INTRAHEPATIC CHOLESTASIS OF PREGNANCY
Synonyms: Cholestasis of pregnancy Obstetric cholestasis Cholestatic jaundice of pregnancy Pruritus/prurigo gravidarum
Key features
Pruritus without primary skin lesions with an onset during the third trimester
Secondary changes correlate with disease duration and vary from subtle excoriations to severe prurigo nodularis
Elevated total serum bile acid levels are diagnostic; histology is nonspecific and IF is negative
Increased risk of prematurity, intrapartum fetal distress, and stillbirths
Recurs in 45%–70% of subsequent pregnancies
Introduction
Intrahepatic cholestasis of pregnancy (ICP) is a rare form of genetically linked, hormone-dependent, reversible cholestasis. It typically presents late during pregnancy with dramatic pruritus. Although maternal prognosis is usually good (a small minority may develop steatorrhea and vitamin K deficiency), fetal risk is significant. As a result, ICP is the most important pruritic gestational condition to consider then promptly diagnose and treat in order to prevent fetal impairment.
History
ICP was first described in 1907 by Kehrer. In the past, much of the confusion arose from applying descriptive names such as “pruritus
gravidarum” for ICP without skin changes or “prurigo gravidarum” if skin lesions associated with scratching were present. While the first term was often combined with the mild unexplained pruritus that occurs in many women during pregnancy (most likely related to an atopic diathesis), the latter was confused with “prurigo of pregnancy” (see below). Because laboratory evaluation, including measurement of serum bile acid levels, was performed in only a minority of women, ICP was often missed.
Epidemiology
There are striking geographic and ethnic differences in the incidence of ICP. For example, it is most commonly observed in South America, with the highest incidence rates in Bolivia and Chile (9%–16%), particularly among Araucanian Indian women (~30%). In contrast, rates of 0.1% to 1.5% have been described in Europe and North America, with relative “hot spots” in Scandinavia and the Baltic states (1%–2%). Some of the variance is probably explained by different reporting criteria; however, endemic clustering and a positive family history in up to 50% of those affected point towards a genetic predisposition. A higher incidence of ICP is also seen in multiple-gestation pregnancies, which may be related to higher hormonal levels (e.g. estrogen) in these patients.
Pathogenesis
The key element is reduced excretion of bile acids, which leads to increased serum levels. This not only provokes severe pruritus in the mother, but also may have deleterious effects on the fetus. Toxic bile acids crossing the placenta can lead to acute fetal anoxia due to abnormal uterine contractility and vasoconstriction of chorionic veins as well as impaired fetal cardiomyocyte function. One predisposing factor is mutations in genes (e.g. ABCB4, ABCB11, ABCC2) that encode bile transporter proteins. While mild dysfunction of these canalicular transporters may not lead to clinical symptoms in non-pregnant individuals, when the transporters’ capacity to secrete substrates is exceeded (as occurs in the setting of high levels of sex hormones during pregnancy), signs and symptoms of cholestasis can develop. Other contributing factors are the cholestatic effect of estrogen and progesterone metabolites, which peak late during pregnancy, and hepatitis C viral infection (see below). Furthermore, dietary factors such as selenium deficiency and increased intestinal permeability (“leaky gut“) have been suggested as possible triggers.
Clinical Features
Patients typically present during their last trimester with a sudden onset of intense, generalized pruritus that often starts on the palms and soles. No primary skin lesions are seen, and secondary changes due to scratching vary from subtle excoriations early on to pronounced prurigo nodularis in those with pruritus of longer duration (Fig. 27.7).
The extensor surfaces of the extremities, buttocks, and abdomen are usually most severely affected.
Although jaundice is often mentioned as a common finding in ICP, it actually occurs in only 10% of patients. Jaundice is usually a complication in those with the most severe and prolonged episodes of ICP. In such patients, concomitant extrahepatic cholestasis may be associated with steatorrhea and subsequent vitamin K deficiency, leading to an increased risk of intra- and postpartum hemorrhage.
Pruritus typically persists until delivery and then it resolves spontaneously within days. A protracted course is very unusual and should prompt one to exclude other liver diseases, especially primary biliary cirrhosis. Recurrence during subsequent pregnancies occurs in 45%–70% of patients, and recurrence with oral contraceptives is routine. No detectable abnormalities are generally present between gestations.
ICP is associated with significant fetal risk, in particular an increase in premature births (20%–60%), intrapartum fetal distress (20%–30%;
e.g. meconium staining of amniotic fluid, abnormal fetal heart rate), and fetal loss (1%–2%). Fetal risk correlates with the elevation in serum bile acid levels, especially when levels exceed 40 μmol/l. Thus, prompt diagnosis and treatment is essential, as is close obstetric surveillance.
Pathology
Histologic findings in the skin and the liver are nonspecific and direct IF of perilesional skin is negative. The diagnosis is confirmed by an increase in total serum bile acid levels (>11 μmol/l in a pregnant woman; normal range in non-pregnant women, 0–6 μmol/l). Levels may range from 3 to 100 times normal. During pregnancy, alkaline phosphatase levels typically increase (placental origin) even in the absence of ICP, and γ-glutamyl transferase levels are usually lower than in the non-pregnant state. Serum levels of transaminases are usually elevated in those with ICP, but may be normal in 30% of patients. In women with jaundice, conjugated (direct) bilirubin levels are increased and the prothrombin time may be prolonged. Hepatic ultrasonography generally is normal but may reveal gallstones in jaundiced patients, who are at increased risk for their development.
Differential Diagnosis
In the absence of primary lesions, the clinical differential diagnosis includes other causes of primary pruritus (see Ch. 6), including those that lead to cholestatic pruritus. Viral hepatitis is a common disorder and should be excluded by appropriate serologies. Of note, a history of hepatitis C viral infection is considered a risk factor for the development of ICP, and in one study, 20% of the women who were HCV RNA-positive developed ICP.
Treatment
Since fetal prognosis correlates with disease severity, the therapeutic goal is reduction of serum bile acid levels. This allows prolongation of the pregnancy and lessens both fetal risk and maternal symptoms. To date, the only successful agent has been oral ursodeoxycholic acid (UDCA). It is a naturally occurring, hydrophilic, non-toxic bile acid that has been used for a variety of cholestatic liver diseases. Although the exact mechanism of action in ICP is still not fully under-stood, there is evidence that UDCA corrects the maternal serum bile acid profile, decreases the passage of maternal bile acids to the fetoplacental unit, and improves the function of the bile acid transport system across the trophoblast. In a recent systematic review and individual participant data meta-analysis, prenatal UDCA was associated with a reduction in stillbirth in combination with preterm birth. The authors concluded that UDCA should be prescribed, especially in women whose disease onset was before 37 gestational weeks and whose serum bile acid concentrations were ≥40 μmol/l.
UDCA is safe for mother and fetus, with its only side effect being mild diarrhea. Use of UDCA for ICP is off-label as it is only approved for primary biliary cirrhosis. The recommended oral dose is 15 mg/kg daily or, independent of body weight, 1 g daily. It should be started as early as possible and administered until delivery.
The use of S-adenosylmethionine, dexamethasone, epomediol, silymarin, phenobarbital or activated charcoal is not recommended as none have been shown to decrease fetal risk. Cholestyramine is contraindicated as it can further reduce vitamin K absorption and increase the risk of bleeding. In jaundiced patients, the prothrombin time should be monitored, and intramuscular vitamin K administered as necessary. Close interdisciplinary collaboration with the obstetrician is essential and close monitoring of the fetus is recommended.
Fig. 27.5 Polymorphic eruption of pregnancy. The clinical spectrum includes: A urticarial papules and plaques, some of which demonstrate a steal phenomenon; B macular erythema, which can be widespread; C targetoid lesions; D tiny vesicles due to marked epidermal spongiosis or dermal edema; and E eczematous plaques, especially as lesions age.
Fig. 27.6 Polymorphic eruption of pregnancy – histopathologic features. In this early lesion, a superficial and deep perivascular and interstitial lymphohistiocytic infiltrate is seen within the dermis. Numerous eosinophils are also present (inset).
Fig. 27.7 Intrahepatic cholestasis of pregnancy. Marked pruritus leads to secondary skin lesions that vary based on disease duration, from subtle linear excoriations and prurigo simplex early on (A) to pronounced prurigo nodularis when the pruritus is longstanding (B). From Ambros-Rudolph CM, Glatz M, Trauner M, et al. The importance of serum bile acid level analysis and treatment with ursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a case series from central Europe. Arch Dermatol 2007;143:757–62. © (2006) American Medical Association. All rights reserved.