Post-ERCP acute infected necrotising pancreatitis in a patient with Cushing’s disease

Abstract

This report discusses the case of patient KT, who suffered from acute necrotising pancreatitis following endoscopic retrograde cholangiopancreatography (ERCP) for treatment of common bile duct (CBD) calculi. After a summary of KT’s complex medical history, the epidemiology and pathophysiology of post-ERCP pancreatitis (PEP) are discussed. Finally, recent research on treatment of severe necrotising pancreatitis is reviewed, focussing on strategies to reduce morbidity and mortality from this devastating complication of a common procedure like ERCP.

Full text

Journal of the Nueld Department of Surgical Sciences
Case Study
Post-ERCP acute infected necrotising pancreatitis in a patient with
Cushing’s disease
Piero Alberti1
1Medical Sciences Division, Univerity of Oxford, UK.
Keywords:
Acute pancreatitis, ERCP, walled-off necrosis,
post-ERCP pancreatitis, Cushing’s
syndrome, steroid-induced pancreatitis,
endoscopic necrosectomy.
Introduction
Acute pancreatitis (AP) is a well-
documented complication of endoscopic retrograde
cholangiopancreatography (ERCP), an important procedure
in the diagnosis and treatment of pancreatobiliary disease1.
Despite increasing endoscopic experience and development
of prevention guidelines, post-ERCP pancreatitis (PEP)
remains a signicant cause of increased morbidity,
mortality, hospitalisation length, and nancial cost. This
report discusses the case of a patient with Cushing’s
disease who developed acute necrotising pancreatitis
following ERCP for treatment of common bile duct (CBD)
calculi. After a discussion of current strategies to reduce
the risk of PEP, evidence on the clinical intersection
between hypercortisolism and AP is summarised. Finally,
recent research on the management of severe pancreatitis
is discussed to review the scientic basis for the current
standard of care.
The case
KT is a 54-year-old woman, who works a senior
manager for a toy company and lives with her husband and
son. On 21st October 2020, she presented to the emergency
department of the John Radcliffe Hospital in Oxford with a
two-hour history of right upper quadrant (RUQ) pain and
nausea. On examination, KT showed a Cushingoid habitus
(moon face, malar ush, hirsutism) and RUQ tenderness
with a positive Murphy’s sign. Alongside a history of non-
alcoholic fatty liver disease and focal nodular hyperplasia,
KT had for several years struggled with diet resistant
hypertension and obesity, which she attributed to Cushing’s
syndrome. KT was not on any prescribed medication, with
no known drug allergies. She did not smoke and drank 5
units of alcohol per week. Blood tests revealed deranged
liver function (bilirubin 58 mg/dl, ALT 1919 U/l). While
ultrasonography showed no change in liver nodules,
magnetic resonance cholangiopancreatography (MRCP)
revealed multiple calculi in KT’s gallbladder, as well as a 6
mm CBD stone and a 15 mm cystic lesion on her pancreas.
KT was referred to the general surgery and gastroenterology
teams for further investigations.
In November 2020, KT also received a provisional
diagnosis of Cushing’s syndrome following a failed
overnight dexamethasone suppression test, elevated 24hr
urinary cortisol levels and an elevated plasma ACTH. In
parallel, she was discussed by the hepatobiliary MDT and
scheduled for endoscopic ultrasound (EUS) and ERCP
followed by cholecystectomy. EUS/ERCP was performed
on 18th December: CBD stones were removed, and a stent
placed in the pancreatic duct (PD) to reduce the risk of PEP
following multiple cannulation attempts. While awaiting
surgery, however, KT developed severe epigastric pain
radiating to her back. She was also tachycardic, hypotensive
and jaundiced (bilirubin 142 mg/dl, CRP 600 mg/l,
amylase 2000 U/l). CT of her abdomen revealed extensive
fat wrapping of the pancreas, suggesting AP. Since her
Glasgow-Imrie score was of only 2 (albumin 28 g/l, calcium
1.95 mmol/l), KT was judged to be at low risk for severe
pancreatitis and was managed conservatively with uids,
pancreatic enzymes and analgaesia. KT was stable in the
following days but gradually developed a small left pleural
effusion with statically raised inammatory markers.
A repeat CT revealed small non-drainable pancreatic
collections with no evidence of necrosis. She was judged to
be safe for outpatient management and discharged on 14th
January 2021 with prophylactic dalteparin treatment due to
the hypercoagulable state of Cushing’s patients.
Despite regular follow-ups, KT was readmitted
Key learning points
1. Despite extensive research and endoscopic experience, acute pancreatitis remains a
signicant complication of diagnostic and therapeutic ERCP.
2. Hypercortisolism in Cushing’s syndrome constitutes a probable risk factor for development
of acute pancreatitis following insults to the pancreas.
3. The complications of severe pancreatitis should be managed conservatively, with surgical
or endoscopic debridement reserved for patients in whom collections become infected.
4. Several strategies can be used to reduce the risk of acute pancreatitis following ERCP but
awareness of these among ERCP practitioners in the UK is currently limited.

on 2nd February after presenting with worsening dyspnoea,
retching and fatigue. Abdominal CT showed marked
pancreatic pathology with large areas of walled-off necrosis,
and signicant enlargement of existing peripancreatic
collections (Figure 1). Collections were drained by both
EUS-guided cystogastrostomy and CT-guided percutaneous
drainage – drained uid grew E. coli and K. pneumoniae on
culture.
KT continued deteriorating with severe abdominal
pain and dyspnoea. On 25th February, she underwent a
repeat cystogastrostomy with endoscopic necrosectomy
through her transgastric stent. Post-operatively, KT then
developed atelectasis and pulmonary oedema, followed by
hypotension, tachycardia, and hypokalaemia. As a result,
she was provided with total parenteral nutrition (TPN)
and transferred to the intensive care unit (ICU). KT’s ICU
stay lasted two months, during which she faced several
complications including sepsis, recurrent pulmonary
embolisms, and fractures of vertebrae T7 and T8.
Remarkably, KT survived this deterioration and was nally
stepped down to ward care on 26th April. She was discharged
from hospital on 5th June 2021 with referral to the physical
and occupational therapy teams.
KT made a very positive recovery in the second
half of 2021. She gradually regained normal mobility and
was able to resume her endocrinological care. She was
diagnosed with Cushing’s disease after MRI of her pituitary,
which revealed a small microadenoma, and inferior petrosal
sinus sampling, which established a central cause for her
elevated ACTH levels (Figure 2).
KT underwent transsphenoidal surgery to remove
her pituitary adenoma on 17th December. This cured
her Cushing’s disease and secondary hypertension but
also made her dependent on exogenous hydrocortisone
treatment. Critically, she was still suffering from RUQ pain
due to her remaining gallbladder calculi, which put her
at risk of recurrent pancreatitis. Indeed, she presented to
surgical triage on 20th April 2022 with RUQ pain radiating
to her back. Her CRP was elevated at 53 mg/l and MRCP
conrmed the presence of multiple gallstones, leading
to a diagnosis of cholecystitis. KT was admitted for
laparoscopic cholecystectomy, which took place under
perioperative IV hydrocortisone cover after discussion
with the endocrinology team. Despite extensive omental
wrapping of Calot’s triangle and multiple adhesions
due to her past procedures, KT’s surgery did not require
Figure 1: KT’s axial abdominal CT scan (2nd February 2021).
Radiological report described multiple areas of walled-off
pancreatic necrosis, enlargement of peripancreatic collec-
tions, pseudocysts and a pancreaticopleural stula.
conversion to open and had no complications. She was then
treated with IV hydrocortisone (50 mg QDS) and stepped
down to an increased oral dose (40 mg daily) once able to
tolerate tablets. After being advised to return to her regular
maintenance regimen (20 mg daily) only after feeling
fully recovered, KT was nally discharged on 30th April, 15
months after her rst presentation to the surgical team.
Post-ERCP acute pancreatitis: epidemiology and
prevention strategies
In contrast to solely diagnostic procedures like
MRCP or EUS, ERCP plays an important role in treating
pancreatobiliary disease. It is associated with several
complications, most commonly acute pancreatitis (AP)
followed by infection, bleeding and perforation2. The
incidence of AP in the UK is estimated as 56 cases per
100,000 people per year. About 75% of cases are due to
gallstones and alcohol abuse, with ERCP belonging to a rarer
group of causes (viral infection, hyperlipidaemia, steroids,
etc.)3. Based on the revised Atlanta classication (2012),
AP is classed into three grades of severity (mild, moderate,
severe) ranging from self limiting inammation to infected
necrosis of pancreatic parenchyma and surrounding tissue
with multi-system organ failure4-6. About 25% of AP cases
are classed as severe and these have an estimated mortality
of 25%, on the background of a 5% mortality for AP overall3.
According to the European Society for
Gastrointestinal Endoscopy (ESGE), PEP has a frequency
of 3.5% among unselected ERCP patients4,7. However,
estimates of incidence in the literature range from 1%
to 40%, largely due to heterogeneity in inclusion criteria
and AP denitions across studies2,8. Consensus from
prospective studies is that diagnostic ERCP is associated
with a lower risk of PEP (1-3%) compared to therapeutic
ERCP (4-5%)8, 9. PEP is mild or moderate in about 90%
of cases, with the remaining 10% being the cause of
most ERCP-related morbidity and mortality. The risk
of PEP among ERCP patients is shaped by the synergy
of patient- and procedure-related factors4,7. Established
patient-related risk factors include female sex, previous
pancreatitis, and sphincter of Oddi dysfunction, whilst the
possible contributions of young age and eubilirubinaemia
remain unclear7,10. Procedure related risk factors include
Figure 2: KT’s pituitary MRI (10th October 2021). Radiolog-
ical report described a 6x6 mm lesion in the right side of the
pituitary gland with minor deviation of the pituitary stalk.

endoscopic balloon dilation of the sphincter of Oddi,
repeated PD contrast injections and multiple cannulation
attempts4,11,12. Inadvertent cannulation of the PD may have
contributed to development of PEP in KT’s case.
Research in the last two decades has focussed
on devising strategies to prevent the development of PEP
in ERCP patients as well as on perfecting stratication
algorithms aimed at identifying patients at high risk of
complications. However, progress on this latter front has
been limited. Imaging-based scoring systems, such as the
CT severity index (CTSI), have remained the gold standard
for grading AP severity, due to their ability to assess local
necrosis, peripancreatic inammation and extrapancreatic
complications (e.g. mesenteric oedema)13-15. Moreover,
comparative studies have shown that CT-based scoring
systems have similar predictive values for severe AP
to commonly used clinical ones (e.g. Glasgow-Imrie
score, Ranson’s criteria). Routine use of CT for severity
prognostication in AP patients is therefore not indicated16.
Overall, prediction accuracy for severe disease in
AP patients remains at around 80%16-19. For example, meta-
analyses have estimated the positive predictive value and
sensitivity of the Glasgow-Imrie score as respectively 40-
50% and 60-70%8,17. Therefore, about half of patients with
predicted severe AP do not develop complications and
roughly a third of patients with a score suggesting mild AP
instead do, as was the case for KT. Without discounting the
desire for reliable predictive tools, clinical recognition of
signs of organ dysfunction remains the most useful strategy
to prognosticate clinical course and severity in AP patients.
By contrast, some modications to the delivery
of ERCP have been clearly shown to reduce the risk of
PEP. Current ESGE guidelines recommend routine rectal
administration of NSAIDs (diclofenac or indomethacin)
before or after ERCP and placement of a prophylactic stent
in the pancreatic duct, as well as limiting cannulation
attempts and using PD guidewires rather than contrast-
assisted methods for deep biliary cannulation7. Meta-
analyses have consistently concluded that PD stents and
rectal diclofenac or indomethacin lead to an approximately
50% reduction in PEP rates20-25. A network meta-analysis
also found that rectal NSAIDs alone were superior to PD
stents, with no added benet from combining the two26.
Nonetheless, a 2014 UK-wide survey of ERCP practitioners,
including gastroenterologists, gastrointestinal surgeons,
and radiologists, found that less than 53% of respondents
used PD stents or NSAIDs and that only 6% routinely
measured amylase after ERCP27. This suggests that
increasing awareness of existing prevention guidelines may
be the most effective strategy to reduce the burden of post-
ERCP pancreatitis in the UK.
Acute pancreatitis and Cushing’s syndrome: the
role of dual pathology in KT’s case
The association between AP and Cushing’s
syndrome is uncommon. Little basic research has been
dedicated to the possible interaction between the
pathophysiologies of the two diseases and clinical evidence
is limited to a small number of case reports28. Clague et al.
described the case of a 53-year-old man with ectopic ACTH
production due to bronchial carcinoma who died after
developing AP and postulated that endogenous steroid
excess may contribute to the pathogenesis of AP29. This
was also suggested by Hiramatsu et al. after observing
a similar case in a 64-year-old woman with Cushing’s
disease30. Cougard et al. described two cases of necrotising
AP occurring after bilateral laparoscopic adrenalectomy for
ectopic ACTH secretion and suggested that hypercortisolism
may exert a specic contribution to an increased risk of AP
in these patients, independently of intraoperative trauma
to the pancreas31.
Treatment with exogenous steroids is a well-
established risk factor for the development of AP. A
nationwide nested case-control study in Sweden concluded
that current oral glucocorticoid use was associated with
an increased risk of developing AP between 4 and 14 days
of drug dispensation32. While the mechanism by which
glucocorticoids may propitiate AP remains unknown, this
latency suggests that effects of glucocorticoids are likely
to be mainly mediated by changes in gene transcription.
Previous studies in rodents have indeed described a
critical inuence of adrenocortical steroids on the exocrine
function of the pancreas: adrenalectomy was found to
selectively inhibit amylase synthesis in acinar cells and
to decrease the density of zymogen granules33,34. A study
in the caerulin-induced animal model of AP observed that
rats treated with hydrocortisone experienced a signicant
increase in pancreatic weight because of increased protein
synthesis and storage. Administration of caerulin in these
animals led to severe interstitial oedema of the pancreas
and increases in serum amylase values to triple the level
observed in control animals35. This suggests that high levels
of corticosteroids may be associated with increased density
of zymogen granules and high sensitivity to secretagogues,
which would increase the likelihood of developing AP
following a pancreatic insult. While studies in humans are
lacking, this hypothesis is consistent with the observation
that the local features of AP in KT’s case were particularly
severe, with amylase levels exceeding 1000 U/l.
Another poorly understood aspect of the dual
pathology between Cushing’s syndrome and AP is how
hypercortisolism may inuence the systemic sequelae of
pancreatic inammation. On the one hand, serum levels
of CRP and inammatory cytokines (TNFa, IL-6, IL-8)
have been shown to be elevated in AP patients, although
none have sufcient sensitivity or specicity for use in
severity prognostication36. On the other hand, several
studies support the notion that peripherally generated
cytokines stimulate activation of the HPA axis to mitigate
the systemic consequences of inammation through the
anti-inammatory effect of glucocorticoids37. Animal
models suggest that this mechanism may be relevant to AP
progression. For example, a study in the caerulin-induced
and closed duodenal loop (CDL) rat models observed that
experimental induction of AP led to signicant elevation of
both IL-8 and corticosterone levels. Critically, adrenalectomy
increased the severity of AP and mortality among CDL rats,
while exogenous hydrocortisone replacement suppressed
IL-8 elevation in adrenalectomised rats and reduced both
AP severity and mortality38. If this counter-regulatory
effect of corticosteroids were to play a signicant role in
the development of systemic complications, AP patients
with hypercortisolism would be expected to be relatively
protected from inammatory sequelae, at the expense of
increased infection risk. KT’s clinical course is consistent
with this speculative hypothesis since she did develop local
and distant infective complications but was nonetheless
able to withstand multiple deterioration episodes. Evidence
thus suggests that hypercortisolism may act as a risk factor
for the development of AP but a mitigating factor in its
progression.
Clearly, no suggestion of a change to the normal
management of AP in Cushing’s patients can be made based
on such a limited number of studies. However, considering

that outcomes in AP strongly depend on clinical acumen
and early diagnosis, keeping a high index of suspicion and
thus a low threshold for investigations (i.e. serum amylase,
CT) constitutes an important piece of advice to medical
professionals faced with Cushing’s patients presenting
with AP symptoms.
Severe necrotising pancreatitis: recent trends in
diagnosis, management, and prevention
According to the Atlanta classication, severe
AP is characterised by the presence of persistent (>48hr)
single-organ or multi-organ (i.e. cardiovascular, respiratory
or renal) failure, which has been shown to act as the main
determinant of AP-related mortality6,39,40. Most patients
with severe AP display radiological evidence of local
complications, which include interstitial pancreatitis (i.e.
peripancreatic uid collections, pancreatic pseudocysts
and stulas) and necrotising pancreatitis (i.e. necrotic
collections and walled-off necrosis)41. Moderate AP, which
is characterised by local complications without infected
necrosis or organ failure, instead leads to prolonged
and complicated hospital stays but only carries a 1-2%
mortality6,42.
The management of pseudocysts and necrotic
collections in severe AP is matter of contention in the surgical
literature since the 1920s but has been majorly informed
by research in the last decade18,43. The treatment options
are percutaneous drainage, endoscopic cystenterostomy
with or without necrosectomy, and video-assisted or open
retroperitoneal debridement. The surgical mortality rate
for these procedures is still between 10 and 20% despite
improvements in uid therapy and antibiotics18,43. The
main conclusion of trials since the 1990s has hence been
that sterile interstitial or necrotising pancreatitis should be
managed conservatively, with invasive treatment reserved
for patients in whom collections become infected or cause
pain or other symptoms (e.g. gastric outlet obstruction)44.
Observational studies also suggest that optimising
conditions for debridement by waiting for collections to
demarcate leads to lower morbidity and mortality45. ESGE
guidelines advise that patients who develop infected
necroses early in their disease course should be managed
with IV antibiotics and percutaneous drainage, with
endoscopic or surgical interventions only considered
beyond 4 weeks from the onset of AP46. This indication is
supported by ndings from a recent study in patients with
walled-off pancreatic necrosis (WOPN), which observed
that in 40% of cases percutaneous drainage led to resolution
without the need for later endoscopic necrosectomy47.
The standard of care followed in KT’s case is based
on an ‘endoscopic step-up approach’ which was validated
by two recent landmark RCTs. The PANTER trial in 2010
rst concluded that a graded approach to patients with
infected WOPN, starting with percutaneous or transluminal
drainage followed by minimally invasive retroperitoneal
necrosectomy if necessary, led to a 29% reduction in
the absolute risk of major complication (i.e. new-onset
multiple organ failure, perforation, enterocutaneous
stula) or death compared to primary open necrosectomy48.
In 2018, the TENSION trial compared this surgical step-
up approach (i.e. percutaneous drainage followed by
minimally invasive debridement) with an endoscopic step-
up approach in which EUS-guided transluminal drainage
was followed by endoscopic necrosectomy. While rates of
major complication or death were found to not signicantly
differ between the two, endoscopic treatment was shown to
result in a lower rate of pancreaticocutaneous stulas and
a reduced need for reinterventions at initial (6 months) and
long-term (mean 7 years) follow-up49,50.
Concluding remarks
The case of KT illustrates how, even with adherence
to clinical guidelines (e.g. PD stents, endoscopic step-
up), ERCP is still associated to an important risk of acute
pancreatitis, which can have catastrophic complications if
severe. In 2002, a panel of the National Institutes of Health
concluded that less invasive techniques like MRCP and EUS
would ‘soon eclipse ERCP’s status as tool for diagnosing
pancreatobiliary disease’51. Two decades later, this forecast
has proven to be overoptimistic. While efforts to limit
its diagnostic use are commendable, ERCP will remain
a cornerstone of pancreatobiliary disease management
for the foreseeable future. Therefore, closer adherence to
guidelines and more extensive studies on candidate agents
for PEP prophylaxis will remain essential strategies to
reduce the incidence, morbidity, and mortality of post-
ERCP pancreatitis in coming years.
Funding
None.
Consent
The patient has consented to the publication of this case
study.
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