Intrahepatic Cholestasis of Pregnancy

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Intrahepatic cholestasis of pregnancy (IHCP) is heralded by the development of pruritus, liver enzyme abnormalities, and occasionally jaundice. Most cases occur within the third trimester of pregnancy (Table 120-2). The worldwide incidence varies; ICHP occurs in less than 1 to 2% of all pregnancies in the United States, Asia, Australia, and Europe, but in Bolivia, Chile, and Scandinavia, the incidence is as high as 14%, with rates of 24% in the Araucanian Indians of Chile. There is a greater prevalence among woman from the Indian subcontinent and the disease is rare in black patients. IHCP recurs in 60 to 70% of subsequent pregnancies and is 5 times more frequent in women with multiple gestation.

The etiology of ICHP is uncertain and is probably multifactorial. Seasonal variations suggest environmental influ

TABLE 120-2. Features of Liver Disease of Pregnancy




Maternal age of onset (years)


26 (range, 16 to 39)

25 (range 14 to 40)

Gestational age of onset (weeks)

29 (range, 7 to 40)

36 (range, 26 to 40)

33 (range, 22 to 40)

70%: 3rd trimester

100%: 3rd trimester

60%: 3rd trimester

30%: before 3rd


30%: postpartum


13: 5% 1st/2nd trimester



42 to 70%


Fivefold increase



with twin pregnancy

60 to 76% male fetus 10 to 15% twin pregnancy


Incidence (in all pregnancies)

1 to 24 %

1 in 7,000 to 15,000

0.17 to 0.85%


60 to 70%


2 to 3%






5 to 75%

> 70%

up to 90%

Abdominal Pain

9 to 24 %

- 60%

a 80%





Increased alkaline phosphatase




Increased bilirubin


a 95%

47 to 62%

Increased AST/ALT

20 to 60%



Increased PT

s 20%

a 90%

s 15%



30 to 40%

> 90%



a 50%

a 80%

Maternal mortality


15 to 50%

up to 8%

Fetal mortality

1 to 2%

40 to 50%

8 to 37%

Adapted from Larson AM. Liver disease in pregnancy. Clin Perspectives Gastroenterol 2001; 4:351(17). AFLP = acute fatty liver of pregnancy; ALT = alanine aminotransferase; AST = aspartate aminotransferase; HELLP = hemolysis, elevated liver enzymes, and low platelets syndrome; ICPH = intrahepatic cholestasis of pregnancy; PT = prothrombin time.

Adapted from Larson AM. Liver disease in pregnancy. Clin Perspectives Gastroenterol 2001; 4:351(17). AFLP = acute fatty liver of pregnancy; ALT = alanine aminotransferase; AST = aspartate aminotransferase; HELLP = hemolysis, elevated liver enzymes, and low platelets syndrome; ICPH = intrahepatic cholestasis of pregnancy; PT = prothrombin time.

ences. Genetic components are suggested given that female relatives of patients with IHCP often develop IHCP and it is seen in successive generations (30 to 50% report a positive family history). Further support for this is the high recurrence rate in subsequent pregnancies. Nearly half of the women who develop IHCP will also develop jaundice when using oral contraceptives, suggesting that the genetic defect is in estrogen processing.

Estrogen concentrations peak in the third trimester of pregnancy, perhaps explaining the onset of illness during this time. Serum bile acids are also markedly increased (10 to 100 times normal), suggesting decreased hepatic capacity to either process or transport them. Both estrogens and monohydroxy bile acids are conjugated within the liver. It has been postulated that a genetic defect in sulfotransferase activity leads to the accumulation of toxic metabolites via glucuronidation. Mutations have been described in the MDR3 gene, which encodes for a biliary canalicular phospholipid translocater. MDR3 has been associated with familial forms of intrahepatic cholestasis and in women with IHCP associated with an elevated GGT. Exogenous progesterone administration or impaired secretion of progesterone metabolites has also been implicated as a trigger for IHCP in predisposed women.

Nearly all affected women report intense pruritus, which typically involves the palms and soles, but may be diffuse. Pruritus is often worse at night and becomes progressively severe as the pregnancy progresses. It may precede abnormalities in liver tests. There appears to be no correlation between serum levels of bile acids and the severity of pruritus.

Pruritus gravidarum, clinical jaundice within 1 to 4 weeks after onset of pruritus, develops in 10 to 60% of patients. The skin appears normal but patients may have excoriations secondary to scratching. Systemic symptoms are generally mild (see Table 120-2). Elevation in bilirubin correlates with jaundice and is rarely greater than 5 to 6 mg/dL. GGT levels are normal to minimally elevated. Prolonged pro-thrombin time (PT) generally reflects the vitamin K deficiency resulting from impaired bile salt formation. Serum bile acids are often as high as 100 times normal (bile acid concentrations change little during normal pregnancy) and are the most sensitive marker for IHCP. They may be the only abnormality, however, absolute levels do not correlate with maternal symptoms, other liver tests, or with prognosis.

Diagnosis is made clinically, based upon history, symptoms, and laboratory studies. Other causes of liver disease, such as viral hepatitis or gallstone disease, must be ruled out. Liver biopsy is rarely needed and histopathology reveals normal portal tracts, and bland cholestasis, with bile plugs predominating in zone 3.

Maternal management of IHCP is symptomatic and the most common approach is early delivery (generally 37 to 38 weeks). Oral vitamin Kshould be started at the time of diagnosis and, when given before delivery, can minimize postpartum hemorrhage. Treating pruritus is more problematic. Antihistamines and benzodiazepines have been used with little success. Studies using phenobarbitol have been contradictory and it may cause neonatal respiratory depression. Dexamethasone (12 mg/d for 7 days with 3 day taper) has been shown to improve pruritus. Controlled trials have not been done, however, and there is a report of worsened liver function with dexamethasone use. Studies with S-adenosyl-methionine have shown conflicting results. In two randomized controlled trials, it significantly decreased pruritus (800 mg/d intravenously or 1,600 mg/d orally). In a third double blind randomized controlled trial, no improvement was seen. Pruritus has been successfully treated with cholestyramine at 8 to 16 g per day, although it is usually poorly tolerated. It must be used with caution as it may worsen maternal absorption of Vitamin K and maternal steatorrhea.

Therapy with ursodeoxycholic acid (UDCA) at dosages of 15 mg/kg/d leads to a reduction in pruritus, a reduction in maternal serum bile acids and maternal aminotransferases, and a reduction in delivery of bile acids to the fetus. UDCA also appears to decrease negative maternal and fetal sequelae. UDCA can cross the placenta, but there have been no reports of fetal toxicity. Because UDCA appears safe to mother and fetus, it is reasonable to consider its use, keeping in mind that it is not approved for this indication in the United States. Larger randomized controlled trials are needed.

Maternal prognosis is excellent with IHCP and there are usually no hepatic sequelae. Symptoms progress until delivery and then promptly disappear. Jaundice resolves rapidly and serum laboratory tests resolve over weeks to months. Acute liver failure does not occur. IHCP is associated with an increased incidence of primary postpartum hemorrhage (20 to 22%), likely due to vitamin K deficiency. The incidence of cholelithiasis is also increased.

Fetal prognosis is less benign. Fetal morbidity and mortality are significantly increased. Premature labor (6 to 60%), meconium-stained amniotic fluid (26 to 58%), fetal distress (17 to 22%), and stillbirth (1 to 3%) are all seen. Early reports of fetal mortality were as high as 10 to 15%; however, with more aggressive management, this is improving (1.7 to 3.5%). Unfortunately, there are no antepartum tests, which predict fetal compromise.

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