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Open access

Taisuke Uchida, Hideki Yamaguchi, Kazuhiro Nagamine, Tadato Yonekawa, Eriko Nakamura, Nobuhiro Shibata, Fumiaki Kawano, Yujiro Asada and Masamitsu Nakazato

Summary

We report a case of rapid pleural effusion after discontinuation of lenvatinib. A 73-year-old woman was diagnosed with poorly differentiated thyroid cancer with right pleural metastasis. Weekly paclitaxel treatment was performed for 18 weeks, but it was not effective. Oral administration of lenvatinib, a multi-target tyrosine kinase inhibitor, reduced the size of cervical and thoracic tumors and lowered serum thyroglobulin levels. Lenvatinib was discontinued on day 28 because of Grade 2 thrombocytopenia and Grade 3 petechiae. Seven days after discontinuation of lenvatinib, the patient was hospitalized because of dyspnea and right pleural effusion. Pleural effusion rapidly improved with drainage and re-initiation of lenvatinib and did not recur. Anorexia caused by lenvatinib led to undernutrition, which resulted in death 13 months after initiation of lenvatinib. Autopsy revealed extensive necrosis with primary and metastatic lesions, suggesting that the patient responded to lenvatinib. Physicians should be aware of the possibility of flare-up in patients with thyroid cancer treated with lenvatinib.

Learning points:

  • Autopsy findings revealed that lenvatinib was efficacious in treating poorly differentiated thyroid cancer without primary lesion resection.

  • Flare-up phenomenon may occur in thyroid cancer treated with lenvatinib.

  • Attention should be paid to flare-up phenomenon within a few days of discontinuing lenvatinib.

Open access

Bidhya Timilsina, Niranjan Tachamo, Prem Raj Parajuli and Ilan Gabriely

Summary

A 74-year-old woman presented with progressive lethargy, confusion, poor appetite and abdominal pain. She was found to have non-PTH-mediated severe hypercalcemia with renal failure and metabolic alkalosis. Extensive workup for hypercalcemia to rule out alternate etiology was unrevealing. Upon further questioning, she was taking excess calcium carbonate (Tums) for her worsening heartburn. She was diagnosed with milk-alkali syndrome (MAS). Her hypercalcemia and alkalosis recovered completely with aggressive hydration along with improvement in her renal function. High index of suspicion should be maintained and history of drug and supplements, especially calcium ingestion, should be routinely asked in patients presenting with hypercalcemia to timely diagnose MAS and prevent unnecessary tests and treatments.

Learning points:

  • Suspect milk-alkali syndrome in patients with hypercalcemia, metabolic alkalosis and renal failure, especially in context of ingestion of excess calcium-containing supplements.

  • Careful history of over-the-counter medications, supplements and diet is crucial to diagnose milk-alkali syndrome.

  • Milk-alkali syndrome may cause severe hypercalcemia in up to 25–30% of cases.

Open access

Seong Keat Cheah, David Halsall, Peter Barker, John Grant, Abraham Mathews, Shyam Seshadri and Singhan Krishnan

Summary

A frail 79-year-old lady with dementia presented with a 2-year history of frequent falls. Recurrent hypoglycaemic episodes were diagnosed and treated with continuous glucose infusion in multiple hospital admissions. Hypoadrenalism and hypothyroidism were ruled out. Whilst hypoglycaemic (blood glucose 1.6 mmol/L), both plasma C-peptide and proinsulin concentrations, were inappropriately elevated at 4210 pmol/L (174–960) and >200 pmol/L (0–7) respectively with plasma insulin suppressed at 12 pmol/L (0–180). Whilst reported cases of proinsulinoma are typically pancreatic in origin, radiological investigations of the pancreas in this patient did not identify abnormalities. Unexpectedly contrast CT identified a heterogeneously enhancing mass (6.6 cm) at the lower pole of the left kidney consistent with renal cell carcinoma. Non-islet cell tumour-induced hypoglycaemia has been associated with renal malignancy; however, a serum IGF2:IGF1 ratio measured at <10 effectively excludes this diagnosis. Concomitantly on the CT, extensive peripherally enhancing heterogeneous mass lesions in the liver were identified, the largest measuring 12 cm. A palliative approach was taken due to multiple comorbidities. On post-mortem, the kidney lesion was confirmed as clear cell renal carcinoma, whilst the liver lesions were identified as proinsulin-secreting neuroendocrine tumours. In conclusion, the diagnosis of proinsulinoma can be missed if plasma proinsulin concentration is not measured at the time of hypoglycaemia. In this case, the plasma insulin:C-peptide ratio was too high to be accounted for by the faster relative clearance of insulin and was due to proinsulin cross-reactivity in the C-peptide assay. In addition, the concomitant malignancy proved to be a challenging red herring.

Learning points:

  • Even in non-diabetics, hypoglycaemia needs to be excluded in a setting of frequent falls. Insulin- or proinsulin-secreting tumours are potentially curable causes.

  • Whilst investigating spontaneous hypoglycaemia, if plasma insulin concentration is appropriate for the hypoglycaemia, it is prudent to check proinsulin concentrations during the hypoglycaemic episode.

  • Proinsulin cross-reacts variably with C-peptide and insulin assays; the effect is method dependent. In this case, the discrepancy between the insulin and C-peptide concentrations was too great to be accounted for by the faster relative clearance of insulin, raising the suspicion of assay interference. The C-peptide assay in question (Diasorin liaison) has been shown to be 100% cross reactive with proinsulin based on spiking studies with a proinsulin reference preparation.

  • Whilst reported cases of proinsulinoma and 99% of insulinomas are of pancreatic origin, conventional imaging studies (CT, MRI or ultrasound) fail to detect neuroendocrine tumours <1 cm in 50% of cases.

  • The concomitant renal mass identified radiologically proved to be a red herring.

  • In view of the rarity of proinsulinoma, no conclusive association with renal cell carcinoma can be established.

Open access

Alessandro Mantovani, Ilaria Teobaldi, Vincenzo Stoico, Fabrizia Perrone, Marina Zannoni, Luca Cima, Massimiliano Bruti, Lucia Mingolla, Maddalena Trombetta and Enzo Bonora

Summary

After basal cell carcinoma, the cutaneous squamous cell carcinoma (cSCC) is the second most frequent non-melanoma skin cancer worldwide, and, classically, arises from the upper coats of the epidermis of sun-exposed areas or from skin areas constantly exposed to a chronic inflammatory stimulus. The occurrence of cSCC seems to be linked to several factors, including exposure to sunlight (or other ultraviolet radiations), immunosuppression, chronic scarring conditions and some familial cancer syndromes. Although the majority of cSCCs are adequately eradicated by surgical excision, a subgroup of cSCC may be linked with an increased risk of recurrence, metastasis and death. The incidence of type 2 diabetes mellitus is constantly increasing worldwide. Importantly, diabetes mellitus is a strong risk factor for cancers (including cutaneous tumors) and is highly related with poor cancer outcomes. At present, in the literature, squamous cell carcinoma developing in association with diabetic foot ulcers has been already reported in some reports; however, additional data are needed to make the clinicians aware of this rare, although possible, complication. Therefore, we herein report an unusual case of an elderly man with T2DM and a positive oncological history, presenting a cSCC involving the skin overlying the first toe of left foot. The growing cSCC appeared approximately 3 years after the appearance of a diabetic ulcer.

Learning points:

  • Diabetic foot ulcers are an important and severe complication of diabetes mellitus and often can result in foot amputation.

  • Chronic and non-healing diabetic foot ulcers are often observed in clinical practice.

  • Clinicians should always take into consideration the malignant degeneration (e.g., cutaneous squamous cell carcinoma) of any chronic non-healing diabetic foot ulcer in elderly T2DM individuals.

  • Timely surgical resection of a chronic, non-healing diabetic foot ulcer might preclude the development of a cutaneous squamous cell carcinoma.

Open access

Ali A Zaied, Halis K Akturk, Richard W Joseph and Augustine S Lee

Summary

Nivolumab, a monoclonal antibody against programmed cell death-1 receptor, is increasingly used in advanced cancers. While nivolumab use enhances cancer therapy, it is associated with increased immune-related adverse events. We describe an elderly man who presented in ketoacidosis after receiving nivolumab for metastatic renal cell carcinoma. On presentation, he was hyperpneic and laboratory analyses showed hyperglycemia and anion-gapped metabolic acidosis consistent with diabetic ketoacidosis. No other precipitating factors, besides nivolumab, were identified. Pre-nivolumab blood glucose levels were normal. The patient responded to treatment with intravenous fluids, insulin and electrolyte replacement. He was diagnosed with insulin-dependent autoimmune diabetes mellitus secondary to nivolumab. Although nivolumab was stopped, he continued to require multiple insulin injection therapy till his last follow-up 7 months after presentation. Clinicians need to be alerted to the development of diabetes mellitus and diabetic ketoacidosis in patients receiving nivolumab.

Learning points:

  • Diabetic ketoacidosis should be considered in the differential of patients presenting with metabolic acidosis following treatment with antibodies to programmed cell death-1 receptor (anti-PD-1).

  • Autoimmune islet cell damage is the presumed mechanism for how insulin requiring diabetes mellitus can develop de novo following administration of anti-PD-1.

  • Because anti-PD-1 works by the activation of T-cells and reduction of ‘self-tolerance’, other autoimmune disorders are likely to be increasingly recognized with increased use of these agents.

Open access

Nikolaos Asonitis, Eva Kassi, Michalis Kokkinos, Ilias Giovanopoulos, Foteini Petychaki and Helen Gogas

Summary

Hypercalcemia of malignancy is the most common cause of hypercalcemia in hospitalized patients. It is associated with a poor prognosis, since it reflects an advanced cancer stage. Among all cancer in females, breast cancer is the most common malignancy, and it has the highest prevalence of hypercalcemia. Approximately 70% of patients with breast cancer have bone metastases and 10% of them will have hypercalcemia as a complication at some point in the disease. Herein, we report a 69-year-old female patient with metastatic breast cancer, who developed severe hypercalcemia in the course of her disease and was diagnosed with humoral hypercalcemia of malignancy (HHM). Intense hydration along with corticoisteroids and antiresorptive medication (calcitonin, bisphosphonates and denosumab) were administered to the patient. Despite the above treatment, serum calcium levels remain elevated and calcimimetic cinacalcet was added. Upon discontinuation of cinacalcet, calcium levels were raised and returned back to the normal levels following re-initiation of the calcimimetic. Her calcium level restored to normal, and she was discharged with the following medical treatment: denosumab monthly, and cinacalcet at a titrated dose of 90 mg per day. The patient is followed as an outpatient and 11 months later, her calcium level remained within the normal range.

Learning points:

  • Hypercalcemia of malignancy is the most common cause of hypercalcemia in hospitalized patients.

  • Breast cancer has the highest prevalence of hypercalcemia.

  • The cornerstone of therapy remains the intense hydration and intravenous bisphosphonates (preferably zoledronic acid).

  • In case of persistent hypercalcemia of malignancy, the administration of calcimimetic cinacalcet could be an additional effective therapeutic option.

Open access

S A A van den Berg and C G Krol

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:

  • Hepatocellular carcinoma may be associated with non-islet cell tumour hypoglycaemia (NICTH).

  • NICTH-induced hypoglycaemia is associated with low insulin and IGF1.

  • Measurement of IGF2 only (without measurement of Pro-IGF2 and IGF1) may be insufficient to prove NICTH.

Open access

Catarina Roque, Ricardo Fonseca, Carlos Tavares Bello, Carlos Vasconcelos, António Galzerano and Sância Ramos

Summary

Primary adrenal lymphoma is a rare malignancy. It frequently presents bilaterally and with symptoms of adrenal insufficiency. Amiodarone may induce secondary organ dysfunction, and thyrotoxicosis develops in 15% of cases. The symptomatology of both conditions is nonspecific, especially in the elderly, and a high suspicion index is necessary for appropriate diagnosis. A 78-year-old female presented to the emergency department with confusion, nausea and vomiting. She had recently been to the emergency department with urinary tract infection, vomiting and acute hypochloremic hyponatremia. Upon re-evaluation, the leukocyturia persisted and because of TSH 0.01 µU/mL and free-T4 68 (10–18) pmol/L, she was admitted to the Endocrinology ward. Further evaluation supported amiodarone-induced thyroiditis type 2. Sepsis ensued, in the setting of nosocomial pneumonia. Hemodynamic instability, hyponatremia, hypoglycemia and vomiting raised the suspicion of adrenocortical insufficiency. Fluid resuscitation and hydrocortisone led to clinical improvement, and adrenal insufficiency was admitted. The thoracoabdominal tomography suggested an endobronchic primary lesion with hepatic and adrenal secondary deposits (6.6 and 7 cm), but this was confirmed neither on pleural effusion nor on bronchofibroscopic fluid analyses. The adrenals were not accessible for biopsy. Despite high-dose hydrocortisone maintenance, the patient died before definite diagnosis. The autopsy confirmed primary non-Hodgkin lymphoma.

Learning points:

  • Primary adrenal lymphoma is a rare cause of adrenal insufficiency, but progression can be fast and fatal.

  • Hyperpigmentation is frequently absent.

  • The presenting symptoms are nonspecific and might mimic infection. Disproportion of the general state with signs of specific organ symptomatology is a diagnostic clue.

  • Infection may precipitate adrenal crisis and worsen thyroid function with further adrenal insufficiency exacerbation.

  • In the context of thyrotoxicosis, there may be little clinical response to a therapeutic trial with standard dose glucocorticoids.

  • High-dose glucocorticoid substitution may be required to achieve clinical stability in thyrotoxic patients.

Open access

Adriana de Sousa Lages, Isabel Paiva, Patrícia Oliveira, Francisco Portela and Francisco Carrilho

Summary

Insulinomas are the most frequent cause of hyperinsulinaemic hypoglycaemia. Although surgical enucleation is the standard treatment, a few other options are available to high-risk patients who are elderly or present with co-morbidities. We present a case report of an 89-year-old female patient who was admitted to the emergency department due to recurrent hypoglycaemia, especially during fasting. Laboratory work-up raised the suspicion of hyperinsulinaemic hypoglycaemia, and abdominal CT scan revealed a 12 mm nodular hypervascular lesion of the pancreatic body suggestive of neuroendocrine tumour. The patient was not considered a suitable candidate for surgery, and medical therapy with diazoxide was poorly tolerated. Endoscopic ultrasound-guided ethanol ablation therapy was performed and a total of 0.6 mL of 95% ethanol was injected into the lesion by a transgastric approach; no complications were reported after the procedure. At 5 months of follow-up, no episodes of hypoglycaemia were reported, no diazoxide therapy was necessary, and revaluation abdominal CT scan revealed a pancreatic nodular lesion with a size involution of about half of its original volume. The patient is regularly followed-up at the endocrinology clinic and shows a significant improvement in her wellbeing and quality of life.

Learning points:

  • Insulinomas are the most frequent cause of hyperinsulinaemic hypoglycaemia.

  • Surgical enucleation is the standard treatment with a few other options available to high-risk patients.

  • Endoscopic ultrasound-guided ethanol ablation therapy is one feasible option in high-risk patients with satisfactory clinical outcomes, significant positive impact on quality of life and low complication rates related to the procedure.

Open access

Ismael Capel, Elisabet Tasa-Vinyals, Albert Cano-Palomares, Irene Bergés-Raso, Lara Albert, Mercedes Rigla and Assumpta Caixàs

Summary

Takotsubo cardiomyopathy (TC) is an atypical, severe but reversible form of acute heart insufficiency. It typically presents with left ventricular failure, transient apical and mid-segments hypokinesis, absence of significant coronary stenosis and new electrographic abnormalities and/or elevation in serum cardiac enzymes. Although TC (‘broken heart syndrome’) has classically been associated with emotional trauma, evidence suggests that other precipitants might exist, including iatrogenic and thyroid-mediated forms. Thyroid disease is a relatively common comorbidity in TC patients. We report a case of TC in a postmenopausal female with no history of emotional trauma or other potential precipitant factors who was diagnosed with amiodarone-induced hyperthyroidism during her hospital stay. Though some case reports of thyroid-related TC exist, we are not aware of any other reported case of TC precipitated by amiodarone-induced hyperthyroidism.

Learning points:

  • TC is a relatively new, rare, transient, severe, but reversible cardiovascular condition that is characterized by an acute left ventricular cardiac failure, which can clinically, analytically and electrocardiographically mimic an acute myocardial infarction.

  • Many precipitant factors have been described in TC, being the most classical and emotional trauma. However, thyroid dysfunction is also a significant condition frequently found in patients with TC.

  • A hypercatecholaminergic state leading to cardiomyocyte damage has been established as the main fact of TC physiopathology. Hyperthyroidism induces an upregulation of β-adrenergic receptors.

  • Both hyperthyroidism and hypothyroidism have been related with TC development. Most reported cases of TC involving thyroid dysfunction correspond to hyperthyroidism due to Graves–Basedow disease, but there are also descriptions with severe hypothyroidism, radioiodine treatment or thyroid surgery.

  • Amiodarone is a class III antiarrhythmic agent widely used, and it is a well-known cause of thyroid dysfunction, which can present either with hypothyroidism or hyperthyroidism, as approximately 40 percent of the amiodarone molecule is composed of iodine.

  • In this case, a type II amiodarone-induced hyperthyroidism was the precipitant factor of a TC in a patient with a pre-existing atrial fibrillation. Given the high prevalence of atrial fibrillation and the wide use of amiodarone, the risk of this iatrogenic effect should be taken into account.