INTRAHEPATIC CHOLESTASIS OF PREGNANCY

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INTRAHEPATIC CHOLESTASIS OF PREGNANCY
Dr .Ashraf Fouda Ob/Gyn. Consultant Damietta
General Hospital E. mail ashraffoda_at_hotmail.com
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Introduction

• Intrahepatic cholestasis is
  characterized by
  pruritus and mild jaundice usually occurring in
  the last trimester of pregnancy.
  
• It can, however, occur earlier in
  gestations.

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Incidence

• It has an uneven worldwide incidence of 1 in
  1,000 to 1 in 10,000 deliveries.

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Introduction

• The disease is reported to affect up to 14 of
  pregnancies in Chile.
• Gonzalez et al. determined the prevalence of
  intrahepatic cholestasis of pregnancy in
  Chile to be 4.7 in singleton pregnancies.

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Introduction

• In twin pregnancies, the incidence
  was 21 .
• The disease is also common in the
  Swedish population.
• Berg et al. reported the incidence in Sweden to
  be between 1 and 1.5 .
• In their study, the incidence
  of intrahepatic cholestasis of pregnancy had
  a distinct seasonal variation, peaking in
  November.

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Introduction

• This disorder is much less common in the United
  States, but appears to have a familial
  predisposition in Sweden.
• In 1987, Wilson reported the first case of
  intrahepatic cholestasis of pregnancy in an
  African-American patient.
• Abedin et al. found that cholestasis of pregnancy
  occurred in up to 1.5 of Asian
  women of Pakistani and Indian origin.

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Introduction

• Intrahepatic cholestasis tends to recur in
  subsequent pregnancies, but the severity may
  vary from one pregnancy to the next.
• In their Chilean study, Gonzalez
  et al. reported a recurrence rate of 70 in
  singleton pregnancies.

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Introduction

• Locatelli et al. found cholestasis of pregnancy
  in 16 of patients with hepatitis C compared
  with 1 of controls, suggesting that
  individuals with hepatitis C are
  more prone to cholestasis of preganacy.

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Clinical Manifestations

• Patients with intrahepatic cholestasis
  usually begin having pruritus at night.
• It progresses, and the patient is soon
  experiencing bothersome
  pruritus continuously.
• Approximately 2 weeks later,
  clinical jaundice will develop in
  50 of cases.
• The jaundice is usually mild, soon plateaus, and
  remains constant until delivery.

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Clinical Manifestations

• The pruritus worsens with the onset of jaundice,
  and the patient's skin can become excoriated.
• The symptoms usually abate within 2 days after
  delivery.

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Clinical Manifestations

• The differential diagnosis must include
• Viral hepatitis and
• Gallbladder disease.

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Clinical Manifestations

• There is usually no
  fever or abdominal discomfort, as in hepatitis,
  and
• No nausea or vomiting, as seen in
  hepatitis and gallbladder disease.

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Laboratory Findings

• Serum alkaline phosphatase levels are increased
  5- to 10-fold in intrahepatic cholestasis of
  pregnancy.
• Alkaline phosphatase, however, is
  normally increased in pregnancy.
• This is due to placental production of
  this enzyme.

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Laboratory Findings

• Serum and urinary excretion of total sulfated
  progesterone metabolites are increased in
  cholestasis of pregnancy, whereas glucuronide
  metabolites are unchanged or low.
• This shows that there is a primary change in the
  reductase metabolism of progesterone in
  cholestasis of pregnancy.

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Laboratory Findings

• Bilirubin is elevated, but usually not above 5
  mg/dl.
• Most is the direct, conjugated
  form.
• Serum 5'-nucleotidase levels are also
  increased.

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Laboratory Findings

• If intrahepatic cholestasis lasts for several
  weeks, liver dysfunction may result in
• Decreased vitamin K reabsorption or
• Decreased prothrombin production, leading to a
  prolongation of the
  prothrombin time.

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Laboratory Findings

• Serum transaminase levels are usually normal or
  moderately elevated, remaining well below the
  levels associated with viral hepatitis.
• Serum cholesterol and triglyceride levels may
  also be markedly elevated.

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Laboratory Findings

• The serum bile acids (chenodeoxycholic acid,
  deoxycholic acid, and cholic acid)
  are increased.
• The levels are often more than 10 times
  the normal concentration.
• These acids are
  deposited in the skin and probably cause the
  extreme pruritus.

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Laboratory Findings

• The degree of pruritus, however, is
  not always related to the serum level of bile
  acids.
• To make the diagnosis of intrahepatic cholestasis
  of pregnancy, the fasting
  levels of serum bile acids should be at least
  three times the upper limit of normal.

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Laboratory Findings

• Elevation of serum bile acids alone cannot be
  used to make the diagnosis.
• The patient must also have clinical symptoms.
• Serum transaminase levels may also be elevated 5
  to 10 times normal.
• Reyes et al. found that serum copper is
  significantly higher and selenium levels are
  significantly lower in individuals with
  cholestasis of pregnancy.

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Laboratory Findings

• Wojcicka-Jagodzinska and colleagues reported that
  carbohydrate metabolism is disturbed in patients
  with intrahepatic cholestasis of pregnancy.
• These patients should therefore be screened for
  gestational diabetes when the diagnosis of
  cholestasis is made.

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Laboratory Findings

• Histologically, the periportal areas show no
  change, and the hepatocellular architecture
  remains undisturbed.
• The centrilobular areas, however, reveal dilated
  bile canaliculi, many containing bile plugs.
• Ultrastructurally, there appears to be some
  destruction and atrophy of microvilli in the bile
  canaliculi.
• These changes tend to regress after pregnancy.

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Perinatal Outcome

• The risk of
• Preterm birth and
• Fetal death may be increased in patients
  suffering from intrahepatic cholestasis of
  pregnancy.

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Perinatal Outcome

• Fisk and Storey studied 83 pregnancies
  complicated by intrahepatic cholestasis over a
  10-year period.
• Meconium staining occurred in 45 of the
  pregnancies, spontaneous preterm labor occurred
  in 44 , and intrapartum fetal distress
  complicated 22 .
• Of the 86 infants, 2 were stillborn and
  1 died soon after birth.
• The overall perinatal mortality in this group of
  patients was 35 per 1,000.

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Perinatal Outcome

• Nonstress tests,
• Serial ultrasonography to assess amniotic fluid
  volume, and
• Estriol determinations failed to predict fetal
  compromise.
• Early intervention was indicated in 49
  pregnancies, 12 because of suspected fetal
  distress.

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Perinatal Outcome

• In light of this study, antepartum fetal
  heart rate testing and intense surveillance
  should be undertaken in gravidas with
  intrahepatic cholestasis of pregnancy.

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Perinatal Outcome

• It may also be prudent to induce labor at term
  or when amniotic fluid studies indicate
  fetal lung maturity.

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Perinatal Outcome

• Heinonen and Kirkinen reviewed 91 cases
  of cholestasis in pregnancy in Finland
  from 1990 to 1996.
• The cesarean section rate was 10
  higher in the group of women with cholestasis.
• The risk of preterm delivery was higher and the
  need for neonatal intensive care was also higher
  .

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Perinatal Outcome

• Matos et al. report a
  full-term infant with unexplained
  intracerebral hemorrhage in a
  patient with cholestasis of pregnancy.

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Management

• Treatment is aimed at reducing the intense
  pruritus.
• Diphenhydramine, hydroxyzine, and other
  antihistamines help
  only slightly.

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Cholestyramine

• Cholestyramine is an anionbinding resin that
  interrupts the enterohepatic circulation,
  reducing the reabsorption of bile acids.
• A total of 8 to 16 g/day in
  three to four divided doses is often helpful
  in relieving pruritus.
• It is most effective if started as soon as the
  pruritus is noted, before it becomes severe.
• It often takes up to 2 weeks to work.

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Cholestyramine

• Because cholestyramine also interferes with
  vitamin K absorption, the prothrombin time should
  be checked at least weekly.
• If prolonged, parenteral vitamin K should be
  administered.
• When the prothrombin time returns to normal, the
  frequency of injections can be decreased.

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Management

• Cholestyramine causes a sensation of bloating and
  often results in constipation.
• Cholestyramine also can interfere with the
  absorption of other ingested medications,
  including prenatal vitamins.
• If the patient cannot tolerate cholestyramine,
  antacids containing aluminum may be used to bind
  bile acids.
• These medications are usually not as effective as
  cholestyramine.

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Management

• Phenobarbital, in a dose of up to 90 mg daily
  given at bedtime, can be helpful.
• Phenobarbital induces hepatic microsomal enzymes,
  increasing bile salt secretion and bile flow.
• This medication usually
  takes more than 1 week to be
  effective.
• It has not been shown to change the serum
  concentration of bile acids.

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Management

• It is important to remember that phenobarbital
  must not be given within 2 hours of
  cholestyramine, or the phenobarbital will be
  bound and excreted without being absorbed.
• The key to treating pregnancy-induced cholestasis
  is to begin therapy as soon
  as the diagnosis is made.

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Management

• Dexamethasone has also been used with some
  success in treating pregnancy-induced
  cholestasis.
• Dexamethasone suppresses fetalplacental estrogen
  production, which is out of balance in the
  patient with cholestasis of pregnancy.
• Leslie et al., however, have shown that
  downstream placental production of estrogen is
  compromised in patients with cholestasis of
  pregnancy.

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Management

• Two studies have investigated using guar gum, a
  gelforming fiber that increases fecal elimination
  of bile acids, to treat the pruritus associated
  with pregnancy-induced cholestasis.
• This dietary fiber was randomly assigned to 24 of
  48 women with cholestasis of pregnancy in
  Finland.

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Management

• In patients taking the guar gum, bile acids
  remained stable, whereas they increased in those
  taking the placebo.
• Pruritus improved in those taking guar gum and
  worsened in the placebo group.
• Similar results were obtained in 48
  patients in a more recent study in Finland.

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Management

• The two most recently studied medications for the
  treatment of intrahepatic cholestasis of
  pregnancy are
  S-adenyl-methionine (SAM-e) and
  ursodeoxycholic acid (UDCA).

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Management

• SAM-e may work by reversing estrogen-induced
  impairment of bile secretion.
• UDCA is a naturally occurring hydrophilic bile
  acid that replaces other more cytotoxic bile
  acids.

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Management

• Nicastri et al. studied 32 women
  with intrahepatic cholestasis.
• There were four study groups
• The first group received DCA
• The second SAM-e
  
• The third both drugs and
  
• The fourth received placebo.
• A combination of both drugs was more effective
  than either drug alone.

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Management

• Palma et al. compared 1 g daily of UDCA with a
  placebo over 3 weeks and found a significant
  decrease in pruritus and a significant decrease
  in liver function studies.
• Other studies have shown similar results.
• It appears that the proper dosage of UDCA is 14
  to 16 mg/kg/day.

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Management

• Because of intolerable pruritus and the possible
  impact on perinatal outcome, delivery may be
  undertaken at term or as soon as fetal lung
  maturity has been documented.
• Jaundice usually disappears within 2
  days after delivery.

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Management

• The patient should be counseled that the
  condition may recur during subsequent
  pregnancies.
• It is also important to note that some patients
  may manifest symptoms of intrahepatic
  cholestasis when taking oral contraceptives.

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Thank you