ABSTRACT FGF21 is a hormone produced primarily by the liver with several metabolic functions, such as induction of heat production, control of glucose homeostasis, and regulation of blood lipid levels. Due to these actions, several laboratories have developed FGF21 analogs to treat patients with metabolic disorders such as obesity and diabetes. Here, we performed a systematic review and meta-analysis of randomized controlled trials that used FGF21 analogs and analyzed metabolic outcomes. Our search yielded 236 articles, and we included eight randomized clinical trials in the meta-analysis. The use of FGF21 analogs exhibited no effect on fasting blood glucose, glycated hemoglobin, HOMA index, blood free fatty acids or systolic blood pressure. However, the treatment significantly reduced fasting insulinemia, body weight and total cholesterolemia. None of the included studies were at high risk of bias. The quality of the evidence ranged from moderate to very low, especially due to imprecision and indirection issues. These results indicate that FGF21 analogs can potentially treat metabolic syndrome. However, more clinical trials are needed to increase the quality of evidence and confirm the effects seen thus far.

ABSTRACT Objective: Congenital hypopituitarism (CH) is a rare disease characterized by one or more hormone deficiencies of the pituitary gland. To date, many genes have been associated with CH. In this study, we identified the allelic variant spectrum of 11 causative genes in Turkish patients with CH. Materials and methods: This study included 47 patients [21 girls (44.6%) and 26 boys (55.4%)] from 45 families. To identify the genetic etiology, we screened 11 candidate genes associated with CH using next-generation sequencing. To confirm and detect the status of the specific familial variant in relatives, Sanger sequencing was also performed. Results: We identified 12 possible pathogenic variants in GHRHR, GH1, GLI2, PROP-1, POU1F1, and LHX4 in 11 patients (23.4%), of which six were novel variants: two in GHRHR, two in POU1F1, one in GLI2, and one in LHX4. In all patients, these variants were most frequently found in GLI2, followed by PROP-1 and GHRHR. Conclusion: Genetic causes were determined in only 23.4% of all patients with CH and 63% of molecularly diagnosed patients (7/11) from consanguineous families. Despite advances in genetics, we were unable to identify the genetic etiology of most patients with CH, suggesting the effect of unknown genes or environmental factors. More genetic studies are necessary to understand the etiology of CH.

ABSTRACT Objective: Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease and a growing global epidemic. In NAFLD, liver fat surpasses 5% of hepatocytes without the secondary causes of lipid accumulation or excessive alcohol consumption. Given the link between NAFLD and insulin resistance, the possible association between the rs2854744 (−202 G>T) promoter polymorphism of insulin-like growth factor binding protein 3 (IGFBP3) gene and NAFLD was investigated in this study. Materials and methods: In this genetic case-control association study, the IGFBP3 rs2854744 genotypes of 315 unrelated individuals, including 156 patients with biopsy-proven NAFLD and 159 controls, were determined using polymerase chain reaction/restriction fragment length polymorphism analyses. Results: The “GT+TT” genotype of the IGFBP3 rs2854744 polymorphism, compared with the “GG” genotype, was associated with a 2.7-fold increased risk of NAFLD after adjustment for confounding factors (P = 0.009; odds ratio [OR] = 2.71; 95% confidence interval [CI] = 1.19-3.18). Additionally, the IGFBP3 rs2854744 “T” allele, in comparison with the “G” allele, was significantly overrepresented in NAFLD patients than the controls (P = 0.008; OR = 1.85; 95%CI = 1.23-2.94). Conclusion: Our findings first indicated that the IGFBP3 rs2854744 “GT+TT” genotype is a marker of increased NAFLD susceptibility; however, it needs to be supported by further investigations in other populations.

ABSTRACT Bisphosphonates (BPs) are medications widely used in clinical practice to treat osteoporosis and reduce fragility fractures. Its beneficial effects on bone tissue have been consolidated in the literature for the last decades. They have a high affinity for bone hydroxyapatite crystals, and most bisphosphonates remain on the bone surface for a long period of time. Benefits of long-term use of BPs: Large and important trials (Fracture Intervention Trial Long-term Extension and Health Outcomes and Reduced Incidence with Zoledronic acid Once Yearly-Pivotal Fracture Trial) with extended use of alendronate (up to 10 years) and zoledronate (up to 6 years) evidenced significant gain of bone mineral density (BMD) and vertebral fracture risk reduction. Risks of long-term use of BPs: The extended use of antiresorptive therapy has drawn attention to two extremely rare, although severe, adverse events. That is, atypical femoral fracture and medication-related osteonecrosis of the jaw are more common in patients with high cumulative doses and longer duration of therapy. BPs have demonstrated safety and effectiveness throughout the years and evidenced increased BMD and reduced fracture risks, resulting in reduced morbimortality, and improved quality of life. These benefits overweight the risks of rare adverse events.

ABSTRACT Objective: To investigate nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) and hepatic fibrosis in biopsies of people with obesity who underwent bariatric surgery and examine the possible association of different variables with a diagnosis of NAFLD and NASH. Materials and methods: Epidemiological, clinical and laboratory data from 574 individuals with obesity of both genders seen by the same physician between 2003 and 2009 who had a liver biopsy during bariatric surgery were examined. Results: Of the 437 patients included, 39.8% had some degree of liver fibrosis, 95% had a histologic diagnosis of NAFLD, and the risk factors were age ≥ 28 years and Homeostatic Model Assessment (HOMA) ≥ 2.5 (p = 0.001 and p = 0.016, respectively). In the NAFLD group, NASH was present in 26% of patients and the associated factors were aspartate aminotransferase and alanine aminotransferase index (AST/ALT) > 1, high-density lipoprotein cholesterol (HDL-c) < 40 mg/dL, total cholesterol (TC) ≥ 200 mg/dL, gamma-glutamyl transferase (GGT) > 38 U/L and triglycerides (TG) levels > 150 mg/dL. The independent risk factors were low HDL-c, elevated AST/ALT and high TG. Conclusion: The variables associated with a diagnosis of NAFLD were HOMA ≥ 2.5 and age ≥ 28 years. NASH was associated with low HDL-c, high TG and AST/ALT ≤ 1.

ABSTRACT Objective: To study associations between polymorphisms in the angiotensin converting enzyme (ACE I/D), actinin 3 (ACTN3 R577X) and paraoxonase 1 (PON1 T(-107)C) genes and chronic diseases (diabetes and hypertension) in women. Materials and methods: Genomic DNA was extracted from saliva samples of 78 women between 18 and 59 years old used for genetic polymorphism screening. Biochemical data were collected from the medical records in Basic Health Units from Southern Brazil. Questionnaires about food consumption, physical activity level and socioeconomic status were applied. Results: The XX genotype of ACTN3 was associated with low HDL levels and high triglycerides, total cholesterol and glucose levels. Additionally, high triglycerides and LDL levels were observed in carriers of the TT genotype of PON1, and lower total cholesterol levels were associated to the CC genotype. As expected, women with diabetes/hypertense had increased body weight, BMI (p = 0.02), waist circumference (p = 0.01), body fat percentage, blood pressure (p = 0.02), cholesterol, triglycerides (p = 0.02), and blood glucose (p = 0.01), when compared to the control group. Conclusion: Both ACTN3 R577X and PON1 T(-107)C polymorphisms are associated with nutritional status and blood glucose and lipid levels in women with diabetes/hypertense. These results contribute to genetic knowledge about predisposition to obesity-related diseases.

ABSTRACT Objective: To explore the diagnostic value of the TUIAS (SW_TH01/II) computer-aided diagnosis (CAD) software system for the ultrasound Thyroid Imaging Reporting and Data System (TI-RADS) features in thyroid nodules. Materials and methods: This retrospective study enrolled patients with thyroid nodules in Shanghai East Hospital between January 2017 and October 2021. The novel CAD software (SW_TH01/II) and three sonographers performed a qualitative analysis of the ultrasound TI-RADS features in aspect ratio, margin irregularity, margin smoothness, calcification, and echogenicity of the thyroid nodules. Results: A total of 225 patients were enrolled. The accuracy, sensitivity, and specificity of the CAD software in “aspect ratio” were 95.6%, 96.2%, and 95.4%, in “margin irregularity” were 90.7%, 90.5%, and 90.9%, in “margin smoothness” were 85.8%, 88.5%, and 83.0%, in “calcification” were 83.6%, 81.7%, and 82.0%, in “homogeneity” were 88.9%, 90.6%, and 82.2%, in “major echo” were 85.3%, 88.0%, and 85.4%, and in “contains very hypoechoic echo” were 92.0%, 90.0%, and 92.4%. The analysis time of the CAD software was significantly shorter than for the sonographers (2.7 ± 1.6 vs. 29.7 ± 12.7 s, P < 0.001). Conclusion: The CAD system achieved high accuracy in describing thyroid nodule features. It might assist in clinical thyroid nodule analysis.

ABSTRACT Objective: COVID-19 is a multisystem immunoinflammatory disorder, and the hypothalamo–pituitary-adrenal (HPA) axis may be affected by SARS-CoV-2 as well as by steroid treatment during the illness. Information on the HPA axis after recovering from COVID-19, especially in those treated with steroids, is sparse. Hence, this study was performed to evaluate the hypothalamo-pituitary-adrenal axis during the post-COVID-19 period in patients treated with steroids during the illness. Subject and methods: This prospective study involved 60 patients aged 18-60 years who had recovered from moderate or severe COVID-19 and had received steroid treatment during the illness. The HPA axis was assessed with a low-dose (1 mcg) adrenocorticotropic hormone stimulation test at 3, 6 and 9 months in the post-COVID period. Results: The HPA axis was suppressed in 31.66% of the patients at 3 months and 5% at 6 months; however, all patients recovered at 9 months. Cumulative steroid use during the illness was inversely correlated with stimulated cortisol at 3 months in the post-COVID period. Fatigue was present in 58.33% of the patients at 3 months and was more prevalent in those with HPA axis suppression. Conclusion: Nearly one-third of the patients with moderate to severe COVID-19 who were treated with steroids had suppressed HPA axis at 3 months, with gradual recovery over a period of 9 months. Cumulative steroid equivalent dose, but not disease severity, was predictive of HPA axis suppression at 3 months.

ABSTRACT Objective: Follicular thyroid carcinoma (FTC) is less frequent but has a worse prognosis than papillary carcinoma. The available evidence on pre-operative characteristics of FTC is controversial. Our objective was to characterize the clinical, ultrasound and histopathological presentation of FTC patients treated Chile. Subjects and methods: Retrospective analysis of 97 patients treated for FTC in 6 large centers in Chile. We analyzed their ultrasonographic features and classified the nodules according to ATA risk of malignancy and TI-RADS score, as well as the cytological findings according to the Bethesda system. We described their clinical and histopathological findings at diagnosis and classified their risk of recurrence and mortality according to ATA 2015 recurrence risk category and the eighth edition of the AJCC/UICC staging system, respectively. Results: Median age was 48 years and 73.2% were females. The median diameter was 38.8 mm; only 9.5% of them were microtumors. According to ATA risk of malignancy, 86% of the nodules were low or intermediate suspicious, while 78% were category 3 or 4A nodules according to the TI-RADS. Regarding the Bethesda system, 65.9% had indeterminate cytology (20.6% category III and 45.3% category IV). At histological examination, most were minimally-invasive and angio-invasive tumors with less than 4 foci (54.7% and 28.4% respectively). More than 90% of FTC were unifocal and there was no lymphovascular or extrathyroidal invasion or lymph node involvement. Four patients (4.1%) had distant metastases at diagnosis. Most patients (95%) had stage I or II disease according to the AJCC/UICC staging system, while the risk of recurrence was low at 51.5% when using the ATA risk of recurrence scale. Conclusions: At diagnosis, most FTCs were nodules of low or intermediate suspicion at ultrasound, nearly two thirds had indeterminate cytology according to the Bethesda system, and nearly 50% of them were of low risk of recurrence.

SUMMARY Hypercalcemia is a frequent condition in clinical practice and when the most frequent causes are excluded, etiological diagnosis can be challenging. A rare cause of PTH-independent hypercalcemia is described in the present case report. A male adult with a history of androgenic-anabolic steroids abuse, and injection of mineral oil and oily veterinary compound containing vitamins A, D and E into muscles for local hypertrophy presented with hypercalcemia, nephrocalcinosis, and end-stage renal disease. On physical examination, the presence of calcified subcutaneous nodules and calcification of musculature previously infused with oily substances drew attention. Laboratory tests confirmed hypercalcemia of 12.62 mg/L, low levels of PTH (10 pg/mL), hyperphosphatemia (6.0 mg/dL), 25(OH)D of 23.3 ng/mL, and elevated 1,25(OH)2D (138 pg/mL). Imaging exams showed diffuse calcification of muscle tissue, subcutaneous tissue, and organs such as the heart, lung, and kidneys. The patient was diagnosed with PTH-independent hypercalcemia secondary to foreign body reaction in areas of oil injection. The patient underwent treatment with hydrocortisone for 10 days, single dose zoledronic acid and hemodialysis. He evolved with serum calcium levels of 10.4 mg/dL and phosphorus of 7.1 mg/dL. In addition, sertraline and quetiapine were prescribed to control body dysmorphic disorder. The medical community should become aware of new causes of hypercalcemia as secondary to oil injection since this should become increasingly frequent due to the regularity with which such procedures have been performed.

ABSTRACT Objective: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive metabolic disorder caused by mutations related to chylomicron metabolism. The objective of this study is to show the development and results of a screening program for FCS in Argentina. Materials and methods: A cross-sectional study was performed. All patients > 18 years with a triglyceride level ≥ 1,000 mg/dL in the period from January 1, 2017 to December 31, 2021 were included. The program was developed in three stages: (1) Review of electronic records and identification of suspected laboratory cases (triglyceride level ≥ 1,000 mg/dL); (2) Identification of suspected clinical cases (all suspected laboratory cases that had no relevant secondary factors) and application of the FCS score to define probable cases (score ≥ 10); (3) Perform genetic tests in probable cases. Results: Globally, 348 suspected laboratory cases (mean age of 49.9 years, 77.3% men) were included. The median triglycerides level was 1,309 mg/dL (interquartile range 1,175-1,607 mg/dL). In total, 231 patients were categorized as suspected clinical cases. After applying the FCS score, 3% of them were classified as “very likely FCS” (probable cases). Four variants of uncertain significance have been identified. No previously reported pathogenic variants were detected. Conclusion: This study shows a screening program for the detection of FCS. Although no patient was diagnosed with FCS, we believe that more programs of these characteristics should be developed in our region, given the importance of early detection of this metabolic disorder.

ABSTRACT Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is an autosomal recessive disorder caused by CYP21A2 gene mutations, and its molecular diagnosis is widely used in clinical practice to confirm the hormonal diagnosis. Hence, considering the miscegenation of the Brazilian population, it is important to determine a mutations panel to optimise the molecular diagnosis. The objective was to review the CYP21A2 mutations’ distribution among Brazilian regions.Two reviewers screened Brazilian papers up to February 2020 in five databases. The pair-wise comparison test and Holm method were used in the statistical analysis. Nine studies were selected, comprising 769 patients from all regions. Low proportion of males and salt-wasters was identified in the North and Northeast regions, although without significant difference. Large gene rearrangements also had a low frequency, except in the Center-West and South regions (p < 0.05). The most frequent mutations were p.I172N, IVS2-13A/C>G, p.V281L and p.Q318X, and significant differences in their distributions were found: p.V281L was more frequent in the Southeast and p.Q318X in the Center-West and Northeast regions (p < 0.05). Thirteen new mutations were identified in 3.8%-15.2% of alleles, being more prevalent in the North region, and six mutations presented a founder effect gene. Genotype-phenotype correlation varied from 75.9%-97.3% among regions. The low prevalence of the salt-wasting form, affected males and severe mutations in some regions indicated pitfalls in the clinical diagnosis. The good genotype-phenotype correlation confirms the usefulness of molecular diagnosis; however, the Brazilian population also presents significant prevalence of novel mutations, which should be considered for a molecular panel.

ABSTRACT Objective: Various studies have shown that diabetes mellitus (DM) increases the risk of thrombosis in the venous system as well as in the arterial system. In this study, it was aimed to evaluate the association between admission blood glucose levels and clinical severity, recurrence, and mortality in pulmonary embolism in patients with DM. Materials and methods: This study was designed as a retrospective cross-sectional study. Patients with DM who were admitted to a tertiary care hospital due to pulmonary embolism (PE) between 2014 and 2019 were included. Demographic characteristics, radiological findings, clinical class of embolism, and mortality data were retrieved from hospital records. Patients with and without recurrent disease, as well as patients who survived and died, were compared. Also, patients were classified according to quartiles of admission blood glucose levels. The quartiles were compared in terms of mortality, clinical, class, and recurrence. Results: Two hundred ninety-three patients with DM and PE were included in the study. Patients with adverse outcome had significantly higher admission blood glucose levels (respectively, 197.9 ± 96.30 mg/dL vs. 170.7 ± 74.26 mg/dL; p = 0.03). Patients in the third and fourth quartile of admission blood glucose levels (>152 mg/dL) had significantly more severe disease with a higher proportion of massive and sub-massive PE and higher pro-BNP levels (respectively, p = 0.01 and 0.02). Conclusion: Non-survived patients and recurrent disease were associated with higher admission blood glucose levels. Also, patients with admission blood glucose levels higher than 152 mg/dL tend to have clinically more severe diseases.

ABSTRACT Objective: The objective of this study was to verify the impact of carbohydrate counting (CC) on glycemic control and body weight variation (primary and secondary outcomes, respectively) between consultations in patients with diabetes mellitus (T1D) followed at a tertiary hospital in southern Brazil in a public health system environment. We also sought to investigate CC adherence. Materials and methods: This retrospective cohort study included 232 patients with T1D who underwent nutritional monitoring at a referral hospital for diabetes care between 2014 and 2018. To assess primary and secondary outcomes, data from 229 patients, 49 of whom underwent CC during this period and 180 individuals who used fixed doses of insulin, were analyzed. The impact of CC on glycemic control was assessed with the mean glycated hemoglobin (HbA1c) level at all consultations during the follow-up period. Results: In the model adjusted for the most confounders (except pregnancy), the mean HbA1c was better in the CC group (8.66 ± 0.4% vs. 9.36 ± 0.39%; p = 0.016), and body weight variation was lower (0.13 ± 0.28 kg vs. 0.53 ± 0.24 kg; p = 0.024). Adherence to CC was reported in 69.2% of consultations. Conclusion: CC optimized the glycemic control of individuals with T1D, resulting in less weight variation than in the fixed insulin dose group, which indicates that CC is an important care strategy for these patients.

ABSTRACT Postprandial hypoglycemia (PPH) is a complex and multifactorial complication of bariatric surgery (BS). PPH may cause severe symptoms or be asymptomatic. The treatment of this condition requires dietary changes, but severe cases require drug therapy. The number of therapeutic options is limited and are often associated with adverse side effects. Different classes of drugs have been used and tested, but the resolution of PPH remains a challenge for physicians and patients. In this review, we gathered articles on PPH after BS from PubMed searches (2001 to 2022) and focused on the main drugs tested for the treatment of this condition, such as acarbose, somatostatin analogues, type 2 sodium-glucose cotransporter inhibitors, calcium channel blockers, and liraglutide. Avexitide and glucagon pump are two new therapeutic options that have been recently tested. For the search, the terms “postbariatric hypoglycemia,” “bariatric surgery,” and “late dumping syndrome” were used. PPH after BS is a frequent condition that should always be evaluated after BS. Treatment should be individualized and the available therapeutic options may be useful based on the condition's pathophysiology.