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Division of Endocrinology and Metabolism, University of Alberta, Edmonton, AB, Canada
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Summary
3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) lyase deficiency is an inborn error of metabolism resulting in a lack of ketogenesis and leucine catabolism. Hallmarks of decompensation include hypoglycemia without ketosis (or hypoketosis), metabolic acidosis, and hyperammonemia. Management includes avoiding fasting and restricting dietary protein and fat. Conversely, type 2 diabetes mellitus (T2DM) requires carbohydrate restriction and/or anti-hyperglycemic agents; thus, managing these co-existing disorders is challenging. A 36-year-old male with HMG-CoA lyase deficiency and T2DM (Hemoglobin A1c (HbA1c): 7.9%) presented with confusion and shock. Blood work revealed metabolic acidosis, hyperammonemia, hyperglycemia, and hypoketosis. The patient was diagnosed with hyperosmolar non-ketotic hyperglycemia and hyperammonemia secondary to HMG-CoA lyase metabolic decompensation requiring intensive care unit admission. Hyperammonemia management was challenging because alternative calories with i.v. dextrose (due to hyperglycemia) and i.v. lipids (due to HMG-CoA lyase deficiency) could not be provided as usual. The patient was started on hemodialysis and i.v. insulin with marked improvement. Once stabilized, metformin and insulin were initiated. T2DM impaired cellular glucose uptake and produced a state similar to hypoglycemia, despite the patient being profoundly hyperglycemic, which led to metabolic decompensation of HMG-CoA lyase deficiency. Managing T2DM and HMG-CoA lyase deficiency warrants special considerations due to the potential for metabolic decompensation with both hyperglycemia and hypoglycemia.
Learning points
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In a patient with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) lyase deficiency and type 2 diabetes mellitus (T2DM), management principles include avoiding hypoglycemia to prevent metabolic decompensation, providing insulin for proper glucose utilization, and moderation of carbohydrate intake to prevent consequences of chronic hyperglycemia.
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The development of insulin resistance in the form of T2DM in HMG-CoA lyase deficiency likely triggered a state similar to hypoglycemia, leading to cellular energy deficiency and subsequently metabolic decompensation.
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It is important to avoid hypoglycemia in patients with HMG-CoA lyase deficiency and T2DM, as the risk of metabolic decompensation is increased due to the lack of ketogenesis in HMG-CoA lyase deficiency.
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Selection of antidiabetic agents in this patient population requires careful consideration, and agents that have a higher risk of hypoglycemia should be avoided.
College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
Department of Medicine, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Jeddah, Saudi Arabia
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Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada
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Summary
Myopathy caused by thyrotoxicosis is not uncommon. Skeletal muscles are commonly involved, but dysphagia is a rare manifestation of thyrotoxicosis. We aim to raise awareness of dysphagia caused by hyperthyroidism and review similar cases in the literature. We present a case of severe dysphagia caused by hyperthyroidism. We also summarize similar case reports in the literature. Our patient is a 77-year-old man who presented with thyrotoxicosis related to Graves’ disease (GD), dysphagia to both liquid and solid food, and weight loss. Further investigations revealed severe esophageal dysphagia and a high risk for aspiration. He required the placement of a G-tube for feeding. After 8 weeks of methimazole treatment, his thyroid function normalized and his dysphagia improved significantly, leading to the removal of the feeding G-tube. We summarize 19 case reports published in the literature of hyperthyroidism leading to dysphagia. Patients with thyrotoxicosis and dysphagia are at higher risk for aspiration pneumonia and thyroid storm. Based on previous case reports, on average, approximately 3 weeks of treatment with anti-thyroidal drugs and beta-blockers is needed before patients can eat normally. We report a case of dysphagia associated with GD, which is rare and needs prompt recognition to restore euthyroid status. Dysphagia generally resolved with normalization of thyroid function.
Learning points
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Myopathy caused by thyrotoxicosis is not uncommon.
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Skeletal muscles are commonly involved, but dysphagia is a rare manifestation of thyrotoxicosis.
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Dysphagia due to hyperthyroidism resolves with normalization of thyroid function.
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Early recognition of dysphagia related to hyperthyroidism and early initiation of therapy may help reverse the dysphagia and prevent complications.
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Banting and Best Diabetes Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada
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Summary
Central diabetes insipidus (CDI) is a rare manifestation of acute myeloid leukemia (AML) with unclear etiology. When present, CDI in AML has most often been described in patients with chromosome 3 or 7 aberrations and no abnormalities on brain imaging. In this case, we present a woman with newly diagnosed AML t(12;14)(p12;q13) found to have diabetes insipidus (DI) with partial anterior pituitary dysfunction and abnormal brain imaging. While in hospital, the patient developed an elevated serum sodium of 151 mmol/L with a serum osmolality of 323 mmol/kg and urine osmolality of 154 mmol/kg. On history, she reported polyuria and polydipsia for 5 months preceding hospitalization. Based on her clinical symptoms and biochemistry, she was diagnosed with DI and treated using intravenous desmopressin with good effect; sodium improved to 144 mmol/L with a serum osmolality of 302 mmol/kg and urine osmolality of 501 mmol/kg. An MRI of the brain done for the assessment of neurologic involvement revealed symmetric high-T2 signal within the hypothalamus extending into the mamillary bodies bilaterally, a partially empty sella, and loss of the pituitary bright spot. A pituitary panel was completed which suggested partial anterior pituitary dysfunction. The patient’s robust improvement with low-dose desmopressin therapy along with her imaging findings indicated a central rather than nephrogenic cause for her DI. Given the time course of her presentation with respect to her AML diagnosis, MRI findings, and investigations excluding other causes, her CDI and partial anterior pituitary dysfunction were suspected to be secondary to hypothalamic leukemic infiltration.
Learning points
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Leukemic infiltration of the pituitary gland is a rare cause of central diabetes insipidus (CDI) in patients with acute myeloid leukemia (AML).
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Patients with AML and CDI may compensate for polyuria and prevent hypernatremia with increased water intake.
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AML-associated CDI can require long-term desmopressin treatment, independent of AML response to treatment.
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Summary
An adrenocorticotropic hormone (ACTH)-producing pheochromocytoma (PCC)/paraganglioma is the cause of ectopic Cushing’s syndrome (CS) in 5.2% of cases reported in the literature. We present a previously healthy 43-year-old woman admitted to our hospital with cushingoid features and hypertensive urgency (blood pressure = 200/120 mmHg). Her 24-h urinary free cortisol was >4270 nmol/day (reference range (RR) = 100–380 nmol/day) with a plasma ACTH of 91.5 pmol/L (RR: 2.0–11.5 pmol/L). Twenty-four-hour urinary metanephrines were increased by 30-fold. Whole-body CT demonstrated a 3.7-cm left adrenal mass with a normal-appearing right adrenal gland. Sellar MRI showed a 5-mm sellar lesion. MIBG scan revealed intense uptake only in the left adrenal mass. She was managed pre-operatively with ketoconazole and phenoxybenzamine and underwent an uneventful left laparoscopic adrenalectomy, which resulted in biochemical resolution of her hypercortisolemia and catecholamine excess. Histology demonstrated a PCC (Grading System for Adrenal Pheochromocytoma and Paraganglioma score 5) with positive ACTH staining by immunohistochemistry. A PCC gene panel showed no mutations and there has been no evidence of recurrence at 24 months. This case highlights the difficult nature of localizing the source of CS in the setting of a co-existing PCC and sellar mass.
Learning points
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An adrenocorticotropic hormone (ACTH)-producing pheochromocytoma (PCC) is an important item to be considered in all patients presenting with ectopic Cushing’s syndrome (CS).
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In exceptionally rare cases, patients with ectopic CS may present with multiple lesions, and a systematic approach considering all potential sources is crucial to avoid misdiagnosis.
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CS with a large adrenal mass but lacking contralateral adrenal atrophy should raise suspicion of an ACTH-dependent process.
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In patients with clinical suspicion of PCC, clinicians should be mindful of the use of steroids and beta-blockers without appropriate alpha blockade as they may precipitate an adrenergic crisis.
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Summary
Familial nonautoimmune hyperthyroidism (FNAH) is rare and occurs due to a constitutively activating thyroid-stimulating hormone receptor (TSHR) germline mutation. Forty-one families with FNAH have been reported so far. In the study, 17 of 41 families were not diagnosed with FNAH until three generations or more were described with hyperthyroidism. We report a case of FNAH diagnosed in the third generation. The index patient was diagnosed with hyperthyroidism at age 3. Large fluctuations in thyroid hormone levels occurred during anti-thyroid drug treatment, and he developed a goiter. The patient’s mother had similar history, requiring two surgical interventions and radioiodine treatment. The younger brother of the index patient did not experience large thyroid hormone level fluctuations, nor increased thyroid growth. A heterozygous TSHR c.1357A>G mutation, resulting in a M453V amino acid exchange, was detected in all three patients leading to FNAH diagnosis, with complete genotype–phenotype segregation. Based on Sorting intolerant from tolerant (SIFT) and PolyPhen2 scores of 0.01 and 0.99, respectively, an effect on protein function can be assumed. As illustrated by this family with FNAH, total thyr oidectomy is necessary for patients with nonautoimmune hyperthyroidism. Development of goiter is common, anti-thyroid drug treatment is often difficult, and remission of hyperthyroidism does not occur after discontinuation of anti-thyroid drug treatment. Thus, early diagnosis and appropriate treatment of FNAH is necessary to avoid predictable, unnecessary complications and further surgical interventions.
Learning points
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In the study, 19/42 cases of familial nonautoimmune hyperthyroidism (FNAH), including the reported case, were not diagnosed as FNAH until the third generation; this lead to suboptimal treatment and frequent relapses of nonautoimmune hyperthyroidism (NAH).
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Detection of thyroid-stimulating hormone receptor (TSHR) mutations in patients with suspected FNAH to confirm diagnosis is essential to ensure proper treatment for the patient and further affected family members.
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NAH will persist without proper treatment by total thyroidectomy.
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Symptoms and age of onset may vary between family members
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All family members with a TSHR germline mutation should be monitored with thyroid-stimulating hormone and for symptoms throughout their lives.
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Summary
Fever of unknown origin is a commonly encountered medical problem. Most common causes include infections, malignancy, and connective tissue diseases. Endocrine causes are rare but are well documented. While fever is common in some endocrine disorders, fever of unknown origin as the sole presenting feature is very rare. We describe a case report of a 63-year-old male who presents with fever of unknown origin. Imaging and biopsy results confirmed the diagnosis of subacute thyroiditis. He was started on prednisone with a good response. We conclude that subacute thyroiditis should be considered in the work up of fever of unknown origin even in the absence of classical signs and symptoms.
Learning points:
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Fever of unknown origin is a rare sole presentation of subacute thyroiditis.
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The classic signs and symptoms may not be manifest at the time of presentation.
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Normal thyroid function tests and elevated markers of inflammation often make infections, malignancy and autoinflammatory conditions the prime consideration.
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Imaging of the thyroid gland may point to a morphologic aberration and prompt a thyroid biopsy.
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After exclusion of infection, a rapid response to steroids may be both diagnostic and therapeutic.
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Summary
Brown tumors (BTs) are expansile osteolytic lesions complicating severe primary hyperparathyroidism (PHPT). Clinical, radiological and histological features of BTs share many similarities with other giant cell-containing lesions of the bone, which can make their diagnosis challenging. We report the case of a 32-year-old man in whom an aggressive osteolytic lesion of the iliac crest was initially diagnosed as a giant cell tumor by biopsy. The patient was scheduled for surgical curettage, with a course of neoadjuvant denosumab. Routine biochemical workup prior to denosumab administration incidentally revealed high serum calcium levels. The patient was diagnosed with PHPT and a parathyroid adenoma was identified. In light of these findings, histological slices of the iliac lesion were reviewed and diagnosis of a BT was confirmed. Follow-up CT-scans performed 2 and 7 months after parathyroidectomy showed regression and re-ossification of the bone lesion. The aim of this case report is to underline the importance of distinguishing BTs from other giant cell-containing lesions of the bone and to highlight the relevance of measuring serum calcium as part of the initial evaluation of osteolytic bone lesions. This can have a major impact on patients’ management and can prevent unnecessary invasive surgical interventions.
Learning points:
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Although rare, brown tumors should always be considered in the differential diagnosis of osteolytic giant cell-containing bone lesions.
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Among giant cell-containing lesions of the bone, the main differential diagnoses of brown tumors are giant cell tumors and aneurysmal bone cysts.
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Clinical, radiological and histological characteristics can be non-discriminating between brown tumors and giant cell tumors. One of the best ways to distinguish these two diagnoses appears to be through biochemical workup.
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Differentiating brown tumors from giant cell tumors and aneurysmal bone cysts is crucial in order to ensure better patient care and prevent unnecessary morbid surgical interventions.
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Summary
Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare, autosomal recessive disorder caused by mutations in the SLC34A3 gene that encodes the renal sodium-dependent phosphate cotransporter 2c (NaPi-IIc). It may present as intermittent mild hypercalcemia which may attract initial diagnostic attention but appreciation of concomitant hypophosphatemia is critical for consideration of the necessary diagnostic approach. A 21-year-old woman was assessed by adult endocrinology for low bone mass. She initially presented age two with short stature, nephrocalcinosis and mild intermittent hypercalcemia with hypercalciuria. She had no evidence of medullary sponge kidney or Fanconi syndrome and no bone deformities, pain or fractures. She had recurrent episodes of nephrolithiasis. In childhood, she was treated with hydrochlorothiazide to reduce urinary calcium. Upon review of prior investigations, she had persistent hypophosphatemia with phosphaturia, low PTH and a high-normal calcitriol. A diagnosis of HHRH was suspected and genetic testing confirmed a homozygous c.1483G>A (p.G495R) missense mutation of the SLC34A3 gene. She was started on oral phosphate replacement which normalized her serum phosphate, serum calcium and urine calcium levels over the subsequent 5 years. HHRH is an autosomal recessive condition that causes decreased renal reabsorption of phosphate, leading to hyperphosphaturia, hypophosphatemia and PTH-independent hypercalcemia due to the physiologic increase in calcitriol which also promotes hypercalciuria. Classically, patients present in childhood with bone pain, vitamin D-independent rickets and growth delay. This case of a SLC34A3 mutation illustrates the importance of investigating chronic hypophosphatemia even in the presence of other more common electrolyte abnormalities.
Learning points:
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Hypophosphatemia is an important diagnostic clue that should not be ignored, even in the face of more common electrolyte disorders.
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HHRH is a cause of PTH-independent hypophosphatemia that may also show hypercalcemia.
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HHRH is a cause of hypophosphatemic nephrocalcinosis that should not be treated with calcitriol, unlike other congenital phosphate wasting syndromes.
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Some congenital phosphate wasting disorders may not present until adolescence or early adulthood.
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Summary
We report a case of metastatic papillary thyroid carcinoma presenting with a recurrent right-sided cervical lymph node necrotic cyst. A 55-year-old woman presented with a 3-month history of a right-sided upper neck mass following an upper respiratory tract infection. Past medical history includes a right-sided nephrectomy secondary to a benign renal tumor and hypertension. She was evaluated by Otolaryngology, and fine-needle aspiration was performed. The mass recurred 2 months following aspiration. Ultrasound of the neck showed a 2.2 × 1.4 × 1.9 cm right cervical lymph node with a small fatty hilum but a thickened cortex. Neck computed tomography (CT) scan showed a well-defined 2.3 cm mass in the right upper neck corresponding to a necrotic cervical lymph node at level IIA. It also revealed a 7 mm calcified left thyroid nodule. Cytology revealed a moderate collection of murky fluid with mildly atypical cells presumed to be reactive given the clinical history of infection. The cyst had re-grown 2 months following aspiration. Excisional biopsy was performed and revealed metastatic classic papillary thyroid carcinoma (PTC). Subsequently, a total thyroidectomy and right neck dissection was performed. Pathology confirmed metastatic unifocal classic PTC of the right thyroid lobe and two lymph node metastases out of a total of 17 resected lymph nodes. The patient underwent radioactive iodine ablation. Subsequent I-131 radioiodine whole-body scan showed no evidence of metastases. In conclusion, metastatic PTC should be considered in the differential diagnosis of a recurrent solitary cystic cervical lymph node.
Learning points:
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Metastatic PTC should be considered in the differential diagnosis of a recurrent solitary cystic cervical lymph node.
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A dedicated thyroid ultrasound is the preferred modality for identifying thyroid lesion over computed tomography.
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There is a risk of non-diagnostic cytology following FNA for cystic neck lesions, largely predicted by the cyst content of the nodule.
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Summary
Multifocal papillary thyroid carcinoma (PTC) is common and the number of tumor foci rarely exceeds ten. The mechanism of multifocal disease is debated, with the two main hypotheses consisting of either intrathyroidal metastatic spread from a single tumor or independent multicentric tumorigenesis from distinct progenitor cells. We report the case of a 46-year-old woman who underwent total thyroidectomy and left central neck lymph node dissection after fine-needle aspiration of bilateral thyroid nodules that yielded cytological findings consistent with PTC. Final pathology of the surgical specimen showed an isthmic dominant 1.5 cm classical PTC and over 30 foci of microcarcinoma, which displayed decreasing density with increasing distance from the central lesion. Furthermore, all malignant tumors and lymph nodes harbored the activating BRAF V600E mutation. The present case highlights various pathological features that support a mechanism of intraglandular spread, namely a strategic isthmic location of the primary tumor, radial pattern of distribution and extensive number of small malignant foci and BRAF mutational homogeneity.
Learning points:
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Multifocal papillary thyroid carcinoma (PTC) is commonly seen in clinical practice, but the number of malignant foci is usually limited to ten or less.
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There is no clear consensus in the literature as to whether multifocal PTC arises from a single or multiple distinct tumor progenitor cells.
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Strategic location of the dominant tumor in the thyroid isthmus may favor intraglandular dissemination of malignant cells by means of the extensive lymphatic network.
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An important pathological finding that may be suggestive of intrathyroidal metastatic spread is a central pattern of distribution with a reduction in the density of satellite lesions with increasing distance from the dominant focus.
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PTCs originating from the isthmus with intraglandular metastatic dissemination behave more aggressively. As such, a more aggressive treatment course may be warranted, particularly with regard to the extent of surgery.
