immune state of active HBV that guides treatment thresholds HBV DNA Level of viremia ALT HBV disease activity (liver inflammation)

*False positive HBsAg uncommon in healthy patients, unless within 2-3 weeks of HBV vaccination

Sarkar M & Terrault N, Hepatology 2014 VVVJJJJJJJJJJJJJJJ NNNNNNNN JJJJJ VVVJJJJJJJJJJJJJJJ NNNNNNNN JJJJJ

Breastfeeding on antivirals is not contraindicated (2017 AASLD Guidelines)

iiiiiiiiiiiiiiiiiiiiiiiiiii

Mother to Child Transmission (MTCT)

• f HBV
• MTCT is reduced with passive/active immunization
• Fails in 10-30% of infants of highly viremic moms
• Third trimester antiviral therapy reduces MTCT to 0-

3% (rare transmission via placenta)

Tan et al. J Viral Hep 2016; Pan et al. NEJM 2016

HBV Treatment During Pregnancy

Antiviral Pregnancy Category Resistance Risk of birth defects Rate of maternal-to- child transmission

Lamivudine C

 No increased risk 3%

Telbivudine B

 0%

Tenofovir B

None reported 0%

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Which of the following are established risk factors for vertical transmission?

• A. High HBV viral load

B. Breastfeeding C. Vaginal delivery

• D. High viral load and

breastfeeding

H i g h H B V v i r a l l

• a

d B r e a s t f e e d i n g V a g i n a l d e l i v e r y H i g h v i r a l l

• a

d a n d b r e a s t f e e d i n g

56% 38% 2% 4%

Pregnancy & Hepatitis B

• 95% of adults clear acute HBV
• But 80-90% of infants with vertical transmission

develop chronic HBV

• Perinatal transmission accounts for 50% of the

global burden of chronic HBV

• Transmission from exposure to maternal blood/

at delivery, and less commonly via placenta

Pregnancy & Hepatitis B

• High HBV DNA levels is most important risk

factor for MTCT

• Insufficient data to advise on the mode of

delivery

• Breastfeeding doesn’t increase perinatal

transmission

Li et al, J Clinical Gastro 2017; AASLD Guidelines 2017; EASL Guidelines 2016

Case 2. What HBV-specific tests to order if woman with abnormal liver tests?

Lab Test What It’s Assessing

HBsAg Active infection (chronic or acute) HBcIgM Acute infection HBcIgG Exposure (cleared or chronic infxn) HBsAb Immunity (from cleared infxn or vaccine) HBeAg/HBeAb Immune state of active HBV that guides treatment thresholds HBV DNA Level of viremia AST, ALT HBV disease activity (liver inflammation)

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Refer ALL HBsAg Positive Women to GI/Hepatology

WHY?

• To assess whether MOM’s liver needs treatment

now

• To assess whether BABY needs to be protected

from vertical transmission

• To discuss drug safety in pregnancy
• To counsel women on natural history of HBV and

liver cancer risk, need for long-term monitoring, post delivery HBV management, and family screening…this is a chronic medical condition

Hepatitis C in Pregnancy Hepatitis C & Pregnancy

• 364% increase in HCV

infection related to injection drug use among persons aged < 30 in southeast U.S. (KY, TN, WV, VA)

• ~ 4% of pregnant

women in U.S. are chronically infected

• Rising number of reproductive-aged

women with HCV, and babies receiving HCV testing

Hughes et al, Am J Obstet Gynecol 2017 Zibbell et al,. CDC MMWR Morb Mortal Wkly Rep 2015 Koneru et al, CDC MMWR Morb Mortal Wkly Rep 2016

Which of the following is not a risk factor for HCV vertical transmission?

• A. High HCV viral load

B. Breastfeeding C. Prolonged rupture of membranes

• D. Invasive fetal monitoring

High HCV viral load Breastfeeding Prolonged rupture of m... Invasive fetal monitoring

1% 9% 19% 71%

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Pregnancy & Hepatitis C

• Overall, pregnancy has little impact on HCV

activity

• Mom may be slightly increased risk of gestational

diabetes and premature rupture of membranes

• Vertical transmission of HCV:

– Transient HCV perinatal infection in ~ 15%  chronic infection in 3-5%

• Increased risk of vertical transmission with HIV-

HCV co-infection, high viral load, prolonged rupture of membranes >6 hrs

Sookoian S et al, Ann Hepatol. 2006 Kanninen et al. Hepatology. 2015

Factors Linked with Risk of MTCT- Mode of Delivery

Variable Studies # women Strength of Evidence Summary of Findings Elective c-section vs. vaginal delivery 4 cohort studies, N=2080 Low No difference, but trends in

• pposite directions in

highest quality studies C-section vs. vaginal delivery 11 cohort studies, N=2308 Moderate No association

Rac M et al, Obstet Gynecol Clin North Am 2014 Cottrell E et al, Ann Intern Med 2013

Factors Linked with Risk of MTCT

• Breastfeeding does not increase MTCT, though avoid if

nipple bleeding

Variable Studies # women Strength of Evidence Summary of Findings Invasive fetal monitoring vs none 3 cohort studies, N=928 Insufficient Inconsistent but one good quality study OR=6.7 (95% CI 1.1-36) Prolonged rupture of membranes vs. none 2 cohort studies, N=245 Low Yes with >6 hrs having OR=9.3 (95% CI 1.5-180)

Rac M et al, Obstet Gynecol Clin North Am 2014 Cottrell E et al, Ann Intern Med 2013

Factors Linked with Risk of MTCT

• Delivery related

Variable Studies # women Strength of Evidence Summary of Findings Elective c-section vs. vaginal delivery 4 cohort studies, N=2080 Low No difference, but trends in

• pposite directions in

highest quality studies C-section vs. vaginal delivery 11 cohort studies, N=2308 Moderate No association Invasive fetal monitoring vs none 3 cohort studies, N=928 Insufficient Inconsistent but one good quality study OR=6.7 (95% CI 1.1-36) Prolonged rupture of membranes vs. none 2 cohort studies, N=245 Low Yes with >6 hrs having OR=9.3 (95% CI 1.5-180)

Cottrell E, Ann Intern Med 2013;158(2):109-13 Rac M, Obstet Gynecol Clin North Am ;41(4):573-92

Society for Maternal and Fetal Medicine 2017

• HCV status should not guide mode of delivery
• Avoid episiotomy
• Avoid prolonged rupture of membranes
• If invasive fetal monitoring, inform women of

increased HCV transmission risk

• Breastfeeding should be encouraged

10/20/2017 8

Hepatitis C in Pregnancy

• Who to screen:

Risk based

Hughes et al, Am J Obstet Gynecol 2017

Hepatitis C in Pregnancy

• Who to screen:

Risk based

Hughes et al, Am J Obstet Gynecol 2017

Hepatitis C in Pregnancy

• Who to screen:

Risk based

Hughes et al, Am J Obstet Gynecol 2017

Hepatitis C in Pregnancy

• Who to screen:

Risk based

Hughes et al, Am J Obstet Gynecol 2017

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Hepatitis C in Pregnancy

• Who to screen:

Risk based

Hepatitis C in Pregnancy

• Who to screen:

Risk based

Hughes et al, Am J Obstet Gynecol 2017

Hepatitis C in Pregnancy

• Who to screen:

Risk based

Hughes et al, Am J Obstet Gynecol 2017

Hepatitis C in Pregnancy

• Who to screen:

Risk based (for now)

• How to screen:

HCV Antibody

• What if positive?:

Check HCV RNA

• What if RNA positive?:
• Refer to GI/hepatology

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Hepatitis C Treatment & Pregnancy

• High efficacy of current oral therapies

– Cure achieved in 95-100% of patients – Short treatment duration (8-12 wks) – Tolerable side effect profile

• Reproductive aged women are prioritized for

treatment- most insurance covers women that want to get pregnant

IDSA-AASLD HCV Guidance 2016

HCV Treatment in Pregnancy

• Most have favorable outcomes in animal studies
• Too limited data in humans to prescribe currently
• Phase I trial of 12 weeks of ledipisvir and

sofosbuvir during 2nd and 3rd trimester completes enrollment in September 2018…stay tuned!

Kanninen T, Hepatology 2015

Liver diseases in pregnancy

• 3 main categories:

– Chronic liver disease – Diseases coincidental to pregnancy – Diseases unique to pregnancy

Diseases coincidental to pregnancy

• Gallstones
• Drug-induced liver

injury

• Budd-Chiari syndrome
• Herpes (HSV) hepatitis
• Hepatitis A

Coincidental to Pregnancy Causes

Cause Comment Appropriate test Gallstones Pregnancy risk Ultrasound Drug-induced History, especially antibiotic use livertox.gov Budd-Chiari = hepatic vein clot Pregnancy risk Ultrasound with doppler Hepatitis A GI symptoms HAV IgM [HSV] – to consider in right clinical setting Flu-like sx, rash (40%), fevers, cytopenias HSV PCR Alcohol History, AST:ALT> 2:1 Tox screen Nonalcoholic fatty liver disease (NAFLD) 1/3 Americans, growing epidemic in adolescents, common in PCOS Ultrasound

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Coincidental to Pregnancy Causes

Cause Comment Appropriate test Gallstones Pregnancy risk Ultrasound Drug-induced History, especially antibiotic use livertox.gov Budd-Chiari = hepatic vein clot Pregnancy risk Ultrasound with doppler Hepatitis A GI symptoms HAV IgM [HSV] – to consider in right clinical setting Flu-like sx, rash (40%), fevers, cytopenias HSV PCR Alcohol History, AST:ALT> 2:1 Tox screen Nonalcoholic fatty liver disease (NAFLD) 1/3 Americans, growing epidemic in adolescents, common in PCOS Ultrasound

Coincidental to Pregnancy Causes

Cause Comment Appropriate test Gallstones Pregnancy risk Ultrasound Drug-induced History, especially antibiotic use livertox.gov Budd-Chiari = hepatic vein clot Pregnancy risk Ultrasound with doppler Hepatitis A GI symptoms HAV IgM [HSV] – to consider in right clinical setting Flu-like sx, rash (40%), fevers, cytopenias HSV PCR Alcohol History, AST:ALT> 2:1 Tox screen Nonalcoholic fatty liver disease (NAFLD) 1/3 Americans, growing epidemic in adolescents, common in PCOS Ultrasound

Coincidental to Pregnancy Causes

Cause Comment Appropriate test Gallstones Pregnancy risk Ultrasound Drug-induced History, especially antibiotic use livertox.gov Budd-Chiari = hepatic vein clot Pregnancy risk Ultrasound with doppler Hepatitis A GI symptoms HAV IgM [HSV] – to consider in right clinical setting Flu-like sx, rash (40%), fevers, cytopenias HSV PCR Alcohol History, AST:ALT> 2:1 Tox screen Nonalcoholic fatty liver disease (NAFLD) 1/3 Americans, growing epidemic in adolescents, common in PCOS Ultrasound

Coincidental to Pregnancy Causes

Cause Comment Appropriate test Gallstones Pregnancy risk Ultrasound Drug-induced History, especially antibiotic use livertox.gov Budd-Chiari = hepatic vein clot Pregnancy risk Ultrasound with doppler Hepatitis A GI symptoms HAV IgM [HSV] – to consider in right clinical setting Flu-like sx, rash (40%), fevers, cytopenias HSV IgM or PCR Alcohol History, AST:ALT> 2:1 Tox screen Nonalcoholic fatty liver disease (NAFLD) 1/3 Americans, growing epidemic in adolescents, common in PCOS Ultrasound

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Coincidental to Pregnancy Causes

Cause Comment Appropriate test Gallstones Pregnancy risk Ultrasound Drug-induced History, especially antibiotic use livertox.gov Budd-Chiari = hepatic vein clot Pregnancy risk Ultrasound with doppler Hepatitis A GI symptoms HAV IgM [HSV] – to consider in right clinical setting Flu-like sx, rash (40%), fevers, cytopenias HSV PCR Alcohol History, AST:ALT> 2:1 Tox screen Nonalcoholic fatty liver disease (NAFLD) 1/3 Americans, growing epidemic in adolescents, common in PCOS Ultrasound

Coincidental to Pregnancy Causes

Cause Comment Appropriate test Gallstones Pregnancy risk Ultrasound Drug-induced History, especially antibiotic use livertox.gov Budd-Chiari = hepatic vein clot Pregnancy risk Ultrasound with doppler Hepatitis A GI symptoms HAV IgM [HSV] – to consider in right clinical setting Flu-like sx, rash (40%), fevers, cytopenias HSV PCR Alcohol History, AST:ALT> 2:1 Tox screen Nonalcoholic fatty liver disease (NAFLD) 1/3 Americans, growing epidemic in adolescents Ultrasound

Nonalcoholic Fatty Liver Disease (NAFLD)

• Most common chronic liver disease in the U.S.
• Leading cause of cirrhosis and liver cancer
• Age of onset getting younger, epidemic in adolescents
• Risk factors: metabolic co-morbidities and PCOS
• You will see pregnant women with fatty liver on

ultrasound

• Still need to exclude other causes of abnormal liver

tests, and refer to hepatology

Trimester-dependent Liver Conditions in Pregnancy

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1st trimester

• Hyperemesis

gravidarum

Tran et al. Am J of Gastro 2016

Trimester-dependent Liver Conditions in Pregnancy

KEY POINTS:

• Only pregnancy-specific cause in1st trim.
• 60-70% have elevated liver enzymes
• AST>ALT, but values usually <500IU/ml
• Must still exclude other causes
• Liver tests normalize by week 20
• No risk of chronic liver damage or failure

1st trimester 2nd trimester

• Hyperemesis

gravidarum

• Intrahepatic cholestasis of

pregnancy

Tran et al. Am J of Gastro 2016

Trimester-dependent Liver Conditions in Pregnancy

Intrahepatic Cholestasis of Pregnancy

• 0.3-5% of pregnancies (more common among

Latinos)

• Clinical presentation: Pruritus, particularly of

palms and soles

– Elevated alk phos with normal ggt – Elevated ALT: may be > 1,000 – Jaundice in < ¼ women, follows onset of pruritus – Elevated serum bile acids (BA) (>10 umol/L) – Elevated INR (from vitamin K deficiency)

Geenes et al, Hepatology 2014; Bacq et al, Hepatology 1997

Intrahepatic Cholestasis of Pregnancy

Management:

• Ursodiol 13-15 mg/kg/day for pruritus until delivery,

75% improve liver tests and fetal outcomes

• Weekly bile acids, as > 40umol/L increases IUFD
• Spontaneous resolution within 6 weeks of delivery

Geenes et al, Hepatology 2014; Bacq et al, Gastro 2012; Glantz et al, Hepatology 2004

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1st trimester 2nd trimester

• Hyperemesis

gravidarum

• Intrahepatic cholestasis of

pregnancy

• Pre/eclampsia & HELLP

Tran et al. Am J of Gastro 2016

Trimester-dependent Liver Conditions in Pregnancy

• Hepatic hematoma

rupture

KEY POINTS:

• 30% of pre-eclampsia have

elevated liver enzymes, usually <500

1st trimester 2nd trimester 3rd trimester

Tran et al. Am J of Gastro 2016

Trimester-dependent Liver Conditions in Pregnancy

• Hyperemesis

gravidarum

• Intrahepatic cholestasis of

pregnancy

• Pre/eclampsia & HELLP
• Acute fatty liver of

pregnancy

• Hepatic hematoma

rupture

Acute fatty liver of pregnancy (AFLP)

• 3rd trimester-early post-partum
• RARE!
• Risk factors: multiples, low maternal

BMI, male fetus

• Homozygous LCHAD deficient
• ffspring spill unmetabolized LC fatty

acids in maternal circulation  microvesicular steatosis

• Management: Immediate delivery, LT

rarely needed

Greenstein et al, Gastro 1994; Ding et al, Gynecol Obstet Invest 2015; Fesenmeier et al, Am J Obstet Gynecol 2005

1st trimester 2nd trimester 3rd trimester

• Hyperemesis gravidarum
• Intrahepatic cholestasis of pregnancy
• Acute fatty liver of

pregnancy

• Pre/eclampsia & HELLP
• Viral hepatitis, gallstones, drug-induced hepatitis, Budd-Chiari
• Hepatic hematoma

rupture

Trimester-dependent Liver Conditions in Pregnancy

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Initial Work-up of Abnormal Liver Tests

• Chronic conditions: HCV Ab, HBsAg, HBcIgM, HBcIgG
• Coincidental to pregnancy: US with doppler, HAV

IgM, [HSV IgM or HSV PCR]

• Pregnancy-specific: bile acid level, cbc, urine protein

Thank you!

• Questions…

Monika Sarkar, MD, MAS Division of GI/Heptology & Liver Transplant monika.sarkar@ucsf.edu