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Open access

Mauro Boronat

Summary

Isolated, adult-onset central hypothyroidism is very rare, and its diagnosis can be challenging. A 42-year-old patient was referred for evaluation of a 2.8 cm thyroid nodule. She referred symptoms that could be attributed to hypothyroidism and thyroid tests showed low TSH and normal-low levels of free T4. However, evaluation of the remaining pituitary hormones and pituitary MRI were normal, yet a radionuclide scanning revealed that the thyroid nodule was ‘hot’ and the tracer uptake in the remaining thyroid tissue was suppressed. Interpretation of these studies led to a misdiagnosis of subclinical hyperthyroidism and the patient was treated with radioiodine. Soon after treatment, she developed a frank hypothyroidism without appropriate elevation of TSH and the diagnosis of central hypothyroidism was made a posteriori. Long term follow-up revealed a progressive pituitary failure, with subsequent deficiency of ACTH and GH. This case should alert to the possibility of overlooking central hypothyroidism in patients simultaneously bearing primary thyroid diseases able to cause subclinical hyperthyroidism.

Learning points:

  • Although rarely, acquired central hypothyroidism can occur in the absence of other pituitary hormone deficiencies.
  • In these cases, diagnosis is challenging, as symptoms are unspecific and usually mild, and laboratory findings are variable, including low, normal or even slightly elevated TSH levels, along with low or low-normal concentrations of free T4.
  • In cases with low TSH levels, the coexistence of otherwise common disorders able to cause primary thyroid hyperfunction, such as autonomous nodular disease, may lead to a misdiagnosis of subclinical hyperthyroidism.
Open access

Mawson Wang, Benjamin Jonker, Louise Killen, Yvonne Bogum, Ann McCormack, and Ramy H Bishay

Summary

Cushing’s disease is a rare disorder characterised by excessive cortisol production as a consequence of a corticotroph pituitary tumour. While the primary treatment is surgical resection, post-operative radiation therapy may be used in cases of ongoing inadequate hormonal control or residual or progressive structural disease. Despite improved outcomes, radiotherapy for pituitary tumours is associated with hypopituitarism, visual deficits and, rarely, secondary malignancies. We describe an unusual case of a 67-year-old female with presumed Cushing’s disease diagnosed at the age of 37, treated with transsphenoidal resection of a pituitary tumour with post-operative external beam radiotherapy (EBRT), ketoconazole for steroidogenesis inhibition, and finally bilateral adrenalectomy for refractory disease. She presented 30 years after her treatment with a witnessed generalised tonic-clonic seizure. Radiological investigations confirmed an extracranial mass infiltrating through the temporal bone and into brain parenchyma. Due to recurrent generalised seizures, the patient was intubated and commenced on dexamethasone and anti-epileptic therapy. Resection of the tumour revealed a high-grade osteoblastic osteosarcoma. Unfortunately, the patient deteriorated in intensive care and suffered a fatal cardiac arrest following a likely aspiration event. We describe the risk factors, prevalence and treatment of radiation-induced osteosarcoma, an exceedingly rare and late complication of pituitary irradiation. To our knowledge, this is the longest reported latency period between pituitary irradiation and the development of an osteosarcoma of the skull.

Learning points:

  • Cushing’s disease is treated with transsphenoidal resection as first-line therapy, with radiotherapy used in cases of incomplete resection, disease recurrence or persistent hypercortisolism.
  • The most common long-term adverse outcome of pituitary tumour irradiation is hypopituitarism occurring in 30–60% of patients at 10 years, and less commonly, vision loss and oculomotor nerve palsies, radiation-induced brain tumours and sarcomas.
  • Currently proposed characteristics of radiation-induced osteosarcomas include: the finding of a different histological type to the primary tumour, has developed within or adjacent to the path of the radiation beam, and a latency period of at least 3 years.
  • Treatment of osteosarcoma of the skull include complete surgical excision, followed by systemic chemotherapy and/or radiotherapy.
  • Overall prognosis in radiation-induced sarcoma of bone is poor.
  • Newer techniques such as stereotactic radiosurgery may reduce the incidence of radiation-induced malignancies.
Open access

Nicolás Cruz-Dardíz, Nadyeschka Rivera-Santana, Marina Torres-Torres, Héctor Cintrón-Colón, Shayanne Lajud, Ernesto Solá-Sánchez, Michelle Mangual-García, and Alex González-Bóssolo

Summary

Lingual thyroid (LT) gland is the most common type of ectopic thyroid tissue, but it is an extremely rare presentation. We present a case of a 41-year-old Hispanic female patient complaining of dysphonia and dysphagia. As part of the evaluation, fiber optic flexible indirect laryngoscopy (FIL) was performed which revealed a mass at the base of the tongue. The morphological examination was highly suspicious for ectopic thyroid tissue and the diagnosis was confirmed with neck ultrasound and thyroid scintigraphy. Although the patient presented subclinical hypothyroidism, levothyroxine therapy was initiated with a favorable response which included resolution of symptoms and mass size reduction. Our case portrays how thyroid hormone replacement therapy (THRT) may lead to a reduction in the size of the ectopic tissue and improvement of symptoms, thus avoiding the need for surgical intervention which could result in profound hypothyroidism severely affecting the patients’ quality of life.

Learning points:

  • Benign LT and malignant LT are indistinguishable clinically and radiographically for which histopathology is recommended.
  • THRT, radioactive iodine 131 (RAI) therapy, and surgical excision are potential management options for LT.
  • THRT may lead to size reduction of the ectopic tissue and resolution of symptoms avoiding surgical intervention.
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

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

Isabella Lupi, Alessandro Brancatella, Mirco Cosottini, Nicola Viola, Giulia Lanzolla, Daniele Sgrò, Giulia Di Dalmazi, Francesco Latrofa, Patrizio Caturegli, and Claudio Marcocci

Summary

Programmed cell death protein 1/programmed cell death protein ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte antigen 4/B7 (CTLA-4/B7) pathways are key regulators in T-cell activation and tolerance. Nivolumab, pembrolizumab (PD-1 inhibitors), atezolizumab (PD-L1 inhibitor) and ipilimumab (CTLA-4 inhibitor) are monoclonal antibodies approved for treatment of several advanced cancers. Immune checkpoint inhibitors (ICIs)-related hypophysitis is described more frequently in patients treated with anti-CTLA-4; however, recent studies reported an increasing prevalence of anti-PD-1/PD-L1-induced hypophysitis which also exhibits slightly different clinical features. We report our experience on hypophysitis induced by anti-PD-1/anti-PD-L1 treatment. We present four cases, diagnosed in the past 12 months, of hypophysitis occurring in two patients receiving anti-PD-1, in one patient receiving anti-PD-1 and anti-CTLA-4 combined therapy and in one patient receiving anti-PD-L1. In this case series, timing, clinical presentation and association with other immune-related adverse events appeared to be extremely variable; central hypoadrenalism and hyponatremia were constantly detected although sellar magnetic resonance imaging did not reveal specific signs of pituitary inflammation. These differences highlight the complexity of ICI-related hypophysitis and the existence of different mechanisms of action leading to heterogeneity of clinical presentation in patients receiving immunotherapy.

Learning points:

  • PD-1/PD-L1 blockade can induce hypophysitis with a different clinical presentation when compared to CTLA-4 blockade.
  • Diagnosis of PD-1/PD-L1 induced hypophysitis is mainly made on clinical grounds and sellar MRI does not show radiological abnormalities.
  • Hyponatremia due to acute secondary adrenal insufficiency is often the principal sign of PD-1/PD-L1-induced hypophysitis and can be masked by other symptoms due to oncologic disease.
  • PD-1/PD-L1-induced hypophysitis can present as an isolated manifestation of irAEs or be in association with other autoimmune diseases
Open access

Jonathan Brown and Luqman Sardar

Summary

A 68-year-old previously independent woman presented multiple times to hospital over the course of 3 months with a history of intermittent weakness, vacant episodes, word finding difficulty and reduced cognition. She was initially diagnosed with a TIA, and later with a traumatic subarachnoid haemorrhage following a fall; however, despite resolution of the haemorrhage, symptoms were ongoing and continued to worsen. Confusion screen blood tests showed no cause for the ongoing symptoms. More specialised investigations, such as brain imaging, cerebrospinal fluid analysis, electroencephalogram and serology also gave no clear diagnosis. The patient had a background of hypothyroidism, with plasma thyroid function tests throughout showing normal free thyroxine and a mildly raised thyroid-stimulating hormone (TSH). However plasma anti-thyroid peroxidise (TPO) antibody titres were very high. After discussion with specialists, it was felt she may have a rare and poorly understood condition known as Hashimoto’s encephalopathy (HE). After a trial with steroids, her symptoms dramatically improved and she was able to live independently again, something which would have been impossible at presentation.

Learning points:

  • In cases of subacute onset confusion where most other diagnoses have already been excluded, testing for anti-thyroid antibodies can identify patients potentially suffering from HE.
  • In these patients, and under the guidance of specialists, a trial of steroids can dramatically improve patient’s symptoms.
  • The majority of patients are euthyroid at the time of presentation, and so normal thyroid function tests should not prevent anti-thyroid antibodies being tested for.
  • Due to high titres of anti-thyroid antibodies being found in a small percentage of the healthy population, HE should be treated as a diagnosis of exclusion, particularly as treatment with steroids may potentially worsen the outcome in other causes of confusion, such as infection.
Open access

Anna Tortora, Domenico La Sala, and Mario Vitale

Summary

Reduced intestinal absorption of levothyroxine (LT4) is the most common cause of failure to achieve an adequate therapeutic target in hypothyroid patients under replacement therapy. We present the case of a 63-year-old woman with autoimmune hypothyroidism previously well-replaced with tablet LT4 who became unexpectedly no more euthyroid. At presentation, the patient reported the onset of acute gastrointestinal symptoms characterized by nausea, loss of appetite, flatulence, abdominal cramps and diarrhea, associated with increase of thyrotropin levels (TSH: 11 mIU/mL). Suspecting a malabsorption disease, a thyroxine solid-to-liquid formulation switch, at the same daily dose, was adopted to reach an optimal therapeutic target despite the gastrointestinal symptoms persistence. Oral LT4 solution normalized thyroid hormones. Further investigations diagnosed giardiasis, and antibiotic therapy was prescribed. This case report is compatible with a malabsorption syndrome caused by an intestinal parasite (Giardia lamblia). The reduced absorption of levothyroxine was resolved by LT4 oral solution.

Learning points:

  • The failure to adequately control hypothyroidism with oral levothyroxine is a common clinical problem.
  • Before increasing levothyroxine dose in a patient with hypothyroidism previously well-controlled with LT4 tablets but no more in appropriate therapeutic target, we suggest to investigate non adhesion to LT4 therapy, drug or food interference with levothyroxine absorption, intestinal infection, inflammatory intestinal disease, celiac disease, lactose intolerance, short bowel syndrome after intestinal or bariatric surgery, hepatic cirrhosis and congestive heart failure.
  • LT4 oral solution has a better absorptive profile than the tablet. In hypothyroid patients affected by malabsorption syndrome, switch of replacement therapy from tablet to liquid LT4 should be tested before increasing the dose of LT4.
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

Ilan Rahmani Tzvi-Ran, Judith Olchowski, Merav Fraenkel, Asher Bashiri, and Leonid Barski

Summary

A previously healthy 24-year-old female underwent an emergent caesarean section without a major bleeding described. During the first post-operative days (POD) she complained of fatigue, headache and a failure to lactate with no specific and conclusive findings on head CT. On the following days, fever rose with a suspicion of an obstetric surgery-related infection, again with no evidence to support the diagnosis. On POD5 a new-onset hyponatremia was documented. The urine analysis suggested SIADH, and following a treatment failure, further investigation was performed and demonstrated both central hypothyroidism and adrenal insufficiency. The patient was immediately treated with hydrocortisone followed by levothyroxine with a rapid resolution of symptoms and hyponatremia. Further laboratory investigation demonstrated anterior hypopituitarism. The main differential diagnosis was Sheehan’s syndrome vs lymphocytic hypophysitis. Brain MRI was performed as soon as it was available and findings consistent with Sheehan’s syndrome confirmed the diagnosis. Lifelong hormonal replacement therapy was initiated. Further complaints on polyuria and polydipsia have led to a water deprivation testing and the diagnosis of partial central insipidus and appropriate treatment with DDAVP.

Learning points:

  • Sheehan’s syndrome can occur, though rarely, without an obvious major post-partum hemorrhage.
  • The syndrome may resemble lymphocytic hypophysitis clinically and imaging studies may be crucial in order to differentiate both conditions.
  • Hypopituitarism presentation may be variable and depends on the specific hormone deficit.
  • Euvolemic hyponatremia workup must include thyroid function test and 08:00 AM cortisol levels.