A 56-year-old man underwent laparoscopic cholecystectomy for acute cholecystitis at another hospital in December 2013. The cholecystectomy was uneventful and the patient was discharged home 3 days later. However, after hospital discharge, the patient presented with recurring upper abdominal pain, tarry stool, and fever. He was admitted to another hospital 4 weeks after the cholecystectomy because of fever, right upper quadrant pain, and haematemesis. Emergency oesophagogastroduodenoscopy and colonoscopy were performed. No bleeding source was identified. Computed tomography (CT) revealed subhepatic fluid collection; old-blood–stained fluid was drained by image-guided catheter drainage. The patient was transferred to the Department of Surgery, Pamela Youde Nethersole Eastern Hospital, Hong Kong, for further treatment.

When the patient arrived at hospital, his blood pressure was approximately 90/60 mm Hg and his pulse rate was 110 beats per minute. Laboratory studies revealed the following values: haemoglobin level, 72 g/L; white blood cell count, 20.3 × 10⁹ /L; platelet count, 388 × 10⁹ /L; total bilirubin, 164 μmol/L; alanine aminotransferase, 187 IU/L; and alkaline phosphatase, 337 IU/L. The patient was treated with intravenous fluid hydration and was transfused with three units of packed red blood cells. He was also given a course of antibiotics. Abdominal CT showed a cystic artery pseudoaneurysm of 1.22 × 1.96 × 1.38 cm (anterior-posterior × transverse × longitudinal dimensions). Two subhepatic collections with haematoma were also visible, over the gallbladder fossa and below hepatic segment 6. Selective right hepatic artery angiography revealed a pseudoaneurysm at the cystic artery. This aneurysm was embolised with stainless steel coils (Fig 1). The catheter for subhepatic collection drainage was then replaced with one with better positioning. Endoscopic retrograde cholangiopancreatography was performed the next day. The cholangiogram showed a dilated biliary tree with haemobilia; most of the blood clots were extracted using a balloon. A cystic duct stump leak was observed after blood clot removal, and a 10-cm-long 11.5-F biliary stent was inserted for biliary drainage (Fig 2). Liver function improved gradually. The patient was discharged from hospital 2 weeks after admission.

Follow-up CT no longer showed pseudoaneurysm and instead showed a resolving collection. Endoscopic retrograde cholangiopancreatography with stent removal was performed 3 months later. The cholangiogram showed a normal biliary tree. The patient recovered and liver function test results were normal.

Hepatic artery or cystic artery pseudoaneurysms are rare complications of laparoscopic cholecystectomy, with cystic artery involvement being reported much less frequently in the literature. Pseudoaneurysm formation is a consequence of vascular injury; important causes include arterial access procedures, accident trauma, and surgical trauma.1 Two-thirds of cases are iatrogenic.1 With the advent of laparoscopic cholecystectomy, iatrogenic hepatobiliary injury is now another cause. Concomitant formation of cystic artery pseudoaneurysm and cystic duct stump leak is a rare complication of laparoscopic cholecystectomy. The majority of pseudoaneurysms present within 6 weeks after the operation.2 3

We have reported a case of laparoscopic cholecystectomy that was complicated by a cystic artery pseudo-aneurysm and a cystic duct stump bile leak, which were managed with angiographic coil embolisation and endoscopic biliary drainage, respectively. The patient presented with the classic Quincke’s triad of haemobilia, namely upper gastrointestinal bleeding, right upper quadrant pain, and obstructive jaundice. The aetiology most likely originated from the infected fluid collection after cholecystectomy, which caused a series of events, including cystic duct stump leak, cystic artery pseudoaneurysm, and haemobilia, in that order. First, bile leakage is a potential complication of cholecystectomy and the cystic duct stump is the most common site of leakage.4 The contributing factor of cystic duct stump leak in the current case was likely cystic duct stump necrosis secondary to mechanical or thermal injury during cholecystectomy, as well as adjacent infection. Second, haemobilia can occur secondary to a cystic artery pseudoaneurysm, although extremely rarely. Artery pseudoaneurysm is a continuous inflammatory process that leads to erosion in the elastic and muscular components of the arterial wall, ultimately resulting in pseudoaneurysm formation. The likely precipitating factors in the current case include initial clip encroachment of the vasculature, mechanical or thermal injury, and continuous inflammation due to the adjacent infected bile or collection.

Pseudoaneurysm can present with bleeding in the form of haemobilia, haematemesis, or melaena. In the current case, upper gastrointestinal bleeding from haemobilia resulted from the cystic artery pseudoaneurysm’s communication with the cystic duct. The resulting symptoms were typical of Quincke’s triad of upper abdominal pain, upper gastrointestinal haemorrhage, and jaundice.5 However, these symptoms are present collectively only in a minority (32%-40%) of patients.5 Thus, detection relies heavily on both clinical reasoning and imaging techniques. If intra-abdominal collection or haemorrhage is suspected clinically, arterial-phase CT is appropriate to detect any pseudoaneurysm. Since gastrointestinal haemorrhage is one of the presentations, urgent oesophagogastroduodenoscopy may be arranged first to rule out any suspected upper gastrointestinal pathology. However, as in the current case, if that procedure fails to show any bleeding source, urgent CT should be considered. Close observation and timely arrangement of appropriate procedures are essential.

Prompt recognition with adequate management was very important in the current case. The treatment of our patient included five objectives: achieving haemostasis, controlling the cystic duct stump leak, relieving obstructive jaundice, controlling the infection with antibiotics, and draining the intra-abdominal collection. Untreated haemobilia poses an immediate threat to life. It can lead to acute haemodynamic instability, necessitating detection, access, and control of the pseudoaneurysm. Arterial-phase CT is a good initial non-invasive mode of detection of laparoscopic cholecystectomy complications. It can be used to evaluate intra-abdominal collection, biliary tree dilatation, and possible bile duct injury, and to visualise pseudoaneurysms or haemorrhage. Arterial-phase CT also allows a three-dimensional assessment of the bile duct and vasculature. Selective arterial angiography can provide a real-time evaluation of pseudoaneurysms and bleeding. At the same time, it can provide the chance of immediate therapeutic intervention. Transarterial embolisation is the treatment of choice for haemostasis, and a high success rate, of 75% to 100%, has been reported.2 3 5 When bleeding control by embolisation fails, repeated sessions of transarterial embolisation for haemostasis or surgical intervention to repair or ligate the artery is necessary. Endoscopic retrograde cholangiopancreatography with stent placement or sphincterotomy is highly effective in diagnosing haemobilia, controlling cystic duct stump leakage, and relieving obstructive jaundice. We favoured stenting over sphincterotomy because of a presumed lower risk of immediate complications.

The lessons to be learnt from this case include the importance of (1) meticulous surgical techniques (such as good haemostasis, careful use of powered devices, proper use of endoclips, and adequate drainage of the operative field), and (2) early recognition and prompt management.

In conclusion, cystic artery pseudoaneurysm is a rare, potentially life-threatening complication of laparoscopic cholecystectomy, and prompt recognition and treatment are essential. Haemobilia may be present many weeks after the initial injury.

The authors have no conflicts of interest to disclose.

1. Green MH, Duell RM, Johnson CD, et al. Haemobilia. Br J Surg 2001;88:773-86.

2. Senthilkumar MP, Battula N, Perera M, et al. Management of a pseudo-aneurysm in the hepatic artery after a laparoscopic cholecystectomy. Ann R Coll Surg Engl 2016;98:456-60. Crossref

3. Nicholson T, Travis S, Ettles D, et al. Hepatic artery angiography and embolization for hemobilia following laparoscopic cholecystectomy. Cardiovasc Intervent Radiol 1999;22:20-4. Crossref

4. Lau WY, Lai EC, Lau SH. Management of bile duct injury after laparoscopic cholecystectomy: a review. ANZ J Surg 2010;80:75-81. Crossref

5. Merrell SW, Schneider PD. Hemobilia—evolution of current diagnosis and treatment. West J Med 1991;155:621- 5.

A 78-year-old woman was diagnosed with atrial fibrillation in September 2015. An echocardiogram showed no evidence of valvular heart disease. She was prescribed dabigatran 110 mg twice a day. In December 2016, she was admitted to our hospital for acute ischaemic stroke, presenting with a sudden onset of decreased level of consciousness. Apart from atrial fibrillation, she also had hypertension, diabetes mellitus, hyperlipidaemia, and a history of hip fracture with bilateral hip implants, requiring a rollator for walking.

On the day of admission, she was reported by her carer to be poorly responsive, with no verbal response and no spontaneous limb movement. She was last seen well 30 minutes previously. Physical examination revealed bilateral pinpoint pupils and no verbal response. She had slight flexion of her four limbs to pain and her National Institutes of Health Stroke Scale (NIHSS) score was 34. The blood pressure was 142/64 mm Hg. There was no hypoglycaemia. Naloxone was given with no improvement. Cerebral computed tomography (CT) showed no early infarct changes but bilateral subcortical white matter hypodensities, compatible with small vessel disease (Fig a). A clinical diagnosis was made of acute ischaemic brainstem stroke. The family confirmed that the patient had been taking dabigatran regularly as prescribed, with the last dose taken about 2 hours before symptom onset. She had taken no sedative medications.

After obtaining informed consent, an intravenous bolus of 5 g idarucizumab was given. Blood for clotting profile, including thrombin time, was taken before treatment and 5 minutes afterwards. Intravenous recombinant tissue plasminogen activator (r-tPA) was then given at 0.6 mg/kg body weight 10 minutes after the start of idarucizumab injection, 2 hours from symptom onset. The prolonged activated partial thromboplastin time (APTT) and thrombin time (TT) normalised after administration of idarucizumab. The Table shows the clotting variables before and after idarucizumab. By the next morning, the patient had regained her speech although her response was slow with dysarthria and dysphagia. She could raise her four limbs against gravity, power being grade 3. Follow-up CT at 24 hours post r-tPA showed no significant infarct and no bleeding (Fig b). Transcranial Doppler ultrasonography showed no evidence of significant vertebrobasilar occlusive disease. By day 2, she had recovered further neurologically, with improvement in alertness, dysarthria and dysphagia, and could tolerate oral feeding. Limb power was grade 4+ over four limbs. Pupils were no longer pinpoint. She was recommenced on dabigatran 150 mg twice a day on day 2 based on her age and creatinine clearance. The patient was discharged on day 7 with her neurological function returned to baseline.

This is the first report in Hong Kong of the successful use of idarucizumab to reverse the anticoagulant effect of dabigatran, followed by intravenous thrombolysis with r-tPA for the treatment of ischaemic stroke. Novel oral anticoagulants (NOACs) are now increasingly used for the prevention of cardioembolic stroke in patients with non-valvular atrial fibrillation. Dabigatran, which acts as a thrombin inhibitor, is one such NOAC. Idarucizumab is a monoclonal antibody that has a high affinity for binding to the immunoglobulin G fragment of dabigatran. A 5-g dose was shown to be able to reverse the anticoagulant effect of dabigatran within minutes and had a good safety profile in the study of Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD trial).1

Patients who develop an acute ischaemic stroke while taking dabigatran are often excluded from treatment with intravenous thrombolysis owing to their bleeding risk. For patients who are not candidates for mechanical thrombectomy or who are in institutions where an endovascular thrombectomy service is not routinely available, giving intravenous thrombolysis after reversal of the anticoagulant effect is a treatment option. There is no pro-anticoagulant effect from idarucizumab itself, and an in-vitro study demonstrated no interaction between idarucizumab and r-tPA–induced thrombolysis.2 As far as we know, there have been five case reports at the time of writing of this article, all from German centres, that have reported the successful use of idarucizumab for this indication; none had any haemorrhagic complications.2 3 Four of these studies reported successful thrombolysis with good neurological recovery, whereas one study reported failed clinical improvement in a patient with infarcts in multiple territories.3 Diener et al4 have published an expert opinion on the management of these ischaemic strokes based on their experience in Germany. They proposed that for patients who have taken dabigatran in the preceding 24 hours from the time of assessment (or 96 hours if the creatinine clearance is <30 mL/min), or for patients in whom time of last dabigatran dose is unknown and who have a prolonged APTT or TT, idarucizumab should be given if the patient is not a candidate for mechanical thrombectomy. In our institution, we do not have point-of-care devices to test clotting function, the turnaround time for APTT and TT results may be hours, and dabigatran concentrations cannot be measured in our laboratory. We therefore propose that for patients in whom time of last dabigatran dose is unknown, idarucizumab can still be considered with the family’s consent to enable early intravenous thrombolysis. For the same reason, we did not wait for the results of APTT or TT to confirm reversal of dabigatran’s effect before initiating intravenous thrombolysis. Idarucizumab rapidly and completely reversed the anticoagulant activity of dabigatran in 88% to 98% of patients in the RE-VERSE AD trial.1

Safety (avoidance of symptomatic intracranial haemorrhages) was our top concern for this patient. As she had multiple risk factors for intracranial haemorrhage (old age, high NIHSS score, cerebral white matter disease and on anticoagulant therapy), we gave r-tPA at a dose of 0.6 mg/kg body weight. This dose was associated with significantly fewer symptomatic intracranial haemorrhages in the recent ENCHANTED trial.5

Following reversal of effect, dabigatran can be resumed as early as 24 hours afterwards. Although our patient had improved by the next day, she still had significant dysphagia and could not tolerate oral feeding. By the second day, she had improved further so dabigatran was resumed at a higher dose based on her age and renal function.

In conclusion, idarucizumab can be considered to reverse the anticoagulant effect of dabigatran in patients with ischaemic stroke within a therapeutic window, so that they may benefit from intravenous thrombolytic therapy.

All authors have disclosed no conflicts of interest.

1. Pollack CV Jr, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015;373:511-20. Crossref

2. Berrouschot J, Stoll A, Hogh T, Eschenfelder CC. Intravenous thrombolysis with recombinant tissue-type plasminogen activator in a stroke patient receiving dabigatran anticoagulant after antagonization with idarucizumab. Stroke 2016;47:1936-8. Crossref

3. Kafke W, Kraft P. Intravenous thrombolysis after reversal of dabigatran by idarucizumab: a case report. Case Rep Neurol 2016;8:140-4. Crossref

4. Diener HC, Bernstein R, Butcher K, et al. Thrombolysis and thrombectomy in patients treated with dabigatran with acute ischemic stroke: Expert opinion. Int J Stroke 2017;12:9-12. Crossref

5. Anderson CS, Robinson T, Lindley RI, et al. Low-dose versus standard-dose intravenous alteplase in acute ischemic stroke. N Engl J Med 2016;374:2313-23. Crossref

Endoscopic retrograde cholangiopancreatography (ERCP) is a standard endoscopic technique for treating biliary obstruction and cholangitis. The presence of surgically altered gastrointestinal anatomy, however, poses a major technical difficulty to the procedure due to the long and tortuous access to the small bowel. We report a three-case series with successful attempts at short double-balloon enteroscopy (DBE)–assisted ERCP in patients with postoperative gastrointestinal anatomy. The enteroscope employed was EC-450BI5, Fujifilm endoscopy (Fig 1) and the sedation agents used in all procedures were dexmedetomidine and fentanyl continuous infusion combined with bolus midazolam.

A 76-year-old man was admitted to our hospital in December 2015 with acute cholangitis that presented as fever and deranged liver function tests (LFT) with predominant elevation of alkaline phosphatase (ALP). He had a history of stroke, hyperlipidaemia, and a Billroth II gastrectomy performed 30 years ago. Blood cultures grew Escherichia coli. Ultrasonography of the hepatobiliary system revealed a 5-mm stone in the common bile duct (CBD).

The first ERCP using a standard side-view duodenoscope and end-view gastroscope failed to identify the papilla. He continued to receive antibiotic treatment, with the fever reduced but liver biochemistry remained elevated. The DBE-assisted ERCP was performed 2 weeks later with an enteroscope of 152-cm working length. The papilla was reached over the afferent limb of the small bowel by manipulation of the overtube only (no balloon inflation), followed by successful cannulation of the CBD. Cholangiogram revealed a 1.2-cm dilated CBD with two intraductal filling defects (Fig 2a). Pre-cut papillotomy on-stent was performed with pre-insertion of a 7-French 7-cm plastic biliary stent. The plastic stent was removed after papillotomy and the papilla was dilated using a controlled radial expansion (CRE) balloon dilator of 12-mm size and subsequently stones were removed by a basket. The ERCP procedure was completed in 115 minutes and there were no complications. The patient’s LFT had normalised at a follow-up 3 weeks later.

An 80-year-old man presented in January 2016 with a history of hypertension, pulmonary fibrosis, and cerebral infarct. A Billroth II gastrectomy had been performed 10 years previously for gastrointestinal bleeding. He had an episode of acute cholangitis 4 months ago. Endoscopic retrograde cholangiopancreatography using a standard end-view gastroscope failed to reach the papilla and the infection resolved after a course of antibiotic. Follow-up magnetic resonance cholangiopancreatography 3 weeks earlier had revealed a 1.2-cm distal CBD stone with the CBD dilated to 1.7 cm. He then attended the hospital again for fever, E coli septicaemia, and an obstructive pattern of liver derangement; bilirubin level was 93 µmol/L and ALP level was 1224 U/L. Percutaneous transhepatic biliary drainage was established and antibiotics were continued until DBE-assisted ERCP was performed 2 weeks later. With the push-pull manoeuvre, the blind end of the afferent loop was reached. Initially, a nearby minor papilla was mistaken as the major papilla and repeated attempts failed to cannulate it.

The true major papilla was then identified 5 cm proximal to the minor papilla and pre-cut papillotomy was performed due to difficult cannulation. The impacted CBD stone was removed following papillotomy and balloon sphincteroplasty was performed with a 12-mm CRE balloon. Subsequent cholangiogram was clear with a 1.5-cm dilated CBD. The operating time was 163 minutes. The patient remained asymptomatic and LFT had normalised at a follow-up 1 month later.

A female patient aged 81 years with a history of mild Parkinson’s disease had undergone gastrectomy 30 years ago for peptic ulcer disease. She presented to our hospital in February 2016 for biliary pancreatitis with sudden onset of jaundice associated with epigastric pain. Amylase level was elevated to 698 U/L, bilirubin level to 35 µmol/L, and an ALP level of 1001 U/L. Ultrasonography of the hepatobiliary system detected grossly dilated intrahepatic ducts (IHD) and the CBD measured up to 2.4 cm in diameter with one obstructing CBD stone measuring 1.5 cm. The first gastroscopy confirmed a previous total gastrectomy with Roux-en-Y reconstruction. Percutaneous transhepatic biliary drainage was attempted but failed due to the resolution of the IHD dilatation. The patient was then managed conservatively with antibiotics and a DBE-assisted enteroscopy was scheduled 3 weeks later. The 152-cm DBE identified the blind end of the afferent limb while the endoscope advanced to 140 cm from the incisors after push-pull manoeuvre (Fig 2b to d). Successful guidewire cannulation was followed with a cholangiogram that showed a dilated CBD with no filling defect. In view of the recent history of biliary obstruction and the possibility of a passed stone, the papilla was dilated to 13.5 mm with the CRE balloon and good bile drainage was observed. The operating time was 130 minutes. The major difficulty encountered was that the tip of the enteroscope was very unstable making it difficult to maintain the distal blind end and it was easily slipped out proximally. As such, repeated endoscope manipulation was required to achieve optimal positioning. Postoperatively, the patient was well, bilirubin normalised, and ALP level had reduced to 266 U/L at 1-month follow-up.

Balloon enteroscopy–assisted ERCP using either single-balloon enteroscopy or DBE has been reported to be an effective modality for ERCP in these patients.1 2 3 Traditional DBE with 200-cm length and narrow (2.2-mm) accessory working channel limits the utilisation of conventional ERCP accessories. Recent attempts with a short 152-cm DBE have been highly successful.1 2 4 To date, there have been approximately 200 reports of patients who have undergone ERCP using this short DBE procedure. The success rate for reaching the blind end of the afferent limb was 86% to 100%; it is not inferior to that achieved using a long-type balloon enteroscope.4 The short-type enteroscope accommodates the use of most available accessories to perform ERCP-related procedures such as sphincterotomy, balloon dilatation, stone extraction, and deployment of plastic or metallic stents.

In our small series, all patients ran an uneventful course during the perioperative and postoperative period and none had any apparent complications. The overall procedural complication rate has been reported to be 8% to 10%, with the rate of major complications of perforation or emphysema being around 3.5%.4 The risk of complications, however, may vary according to different surgical approaches with consequent significant differences in the endoscopic techniques anticipated.3 4 5 Since it is a relatively new and evolving endoscopic technique, these rates are still experience-dependent and patients should be closely observed after the procedure.

The ERCP in the patient with Roux-en-Y reconstruction posed particular technical difficulties. The endoscopist should review previous surgical reports in detail to map and anticipate the endoscopic view at the anastomotic site. On reaching the Roux-en-Y anastomosis, identification of the pancreatobiliary limb is often difficult. After choosing either limb, the endoscopist could perform endoscopic marking by a clip or Indian ink tattoo at the entrance of the chosen limb (Fig 2c). If the chosen limb is confirmed wrong under fluoroscopy, the endoscopist can return the endoscope to the Roux-en-Y anastomosis and then insert the endoscope into the other limb. A marking at the entrance of a limb has been shown to be useful as it avoids repeated misidentification of the limb to be entered.6

Barotrauma is the major cause of intestinal perforations and may be a result of excessive air insufflation forming a closed loop between the blind end and the inflated overtube or enteroscope balloon.7 Use of carbon dioxide insufflation instead of air insufflation may reduce the chance of this closed-loop phenomenon. Additionally, use of a transparent hood at the tip of the enteroscope with instillation of water into the intestinal lumen has also been suggested to maintain the endoscopic view without gas insufflation and avoid consequent barotrauma.8

With regard to the cannulation techniques, the catheter exits from a 7 o’clock direction of the enteroscope during DBE-assisted ERCP. Endoscopists should attempt to locate the papilla at 6 o’clock of the endoscopic view to facilitate biliary cannulation (Fig 2b). In case of an unstable endoscopic manoeuvre, an inflated enteroscope balloon may help to grip the intestine and stabilise the manipulation. In cases where the papilla is located at 11 to 12 o’clock in the endoscopic view, the overtube balloon should remain inflated and the enteroscope rotated to solve difficult cannulation.6

In conclusion, short DBE-assisted ERCP is a safe and effective endoscopic method to treat patients with surgically altered anatomy and biliary conditions. Nonetheless local experience in enteroscopy-assisted ERCP, particularly using the short DBE, is scant because of the unavailability of the endoscopic devices. Further discussion and training opportunities are encouraged to consolidate experience and minimise procedural complications in future practice.

1. Moreels TG. Altered anatomy: enteroscopy and ERCP procedure. Best Pract Res Clin Gastroenterol 2012;26:347-57. Crossref

2. Cheng CL, Liu NJ, Tang JH, et al. Double-balloon enteroscopy for ERCP in patients with Billroth II anatomy: results of a large series of papillary large-balloon dilation for biliary stone removal. Endosc Int Open 2015;3:E216-22. Crossref

3. Mönkemüller K, Bellutti M, Neumann H, Malfertheiner P. Therapeutic ERCP with the double-balloon enteroscope in patients with Roux-en-Y anastomosis. Gastrointest Endosc 2008;67:992-6. Crossref

4. Kato H, Tsutsumi K, Harada R, Okada H, Yamamoto K. Short double-balloon enteroscopy is feasible and effective for endoscopic retrograde cholangiopancreatography in patients with surgically altered gastrointestinal anatomy. Dig Endosc 2014;26 Suppl 2:130-5. Crossref

5. Katanuma A, Yane K, Osanai M, Maguchi H. Endoscopic retrograde cholangiopancreatography in patients with surgically altered anatomy using balloon-assisted enteroscope. Clin J Gastroenterol 2014;7:283-9. Crossref

6. Hatanaka H, Yano T, Tamada K. Tips and tricks of double-balloon endoscopic retrograde cholangiopancreatography (with video). J Hepatobiliary Pancreat Sci 2015;22:E28-34. Crossref

7. De Koning M, Moreels TG. Comparison of double-balloon and single-balloon enteroscope for therapeutic endoscopic retrograde cholangiography after Roux-en-Y small bowel surgery. BMC Gastroenterol 2016;16:98. Crossref

8. Yamamoto H. Be aware of the fatal risk of air embolism. Dig Endosc 2014;26:23. Crossref

An 85-year-old man presented with a history of odynophagia since March 2015. He was a chronic smoker but did not drink alcohol. He had a medical history of hypertension, diabetes mellitus, and gout. He was first seen by us in April 2015. At the first presentation, physical examination revealed an irregular 3-cm ulcerative mass arising from the left tonsil (Fig 1). The rest of his oral cavity was otherwise normal and there was no cervical lymphadenopathy. Carcinoma of the left tonsil was suspected. Computed tomographic (CT) scan of the head and neck disclosed a non-specific soft tissue thickening and mucosal contrast enhancement at the left side of the oropharynx. Transoral punch biopsy of the left tonsillar mass was performed. Histopathology revealed no evidence of malignancy with heavy stromal infiltration by neutrophils, lymphocytes, and plasma cells plus focal microabscess formation. No granuloma or fungal elements were seen.

Subsequent upper gastrointestinal endoscopy was performed and disclosed the left tonsillar mass with no other abnormalities within the hypopharynx, oesophagus, or stomach. Because of the progressive odynophagia, a nasogastric feeding tube was inserted; as there was no improvement and the diagnosis was still elusive, left tonsillectomy was performed on the same day and was uneventful.

Histopathological examination of the left tonsil showed lymphoid tissue with preserved architecture present beneath the stratified squamous epithelium. Hyperplastic lymphoid follicles with germinal centre surrounded by mantle cells were present. Plasma cells were seen at the interfollicular area. There were no malignant cells. Immunostaining revealed more than 90% of plasma cells per high-power field with an immunoglobulin (Ig) G4:IgG ratio of more than 40% (Fig 2). The final diagnosis was IgG4-related disease of the left tonsil.

The patient refused workup with positron emission tomography–CT scan but clinically there was no feature of systemic IgG4-related disease so steroids were not prescribed. His odynophagia gradually improved and he could tolerate oral feeding with congee. The feeding nasogastric tube was removed. Unfortunately, the patient had a depressive mood and general debility. He eventually died of pneumonia in September 2015.

Immunoglobulin G4–related disease is a fibroinflammatory condition often associated with elevated serum IgG4 level.1 It is a multi-organ entity that encompasses various conditions formerly considered to be unrelated, single-organ diseases.2 It is notorious for its resemblance to malignant disease such as carcinoma of the pancreas. It is a source of undue anxiety for both patients and clinicians as the diagnosis may be difficult if the index of clinical suspicion for IgG4-related disease is low. Systemic symptoms (asthenia, weight loss, or fever) may occur in a minority of patients. The disease can affect the pancreas (autoimmune pancreatitis with abdominal pain), biliary tree (sclerosing cholangitis with jaundice), salivary glands or lacrimal gland (parotid, submandibular and lacrimal gland enlargement), lymph nodes, kidneys (tubulointerstitial nephritis with renal failure), and retroperitoneum (ureteric stricture).2

Measuring the serum IgG4 level is useful to establish the diagnosis of this uncommon disease3 and may avoid unnecessary diagnostic surgery. Although serum IgG4 level was initially thought to be a key diagnostic feature of IgG4-related disease, more recent evidence has devalued the significance of a raised level. The key to diagnosis is immunohistochemical demonstration of tissue infiltration by IgG4-bearing plasma cells and morphological evidence of lymphoplasmacytic infiltrates, storiform fibrosis, and obliterative phlebitis.2 Serum IgG4 assay was not done as this investigation was not available at our hospital. Nonetheless the diagnosis of IgG4-related disease of tonsil in this patient was obvious based on the histopathological examination with IgG4 immunostains.

Umehara et al4 proposed a set of criteria for the diagnosis of IgG4-related disease designed to be used irrespective of the specific organ involvement. The criteria are (1) serum IgG4 concentration of >135 mg/dL and (2) >10 IgG-positive plasma cells demonstrated per high-power field, of which >40% are IgG4-positive cells. Nevertheless the sensitivity is low for the diagnosis of autoimmune pancreatitis based on these criteria.

Of note, IgG4-related disease can manifest at the head and neck region. Kuttner’s tumour of the submandibular gland has been well reported and often masquerades as carcinoma.5 Nonetheless IgG4-related disease within the oral cavity is very rare. To the best of our knowledge, only one case of simultaneous IgG4-related lesions affecting the left border of the tongue and right tonsil has been reported in the literature.6 This patient presented with an elevated and nodular mass devoid of surface ulceration, associated with a generalised skin rash. The oral and cutaneous lesions gradually resolved after therapy with steroid.6 In contrast, our patient had an ulcerative mass without any skin rash. Both cases were initially suspected to be squamous cell carcinoma because of the alarming clinical features.

Steroid remains the mainstay of treatment for IgG4-related disease. It should be started early in order to prevent tissue fibrosis and thus irreversible organ damage, except in cases of asymptomatic disease of the submandibular gland or lymph node.7 Radiological abnormalities often vanish following the commencement of steroid therapy. Unfortunately, disease relapse is not uncommon after steroid therapy is tapered. There is no evidence to support the effectiveness of adding conventional steroid-sparing agents (eg azathioprine, methotrexate, or cyclophosphamide) to sustain remission for IgG4-related disease.7 Although remission can be achieved in more than 80% of patients with induction steroid therapy, some clinicians support the use of maintenance steroid at 5 mg or 2.5 mg daily for a durable response. However, disease may flare in a quarter of patients despite maintenance therapy. Moreover, the optimal duration for maintenance treatment is uncertain and the morbidity associated with steroid, although in low dose, is not negligible. Fortunately, repeated induction therapy with steroid for disease relapse is normally effective.7

In summary, IgG4-related disease can involve the tonsils and masquerade as tonsil carcinoma. Clinicians should consider IgG4-related disease as one of the differential diagnoses for a suspicious tonsillar mass. Early diagnosis of tonsillar mass with biopsy is essential to exclude tonsil carcinoma and to allow prompt steroid treatment for IgG4-related disease of tonsil which is curable.

1. Deshpande V, Zen Y, Chan JK, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol 2012;25:1181-92. Crossref

2. Stone JH, Brito-Zerón P, Bosch X, Ramos-Casals M. Diagnostic approach to the complexity of IgG4-related disease. Mayo Clin Proc 2015;90:927-39. Crossref

3. Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med 2001;344:732-8. Crossref

4. Umehara H, Okazaki K, Masaki Y, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol 2012;22:21-30. Crossref

5. Chow TL, Chan TT, Choi CY, Lam SH. Kuttner’s tumour (chronic sclerosing sialadenitis) of the submandibular gland: a clinical perspective. Hong Kong Med J 2008;14:46-9.

6. Khurram SA, Fernando M, Smith AT, Hunter KD. IgG4-related sclerosing disease clinically mimicking oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol 2013;115:e48-e51. Crossref

7. Khosroshahi A, Wallace ZS, Crowe JL, et al. International consensus guidance statement on the management and treatment of IgG4-related disease. Arthritis Rheumatol 2015;67:1688-99. Crossref

A 37-year-old Chinese woman was admitted to the First Affiliated Hospital, College of Medicine, Zhejiang University, China in July 2009 with pain in the upper back and hip for 9 months. She denied any chronic medication or illness. Her serum calcium level was 2.73 mmol/L (reference range [RR], 2.08-2.60 mmol/L), phosphorus 0.68 mmol/L (RR, 0.81-1.62 mmol/L), alkaline phosphatase 366 IU/L (RR, 30-115 IU/L), and intact parathyroid hormone (iPTH) 1154 pg/mL (RR, 12-65 pg/mL). T-score and Z-score for femoral bone mineral density were -2.7 and -2.8, respectively. Cervical computed tomography (CT) scan and thyroid, parathyroid, and abdominal (including pancreas, adrenals) ultrasonography were unremarkable. Anterior planar technetium (^99mTc) sestamibi (MIBI) scintigraphy images of the neck and chest showed a focal shadow with intense tracer uptake in the superior thorax at 15 minutes (Fig a) and 120 minutes (Fig b) following injection of ^99mTc-MIBI. Thoracic CT revealed a contrast-enhanced nodule with soft tissue density of 2.9 x 1.3 cm in the anterior mediastinum (Fig c). Thoracic and abdominal CT showed a brown tumour in the right omoplate, the fourth posterior left rib, and iliac bone (Figs d and e).

A mid-sternal thoracotomy was performed. A dark red mass of 4 x 2.4 x 1 cm was found in the thymus isthmus and resected. The mediastinal mass was covered with a thin fibrous capsule and on section showed a greyish cut surface. Histology confirmed the presence of ectopic parathyroid adenoma composed predominantly of oxyphil cells arranged in acinar pattern. Serum calcium level was 2.18 mmol/L and iPTH 17.2 pg/mL 16 hours after surgery. Hypocalcaemia (serum calcium, 1.68 mmol/L) and hungry bone syndrome occurred 3 days after surgery and gradually improved over a week with calcium carbonate and calcitriol supplementation that was started after surgery and continued thereafter. Serum calcium and iPTH remained normal after 5 years’ follow-up.

A diagnosis of primary hyperparathyroidism in a symptomatic patient is made in the presence of hypercalcaemia, hypophosphataemia, and raised levels of alkaline phosphatase and iPTH,1 as demonstrated in our case. Primary hyperparathyroidism occurs in approximately 1% of the adult population, commonly due to solitary parathyroid adenomas (85%).1 Primary hyperparathyroidism due to ectopic parathyroid adenomas can pose diagnostic and management challenges, especially when imaging studies provide limited sensitivity.2

The embryological origin of the parathyroid glands is the endoderm of the third and fourth pharyngeal pouches, from where these glands migrate to their usual position behind the thyroid gland. It is well known that parathyroid glands can be found in aberrant locations, mainly in the thyroid parenchyma or in the mediastinum.3 The high incidence of ectopic inferior parathyroid glands has been attributed to abnormal migration during embryogenesis. Since parathyroid glands lack capsular fixation, an ectopic parathyroid gland may also develop from a gland that is initially present in a normal anatomic position but which enlarges and is displaced to an ectopic location where there is little resistance.

Ultrasonography is commonly used to locate enlarged parathyroid glands due to its convenience and low cost. Its ability to detect abnormalities, however, depends on the experience and skill of the operator so sensitivity in the localisation of enlarged parathyroid glands varies greatly (44%-87%).2 Ectopic parathyroid adenomas may be detected with MIBI at a sensitivity level almost identical to that of orthotopic adenomas. Focal increased activity separated from the lower pole of the thyroid on MIBI images gives a high probability for locating ectopic parathyroid adenoma in the thymus. Of note, ^99mTc-MIBI is a non-specific tracer that is taken up by mitochondria so any mitochondria-rich cells may show uptake. Mitochondrial density in an adenoma is also a major factor that can cause prolonged retention of ^99mTc. This is evidenced by the number of mitochondrion in lesions detected by scintigraphy that is significantly higher than in those that are missed, with the highest ratio of mitochondria per cell found in oxyphil cells. The typical pattern in a parathyroid adenoma demonstrates a prolonged retention of ^99mTc-MIBI in the adenoma with rapid washout of the tracer from normal thyroid tissue. The degree of MIBI uptake in parathyroid adenomas has been reportedly correlated with the size of gland and the cytological composition (greater uptake seen in adenomas with dominance of oxyphil cells over chief cells).2

Of note, CT may further contribute to the identification of ectopic parathyroids and the differential diagnosis from other lesions. In our cases, the parathyroid glands were not located by ultrasonography although a combination of MIBI scintigraphy and CT imaging accurately localised the tumour in the anterior mediastinum. This highlights the usefulness of combining multiple imaging techniques to locate an ectopic active parathyroid gland. These combinations are cost-effective, and considered an approach to routine preoperative localisation of ectopic parathyroid adenomas, especially in cases with a negative MIBI scan.4

Hungry bone syndrome refers to the rapid, profound, and prolonged hypocalcaemia associated with hypophosphataemia following parathyroidectomy as a result of extensive remineralisation.5 Various risk factors of hungry bone syndrome include older age, large parathyroid adenoma, overt bone disease, and vitamin D deficiency. Consequently, transient hypocalcaemia is frequently encountered postoperatively; the presence of mild hypocalcaemia provides reassurance that the hyperactive adenomatous gland has been successfully removed.

For any hypercalcaemia and high level of PTH without parathyroid adenoma in the neck, physicians should remain alert and continue to search for ectopic locations using a combination of imaging techniques. The mediastinum must be cautiously explored since it is a very common location for ectopic parathyroid adenoma. The combination of several imaging techniques has an incremental effect on the localisation of ectopic parathyroid adenomas compared with use of either one technique alone.

1. AACE/AAES Task Force on Primary Hyperparathyroidism. The American Association of Clinical Endocrinologists and the American Association of Endocrine Surgeons position statement on the diagnosis and management of primary hyperparathyroidism. Endocr Pract 2005;11:49-54. Crossref

2. Haber RS, Kim CK, Inabnet WB. Ultrasonography for preoperative localization of enlarged parathyroid glands in primary hyperparathyroidism: comparison with (99m) technetium sestamibi scintigraphy. Clin Endocrinol (Oxf) 2002;57:241-9. Crossref

3. Noussios G, Anagnostis P, Natsis K. Ectopic parathyroid glands and their anatomical, clinical and surgical implications. Exp Clin Endocrinol Diabetes 2012;120:604-10. Crossref

4. Elaraj DM, Sippel RS, Lindsay S, et al. Are additional localization studies and referral indicated for patients with primary hyperparathyroidism who have negative sestamibi scan results? Arch Surg 2010;145:578-81. Crossref

5. Witteveen JE, van Thiel S, Romijn JA, Hamdy NA. Hungry bone syndrome: still a challenge in the post-operative management of primary hyperparathyroidism: a systematic review of the literature. Eur J Endocrinol 2013;168:R45-53. Crossref