Bullous Eruption with Cholestasis in Pregnancy

Abstract

A 26-year-old female, 27 weeks pregnant (G2P1) presented to our clinic with a 2-week history of a progressively worsening, urticarial and bullous eruption that started on the abdomen and subsequently spread to the trunk and extremities. She reported significant nocturnal pruritus, disrupting her sleep andpredominately affecting her palms and soles. Her previous pregnancy had been uneventful. She was also not known to have atopy or any preceding dermatologic conditions. Clinical examination revealed pink to erythematous urticarial papules and plaques, with bullae at the periphery, distributed over the extremities and trunk, involving the umbilicus and sparing the peri-umbilical striae (Figure 1). Laboratory investigations were significant for elevated bile salts 16.5 μmol/L (normal < 10 μmol/L in pregnant women). All other investigations were unremarkable. Two 4-mm punch biopsies were taken from the abdomen for histopathology with hematoxylin and eosin (H&E) staining and immunofluorescence studies (Figure 2).

The clinicopathologic correlation was suggestive of pemphigoid gestationis (PG) with co-existing intrahepatic cholestasis of pregnancy. The patient's obstetrician started treatment with ursodeoxycholic acid (UCDA) 500 IU three times per day. Dermatologic management consisted of oral prednisolone 0.5 mg/kg, antihistamines, topical steroids, and emollients. The patient demonstrated improvement in pruritus and skin lesions, noted at a 2-week follow-up visit where most of the lesions resulted in post-inflammatory hyperpigmentation. The improvement continued throughout her pregnancy. Attempts to taper the dose of oral prednisolone resulted in a flare of disease, marked by the appearance of new bullae. Thus, she remained on the same dose until delivery. The patient delivered a healthy baby girl. There was no noted flare with delivery or in the postpartum period.

PG is an autoimmune bullous disorder with clinical and histologic overlap with bullous pemphigoid (BP). PG may occur at any stage of pregnancy but tends to favour the third trimester. The aetiology is due to anti-basement membrane zone auto-antibodies to BPAG2 (BP 180, collagen XVII). There is a strong association with HLA-DRs DRB1*0301 (HLA-DR3) and DRB1*0401/040X (HLA-DR4) [1]. Clinically, patients may experience intense pruritus with erythematous urticarial papules and plaques classically on the abdomen that often spread to the rest of the body [2]. Mucosal surfaces are often spared [1]. Histopathology, as in this case, demonstrated eosinophilic spongiosis of the epidermis with oedema of the upper and mid dermis. A perivascular lymphohistiocytic inflammation with abundant eosinophils was noted (Figure 2a). Direct Immunofluorescence (DIF) was significant for linear deposition of C3 (2 + ) and IgG (1 + ) along the basement membrane (Figure 2b).

Immunofluorescence studies are considered the gold standard for diagnosis of PG, and permit to differentiate PG from other entities. Linear C3 deposition along the BMZ with additional deposition of IgG is characteristic of PG [2]. Foetal risks observed in PG are low birth weight, prematurity, or a transient bullous eruption that resolves in several weeks [1], due to passage of maternal antibodies. There is no risk of stillbirth [2]. PG tends to be exacerbated by delivery, post-delivery use of oral contraceptives and can recur in subsequent pregnancies. When recurrent, it tends to have an earlier and more severe onset and course [1]. The main clinical differential is polymorphic urticarial papules and plaques of pregnancy (PUPPP), which classically involve the striae, carry no risk to the foetus, and do not tend to recur [1]. The suggested cornerstone of treatment of PG consists of topical or systemic corticosteroids. Immunoglobulin therapy, azathioprine, and dapsone have been used for refractory cases, with antihistamines often used as adjuvant therapy [3]. Recently, dupilumab was used successfully for a patient with PG, with improvement in symptoms and skin lesions after 4 weeks of therapy [4].

Intrahepatic cholestasis of pregnancy (ICP) is characterised by severe pruritus with no primary skin lesions; jaundice may or may not be present. Pruritus is initially confined to the palms and soles and later generalises. Like PG, ICP may recur in future pregnancies. There is no significant risk for the mother, however, prolonged cholestasis may result in Vitamin K deficiency or coagulopathy [5]. Risks to the foetus include preterm delivery or intrapartum foetal distress [2]. Stillbirth is an uncommon complication [2]. A meta-analysis comparing perinatal outcomes in patients with ICP and healthy controls found that stillbirths exceeded the general population rate only when total bile acid levels were 100 μmol/L or higher [6]. A reassuring feature in our case was that the serum bile acids were only mildly elevated and was rapidly corrected with UCDA. UCDA improves pruritus and prognosis by normalisation of impaired hepatobiliary secretion, protection of cholangiocytes against the cytotoxicity of hydrophobic bile acids, and protection of hepatocytes against bile acid-induced apoptosis [7]. As pregnancy advances, bile acids may increase, thus, monitoring of ICP is advisable for the well-being of the foetus.

Sara Al Janahi and Yusra Al Ali were both directly involved in the care and management of this patient, as well as writing the manuscript.

The patient in this manuscript has given written informed consent for participation in the study and the use of their deidentified, anonymized, aggregated data and their case details (including photographs) for publication. Ethical approval: not applicable.

The authors declare no conflicts of interest.