INTRAHEPATIC CHOLESTASIS OF PREGNANCY

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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. . Incidence. It has an uneven w

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INTRAHEPATIC CHOLESTASIS OF PREGNANCY

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1. INTRAHEPATIC CHOLESTASIS OF PREGNANCY

2. 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.

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

4. 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. Introduction

5. 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. Introduction

6. 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. Introduction

7. 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. Introduction

8. 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. Introduction

9. 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.

10. 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. Clinical Manifestations

11. The differential diagnosis must include: Viral hepatitis and Gallbladder disease. Clinical Manifestations

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

13. 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.

14. 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. Laboratory Findings

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

16. 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. Laboratory Findings

17. 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. Laboratory Findings

18. 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. Laboratory Findings

19. 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. Laboratory Findings

20. 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. Laboratory Findings

21. 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. Laboratory Findings

22. 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. Laboratory Findings

23. Perinatal Outcome The risk of: Preterm birth and Fetal death may be increased in patients suffering from intrahepatic cholestasis of pregnancy.

24. 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. Perinatal Outcome

25. 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. Perinatal Outcome

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

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

28. 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 . Perinatal Outcome

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

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

31. 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. Cholestyramine

32. 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. Cholestyramine

33. 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. Management

34. 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. Management

35. 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. Management

36. Dexamethasone has also been used with some success in treating pregnancy-induced cholestasis. Dexamethasone suppresses fetal—placental 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. Management

37. 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. Management

38. 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. Management

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

40. 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. Management

41. 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. Management

42. 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. Management

43. 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. Management

44. 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. Management

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