A case of congenital hyperinsulinism with ABCC8 variants treated with octreotide long-acting release for four years

Abstract.

Congenital hyperinsulinism (CHI) is a rare disorder resulting in hypoglycemia due to increased insulin secretion and is subdivided into focal and diffuse forms. CHI is associated with neurological damage due to hypoglycemia, making adequate blood glucose management crucial. Although subcutaneous octreotide injection can effectively treat CHI, frequent octreotide administration may be burdensome for patients and their families. Here, we describe a boy with early neonatal-onset persistent CHI treated with octreotide long-acting release (LAR). At first, he received treatment with continuous glucose infusion, diazoxide, and glucagon. Genetic analysis revealed the patient was a compound heterozygote for ABCC8, with diffuse form predicted. Although the focal form can be treated by surgery, the diffuse form requires long-term drug therapy. Therefore, he was treated with octreotide subcutaneous injections and subsequently transitioned to octreotide LAR to avoid the inconvenience of frequent injections. He has been receiving octreotide LAR for four years and has not experienced developmental delays or any apparent side effects, such as necrotizing enterocolitis. The dosing interval can be extended without increasing hypoglycemia. Octreotide LAR reduced the burden on the patient and his family. Octreotide LAR can be an effective long-term treatment for CHI. However, further cases are needed for verification.

Highlights

● The patient presented with diffuse form CHI due to the variants in ABCC8.

● Octreotide LAR can be an effective and safe long-term treatment for CHI.

● Octreotide LAR reduced the burden on the patient and his family.

Introduction

Congenital hyperinsulinism (CHI, OMIM #256450) is a rare disorder in which pancreatic beta cells secrete excessive insulin, resulting in hypoglycemia. Several genes have been associated with CHI (1). In CHI, proper glycemic control is crucial to mitigate severe and permanent neurological damage induced by hypoglycemia (2, 3). CHI can be subdivided into focal and diffuse forms. The focal form results from inheritance of a paternal ABCC8 or KCNJ11 variant combined with somatic loss of heterozygosity of the maternal allele at 11p15 (4,5,6). While the focal form can be cured by excision of the lesion, in diffuse form, local surgery is not possible. Therefore, medical treatment is the primary approach (7, 8).

Japanese treatment guidelines recommend continuous intravenous glucose infusion and oral diazoxide as the initial treatment for CHI. However, diazoxide is ineffective against CHI with ABCC8 or KCNJ11 variants (9). For such cases, second-line treatment with subcutaneous octreotide or intravenous glucagon is recommended. Although glucagon is also an effective treatment (10), it is unsuitable for home therapy because of the tendency of deposit formation in the infusion line (11) and because neither the drug nor the device is licensed. In 2021, octreotide became covered by Japanese national insurance for the treatment of hypoglycemia in patients with CHI, and is used as frequent subcutaneous injection. Octreotide is a somatostatin analog with a strong affinity for somatostatin receptor subtype 2 (10). Somatostatin inhibits the secretion of growth hormone and thyroid-stimulating hormone (TSH) from the anterior pituitary gland, as well as glucagon and insulin from the pancreas (12). Octreotide has a short half-life of approximately two hours; therefore, frequent or continuous subcutaneous injections are needed to stabilize blood glucose levels (13). Such a treatment can be burdensome for patients. On the other hand, the efficacy of long-acting octreotide has been demonstrated in other diseases, such as neuroendocrine tumors (14) and acromegaly (15). However, there are very few case reports describing its use in CHI, and most of them report only short-term use (13, 16,17,18).

Here, we describe a patient with persistent CHI and ABCC8 variants who has been under octreotide LAR treatment for 4 years.

Case Report

The patient is a 4-yr-old boy with no family history of diabetes or hypoglycemia. His mother had been diagnosed with fetal overgrowth at the last trimester of pregnancy. The patient was born at 38 wk of gestation by vaginal delivery without distress. He was large for gestational age; his height was 52.1 cm (+2.02 SD) and his weight was 3,898 g (+2.98 SD). He presented with hypoglycemia from day 1 of life. No interventions were performed due to his good general condition. He was discharged from the maternity hospital on day 5. At day 8, he was admitted at the maternity hospital because of poor feeding. His blood glucose level was 13 mg/dL at the visit. He was fed milk and glucose and then transported to the regional pediatric unit. He experienced a seizure at the time of his post-transfer visit. Because his hypoglycemia persisted after glucose infusion, the patient was transferred to the core hospital. His insulin level while experiencing hypoglycemia was 38.8 µU/mL (diagnostic criteria for CHI: >1 µU/mL) (Table 1). In addition, a glucose infusion rate (GIR) of at least 10 mg/kg/min was required to maintain normal blood glucose levels. His blood glucose level increased after intravenous glucagon infusion, leading to a diagnosis of CHI. Hypoglycemia persisted with oral diazoxide alone, the patient’s blood glucose level increasing only with continuous intravenous glucagon. He was eventually transferred to our hospital for close examination and further intensive treatment at 23 d of age. At the time of transfer, the patient’s general condition was good, with no abnormalities on physical examination. His blood glucose level was mildly low, while his insulin level was high. Ultrasonography showed no morphological abnormalities in the pancreas. In addition to continuous intravenous infusion of glucose and glucagon and oral administration of diazoxide, subcutaneous injection of octreotide was initiated (Fig. 1). At the time, octreotide was not covered by insurance, so it was administered after obtaining specific approval from the hospital. Initially, octreotide was administered three times a day. At that time, the patient was fed standard infant formula, but starting from 1 mo of age, we began using a combination of a specialized formula for glycogen storage disease and a standard infant formula. Even after increasing the dose of octreotide to the maximum amount each time, the patient’s blood glucose level before feeding remained highly variable. Therefore, one month after initiation, the dosage was changed to seven daily injections. Diazoxide and glucagon were tapered off. After obtaining informed consent from the patient’s parents, genetic analysis by Sanger sequencing was performed, which identified compound heterozygous variants (NM_000352.6: c.[742C>T];[1774delC], NP_000343.2: p.[Arg248*];[Leu592Cysfs*13]) in ABCC8 (Fig. 2). The parents were heterozygotes for each variant. Of the ABCC8 variants, p.Arg248* has been reported in CHI (1), whereas Leu592Cysfs*13 is a novel variant. Based on a suspicion that the lesions were probably diffuse, an ¹⁸F-DOPA PET scan was not performed. Extended octreotide administration was deemed necessary, and long-term frequent injections were considered burdensome for the family. Continuous subcutaneous injection was considered but could not be implemented due to difficulty obtaining the required device, as octreotide was prescribed off-label. At 80 d of age, the patient’s treatment was switched from frequent subcutaneous injections of octreotide to a long-acting formulation. Off-label use of octreotide LAR was approved at the hospital, written information was provided to the patient’s parents, and informed consent was obtained. The initial dose of octreotide LAR was set at 5 mg per administration. Since the daily dose of octreotide for continuous subcutaneous administration was 25 μg/kg/d, this 5 mg dose was equivalent to approximately 28 d of treatment. Furthermore, as previous reports indicated that the initial dose ranged from 5 to 10 mg (13), the minimum dose of 5 mg was selected. The contents of a 10 mg prefilled vial were reconstituted, and half the volume was transferred into a separate syringe for administration. The dosing interval was initially scheduled for every 28 d, but as hypoglycemia began to occur more frequently, the dose was increased to 6.5 mg, and the second dose was administered 21 d after the first dose. Octreotide subcutaneous injections were also administered concurrently during the first two weeks. He was discharged at 4 mo of age. Following discharge, the octreotide LAR dose was calculated at each outpatient visit by multiplying the daily equivalent of 25 μg/kg by the number of days until the subsequent visit. At the initial outpatient visit, the dose of octreotide LAR was 7 mg. Thereafter, doses were administered at approximately one-month intervals using the same calculation method. The dose was maintained at approximately 25 μg/kg/d throughout treatment. As the patient grew, his feeding frequency decreased, and he showed a poor appetite for weaning food. Although severe hypoglycemia (50 mg/dL or lower) was not frequently observed, fasting hypoglycemia increased. At 9 mo of age, the patient was started on cornstarch intake. At 1 yr and 3 mo of age, his blood glucose levels stabilized within a stable range (mean 95–100 mg/dL, with hypoglycemia < 50 mg/dL occurring 0–2 times per month), and episodes of hypoglycemia below 50 mg/dL have become rare. At age 2, his food intake increased, and his HbA1c increased into the 5% range. At 2 yr and 3 mo of age, the patient’s blood glucose level remained stable, and the glucose infusion rate (GIR) was reduced, with the infusion fully halted 5 mo later (Fig. 1). At the age of 4, his height, weight, and BMI were 100.5 cm (+0.07 SD), 20.3 kg (+1.97 SD), and 20.1, respectively (Figs. 3 and 4). While his height is average, he is classified as obese. At the age of 4 yr and 3 mo, his developmental quotient score on the Kyoto Scale of Psychological Development was 100 (cognitive score 98, language-social score 100). Regular blood tests and abdominal ultrasounds were conducted to monitor for side effects, and no other apparent side effects, including decreases in TSH or insulin-like growth factor 1 due to octreotide, were observed (Table 2). Although the medication was typically administered at approximately four-week intervals, adjusting the dosage to account for a five-week gap between visits did not result in an increase in hypoglycemia. His blood glucose measurements were taken four times a day (before each meal and before bedtime). The average blood glucose level for one month was 95–100 mg/dL. Hypoglycemia below 50 mg/dL occurred 0–2 times per month, but all episodes were asymptomatic. Therefore, considering the burden on the family, the administration interval was changed to five weeks.

Table 1. Laboratory data at diagnosis.

Fig. 1.

Clinical course of the patient. The black diamond indicates the HbA1c level. Drug bars indicate treatment duration. Random glucose and insulin values were excluded due to inconsistent measurement timing.

Fig. 2.

Sanger sequencing analysis of ABCC8 for the current case.

Fig. 3.

Growth charts of the patient.

Fig. 4.

Obesity charts of the patient.

Table 2. Laboratory data of the 4-yr-old patient with congenital hyperinsulinism.

Discussion

We describe the four-year course of octreotide LAR therapy in a CHI patient with a compound heterozygous variant in ABCC8. This is the first report of octreotide LAR treatment in Japan. Most reports have been conducted overseas and only for short-term use. Although mild hypoglycemia occurs occasionally, no apparent developmental delay has been observed to date.

In the present case, blood glucose control was poor under subcutaneous octreotide injections administered three times a day, which required frequent injections, necessitating an increase in injection frequency to seven times daily. It has been reported that CHI patients with ABCC8 variants who had not undergone pancreatectomy required an average of 6 yr of medication until achieving spontaneous remission (19). Long-term subcutaneous administration of octreotide places a significant burden on patients and their families. Furthermore, administering injections several times a day at home or using pump therapy is not always practicable (13). In this case, hypoglycemia could not be prevented without administering octreotide injections seven times daily, which was a significant burden for the patient and family. Therefore, octreotide LAR was introduced for this patient. Several studies report the use of octreotide LAR in patients with CHI (13, 16,17,18) (Table 3). These reports, as in our case, indicate that octreotide LAR was effective in most patients (13, 16,17,18). Regarding treatment satisfaction, LAR formulations have been particularly well tolerated by families compared with subcutaneous injections (16). The feasibility of continuing treatment for the patient and family should also be considered.

Table 3. Clinical features of patients treated with octreotde LAR treatment.

Of the three reports describing the switch from subcutaneous octreotide to octreotide LAR (13, 16, 18), two determined the LAR dosage by multiplying the daily dose of the subcutaneous formulation by the number of days between LAR administrations (16, 18). We also used this method to determine the LAR dosage for our patient. In the remaining report, doses of 5 mg, 7 mg, or 10 mg were selected (13). In this case, subcutaneous octreotide was administered concurrently for two weeks following the initiation of octreotide LAR. Other reports have described approaches such as discontinuing subcutaneous octreotide after the third dose of octreotide LAR, or tapering the dose over a two-month period (16, 18).

According to one report, initiation of octreotide LAR treatment was described between 1.13 and 8.5 yr (16); however, there has recently been an increase in reports of its use in early infancy (13, 17, 18). Octreotide has side effects that suppress gastrointestinal motility and splanchnic blood flow (16, 20). In case reports and reviews of necrotizing enterocolitis associated with octreotide use, the time of initiation of octreotide ranged from 4 to 21 d after birth (20). Therefore, its administration is not recommended for the early neonatal period due to the risk of necrotizing enterocolitis (16). In our case, treatment with a very small dose of octreotide administered subcutaneously was initiated at 23 d of age and the dose was gradually increased; treatment with octreotide LAR was started at 80 d of age. No significant adverse effects were observed. Future studies should determine the optimal initiation timing for long-acting formulations. The long-term safety and efficacy of octreotide LAR remain unclear. While most reports concern short-term use, one patient received long-acting octreotide for over six years, with a decrease in IGF-1 observed (13). In this case, neither decreased IGF-1 nor growth impairment was observed.

On the other hand, cases of treatment with lanreotide, a long-acting somatostatin analog with high affinity for somatostatin receptor subtype 2, have also been reported (13, 21,22,23,24,25). Since lanreotide was launched before octreotide LAR, more reports of lanreotide are available. Several cases of lanreotide use for more than 4 yr have been reported (13, 21, 22). Reported side effects include nodules at the injection site, biliary sludge, and gallstones. These adverse events did not differ from those reported for short-term use or subcutaneous injection formulations. In recent years, pasireotide, a second-generation somatostatin analog, has also been reported to be effective for severe CHI (26). However, regarding pasireotide, the first reported case of its use in treating children with congenital hyperinsulinism was in 2021 (26). Since this treatment option was not available when our patient’s treatment was initiated, it was not considered.

Our patient has been able to continue treatment for 4 yr without significant problems. With careful follow-up, long-term treatment may be possible. The accumulation of more cases is needed to elucidate the safety and efficacy of octreotide LAR.

Conclusion

We describe the four-year course of octreotide LAR therapy in a CHI patient with compound heterozygous variants in ABCC8. A novel variant of ABCC8, p.Leu592Cysfs*13, was identified in the patient. Octreotide LAR can be an effective and safe long-term treatment for CHI. However, further case accumulation is needed to establish the safety and efficacy of octreotide LAR.

Conflict of interests

The authors have no financial relationships relevant to this article to disclose.