Liver Disease in Pregnancy - Louisville

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PowerPoint PresentationLiver Disease in Liver Disease in PregnancyPregnancy
Luis S. Marsano, MDLuis S. Marsano, MD Professor of MedicineProfessor of Medicine
Division of Gastroenterology, Hepatology and NutritionDivision of Gastroenterology, Hepatology and Nutrition University of Louisville, Louisville VAMC, and Jewish University of Louisville, Louisville VAMC, and Jewish
HospitalHospital
Intrahepatic Cholestasis of Intrahepatic Cholestasis of PregnancyPregnancy Hyperemesis GravidarumHyperemesis Gravidarum HELLP SyndromeHELLP Syndrome PrePre--Eclampsia/EclampsiaEclampsia/Eclampsia Acute fatty liver of PregnancyAcute fatty liver of Pregnancy
Diseases During PregnancyDiseases During Pregnancy Gallstone diseaseGallstone disease Viral Hepatitis (A,B,C,D,E,HSV)Viral Hepatitis (A,B,C,D,E,HSV) Primary Biliary CirrhosisPrimary Biliary Cirrhosis Primary Sclerosing CholangitisPrimary Sclerosing Cholangitis AutoAuto--Immune Hepatitis
Pregnancy in CirrhosisPregnancy in Cirrhosis Esophageal VaricesEsophageal Varices AscitesAscites Hepatic EncephalopathyHepatic Encephalopathy Splenic artery aneurism ruptureSplenic artery aneurism rupture PostPost--partum Uterine Hemorrhagepartum Uterine Hemorrhage
Pregnancy after Liver Pregnancy after Liver TransplantTransplant
Immune Hepatitis
Effects of Pregnancy in Hepatobiliary Effects of Pregnancy in Hepatobiliary SystemSystem
Bile composition: cholesterol supersaturation, decreased Bile composition: cholesterol supersaturation, decreased chenodexycholic acid. increased cholic acid, and increased bile chenodexycholic acid. increased cholic acid, and increased bile acid acid pool. pool. Greater residual GB volume in fasting and fed state, with less GGreater residual GB volume in fasting and fed state, with less GB B contractibility. Prevalence of GB stones is 2.5contractibility. Prevalence of GB stones is 2.5--12%.12%. Progressive increase in blood volume, with peak at week 30, withProgressive increase in blood volume, with peak at week 30, with 50% greater volume, due to increased renin, aldosterone, and 50% greater volume, due to increased renin, aldosterone, and steroid hormones.steroid hormones. Decreased serum protein concentration by hemodilution; 20% by 2Decreased serum protein concentration by hemodilution; 20% by 2ndnd
trimester. Raising AFP.trimester. Raising AFP. Accelerated synthesis of CYP P450 gene superfamily products, Accelerated synthesis of CYP P450 gene superfamily products, coagulation products, globulins and ceruloplasmin.coagulation products, globulins and ceruloplasmin. Progressive elevation of Alkaline phosphatase with peak of 2X ULProgressive elevation of Alkaline phosphatase with peak of 2X ULN N by end of pregnancy.by end of pregnancy. GGT normal or slightly decreased.GGT normal or slightly decreased. Spider nevi & palmar erythema in 50% Spider nevi & palmar erythema in 50%
Physiologic changes in PregnancyPhysiologic changes in Pregnancy TestTest Effect of PregnancyEffect of Pregnancy BilirubinBilirubin UnchangedUnchanged
ALS & ASTALS & AST UnchangedUnchanged
Prothrombin timeProthrombin time UnchangedUnchanged
Alkaline phosphataseAlkaline phosphatase Increase 2Increase 2--4 fold (2 X ULN) (placenta)4 fold (2 X ULN) (placenta)
Bile acidsBile acids Increase 2Increase 2--3 fold 3 fold (glycocholate, taurocholate, chenodeoxycholate)(glycocholate, taurocholate, chenodeoxycholate)
FibrinogenFibrinogen Increases 50%Increases 50%
GlobulinsGlobulins Increases alpha & beta; Decreases gammaIncreases alpha & beta; Decreases gamma
Alpha fetoproteinAlpha fetoprotein Increases (specially with twins)Increases (specially with twins)
HemoglobinHemoglobin Decrease in late pregnancyDecrease in late pregnancy
Leukocyte countLeukocyte count IncreasesIncreases
TriglyceridesTriglycerides IncreaseIncrease
Timing of Diseases Unique to,Timing of Diseases Unique to, or Triggered by Pregnancyor Triggered by Pregnancy
DiseaseDisease TrimesterTrimester
HELLP syndromeHELLP syndrome Late 2Late 2ndnd & 3& 3rdrd..
PreeclampsiaPreeclampsia Late 2Late 2ndnd & 3& 3rdrd..
Acute fatty liver of pregnancyAcute fatty liver of pregnancy 33rdrd..
BuddBudd--Chiari syndromeChiari syndrome Post partumPost partum
Hyperemesis Gravidarum (HG)Hyperemesis Gravidarum (HG) Occurs in 0.3% of pregnancies.Occurs in 0.3% of pregnancies. Clinical Features: Clinical Features:
Intractable vomiting in 1Intractable vomiting in 1stst trimester, requiring IV trimester, requiring IV hydration. hydration. Starts between 4Starts between 4--10 week of pregnancy and resolves 10 week of pregnancy and resolves by week 20. In 10% persists until delivery. by week 20. In 10% persists until delivery.
Risk factors: Risk factors: Hyperthyroidism, Hyperthyroidism, psychiatric illness, psychiatric illness, molar pregnancy, molar pregnancy, preexisting diabetes, and preexisting diabetes, and multiple pregnancies.multiple pregnancies.
Hyperemesis Gravidarum (HG)Hyperemesis Gravidarum (HG) Pathogenesis: Immunological, hormonal, and Pathogenesis: Immunological, hormonal, and psychological factors associated with pregnancy may psychological factors associated with pregnancy may play an etiologic role. play an etiologic role.
Increased levels of human chorionic gonadotropin (HCG) in HG Increased levels of human chorionic gonadotropin (HCG) in HG may cause stimulation of secretory processes of the upper may cause stimulation of secretory processes of the upper gastrointestinal tract and stimulation of the thyroid gland. gastrointestinal tract and stimulation of the thyroid gland. Elevations of estrogen, decreases in prolactin levels, and Elevations of estrogen, decreases in prolactin levels, and overactivity of the hypothalamicoveractivity of the hypothalamic--pituitarypituitary--adrenal axis. adrenal axis. Immune and inflammatory mechanisms may also contribute to Immune and inflammatory mechanisms may also contribute to HG. Increased levels of tumor necrosis factor alpha have been HG. Increased levels of tumor necrosis factor alpha have been observed in HG patients. Higher levels of immunoglobulin G observed in HG patients. Higher levels of immunoglobulin G (IgG), immunoglobulin M (IgM), C3, and C4 levels, as well as (IgG), immunoglobulin M (IgM), C3, and C4 levels, as well as increased lymphocyte counts and natural killer and extraincreased lymphocyte counts and natural killer and extra--thymic thymic T cell levels have been observed in HG patients.T cell levels have been observed in HG patients.
Hyperemesis Gravidarum (HG)Hyperemesis Gravidarum (HG) Laboratory:Laboratory:
Liver dysfunction occurs in 50% patients with aminotransferases Liver dysfunction occurs in 50% patients with aminotransferases up to up to 2020--fold elevation (ALT 400fold elevation (ALT 400--1000 U/L) and with occasional jaundice.1000 U/L) and with occasional jaundice. Other complications include disturbances in electrolytes and in Other complications include disturbances in electrolytes and in water water and acidand acid--base balance that can usually be treated adequately with base balance that can usually be treated adequately with hydration.hydration. Liver biopsy normal or with bland cholestasis. Needed only to exLiver biopsy normal or with bland cholestasis. Needed only to exclude clude more serious disease.more serious disease.
Effect in Fetus: Not clear. Effect in Fetus: Not clear. Increased rates of fetal abnormalities including undescended tesIncreased rates of fetal abnormalities including undescended testicles, ticles, hip dysplasia, and Down Syndrome have been reported. hip dysplasia, and Down Syndrome have been reported. In one large cohort study, infants of HG mothers were found to hIn one large cohort study, infants of HG mothers were found to have ave lower birth weights and higher rates of being small for gestatiolower birth weights and higher rates of being small for gestational agenal age
Hyperemesis Gravidarum (HG)Hyperemesis Gravidarum (HG)
Treatment: Treatment: Hospitalization is necessary for rehydration, nutritional supporHospitalization is necessary for rehydration, nutritional support, t, and symptomatic measures with antiemetics; occasionally and symptomatic measures with antiemetics; occasionally steroids are used. steroids are used. Eat small, frequent, lowEat small, frequent, low--fat meals. fat meals. NasoNaso--jejunal feeding can be very helpful.jejunal feeding can be very helpful.
Safety of drugs used in pregnancySafety of drugs used in pregnancy--associated associated liver diseasesliver diseases
(Drug FDA pregnancy category Comments)(Drug FDA pregnancy category Comments)
AntiemeticsAntiemetics PromethazinePromethazine CC Possible respiratory depression if drug is Possible respiratory depression if drug is administered near time of deliveryadministered near time of delivery MetoclopramideMetoclopramide BB Available evidence suggests safe use during Available evidence suggests safe use during pregnancypregnancy OndansetronOndansetron BB Additional studies are needed to determine Additional studies are needed to determine safety to the fetus, particularly during the first trimestersafety to the fetus, particularly during the first trimester ProchlorperazineProchlorperazine CC There are isolated reports of congenital There are isolated reports of congenital anomalies; however, some included exposures to other drugs. anomalies; however, some included exposures to other drugs. Jaundice, extrapyramidal signs, hyperJaundice, extrapyramidal signs, hyper--/hyporeflexes have been /hyporeflexes have been noted in newbornsnoted in newborns
From: Lee MN, and Brady CW. World J Gastroenterol 2009 February 28; 15(8): 897-906
Intrahepatic Cholestasis of Pregnancy (ICP)Intrahepatic Cholestasis of Pregnancy (ICP)
In USA in 0.1% of pregnancies; 20% have jaundice.In USA in 0.1% of pregnancies; 20% have jaundice. Clinical Features:Clinical Features:
Severe pruritus usually with onset at week 25 or later, generaliSevere pruritus usually with onset at week 25 or later, generalized, but zed, but most severe in palms and soles, worse at night. most severe in palms and soles, worse at night. Only 20% have mild jaundice, usually less than 5 mg/dL. JaundiceOnly 20% have mild jaundice, usually less than 5 mg/dL. Jaundice without pruritus is rare.without pruritus is rare. More common with advanced maternal age & multiparity.More common with advanced maternal age & multiparity. May have clinical or subclinical steatorrhea that may cause defiMay have clinical or subclinical steatorrhea that may cause deficiency of ciency of fat soluble vitamins, specially vit K.fat soluble vitamins, specially vit K. There is increased risk of gallstone formation. There is increased risk of gallstone formation. Cholestasis disappears after delivery and recurs in 60Cholestasis disappears after delivery and recurs in 60--70% of 70% of pregnancies. pregnancies. If cholestasis does not disappear with delivery, should suspect If cholestasis does not disappear with delivery, should suspect PBC or PBC or PSC. PSC. Cholecystectomy increases risk of recurrence. Have increased risCholecystectomy increases risk of recurrence. Have increased risk of k of cholestasis when taking oral contraceptives.cholestasis when taking oral contraceptives.
Intrahepatic Cholestasis of Pregnancy (ICP)Intrahepatic Cholestasis of Pregnancy (ICP)
Laboratory Features: Laboratory Features: Have high fasting bile acids, sometimes 100 fold, which correlatHave high fasting bile acids, sometimes 100 fold, which correlate with e with fetal risk. Increase in cholic acid and decrease in chenodeoxychfetal risk. Increase in cholic acid and decrease in chenodeoxycholic acid olic acid leads to a marked elevation in the cholic/ chenodeoxycholic acidleads to a marked elevation in the cholic/ chenodeoxycholic acid ratio. ratio. The glycine/taurine ratio is also reduced.The glycine/taurine ratio is also reduced. Bilirubinuria may be present, serum alkaline phosphatase modestlBilirubinuria may be present, serum alkaline phosphatase modestly y elevated, GGT is normal or marginally high. elevated, GGT is normal or marginally high. Serum ALT & AST usually mildly elevated, but as high as 1000 U/LSerum ALT & AST usually mildly elevated, but as high as 1000 U/L or or more (10more (10--20 X ULN)20 X ULN) Liver Bx shows bland cholestasis with none or minimal hepatocellLiver Bx shows bland cholestasis with none or minimal hepatocellular ular necrosis.necrosis.
Fetal Risk:Fetal Risk: Have increased risk of fetal distress, stillbirth and premature Have increased risk of fetal distress, stillbirth and premature delivery (up delivery (up to 60%). to 60%). Should monitor for placental insufficiency.Should monitor for placental insufficiency. Fetal or perinatal mortality 0.4Fetal or perinatal mortality 0.4--1.4%.1.4%.
Laboratory in ICPLaboratory in ICP % Abnormal Mean Range
Bilirubin 25 2.9 0.4-8.4 Alk. Phosphatase 70 2.4 fold Nl – 12.5 fold AST 60 119 Nl – 736 ALT 55 131 Nl – 1030 Bile acids 90 47 mcM Nl – 430 Cholic acid 70 17 mcM Nl - 109
Intrahepatic Cholestasis of Pregnancy (ICP)Intrahepatic Cholestasis of Pregnancy (ICP)
Pathogenesis:Pathogenesis: Unknown. Unknown. Most common in Chile and Scandinavia, and many have family Most common in Chile and Scandinavia, and many have family history of ICP (genetic predisposition?). history of ICP (genetic predisposition?). More common in winter, and with low serum selenium and More common in winter, and with low serum selenium and selenoenzyme glutathione peroxidase activity (environmental selenoenzyme glutathione peroxidase activity (environmental factors). factors). Elevated estrogen and/or progesterone can cause ICP in nonElevated estrogen and/or progesterone can cause ICP in non-- pregnant women, and some patients have impaired pregnant women, and some patients have impaired detoxification by the sulfation pathway (metabolic ?).detoxification by the sulfation pathway (metabolic ?). Mutations in the phospholipid translocator known as the ATPMutations in the phospholipid translocator known as the ATP--
cassette transporter B4 (ABCB4) or multidrug resistant proteincassette transporter B4 (ABCB4) or multidrug resistant protein--3 3 (MDR3) are associated with 15% of cases of ICP.(MDR3) are associated with 15% of cases of ICP. Increased fetal death may be due to bile acid mediated Increased fetal death may be due to bile acid mediated vasospasm of placental vessels, causing asphyxia.vasospasm of placental vessels, causing asphyxia.
Intrahepatic Cholestasis of Pregnancy (ICP)Intrahepatic Cholestasis of Pregnancy (ICP)
Management:Management: Mother:Mother: palliative.palliative.
•• UDCA 20UDCA 20--25 mg/kg helps itching by changing bile acid 25 mg/kg helps itching by changing bile acid content in maternal serum, and amniotic fluid, and also content in maternal serum, and amniotic fluid, and also increasing placental bile acid transport. Also decreases bile increasing placental bile acid transport. Also decreases bile acids in the fetus. acids in the fetus.
•• Exogenous progesterone must be discontinue. Exogenous progesterone must be discontinue. •• Cholestyramine 8Cholestyramine 8--24 g/d may help, but worsens steatorrhea 24 g/d may help, but worsens steatorrhea
and fatand fat--soluble vitamin deficiency; does not help the fetus. soluble vitamin deficiency; does not help the fetus. •• SAMe has mixed therapeutic results. SAMe has mixed therapeutic results. •• Ultraviolet B light may also help.Ultraviolet B light may also help.
Intrahepatic Cholestasis of Pregnancy (ICP)Intrahepatic Cholestasis of Pregnancy (ICP)
Management: Management: Fetus:Fetus:
•• Close monitoring for chronic placental insufficiency.Close monitoring for chronic placental insufficiency. •• Fetal complications correlate with maternal bile acid (BA) Fetal complications correlate with maternal bile acid (BA)
levels.levels. •• Premature delivery, asphyxial events, and meconium staining Premature delivery, asphyxial events, and meconium staining
occur only in the 19% of cases with maternal BA levels occur only in the 19% of cases with maternal BA levels greater than 40 mol/L. greater than 40 mol/L.
•• Delivery of baby as soon as is mature.Delivery of baby as soon as is mature. •• Dexamethasone (12 mg/day for 7 days) has been use to Dexamethasone (12 mg/day for 7 days) has been use to
promote fetal lung maturity.promote fetal lung maturity.
Safety of drugs used in pregnancySafety of drugs used in pregnancy--associated associated liver diseasesliver diseases
(Drug FDA pregnancy category Comments)(Drug FDA pregnancy category Comments)
Intrahepatic cholestasisIntrahepatic cholestasis Ursodeoxycholic acidUrsodeoxycholic acid BB Relatively low riskRelatively low risk SS--adenosyladenosyl--LL--methioninemethionine Not evaluated by FDA Relatively low Not evaluated by FDA Relatively low riskrisk CholestyramineCholestyramine CC Cholestyramine is not absorbed Cholestyramine is not absorbed systemically, but may interfere with vitamin absorptionsystemically, but may interfere with vitamin absorption
From: Lee MN, and Brady CW. World J Gastroenterol 2009 February 28; 15(8): 897-906
Preeclampsia & EclampsiaPreeclampsia & Eclampsia Hypertension, edema & proteinuria in late 2Hypertension, edema & proteinuria in late 2ndnd, or 3, or 3rdrd trimester.trimester. Occurs in 3Occurs in 3--10% of pregnancies.10% of pregnancies. Hypertension: Hypertension:
systolic pressure greater than 140 mmHg and a diastolic pressuresystolic pressure greater than 140 mmHg and a diastolic pressure greater than greater than 90 mmHg 90 mmHg on at least two occasions that are at least 4 to 6 h apart on at least two occasions that are at least 4 to 6 h apart in a previously normotensive patient, after the 20in a previously normotensive patient, after the 20thth week of pregnancy week of pregnancy BP should be measured in a sitting position for ambulatory patieBP should be measured in a sitting position for ambulatory patients or in a semints or in a semi-- reclining position for hospitalized patients, with thereclining position for hospitalized patients, with the right arm being in a roughly right arm being in a roughly horizontal position at heart level.horizontal position at heart level.
Proteinuria:Proteinuria: equal to or greater than 300 mg of protein in a 24 h equal to or greater than 300 mg of protein in a 24 h urine collection, or 1+ protein or greater on urine dipstick tesurine collection, or 1+ protein or greater on urine dipstick testing of ting of two random urine samples collected at least 4 to 6 h apart. two random urine samples collected at least 4 to 6 h apart. Eclampsia: Eclampsia: preeclampsia + neurologic symptoms such as preeclampsia + neurologic symptoms such as headaches, visual disturbances, and seizures or coma.headaches, visual disturbances, and seizures or coma.
Preeclampsia & EclampsiaPreeclampsia & Eclampsia Risk factorsRisk factors nulliparity, extremes of maternal age, nulliparity, extremes of maternal age, insulin resistance, obesity, and infection.insulin resistance, obesity, and infection. Liver involvement is infrequent. Indicates severe Liver involvement is infrequent. Indicates severe preeclampsia with significant perinatal morbidity and preeclampsia with significant perinatal morbidity and mortality.mortality. Is the commonest cause of hepatic tenderness without Is the commonest cause of hepatic tenderness without hepatomegaly, and liver dysfunction in pregnancy.hepatomegaly, and liver dysfunction in pregnancy. Laboratory: Laboratory:
Aminotransferases are variable, from mild to 10Aminotransferases are variable, from mild to 10--fold to 20fold to 20--fold fold elevations.elevations. Bilirubin is usually less than 5 mg/dLBilirubin is usually less than 5 mg/dL May be complicated by HELLP Syndrome.May be complicated by HELLP Syndrome.
Preeclampsia & EclampsiaPreeclampsia & Eclampsia Liver histology: Liver histology: hepatic sinusoidal deposition of fibrin hepatic sinusoidal deposition of fibrin along with periportal hemorrhage, liver cell necrosis, and along with periportal hemorrhage, liver cell necrosis, and in severe cases, infarction; these changes are likely due in severe cases, infarction; these changes are likely due to vasoconstriction of hepatic vasculature. Microvesicular to vasoconstriction of hepatic vasculature. Microvesicular fatty infiltration has also been observed in some cases of fatty infiltration has also been observed in some cases of preeclampsia, suggesting a possible overlap with acute preeclampsia, suggesting a possible overlap with acute fatty liver of pregnancyfatty liver of pregnancy Pathophysiology:Pathophysiology: procoagulant and proprocoagulant and pro--inflammatory inflammatory states that create glomerular endotheliosis, increased states that create glomerular endotheliosis, increased vascular permeability, and a systemic inflammatory vascular permeability, and a systemic inflammatory response that results in endresponse that results in end--organ damage and organ damage and hypoperfusion.hypoperfusion.
Preeclampsia & EclampsiaPreeclampsia & Eclampsia Maternal mortality:Maternal mortality:
rare in developed countries; rare in developed countries; up to 15%up to 15%--20% in developing countries. 20% in developing countries.
Fetal mortality rate is rare, occurring in 1%Fetal mortality rate is rare, occurring in 1%--2% of births. 2% of births. Maternal and neonatal morbidity may include: Maternal and neonatal morbidity may include:
placental abruption, placental abruption, preterm delivery, preterm delivery, fetal growth restriction or fetal growth restriction or maternal renal failure pulmonary edema, or cerebrovascular accidmaternal renal failure pulmonary edema, or cerebrovascular accident.ent.
Preeclampsia & EclampsiaPreeclampsia & Eclampsia Treatment for preeclampsia is delivery of the fetus and Treatment for preeclampsia is delivery of the fetus and placenta. placenta. If mild preeclampsia is evident before fetal lung maturity If mild preeclampsia is evident before fetal lung maturity at 36 wk gestation, consider expectant management with at 36 wk gestation, consider expectant management with intensive monitoring. intensive monitoring. Pharmacological agents used in preeclampsia include Pharmacological agents used in preeclampsia include
antihypertensives such as calcium channel blockers and antihypertensives such as calcium channel blockers and lowlow--dose aspirin. dose aspirin.
Magnesium sulfate may be administered if eclampsia Magnesium sulfate may be administered if eclampsia develops.develops.
HELLP SyndromeHELLP Syndrome
Severe preeclampsia is complicated by HELLP Severe preeclampsia is complicated by HELLP Syndrome in 2%Syndrome in 2%--12% of cases (0.2%12% of cases (0.2%--0.6% of all 0.6% of all pregnancies).pregnancies). Diagnostic criteria: Diagnostic criteria:
HH: Abnormal smear (microangiopathy), LDH > 600 U/L, High : Abnormal smear (microangiopathy), LDH > 600 U/L, High Indirect BilirubinIndirect Bilirubin ELEL: AST > 70 U/L, (AST/ALT elevation up to 10: AST > 70 U/L, (AST/ALT elevation up to 10--20 fold)20 fold) LPLP: plat < 150,000; : plat < 150,000;
•• Class 1: < 50K, Class 1: < 50K, •• Class 2: 50Class 2: 50--99K, 99K, •• Class 3: 100Class 3: 100--149K)149K)
HELLP SyndromeHELLP Syndrome
Symptoms: Symptoms: Epigastric and/or RUQ abdominal pain and tenderness, nausea Epigastric and/or RUQ abdominal pain and tenderness, nausea and vomiting, malaise, headache, edema and weight gain, and vomiting, malaise, headache, edema and weight gain, hypertension, and proteinuria; hypertension, and proteinuria; Less commonly renal failure (with increased uric acid), diabetesLess commonly renal failure (with increased uric acid), diabetes insipidus, and antiphospholipid syndrome.insipidus, and antiphospholipid syndrome. Late findings include Late findings include intravascular coagulopathy (DIC), intravascular coagulopathy (DIC), pulmonary pulmonary edema, placental abruption, and retinal detachment.edema, placental abruption, and retinal detachment. Jaundice is uncommon (5%); T. bili < 5 mg/dL unless has Jaundice is uncommon (5%); T. bili < 5 mg/dL unless has massive liver necrosismassive liver necrosis Some patients have no obvious preeclampsiaSome patients have no obvious preeclampsia
HELLP SyndromeHELLP Syndrome Most patients present between 27 and 36 weeksMost patients present between…