Discussion
Our case report illustrates a new type of cloxacillin-induced liver
injury, acute vanishing bile duct syndrome. Strengths of this study
include the collaboration between the clinicians and pathologists in
managing this patient by having liver biopsy to determine the specific
pattern of her cholestasis and liver failure, as opposed to
undifferentiated DILI. The patient was also followed closely as an
outpatient by her medical providers, including LT team, which provided
information about the persistence of her disease after discharge. One
limitation of this study is the fact that the patient reported a
penicillin allergy, which may have made her more susceptible to a
cloxacillin reaction than non-allergic patients, though reported
penicillin allergies are often unreliable27. The other
limitation is that patient unfortunately had a fall and developed
multiple traumatic fractures, which likely contributed and accelerated
deterioration of her liver disease and her passing away before getting
the LT.
Using Google Scholar, we found four additional cases of
cloxacillin-induced livery injury requiring a liver biopsy. One
retrospective study examined a series of drug rechallenge cases, from
the Global Safety Database, where patients who had possible DILI were
given the same drug while monitoring liver enzymes27.
One of the 88 confirmed positive rechallenge cases was caused by
cloxacillin-related injury, and liver biopsy showed a portal lymphocytic
infiltrate with some eosinophils28. A similar
retrospective study examined 77 possible or probable DILI cases
secondary to penicillinase-resistant penicillins reported to the Swedish
Adverse Drug Reactions Advisory Committee29. One case
related to cloxacillin underwent liver biopsy which showed cholestasis
with moderate inflammation including some eosinophilic
infiltrate29. No specific demographic or clinical
information was reported for either of those two cases.
There have been only two case reports of cloxacillin-induced liver
injury that included both clinical and histopathologic
information25-26. Both patients were female, aged 69
and 77 years, and presented with jaundice and pruritis. Additionally,
the first patient had hepatomegaly and the second had weakness and
maculopapular rash. They both had a cholestatic liver injury pattern,
but their ALP (1126 and 394), AST (18 and 313) and total bilirubin (255
and 221) levels were lower than those seen in our case. Eosinophilia was
only noted in the second patient. Both liver biopsies showed moderate to
severe intrahepatic cholestasis, which was canalicular in the first case
and hepatocellular in the second. Both also had up to moderate portal
inflammation, and mild lobular necroinflammation. Additionally, the
first case showed occasional hepatocyte variation and multinucleation,
Kupffer cell hyperplasia with lipofuscin and ceroid pigmentation, and
minimal steatosis. Normal bile ducts were seen in the first case and no
abnormalities were documented in the second. Prednisone was only used
for the second patient, but both had normal liver enzymes and recovered
clinically within 60 and 10 days, respectively.
Altogether, lobular or portal inflammation was described in all four
reported cases of cloxacillin-induced liver injury, whereas eosinophils
were documented in three cases. Three patients had cholestasis with
moderate to severe or prominent cholestasis in canalicular or
hepatocellular patterns in two cases. Bile ducts were reported as normal
in one case and assumed to be normal in the other three. Both cases that
were followed clinically had a full recovery.
The prognosis of drug-induced VBDS has been variable in general. In a
case series of 8 patients with drug-induced VBDS followed with
sequential liver biopsies, three recovered clinically, three recovered
biochemically and clinically, and one developed biliary
cirrhosis30. In a 10-year retrospective study, from
2004 to 2014, by the US DILI network, 26 of 363 (7%) patients that
underwent a liver biopsy had bile duct loss (14 lost >50%
bile ducts, while 12 lost 25-50% bile ducts)31.
Compared to patients without bile duct loss, patients with bile duct
loss had a higher risk of developing chronic liver disease, persistent
cholestasis after six months (94% vs 47%), and death within two years
of follow up (27% vs 9%).
Treatment for drug-induced VBDS is largely similar to that for other
types of drug-induced cholestasis, including immediate withdrawal of the
culprit drug and preventing re-exposure, as well as ursodexycholic acid
to protect against toxic bile salts15,32-33. Steroids
and other immunosuppressants may be used when there is an indication of
allergic reaction such as eosinophilia, lymphadenopathy, rash or
syndromes like Stevens-Johnson syndrome33.
Plasmapheresis has been used successfully in a case of loxprofen-induced
ductopenia in an adolescent female unresponsive to initial treatment
measures14. In cases that progress to biliary
cirrhosis, supportive management and LT would be
indicated18.
Our case shows that cloxacillin-induced cholestasis can be secondary to
acute ductopenia, which is associated with more severe clinical
presentations and worse outcome than the previously described bland
cholestasis. Liver biopsy is therefore important to helping identify
patients with VBDS early in the disease process. A lower threshold for
liver transplantation assessment is recommended for those cases.