Hepatobiliary Disease in Pregnancy

8/3/2019 Hepatobiliary Disease in Pregnancy

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Hepatobiliary Disease inHepatobiliary Disease in

PregnancyPregnancyTannys VauseTannys Vause

Academic Half DayAcademic Half DayMay 11, 2005May 11, 2005


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ObjectivesObjectives

Review normal liver function during pregnancyReview normal liver function during pregnancy

Discuss etiology, diagnosis and management ofDiscuss etiology, diagnosis and management of

acute fatty liver in pregnancyacute fatty liver in pregnancy

Discuss etiology, diagnosis and management ofDiscuss etiology, diagnosis and management of

intrahepatic cholestasis in pregnancyintrahepatic cholestasis in pregnancy

Review differential diagnosis for liver dysfunctionReview differential diagnosis for liver dysfunction

in pregnancyin pregnancy


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Approach to Liver Disease inApproach to Liver Disease in

PregnancyPregnancy Liver disease occurs in approximately 3%Liver disease occurs in approximately 3%

of deliveriesof deliveries

There are 2 liver diseases which areThere are 2 liver diseases which arespecific to pregnancyspecific to pregnancy

Acute fatty liver of pregnancyAcute fatty liver of pregnancy

Intrahepatic cholestasis of pregnancyIntrahepatic cholestasis of pregnancy

Liver dysfunction may also be seen inLiver dysfunction may also be seen inpatients with hepatitis and as a result ofpatients with hepatitis and as a result ofHELLP syndromeHELLP syndrome


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The Liver in Normal PregnancyThe Liver in Normal Pregnancy

Physical ExaminationPhysical Examination

SkinSkin -- palmar erythema and spider angiomaspalmar erythema and spider angiomas

are usually signs of chronic liver disease, but canare usually signs of chronic liver disease, but can

be normal findings in pregnancybe normal findings in pregnancy

secondary to high estrogen levelssecondary to high estrogen levels

LiverLiver

In the third trimester, the enlarging uterusIn the third trimester, the enlarging uterusdisplaces the liver superiorly and posteriorlydisplaces the liver superiorly and posteriorly

a palpable liver is abnormala palpable liver is abnormal


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HemodynamicsHemodynamics

cardiac output increases until the secondcardiac output increases until the second

trimester, then plateaus until deliverytrimester, then plateaus until delivery

absolute hepatic blood flow remainsabsolute hepatic blood flow remains

unchanged, as the percentage of cardiacunchanged, as the percentage of cardiac

output to the liver decreasesoutput to the liver decreases


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Liver function testsLiver function tests

AlbuminAlbumin

decreases secondary to hemodilutiondecreases secondary to hemodilution

Alkaline PhosphataseAlkaline Phosphatase

22--4 times normal in the third trimester4 times normal in the third trimester

increases secondary to placental ALPincreases secondary to placental ALP

Alkaline phosphatase may remain elevated for upAlkaline phosphatase may remain elevated for upto six weeks after deliveryto six weeks after delivery


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ALTALT

slightly higher in second trimester but still withinslightly higher in second trimester but still within

normal rangenormal range

ASTAST

unchangedunchanged

LDHLDH unchangedunchanged


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BilirubinBilirubin

Total and Free are lower throughout pregnancyTotal and Free are lower throughout pregnancy

Conjugated is lower during T2 and T3Conjugated is lower during T2 and T3

Bile acidsBile acids

unchangedunchanged

Coagulation FactorsCoagulation Factors PTT/INRPTT/INR -- unchangedunchanged

FibrinogenFibrinogen -- slightly elevatedslightly elevated


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Serum lipidsSerum lipids

Total cholesterol and triglyceridesTotal cholesterol and triglycerides

increase markedly during pregnancyincrease markedly during pregnancy


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UltrasoundUltrasound

biliary tract is usually normalbiliary tract is usually normal

PathologyPathology standard and ultrastructural examination ofstandard and ultrastructural examination of

the liver during normal pregnancy reveals nothe liver during normal pregnancy reveals no

specific abnormalitiesspecific abnormalities


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Acute Fatty Liver inAcute Fatty Liver in

PregnancyPregnancy


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Acute Fatty Liver of PregnancyAcute Fatty Liver of Pregnancy

Affects 1 in 6,692Affects 1 in 6,692 15,900 pregnancies15,900 pregnancies

In 1975, maternal survival was 72%, withIn 1975, maternal survival was 72%, withneonatal survival slightly lowerneonatal survival slightly lower

maternal mortality of 18%maternal mortality of 18% fetal mortality of 23%fetal mortality of 23%

improved outcomes have been attributed toimproved outcomes have been attributed toearly recognition of the disorder followed byearly recognition of the disorder followed by

prompt deliveryprompt delivery association with nulliparity, twin gestations, maleassociation with nulliparity, twin gestations, male

fetus and prefetus and pre--eclampsia or eclampsiaeclampsia or eclampsia


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EtiologyEtiology

Remains unknownRemains unknown

Similar histologically and clinically toSimilar histologically and clinically to

Reyes syndrome and Jamaican vomitingReyes syndrome and Jamaican vomitingsicknesssickness

These diseases are characterized byThese diseases are characterized by

microvesicular fatty infiltration ofmicrovesicular fatty infiltration of

hepatocytes without inflammation orhepatocytes without inflammation or

necrosisnecrosis


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EtiologyEtiology

Presentation is also similar to thosePresentation is also similar to those

people with metabolic defects in thepeople with metabolic defects in the

intramitochondrialintramitochondrial FF--oxidation pathwayoxidation pathway

Also occurs more frequently in womenAlso occurs more frequently in women

whose fetuses have a deficiency of longwhose fetuses have a deficiency of long

chain 3chain 3--hydroxyacylhydroxyacyl--CoA (enzymeCoA (enzyme

deficiency is similar to that in Reyes)deficiency is similar to that in Reyes)


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Clinical ManifestationsClinical Manifestations

Generally occurs in the second half ofGenerally occurs in the second half of

pregnancypregnancy

Mean gestational age is 34.5 weeksMean gestational age is 34.5 weeks(range 28(range 28--39 weeks)39 weeks)


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The duration of prodromal symptoms andThe duration of prodromal symptoms and

signs is variablesigns is variable

Often presents with nausea and vomiting,O

ften presents with nausea and vomiting,followed by severe abdominal pain andfollowed by severe abdominal pain and

headacheheadache


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The right upper quadrant is generallyThe right upper quadrant is generallytender, but the liver is not enlarged totender, but the liver is not enlarged topalpationpalpation

Within a few days, jaundice appears, andWithin a few days, jaundice appears, andthe patient becomes somnolent andthe patient becomes somnolent andeventually comatoseeventually comatose

Hematemesis and spontaneous bleedingHematemesis and spontaneous bleedingresult when the patient developsresult when the patient developshypoprothrombinemia and DIChypoprothrombinemia and DIC


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Oliguria, metabolic acidosis, andOliguria, metabolic acidosis, and

eventually anuria occur in approximatelyeventually anuria occur in approximately

50 percent of patients50 percent of patients

Diabetes insipidus may also accompanyDiabetes insipidus may also accompany

the disease, but may not manifest itselfthe disease, but may not manifest itself

until postpartumuntil postpartum

These patients may respond to dDAVPThese patients may respond to dDAVP

after deliveryafter delivery


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If the disease is allowed to progress, laborIf the disease is allowed to progress, labor

begins and the patient delivers a stillbornbegins and the patient delivers a stillborn

infantinfant

Uteroplacental insufficiency may be theUteroplacental insufficiency may be the

cause of fetal distress and fetal death incause of fetal distress and fetal death in

these patients.these patients.


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During the immediate postpartum period,During the immediate postpartum period,

the mother becomes febrile, comatosethe mother becomes febrile, comatose

and, without therapy, dies within a fewand, without therapy, dies within a few

daysdays

DIC, renal failure, profound hypoglycemia,DIC, renal failure, profound hypoglycemia,

and occasionally pancreatitis are the mostand occasionally pancreatitis are the most

often cited immediate causes of deathoften cited immediate causes of death


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Lab InvestigationsLab Investigations

Serum transaminasesSerum transaminases

elevated, but usually below 500 IU/Lelevated, but usually below 500 IU/L

Coagulation factorsCoagulation factors

INR increases before PTT because of vitaminINR increases before PTT because of vitaminK dependent clotting factors made in the liverK dependent clotting factors made in the liver

fibrinogen decreases, Dfibrinogen decreases, D--dimer increases withdimer increases withDICDIC

BilirubinBilirubin

mildly elevatedmildly elevated


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Serum ammoniaSerum ammonia -- elevatedelevated

Serum glucoseSerum glucose -- decreaseddecreased


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Further InvestigationsFurther Investigations

Liver BiopsyLiver Biopsy

liver biopsy not advised for diagnosis in mostliver biopsy not advised for diagnosis in most

cases due to coagulopathycases due to coagulopathy

if biopsy is necessary, FFP can beif biopsy is necessary, FFP can be

administered to correct coagulpathyadministered to correct coagulpathy

pericentral microvesicular fatty changepericentral microvesicular fatty change

minimal inflammatory cell infiltration or hepaticminimal inflammatory cell infiltration or hepaticnecrosisnecrosis

periportal areas are usually preservedperiportal areas are usually preserved


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HistologyHistology


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Further InvestigationsFurther Investigations

CTCT

diagnosis can occasionally made using CT,diagnosis can occasionally made using CT,

however there are a large number of falsehowever there are a large number of false--

negativesnegatives

decreased attenuation over the liver isdecreased attenuation over the liver is

consistent with fatty infiltrationconsistent with fatty infiltration

MRIMRI fatty infiltration can be visualized with T2fatty infiltration can be visualized with T2--

weighted imagesweighted images


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ManagementManagement

Once diagnosis is made, delivery shouldOnce diagnosis is made, delivery should

be carried out as soon as possiblebe carried out as soon as possible

Need to ensure patient is stableNeed to ensure patient is stable invasive hemodynamic monitoringinvasive hemodynamic monitoring

correct coagscorrect coags

IV fluids containing adequate glucoseIV fluids containing adequate glucose

if ammonia levels are elevated, treat withif ammonia levels are elevated, treat with

lactuloselactulose


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Vaginal delivery is preferableVaginal delivery is preferable

May use cervical ripening agents if neededMay use cervical ripening agents if needed

C/S can be performed if it appears vaginalC/S can be performed if it appears vaginaldelivery cannot be carried out in a timelydelivery cannot be carried out in a timely

fashion or if patient is deterioratingfashion or if patient is deteriorating


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If coagulopathy is corrected, regionalIf coagulopathy is corrected, regional

anesthesia is preferable because it allowsanesthesia is preferable because it allows

adequate assessment of LOCadequate assessment of LOC

GA should be avoided if possible becauseGA should be avoided if possible because

of hepatotoxicity of some anestheticof hepatotoxicity of some anesthetic

agentsagents

Narcotic doses need to be adjusted asNarcotic doses need to be adjusted as

metabolized by the livermetabolized by the liver


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If delivery is carried out before hepaticIf delivery is carried out before hepatic

encephalopathy and renal failure develop,encephalopathy and renal failure develop,

patients recover rapidlypatients recover rapidly


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Recurrence RiskRecurrence Risk

Little risk of recurrence in subsequentLittle risk of recurrence in subsequent

pregnanciespregnancies


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Intrahepatic CholestasisIntrahepatic Cholestasis

of Pregnancyof Pregnancy


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BackgroundBackground

Incidence of 1 in 1,000Incidence of 1 in 1,000--10,00010,000

pregnanciespregnancies

Uneven incidence worldwideUneven incidence worldwide High incidence in Chile and SwedenHigh incidence in Chile and Sweden

Seems to have a seasonal variation,Seems to have a seasonal variation,

peaking in Novemberpeaking in November


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PathogenesisPathogenesis

Cause is unknownCause is unknown

Evidence suggests both genetic andEvidence suggests both genetic and

hormonal factors play a rolehormonal factors play a role GeneticGenetic

could explain familial cases and a higher incidencecould explain familial cases and a higher incidence

in some ethnic groupsin some ethnic groups

heterozygous mutations in the MDR3 gene hasheterozygous mutations in the MDR3 gene hasbeen found in a large consanguineous familybeen found in a large consanguineous family

likely autosomal dominantlikely autosomal dominant


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HormonalHormonal

EstrogensEstrogens

estrogens are known to cause cholestasis in bothestrogens are known to cause cholestasis in both

experimental and clinical conditionsexperimental and clinical conditions

ICP occurs mainly in the third trimester, whenICP occurs mainly in the third trimester, when

estrogens reach their peakestrogens reach their peak

also more common in twin pregnancies, whichalso more common in twin pregnancies, which

have higher circulating estrogen levelshave higher circulating estrogen levels


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HormonalHormonal

ProgesteroneProgesterone

administration of progesterone may be a risk factoradministration of progesterone may be a risk factor

for ICPfor ICP

the formation of large amounts of progesteronethe formation of large amounts of progesterone

metabolites may result in saturation of the hepaticmetabolites may result in saturation of the hepatic

transport system utilized for biliary excretiontransport system utilized for biliary excretion


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Generally occurs in second and thirdGenerally occurs in second and third

trimesterstrimesters

Usually begins with pruritis at nightUsually begins with pruritis at night Pruritis is often generalized, butPruritis is often generalized, but

predominates on palms and soles of feetpredominates on palms and soles of feet

Progresses to continuous pruritisProgresses to continuous pruritis


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May have excoriations due to scratchingMay have excoriations due to scratching

Abdominal pain is uncommonAbdominal pain is uncommon

Occasionally may have dark urine andOccasionally may have dark urine andpale stoolpale stool


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~2 weeks after start of symptoms,~2 weeks after start of symptoms,

jaundice develop in 50%jaundice develop in 50%

Accounts for 20Accounts for 20--25% of cases of jaundice25% of cases of jaundiceduring pregnancyduring pregnancy

Jaundice is usually mild, but persists untilJaundice is usually mild, but persists until

deliverydelivery

Symptoms usually abate about 2 daysSymptoms usually abate about 2 days

after deliveryafter delivery


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Differential Diagnosis for pruritisDifferential Diagnosis for pruritis

without a primary skin lesionwithout a primary skin lesion

cholestasischolestasis

xerosis (dry skin)xerosis (dry skin)

medicationsmedications

uremiauremia

iron deficiencyiron deficiency

leukemialeukemia

HIVHIV

polycythemiapolycythemia

lymphomalymphoma

thyroid disordersthyroid disorders

diabetesdiabetes

visceral malignanciesvisceral malignancies

multiple sclerosismultiple sclerosis


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ALPALP

increases 5increases 5--10 fold10 fold

Serum total bile acidsSerum total bile acids may increase to more then 10x normalmay increase to more then 10x normal

Total bilirubinTotal bilirubin

mildly increasedmildly increased

AST, ALTAST, ALT

may increase to >1,000 U/Lmay increase to >1,000 U/L


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GGTGGT

normal or slightly elevatednormal or slightly elevated

Coagulation factorsCoagulation factors INRINR

usually normalusually normal

may be increased scondary to Vitamin K deficiencymay be increased scondary to Vitamin K deficiency

due to cholestasis or due to the use of bile aciddue to cholestasis or due to the use of bile acidsequestrantssequestrants


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DiagnosisDiagnosis

Fasting serum bile acids must be moreFasting serum bile acids must be more

then 3 times the upper limit of normalthen 3 times the upper limit of normal

Clinical symptoms must also be presentClinical symptoms must also be presentfor diagnosisfor diagnosis

Need to exclude other causes of jaundiceNeed to exclude other causes of jaundice

and pruritus including viral hepatitis,and pruritus including viral hepatitis,

primary biliary cirrhosis and biliary tractprimary biliary cirrhosis and biliary tract

diseasedisease


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DiagnosisDiagnosis

UltrasoundUltrasound

reveals no biliary duct dilation, hepaticreveals no biliary duct dilation, hepatic

parenchyma appear normalparenchyma appear normal

Liver BiopsyLiver Biopsy

rarely necessary for diagnosisrarely necessary for diagnosis

histologically shows:histologically shows:

centrilobular areas reveal dilated bile canaliculicentrilobular areas reveal dilated bile canaliculi

these changes tend to regress after pregnancythese changes tend to regress after pregnancy


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Treatment focuses on reducing symptomsTreatment focuses on reducing symptoms

Benadryl, hydroxyzine and otherBenadryl, hydroxyzine and other

antihistamines may help only slightlyantihistamines may help only slightlyAntihistamines may aggravate respiratoryAntihistamines may aggravate respiratory

difficulties in preterm babiesdifficulties in preterm babies


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CholestyramineCholestyramine

anion binding resin that interrupts theanion binding resin that interrupts theenterohepatic circulation, reducingenterohepatic circulation, reducing

reabsorption of bile acidsreabsorption of bile acids dose 8dose 8--16 g/day in three to four divided doses16 g/day in three to four divided doses

may take up to 2 weeks to work, so shouldmay take up to 2 weeks to work, so shouldstart as soon as pruritis is notedstart as soon as pruritis is noted

check INR qweekly, as affects vitamin Kcheck INR qweekly, as affects vitamin Kabsorptionabsorption

may cause bloating and constipationmay cause bloating and constipation


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Ursodeoxycholic acid (UDCA)Ursodeoxycholic acid (UDCA)

increases bile flowincreases bile flow

causes significant decrease in pruritus andcauses significant decrease in pruritus and

decrease liver function studiesdecrease liver function studies

dose 500 mg BIDdose 500 mg BID


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DeliveryDelivery

In most cases, delivery should beIn most cases, delivery should be

accomplished by 38 weeksaccomplished by 38 weeks

If cholestasis is severe, delivery should beIf cholestasis is severe, delivery should be

considered at 36 weeks if fetal lung maturity isconsidered at 36 weeks if fetal lung maturity is

documenteddocumented


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OutcomesOutcomes

Perinatal OutcomePerinatal Outcome

Main complications are prematurity,Main complications are prematurity,

meconuimmeconuim--stained amniotic fluid andstained amniotic fluid and

intrauterine demiseintrauterine demise

Probability of fetal complications is directlyProbability of fetal complications is directly

related to bile acid levelsrelated to bile acid levels

Fetal complications are generally not seenFetal complications are generally not seenuntil bile acid levels are >40 mmol/L (furtheruntil bile acid levels are >40 mmol/L (further

studies need to be done to validate this level)studies need to be done to validate this level)


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OutcomesOutcomes

Perinatal OutcomePerinatal Outcome

Antepartum FHR testing and fetal surveillanceAntepartum FHR testing and fetal surveillance

should be undertakenshould be undertaken

May induce labour at term, or when amnioticMay induce labour at term, or when amniotic

fluid studies indicate FLMfluid studies indicate FLM


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OutcomesOutcomes

Maternal OutcomeMaternal Outcome

Maternal prognosis is goodMaternal prognosis is good

Pruritis usually begins to resolve around 2Pruritis usually begins to resolve around 2

days postpartumdays postpartum

There are generally no hepatic sequelaeThere are generally no hepatic sequelae

Recurs in 60Recurs in 60--70% of subsequent pregnancies70% of subsequent pregnancies

Recurrent episodes are variable in severityRecurrent episodes are variable in severity


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OutcomesOutcomes

Maternal OutcomeMaternal Outcome

May be at increased risk for gallstonesMay be at increased risk for gallstones

OCPOCP administration rarely results inadministration rarely results in

recurrent cholestasis, however LFTS shouldrecurrent cholestasis, however LFTS should

be checked after 3be checked after 3--6 months6 months


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Differential DiagnosisDifferential Diagnosis

When patients present with signs of liverWhen patients present with signs of liver

disease, appropriate workup needs to bedisease, appropriate workup needs to be

undertaken to determine the causeundertaken to determine the cause

Generally a combination of clinicalGenerally a combination of clinical

manifestations and lab results can helpmanifestations and lab results can help

diagnose a patientdiagnose a patient

Rarely is invasive testing ie. liver biopsyRarely is invasive testing ie. liver biopsynecessary for diagnosisnecessary for diagnosis


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Differential Diagnosis of LiverDifferential Diagnosis of Liver

Disease in PregnancyDisease in PregnancySerumSerum

TransaminasesTransaminases

BilirubinBilirubin CoagulopathyCoagulopathy HistologyHistology OtherOther

FeaturesFeatures

AcuteAcute

Hepatitis BHepatitis B

>1000>1000 >5>5 -- Hepatocellular Hepatocellular

necrosisnecrosis

Potential forPotential for

perinatalperinatal

transmissiontransmission

Acute FattyAcute Fatty

LiverLiver


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SummarySummary

Need to be familiar with the normal liverNeed to be familiar with the normal liver

during pregnancy in order to determineduring pregnancy in order to determine

what is abnormalwhat is abnormal

Acute Fatty LiverAcute Fatty Liver

Need to have a high suspicion for acute fattyNeed to have a high suspicion for acute fatty

liver as outcomes can be poorliver as outcomes can be poor

Management of acute fatty liver is delivery asManagement of acute fatty liver is delivery assoon as diagnosis is made and patient issoon as diagnosis is made and patient is

stabilizedstabilized


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SummarySummary

Intrahepatic cholestasisIntrahepatic cholestasis Intrahepatic cholestasis is usually identified byIntrahepatic cholestasis is usually identified by

pruritis and diagnosis is confirmed withpruritis and diagnosis is confirmed withincreased serum bile acidsincreased serum bile acids

Treatment is mainly symptomatic, withTreatment is mainly symptomatic, withantihistamines, cholestyramine andantihistamines, cholestyramine andursodeoxycholic acidursodeoxycholic acid

Delivery should be pursued at 38 weeks, orDelivery should be pursued at 38 weeks, or

earlier if FLM is confirmedearlier if FLM is confirmed Fetal monitoring is crucial, as there is a higherFetal monitoring is crucial, as there is a higher

incidence of stillbirthincidence of stillbirth


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ReferencesReferences

Gabbe: ObstetricsGabbe: Obstetrics Normal and Problem Pregnancies, 4Normal and Problem Pregnancies, 4thth ed., 2002ed., 2002

First Principles of Gastroenterology: The Basis of Disease andFirst Principles of Gastroenterology: The Basis of Disease and

an Approach to Managementan Approach to Management,,

http://gastroresource.com/GITextbook/en/Default.htmhttp://gastroresource.com/GITextbook/en/Default.htm

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Hepatobiliary Disease in Pregnancy