intrahepatic cholestasis of pregnancy

Intrahepatic Cholestasis of Pregnancy Karen M. Davidson

Intrahepatic cholestasis of pregnancy (ICP) is a disease of the third trimester of pregnancy involving pruritis and elevated bile acid levels. Its pathogenesis likely involves a genetic hypersensitivity to estrogen. Once thought to be benign for both mother and fetus, ICP has been associated with increased rates of fetal morbidity and mortality and an increased risk of maternal coagulopathy. Optimal obstretic management includes delivery after establishment of fetal lung maturity. Many treatments have been proposed for the maternal medical management of ICP, none of which is ideal. Copyright �9 1998 by W.B. Saunders Company

ntrahepat ic cholestasis o f pregnancy (ICP) is a disease characterized by skin pruritis and

biochemical cholestasis occurr ing primarily in the third tr imester of pregnancy. Evidence of cholestasis persists until delivery, at which time a rapid resolution of pruritis and cholestasis occurs. Although thought to be benign for 'mothers, ICP has been associated with an increased incidence of meconium-sta ined amniot ic fluid, fetal distress, spontaneous p re t e rm delivery, and intrauterine fetal demise. The pathogenesis of the disease has not been fully elucidated, and the optimal t rea tment is still unde r debate.

Epidemiology

ICP occurs with a strikingly uneven prevalence th roughout the world. In most countries, ICP is a rare disorder, occurring with an incidence ranging f rom 1 in 1,000 to 1 in 10,000 deliveries) There is a markedly increased incidence in Swe- den and Chile, where the disease occurs in 2% and 14% of deliveries, respectively. 1 Certain tribes of Indians in Chile have prevalence rates as high as 24%, 2 suggesting a role for genetic factors in the deve lopment o f ICP. In addition, ICP shows consistent seasonal variations, with an increased incidence in winter months, sA

ICP occurs with equal f requency th roughout all maternal ages, and occurs in both multipa-

From the Division of Maternal Fetal Medicine, Department of Obstet- rics and Gynecology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. Address reprint requests to Karen M. Davidson, MD, Division of Maternal Fetal Medicine, Brigham and Women's Hospital, 75 Fran- cis St, Boston, MA 02115. Copyright �9 1998 by W.B. Saunders Company 0146-0005/98/2202-0003508.00/0

rous and pr imiparous women. It frequently re- curs in mul t iparous women who have had previously affected pregnancies and is more c o m m o n in multiple gestations. 5'6 In a retrospective study pe r fo rmed in Sweden, 7 ICP was more c o m m o n in women who had mothers or sisters with a history of ICP.

Pathogenes is o f ICP

Cholestasis describes the blockage or suppression of bile flow caused by intrahepatic or extra- hepatic causes. When the liver has a diminished capacity for absorpt ion or excretion of bile, some of the normally excreted bile acid causes partial or total destruction of the liver cell m e m b r a n e and is released into the blood, s The very high serum bile acid levels found in ICP are indicative of a disturbed enterohepat ic circulation with a decreased capacity of hepatocytes to t ransport bile acids. 9'1~

The cause of ICP is unknown, however, there is much indirect evidence to suggest that estrogen plays a pivotal role in the deve lopment of ICP. ICP only occurs in pregnancy, and resolves p r o m p d y after delivery. Patients with increased estrogen levels, such as those carrying twins, have an increased incidence of the disease. Addition- ally, ICP resembles contraceptive p i l l - induced cholestatic hepatitis. There is an increased risk of developing ICP dur ing pregnancy in patients with a history of this form of hepatitis.

In exper imenta l models, estrogen is capable of altering bile excret ion to a variable extent in normal volunteers. Patients with a past history of ICP show a more dramatic alteration in bile excretion in response to estrogen ingestion. 12 Es- t rogen is not the only factor involved in the

104 Seminars in Perinatology, Vol 22, No 2 (April), 1998: pp 104-111

Intrahepatic Cholestatis of Pregnancy 105

pathogenesis of the disease, however, because ICP does not develop in all of the pregnancies of some patients, and ICP does not develop in many women with a history of contraceptive pi l l - induced cholestasis. The development of ICP likely involves the interaction of pregnancy with a number of o ther factors, including a genetic predisposition.

Observations of the markedly increased prevalence in certain countries a round the world, including Chile and Sweden, have suggested a role for genetic factors in the development of ICP. ICP is more common in women who have a mother or sister with a history of ICP. 7 Studies of family pedigrees with many generations of women affected by ICP point toward a possible inheri tance of a predisposition toward ICP in a Mendelian autosomal dominant pa t t e rn ) s'l~ A study of HLA haplotype distribution in Chile, however, showed no differences between those patients with a history of ICP and normal con- trois after controlling for patient race) 5 Like- wise, a recent study of Class II HLA alleles found no significant difference between patients with ICP and controls) 6 It is not likely, therefore, that an HLA allele primarily confers susceptibility or resistance to ICP.

Recent hypotheses suggest that ICP may be caused by an inheri ted deficiency of sulphotransferase activity, the enzyme used for detoxifica- don of bile acids in the liver. Pregnancy has been shown to decrease sulphotransferase activity. 17 No fur ther decrease, however, was noted spe- cifically in patients with ICP. It was felt that an additional componen t of the bile acid detoxification process may be differentially diminished in patients susceptible to ICP.

Another recent hypothesis suggests that ICP may be caused by an inheri ted hypersensitivity to estrogens at the gene level in the liver. TM Estro- gen or another pregnancy ho rmone may elicit a change in the expression of actin genes, which participate in the regulation of the structure and function of actin microfilaments. The actin microfilaments are necessary as a mediator of bile secretion by hepatocytes. An alteration of the structure or function of the microfilaments may result in cholestasis. Research is currently ongo- ing to test this hypothesis.

Clinical Course The hallmark of ICP is skin pruritis without evidence of skin lesions occurring in late preg-

nancy. Pruritis generally starts in the palms and soles, later extending to the truck and extremi- ties. In severe cases, it can involve the face, neck, and ears and only rarely involves mucosal sur- faces. Most patients repor t nocturnal exacerba- tions of pruritis, leading to severe sleep depriva- tion and fatigue. Mild jaundice is seen in 20% of patients, often accompanied by dark urine and hyperbilirnbinemia.19 Additionally, some patients repor t anorexia, nausea, and vomiting. Physical examination findings are remarkable for a lack of evidence of chronic or acute liver disease, with a non tender liver of normal size. Approximately 80% of patients show signs and symptoms of ICP after 30 weeks' gestation, with a rare patient presenting before 25 weeks) 9 A complete resolution of pruritis frequently occurs within days of delivery, whereas laboratory abnormalities may take 4 to 6 weeks to re turn to normal values)

The most specific laboratory evidence of ICP is serum bile acid levels, which are consistently elevated to values 100 times above normal. 9 In patients followed-up prospectively, serum bile acid elevations, especially cholic acid, can pre- cede onset of clinical symptoms by several weeks, z~ Mild to moderate elevations of serum aminotransferases to values 2 to 10 times normal are seen in 20% to 60% of patients. 6"~~ Alkaline phosphatase levels rise variably in ICPfl 1 Although sensitive markers of o ther types ofcho- lestasis, T-glutamyl transpeptidase and 5'- nucleotidase are not increased in ICPfl ~ In patients with clinical jaundice, serum total and direct bilirubin levels are mild to moderately elevated, only rarely above 10 m g / d L ) 9

Liver biopsy findings show mild cholestasis with intracellular bile pigment and canalicular bile plugs. Electron microscopy sections display dilated canaliculi with loss of microvilli and thickening of the pericanalicular filamentous network. ~s

The diagnosis of ICP requires exclusion of o ther causes of pruritis, jaundice, and abnormal liver function test results. Patients should have no evidence of biliary colic, or o ther manifesta- tions of gallstone disease, as seen on right upper quadrant ultrasound examination. Patients with ICP do not display evidence o f fever, acutely tender upper abdomen, or markedly elevated bilirubin levels, all o f which are more consistent with hepatitis. Profuse vomiting, mental status

106 Karen M. Davidson

changes, severe coagulopathies, or hypertension should raise the question of acute fatty liver of pregnancy or preeclampsia. Most importantly, in ICP, the patient 's symptoms and laboratory abnormalities must disappear after delivery. If this does not occur, o ther forms of cholestasis, including primary biliary cirrhosis, must be considered.

Although not u n c o m m o n in pregnancy, cho- lelithiasis occurs more frequently and with an earlier onset in patients with I C P . 24 It is thought that ICP may lead to functional and metabolic changes, which predispose patients to forming gallstones. Urinary tract infections may also be more common in patients with ICP, with several studies report ing a 50% incidence of urinary tract infection at the onset of I C P . 25'26 Trea tment of the infection in some patients coincides with an improvement in pruritis and laboratory abnormalities. Acute fatty liver of pregnancy (AFLP) has been repor ted to coexist in a series of seven patients in Chile and one patient in France. 27'2s The presence of ICP was credited for the early diagnosis of AFLP, because the patients' symptoms of pruritis brought them to medical attention. ICP currently has not been implicated as causative factor in AFLP, but it is important to be aware of the possibility of the two disorders occurring simultaneously.

Maternal Outcome Although long-term outcome is good for the mother affected by ICP, morbidity during pregnancy can be considerable. Nocturnal itching can lead to severe fatigue, whereas anorexia and nausea can result in poor maternal weight gain. Cholestasis frequently leads to malabsorption of fat-soluble vitamins, 29 worsening maternal nutri- tional status. In addition, ICP has been associated with a 20% incidence of postpartum hemorrhage, a~ and one case of an epidural hematoma in a patient with ICP recently has been reported, as The tendency toward bleeding found in patients with ICP may be caused by inadequate absorption of vitamin K, which prevents the normal synthesis of coagulation factors by the liver. There have been no maternal deaths repor ted as a result of ICP.

Fetal Morbidity and Mortality Early reports of ICP considered the disease to be benign for both mother and fetus. 34"~6 Subse-

quent reports have shown a consistent pattern of increased rates of fetal morbidity and mortality. 4'3~ Overall perinatal mortality rates in early observational studies were 10% to 11%. 3~ Thick meconium was repor ted in these studies in 27% to 58% of pregnancies, 3~ spontaneous pre term delivery in 36% to 44%, a~ and intra- par tum fetal distress in 22% to 33%. 31'32 At- tempts to correlate risk of fetal morbidity and mortality with maternal disease severity have been met with mixed success. Laatikainen and Tulenhe imo 39 found a correlation between serum bile acids and the incidence of meconium and intrapartum fetal distress. Several o ther studies were unable to correlate any aspect of maternal disease severity with likelihood of fetal morbidity o r mortality. 6'~1'4~

The mechanism by which ICP leads to poor fetal outcome is not entirely clear, but is felt to be secondary to toxic effects of maternal bile acids. 42 Fetomaternal bile acid homeostasis requires normal placental transfer of bile acids from the fetus back to the mother , where a normally functioning matemal hepatobiliary system can detoxify and excrete these toxic metabolites. Marked increases in maternal serum bile acid concentrat ions are thought to impair placental clearance of fetal bile acids. This leads to danger- ous accumulations of bile acids within the fetal liver and marked alterations in fetal liver metabolism. 43'44 Embryonic rat development has been shown to be adversely affected by bile acids, both in the period of differentiation and in organo- genesis. 45"~7 Additionally, infusion of cholic acid to fetal sheep increases the incidence of meconium passage, likely because of increased co- Ionic motility. 48 Bile acids also stimulate prosta- glandin release in the rat, increase myometrial responsiveness to oxytocin, 46 and increase myometrial contractility. 47 It is hypothesized that these events may combine to initiate premature labor and delivery. 49

The etiology of intrauterine fetal demise in ICP also is not clear. It has been hypothesized that a reduction in the size of the space of the placenta in ICP from trophoblast swelling and villous edema may impair fetal oxygenation by reducing maternal blood flow through the intervillous space. 5~ More recent studies, however, have noted no difference in placental intervillous perfusion and umbilical circulation between patients with ICP and normal controls. 51'52 In

lntrahepatic Cholestatis of Pregnancy 107

keeping with these findings, fetuses of women with ICP are not typically growth restricted and have normal Doppler umbilical artery velocimetry, suggesting that chronic placental insuffi- ciency probably is not a key componen t in the etiology of fetal demise. 52"5~ Meconium has been shown to cause acute umbilical vein constriction in experimental models, leading to an acute reduction in umbilical flow and subsequent fetal death. 54'55 Furthermore, autopsy specimens in cases of intrauterine fetal demise from ICP are consistent with death from acute anoxiaP 3

Obstetric Management

Given the risks of fetal morbidity and mortality, many protocols have been proposed to improve obstetric outcome. A review of fetal ou tcome with ICP at one institution from 1965 to 1974 showed a perinatal mortality rate of 107 in 1,000P 2 A policy of expectant management was practiced, with no antepartum fetal surveillance. During the subsequent 10 years at the same institution, the perinatal mortality rate was cut to 35 in 1,000 with the institution of intensive fetal surveillance and elective delivery once fetal lung maturity was achieved, s~ The investigators admit, however, that the fetal deaths were not predictable f rom the antepartum fetal testing that was per formed and that severity of maternal disease was not correlated with fetal outcome.

In a recent study by Rioseco et al, 6 a protocol of obstetric management in ICP was evaluated retrospectively. Patients with ICP were monitored with weekly nonstress tests starting at 34 weeks' gestation. Induct ion of labor was performed at 38 weeks with documented lung maturity in cases of mild disease, or at 36 weeks with mature indices in patients with jaundice. Thei r policy of active intervention resulted in a perinatal mortality rate that was not statistically different f rom a control group of normal obstetric patients. Patients with ICP demonstra ted many of the previously recognized obstetric complications, including a threefold increase in spontaneous pre term delivery, and a twofold increase in meconium-stained fluid. The investigators concluded that active intervention improves perinatal outcome to levels comparable with control patients. Of note, however, is that each of the intrauterine fetal deaths in the ICP patients oc- curred within 6 days of a reassuring nonstress

test, implying that the precipitant behind fetal death may be an acute, unpredictable event.

Another recent study came to a similar conclusion in their patient population. 41 The outcome of patients with ICP was compared with the outcome of control patients with a history of intrauterine fetal death in a previous pregnancy. Both groups of patients underwent weekly nonstress test and amniotic fluid volume assessment starting at 34 weeks. Patients underwent follow- up expectantly until spontaneous onset of labor, evidence of nonreassuring testing, or 42 weeks' gestation. Two patients with ICP exper ienced an intrauterine fetal death for a perinatal mortality rate of 25 in 1,000. Both fetuses died within 5 days of reassuring testing. There were no fetal deaths in the control group. The investigators concluded that fetal death in ICP may not be predictable by traditional antepar tum surveillance, and that delivery after documenta t ion of fetal lung maturity may be a better me thod of decreasing fetal mortality rates in ICP.

Maternal Medical Management

The goal of t reatment in ICP is to decrease maternal symptoms and decrease the level of serum bile acids, which may be involved in poor fetal and obstetric outcome. The ideal medical treatment would work quickly and have little or no side effects to the mother or developing fetus. No medical t reatment currently is available that fulfills each of these criteria.

Pruritis is improved in some patients with the use of physical and psychological rest and a low- fat diet. 56 Likewise, antihistamines, benzodiaze- pines, and minor tranquilizers can give partial relief f rom pruritiS. 19 None of these therapies produce a change in the laboratory abnormalities of the disease or improve obstetric outcome.

Phenobarbital in low doses induces micro- somal enzymes leading to a decrease in bile acid synthesis and an increase in bile acid secretion. Several studies have noted an improvement in pruritis in approximately 50% of patients taking phenobarb i ta l ) 7'5s Other studies, however, have not found any significant symptomatic relief f rom itching, 59'6~ and no study has demonstrated an improvement in the laboratory evidence of cholestasis. It is hypothesized that the modest improvement in pruritis in some patients may be caused by central nervous system depression,

1 08 Karen M. Davidson

and not to any direct effect on bile acid metabolism.

Dexamethasone t reatment for ICP has been described in two reports. 6~ Dexamethasone theoretically improves ICP by suppression of fe- toplacental estrogen production. In 10 patients treated with dexamethasone in one observational study, all patients noted an improvement in pruritis and bile acid levels. A case repor t f rom Australia, however, noted a marked worsening of patient status after the initiation of dexamethasone therapy. More research is necessary before dexamethasone can be recommended,

Cholestyramine is a widely used t reatment for ICP-related pruritis. It acts as an anionic ex- change resin, binding to bile acids in the intestinal lumen and increasing bile acid fecal excretion. It has been shown to at tenuate pruritis in a majority of patients with I c P Y It is not, however, capable of improving biochemical parameters of ICP or fetal outcome. In addition, it has been associated with an increase in steatorrhea in most patients. More importantly, cholestyramine may worsen the malabsorption of fat-soluble vitamins, especially vitamin K~ 22'57'5s'62 leading to coagulopathies. Because both ICP and cholestyramine may independent ly lead to vitamin K deficiency, the combination of pro longed high- dose cholestyramine and concur ren t ICP may fur ther increase the risk of coagulopathy. 22 A case repor t of a severe fetal intracranial hemorrhage during t reatment with cholestyramine for ICP, has raised the possibility that severe maternal vitamin K deficiency may lead to fetal vitamin K deficiency and coagulopathy. 63 It has therefore been r ecommended that in patients treated with prolonged cholestyramine, parenteral vitamin K be administered and coagulation studies be monitored.

Epomeidol is a terpenoid compound that has been shown to reverse estrogen-induced cholestasis in rats, apparently by recovering liver cell plasma membrane fluidity. 64'65 In one series of seven padents with severe ICP, 66 epomeidol significantly improved the severity of pruritis in six patients. No changes were no ted in the laboratory abnormalities in any patient. No side effects were noted. More studies are necessary to deter- mine the efficacy and safety of this treatment.

The two most widely studied medications for ICP are S-adenyl-methionine (SAMe) and ursodeoxycholic acid (UDCA). In a rat model, SAMe

prevents the negative effects of ethinyl estradiol on bile flow and increases the bioavailability of sulphates necessary for the detoxification of bile acids. 67"7~ SAMe therefore is theoretically capable of not only preventing, but also reversing the estrogen-induced impairment of bile secretion. 7a In an observational study, nine patients treated with a regimen of 800 mg of parenteral SAMe were all noted to have an improvement in pruritis and biochemical parameters of cholestasis, with no side effects noted. 72 In two single blind, randomized control led studies, Frezza et a173'74 found a significant decrease in pruritis, bile acids, and aminotransferases after a 20-day treatment course of 800 mg of parenteral SAMe. Pa- tients receiving placebo or 200 mg of SAMe noted no such improvement. No side effects were noted in any patient and fetal outcome was not significantly different between t reatment arms. In contrast, Ribalta 56 per formed a randomized controlled trial with 800 mg of parenteral SAMe versus placebo and noted no significant differences in pruritis or in bile acid levels. There were no side effects of t reatment and no differences in fetal outcome. O f note, this study enrolled only patients with severe, early-onset ICP. It was hypothesized that SAMe may not be as effective if cholestasis is already well estab- lished at the onset of treatment.

Ursodeoxycholic acid (UDCA) is a naturally occurring hydrophilic bile acid that modifies the bile acid pool composition by replacing o ther bile acids that are more cytotoxic to liver cell membranes. 75-7s It also inhibits intestinal absorption of more cytotoxic bile acids 79'8~ and may modify the immune mechanism of liver injury in cholestasis, sl In several small case series, UDCA given orally was found to significantly reduce pruritis, bile acids, and transaminases. 82"s4 No maternal side effects were noted in these small series. Although no adverse fetal effects were noted in these series, there has been a concern for the safety of UDCA on the developing fetus. No fetal effects were noted in three studies in rats, mice, and rabbits, s5'86 In two other rat studies, however, UDCA was noted to be incorpo- rated into the bile acid pool s7 and shown to in- duce cytotoxic and embryotoxic effects, a7 It has been suggested that UDCA may potentiate toxic fetal effects by increasing the bile acid p o o l No adequate human studies have been per formed to evaluate this possibility.

Intrahepatic Cholestatis of Pregnancy 1 0 9

A recent randomized trial was performed to directly compare the efficacy and safety of UDCA and SAMe. 88 Twenty patients were selected ran- domly to receive either a 20-day course of oral UDCA or intramuscular injections of SAMe. All patients receiving UDCA noted a significant improvement in pruritis score and a significant drop in bile acid levels. Pruritis persisted without significant change in all patients treated with SAMe, and no change was noted in bile acid levels. No adverse maternal side effects were noted in ei ther group. There were also no adverse fetal effects in either group. They concluded that in their small randomized trial, UDCA was clearly superior to SAMe in symptomatic and laboratory improvement for ICP. It is important to note that the administration of SAMe in this trial was by daily intramuscular in- ject ion as opposed to intravenous administration, as was used in all previous trials of SAMe. It is not clear if this would impact patients' symptomatic score of pruritis. Additionally, conclu- sions cannot be drawn regarding fetal safety of UDCA in a sample as small as 10 patients. Al- though these medications likely are to be used in the future for the t reatment of ICP, more research is necessary to establish their efficacy and safety.

Conclusion

ICP is a disease characterized by the onset of pruritis and elevations in bile acids in late pregnancy, with p rompt resolution soon after delivery. The pathogenesis of ICP is unknown but probably involves a genetic hypersensitivity of the hepatobiliary system to estrogen. Maternal morbidity is minimal, but fetal morbidity and mortality can be substantial. The most likely ex- planation for intrauterine fetal death appears to be one of an acute anoxic event, which is poorly predicted by maternal disease severity or conven- tional antepar tum testing. Optimal obstetric management should include delivery after estab- l ishment of fetal lung maturity. Many treatments have been proposed for the maternal medical management of ICP, none of which is ideal. Fur- ther research is necessary to establish the efficacy and safety of the two most promising treatments, UDCA and SAMe.

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1 1 0 Karen M. Davidson

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