The Pregnant Patient and the Hepatic Disease

Berrin Günaydın, MD, PhDGazi University School of Medicine

Department of Anesthesiology, Ankara, Turkey

www.berringunaydin.com

PREGNANCY ANDSERIOUS MEDICAL PROBLEMS

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OUTLINEO

verv

iew

Physiologic changes related to liver during pregnancy

Abnormalities associated with liver disease

Classification of liver diseases in pregnancy

Pregnant Cases with liver diseases

General Considerations

Anesthetic Management

Neuraxial & General Anesthesia

Blood volume and cardiac output rise by 35%–50%

AP levels rise 3 – 4 fold due to placental production & increased maternal burn turnover (3rd trimester)

Coagulation factors (VII, VIII, IX & X) & serum fibrinogen levels increase (create a hypercoagulable state)

Gallbladder contractilityHemoglobin and uric acid levelsAlbumin, total serum protein, & Antithrombin III concentrations

Physiologic and Biochemical Changes

Hepatic flow is UNALTERED resulting in the 35% decline in the proportion of cardiac output delivered to the liver

Coagulation abnormalities associated with liver disease

Lab

ora

tory

in

vest

igati

on

Impaired synthesis of coagulation factors (I, II, V, VII, & X)

Cholestasis leads to malabsorption of vitamin K as a cofactor in the synthesis of factors II, VII, IX & X

Presumptive evidences, determinants or indicators for liver disease

Hepatomegaly

Serum bilirubin and

bile acid levels

AST & ALT*

NO liver weight increase + NO change in AST, ALT, GGT, Bilirubin levels & Prothrombin

time

CLASSIFICATION

LIVER DISEASES

Most unique to pregnancy

(INDUCED by pregnancy)

Either Coincidental or Preexisting

( NOT INDUCED by pregnancy)

I.Liver diseases unique to pregnancy

INTRAHEPATIC CHOLESTASIS OF PREGNANCY (ICP)

<4%

(2nd or 3rd trimester)

PREECLAMPSIA/ECLAMPSIA

2-8%

(3rd trimester)

HELLP SYNDROME

0.1-0.6%

(3rd trimester)

ACUTE FATTY LIVER OF PREGNANCY (AFLP)

1:10 000 – 1:15 000

(3rd trimester)

HYPEREMESIS GRAVIDARUM <2%(1st trimester)

Kamimura et al. Advances in understanding and treating liver disease during pregnancy

WJG 2015;7:5183-190

ICP

PREVALANCE

0.1-1.5% (WJG 2013)

0.6% in Gazi University

DIAGNOSİS

Elevated Bile Acid (BA) levels

CLINICAL PRESENTATION

Pruritis, Jaundice (50%)

MANAGEMENT

-Deliver at 38 weeks (if mild)

-Consider early delivery (at 36 weeks) in severe cases (fetal

distress/death, jaundice, unbearable maternal pruritis)

PROGNOSIS

Disappears rapidly after delivery

Rarely progresses to cirrhosis

ICP (Serum Bile Acid Levels)

Mild 10-39 μmol/mL

Moderate 40-99 μmol/mL

Severe >100 μmol/mL

Risk of preterm deliveryMeconium staining of amniotic fluid

Fetal bradycardiaNonreassuring FHR

Fetal loss

ICP

Treatment

Outcome

• Delivery at fetal maturity• Ursodeoxycholic acid

• Maternal outcome is generally GOOD• (No increased risk in maternal death rate)• BUT fetus is at increased risk in moderate and severe cases

B

Steatorrhea because of fat malabsorption

may adversely affect vitamin K absorption

Impair

COAGULATION????

WHY are patients with ICP important?

Retrospective cohort study from Northwestern University

319 parturients with or without coagulation tests were reviewed

-Lack of abnormal coagulation studies even with liver enzyme

elevations >5 times normal

NO neuraxial hematoma

-2.4% PPH after vaginal delivery

6.3% PPH after CS

1st outcome

abnormal hemostasis

(PT> 14.5 sec, INR >1.2)

2nd outcome postpartum

hemorrhage (PPH)

DeLeon et al. The incidence ocoagulapathy in pregnant patients With ICP : should we delay or avoid neuraxial anesthesia. J Clin Anesth 2014

ICP of 2 parturients in Gazi UniversityCase 1 (MC) Case 2 (SK)

Age (year) 29 34

BMI (kg/m2) 30 31

Gestational age (week) 37 373

Parity Parous Parous

Delivery Mode - Anesthesia Repeat CS-General Repeat CS-General

Serum acid bile level (μmol/mL)

20.6 14.3

AST (U/L) (0-40) 70 61

ALT (U/L)(0-40) 147 117

AP (U/L)(30-120) 317 195

Platelet count (/mL) (130-400) 194 X10-3 152 X10-3

PT% (70-140) 107 131

PT-INR (0.8-1.25) 0.97 0.86

PT (sec)(10-14) 11.2 10

APTT (sec)(18-26) 24.9 26

Induction & maintenance of anesthesia Other medications

General Anesthesia in 2 patients with mild ICP

-After delivery of the babyOxytocin 20 IU in 1000 ml RL-Sugammadex 2 mg/kg (reversal of neuromuscular block-Mutltimodal analgesia

After preoxygenation RSI with IV propofol 2 mg/kg & rocuronium 0.5 mg/kg followed by TIVA

AFLP is an uncommon reversble peripartum liver failure

PATHOGENESIS

impaired beta oxidation of fatty acids in the hepatic mitochondria of the fetus. Defect due to genetic mutation of LC3OHCoAD causes this condition in the mother

MANAGEMENT

Early diagnosis, prompt delivery and intensive supportive treatment by close monitoring

Consider plasmapheresis & liver transplantation in severe cases

CLINICAL PRESENTATION

Fatigue, vomiting , headache, hypoglycemia, lactic acidosis

PROGNOSISHigh maternal (23%) &

fetal (18%) mortality

ANESTHESIA Anesthesia selection should be individualized Gynecol Obstet Invest 2013

Kamimura et al. (WJG) 2015

AFLPHALLMARK LABORATORY FINDINGS

-Prolonged prothrombin time

-Depressed antitrombin III

-Elevated liver enzymes

Persistent DIC, elevated direct bilirubin, creatinine, AP, leukocytosis in almost all cases

-Profound hypoglycemia (secondary to impaired gylcogeneolysis)

SIMILARITIES BETWEEN PREECLAMPSIA/ECLAMPSIA

-Occurs near term, nulliparity, twin

-Hepatic involvement might occur with preeclampsia in the form of HELLP syndrome

PERIOPERATIVE ANESTHETIC CARE

PPH is anticipated by establishing adequate IV access with readily available cross matched

blood and blood products

ANESTHESIA General anesthesia with RSI in case of severe coagulopathy

Gynecol Obstet Invest 2013

Kamimura et al. (WJG) 2015

Zhou, Zhang, Ge S. Retrospective analysis of acute fatty liver of pregnancy (AFLP) 28 cases. Gynecol Obstet Invest 2013;76(2):83-9

Symptoms, signs, laboratory findings, clinical courses, perioperative and anesthetic managements and maternal and neonatal outcomes of 28 cases from Shanghai Public Health Clinical Center were retrospectively reviewed over 5 years

2 maternal deaths (7.1%) without fetal deathsCSs were performed under neuraxial (n=16) and

general anesthesia (n=12) with RSI

A

B

C

D

E

G

Viral Hepatitis

Incidence in pregnancy

1:1000

1:500

RNA DNA

HYBRID

Specific Diagnosis of Chronic Hepatitis B (CHB)

Liver function tests

Serologic tests

HBsAg

HBeAg

HBc-Ig M

HBc-Ig G

Anti-HBs

Anti-HBe

HBV DNA

Most important independent risk factor in pregnancy

Hepatitis C Hepatitis B Hepatitis A Characteristics

Non A non B hepatitis

Serum hepatitis Infectious hepatitis Older name

RNA 30-60 nm DNA 42 nm RNA 27 nm Virus type & size

30 – 160 days 30 – 180 days 15 – 50 days Incubation period

Parentral sporadic Parentral/body fluid Fecal – oral Transmission

uncommon common Not observed Vertical transmission

Hepatitis C antibodyRNA by PCR

HBs Ag, HBs Ab (IgM & IgG types)HBe Ag & Ab, Hepatitis B virus DNA

Hepatitis A antibody (IgM & IgG types)

Serologic diagnosis

HIV co- infected Prodrome or HBe Ag Positive

Prodrome Maximum infectivity

50 – 85% 5 – 10% None Carrier state

Asymptomatic to severe relapsing

Asymptomatic to fulminant

Asymptomatic to fulminant

Acute clinical forms

Chronic persistent Chronic active Cirrhosis

Chronic persistent Chronic active Cirrhosis

None Chronic clinical forms of hepatitis

Hepatitis B (HB) Marker Test Results

Marker Acute Infection

Chronic Infection

Past Infection

HBsAg (HB surface antigen) + + -

Anti-HBs (Anti-HB surface antigen antibody) - - +

HB e Ag (HB e Antigen) Early+Then-

± -

Anti-Hbe (Anti-Hbe antigen antibody) Early-Then+

± +

Anti-HBc IgM (Anti-HB core immunoglobulin M antibody)

+ - -

Anti-HBc IgG (Anti-HB core immunoglobulin G antibody)

+ + +

Hepatitis B virus DNA (HBV DNA) Early+Then-

± -

Alanine aminotransferase (ALT) Increased markedly

Increased

mild/moderate

Normal

CHB in 3 parturients in Gazi University

Case 1 (DOY) Case 2 (FB) Case 3 (FS)

Age (year) BMI (kg/m2)

41 33

24 20

40 years,35

Gestational age (week) 381 35 265

Parity 2 3 3

Delivery Mode & IndicationAnesthesia typeDrugs

Repeat CS under spinal &

spinal

NSVD

Tenofovir

Repeat CS under general,

epidural &spinal

AST (U/L) - 32.4 24.2

ALT (U/L) - 37.1 27.9

Alkalen Phosphatase (U/L) - 201 77

Platelet count 168X10-3 179.5X10-3 188X10-3

PT% - 140 75

PT-INR - 0.82 1.19

PT (sec) - 10 13.9

APTT (sec) - 26 26.4

Case 2 (FB)

She has been using tenofovir (viread) tb (245 mg) once daily since 1st trimester

HBV DNA 13 wks 170 000 000 copy/mL 22 wks 570 000 copy/ mL 35 wks 600 000 copy/mL 39 wks 63 000 copy/mL

B

Intrathecal12 mg hyperbaric bupivacaine+10 μg fentanyl +150 μg morphine

Spinal Anesthesia for Case 1 and 3

Chronic Hepatitis C in 5 parturients in Gazi University

Cases 1 2 3 4 5

HBsAg (s/CO) - - - - -

Anti-HBs (mIU/mL)

P552 P205.67 - - -

Anti-HBc Total - - - - -

Anti-HCV (s/CO) + (1.36) ?POZ0.96 ?POZ1.36 ?Positive +(5.79)

Anti-HIV (Combo) s-CO)

- - - - -

HCV RNA (copy/mL)

- - - - -

Anti-HEV - - - - -

Anti-HDV - - - - -

Anti-HAV Total - + + + +

Anti-HAV IgM + - - - -

Chronic Hepatitis C in 5 parturients in Gazi University

Cases 1 2 3 4 5

Age (year) 38 32 38 35 40

Gestation (week) G:P

38 38 264:2

373:2

405:2

Delivery ModeAnesthesia

RepeatCSSpinal

RepeatCSSpinal

PretermRepeatCSGeneral

CPD-CSSpinal

NSVD

AST (U/L) (0-40)ALT (U/L) (0-40)AP (U/L)(53-141)

203441

121266

2517

147

46

Platelet count/UL 205X10-3 261X10-3 96X10-3 228X10-3 228X10-3

PT% - - 120 - -

PT-INR - - 0.91 - -

PT (sec) - - 10.5 - -

APTT (sec) - - 20.5 - -

General considerations regarding liver

disease in pregnancy

General Anesthesia

Neuraxial Anesthesia

Anesthetic management of liver dieases in the pregnant patient

Spinal

Epidural

Neuraxial Anesthesia

or

Smaller doses of local

anesthetics

Rapid onset of sympathetic

block

Spinal Anesthesia

Controlled onset of

sympathetic block

Epidural Anesthesia

Accumulation should be

considered after repeated doses &

continuous infusions

Neuraxial Anesthesia

Local Anesthetics

Lidocaine Ropivacaine Bupivacaine

Amide typeEster type

Chloroprocaine

t1/2elim 3 fold

Vd increases

Pseudocholin esterase

production decreases

Clearance is less in end stage liver

disease than normal

α1 acid GP is synthesized even in end stageliver disease

General AnesthesiaIndications

• Coagulopathy• Obstetric

Hemorrhage• Severe fetal

compromise• Altered

mental status

Monitoring• Standart (ECG,

HR, BP, SpO2, ETCO2)

• Large IV access

• Arterial and central lines for patients with acites & CV compromise

IV Induction Drugs

• Propofol has a short half life even in patients with decompansated cirrhosis

• Thiopental dose is reduced due to decreased Vd

Safety of halogenated agents

Halothane is

avoidedIsoflurane

Sevoflurane Desflurane

Liver cell injury is not possible with Xenon anesthesia (Bovill J 2008)

(Xenon: A solution for anesthesia in liver disease Hepat Mont 2012)

Intu

bat

ion

Awake intubation for bleeding esophageal varices

Nasogastric suction is contraindicated

Atraumatic tracheal intubation can be provided by profound neuromuscular blockade

Reversal of muscular blockade

Rocuronium has a prolonged effect which can be completely antagonized by sugammadex

General Anesthesia

Safety of neuromuscular blocking (NMB) drugs

Pancuronium is avoided

(because of the decline

in HBF)

Vecuronium

Atracurium Succynylcholine for RSI

Using NMB monitoring is beneficial with any NMB drug

Hepat Mon 2014

Part I. Halothane vs Isoflurane on the 3rd Postop. day

Res Med 1997

Part II. Halothane vs Isoflurane on the 3rd Postanesthesia day

Res Med 1997

General Anesthesia P

ost

op

era

tiv

e A

nalg

esi

aParacetamol???

Acute toxic dose is 7.5 gram

NSAI???

Dose is reduced

Ibuprophen, etodolac, diclophenac are safeOpoioids & Non-opioids???

(opioids are administered cautiously –advanced liver disease may lead to hepatic encephalopathy)

TAP Block

Metabolism of Acetaminophen

N-acetylparabenzoquinoneimine Acetaminophen glutathione conjugate

Acetaminophen glucuronide

urine

OH

NH C

O

CH3

NH C

O

CH3

O SO3-

NC

O

CH3

O

NC

O

CH3

OH

SG

Acetaminophen

Acetaminophen sulfate

Phenosulfotransferase

NH C

O

CH3

O C6H8O6-

UDP-glucuronosyl-transferase

50%

40%

<5%

5-15%CytoP450

Glutathione (GSH)

Acetaminophen Over dose!

NAPQI- N-acetylparabenzoquinoneimine

Acetaminophen glucuronide

urine

OH

NH C

O

CH3

NH C

O

CH3

O SO3-

NC

O

CH3

O

Acetaminophen

Acetaminophen sulfate

Phenosulfotransferase

NH C

O

CH3

O C6H8O6-

UDP-glucuronosyl-transferase

50%

40%

<5%

50%CytoP450

Glutathione (GSH)

Saturated

Liver and renal injury occursby binding to cellular proteins

NC

O

CH3

OH

SG

Anesthetic Management of the parturient with liver disease

Pregnant Woman with inactive viral hepatitis ormild ICP uncomplicated liver transplantation may be managed in the

same manner as a healthy parturient (assuming that hepatic synthetic and metabolic function are intact)(coagulopathy should be excluded or corrected before regional anesthesia)

In contrast parturient with acute hepatic failure might be challenging

30 yr-old nulliparous, long term Hepatitis B virus (HBV) carrierAdmitted at 37 weeks’ gestation with diarrhea (persisted 11 days)Laboratory results suggested acute exacerbation of CHB

Total bilirubin 17.9 mg/dLAST 1104 IU/mLINR 2.95HBs Ag +Anti-HBc 97.1%HBe Ag 299.9HBV DNA 350 cpmHBc Ig M -Anti HAV -Anti HAV Ig M -

3 days after admission because of spontaneous rupture of membranes and late FHR decelarations, emergency CS was performed under general anesthesia (droperidol+fentanyl in 50% N2O) with RSI (vecuronium) due to coagulopathy

10 units of FFP was infused & INR improved to 1.752844 g male baby was born with 7 & 9 Apgar scoresBaby was vaccinated to minimize the the risk of

vertical transmission of HBV infection

• 8 hours after surgery multi organ failure (MOF) developed rapidly including worsening of coagulopathy, pulmonary insufficiency, anuria, & coma

• CT revealed brain edema• EEG revealed diffuse teta waves without laterality• Total bilirubin level was 14.5 mg/dL and INR was 3.07• Despite intensive life support, patient died on the

postoperative 3rd day because of irreversble MOF

KEY POINTS

ALL pregnants should be screened for HBV

ALL newborns should be vaccinated against HBV

Prevent transmission of viral hepatitis to the health care team

GOALS CONCERNS

Poor prognosis or outcome for mother and baby if not recognized, diagnosed and evaluated

Effects of local and general anesthetic drugs on the liver

Effects of anesthesia type on hepatic blood flow & oxygenation

Prompt delivery (AFLP) with appropriate anesthetic management

Prevention of further hepatic injury by optimizing hepatic blood flow & oxygenation

GOALS CONCERNS

Poor prognosis or

outcome for mother and

baby if not recognized,

diagnosed and evaluated

correctly

Effects of local and

general anesthetic drugs

on the liver

Effects of anesthesia type

on hepatic blood flow &

oxygenation

Prompt delivery

particularly for disease

induced by pregnancy

(AFLP)

Prevention of further hepatic

injury by optimizing hepatic

blood flow & oxygenation

Use of neuraxial anesthesia and/or analgesia may not necessarily be delayed in parturients with isolated ICP

General anesthesia with RSI may be the best choice for AFLP patients with severe coagulopathy

Take home messages

Whenever possible neuraxial anesthesia is recommended after excluding or correcting coagulapathy

Optimal care of parturients with liver diseases requires MULTIDISCIPLINARY APPROACH

Hepatic blood flow and oxygenation should be maintained

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