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Open access

Florence Gunawan, Elizabeth George and Mark Kotowicz

Summary

Denosumab is a fully human MAB that acts as a potent anti-resorptive by inhibiting activation of osteoclasts by inhibiting the receptor activator of nuclear factor-kappa B (RANK) ligand. Hypocalcaemia has been reported as one of the serious adverse sequelae of use of denosumab. We present a case of refractory hypocalcaemia following administration of a single dose of denosumab in a patient with metastatic castrate-resistant prostate cancer. The patient’s serum calcium and vitamin D concentrations and renal function were normal prior to denosumab administration. Serum alkaline phosphatase (ALP) level was however elevated pre-morbidly consistent with known bone metastases. The patient was treated with high-dose oral and IV calcium without any appreciable response in serum calcium. During his 30-day hospital admission, he demonstrated disease progression with development of new liver metastases and bone marrow involvement. Normocalcaemia was not achieved despite 1 month of aggressive therapy. Given the patient was asymptomatic and prognosis guarded, he was eventually discharged for ongoing supportive care under the palliative care team.

Learning points:

  • Denosumab is a potent anti-resorptive therapy and hypocalcaemia is one of the known adverse effects.
  • Serum calcium and vitamin D concentrations must be replete prior to administration of denosumab to reduce the risk of hypocalcaemia.
  • Denosumab has been proven to be more effective than zoledronic acid in preventing skeletal-related adverse effects in patients with metastatic castrate-resistant prostate cancer.
Open access

Shivani Patel, Venessa Chin and Jerry R Greenfield

Summary

Durvalumab is a programmed cell death ligand 1 inhibitor, which is now approved in Australia for use in non-small-cell lung and urothelial cancers. Autoimmune diabetes is a rare immune-related adverse effect associated with the use of immune checkpoint inhibitor therapy. It is now being increasingly described reflecting the wider use of immune checkpoint inhibitor therapy. We report the case of a 49-year-old female who presented with polyuria, polydipsia and weight loss, 3 months following the commencement of durvalumab. On admission, she was in severe diabetic ketoacidosis with venous glucose: 20.1 mmol/L, pH: 7.14, bicarbonate 11.2 mmol/L and serum beta hydroxybutyrate: >8.0 mmol/L. She had no personal or family history of diabetes or autoimmune disease. Her HbA1c was 7.8% and her glutamic acid decarboxylase (GAD) antibodies were mildly elevated at 2.2 mU/L (reference range: <2 mU/L) with negative zinc transporter 8 (ZnT8) and islet cell (ICA) antibodies. Her fasting C-peptide was low at 86 pmol/L (reference range: 200–1200) with a corresponding serum glucose of 21.9 mmol/L. She was promptly stabilised with an insulin infusion in intensive care and discharged on basal bolus insulin. Durvalumab was recommenced once her glycaemic control had stabilised. Thyroid function tests at the time of admission were within normal limits with negative thyroid autoantibodies. Four weeks post discharge, repeat thyroid function tests revealed hypothyroidism, with an elevated thyroid-stimulating hormone (TSH) at 6.39 mIU/L (reference range: 0.40–4.80) and low free T4: 5.9 pmol/L (reference range: 8.0–16.0). These findings persisted with repeat testing despite an absence of clinical symptoms. Treatment with levothyroxine was commenced after excluding adrenal insufficiency (early morning cortisol: 339 nmol/L) and hypophysitis (normal pituitary on MRI).

Learning points:

  • Durvalumab use is rarely associated with fulminant autoimmune diabetes, presenting with severe DKA.
  • Multiple endocrinopathies can co-exist with the use of a single immune checkpoint inhibitors; thus, patients should be regularly monitored.
  • Regular blood glucose levels should be performed on routine pathology on all patients on immune checkpoint inhibitor.
  • Clinician awareness of immunotherapy-related diabetes needs to increase in an attempt to detect hyperglycaemia early and prevent DKA.
Open access

N F Lenders and J R Greenfield

Summary

Adrenal oncocytomas are rare tumours, with only approximately 160 cases reported in the literature. We report the use of urinary steroid profiling as part of their diagnostic evaluation and prognostication. A 45-year-old woman presented with clinical features of hyperandrogenism. Serum biochemistry confirmed androgen excess and computed tomography (CT) demonstrated a 3.2 cm adrenal tumour with density 39 HU pre-contrast. Urine steroid profiling showed elevated tetrahydro-11 deoxycortisol (THS), which is associated with adrenal malignancy. Laparoscopic adrenalectomy was performed, and histopathology diagnosed adrenal oncocytoma. Serum and urinary biochemistry resolved post-operatively and remained normal at 1-year follow-up.

Learning points:

  • Differential diagnosis of adrenal masses is challenging. Current techniques for differentiating between tumour types lack sensitivity and specificity.
  • 24-h urinary steroid profiling is a useful tool for reflecting steroid output from adrenal glands. Gas chromatography-mass spectrometry (GC-MS) of urinary steroid metabolites has sensitivity and specificity of 90% for diagnosing adrenocortical carcinoma.
  • Adrenal oncocytoma are rare tumours. Differentiating between benign and malignant types is difficult. Data guiding prognostication and management are sparse.
Open access

Nirusha Arnold, Victor O’Toole, Tien Huynh, Howard C Smith, Catherine Luxford, Roderick Clifton-Bligh and Creswell J Eastman

Summary

Parathyroid-independent hypercalcaemia of pregnancy, due to biallelic loss of function of the P450 enzyme CYP24A1, the principal inactivator of 1,25(OH)2D results in hypervitaminosis D, hypercalcaemia and hypercalciuria. We report two cases of this disorder, with intractable hypercalcaemia, one occurring during gestation and into the postpartum, and the other in the postpartum period. Case 1, a 47-year-old woman with a twin pregnancy conceived by embryo transfer, presented with hypercalcaemia at 23 weeks gestation with subnormal serum parathyroid hormone (PTH) and normal serum 25-OH D levels. She was admitted to hospital at 31 weeks gestation with pregnancy-induced hypertension, gestational diabetes and increasing hypercalcaemia. Caesarean section at 34 weeks gestation delivered two healthy females weighing 2.13 kg and 2.51 kg. At delivery, the patient’s serum calcium level was 2.90 mmol/L. Postpartum severe hypercalcaemia was treated successfully with Denosumab 60 mg SCI, given on two occasions. CYP24A1 testing revealed she was compound heterozygous for pathogenic variants c.427_429delGAA, (p.Glu143del) and c.1186C>T, (p.Arg396Trp). Case 2, a 36-year-old woman presented 4 days after the delivery of healthy twins with dyspnoea, bradycardia, severe headaches, hypertension and generalized tonic-clonic seizures after an uneventful pregnancy. She was hypercalcaemic with a suppressed PTH, normal 25(OH)D, and elevated 1,25(OH)2D levels. Her symptoms partially responded to i.v. saline and corticosteroids in the short term but bisphosphonates such as Pamidronate and Zoledronic acid did not result in sustained improvement. Denosumab 120 mg SCI successfully treated the hypercalcaemia which resolved completely 2 months post-partum. CYP24A1 testing revealed she was homozygous for the pathogenic variant c.427_429delGAA, (p.Glu143del).

Learning points:

  • Hypercalcaemia in pregnancy can be associated with considerable morbidity with few options available for management.
  • In non-PTH-related hypercalcaemia the diagnosis of CYP24A1 deficiency should be considered.
  • Making a definitive diagnosis of CYP24A1 deficiency by genetic testing delays the diagnosis, while the availability of serum 24,25-dihydroxyvitamin D (24,25(OH)2D) will expedite a diagnosis.
  • In pregnant women with CYP24A1 deficiency hypercalcaemia can worsen in the post-partum period and is more likely to occur with twin pregnancies but generally resolves within 2–3 months.
  • Therapeutic alternatives are limited in pregnancy and their effectiveness is short-lived and mostly ineffective. Denosumab used in both our patients after delivery was the most effective agent normalizing calcium and may have benefit as a long-term therapeutic agent in preventing complications in patients with CYP24A1 deficiency.
Open access

Hui Yi Ng, Divya Namboodiri, Diana Learoyd, Andrew Davidson, Bernard Champion and Veronica Preda

Summary

Co-secreting thyrotropin/growth hormone (GH) pituitary adenomas are rare; their clinical presentation and long-term management are challenging. There is also a paucity of long-term data. Due to the cell of origin, these can behave as aggressive tumours. We report a case of a pituitary plurihormonal pit-1-derived macroadenoma, with overt clinical hyperthyroidism and minimal GH excess symptoms. The diagnosis was confirmed by pathology showing elevated thyroid and GH axes with failure of physiological GH suppression, elevated pituitary glycoprotein hormone alpha subunit (αGSU) and macroadenoma on imaging. Pre-operatively the patient was rendered euthyroid with carbimazole and underwent successful transphenoidal adenomectomy (TSA) with surgical cure. Histopathology displayed an elevated Ki-67 of 5.2%, necessitating long-term follow-up.

Learning points:

  • Thyrotropinomas are rare and likely under-diagnosed due to under-recognition of secondary hyperthyroidism.
  • Thyrotropinomas and other plurihormonal pit-1-derived adenomas are more aggressive adenomas according to WHO guidelines.
  • Co-secretion occurs in 30% of thyrotropinomas, requiring diligent investigation and long-term follow-up of complications.
Open access

Kingsley Okolie, Daniel Chen, Raf Ghabrial and Robert Schmidli

Summary

Multinodular goitre is not associated with eye disease, unless in a rare case of Marine–Lenhart syndrome where it coexists with Grave’s disease. Therefore, other causes of exophthalmos need to be ruled out when the eye disease is seen in a patient with multinodular goitre. Confusion can arise in patients with features suggestive of Graves’ ophthalmopathy in the absence of thyroid-stimulating hormone receptor autoantibodies and no evidence of other causes of exophthalmos. We present a case of multinodular goitre in a patient with exophthalmos which flared up after iodine contrast-based study. A 61-year-old Australian presented with a pre-syncopal attack and was diagnosed with toxic multinodular goitre. At the same time of investigations, to diagnose the possible cause of the pre-syncopal attack, computerised tomographic (CT) coronary artery angiogram was requested by a cardiologist. A few days after the iodine contrast-based imaging test was performed, he developed severe eye symptoms, with signs suggestive of Graves’ orbitopathy. MRI of the orbit revealed features of the disease. Although he had pre-existing eye symptoms, they were not classical of thyroid eye disease. He eventually had orbital decompressive surgery. This case poses a diagnostic dilemma of a possible Graves’ orbitopathy in a patient with multinodular goitre.

Learning points:

  • Graves’ orbitopathy can occur in a patient with normal autothyroid antibodies. The absence of the thyroid antibodies does not rule out the disease in all cases.
  • Graves’ orbitopathy can coexist with multinodular goitre.
  • Iodine-based compounds, in any form, can trigger severe symptoms, on the background of Graves’ eye disease.
Open access

Yang Timothy Du, Lynette Moore, Nicola K Poplawski and Sunita M C De Sousa

Summary

A 26-year-old man presented with a combination of permanent neonatal diabetes due to pancreatic aplasia, complex congenital heart disease, central hypogonadism and growth hormone deficiency, structural renal abnormalities with proteinuria, umbilical hernia, neurocognitive impairment and dysmorphic features. His older brother had diabetes mellitus due to pancreatic hypoplasia, complex congenital heart disease, hypospadias and umbilical hernia. Their father had an atrial septal defect, umbilical hernia and diabetes mellitus diagnosed incidentally in adulthood on employment screening. The proband’s paternal grandmother had a congenital heart defect. Genetic testing of the proband revealed a novel heterozygous missense variant (Chr18:g.19761441T>C, c.1330T>C, p.Cys444Arg) in exon 4 of GATA6, which is class 5 (pathogenic) using American College of Medical Genetics and Genomics guidelines and is likely to account for his multisystem disorder. The same variant was detected in his brother and father, but not his paternal grandmother. This novel variant of GATA6 likely occurred de novo in the father with autosomal dominant inheritance in the proband and his brother. The case is exceptional as very few families with monogenic diabetes due to GATA6 mutations have been reported to date and we describe a new link between GATA6 and renal pathology.

Learning points:

  • Monogenic diabetes should be suspected in patients presenting with syndromic features, multisystem congenital disease, neonatal-onset diabetes and/or a suggestive family history.
  • Recognition and identification of genetic diabetes may improve patient understanding and empowerment and allow for better tailored management.
  • Identification of a genetic disorder may have important implications for family planning.
Open access

Benjamin Kwan, Bernard Champion, Steven Boyages, Craig F Munns, Roderick Clifton-Bligh, Catherine Luxford and Bronwyn Crawford

Summary

Autosomal dominant hypocalcaemia type 1 (ADH1) is a rare familial disorder characterised by low serum calcium and low or inappropriately normal serum PTH. It is caused by activating CASR mutations, which produces a left-shift in the set point for extracellular calcium. We describe an Australian family with a novel heterozygous missense mutation in CASR causing ADH1. Mild neuromuscular symptoms (paraesthesia, carpopedal spasm) were present in most affected individuals and required treatment with calcium and calcitriol. Basal ganglia calcification was present in three out of four affected family members. This case highlights the importance of correctly identifying genetic causes of hypocalcaemia to allow for proper management and screening of family members.

Learning points:

  • ADH1 is a rare cause of hypoparathyroidism due to activating CASR mutations and is the mirror image of familial hypocalciuric hypercalcaemia.
  • In patients with ADH1, symptoms of hypocalcaemia may be mild or absent. Basal ganglia calcification may be present in over a third of patients.
  • CASR mutation analysis is required for diagnostic confirmation and to facilitate proper management, screening and genetic counselling of affected family members.
  • Treatment with calcium and activated vitamin D analogues should be reserved for symptomatic individuals due to the risk of exacerbating hypercalciuria and its associated complications.
Open access

Ming Li Yee, Rosemary Wong, Mineesh Datta, Timothy Nicholas Fazio, Mina Mohammad Ebrahim, Elissa Claire Mcnamara, Gerard De Jong and Christopher Gilfillan

Summary

Mitochondrial diseases are rare, heterogeneous conditions affecting organs dependent on high aerobic metabolism. Presenting symptoms and signs vary depending on the mutation and mutant protein load. Diabetes mellitus is the most common endocrinopathy, and recognition of these patients is important due to its impact on management and screening of family members. In particular, glycemic management differs in these patients: the use of metformin is avoided because of the risk of lactic acidosis. We describe a patient who presented with gradual weight loss and an acute presentation of hyperglycemia complicated by the superior mesenteric artery syndrome. His maternal history of diabetes and deafness and a personal history of hearing impairment led to the diagnosis of a mitochondrial disorder.

Learning points:

  • The constellation of diabetes, multi-organ involvement and maternal inheritance should prompt consideration of a mitochondrial disorder.
  • Mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS) and maternally inherited diabetes and deafness (MIDD) are the most common mitochondrial diabetes disorders caused by a mutation in m.3243A>G in 80% of cases.
  • Metformin should be avoided due to the risk of lactic acidosis.
  • There is more rapid progression to insulin therapy and higher prevalence of diabetic complications compared to type 2 diabetes.
  • Diagnosis of a mitochondrial disorder leads to family screening, education and surveillance for future complications.
  • Superior mesenteric artery syndrome, an uncommon but important cause of intestinal pseudo-obstruction in cases of significant weight loss, has been reported in MELAS patients.
Open access

Melissa Katz, Simon Smith, Luke Conway and Ashim Sinha

Summary

Diabetes mellitus is a well-recognised risk factor for melioidosis, the disease caused by Burkholderia pseudomallei, which is endemic in northern Australia and Southeast Asia. We present the initial diagnostic dilemma of a febrile patient from northern Australia with type 1 diabetes mellitus and negative blood cultures. After a 6-week history of fevers and undifferentiated abdominal pain, MRI of her spine revealed a psoas abscess. She underwent drainage of the abscess which cultured B. pseudomallei. She completed 6 weeks of intravenous (IV) ceftazidime and oral trimethoprim/sulphamethoxazole (TMP/SMX) followed by a 12-week course of oral TMP/SMX. We postulate that the likely route of infection was inoculation via her skin, the integrity of which was compromised from her insulin pump insertion sites and an underlying dermatological condition.

Learning points:

  • Diabetes mellitus is the strongest risk factor for developing melioidosis.
  • Atypical infections need to be considered in individuals with diabetes mellitus who are febrile, even if blood cultures are negative.
  • There is heterogeneity in the clinical presentation of melioidosis due to variable organ involvement.
  • Consider melioidosis in febrile patients who have travelled to northern Australia, Asia and other endemic areas.