Summary

Graves’ disease is associated with tachydysrythmia, cardiac ischaemia and cardiomyopathy – all uncommon in young adults without previous cardiac disease. We present three young individuals who developed cardiac complications after periods of uncontrolled Graves’ disease. Subject 1: A 34-year-old female had severe thyrotoxic symptoms for weeks. Investigations showed fT4: 98.4 (11–25 pmol/L), fT3: 46.9 (3.1–6.8 pmol/L), TSH <0.01 (0.27–4.2 mU/L) and thyrotrophin receptor antibody (TRAb): 34.8 (<0.9 U//l). She had appropriate treatment but several weeks later she became breathless despite improving thyroid function. Echocardiography showed a pericardial effusion of 2.9 cm. She responded well to steroids and NSAIDs but developed active severe Graves’ orbitopathy after early total thyroidectomy. Subject 2: A 28-year-old male developed thyrotoxic symptoms (fT4: 38 pmol/L, fT3: 13.9 pmol/L, TSH <0.01 (for over 6 months) and TRAb: 9.3 U/L). One month after starting carbimazole, he developed acute heart failure (HF) due to severe dilated cardiomyopathy – EF 10–15%. He partially recovered after treatment – EF 28% and had early radioiodine treatment. Subject 3: A 42-year-old woman who had been thyrotoxic for several months (fT4: 54.3; fT3 >46.1; TSH <0.01; TRAb: 4.5) developed atrial fibrillation (AF) and heart failure. Echocardiography showed cardiomegaly – EF 29%. She maintains sinus rhythm following early total thyroidectomy (EF 50%). Significant cardiac complications may occur in previously fit young adults, who have had uncontrolled Graves’ disease for weeks to months. Cardiac function recovers in the majority, but early definitive treatment should be discussed to avoid Graves’ disease relapse and further cardiac decompensation.

Learning points:

• Cardiac complications of Graves’ disease are uncommon in young adults without previous cardiac disease.

• These complications may however occur if Graves’ disease had been poorly controlled for several weeks or months prior to presentation.

• Persistent symptoms after adequate control should alert clinicians to the possibility of cardiac disease.

• Specific treatment of Graves’ disease and appropriate cardiac intervention results in complete recovery in the majority and carries a good prognosis.

• Early definitive treatment should be offered to them to prevent cardiac decompensation at times of further relapse.

Summary

This case is the first to describe a patient who experienced concomitant agranulocytosis and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis as an adverse effect of propylthiouracil treatment for Graves’ disease. A 42-year-old female with Graves’ disease presented to the emergency department (ED) with a 2-week history of fevers, night sweats, transient lower limb rash, arthralgia, myalgia and fatigue. She had been taking propylthiouracil for 18 months prior to presentation. On admission, agranulocytosis was evident with a neutrophil count of 0.36 × 10⁹/L and immediately propylthiouracil was stopped. There was no evidence of active infection and the patient was treated with broad-spectrum antibodies and one dose of granulocyte colony-stimulation factor, resulting in a satisfactory response. On further investigation, ANCAs were positive with dual positivity for proteinase 3 and myeloperoxidase. There was no evidence of end-organ damage secondary to vasculitis, and the patient’s constitutional symptoms resolved completely on discontinuation of the drug precluding the need for immunosuppressive therapy.

Learning points:

• Continued vigilance and patient education regarding the risk of antithyroid drug-induced agranulocytosis is vital throughout the course of treatment.

• ANCA-associated vasculitis is a rare adverse effect of antithyroid drug use.

• Timely discontinuation of the offending drug is vital in reducing end-organ damage and the need for immunosuppressive therapy in drug-induced ANCA-associated vasculitis.

• Similarities in the pathogenesis of agranulocytosis and drug-induced ANCA-associated vasculitis may offer insight into an improved understanding of vasculitis and agranulocytosis.

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.

Summary

We report the renal histology of a 66-year-old man with hypertension, cardiovascular disease, and a 30-year history of type 2 diabetes mellitus with proliferative diabetic retinopathy, diabetic neuropathy, and diabetic foot status post toe amputation. Urinary protein excretion was 1.4 g/gCr, serum creatinine level 0.86 mg/dL, estimated glomerular filtration rate 69 mL/min/1.73 m², and HbA1c 13–15%, despite using insulin. Light microscopy showed global glomerulosclerosis in 37% of the glomeruli, but the remaining glomeruli were intact. Significant polar vasculosis was present, while arteriolar sclerosis was mild. Electron microscopy revealed a thickened glomerular basement membrane, which is compatible with the early stage of diabetic glomerulopathy. The presented case was unique because glomerular changes seen typically in diabetes were not seen in the patient, despite the long-standing history of diabetes and diabetic comorbidities, while prominent polar vasculosis was found. Polar vascular formation helps preserve the glomeruli by allowing hyperosmotic blood bypass the glomeruli; this decreases intraglomerular pressure and minimizes glomerular endothelial damage.

Learning points:

• A 66-year-old man with a 30-year history of type 2 diabetes mellitus with poor glycemic control underwent renal biopsy, which showed scarce glomerular changes typically seen in diabetic kidney disease and instead revealed significant polar vasculosis.

• Past studies demonstrated that the increased small vessels around the vascular hilus in diabetic patients originated from the afferent arterioles and drained into the peritubular capillaries.

• Polar vascular formation may preserve glomerular function by allowing the blood flow to bypass the glomeruli and decreasing the intraglomerular pressure, which minimizes endothelial damage of the glomerular tufts.

Summary

Diabetic myonecrosis, also known as diabetic muscle infarction is a rare complication of diabetes mellitus usually associated with longstanding suboptimal glycaemic control. Although theories of atherosclerosis, diabetic microangiopathy, vasculitis, ischaemia-reperfusion injury and hypercoagulable state have been proposed to explain the pathophysiology, none of these have been able to individually explain the pathophysiology in entirety. Diabetic renal disease is the most common risk factor for developing DMN and its recurrence. The diagnosis is often missed due to lack of awareness and the presentation mimicking other conditions associated with DM. The routine laboratory investigations are often non-specific and do not provide much value in the diagnosis as well. Muscle biopsy can provide a definite diagnosis but is not currently recommended due to its invasiveness and association with prolonged time to symptoms resolution. Magnetic resonance imaging, in combination with classic history and risk factors can clinch the diagnosis. Treatment is generally analgesia and rest, although the former’s use may be limited in the presence of renal disease.

Learning points:

• Diabetic myonecrosis is a rare complication of diabetes mellitus associated with longstanding suboptimal glycaemic control.

• Diabetic renal disease is a known risk factor, although the evidence is merely observational.

• Although muscle biopsy could provide a definite diagnosis, it is not recommended as it can prolong the disease process and should be reserved only for cases not responding to conventional treatment.

• Typical MRI findings in combination with classic symptoms and risk factors can clinch the diagnosis

• Current treatment recommendations include NSAIDs and/or aspirin (if not contraindicated) alongside bed rest. Physiotherapy is not recommended in the acute phase but should be started as soon as patient is discharged from hospital.

• Optimal glycaemic control is key to prevent recurrence.

Learning points:

• Diagnosis of Cushing’s syndrome during pregnancy is complicated by several physiological alterations in hypothalamic–pituitary–adrenal axis regulation occurring in normal pregnancy.

• Cushing’s syndrome (CS) exacerbation during pregnancy can be associated with aberrant expression of LHCG receptor on primary adrenocortical tumour or hyperplasia in some cases, but not in this patient.

• Placental-derived ACTH, which is not subject to glucocorticoid negative feedback, stimulated cortisol secretion from this adrenal adenoma causing transient CS exacerbation during pregnancy.

• Following delivery and tumour removal, suppression of HPA axis can require several months to recover and requires glucocorticoid replacement therapy.

Learning points:

• Thyrotoxicosis is associated with right ventricular dysfunction and pulmonary hypertension apart from left ventricular dysfunction described in typical thyrotoxic cardiomyopathy.

• Symptoms and signs of right ventricular dysfunction and pulmonary hypertension should be sought in all patients with newly diagnosed thyrotoxicosis.

• Thyrotoxicosis should be considered in all cases of right ventricular dysfunction or pulmonary hypertension not readily explained by other causes.

• Prompt restoration of euthyroidism is warranted in patients with thyrotoxicosis complicated by right ventricular dysfunction with or without pulmonary hypertension to allow timely resolution of the abnormal cardiac parameters before development of overt right heart failure.

Learning points:

• Severe Cushing’s syndrome is not always caused by ectopic ACTH secretion.

• Hypercortisolism is a state of immunosuppression, being associated with an increased risk for opportunistic infections.

• Infectious pulmonary infiltrates may lead to imaging diagnostic dilemmas when investigating a suspected ectopic ACTH secretion.

• Cushing’s syndrome carries an increased thromboembolic risk that may even persist after successful surgical management.

• Antibiotic and venous thromboembolism prophylaxis should be considered in every patient with severe Cushing’s syndrome.

Learning points:

• Thioamide-induced agranulocytosis is an uncommon but potentially life-threatening complication of which all prescribers and patients need to be aware.

• A multi-modal preoperative pharmacological approach can be successful, even when thioamides are contraindicated, when needing to prepare a thyrotoxic patient for semi-urgent total thyroidectomy.

• There is not enough evidence to confidently predict the safe timing when considering total thyroidectomy in this patient cohort, and therefore it should be undertaken when attempts have first been made to safely reduce thyroid hormone levels.

• Thyroid storm is frequently cited as a potentially severe complication of thyroid surgery undertaken in thyrotoxic patients, although the evidence does not demonstrate this as a common occurrence.

Learning points:

• The discrimination between a Cushing’s disease and ectopic Cushing’s syndrome is challenging and has many caveats.

• Ectopic ACTH/CRH co-secreting tumors are very rare.

• Dynamic tests as well as BIPSS may be compatible with Cushing’s disease in ectopic CRH-secretion.

• High levels of CRH may induce hyperplasia of the corticotroph cells in the pituitary. This could be the cause of a preserved pituitary response to dexamethasone and CRH.

• Clinical features of ACTH-dependent hypercortisolism with rapid development of Cushing’s syndrome, hyperpigmentation, high circulating levels of cortisol with associated hypokalemia, peripheral edema and proximal myopathy should be a warning flag of ectopic Cushing’s syndrome and lead to further investigations.