Short chain fatty acids significantly decreased the degree of reperfusion injury in the gut in a rat model of mesenteric ischemia reperfusion.

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Introduction: Hypogonadotropic hypogonadism is a common disorder encountered in endocrine practice with a prevalence of 1 in 10,000 men (1). We describe a patient with possible mitochondrial mutation causing him to have concurrent central hypogonadism and NARP syndrome (neuropathy, ataxia, retinitis pigmentosa). Case: 65 year old male with central hypogonadism diagnosed at age 17 was on testosterone replacement therapy off and on since then. He was diagnosed with NARP at age 49. On exam, he was OX3, BP 147/83mmHg, HR 63 bpm, wt 185lbs. Pupils were sluggish to light. Unable to assess visual fields as patient is legally blind. No gynecomastia. Cardiac and pulmonary exam were normal. Testicles were soft and the volume was 12mL. Prostate was enlarged, non tender and without nodules. He had ataxic gait, abnormal finger to nose test and strength was normal. LH <0.2 mIU/ml (N 1.2 - 10.6 mIU/ml), FSH < 0.2 mIU/ml (N 0.7 - 10.8mIU), total testosterone as low as 12ng/dL when off and 260ng/dL (N 250-1110ng/dL) while on testosterone IM. CBC, CMP, prolactin, ACTH, cortisol, Igf-I, TSH and PSA wnl. MRI brain showed cerebellar atrophy and normal pituitary. Discussion: NARP is a mitochondrial disorder characterized by neuropathy, ataxia and retinitis pigmentosa primarily affecting the nervous system. NARP results from point mutation at base pair 8993 of the mitochondrial genome in the ATPase 6 gene. Symptoms typically consist of proximal neurogenic muscle weakness, sensory neuropathy, ataxia, and retinitis pigmentosa. According to Al-Gadi et al, hypogonadism has been reported in mitochondrial disease (2). RRM2B is a nuclear-encoded mitochondrial maintenance gene. Mitochondrial DNA depletion due to ar-RRM2B mutations have been reported in association with hypogonadism. A mutation of m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotrophic hypogonadism has also been reported in a case report of two patients (3). Upon literature review, no prior cases of hypogonadotropic hypogonadism in patients with NARP have been reported. The impairment of the hypothalamic-pituitary axis appears to manifest in severe mitochondrial phenotypes. For example, the association of central hypogonadism with Kearns Sayre Syndrome (KSS). Given that both disorders are related to mitochondrial dysfunction, we propose that the hypogonadism may be linked to NARP syndrome. References Rohayem, J.et al. (2016), Causes of hypogonadotropic hypogonadism predict response to gonadotropin substitution in adults. Andrology Al-Gadi.et al. (2018). Endocrine Disorders in Primary Mitochondrial Disease. JES Kytövuori, L. et al. (2016, August 8). A novel mutation m.8561C>G in MT- ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.

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Introduction: Pembrolizumab t is used to treat various cancers. It is associated with immune related adverse events (IRAEs) that can be life threatening [1,4]. We describe a patient who presented autoimmune Diabetes after the use of Pembrolizumab. Case: 64 y/o African American female PMHX of lung non-small cell lung cancer diagnosed in 2017 Clinical stage IV with gluteal metastasis, and dementia. Pt was referred by Oncology. The patient had a family history of Type 1 DM. and complained of dizziness, and unintentional weight loss (30 pounds) over a year. She had received 2 cycles of Pembrolizumab. The last cycle given 5 weeks before presentation to Endocrinology.Physical examination revealed cachectic female (weight 35 kg, height 147cm), dry mouth, BP 135/82, Plasma glucose 383mg%, A1c 7, negative Islet cell antibodies, positive anti-GAD, undetectableserum C-peptide. Cortisol 27, Acth 21 at 8 am and TSH 2.3. Discussion: In a systematic literature review, the early pattern of Diabetes onset with the use of checkpoint inhibitors was evaluated and on average after 4.5 treatment cycles [4].The incidence of immune checkpoint inhibitor-induced Type 1 Diabetes is estimated at 1% [3].This appeared to be earlier for the combination of anti-cytotoxic T-Lymphocyte associated antigen 4 monoclonal antibody and PD-1 therapy. The onset of β cell inflammation is often fulminant, suggested by the relatively low glycated hemoglobin levels, while C-peptide levels are usually low or undetectable at diagnosis and mostly positive GAD antibodies [5]. This side effect is predominantly found in patients exposed to blockade of the PD-1/PD-Ligand pathway. The IRAEs are primarily managed by immunosuppression with corticosteroids and discontinuation of immunotherapy except in autoimmune Diabetes which is irreversible. Physicians should be aware of and patients educated about the important multiorgan side effects since a growing number of patients are treated with checkpoint blockade.Azoury SC, Straughan DM, Shukla V. Immune checkpoint inhibitors for cancer therapy: clinical efficacy and safety. Curr Cancer Drug Targets 2015;15: 452-462Weber JS, Postow M, Lao CD, et al. Management of adverse events following treatment with anti-programmed death-1 agents. Oncologist 2016;21:1230-40Stamatouli AM, Quandt Z, Perdigoto AL, Clark PL, Kluger H,Weiss SA et al Collateral damage: insulin-dependent diabetes induced with checkpoint inhibitors. Diabetes 2018;67(8):1471-1480de Filette JMK, Pen JJ, Decoster L, et al. Immune checkpoint inhibitors and Type 1 Diabetes mellitus: a case report and systematic review. Eur J Endocrinol. 2019;181(3):363–374.Akturk HK, Kahramangil D, Sarwal A, Hoffecker L, Murad MH, Michels AW. Immune checkpoint inhibitor-induced Type 1 Diabetes: a systematic review and meta-analysis. Diabet Med. 2019;36(9):1075–1081.