This is the case of a 20-year-old man presenting a hypothalamopituitary histiocytosis and positive for serum anti-insulin receptor antibodies with a follow-up characterized by alternating periods of diabetes mellitus with extreme insulin resistance and periods of normoglycemia.
The patient #1509232 is a young male with a history of polyuria and polydipsia since he was 11 years old. This symptom was neglected. The patient had a normal academic progression and medical work-up (at age of 14 years and 17 years) excluding several times the diagnosis of diabetes mellitus, as no hyperglycemia has been detected. At the age of 20 years and 5 months he became polyphagic and his weight increased from 60 to 90 kg without any other complaint. Finally, 5 months later, a brain MRI was performed and a large hypothalamus mass (20x20mm) with thickening of the pituitary stalk and compression of the third ventricle was observed. A strong contrast enhancement was observed after administration of gadolinium.
The patient was admitted in the department of endocrinology and the biological explorations concluded to a panhypopituitarism associated with diabetes insipidus. At the initial assessment, the following was also discovered: (i) the patient presented stage I obesity (BMI=26.6 kg/m2), (ii) delayed bone age relative to chronological age (resp., 16 years for a chronological age of 20), and (iii) a growth delay with a deceleration of linear growth at age of 15 years.
A stereotactic biopsy of the brain mass was performed at age of 21 years (M1) and immunohistochemistry showed positive staining for CD1a and PS100, supporting the diagnosis of LCH. Presence of BRAF V600E mutation was explored because this mutation in LCH is associated with more severe disease than did those with wild-type BRAF and irreversible damage, such as neurologic and pituitary injuries. In addition, presence of BRAF V600E mutation may offer the possibility of a targeted therapy by BRAF inhibitor (vemurafenib or PLX8394, a second-generation BRAF inhibitor). Unfortunately, the mutation was not observed and this has limited the possibility to use BRAF inhibitors). Disease work-up failed to find any extra pituitary-hypothalamic extension.
The patient was referred to the oncology department to start vinblastine (one infusion of 10mg per week) and purinethol (100mg per day) according to the French guidelines HL2010 protocol. He did not receive corticosteroids. The patient signed an informed consent to be enrolled in the French LCH registry according to regulation.
One month after, the patient was admitted to the emergency room for altered consciousness (M0). The blood tests showed hypernatremia at 164mmol/l and hyperglycemia at 25.8mmol/l without ketosis. Importantly, blood glucose levels were in the normal range 6 months before and at the time of the brain biopsy. After continuous administration of fluids and rapid acting insulin analogue (124UI/24hr), he was admitted to the diabetology department.
The search for type 1 diabetes (anti-GAD and anti-IA2 antibodies) was negative. C-peptide level was 9µg/l in the fasting state (normal range: 0.8-4.2 µg/l). The lipid profile showed hypertriglyceridemia at 5.7mmol/l (5,4g/l) and low HDL-cholesterol level at 0.41 mmol/l (0.16g/l). Blood pressure was normal at 125/68mmHg. The abdominal CT-scan found liver steatosis without any pancreatic abnormalities. The weight gain of 19kg during the last 3 months (body mass index: 32kg/m2) was linked to eating disorder (especially binge-eating disorder). It was decided to continue the first-line therapy up to 6 infusions of vinblastine.
Intriguingly, soon after the diagnosis of diabetes mellitus, daily insulin needs grew up to 400UI per day (4.2UI/kg), indicating a significant insulin resistance state. We did not observe acanthosis nigricans or loss of subcutaneous tissue and we excluded hypersecretion of hyperglycemic hormones. We tested the hypothesis of antibodies against insulin receptors as a cause of insulin resistance. The screening for serum anti-insulin receptor antibodies was performed using a radioreceptor assay as described. In summary, Chinese Hamster Ovary cells overexpressing insulin receptor (CHO-IR) were incubated or not for 90 min at 22°C with control and patient's serum at different dilutions, washed, and then incubated for 90 min at 22°C with a tracer concentration of 125I-insulin with or without unlabeled insulin.
The ability of patient's serum to inhibit binding of [125I]insulin was expressed as a percent decrease of insulin binding at 1:3 dilution as compared to the reference value. At the diabetes diagnosis, insulin receptor antibodies were positive (42% decrease in insulin binding), allowing the diagnosis of type B insulin resistance, a disease often associated with autoimmune disorders or hematological diseases. We then excluded systemic lupus erythematous, multiple myeloma, and Hodgkin's disease. Interestingly, insulin receptor antibodies levels decreased when first-line therapy was achieved (19% decrease in insulin binding) in parallel to a spectacular decrease in daily insulin needs.
Insulin therapy could be discontinued and replaced by a monotherapy with metformin (850mg twice a day). HbA1c remained stable at 6.5% (48 mmol/mol) until M8. In contrast, no improvement of binge-eating disorder was observed and body mass index kept increasing significantly during this period
Seven months after initial diagnosis of diabetes mellitus, intensification of hypoglycemic therapy with sulfonylurea and liraglutide LAR added to metformin was needed because glucose levels increased. The change in glucose levels was observed at the same time as a further increase of serum insulin receptor autoantibodies at M8 and M10 (43 and 42 percent decrease of insulin binding to its receptor upon incubation of CHO-IR cells with patient's serum at 1:3 dilution, resp.).
Although a significant decrease of the size of the brain mass was observed when compared to initial evaluation, persistence of contrast enhancement after gadolinium administration suggested an incomplete response to therapy.
A second-line therapy was started, consisting in 6 cycles of cladribine (5mg/m2/24h, 5 days/week, each month) from month 12 to month 18 after the diagnosis. At M30, brain MRI showed a decrease of both tumor volume and contrast enhancement.
In addition, glucose levels were controlled with the association of metformin and liraglutide (HbA1c level decreased to 7.5% or 58mmol/mol). Diabetes improvement was associated with a decrease of insulin receptor antibodies levels until M31. Unfortunately, a new recurrence of uncontrolled diabetes (HbA1c: 11.2%, 99 mmol/mol) occurred at M32 needing insulin therapy. Insulin receptor antibodies were once again positive (36% inhibition of insulin binding by patient's serum at 1:3 dilution), while brain MRI did not reveal tumor recurrence.
It was decided to initiate new cycles of cladribine. The patient received a first cycle at M32 after diagnosis and a second one month later. During this period, insulin daily doses decreased from 300UI to 36UI at the end of cladribine cycles. Additionally, HbA1c level decreased from 11.2% to 8.6% (from 99 to 70 mmol/mol). The PET-MRI made during the relapse of diabetes at M32 showed a nodular thickening of the floor of the third ventricle and pituitary infundibulum with no [18F]-FDG-uptake.
Control of diabetes was maintained until M35 and PET-MRI was unchanged at that time. The follow-up was marked by a very complex clinical disorder, with behavioural difficulties, polyphagy and agressivity; neurological difficulties, loss of memory; and very instable basal metabolic situation, hyperglycemia, and recurrent hypernatremia episodes. Four years after the diagnosis of LCH, the patients is actually frequently hospitalized in a psychiatric hospital.