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Background Partial lipodystrophy (PL) syndromes are characterized by deficiency of subcutaneous fat, increased liver fat and insulin resistance (IR). Nonalcoholic fatty liver disease (NAFLD) is an important cause of morbidity and mortality in both PL and obesity. Hepatic lipid derives from re-esterification of free fatty acids (FFA) from adipose tissue lipolysis and dietary sources, as well as de novo lipogenesis. Hepatic TG can be used for energy by β-oxidation, stored in hepatocytes as lipid droplets or secreted as VLDL. Hepatosteatosis develops when the rate of intrahepatic TG production is greater than the rate of TG disposal (oxidation and secretion). Here we investigate the contributions of insulin resistance and adipose tissue to hepatic steatosis in patients with PL vs non-syndromic, obesity associated NAFLD (NAFLD). Methods Single-center retrospective analysis of subjects with NAFLD (N=73) and PL (N=28). Fibroscan Controlled Attenuated Parameter (CAP) was used to estimate liver fat. A1c, β-hydroxybutyrate, and circulating lipids by NMR were measured simultaneously and within 6 months of CAP measurement. Insulin resistance was estimated by HOMA-IR (fasting glucose x insulin ÷ 405) and LP-IR (a lipoprotein-based measure of IR derived from circulating lipid particles). Results The PL group was 86% female vs 48% in NAFLD (P Conclusions Patients with PL have comparable liver fat vs. non-syndromic NAFLD despite worse insulin resistance. To understand the lower liver fat relative to insulin resistance in PL, we examined input, oxidation, and export of lipid from the liver. Surprisingly, despite lower adipose mass in PL vs NAFLD, FFA input to the liver was similar. Hepatic fat oxidation and export, estimated by β-hydroxybutyrate and large VLDL respectively, were both higher in PL. This suggests a shift of fat storage out of the liver into the circulation in PL. Presentation: Saturday, June 11, 2022 1:18 p.m. - 1:23 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Inborn errors of immunity (IEIs) consist of numerous rare, inherited defects of the immune system that affect about 500,000 people in the United States. As advancements in diagnosis through genetic testing and treatment with targeted immunotherapy and bone marrow transplant emerge, increasing numbers of patients survive into adulthood posing fresh clinical challenges. A large spectrum of hepatobiliary diseases now present in those with immunodeficiency diseases, leading to morbidity and mortality in this population. Awareness of these hepatobiliary diseases has lagged the improved management of the underlying disorders, leading to missed opportunities to improve clinical outcomes. This review article provides a detailed description of specific liver diseases occurring in various inborn errors of immunity. A generalized approach to diagnosis and management of hepatic complications is provided, and collaboration with hepatologists, immunologists, and pathologists is emphasized as a requirement for optimizing management and outcomes.

Bile duct involvement is a key finding of primary biliary cholangitis (PBC). The aim of this study was to evaluate baseline ductopenia and disease progression.Retrospective longitudinal histological follow-up of treatment-naive patients with PBC.Eighty-three patients were included, with ductopenia correlated to fibrosis stage at baseline. The cumulative incidence of severe ductopenia remained stable after 5 years, whereas fibrosis continually increased over time. Baseline AST-to-Platelet Ratio Index and elevated alkaline phosphatase2 times the normal with abnormal bilirubin were associated with ductopenia progression.Bile duct injury does not seem to follow the same course as fibrosis in PBC.

Background Unintentional weight loss, ascites, and altered mental status typically raise concerns for hepatologic-cardiac-oncologic disease. Herein we present a case that after exhaustive workup the etiology of the aforementioned findings was attributed to a combination of anorexia and severe hypothyroidism, states where slowed metabolism and altered nutritional status can interact synergistically. Clinical Case A 71 y/o lady with a history of hypothyroidism after RAI for Graves’ disease, anxiety, depression, presented with 20-30 lbs unintentional weight loss over 5 months. She had poor appetite, nausea, constipation, increased abdominal girth, anasarca, fatigue, weakness, and altered mental status. On exam she had bradycardia, hypotension and hypothermia (BP 97/51, HR 54, RR 18, Temp 94, BMI 15.8). Labs revealed a TSH of 36, FT4 0.98, Tbili 0.3, alk phos 491, AST 435, ALT 651, gGT 151, albumin 2.3, prealbumin 14.7, INR 1.03, and pancytopenia. Treatment with IV levothyroxine resulted in mental status improvement. Over the next few months extensive testing revealed mild element deficiencies (zinc 44- nl range 60 - 130 mcg/dL, vit A 32- nl range 38 - 98 mcg/dL), no evident infectious/hematologic or inflammatory disease. Despite 3 paracenteses, 2 liver biopsies, multiple imaging studies (abdominal U/S, ECHO, XRs, CT chest/abdomen/pelvis, MRI abdomen/pelvis, enterography, MRI brain, PET scan), EGD/colonoscopy, bone marrow bx, and explorative laparoscopic abdominal surgery, no clear explanation was found. During the workup her liver enzymes remained elevated, TSH and fT4 normalized, but T3 remained low at 50 (76 - 181 ng/dL). Psychiatric evaluation revealed mild cognitive impairment, presumed to be secondary to depression and underlying disease. By exclusion, she was diagnosed with anorexia with a possible component of persistent hypothyroidism. She was fed through NG tube and followed closely by nutrition with a personalized high protein and calorie meal plan. Eight months later she had gained 5 lbs, her liver enzymes/electrolytes and CBC normalized, and most of her symptoms resolved. Conclusion Hypothyroidism can cause LFT abnormalities, and though rare, there are >50 cases of hypothyroidism induced ascites reported. Usually LFTs and ascites normalize promptly with hormone supplementation. However, our patient’s case was complicated by severe anorexia, with nutritional status essentially equivalent to kwashiorkor sufferers. Though extremely rare in the developed world and in adults, kwashiorkor like physiology has been described in patients with anorexia, with impressive liver abnormalities, presumed to be due to autophagy. Though certainly this is a rare diagnosis, it does point to the fact that in our test driven culture, it is worth pausing, re-evaluating history and physical and thinking outside the box prior to subjecting our patients to countless tests and procedures.

Background Leptin is an adipocyte-derived peptide hormone that acts in the hypothalamus to stimulate pathways that inhibit feeding and promote energy expenditure. Mutations in the gene encoding leptin or its receptor (LR) are rare and typically lead to extreme obesity. We describe a patient who presented with severe hypertriglyceridemia, non-alcoholic fatty liver (NAFL) and a clinical phenotype of partial lipodystrophy, who upon whole exome sequencing harbored a novel homozygous mutation in the Ig domain of the LR. Clinical case A 45-year-old woman with a past medical history of hypertension presented with abdominal pain and was diagnosed with hypertriglyceridemic pancreatitis. She denied alcohol or recreational drug use. Her BMI was 26 kg/m2, BP 167/109 mmHg, HR 106, and she had prominent central obesity with a paucity of adipose tissue on the extremities and gluteal region. Triglycerides (Tg) were 2,076 mg/dl, lipase 366 u/l, A1c of 6.0%, ALT 70 u/l, AST 27 u/l. Proteinuria was present, but serum and urine protein electrophoreses were normal. Abdominal CT was suggestive of liver steatosis and pancreatitis. Given her lipodystrophic features, elevated Tg, and fatty liver, we performed whole exome sequencing which revealed a novel homozygous mutation in the leptin receptor (p.S389N) that is predicted to be deleterious. Compared to other reported cases with LR mutations, our patient did not report excessive appetite and denied frequent childhood infections. Further workup showed low fasting leptin, 4.2 ng/ml (8.0-38.9 ng/ml for women with BMI 25-30s), fasting glucose of 114mg/dl and insulin of 21 ulU/ml. IGF-I was 141 ng/ml, FSH 4.6 mIU/mL, LH 3.8 U/ml, estradiol 60 pg/Ml, free testosterone 2.1 pg/ml, TSH 2.67 mlu/l, fT4 1.3ng/dl. Her family history was significant for pancreatitis in mother and maternal grandfather, nonalcoholic steatohepatitis (NASH) in her 14-year-old son and liver problems in her sister, but so far, no other members have been tested for the mutation. She was treated with fenofibrate for hypertriglyceridemia with subsequent decrease of Tg levels to 503 mg/dl. Conclusion Our case is unique in that our patient’s clinical features are less severe in comparison to those reported with other LR mutations. Given that this is a novel homozygous mutation in the Ig region of the LR, and it is predicted to be deleterious, it is still unclear how it relates to her lipodystrophic features and overall clinical presentation. This case highlights the gap in knowledge and the diversity in clinical presentations that may accompany LR mutations and would have been missed if it were not for whole exome sequencing. At the same time, this case raises questions regarding the role of the leptin in hypertriglyceridemia, NASH and NAFL, and to what degree emerging therapies for leptin deficiency can prevent the progression of NASH and NAFL disease, since currently there are no clear therapeutic guidelines.

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i’s) are the newest class of anti-hyperglycemic drugs. Their mechanism of action involves increasing urinary glucose excretion by preventing glucose reabsorption in the proximal renal tubules, yet they can also promote ketogenesis under certain circumstances. Numerous reports suggest an association between SGLT2i’s and diabetic ketoacidosis (DKA), but the medical literature remains sparse. Since the use of these drugs for diabetes has increased dramatically due to favorable cardiac outcomes, identification of patients at greatest risk for this life-threatening complication is essential. Therefore, in an effort to better understand the circumstances in which SGLT2i associated DKA occurs we reviewed all available cases at our hospital over a 5-year period. Patients and Methods: We retrospectively reviewed all cases of ketoacidosis associated with SGLT2i use at our hospital from 2013 to October 2018 using an electronic medical record search algorithm. Terms included canagliflozin, dapagliflozin, empagliflozin, SGLT2 inhibitors, metabolic acidosis, ketoacidosis, diabetes, and DKA. Patients that developed DKA without being treated with SGLT2i were excluded. Results: We identified 77 cases, 21 of which met criteria for DKA associated with SGLTi use. 64% were female and 36% were male, average age was 57.8 years, BMI 29.8 kg/m2, and mean diabetes duration was 11 years. The majority carried diagnoses of T2DM (94%) and 83.4% had no history of DKA prior to using an SGLT2i. The most common presenting symptoms were nausea, vomiting (38%), abdominal pain (28.5%) and altered mental status (19%). Common precipitants were poor oral intake (57.14%) and infection (23.8%). Average blood glucose concentrations at presentation were 329 + 36 mg/dl, interestingly, 52% of the episodes were euglycemic DKA (euDKA) with blood glucose

Introduction Sarcoidosis is a granulomatous disease that can affect multiple organ systems including the central nervous system in 5-15% of patients, yet it is a rare cause of intrasellar lesions (

Background The objective of the study was to better understand the impact of antitrypanosomal treatment on the evolution of Chagas-related, prognostically important electrocardiogram (ECG) abnormalities. Methods Initial and posttreatment ECGs were obtained in a prospective cohort of Chagas patients treated with nifurtimox or benznidazole and compared to an untreated cohort. Electrocardiogram disease progression was compared in those with and without baseline abnormalities pre- and posttherapy. Results Fifty-nine patients were recruited in the treatment arm and followed for an average of 3.9 years. There were no differences between ECG groups with regards to follow-up, age, baseline ejection fraction, or therapy. In the treated cohort, 0 of 30 patients with normal ECGs developed an abnormal ECG compared with 7 of 29 patients with baseline ECG abnormalities who developed new ECG abnormalities (P = .005). In an untreated cohort of 30 patients, 3 of 7 with normal ECGs developed an abnormality compared with 14 of 23 patients with baseline abnormalities (P = .67). Untreated patients had a higher likelihood of developing new EKG abnormalities (56.7% vs 11.9%, P < .001) despite shorter follow-up, and in a multivariate analysis adjusting for baseline EKG status across both treated and untreated cohorts, treated patients were still less likely to have progression of their EKG disease (odds ratio = 0.13, P < .001). The corrected QT (QTc) interval was not significantly affected by either study medication (415 vs 421 ms, initial vs posttreatment QTc; P = .06). Conclusions Over an average follow-up of 3.9 years, treated patients with normal baseline ECGs did not have significant changes during a course of treatment; however, those with baseline abnormal ECGs had significant progression of their conduction system disease despite treatment, and those without treatment also experienced a progression of ECG disease. These preliminary results suggest that Chagas patients with normal ejection fraction and normal ECG may benefit the most from antitrypanosomal treatment., In this study, we describe the evolution of electrocardiogram (ECG) changes in a contemporary United States-based cohort of treated patients, and we suggest that patients who already have prognostically important baseline ECG abnormalities will have continued progression of their conduction system disease despite antitrypanosomal pharmacotherapy.

Background: American College of Cardiology and American Heart Association guidelines recommend coronary angiography (CA) in all newly diagnosed patients with heart failure with reduced ejection fraction (HFrEF) as a screening method for obstructive coronary artery disease (CAD). This is a class IIa