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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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The Liver in Normal PregnancyThe Liver in Normal Pregnancy
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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The Liver in Normal PregnancyThe Liver in Normal Pregnancy
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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The Liver in Normal PregnancyThe Liver in Normal Pregnancy
Liver function testsLiver function tests
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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The Liver in Normal PregnancyThe Liver in Normal Pregnancy
Liver function testsLiver function tests
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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The Liver in Normal PregnancyThe Liver in Normal Pregnancy
Serum lipidsSerum lipids
Total cholesterol and triglyceridesTotal cholesterol and triglycerides
increase markedly during pregnancyincrease markedly during pregnancy
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The Liver in Normal PregnancyThe Liver in Normal Pregnancy
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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Clinical ManifestationsClinical Manifestations
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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Clinical ManifestationsClinical Manifestations
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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Clinical ManifestationsClinical Manifestations
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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Clinical ManifestationsClinical Manifestations
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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Clinical ManifestationsClinical Manifestations
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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Lab InvestigationsLab Investigations
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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ManagementManagement
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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ManagementManagement
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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ManagementManagement
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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PathogenesisPathogenesis
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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PathogenesisPathogenesis
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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Clinical ManifestationsClinical Manifestations
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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Clinical ManifestationsClinical Manifestations
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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Clinical ManifestationsClinical Manifestations
~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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Lab InvestigationsLab Investigations
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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Lab InvestigationsLab Investigations
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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ManagementManagement
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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ManagementManagement
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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ManagementManagement
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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ManagementManagement
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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