Keywords
gestational alloimmune liver disease - drug-induced liver injury - pregnancy - transaminitis
- liver - hepatocellular damage - liver dysfunction - antibodies - intravenous immunoglobulin
Background
Gestational alloimmune liver disease (GALD) occurs in 4 of 100, 000 pregnancies, characterized
by maternal antibody-facilitated destruction of fetal hepatocytes.[1]
[2] As there are usually no prenatal indicators of the underlying disease process, GALD
is often diagnosed postnatally in the setting of acute-onset fulminant neonatal liver
failure. Recurrence risk is significant (∼90%), but preventative treatment with intravenous
immunoglobulin (IVIG) can improve outcomes in subsequent pregnancies.[3]
[4]
[5] We describe a case of a pregnant patient receiving IVIG for a history of GALD who
developed drug-induced liver injury (DILI) precluding further IVIG treatment.
Case
A 33-year-old G3P0110 at 196/7 weeks with a dichorionic diamniotic twin pregnancy was transferred to our tertiary
center for prenatal care given her complex obstetric history.
In the preceding year, she had had a 36-week medically induced preterm vaginal delivery
for oligohydramnios following an otherwise uncomplicated pregnancy. The infant's postnatal
course was complicated by neonatal hypotonia, hypoglycemia, and hypotension requiring
vasopressor support on the day of life (DOL) #2, followed by the development of acute
kidney injury, hepatic failure with coagulopathy, and respiratory failure requiring
extracorporeal membrane oxygenation on DOL #3 to 4. Although initially concerning
for sepsis, extensive postnatal workup, including liver and salivary gland biopsies,
were suggestive of gestational alloimmune liver disease (GALD; [Fig. 1]). Despite exchange transfusions and IVIG), the neonate continued to decompensate
and ultimately died secondary to massive acute pulmonary hemorrhage on DOL #28; underlying
GALD diagnosis was confirmed on neonatal autopsy ([Fig. 1]).
Fig. 1 Hepatic and extrahepatic tissue histopathology from neonatal autopsy consistent with
gestational alloimmune liver disease with neonatal hemochromatosis phenotype (GALD-NH).
Microscopic examination notable for extensive lobular collapse with pericellular and
perivenular fibrosis on trichrome and reticulin stains (A, B), marked cholestasis with reactive bile ductular proliferation, hepatocyte giant
cell transformation with pseudorosette formation, as well as extensive ballooning
degeneration with cytoplasmic rarefaction. Extrahepatic iron deposition was observed
in (C) pancreas, (D) thyroid, (E) thymus, (F) submandibular gland, (G) heart, consistent with findings on (H) premortem neonatal salivary gland biopsy.
The patient's early prenatal care in this subsequent twin pregnancy was uncomplicated
with negative routine prenatal screening labs and low-risk cell-free DNA screening.
Anatomy sonogram demonstrated normal-appearing, appropriately and concordantly grown,
dichorionic diamniotic twins with normal amniotic fluid levels, normal-appearing placentas,
and a cervical length of 4 cm. She transferred to our higher-level prenatal care center
for initiation of IVIG prophylaxis for the remainder of the pregnancy given her high
risk for GALD recurrence.
Weekly IVIG (Privigen 60 g) was initiated for fetal hepatoprotection. Her complete
blood cell counts, basic metabolic panels, and liver function tests were serially
monitored as an outpatient, initially notable for transient, mild elevations in transaminases
after infusions. Moderate transaminitis was noted after her third infusion, progressing
to severe transaminitis with new scleral icterus following her fourth infusion. She
was admitted at 250/7 weeks for closer monitoring and expedited evaluation.
Her admission labs revealed elevated aspartate aminotransferase (AST) and alanine
aminotransferase (ALT; 1,866 U/L and 1,089 U/L, respectively), elevated total bilirubin
(11 mg/dL), elevated alkaline phosphatase (238 U/L), prolonged prothrombin time (PT;
14.4 seconds), hypoalbuminemia (3.2 g/dL), and elevated International Normalized Ratio
(INR; 1.16). Her workup was notable for elevated ceruloplasmin 65 mg/dL, ammonia 42
Umol/L, and total bile acids 140 Umol/L. Fibrinogen, lactate dehydrogenase, glucose,
creatinine, white blood cells, platelets, urine protein/creatinine ratio, ammonia,
acute viral serologies (Hepatitis A/B/C/E, Epstein–Barr virus, Cytomegalovirus, Herpes
Simplex virus), and autoimmune antibodies (anti-nuclear, anti-smooth muscle, anti-mitochondrial,
anti-liver kidney microsomal) were all within normal range. The patient was mentating
appropriately with normal vital signs and no reported pain, gastrointestinal upset,
or persistent pruritis. She reported taking only a daily prenatal vitamin with no
new medications other than IVIG. Fetal heart rate tracings were reassuring throughout
admission. She had an abdominal ultrasound only notable for prominent portal triads,
suggestive of acute hepatitis. As her transaminitis was persistent with worsening
hepatic synthetic function (INR peak 1.5, albumin nadir 2.3 g/dL), the decision was
made to perform an ultrasound-guided liver biopsy ([Fig. 2]).
Fig. 2 Clinical course of hepatitis lab abnormalities and interventions. *Lab values plotted on two separate axis scales, according to similar units (AST, ALT,
Alk Phos—solid lines corresponding to the left vertical axis; INR, Albumin, Tbili—dotted
lines corresponding to the right vertical axis). *Clinical events over time are reflected
on the horizontal axis. (A) IVIG infusion #3, (B) IVIG infusion #4 (no further IVIG infusions given thereafter), (C) admission for hepatitis evaluation, (D) liver biopsy, (E) initiation of prednisone therapy, (F) postpartum admission. Alk Phos, alkaline phosphatase; ALT, alanine aminotransferase;
AST, aspartate aminotransferase; INR, International Normalized Ratio; IVIG, intravenous
immunoglobulin; Tbili, total bilirubin.
Pathology revealed markedly active hepatitis with bridging necrosis, cholestatic features,
widespread mononuclear infiltrates, and negative staining for iron and periodic acid–Schiff
with diastase, findings suggestive of DILI ([Fig. 3]). In consultation with gastroenterology, the patient was initiated on prednisone
(60 mg daily) with gradual improvement in her labs, and she was discharged home at
262/7 weeks on an oral steroid taper.
Fig. 3 Histopathology from liver biopsy demonstrating evidence of drug-induced liver injury.
Hematoxylin and eosin (H&E)-stained section showing markedly active hepatitis with
bridging necrosis, cholestatic features, and widespread mononuclear infiltrates.
The patient represented 3 days later following an extramural delivery at 265/7 weeks due to preterm labor. The subsequent neonatal demise of Twin A on DOL #1 was
autopsy-confirmed due to sequelae of extreme prematurity. Twin B's course was notable
for normal coagulation panels, transaminases, ferritin, and serial abdominal ultrasounds,
but markedly elevated alpha-fetoprotein of >375,000 ng/mL. As definitive diagnosis
by salivary gland biopsy was precluded by the neonate's small size, empiric IVIG was
given for GALD risk and no further clinical concerns for GALD were observed. The neonate
progressed appropriately with discharge home on DOL #75. The patient's postpartum
course was uncomplicated with continually downtrending liver function tests on low-dose
prednisone (5 mg daily).
Discussion
GALD is a rare autoimmune syndrome characterized by maternal antibody-mediated destruction
of fetal hepatocytes. A similar pathophysiology is seen in the more common example
of Rh alloimmunization in which an RhD-negative mother develops antibodies that target
and destroy red blood cells in an RhD-positive fetus, leading to fetal anemia. In
the case of GALD, placentally transferred maternal IgG antibodies target a hepatocyte
protein that is uniquely expressed on fetal hepatocytes (vs. a paternally inherited
alloantigen).[1]
[6] The mechanism of initial sensitization is unknown but can incite disease even in
a first pregnancy.[6]
[7] Maternal antibody attachment to a fetal hepatocyte protein activates the fetal complement
cascade with the formation of the membrane attack complex and osmolytic hepatocyte
death.[6] Consequently, major metabolic functions of the fetal liver are compromised (such
as iron dysregulation via loss of hepcidin enzymes), leading to fetal iron toxicity
and extrahepatic iron deposition—the classic phenotype of in-utero GALD with neonatal
hemochromatosis (GALD-NH).[8]
Diagnosing GALD can be challenging. It is often only identified postnatally during
the evaluation of acute-onset fulminant neonatal liver failure with a definitive diagnosis
of GALD-NH usually made by extrahepatic iron deposition seen on neonatal salivary
gland biopsy.[6] In the rarer cases lacking congenital extrahepatic findings, pathologic diagnosis
may be made via diffuse immunohistochemical staining for the terminal complement complex
(C5b-9) in fibrotic hepatocytes.[9]
[10]
[11] Prenatal diagnosis is rare, especially in the absence of pertinent history, as sonographically
detectable sequelae of GALD are nonspecific and highly variable in presentation. Some
case reports have identified fetal growth restriction, ascites, oligohydramnios, placentomegaly,
and even hydrops fetalis as early signs of the underlying alloimmune hepatic disease,
but these may all also be seen secondary to more common etiologies.[11] This patient's index pregnancy was affected by oligohydramnios but otherwise had
no features of congenital liver disease, and all fetal imaging in the current described
pregnancy was normal. Regardless of the timing of diagnosis, knowledge of maternal
sensitization is relevant to the care of all subsequent pregnancies as recurrence
risk is upwards of 90%.[4]
Since GALD is an antibody-mediated disorder, prevention of recurrence in an ongoing
pregnancy focuses on maternal immunomodulation. The use of IVIG for this purpose has
been well-studied for RhD alloimmunization with efficacy in preventing and even reversing
fetal anemia.[12] Optimal outcomes are seen when therapy is initiated early (∼13 weeks, aligning with
the physiologic onset of placental IgG transfer) and is uninterrupted throughout gestation
(to account for the competing half-lives of IVIG vs. maternal antibodies).[5]
[12] The underlying mechanism for IVIG prophylaxis in alloimmunization is not entirely
clear but is proposed to be related to the downregulation of the maternal immune response,
competitive binding to Fc receptors, or direct inhibition of circulating alloantibodies.[12] The literature on IVIG prophylaxis for GALD is growing. There are several case studies
that have shown high-dose IVIG can reduce the risk of fetal/neonatal loss and overall
GALD recurrence (as much as a 68% disease reduction in one study—94% with no liver
disease after IVIG vs. only 30% after no antenatal treatment).[3]
[4]
[5]
[13] A recent study proposed a treatment protocol of IVIG (dosed at 1 g/kg, maximal dose
60 g) at 14, 16, and 18 weeks, advancing to weekly thereafter until 1 week prior to
delivery—our intended treatment plan for this patient.[5] Our patient began infusions at approximately 20 weeks due to late transfer of care,
and her duration of therapy was short-lived due to the unanticipated development of
DILI necessitating IVIG discontinuation.
Even in pregnancy, IVIG is generally considered a safe therapy. Late adverse effects
are typically renal or hematologic, but overall rare.[14]
[15]
[16] Transaminitis from IVIG is even more infrequently reported and usually limited to
a transient inflammatory reaction.[2] This was the suspected etiology for this patient's early mild transaminitis after
starting therapy and was not a contraindication to continued treatment when initially
limited to mild, transient elevations with no concerning symptoms. Such transaminase
elevations have historically been thought to be triggered in part by sugar-based diluents
(especially maltose) used in some formulations of IVIG, although the exact mechanism
of transaminitis is unknown.[2]
[17] In this case, Privigen was used, which is a human plasma-derived product containing
IgA with an L-proline stabilizer and no carbohydrate stabilizers or preservatives.
Severe DILI from IVIG has not yet been reported in the obstetric literature. A 1996
case report has described the development of concomitant aseptic meningitis and hepatitis
in a non-pregnant woman who received an IVIG infusion.[18] Some monoclonal antibody therapies (infliximab, pembrolizumab, and rituximab) have
been rarely associated with DILI, but these differ from IVIG in composition and pharmacokinetics.[19] Our patient demonstrated an acute hepatitis phenotype following multiple infusions
of IVIG with an otherwise negative hepatitis workup. She did have mildly elevated
ammonia and significantly elevated bile acids, which could be concerning for acute
fatty liver of pregnancy or intrahepatic cholestasis of pregnancy. However, the timing
of onset after IVIG, the severity of transaminitis, hyperbilirubinemia, and evolving
synthetic dysfunction, as well as the absence of gastrointestinal upset, encephalopathy,
persistent pruritus, or other associated lab abnormalities (such as hyperglycemia
or leukocytosis) make these alternative diagnoses less likely.[20]
[21] Further, liver biopsy histopathology was consistent with drug-induced hepatocellular
injury.[22]
Most cases of DILI will recover following cessation of the inciting drug, though severe
cases may progress to acute liver failure even after discontinuation. Hepatocellular
DILI, especially when associated with hyperbilirubinemia (more than twice the upper
limit of normal) and ALT elevations (more than three times the upper limit of normal)
may portend a particularly poor prognosis with a greater risk for acute liver failure,
transplant requirement, and mortality.[23] Aside from drug discontinuation, there are no definitive therapies for DILI. Corticosteroids
may be considered, though the literature is mixed regarding their efficacy for this
purpose.[24] Thus, prompt diagnostic evaluation of DILI is crucial to reducing morbidity by ensuring
timely discontinuation of the causative drug. In pregnancy, this may be even more
prudent to optimize obstetric outcomes. It is likely that this patient's preterm labor
and preterm birth may have been related to the preceding acute hepatitis as other
known etiologies of hepatitis (viral and autoimmune) are associated with increased
preterm birth risk.[25]
[26]
This patient strongly desires future fertility. An alternative GALD prophylaxis would
be needed in future pregnancies as reexposure to the inciting IVIG after confirmed
DILI is not recommended.[24] In neonates, GALD-NH therapy often involves both IVIG and plasma exchange.[6]
[27] Antenatal use of plasmapheresis for GALD prevention has not yet been studied but
may be a promising option. A recent case described good obstetric outcomes after dual
therapy with IVIG and double-filtration plasmapheresis for maternal antibody depletion
in the setting of anti-M alloimmunization.[28]
Understanding of the pathophysiology, prenatal diagnosis, and antenatal prevention
of GALD is growing, but many questions remain unanswered. This case demonstrates that
while IVIG is an accepted, effective preventative therapy for GALD, it may not be
entirely benign, warranting close lab and symptom monitoring throughout treatment.
Persistent or worsening transaminitis, particularly if accompanied by hyperbilirubinemia
or clinical jaundice, should prompt concern for possible DILI and discontinuation
of IVIG until the hepatitis workup has been completed.
