Keywords
intrahepatic cholestasis of pregnancy - plasmapheresis - bile acid - hepatitis C
Intrahepatic cholestasis of pregnancy (ICP) is a rare complication of pregnancy which
manifests as pruritus due to increased bile acids, usually during the third trimester
of pregnancy.[1] Although the etiology of ICP is unknown, it appears that both genetic and environmental
factors play a role in its development.[2]
Fetal complications such as prematurity and stillbirth may result; therefore, delivery
is often induced as early as possible (i.e., typically 36 weeks). ICP then typically
resolves in days to weeks. Temporizing treatment is often aimed at symptom relief
by lowering bile acid levels by preventing its absorption with ursodeoxycholic acid
(UDCA) or cholestyramine.
Therapeutic plasma exchange (TPE; also known as plasmapheresis) is the replacement
of patient plasma with a replacement fluid such as 5% albumin. A common TPE procedure
is called a “one plasma volume” replacement that replaces approximately 63% of the
patient's starting plasma volume. The rationale for using TPE in ICP is to remove
bile acid from the plasma which will then cause bile acid to be removed from the affected
tissues via equilibration between the two compartments. Such an equilibration typically
occurs in large part over the 2 days following the procedure.
Direct removal by TPE or other mechanisms can also be used to provide dramatic relief
lasting up to 5 days in cases refractory to medical therapies. A case report in 2005
demonstrated that TPE provided substantial and instantaneous relief for a patient
with severe ICP that was refractory to medical therapy.[3] That 2005 case report initially informed us of the potential utility of TPE in ICP.
In addition, other case reports demonstrated that TPE provided symptom relief for
pregnant patients with cholestasis due to other causes such as primary biliary cirrhosis[4] and progressive familial intrahepatic cholestasis.[5]
Women infected with hepatitis C seem to be at increased risk of ICP including a slightly
earlier onset of symptoms.[6] The patient reported here is unusual because rather than an onset at ∼23 to 31 weeks
as has been reported previously, her onset of symptoms was 8 weeks.
Methods
We performed a retrospective chart review of the patient's medical record.
Results
We present a 26-year-old G2P1001, whose previous pregnancy resulted in a full-term
vaginal delivery of a healthy girl. She has a history of active hepatitis C since
birth, for which she has failed two previous antiviral regimens secondary to therapy-induced
leukopenia. She is not on any medications and is awaiting novel hepatitis C regimens
which do not involve interferon. The patient is otherwise healthy, with no other treated
medical conditions.
She had an uncomplicated pregnancy until she started having diffuse itching without
visible skin manifestations starting around 8 weeks' gestation. This was soon diagnosed
as ICP. She did not have this problem with her first pregnancy 2 years prior. At 15
weeks' gestation, she developed severe insomnia secondary to her itching. The onset
of ICP symptoms at such an early gestational age is a relatively rare.
Initial therapeutic recommendations included cold baths, UDCA, and diphenhydramine.
She was granted initial relief by these therapies, but her symptoms continued to progress
despite optimal medical therapy. Her bile acids were markedly high throughout pregnancy
(25–89 µmol/L), despite treatment with cholestyramine and UDCA. Bilirubin and lactate
dehydrogenase remained normal, and her aspartate transaminase/alanine transaminase
was mildly elevated ([Fig. 1]). Mild symptomatic relief was reported with UDCA. All other medications were discontinued
secondary to side effects and failure to provide significant relief of her symptoms.
Fig. 1 Serum ALT, AST, and bile acid levels along with dates of TPE. ALT, alanine transaminase;
AST, aspartate transaminase; TPE, therapeutic plasma exchange.
As she had failed conventional medical therapy, it was decided to give her a trial
of TPE, as this has been reported to provide lasting relief in patients with ICP,
lasting up to 5 days. Seven TPEs with 5% albumin were administered over 4 weeks. The
dates were 6/17, 6/24, 7/1, 7/8, 7/11, 7/15, and 7/1 (see [Fig. 1]). Although the first TPE did not totally relieve her itching, it made it bearable.
These effects initially lasted about 2 days; therefore, TPE was planned for twice
a week until her initially scheduled delivery at 36 weeks' gestation. Later TPEs provided
minimal relief and, per patient reports, may have actually worsened her itching. As
a result, TPE was discontinued at 32 weeks' gestation.
Due to the progressive nature of her symptoms and out of concern for possible complications
to her child, her planned delivery was bumped up to 34 weeks. Although the initial
recommendation before TPE was to use TPE as a bridge to delivery at 36 to 37 weeks,
extensive counseling and collaboration led to a revised plan of 34 weeks with betamethasone.
The main factor was the concern for increased risk of unpredictable fetal demise due
to both the magnitude of bile acid level and the rapid rate of increase of bile acid
levels despite multiple therapies. In the interim, she was able to get some mild relief
of her pruritus and insomnia with continued UDCA use and zolpidem, respectively.
She had an uncomplicated delivery induced at 34 weeks, and reported 90% relief of
symptoms at 2 weeks postpartum. Her child had an uncomplicated neonatal intensive
care unit stay for observation with no evidence of sequelae from premature delivery.
Discussion
Case reports and series have demonstrated that TPE often provides dramatic relief
of itching and related insomnia in patients who have cholestatic disease refractory
to standard medical management, regardless of the cause of cholestasis. This effect
usually lasts for 4 to 5 days. Our patient never received quite the dramatic symptomatic
improvement reported in these case reports, and what little effect she did received
lasted at best, 1 to 2 days.
In addition, her bile acids level remained elevated despite treatment with both TPE
and oral medications. This fact underscores that TPE is not a cure-all of ICP. Its
place as a second-line therapy is secondary to multiple factors, including cost, potential
exposure to donors if plasma is used as a replacement fluid, and general effectiveness
of easier to use oral medications. We speculate that the comorbidity of hepatitis
C may have contributed to the early onset of symptoms and the refractoriness to TPE,
but we do not immediately have an explanation, mechanism, causality, or interaction.
We also speculate that charcoal administration could be a potential adjunct therapy.
This is based on a report of charcoal being associated with a significant decrease
in bile acid levels but not symptom relief.[7] We speculate that including charcoal as part of a combination of therapies might
further chip away at the bile acid level and might provide a decrement that would
be sufficient to go past the threshold for noticeable symptom relief. On the contrary,
the likely side effects of charcoal may cause patients to refuse a therapy that has
not been proven to provide consistent symptom relief.
The most feared adverse outcome of ICP is fetal demise; however, the reasons this
happens are currently unknown. About 90% of cases of fetal demise secondary to ICP
occur after 37 weeks; therefore, inducing delivery prior to 40 weeks is a sensible
option for many patients with relatively treatable ICP. Delivery earlier than 37 weeks
is often considered in the face of disease refractory to therapy or a prior history
of fetal demise in the setting of ICP. The current consensus is delivery at 36 weeks
for such patients. Patients who have experienced ICP in one pregnancy have a 45% chance
of experiencing this complication in future pregnancies; therefore, patients should
be informed of this in a larger discussion of potential future pregnancies.
