Clinical Overview > Gland/Organ > Liver
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Search for other papers by S A A van den Berg in
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Search for other papers by C G Krol in
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Summary
We present a patient (87 years, female) who was admitted to the emergency department because of loss of consciousness. Previous medical history included advanced-stage hepatocellular carcinoma and associated weight loss. She was found on the ground in an unresponsive state by her daughter and was determined to be hypoglycaemic. Upon bolus administration of 100 mL intravenous glucose (10%), glucose levels increased to 2.9 mmol/L and the patient regained full consciousness. She was admitted to the hospital for further examination, and treatment and continuous intravenous glucose infusion was initiated. As the patient was known to suffer from advanced-stage hepatocellular carcinoma, tumour-associated hypoglycaemia was suspected. Insulin, c-peptide and IGF1 concentrations were indeed low, cortisol concentration was high and IGF2 and Pro-IGF2 were borderline low and borderline high normal respectively. IGF2:IGF1 ratio was 23, confirming the diagnosis of non-islet cell tumour hypoglycaemia. During the initial phase of treatment, euglycaemia was maintained by continuous variable glucose infusion (5%, varying between 1 and 2 L/24 h), and the patient was advised to eat small snacks throughout the day. After euglycaemia was established and the diagnosis was confirmed, prednisolone was started (30 mg, 1 dd) and glucose infusions were halted. Under prednisolone treatment, glucose levels were slightly increased and no further hypoglycaemic episodes occurred. At her request, no surgery was performed. After 19 days, the patient was discharged to a hospice and died 3 weeks later.
Learning points:
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Hepatocellular carcinoma may be associated with non-islet cell tumour hypoglycaemia (NICTH).
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NICTH-induced hypoglycaemia is associated with low insulin and IGF1.
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Measurement of IGF2 only (without measurement of Pro-IGF2 and IGF1) may be insufficient to prove NICTH.
Search for other papers by María Clemente in
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Search for other papers by Alejandro Vargas in
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Search for other papers by Gema Ariceta in
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Search for other papers by Rosa Martínez in
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Search for other papers by Ariadna Campos in
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Search for other papers by Diego Yeste in
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Summary
HNF4A gene mutations have been reported in cases of transient and persistent hyperinsulinaemic hypoglycaemia of infancy (HHI), particularly in families with adulthood diabetes. The case of a patient with HHI, liver impairment and renal tubulopathy due to a mutation in HNF4A is reported.
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Urine specimen study in cases of HHI with diazoxide response is necessary to rule out specific metabolic conditions (l-3-hydroxyacyl-coenzyme A dehydrogenase deficiency) or tubular renal involvement.
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Hyperinsulinaemic hypoglycaemia due to the heterozygous mutation (p.Arg63Trp, c. 187C > T) in the HNF4A gene is associated with renal tubulopathy and liver involvement.
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Follow-up of patients diagnosed of HHI is mandatory to detect associated conditions.
Search for other papers by Shinobu Takayasu in
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Search for other papers by Shingo Murasawa in
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Search for other papers by Satoshi Yamagata in
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Search for other papers by Kazunori Kageyama in
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Search for other papers by Takeshi Nigawara in
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Search for other papers by Yutaka Watanuki in
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Search for other papers by Daisuke Kimura in
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Search for other papers by Takao Tsushima in
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Search for other papers by Yoshiyuki Sakamoto in
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Search for other papers by Kenichi Hakamada in
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Search for other papers by Ken Terui in
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Search for other papers by Makoto Daimon in
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Summary
Patients with Cushing’s syndrome and excess exogenous glucocorticoids have an increased risk for venous thromboembolism, as well as arterial thrombi. The patients are at high risk of thromboembolic events, especially during active disease and even in cases of remission and after surgery in Cushing’s syndrome and withdrawal state in glucocorticoid users. We present a case of Cushing’s syndrome caused by adrenocorticotropic hormone-secreting lung carcinoid tumor. Our patient developed acute mesenteric ischemia after video-assisted thoracoscopic surgery despite administration of sufficient glucocorticoid and thromboprophylaxis in the perioperative period. In addition, our patient developed hepatic infarction after surgical resection of the intestine. Then, the patient was supported by total parenteral nutrition. Our case report highlights the risk of microthrombi, which occurred in our patient after treatment of ectopic Cushing’s syndrome. Guidelines on thromboprophylaxis and/or antiplatelet therapy for Cushing’s syndrome are acutely needed.
Learning points:
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The present case showed acute mesenteric thromboembolism and hepatic infarction after treatment of ectopic Cushing’s syndrome.
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Patients with Cushing’s syndrome are at increased risk for thromboembolic events and increased morbidity and mortality.
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An increase in thromboembolic risk has been observed during active disease, even in cases of remission and postoperatively in Cushing’s syndrome.
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Thromboprophylaxis and antiplatelet therapy should be considered in treatment of glucocorticoid excess or glucocorticoid withdrawal.
Search for other papers by Etienne Larger in
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Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Search for other papers by Nicolai J Wewer Albrechtsen in
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Search for other papers by Lars H Hansen in
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Search for other papers by Richard W Gelling in
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Sorbonne University, UPMC, University of Paris 6, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
Search for other papers by Jacqueline Capeau in
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Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Search for other papers by Carolyn F Deacon in
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Search for other papers by Ole D Madsen in
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Department of Education Planning and Development, Faculty of Medicine, Toho University, Tokyo, Japan
Search for other papers by Fumiatsu Yakushiji in
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Search for other papers by Pierre De Meyts in
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Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Search for other papers by Jens J Holst in
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Search for other papers by Erica Nishimura in
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Summary
Glucagon stimulates hepatic glucose production by activating specific glucagon receptors in the liver, which in turn increase hepatic glycogenolysis as well as gluconeogenesis and ureagenesis from amino acids. Conversely, glucagon secretion is regulated by concentrations of glucose and amino acids. Disruption of glucagon signaling in rodents results in grossly elevated circulating glucagon levels but no hypoglycemia. Here, we describe a patient carrying a homozygous G to A substitution in the invariant AG dinucleotide found in a 3′ mRNA splice junction of the glucagon receptor gene. Loss of the splice site acceptor consensus sequence results in the deletion of 70 nucleotides encoded by exon 9, which introduces a frame shift and an early termination signal in the receptor mRNA sequence. The mutated receptor neither bound 125I-labeled glucagon nor induced cAMP production upon stimulation with up to 1 µM glucagon. Despite the mutation, the only obvious pathophysiological trait was hyperglucagonemia, hyperaminoacidemia and massive hyperplasia of the pancreatic α-cells assessed by histology. Our case supports the notion of a hepato–pancreatic feedback system, which upon disruption leads to hyperglucagonemia and α-cell hyperplasia, as well as elevated plasma amino acid levels. Together with the glucagon-induced hypoaminoacidemia in glucagonoma patients, our case supports recent suggestions that amino acids may provide the feedback link between the liver and the pancreatic α-cells.
Learning points:
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Loss of function of the glucagon receptor may not necessarily lead to the dysregulation of glucose homeostasis.
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Loss of function of the glucagon receptor causes hyperaminoacidemia, hyperglucagonemia and α-cell hyperplasia and sometimes other pancreatic abnormalities.
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A hepato–pancreatic feedback regulation of the α-cells, possibly involving amino acids, may exist in humans.
Search for other papers by Jerena Manoharan in
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Search for other papers by Caroline L Lopez in
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German Cancer Consortium (DKTK), Dresden, Germany, German Cancer Research Center (DKFZ), Heidelberg, Germany, National Center for Tumor Diseases (NCT), Dresden, Germany
Search for other papers by Karl Hackmann in
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Search for other papers by Max B Albers in
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Search for other papers by Anika Pehl in
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Search for other papers by Peter H Kann in
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Search for other papers by Emily P Slater in
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German Cancer Consortium (DKTK), Dresden, Germany, German Cancer Research Center (DKFZ), Heidelberg, Germany, National Center for Tumor Diseases (NCT), Dresden, Germany
Search for other papers by Evelin Schröck in
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Search for other papers by Detlef K Bartsch in
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Summary
We report about a young female who developed an unusual and an aggressive phenotype of the MEN1 syndrome characterized by the development of a pHPT, malignant non-functioning pancreatic and duodenal neuroendocrine neoplasias, a pituitary adenoma, a non-functioning adrenal adenoma and also a malignant jejunal NET at the age of 37 years. Initial Sanger sequencing could not detect a germline mutation of the MEN1 gene, but next generation sequencing and MPLA revealed a deletion of the MEN1 gene ranging between 7.6 and 25.9 kb. Small intestine neuroendocrine neoplasias (SI-NENs) are currently not considered to be a part of the phenotype of the MEN1-syndrome. In our patient the SI-NENs were detected during follow-up imaging on Ga68-Dotatoc PET/CT and could be completely resected. Although SI-NENs are extremely rare, these tumors should also be considered in MEN1 patients. Whether an aggressive phenotype or the occurrence of SI-NENs in MEN1 are more likely associated with large deletions of the gene warrants further investigation.
Learning points
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Our patient presents an extraordinary course of disease.
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Although SI-NENs are extremely rare, these tumors should also be considered in MEN1 patients, besides the typical MEN1 associated tumors.
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This case reports indicate that in some cases conventional mutation analysis of MEN1 patients should be supplemented by the search for larger gene deletions with modern techniques, if no germline mutation could be identified by Sanger sequencing.
Search for other papers by S Solomou in
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Search for other papers by R Khan in
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Search for other papers by D Propper in
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Search for other papers by D Berney in
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Search for other papers by M Druce in
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Summary
A 33-year-old male was diagnosed with a metastatic neuroendocrine carcinoma of uncertain primary. He defaulted from follow-up without therapy and some months later developed episodic severe hypoglycaemia, which was found to be associated with inappropriately elevated insulin and C-peptide levels. It was considered likely that the neuroendocrine tumour was the source of the insulin secretion. Diazoxide and somatostatin analogue were used to control hypoglycaemia. Much later in the course of the disease, he developed metabolic derangement, increased skin pigmentation and psychological disturbance, without frankly Cushingoid physical findings. Investigations revealed highly elevated cortisol levels (the levels having previously been normal) with markedly raised ACTH levels, consistent with the co-secretion of ACTH and insulin by the tumour. Treatment with metyrapone improved his psychological state and electrolyte imbalance. Unfortunately, despite several cycles of first-, second- and third-line chemotherapy from the start of the first hormonal presentation onwards, imaging revealed widespread progressive metastatic disease and the patient eventually passed away. This case highlights the importance of keeping in mind the biochemical heterogeneity of endocrine tumours during their treatment.
Learning points
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The clinical presentation of insulin-secreting tumours includes symptoms of neuroglycopaenia and sympathetic overstimulation.
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Tumour-associated hypoglycaemia can be due to pancreatic insulinomas, and although ectopic hormone production occurs in a number of tumours, ectopic secretion of insulin is rare.
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A possible switch in the type of hormone produced can occur during the growth and progression of neuroendocrine tumours and, when treating neuroendocrine tumours, it is important to keep in mind their biochemical heterogeneity.
Search for other papers by Betty Korljan Jelaska in
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Search for other papers by Sanja Baršić Ostojić in
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Search for other papers by Nina Berović in
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Search for other papers by Višnja Kokić in
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Summary
Glycogen storage disease (GSD) type I is characterized by impaired production of glucose from glycogenolysis and gluconeogenesis resulting in severe hypoglycaemia and increased production of lactic acid, triglyceride and uric acid. The most common type, glycogenosis type Ia, demands a balanced, sufficient carbohydrate intake to preserve normal 24-h glycaemia. Insufficient intake of carbohydrates can cause hypoglycaemia, as the missing glucose-6-phosphatase enzyme cannot free the glucose stored as liver glycogen and nor is gluconeogenesis possible. The principle means of handling this disorder is to avoid starving by taking regular meals during the day and night. Such a dietary regimen could lead to obesity. Herein, we present the case of an adult patient with glycogenosis type Ia suffering from hyperuricaemia, dyslipidaemia and arterial hypertension. The accumulation of these cardiovascular risk factors could lead to the early onset of atherosclerosis, which should be postponed by contemporary methods of surveillance and treatment.
Learning points
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Continuous subcutaneous glucose monitoring may be of value in every adult patient with GSD type I to evaluate the actual prevalence of eventual hypoglycaemic and hyperglycaemic episodes.
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Good dietary management minimizes the metabolic abnormalities of the disease and decreases the risk of long-term complications.
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Treatment of obesity in patients with GSD reduces the risk of earlier atherosclerosis and cardiovascular disease.