We report on a 51-year-old female patient with MEN1 syndrome characterised by a heterozygous Q453X mutation in exon 10, which was diagnosed 5 years ago.
Q What are the 3 commonest features of MEN1 syndrome ?
- Pituitary Adenoma
- Enteropancreatic neuroendocrine tumors
Q Which gene is involved in MEN1 ?
- A tumor suppressor gene called MEN1 which encodes for a protein menin
- Located on chromosome 11
Q Do mutations in MEN1 and clinical features correlate ?
No. There is little genotype phenotype correlation
Due to hyperparathyroidism and a pancreatic tumour, she underwent parathyroidectomy and pancreatic tail resection in the past.
Q What type of parathyroidectomy is done in patients with MEN1 syndrome ?
Since MEN1 syndrome is associated with parathyroid hyperplasia either of the following is done:
- Subtotal parathyroidectomy- 3.5 parathyroid glands are removed
- Total parathyroidectomy with auto implantation of parathyroid tissue in the arm.
Histopathology of the pancreatic tumour revealed a glucagonoma with positive immunostaining for glucagon, chromogranin A and synaptophysin; negative immunostaining for gastrin, insulin, serotonin, somatostatin and pancreatic polypeptide. Moreover, the tumour showed the expression of somatostatin receptor type 2 (SSTR2), implicating responsiveness to somatostatin analogue therapy.
Q What are clinical featured of Glucogonoma ?
- Weight loss
- Necrolytic migratory erythema
As comorbidity, a multifactorial terminal kidney failure with haemodialysis three times a week has existed for almost 3 years. In the further course of disease, the glucagonoma relapsed with hepatic metastases, currently controlled as a stable disease under conservative treatment using everolimus 10 mg/day p.o. and octreotide long-acting release (LAR) 30 mg i.m. every 3 weeks.
Q Which drugs are considered for chemotherapy of advance inoperable Pancreatic NET ?
- Somatostatin analogues
Q What kind of drug is everolimus ?
It is an mTOR inhibitor
Everolimus for Advanced Pancreatic Neuroendocrine Tumors
In the present case, the patient came to the emergency room with dyspnoea and cough. Based on atypical bilateral infiltrations in the X-ray and highly elevated c-reactive protein (CRP), she was hospitalised with the diagnosis of pneumonia and treated with antibiotics while everolimus was paused; the last octreotide LAR injection was given 2 weeks prior to this. In the following days, her symptoms improved with normalising infection parameters. After 10 days of hospitalisation, however, her condition rapidly declined with progressive dyspnoea, orthopnoea and somnolence leading to admission to the intensive care unit.
Q Are infections common in patient on everolimus ?
Yes. In a published meta-analysis the risk of all grade infection was 21% in patient on everolimus. (Ref)
Q Which opportunistic infection should be considered in this case ?
Pneumocystis pneumonia must be considered in this patient.
On admission, the patient showed sinus tachycardia and hypotension. Echocardiography revealed acute heart failure with a severely impaired left ventricular ejection fraction (LVEF) of 10%. Heart disease was not known previously. Only moderate valvular dysfunction and no significant hypertrophy or dilatation was seen indicating a rather recent development of heart disease. Infusions with dobutamine and nitroprusside sodium were immediately started, but could not improve LVEF. Despite treatment, the patient developed cardiogenic shock, leading to intubation. By using PiCCO technology for haemodynamic measurements, we could confirm cardiogenic shock and clearly ruled out septic shock based on the following data: severely decreased cardiac index of 0.8 l/min per m2 (reference 3–5 l/min per m2), highly elevated systemic vascular resistance index of 3800 dyn×s×cm−5×m2 (reference 1700–2500 dyn×s×cm−5×m2).
Q What is the relationship between heart failure and NET ?
Carcinoid syndrome is known to be associated with tricuspid and pulmonary value lesions.
Angiography ruled out coronary artery disease. Myocardial biopsy showed hypertrophy of cardiomyocytes and slight interstitial dilatation, but no signs of inflammation or metabolic heart disease. No cardiotoxic medication could be found in her previous medical history. Serum PCR for cardiotropic viral pathogens including parvovirus B19, coxsackie-A/B-virus, ECHO-virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), HHV-1, HHV-2, HHV-6, and HHV-8 was negative. No bacterial or fungal pathogen could be isolated from repeatedly collected samples of body fluids. At this point, the aetiology of heart failure remained unclear.
An association between glucagonoma and heart failure is not known. However, we found one case report by Chang-Chretien et al. (4) describing a 54-year-old female patient with glucagonoma-induced cardiomyopathy. This patient presented an LVEF of 15% with no valvular disease, clean coronary arteries, and in histopathology with only signs of myocardial hypertrophy and interstitial fibrosis – very similar to our patient. Surgical removal of the tumour led to complete normalisation of left ventricular function within 8 months. As pathomechanism, the authors suspected tachycardiomyopathy based on the chronotropic effect of glucagon.
Assuming that glucagonoma induced heart failure in our patient, we started therapy with continuous infusion of octreotide at a rate of 50 μg/h after an initial bolus of 50 μg, as surgery was not an option. In the following days, left ventricular (LV) function gradually improved, catecholamine treatment could be ended and the patient was extubated under stable haemodynamic conditions. Within 3 weeks, LVEF recovered up to 45% with a cardiac index of 3.7 l/min per m2. We determined the levels of chromogranin A, which is used as biomarker in NETs and correlates with hormone secretion (5). The levels of chromogranin A were at 1100 μg/l (reference 19–150 μg/l) under stable disease 1 year ago. Intriguingly, it was significantly increased to 4174 μg/l at the point of acute heart failure, and it markedly decreased after 1 day (1918 μg/l) and was back to baseline after 3 weeks (1223 μg/l) upon continuous octreotide treatment. Glucagon levels could not be determined due to the lack of a reliable test.
Learning points from this case
- Heart failure can be precipitated by glucagonoma.
- IV Octreotide infusion can be used for treatment of this type of heart failure.