Diagnosis and Treatment > Signs and Symptoms
Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
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Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
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Department of General Surgery, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
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Summary
Spontaneous remission of primary hyperparathyroidism (PHPT) due to necrosis and haemorrhage of parathyroid adenoma, the so-called ‘parathyroid auto-infarction’ is a very rare, but previously described phenomenon. Patients usually undergo parathyroidectomy or remain under close clinical and biochemical surveillance. We report two cases of parathyroid auto-infarction diagnosed in the same tertiary centre; one managed surgically and the other conservatively up to the present time. Case #1 was a 51-year old man with PHPT (adjusted (adj.) calcium: 3.11 mmol/L (reference range (RR): 2.20–2.60 mmol/L), parathyroid hormone (PTH) 26.9 pmol/L (RR: 1.6–6.9 pmol/L) and urine calcium excretion consistent with PHPT) referred for parathyroidectomy. Repeat biochemistry 4 weeks later at the surgical clinic showed normal adj. calcium (2.43 mmol/L) and reduced PTH. Serial ultrasound imaging demonstrated reduction in size of the parathyroid lesion from 33 to 17 mm. Twenty months later, following recurrence of hypercalcaemia, he underwent neck exploration and resection of an enlarged right inferior parathyroid gland. Histology revealed increased fibrosis and haemosiderin deposits in the parathyroid lesion in keeping with auto-infarction. Case #2 was a 54-year-old lady admitted with severe hypercalcaemia (adj. calcium: 4.58 mmol/L, PTH 51.6 pmol/L (RR: 1.6–6.9 pmol/L)) and severe vitamin D deficiency. She was treated with intravenous fluids and pamidronate and 8 days later developed symptomatic hypocalcaemia (1.88 mmol/L) with dramatic decrease of PTH (17.6 pmol/L). MRI of the neck showed a 44 mm large cystic parathyroid lesion. To date, (18 months later), she has remained normocalcaemic.
Learning points:
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Primary hyperparathyroidism (PHPT) is characterised by excess parathyroid hormone (PTH) secretion arising mostly from one or more autonomously functioning parathyroid adenomas (up to 85%), diffuse parathyroid hyperplasia (<15%) and in 1–2% of cases from parathyroid carcinoma.
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PHPT and hypercalcaemia of malignancy, account for the majority of clinical presentations of hypercalcaemia.
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Spontaneous remission of PHPT due to necrosis, haemorrhage and infarction of parathyroid adenoma, the so-called ‘parathyroid auto-infarction’, ‘auto-parathyroidectomy’ or ‘parathyroid apoplexy’ is a very rare in clinical practice but has been previously reported in the literature.
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In most cases, patients with parathyroid auto-infarction undergo parathyroidectomy. Those who are managed conservatively need to remain under close clinical and biochemical surveillance long-term as in most cases PHPT recurs, sometimes several years after auto-infarction.
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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:
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Suspect milk-alkali syndrome in patients with hypercalcemia, metabolic alkalosis and renal failure, especially in context of ingestion of excess calcium-containing supplements.
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Careful history of over-the-counter medications, supplements and diet is crucial to diagnose milk-alkali syndrome.
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Milk-alkali syndrome may cause severe hypercalcemia in up to 25–30% of cases.
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Summary
The use of in vivo confocal microscopy (IVCM) is rapidly emerging as an important clinical tool to evaluate changes in corneal sensory nerves as a surrogate measure for diabetic peripheral neuropathy. Commonly used metrics to document and grade the severity of diabetes and risk for diabetic peripheral neuropathy include nerve fiber length, density, branching and tortuosity. In addition to corneal nerves, thinning of the retinal fiber layer has been shown to correlate with the severity of diabetic disease. Here, we present a case report on a pre-diabetic 60-year-old native American woman with abnormal corneal nerve morphology and retinal nerve fiber layer thinning. Her past medical history was positive for illicit substance abuse. IVCM showed a decrease in nerve fiber density and length, in addition to abnormally high levels of tortuosity. OCT revealed focal areas of reduced retinal nerve fiber layer thickness that were asymmetric between eyes. This is the first report of abnormally high levels of tortuosity in the corneal sub-basal nerve plexus in a patient with a past history of cocaine abuse. It also demonstrates, for the first time, that illicit substance abuse can have long-term adverse effects on ocular nerves for years following discontinued use of the drug. Studies using IVCM to evaluate changes in corneal nerve morphology in patients with diabetes need to consider a past history of illicit drug use as an exclusionary measure.
Learning points:
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Multiple ocular and systemic factors can impede accurate assessment of the corneal sub-basal nerve plexus by IVCM in diabetes.
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Although current history was negative for illicit substance abuse, past history can have longstanding effects on corneal nerves and the retinal nerve fiber layer.
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Illicit drug use must be considered an exclusionary measure when evaluating diabetes-induced changes in corneal nerve morphology and the retinal nerve fiber layer.
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Summary
Parathyroid carcinoma is an extremely rare disorder with little treatment options. It could be misdiagnosed in medical centers with little experience in management of such cases. Our clinical case shows that the initial misdiagnosis of a parathyroid carcinoma in a young woman has led to the development of multiple lung metastases, thus making its treatment hardly possible. Initiation of treatment with sorafenib – a multi-kinase inhibitor approved for treatment of different types of cancer but not parathyroid carcinoma – has led to a significant decrease in the size of lung metastases and has prevented the progression of hyperparathyroidism, which is usually severe in cases of parathyroid carcinoma. The detection of a germline CDC73 mutation in this patient has raised additional concerns about the necessity of periodic screening for early detection of renal, jaw and uterine lesions.
Learning points:
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Diagnosis of parathyroid carcinoma may be challenging due to the absence of reliable diagnostic criteria. Thus, thorough histological examination is needed using immunohistochemical staining of resected tissue in suspicious cases.
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CDC73 genetic testing should be considered in patients with parathyroid carcinoma.
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Sorafenib may be a promising treatment of patients with parathyroid carcinoma with distant metastases.
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Parathyroid carcinoma is a rare disease leading to severe hypercalcemia due to hyperparathyroidism. Surgery is the primary treatment option. A more progressive form of the disease is characterized by parathyrotoxicosis, and subsequent hypercalcemia is the most common cause of death. We report a case presenting with severe hypercalcemia due to parathyrotoxicosis from parathyroid carcinoma treated for the first time using the monoclonal antibody denosumab as a rescue therapy and present long-term follow-up data. The 71-year-old patient presented with severe hypercalcemia due to metastatic parathyroid carcinoma. Despite undergoing treatment with bisphosphonates, cinacalcet hydrochloride, and forced diuresis, the patient`s condition deteriorated rapidly due to resistant hypercalcemia. Surgery performed because of spinal metastasis and forced diuresis lowered calcium levels, albeit they remained in the hypercalcemic range and significantly increased when forced diuresis was stopped. Considering a palliative situation to overcome hypercalcemia, we decided to administer denosumab, a monoclonal antibody that binds to the receptor activator of nuclear factor-kappa B ligand. After a single subcutaneous administration of 60 mg denosumab, calcium levels normalized within one day. Subsequent denosumab injections led to permanent control of serum calcium for more than 2 years despite rising parathyroid hormone levels and repeated surgeries. Together with recent cases in the literature supporting our observation, we believe that denosumab is relevant for future trials and represents an effective tool to control hypercalcemia in patients with advanced stages of parathyroid cancer.
Learning points
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Severe hypercalcemia is the most common cause of death in patients with parathyroid carcinoma.
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The monoclonal antibody denosumab rapidly lowered severely elevated serum calcium levels due to parathyrotoxicosis.
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Denosumab was effective in the long-term treatment of hypercalcemia despite progression of parathyroid carcinoma.
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Summary
Drugs that inhibit the sodium-glucose co-transporter-2 (SGLT2) are an exciting novel, insulin-independent treatment for diabetes that block glucose reabsorption from the proximal tubules of the kidney, leading to increased glucose excretion and lower blood glucose levels. Inhibition of SGLT2 activity also reduces sodium reabsorption, which together with glycosuria produces a mild diuretic effect with the potential for dehydration and hyperkalemia. We report on a 60-year-old man with uncontrolled type 2 diabetes treated with insulin, glimepiride, metformin and canagliflozin, who was admitted with altered mental status after a syncopal episode. He had a 1-week history of ingestion of Tums for heartburn followed by poor appetite and lethargy. Laboratory work-up showed acute kidney injury, diabetic ketoacidosis (DKA), and parathyroid hormone-independent severe hypercalcemia of 17.4 mg/dl. DKA resolved with insulin treatment, and saline hydration led to improvement in hypercalcemia and renal function over 48 h, but was accompanied by a rapid increase in the serum sodium concentration from 129 to 162 mmol/l despite changing fluids to 0.45% saline. Urine studies were consistent with osmotic diuresis. Hypernatremia was slowly corrected with hypotonic fluids, with improvement in his mental status over the next 2 days. This is the first report of hypercalcemia associated with the use of a SLGT2 inhibitor. Although the exact mechanism is unknown, canagliflozin may predispose to hypercalcemia in patients ingesting excessive calcium because of dehydration from osmotic diuresis, with reduced calcium excretion and possible increased intestinal calcium absorption. Saline therapy and osmotic diuresis may lead to hypernatremia from electrolyte-free water loss.
Learning points
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Canagliflozin, an SGLT2 inhibitor, may cause hypercalcemia in susceptible patients.
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Although the exact mechanisms are unknown, dehydration from osmotic diuresis and increased intestinal calcium absorption play a role.
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Close monitoring of serum calcium levels is recommended in patients treated with SGLT2 inhibitors who are elderly, have established hypercalcemia, or take oral calcium supplements.
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Saline therapy and osmotic diuresis may lead to hypernatremia from electrolyte-free water loss in susceptible patients.
