Endocrinology, Diabetes and Metabolism Case Reports最新文献

Summary: Alkaptonuria is a rare autosomal recessive metabolic disorder caused by a deficiency in homogentisate 1,2-dioxygenase (HGD), leading to the accumulation of homogentisic acid (HGA) in connective tissues, cartilage, and bones. This accumulation results in multisystem involvement, including early-onset spondyloarthropathy. We present a 54-year-old female from South Tyrol with chronic back and knee pain, accompanied by typical signs of alkaptonuria: ochronosis and darkening of the urine. Molecular genetic testing confirmed the diagnosis of alkaptonuria and identified a previously unreported mutation. Following treatment with nitisinone, a protein-restricted diet, and therapy for osteoporosis, the patient showed significant improvement in symptoms. This case underscores the need to consider rare metabolic disorders in the differential diagnosis of chronic musculoskeletal pain and highlights the importance of early diagnosis and intervention for effective management.

Learning points: In cases of early or unexplained degenerative spinal and joint changes in younger individuals, consider secondary metabolic causes. In the presence of the symptom triad - ochronosis, dark urine, and arthropathy - alkaptonuria should be suspected. Alkaptonuria is caused by a rare autosomal recessive defect in homogentisate 1,2-dioxygenase, leading to accumulation of homogentisic acid, which primarily results in the destruction of joints and heart valves. Diagnosis is established through biochemical testing and molecular genetic analysis of the HGD gene. Therapeutic options now include nitisinone as a causal treatment (available since 2020); however, due to often delayed diagnosis, symptomatic management and treatment of sequelae (pain control, joint care, and osteoporosis therapy) continue to play a major role.

Summary: HDR syndrome is a rare, heterogeneous genetic disorder characterised by a triad of hypoparathyroidism, sensorineural deafness, and renal disease. The defect in most patients is caused by deletions in chromosome 10p14 or mutations in the GATA3 gene. HDR syndrome is also associated with several atypical features, including eye, skin, neurological, cardiac, gastrointestinal, and urogenital involvement. We report the case of a 27-year-old Caucasian woman with HDR syndrome (GATA3 NM_001002295.1: c.977C>A p. (Thr326Asn)), who presents with multiple atypical associated features. She has also had recurrent benign ovarian cystic teratomas, although it is unclear whether these are related to HDR syndrome, as this has never been reported.

Learning points: HDR syndrome is a rare autosomal genetic disorder characterised by a triad of hypoparathyroidism, sensorineural deafness, and renal disease. It may be associated with atypical features involving various organs, which will require investigation and management. There is a paucity of evidence and guidance on managing hypocalcaemia in HDR syndrome. Given that HDR syndrome causes agenesis rather than a receptor issue, calcium levels should be targeted between 2.0 and 2.2 mmol/L, similar to the management of hypoparathyroidism caused by surgery or autoimmune disease.

Summary: Treatment-induced neuropathy of diabetes (TIND) refers to the acute onset of neuropathic symptoms in patients with poorly controlled diabetes, typically as a consequence of an abrupt change in glucose levels during medical management. We present the case of a 50-year-old female with a long-standing history of poorly controlled type 2 diabetes mellitus (T2DM) complicated by progressive lower extremity weakness and associated paresthesias. Comprehensive workup was unremarkable, and symptoms could not be controlled with muscle relaxant therapies. Further chart review revealed an abrupt drop in HbA1c levels roughly 6 months before her admission. The temporal association between the rapid lowering of HbA1c and the emergence of neurological signs strongly suggested the diagnosis of TIND, which was confirmed by EMG studies. A syncopal episode further complicated the patient's clinical course, and she was found to be orthostatic during hospital admission. The patient was started on duloxetine and given an increased dose of gabapentin, which improved her symptoms.

Learning points: TIND is an acute small-fiber neuropathy caused solely by iatrogenic factors and is often unrecognized as a complication of diabetes management. Neuropathic and autonomic symptoms worsen as both the magnitude and rate of change in HbA1c levels increase. Clinicians should be mindful of complications from rapidly lowering glucose levels and aim for an HbA1c reduction of less than 2 percentage points over 3 months.

Summary: A 39-year-old woman presented with a 5-year history of severe intermittent headaches, rhinitis, hemoptysis, unintentional weight loss of 40 kg over a year, and unilateral vision loss. Then, she noticed polyuria, amenorrhea, muscle weakness, and cold intolerance. Diagnosis of granulomatosis with polyangiitis (GPA) was confirmed with elevated c-ANCA levels and PR3-positive antibodies. Physical examination revealed hypotension, absence of pubic and axillary hair, and classical signs of hypothyroidism. The patient reported multiple previous hospitalizations due to episodes of hypernatremia, hypotension, and hypoglycemia. The biochemical evaluation showed early signs of chronic kidney disease and central adrenal, thyroid, and gonadotropin deficiencies. Pituitary MRI revealed a heterogeneous pituitary gland with peripheral enhancement, central necrosis, and extension to adjacent structures, as well as the absence of posterior pituitary bright spot on T1-weighted imaging. A diagnosis of GPA with pituitary involvement was established. Remission therapy with corticosteroids and rituximab was started. After disease control, pituitary hormonal deficiencies persisted, requiring long-term hormone replacement therapy.

Learning points: Pituitary involvement in cases with GPA is a rare manifestation frequently misdiagnosed. It is important to be aware of hypophysitis as a GPA activity complication that warrants a prompt diagnostic approach and treatment. The pathophysiology of hypophysitis may be mediated by a granulomatous lesion or due to vascular damage. Pituitary dysfunction in GPA may occur at any moment, as an initial manifestation or as a concomitant syndrome together with other organ compromise. Deficiency of arginine vasopressin and central hypogonadism are the most frequent pituitary hormonal alterations. Pituitary dysfunction usually persists despite remission of systemic activity, requiring long-term hormone replacement therapy and surveillance.

Summary: This case series presents two postmenopausal women with beta-thalassemia trait who developed osteoporosis. Case 1 involves a woman in her 70s presenting with persistent lower back pain; imaging revealed a compression fracture at L2, and a DEXA scan confirmed osteoporosis with a forearm T-score of -3.8 and a femoral neck T-score of -2.5. Case 2 describes a woman in her late 50s with generalized bone pain and severe osteoporosis identified through DEXA scanning, with a lumbar spine T-score of -3.3. Both patients lacked classical secondary causes of bone loss, and laboratory evaluations were unremarkable. Family history was notable for osteoporosis in first-degree relatives, though the relatives' thalassemia status was unknown. Both patients declined injectable therapies and were managed with oral alendronate, calcium, and vitamin D supplementation. These cases highlight beta-thalassemia trait as a potential underrecognized risk factor for osteoporosis in postmenopausal women, suggesting the need for further research and consideration in clinical guidelines.

Learning points: Beta-thalassemia trait may predispose to osteoporosis, even without iron overload or transfusion dependence. Postmenopausal women with beta-thalassemia trait should undergo early DEXA screening to prevent fractures. Patient preference impacts management: oral bisphosphonates are viable when injectables are refused. Guideline gaps: current osteoporosis protocols do not address beta-thalassemia trait as a risk factor.

Summary: Hypercalcemia is a prevalent electrolyte disturbance commonly associated with primary hyperparathyroidism, cancer, or medication adverse effects. Thiazide diuretics reduce urinary calcium excretion, increasing calcium reabsorption and hypercalcemia. Tirzepatide, a dual GIP and GLP-1 receptor agonist, is increasingly used for type 2 diabetes and obesity. While GIP/GLP-1 agonists typically have negligible effects on calcium homeostasis, the interaction between tirzepatide and thiazides remains unstudied. We report a 65-year-old female with obesity, hypertension, CKD3, and T2DM on chronic HCTZ who developed symptomatic hypercalcemia (corrected calcium: 4.58 mmol/L; normal range: 2.12-2.62 mmol/L), resulting in altered mental status days after initiating tirzepatide. PTH and vitamin D levels were low, and imaging ruled out malignancy. Discontinuation of tirzepatide/HCTZ, IV hydration, and calcitonin normalized her calcium by hospital day 4. This case highlights a potential association between HCTZ and tirzepatide in causing severe hypercalcemia. No prior reports link tirzepatide (or its combination with thiazides) to hypercalcemia. The mechanism likely involves thiazide-induced calcium reabsorption and tirzepatide's effects on bone turnover. As the use of tirzepatide and other GLP-1/GIP agonists becomes more prevalent, clinicians need to closely monitor calcium levels in thiazide-treated individuals, particularly those with CKD. Additional research is also needed to elucidate the drug's interaction with calcium metabolism.

Learning points: Clinicians should be aware of the potential for severe hypercalcemia when tirzepatide is co-administered with chronic thiazide diuretics, particularly hydrochlorothiazide (HCTZ), in patients with pre-existing CKD. Tirzepatide, a dual GIP and GLP-1 receptor agonist, may influence calcium metabolism through mechanisms including increased osteoblastic activity and altered PTH regulation, especially in individuals with impaired renal clearance. Baseline and follow-up serum calcium monitoring is strongly recommended within 1-2 weeks of initiating tirzepatide in patients receiving thiazide diuretics or those with CKD. This case suggests a possible drug-drug interaction between tirzepatide and HCTZ leading to symptomatic hypercalcemia, highlighting the need for pharmacovigilance as newer agents are integrated into routine diabetes care. Severe hypercalcemia can present with nonspecific symptoms such as altered mental status, fatigue, constipation, and polyuria; clinicians should maintain a high index of suspicion in susceptible populations. Prompt cessation of the suspected offending agents, hydration, and short-term use of calcitonin can result in rapid and sustained normalization of calcium levels without the need for bisphosphonates.

Summary: Primary hyperparathyroidism (PHPT) is a rare condition during pregnancy, but it is associated with significant maternal and fetal risks, including miscarriage, preeclampsia, and preterm birth. Hyperparathyroidism-jaw tumor (HPT-JT) syndrome is a rare genetic form of PHPT caused by mutations in the CDC73 gene. Managing PHPT during pregnancy is particularly challenging. While surgery remains the definitive treatment, it carries increased risk of complications during pregnancy. Pharmacological options are generally contraindicated or have limited safety data, limiting available therapeutic strategies. We report the case of a 19-year-old woman with genetically confirmed HPT-JT syndrome who became pregnant while awaiting parathyroidectomy. Given the stability of serum calcium levels, absence of complications, and concerns regarding adherence to follow-up, a conservative management strategy was adopted, consisting of oral hydration, dietary calcium restriction, and close monitoring throughout gestation. The pregnancy progressed uneventfully, and a successful postpartum parathyroidectomy led to biochemical normalization. This case illustrates the challenges in managing PHPT during pregnancy and supports the potential safety of individualized conservative approaches in selected cases with stable disease.

Learning points: Primary hyperparathyroidism (PHPT) during pregnancy is rare but may be associated with significant maternal and fetal risks; individualized management is essential. While parathyroidectomy is the only definitive treatment for PHPT, deferring surgery until the postpartum period may be a reasonable option in selected stable cases without complications. Conservative management with hydration and dietary calcium restriction may be a safe alternative in selected pregnant patients with stable, mild-to-moderate hypercalcemia. Genetic evaluation is critical in young patients with PHPT and relevant family history, as hereditary syndromes such as HPT-JT syndrome require long-term multidisciplinary surveillance.

Summary: Pheochromocytomas are rare neuroendocrine tumors derived from adrenal chromaffin cells that result in hyperactivity of the sympathetic nervous system. We present the case of a patient with biochemical evidence of pheochromocytoma, but surgical pathology revealed absence of tumor. This is an 80-year-old female with a past medical history of metastatic follicular lymphoma and hypertension with an incidental 1.4 cm right-sided adrenal nodule noted on a PET-CT scan. Her hypertension was treated with three different antihypertensive agents. Subsequent imaging with non-contrast CT of abdomen and pelvis showed a right adrenal incidentaloma with 16 Hounsfield units. Abdominal MRI with and without contrast revealed atypical signal loss on the out-of-phase imaging. Plasma normetanephrines were approximately 2.4 times higher than the upper limit of normal. Her urinary normetanephrines were higher than the upper limit of normal, suggestive of pheochromocytoma. The patient proceeded with robotically assisted laparoscopic right adrenalectomy and postoperatively required vasopressors. Surgical pathology showed adrenal cortical hyperplasia and medullary infarction associated with fibrosis. However, the noted phases of necrosis with predominant fibrosis match the time interval between clinical diagnosis and surgical management. Postoperative metanephrines normalized 4 weeks after surgery, indicating successful surgical resection of autonomous secretion of metanephrines. This is the only known case of biochemical evidence of pheochromocytoma with no histologic evidence of tumor.

Learning points: Biochemical evidence, clinical presentation and imaging studies of pheochromocytoma are crucial for its diagnosis. Due to the vascular nature of pheochromocytoma, there is a potential for the tumor to infarct. Plasma normetanephrines of greater than twice the upper limit of normal have high specificity for pheochromocytoma.

Summary: Thyroid storm represents a severe expression of thyrotoxicosis and is commonly associated by multiple organ dysfunction and liver abnormality. Thyrotoxicosis with concurrent autoimmune hepatitis is rare but could confound liver dysfunction, hence complicating diagnosis and subsequent management. We present the case of a 37-year-old woman with thyroid storm complicated by multiple organ failure and resistant hyperthyroidism. Despite initial medical therapy, her condition deteriorated with rising bilirubin and worsening right heart failure. Therapeutic plasma exchange (TPE) was initiated, leading to transient clinical and biochemical improvements. However, subsequent neurological decline and hepatic decompensation revealed an underlying autoimmune hepatitis, confirmed via biopsy at later stage. Intensive multimodal management, including further TPE sessions, ultimately stabilized her condition, allowing a safe and successful thyroidectomy. This report underscores the diagnostic challenge posed by overlapping autoimmune pathologies, the need for vigilant monitoring of thyroid and hepatic parameters, and the pivotal role of TPE as a rescue therapy.

Learning points: Dual autoimmune pathologies, such as autoimmune hepatitis and Graves' disease, can overlap and complicate diagnosis. Persistent or worsening liver dysfunction despite improvement in other thyroid parameter may signal underlying liver pathology. Importance of monitoring for rebound thyrotoxicosis and liver dysfunction in thyroid storm. Therapeutic plasma exchange (TPE) as a critical rescue therapy in thyroid storm and metabolic or hepatic encephalopathy.

Summary: Carboxyl ester lipase (CEL) is a major component of pancreatic juice and is responsible for the duodenal hydrolysis of cholesteryl esters. Maturity-onset diabetes of the young (MODY) is a form of diabetes mellitus characterized by early onset and dominant inheritance of beta-cell dysfunction. CEL gene mutations cause the type of MODY denoted as MODY8. Herein, we describe a Japanese patient who harbored a heterozygous A689P mutation in the variable number of tandem repeats (VNTRs)-containing exon 11 of the CEL gene. The patient was not obese and his diabetes was characterized by onset in late adolescence, impaired insulin secretion and metabolic dysfunction-associated steatotic liver disease (MASLD). The C-terminal region of CEL has been postulated to be critical for its secretion and activity. Therefore, the A689P mutation may cause pancreatic exocrine insufficiency and eventually contribute to MASLD, which is associated with reduced lipid catabolism. MODY8 is also considered to be a protein-misfolding disease because a heterozygous single nucleotide deletion causes the production of mutant CEL protein leading to diabetes and exocrine dysfunction. In the present case, MASLD and diabetes characterized by impaired insulin secretion were observed. The CEL A689P missense mutation will expand the known genotype-phenotype correlation in diabetes if it can be demonstrated that the variant is pathogenic.

Learning points: The CEL gene encodes the digestive enzyme carboxyl ester lipase, also known as bile salt-stimulated/dependent lipase. CEL is expressed in pancreatic acinar tissue but not in pancreatic β cells. MODY caused by mutations in the CEL gene (MODY8) is characterized by dominantly inherited diabetes mellitus manifesting in early adulthood. A classical feature of MODY8 is pancreatic exocrine dysfunction, often with onset in childhood. Known pathogenic mutations in the CEL gene affect the variable number tandem repeat (VNTR) region in exon 11. Our case suggests that some missense mutations of the CEL VNTR could have a phenotypic implication by being associated with impaired glucose-stimulated insulin secretion and reduced utilization of lipid as an energy source which leads to MASLD.