Youngest pancreas transplantation alone in the UK for type 1 diabetes and severe subcutaneous insulin resistance

Background

This is a case report of a young woman with severely unstable type 1 diabetes mellitus secondary to severe peripheral insulin resistance, who became the youngest patient in the UK to receive a whole organ pancreas transplant.

In addition to conventional home blood glucose monitoring and subcutaneous insulin regimens, there are alternative therapies to type 1 diabetic patients, especially for those who experience frequent severe complications of hypoglycaemia and diabetic ketoacidosis. These may include whole organ pancreas transplantation, islet cell transplantations and closed-loop insulin delivery systems.

Pancreas transplantation alone (PTA) is indicated in patients with diabetes with preserved renal function, complicated by recurrent life-threatening metabolic complications, such as hypoglycaemia and diabetic ketoacidosis, despite intensive insulin therapy.1 In the UK, between 1 April 2010 and 31 March 2020, 1672 simultaneous pancreas-kidney transplants were performed and 130 PTA.2 This is especially rare in the paediatric population.

We report a case whereby there was failure to control a paediatric patient’s blood glucose with medical therapy, causing severe life-threatening complications. Although solid organ pancreas transplants are not usually considered in the paediatric population, a PTA ultimately became the life-saving intervention for the patient. Due to the patient’s multiple physical and mental co-morbidities, this case demonstrates how a multidisciplinary approach between transplant surgeons, diabetologists, nephrologists and psychiatrists is crucial to the successful transplantation.

Case presentation

The patient was diagnosed with type 1 diabetes mellitus during her middle childhood. This was well controlled within the first 2 years of her diagnosis. However, her diabetic control subsequently deteriorated as she gradually developed resistance to subcutaneous insulin injections. As a result, the patient frequently developed severe episodes of diabetic ketoacidosis and hypoglycaemia with hypoglycaemic unawareness, leading to over 200 hospital admissions in her adolescent years.

As the control of her diabetes worsened it became not possible to manage her care with subcutaneous insulin, and she required intravenous insulin to achieve adequate control. This resulted in 18 months of home intravenous insulin through a central venous catheter, along with hourly blood glucose monitoring overnight that was supervised by 24-hour nursing support at home. During this time, she developed 19 episodes of septicaemia secondary to line infections requiring multiple hospital admissions with great challenges in getting intravenous access. She was then referred to a national quaternary pancreas transplant centre.

In addition to her diabetes, the patient developed frequent episodes of non-epileptic seizures, which was diagnosed as functional movement disorder with pseudoseizures. This was managed by her paediatric neurologist. These episodes were exacerbated when the patient was under stress or experiencing hyperglycaemia, resulting in the patient being more reliant on her wheelchair. The patient also suffered from severe anxiety, which she worked through with a paediatric and adolescent psychologist.

Investigations

The patient underwent intensive biochemical and radiological investigations at her regional tertiary centre. Her diagnosis of type 1 diabetes mellitus was confirmed with positive glutamic acid decarboxylase antibodies and islet cell antibodies.

However, a series of insulin assays gave conflicting results with insulin levels ranging from <0.5 to 129 mIU/L (normal fasting insulin level is <25 mIU/L) during episodes of laboratory-confirmed hypoglycaemia. The patient had a pretransplant Homeostatic Model Assessment for Insulin Resistance of 1.8 and a C-peptide level of 15 pmol/L, which did not correlate with her clinical presentation. Due to the variable insulin levels, an endogenous source of insulin such as an insulinoma was excluded radiologically with negative MRI of the abdomen, CT of the pancreas with contrast and positron emitting tomography scans. A maturity onset diabetes of the young screening excluded diabetes associated with hyperinsulinism. Self-administration of insulin was also suspected given the conflicting results of her insulin assays. However, she continued to develop episodes of hypoglycaemia and diabetic ketoacidosis despite being an inpatient with one-on-one nursing care and monitored insulin administration.

Differential diagnosis

On reviewing the results of her investigations by adolescent diabetologists and adult type 1 diabetes specialists, an organic cause for her subcutaneous insulin resistance was not found.

The patient’s emotional distress surrounding her adolescent life with diabetes in addition to her biological father’s death from hypoglycaemia, as a complication of type 1 diabetes mellitus, may have affected her hypoglycaemic stress response.

Treatment

After multidisciplinary discussions between adolescent and adult diabetologists, transplant surgeons, nephrologists, and psychiatrists, it was agreed that a PTA would be a life-saving option for the patient. This decision was made based on several key factors: (1) the patient was suffering from frequent life-threatening episodes of metabolic complications due to severely unstable diabetes; (2) intravenous insulin (which she depended on) was not a sustainable option due to frequent line sepsis and limited venous access; and (3) the continued rate of deterioration of her diabetic control.

Alternative therapies such as closed loop insulin delivery systems were not widely available at the time. Islet cell transplantation was briefly considered by the diabetologists. Even though it may have protected the patient from severe hypoglycaemic episodes, it was unlikely that it would make the patient insulin-independent.

There was a strong emphasis on her mental health prior to her transplant, given her history of anxiety. In addition to her sessions with paediatric psychology, she was counselled by the transplant psychologist on key issues such as the importance of immunosuppression compliance, risks of post-transplant depression and transplant graft failure. The patient did not develop secondary diabetic complications such as retinopathy, neuropathy or nephropathy prior to transplantation, with creatinine at 49 μmol/L. Her blood glucose control was optimised by the diabetologists, who trialled intramuscular insulin for 9 months before starting her on newer forms of subcutaneous insulin such as insulin degludec, resulting in fewer episodes of hypoglycaemia. This was important in reducing her dependence on intravenous insulin, and hence reducing the risk of line sepsis, especially in the event of an organ offer.

The patient received her PTA, after more than 1½ years on the transplant waiting list. The patient arrived via a prearranged air ambulance and was admitted to the adult transplant ward as per the patient’s request. Her insulin regime consisted of a subcutaneous insulin pump with Humulin S, along with once daily subcutaneous insulin degludec. This was switched to an intravenous insulin sliding scale preoperatively. The organ was from a donation after circulatory death (donor age was late 20s), with a cold ischaemic time of 12 hours and warm ischaemic time of 43 min, and an HLA-A, HLA-B, HLA-DR mismatch of 1-1-1. The patient had a body mass index of 28.2 kg/m² at the time of transplant, and the donor was not size-matched. Induction immunosuppression included alemtuzumab, prednisolone and tacrolimus as per our centre’s protocol. The organ was transplanted into the recipient’s right iliac fossa via a midline laparotomy. The organ’s portal vein was anastomosed to the inferior vena cava. The splenic artery and superior mesenteric artery, reconstructed via a Y-graft of donor iliac vessels, were anastomosed onto the right common iliac artery. The enteric anastomosis involved the donor duodenum which was anastomosed side-to-side with the recipient’s small bowel, approximately 90 cm from her ileo-caecal valve. There was immediate graft function intraoperatively indicated by stabilisation of the patient’s blood glucose and freedom from exogenous insulin infusions or injections. Mechanical venous thromboembolism prophylaxis was used preoperatively and 5000 IU of subcutaneous heparin was administered two times per day postoperatively.

Outcome and follow-up

The patient’s postoperative recovery was uncomplicated. The patient remained insulin-independent with blood glucose levels between 4 and 6 mmol/L. The patient was reviewed on the transplant ward by her renal psychologist post-transplantation to assess her mental well-being and continue counselling her on immunosuppression adherence. She was discharged from the ward on day 7 with a maintenance immunosuppression regimen consisting of tacrolimus, mycophenolate mofetil and prednisolone. Her haemoglobin A1c was 76 mmol/mol and 41 mmol/mol at 2 and 7 weeks post-transplant, respectively. This was compared with 84 mmol/mol 8 weeks prior to transplant. On routine percutaneous biopsy of the pancreas graft 3 months post-transplant, she was diagnosed with T-cell mediated rejection that was treated successfully with pulsed methylprednisolone.

There were significant long term benefits for the patient from her PTA. She had been entirely insulin-independent post-transplant, and did not experience further life-threatening complications of severe hypoglycaemic attacks and associated line sepsis from her dependence on intravenous insulin. Since her transplant the patient reported reduction in the frequency of pseudoseizures, allowing her to be less dependent on a wheelchair. The patient’s quality of life had significantly improved postoperatively, as she completed her Advanced Levels examinations and an undergraduate degree in psychology, as she intended to pursue a career as a child psychologist. She also competed at the British Transplant Games and took gold in archery. She was seen at our unit 2 years post-transplant and described her life as ‘a thousand percent better’. Her care was subsequently transferred back to her local transplant centre at the patient’s request due to the long distance required to travel. In the case of graft failure, the availability of newer closed loop insulin delivery systems which was not accessible to the patient at the time of her transplant would play an important role in the ongoing management of her diabetes.