Patient Demographics > Age > Adult

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Clara Cunha Department of Endocrinology, Hospital Egas Moniz, Lisbon, Portugal

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Filipa Mousinho Department of Haematology, Hospital São Francisco Xavier, Lisbon, Portugal

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Catarina Saraiva Department of Endocrinology, Hospital Egas Moniz, Lisbon, Portugal

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João Sequeira Duarte Department of Endocrinology, Hospital Egas Moniz, Lisbon, Portugal

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Summary

Primary thyroid lymphoma (PTL) is a rare malignancy, accounting for less than 5% of all thyroid neoplasms. The follicular subtype is even more rare, accounting for approximately 10% of all PTL cases. We report a case of a 64-year-old woman, who presented with a rapidly growing goitre with mass effect and B symptoms. She had a history of Hashimoto’s thyroiditis and her thyroid ultrasound revealed diffuse goitre with a dominant nodule (56 × 63 × 60 mm) within the right thyroid lobe. Ultrasound-guided percutaneous fine-needle aspiration of the right thyroid nodule was classified as benign, according to Bethesda System, with lymphocytic thyroiditis. A CT scan of the neck showed diffuse enlargement of the thyroid gland extending towards the anterior mediastinum with tracheal deviation and lymphadenopathy within levels VII and right II–IV. The core needle biopsy of the right thyroid nodule revealed a follicular non-Hodgkin’s B cell lymphoma with a Ki67 of 60%. According to the Ann Arbor staging system, she was at stage IIIE. She underwent chemotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) with remarkable clinical improvement and is currently in remission 2 years after the diagnosis. PTL is an extremely rare malignancy that usually arises in a lymphocytic thyroiditis background, presenting as a rapidly enlarging goitre, which can lead to compressive symptoms or airway comprise.

Learning points

  • Primary thyroid lymphoma (PTL) is a rare malignancy, accounting for less than 5% of thyroid neoplasms.

  • PTL should be suspected when a patient presents with a rapidly enlarging goitre, especially in the setting of Hashimoto’s thyroiditis.

  • Fine-needle aspiration has a limited capacity for PTL diagnosis due to similar cytomorphological features of lymphoma with thyroiditis. Therefore, in case of clinical suspicion and if fine needle aspiration fails to diagnose PTL, a tissue biopsy should be performed.

  • Treatment is dependent on both the stage and histology of PTL. Chemotherapy and local radiotherapy remain the mainstay treatment for PTL.

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Melanie Scheive Indiana University School of Medicine, Indianapolis, Indiana, USA

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Neha Patel Indiana University School of Medicine, Indianapolis, Indiana, USA

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Zeb Saeed Indiana University School of Medicine, Indianapolis, Indiana, USA

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Summary

Thyrotoxic periodic paralysis (TPP) is a rare complication of hyperthyroidism triggered by precipitants that increase the activity of the sodium-potassium pump in the skeletal muscle. In our case study, a previously healthy 34-year-old male presented to the emergency department with new onset thyrotoxicosis, secondary to Graves’ disease. Given the severity of his triiodothyronine (T3) thyrotoxicosis, he was admitted and started on a high dose of beta-blocker, thioamides, and intravenous hydrocortisone. On the second day of his hospitalization, he developed acute flaccid paralysis of his lower extremities. Subsequent stroke workup was negative, and his electrolytes revealed severe hypokalemia and hyperglycemia consistent with TPP. He was treated with potassium and had a complete recovery of his paralysis and hypokalemia within hours. The patient has not had any recurrence since this singular episode in the hospital. This case highlights the scenario where the treatment of hyperthyroidism with high-dose corticosteroids to reduce the conversion of thyroxine to T3 inadvertently resulted in TPP. Clinicians should be aware of this potentially rare but serious consequence of using steroids to manage hyperthyroidism.

Learning points

  • High-dose steroids used to treat hyperthyroidism in hospitalized patients may rarely precipitate thyrotoxic periodic paralysis (TPP) by inducing hypokalemia and hyperglycemia.

  • TPP should be included in the differential diagnosis for acute flaccid paralysis in hospitalized patients with hyperthyroidism.

  • Since TPP is associated with trans-cellular shifts in potassium instead of total body potassium depletion, conservative repletion of potassium is recommended to avoid rebound hyperkalemia.

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Samuel R Miller Medical Oncology, Royal North Shore Hospital, Sydney, Australia

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Shejil Kumar Endocrinology, Royal North Shore Hospital, Sydney, Australia

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Alexander Yuile Medical Oncology, Royal North Shore Hospital, Sydney, Australia

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Alexander M Menzies Melanoma Institute Australia; The University of Sydney; Faculty of Medicine and Health; The University of Sydney, Royal North Shore and Mater Hospitals, Sydney, Australia

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Summary

Hypercalcaemia is a common complication seen in malignancy, frequently due to paraneoplastic parathyroid hormone-related peptide production or osteolytic bony metastases. We present a 58-year-old female with immunotherapy-mediated hypophysitis causing secondary cortisol deficiency resulting in severe glucocorticoid-responsive hypercalcaemia. Whilst hypophysitis is a well recognised adverse event in those receiving immunotherapy for advanced malignancy, it does not typically present with hypercalcaemia. The mechanism responsible for hypercalcaemia due to hypocortisolaemia has not been fully elucidated although hypotheses include the effects of volume depletion and thyroxine’s action on bone. Prompt treatment with glucocorticoids caused an improvement in the patient’s symptoms and corrected her hypercalcaemia which later returned after an attempted glucocorticoid wean. With the increasing uptake of immunotherapy, clinicians should be aware of this unusual presentation of immunotherapy-related hypophysitis and secondary hypocortisolaemia which can be life-threatening if the diagnosis is delayed.

Learning points

  • Immunotherapy can cause inflammation of the pituitary gland resulting in secondary hypocortisolaemia, which can, though rarely, present as hypercalcaemia.

  • Secondary hypocortisolaemia requires prompt recognition and treatment with glucocorticoids. Glucocorticoid replacement leads to rapid clinical and biochemical improvement in these patients.

  • The differential diagnosis for glucocorticoid-responsive hypercalcaemia extends beyond granulomatous disorders (e.g. sarcoidosis, tuberculosis) to adrenocorticotrophic hormone and cortisol deficiency, particularly in patients receiving immunotherapy.

  • Hypocortisolaemia can lead to hypercalcaemia through various proposed mechanisms. Low serum glucocorticoids are associated with reduced blood volume, thus reducing renal calcium excretion. In addition, without glucocorticoid’s inhibitory action, thyroxine appears to drive calcium mobilisation from bone.

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Bridget Cooper St Vincent’s Hospital, Garvan Institute of Medical Research, University of New South Wales, Australia

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Kenrick Blaker St Vincent’s Hospital, Garvan Institute of Medical Research, University of New South Wales, Australia

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Jerry R Greenfield St Vincent’s Hospital, Garvan Institute of Medical Research, University of New South Wales, Australia

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Summary

We present a case of a 42-year-old man who developed acute onset severe hypertriglyceridaemia within days of commencing olanzapine therapy. Despite having a family history of metabolic syndrome, he had no personal history of hyperlipidaemia and had normal fasting lipids 1 week prior to treatment initiation. His case is consistent with a diagnosis of multifactorial chylomicronaemia syndrome with a possible undiagnosed underlying genetic lipid metabolism disorder. Our case highlights the difficulty in identifying patients at risk of severe hypertriglyceridaemia prior to the commencement of olanzapine.

Learning points

  • Atypical antipsychotic medications, in particular olanzapine and clozapine, are associated with metabolic side effects.

  • Olanzapine can precipitate acute onset severe hypertriglyceridaemia consistent with multifactorial chylomicronaemia syndrome.

  • It is difficult to predict individuals at risk of olanzapine-induced hypertriglyceridaemia.

  • This case demonstrates the importance of metabolic screening prior to the commencement of olanzapine and the possibility of repeating fasting serum lipids soon thereafter.

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Madoka Toyoda Department of Surgery, Yokohama City University, Yokohama, Japan

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Nobuyasu Suganuma Department of Surgery, Yokohama City University, Yokohama, Japan

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Akari Takahashi Department of Surgery, Yokohama City University, Yokohama, Japan

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Taku Masuda Department of Surgery, Yokohama City University, Yokohama, Japan

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Masami Goda Department of Surgery, Yokohama City University, Yokohama, Japan

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Tatsuya Yoshida Department of Surgery, Yokohama City University, Yokohama, Japan

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Norio Yukawa Department of Surgery, Yokohama City University, Yokohama, Japan

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Shoji Yamanaka Department of Surgical Pathology, Yokohama City University, Yokohama, Japan

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Yasushi Rino Department of Surgery, Yokohama City University, Yokohama, Japan

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Munetaka Masuda Department of Surgery, Yokohama City University, Yokohama, Japan

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Summary

Emergencies due to malignancies usually have a severe clinical course and require urgent treatment. These scenarios are dubbed ‘oncologic emergencies’. Parathyroid tumours often cause hypercalcaemia but not oncologic emergencies. We present a case of parathyroid carcinoma with severe hypercalcaemia and pancreatitis, resolved by surgical resection of the tumour assisted by extracorporeal membrane oxygenation (ECMO). A 66-year-old woman presented to our hospital because of haematuria. Laboratory findings were as follows: white blood cell count: 30 000, C-reactive protein: 17.7, calcium: 21.9, creatine kinase: 316, creatine kinase-myoglobin binding: 20, troponin I: 1415.8, amylase: 1046, lipase: 499, blood urea nitrogen: 57, and creatinine: 2.42. ECG was unremarkable. CT revealed a 4-cm low-density irregular tumour in the left lobe of the thyroid gland and severe pancreatitis. We diagnosed hypercalcaemia and pancreatitis due to parathyroid carcinoma. Volume expansion with isotonic saline was started immediately. Calcitonin, followed by denosumab, calcimimetic agents, and continuous hemodiafiltration were administered. The patient’s general condition worsened due to uncontrolled hypercalcaemia. Urgent tumour resection was planned, assisted with ECMO for cardiopulmonary support and surgical field venous pressure reduction. Tumour histology was suggestive of parathyroid carcinoma. Hypercalcaemia and the patient’s general condition improved gradually postoperatively. Hypercalcaemia is one of the oncologic emergency symptoms, commonly occurring because of lytic bone metastasis. However, reports about parathyroid carcinoma-causing life-threatening hypercalcaemia and pancreatitis are scarce; the fatality of this condition is estimated to be 30–70%. We report a case of survival of hypercalcaemia of malignancy.

Learning points

  • Parathyroid carcinoma is relatively rare and sometimes causes emergent conditions such as hypercalcaemia and severe pancreatitis.

  • General therapy for hypercalcaemia including aggressive saline dehydration, administration of furosemide, calcitonin, zoledronic acid, and evocalcet, and dialysis is sometimes ineffective for parathyroid carcinoma. Therefore, careful planning of therapy in case of exacerbation is important.

  • During an emergency, rapid surgical treatment despite high calcium level is the best potential therapeutic strategy.

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Tomoko Kobayashi Department of Endocrinology and Diabetes, Nagoya University Hospital, Nagoya, Japan

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Takuya Iwata Department of Endocrinology and Diabetes, Nagoya University Hospital, Nagoya, Japan

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Katsunari Handa Department of Endocrinology and Diabetes, Nagoya University Hospital, Nagoya, Japan

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Hiroshi Arima Department of Endocrinology and Diabetes, Nagoya University Hospital, Nagoya, Japan

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Summary

A 76-year-old female with type 2 diabetes mellitus presented with hematuria, low back pain, and intermittent fever for 7 days. She was admitted to our hospital and diagnosed with Streptococcus agalactiae (GBS) bacteremia. CT showed an air density within the right iliopsoas muscle, and an MRI of the spine revealed hyperintensity in the right half of the L1–L2 intervertebral disk, leading to the diagnosis of a paraspinal abscess and L1–L2 pyogenic spondylitis. Antibiotic therapy was started and the clinical symptoms, as well as serologic biomarkers and radiologic images of the paraspinal abscess, were improved. The therapy was stopped on day 72 despite vertebral destruction progression. Vertebral endplate ossification was observed on day 108, and further bone formation was noted on day 177. Our case study with radiologic findings over 6 months demonstrated how bone destruction with pyogenic spondylitis, which had been treated with antibiotic therapy, improved after cessation of antibiotics.

Learning points

  • Although GBS is a rare cause of spondylitis, diabetic mellitus is a risk factor for the development of invasive GBS infections, especially under poor glycemic control.

  • Bone destruction of pyogenic spondylitis can improve after discontinuation of antibiotic therapy.

  • It may be important to decide the period of antibiotic therapy based on clinical conditions, serologic biomarkers, and soft tissue findings rather than bone findings.

  • When elderly diabetic patients present with back pain and fever, spondylitis should be considered in the differential diagnosis to avoid potential diagnostic delays or misdiagnosis.

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Mudassir Ali Department of Endocrinology, Royal Victoria Infirmary, Newcastle Upon Tyne, UK

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Mona Abouzaid Department of Endocrinology, Royal Victoria Infirmary, Newcastle Upon Tyne, UK

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Lucy Clarke Department of Ophthalmology, Royal Victoria Infirmary, Newcastle Upon Tyne, UK

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Gordon Lau Department of Ophthalmology, Royal Victoria Infirmary, Newcastle Upon Tyne, UK

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Anna Mitchell Department of Endocrinology, Royal Victoria Infirmary, Newcastle Upon Tyne, UK

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Catherine Napier Department of Endocrinology, Royal Victoria Infirmary, Newcastle Upon Tyne, UK

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Simon Pearce Department of Endocrinology, Royal Victoria Infirmary, Newcastle Upon Tyne, UK

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Summary

This is a report of a rare case of Graves’ hyperthyroidism associated with severe bilateral Graves’ orbitopathy, in a patient with an anophthalmic eye socket. On clinical review her prosthetic eye (left eye) was tilting upwards, along with worsening of Graves’ orbitopathy (GO) in the only seeing eye. As she refused IV glucocorticoids, she was offered rituximab which only caused a transient improvement in the clinical activity score of the eye. She had persistent right upper lid retraction of 6 mm, associated with lagophthalmos. To protect her seeing eye from corneal ulceration, the patient received a botulinum toxin injection to the right upper eyelid to induce blepharoptosis as an interim measure prior to right upper eyelid blepharotomy in April 2021. This patient remains biochemically euthyroid on block and replace therapy and her TRAb level is falling over time. Treatment for active GO is ongoing and the patient required a redo blepharotomy for painful corneal exposure in the right eye.

Learning points

  • Graves’ orbitopathy (GO) does not actually primarily affect the eyeball itself but the orbital contents as well.

  • Patients with severe GO in an only seeing-eyed patient should be referred early to a multidisciplinary Joint Thyroid Eye clinic for expert review and management.

  • Patient outcomes including sight loss are likely to be improved by the extended range of medical and surgical treatment modalities available at specialist clinics treating GO, including the use of immunomodulatory drugs like rituximab or teprotumumab.

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Aneez Joseph Department of Endocrinology, Diabetes and Metabolism, Christian Medical College and Hospital, Vellore, India

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Kripa Elizabeth Cherian Department of Endocrinology, Diabetes and Metabolism, Christian Medical College and Hospital, Vellore, India

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Nitin Kapoor Department of Endocrinology, Diabetes and Metabolism, Christian Medical College and Hospital, Vellore, India

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Thomas V Paul Department of Endocrinology, Diabetes and Metabolism, Christian Medical College and Hospital, Vellore, India

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Summary

Tenofovir-induced osteomalacia secondary to proximal renal tubular dysfunction is not an uncommon complication known to occur. A 46-year-old woman was referred for the evaluation of osteoporosis which was diagnosed elsewhere. She had polyarthralgia, bony pains and proximal muscle weakness of 1 year duration. She was diagnosed to have HIV infection and was on antiretroviral therapy that consisted of tenofovir, lamivudine and efavirenz for the past 12 years. She had attained menopause 5 years back. On examination, she had bone tenderness, proximal myopathy and painful restriction of movement of her lower limbs. Investigations showed features of renal tubular acidosis, hypophosphatemia and raised alkaline phosphatase that were suggestive of osteomalacia. X-ray of the pelvis showed diffuse osteopenia and an MRI of the pelvis done showed multiple insufficiency fractures involving the head of femur on both sides. Following this, her tenofovir-based regimen was changed to abacavir, efavirenz and lamivudine with addition of neutral phosphate supplements and calcitriol. On follow-up after 6 months, she had significant improvement in her symptoms as well as in the bone mineral density at the lumbar spine (33.2%), femoral neck (27.6%), trabecular bone score (13.2%) and reduction in the buckling ratio at the narrow neck (6.3%), inter-trochanteric region (34%) and femoral shaft (28.8%). Tenofovir-induced osteomalacia is encountered in individuals on prolonged treatment with tenofovir. Treatment consists of changing to a non-tenofovir-based regimen, as well as supplementation of phosphate and calcitriol. Treatment results in remarkable improvement in symptoms and most densitometric indices.

Learning points

  • Tenofovir is a nucleotide reverse transcriptase inhibitor (NRTI) and is a major drug in the treatment of retroviral and hepatitis B infections.

  • Tenofovir-related hypophosphatemic osteomalacia is related to proximal tubulopathy and is not an uncommon occurrence.

  • Treatment mandates changing to a non-tenofovir-based regimen with supplementation of neutral phosphate and calcitriol.

  • Treatment results in a significant improvement in bone mineral density, trabecular bone score and hip geometric parameters.

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L Aliberti Department of Medical Sciences, Section of Endocrinology and Internal Medicine, University of Ferrara, Ferrara, Italy

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I Gagliardi Department of Medical Sciences, Section of Endocrinology and Internal Medicine, University of Ferrara, Ferrara, Italy

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M Pontrelli Department of Medical Sciences, Section of Endocrinology and Internal Medicine, University of Ferrara, Ferrara, Italy

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M C Zatelli Department of Medical Sciences, Section of Endocrinology and Internal Medicine, University of Ferrara, Ferrara, Italy

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M R Ambrosio Department of Medical Sciences, Section of Endocrinology and Internal Medicine, University of Ferrara, Ferrara, Italy

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Summary

Tumour-induced osteomalacia (TIO) is due to an overproduction of fibroblast growth factor 23 (FGF23) by mesenchymal tumours, causing hypophosphatemia, osteomalacia and muscle weakness. TIO is usually cured by tumour resection, but neoplasms may be unidentifiable and unresectable or the patient may refuse surgery. In these cases, medical treatment with oral phosphate and calcitriol is mandatory, but it is not fully effective and it is associated with low compliance. Burosumab, a human MAB against FGF23 employed to treat X-linked hypophosphatemia (XLH), has recently been approved for TIO in the USA. Maximum burosumab dose in XLH is 90 mg administered for 2 weeks; there are no data on clinical efficacy and safety of this dose in TIO. We reported the case of a 73 years old male with multiple non-traumatic fractures, low bone mineral density, pain and reduced independence of activities of daily living. Biochemical evaluation showed hypophosphatemia, high alkaline phosphatase (ALP) and C-terminal telopeptide (CTX) and normal albumin-corrected total calcium and parathyroid hormone. Tubular phosphate reabsorption was low (80%), whereas C-terminal tail of FGF23 (cFGF23) was elevated. A 68Ga-DOTATOC PET was performed, identifying a lesion in the first left rib. The patient refused surgery; therefore, burosumab therapy was started. After 18 months of treatment (maximum dose: 60 mg administered for 2 weeks), plasma phosphate normalized and ALP levels improved (138 U/L). Patient clinical symptoms as well as pain severity and fatigue improved. Neither adverse events nor tumour progression was reported during follow-up except for a painless fracture of the second right rib.

Learning points

  • Our case shows efficacy and safety of burosumab treatment administered every 2 weeks in a tumour-induced osteomalacia (TIO) patient.

  • After 18 months of treatment at a maximum dose of 60 mg every 2 weeks, we found plasma phosphate normalization and ALP reduction as well as improvement in clinical symptoms and fatigue.

  • Neither adverse events nor tumour progression was reported during follow-up, except for a painless fracture of the second right rib.

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Rikako Nakajima Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Motohiro Sekiya Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Yasuhisa Furuta Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Takafumi Miyamoto Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Masashi Sato Department of Gastroenterology, Faculty of Medicine, University of Tsukuba

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Kuniaki Fukuda Department of Gastroenterology, Faculty of Medicine, University of Tsukuba
Department of Gastroenterology, Kasumigaura Medical Center, 2-7-14 Shimotakatsu, Tsuchiura, Ibaraki, Japan

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Keiichiro Hattori Department of Hematology, Faculty of Medicine, University of Tsukuba

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Yasuhito Suehara Department of Hematology, Faculty of Medicine, University of Tsukuba

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Mamiko Sakata-Yanagimoto Department of Hematology, Faculty of Medicine, University of Tsukuba

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Shigeru Chiba Department of Hematology, Faculty of Medicine, University of Tsukuba

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Yuka Okajima Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Takashi Matsuzaka Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan
Transborder Medical Research Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Satoru Takase Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, the University of Tokyo, Bunkyo, Tokyo, Japan

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Mikio Takanashi Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, the University of Tokyo, Bunkyo, Tokyo, Japan

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Hiroaki Okazaki Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, the University of Tokyo, Bunkyo, Tokyo, Japan

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Yusuke Takashima Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Mikiko Yuhara Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Yuta Mitani Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Nako Matsumoto Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Yuki Murayama Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Mariko Ohyama Osawa Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Nami Ohuchi Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Daichi Yamazaki Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Sayuri Mori Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Yoko Sugano Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Yoshinori Osaki Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Hitoshi Iwasaki Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Hiroaki Suzuki Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Hitoshi Shimano Department of Endocrinology and Metabolism, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan

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Summary

In this study, we herein describe a 47-year-old Japanese woman who manifested inheritable non-alcoholic steatohepatitis (NASH) and severe dyslipidemia. Interestingly, her NASH progression was ameliorated by treatment with a sodium–glucose co-transporter 2 (SGLT2) inhibitor. This inheritability prompted us to comprehensively decode her genomic information using whole-exome sequencing. We found the well-established I148M mutation in PNPLA3 as well as mutations in LGALS3 and PEMT for her NASH. Mutations in GCKR may contribute to both NASH and dyslipidemia. We further mined gene mutations potentially responsible for her manifestations that led to the identification of a novel M188fs mutation in MUL1 that may be causally associated with her mitochondrial dysfunction. Our case may provide some clues to better understand this spectrum of disease as well as the rationale for selecting medications.

Learning points

  • While the PNPLA3 I148M mutation is well-established, accumulation of other mutations may accelerate susceptibility to non-alcoholic steatohepatitis (NASH).

  • NASH and dyslipidemia may be intertwined biochemically and genetically through several key genes.

  • SGLT2 inhibitors emerge as promising treatment for NASH albeit with interindividual variation in efficacy. Genetic background may explain the mechanisms behind the variation.

  • A novel dysfunctional mutation in MUL1 may lead to metabolic inflexibilities through impaired mitochondrial dynamics and function.

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