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International Journal of Genomics 2024related hypertriglyceridemia occurs due to biallelic variants of this gene. Here, genotype-phenotype architecture of all pathogenic variants is investigated among...
related hypertriglyceridemia occurs due to biallelic variants of this gene. Here, genotype-phenotype architecture of all pathogenic variants is investigated among heterozygous and homozygous individuals. Clinical heterogeneity of various types of the variants is also described, and pancreatitis in more than half of homozygotes carrying chain-termination variants is highlighted as well. For this study, patients were selected who had a plasma triglyceride level above 250 mg/dL. The coding and intronic regions of the gene were amplified using the Sanger sequencing to investigate the presence of variants. The genotypes, lipid profiles, and detailed clinical features were documented for all -related patients and heterozygous individuals. Pathogenicity of the variants was predicted and categorized using available bioinformatics tools such as MutationTaster and PolyPhen-2 and ACMG criteria. MetaDome and Phyre2 were applied for structural and functional in silico analyses. 40% (12 out of 30) of variants were chain-termination (nonsense and frameshift) variants. These types of variants were determined in 60.53% of patients. 55% of these patients showed pancreatitis followed by lipemia retinalis (29%), abdominal pain (24%), hepatosplenomegaly (24%), and xanthomas (18%). The mean age of onset was about 22 years old. In at least 50% of 38 homozygous individuals, the TG level was more than 2000 mg/dL. More than 25% of heterozygous individuals showed at least one symptom. Pancreatitis and a severe form of HTG were found in 5 and 2% of heterozygous individuals, respectively. The main clinical features of -related hypertriglyceridemia include pancreatitis, lipemia retinalis, abdominal pain, hepatosplenomegaly, and xanthomas. Nonsense and frameshift homozygous variants usually lead to a severe form of hypertriglyceridemia. Pancreatitis is one of the main consequences of these types of mutations; thus, it is important to consider this point when evaluating asymptomatic individuals. Heterozygous individuals may become symptomatic due to the role of unknown modifying agent including environmental genetic factors.
PubMed: 38938447
DOI: 10.1155/2024/6653857 -
Journal of Pediatric Gastroenterology... Jun 2024The aim of our study was to assess the impact of the very early introduction of refeeding on the course of acute pancreatitis (AP) in children. Additionally, we...
OBJECTIVES
The aim of our study was to assess the impact of the very early introduction of refeeding on the course of acute pancreatitis (AP) in children. Additionally, we evaluated the effect of nutrition on inflammatory markers, including cytokines.
METHODS
This prospective randomised study was conducted in three university hospitals in Poland. Patients, aged 1-18 years with AP, were randomised into two groups: A-refeeding within 24 h of hospital admission (very early), and B-refeeding at least 24 h after admission (early nutrition). The severity of AP was assessed after 48 h. The serum concentrations of four cytokines (tumour necrosis factor α [TNFα], interleukin-1β [IL-1β], interleukin-6 [IL-6] and interleukin-8 [IL-8]) and C-reactive protein, as well as the activity of amylase, lipase and aminotransferases, were measured during the first 3 days of hospitalisation.
RESULTS
A total of 94 children were recruited to participate in the study. The statistical analysis included 75 patients with mild pancreatitis: 42-group A and 33-group B. The two groups did not differ in the length of hospitalisation (p = 0.22), AP symptoms or results of laboratory tests. Analysis of cytokine levels was conducted for 64 children: 38-group A and 26-group B. We did not find a difference in concentrations of the measured cytokines, except for IL-1β on the third day of hospitalisation (p = 0.01).
CONCLUSIONS
The time of initiation of oral nutrition within 24 h (very early) or after 24 h (early) from the beginning of hospitalisation had no impact on the length of hospitalisation, concentrations of TNF-α, IL-1β, IL-6 and IL-8, activity of amylase and lipase or occurrence of symptoms in children with mild AP.
PubMed: 38938000
DOI: 10.1002/jpn3.12301 -
Pancreatology : Official Journal of the... Jun 2024The impact of chronic pancreatitis (CP) on quality of life (QOL) of children is not well established. Our objective was to evaluate the QOL, identify contributing...
BACKGROUND AND OBJECTIVES
The impact of chronic pancreatitis (CP) on quality of life (QOL) of children is not well established. Our objective was to evaluate the QOL, identify contributing factors, and determine the prevalence of anxiety and depression in children with CP in India.
METHODS
Children (8-18y old) with CP were prospectively enrolled across three pediatric gastroenterology centres in India. QOL was assessed using the pediatric QOL inventory (PedsQL 4.0) scale, administered to both children and their parents. Anxiety and depression was studied using the Revised Children's Anxiety and Depression Scale (RCADS 25). Contributing factors were identified using binary logistic regression analysis. The data was compared against published QOL data in healthy Indian children.
RESULTS
121 children with CP (boys-57.9 %, age at QOL-14 ± 3.2years) were enrolled. A majority (82.7 %) had pain and advanced disease (Cambridge grade IV- 63.6 %). Children with CP had poorer QOL compared to controls (total score 74.6 ± 16 vs. 87.5 ± 11.1, p < 0.0001). QOL scores were similar across centres. Older children were similar to younger ones, except for a poorer emotional QOL. Taking QOL < -2 standard deviation (SD) of controls, ∼35 % had poor physical (50.9 ± 11.9) and 20 % had poor psychosocial (PS) QOL score (52.1 ± 7.2). On analysis, presence of pain and lower socio-economic status (SES) adversely affected both physical and PS-QOL. Additionally, girls had poorer PS-QOL than boys (Odds ratio 3.1, 95%CI:1.23-7.31). Anxiety and depression were uncommon (2,1.6 %).
CONCLUSIONS
Patients with CP had impaired physical and psycho-social QOL. Presence of pain and lower SES adversely affected QOL. Psychiatric comorbidities were uncommon.
PubMed: 38937206
DOI: 10.1016/j.pan.2024.06.009 -
Science (New York, N.Y.) Jun 2024Inflammation and tissue damage associated with pancreatitis can precede or occur concurrently with pancreatic ductal adenocarcinoma (PDAC). We demonstrate that in PDAC...
Inflammation and tissue damage associated with pancreatitis can precede or occur concurrently with pancreatic ductal adenocarcinoma (PDAC). We demonstrate that in PDAC coupled with pancreatitis (ptPDAC), antigen-presenting type I conventional dendritic cells (cDC1s) are specifically activated. Immune checkpoint blockade therapy (iCBT) leads to cytotoxic CD8 T cell activation and elimination of ptPDAC with restoration of life span even upon PDAC rechallenge. Using PDAC antigen-loaded cDC1s as a vaccine, immunotherapy-resistant PDAC was rendered sensitive to iCBT with elimination of tumors. cDC1 vaccination coupled with iCBT identified specific CDR3 sequences in the tumor-infiltrating CD8 T cells with potential therapeutic importance. This study identifies a fundamental difference in the immune microenvironment in PDAC concurrent with, or without, pancreatitis and provides a rationale for combining cDC1 vaccination with iCBT as a potential treatment option.
Topics: Animals; Mice; Cancer Vaccines; Carcinoma, Pancreatic Ductal; CD8-Positive T-Lymphocytes; Dendritic Cells; Immune Checkpoint Inhibitors; Immunotherapy; Mice, Inbred C57BL; Pancreatic Neoplasms; Pancreatitis; Tumor Microenvironment
PubMed: 38935717
DOI: 10.1126/science.adh4567 -
Current Opinion in Gastroenterology Jun 2024Diabetes mellitus (DM) is relatively common following acute pancreatitis (AP), even after mild acute pancreatitis (MAP), the most frequent AP presentation, in which...
PURPOSE OF REVIEW
Diabetes mellitus (DM) is relatively common following acute pancreatitis (AP), even after mild acute pancreatitis (MAP), the most frequent AP presentation, in which there is no overt beta cell injury. Post-AP related diabetes is widely misdiagnosed, resulting in potentially inappropriate treatment and worse outcomes than type 2 diabetes (T2D). Thus, it is important to understand risk across the spectrum of AP severity.
RECENT FINDINGS
Biological mechanisms are unclear and may include local and systemic inflammation leading to beta cell dysfunction and insulin resistance, altered gut barrier and/or gut peptides and possibly islet autoimmunity, though no studies have specifically focused on MAP. While studies examining clinical risk factors on MAP exclusively are lacking, there are studies which include MAP. These studies vary in scientific rigor, approaches to rule out preexisting diabetes, variable AP severity, diagnostic testing methods, and duration of follow-up. Overall, disease related factors, including AP severity, as well as established T2D risk factors are reported to contribute to the risk for DM following AP.
SUMMARY
Though numerous studies have explored risk factors for DM after AP, few studies specifically focused on MAP, highlighting a key knowledge gap that is relevant to the majority of patients with AP.
PubMed: 38935336
DOI: 10.1097/MOG.0000000000001055 -
Current Opinion in Gastroenterology Jun 2024The burdens of pancreatic ductal adenocarcinoma (PDAC) and acute pancreatitis are increasing globally. We reviewed current literature on whether acute pancreatitis is a...
PURPOSE OF REVIEW
The burdens of pancreatic ductal adenocarcinoma (PDAC) and acute pancreatitis are increasing globally. We reviewed current literature on whether acute pancreatitis is a causal factor for PDAC and examined clinical manifestations of PDAC-associated acute pancreatitis.
RECENT FINDINGS
Recent findings detail the timing of acute pancreatitis before and after PDAC occurrence, further solidifying the evidence for PDAC-associated acute pancreatitis and for acute pancreatitis as a causal risk factor for PDAC. The risk of PDAC remains elevated above the general population in patients with distant history of acute pancreatitis. PDAC risk also increases with recurrent acute pancreatitis episodes, independent of smoking and alcohol. Mechanisms linking acute pancreatitis to PDAC include inflammation and neutrophil infiltration, which can be attenuated by suppressing inflammation and/or epigenetic modulation, thus slowing the progression of acinar-to-ductal metaplasia. Clinical presentation and management of acute pancreatitis in the context of PDAC are discussed, including challenges acute pancreatitis poses in the diagnosis and treatment of PDAC, and novel interventions for PDAC-associated acute pancreatitis.
SUMMARY
PDAC risk may be reduced with improved acute pancreatitis prevention and treatment, such as antiinflammatories or epigenetic modulators. Increased acute pancreatitis and PDAC burden warrant more research on better diagnosis and management of PDAC-associated acute pancreatitis.
PubMed: 38935270
DOI: 10.1097/MOG.0000000000001051 -
British Journal of Haematology Jun 2024Studies on asparaginase enzyme activity (AEA) monitoring in Chinese patients receiving PEG-asparaginase remain limited. We monitored AEA in paediatric patients diagnosed...
The correlation of asparaginase enzyme activity levels after PEG-asparaginase administration with clinical characteristics and adverse effects in Chinese paediatric patients with acute lymphoblastic leukaemia.
Studies on asparaginase enzyme activity (AEA) monitoring in Chinese patients receiving PEG-asparaginase remain limited. We monitored AEA in paediatric patients diagnosed with acute lymphoblastic leukaemia (ALL) and treated according to the Chinese Children's Cancer Group study protocols, CCCG-ALL-2015/CCCG-ALL-2020 protocols. We measured the AEA at days 7 ± 1 and 14 ± 1 and analysed their association with patient characteristics and PEG-asparaginase-related adverse effects (AEs). We measured 2147 samples from 329 patients. Mean AEA levels (interquartile range) were 931 iu/L (654-1174 iu/L) at day 7 ± 1 and 664 iu/L (463-860 iu/L) at day 14 ± 1. The AEA levels were higher in younger children and increased with the cumulative dose numbers. PEG-asparaginase inactivation rate was 19.1%, and the silent inactivation (SI) rate was 12.5%. Nine patients were identified with allergic-like reactions. Hypofibrinogenaemia, hypertriglyceridaemia, pancreatitis and thrombosis were associated with older age, whereas hypoglycaemia was associated with younger age. The risk of hypertriglyceridaemia and hypoglycaemia increased with cumulative dose numbers of PEG-asparaginase. Except for hypofibrinogenaemia, elevated AEA levels did not increase the risk of PEG-asparaginase-related AEs. Drug monitoring can be utilized as guidance for treatment decision-making. Individualizing asparaginase doses do not reduce toxicities. The treatment target of PEG-asparaginase remains to achieve sustained and adequate activity.
PubMed: 38934331
DOI: 10.1111/bjh.19605 -
Molecular Genetics and Metabolism... Sep 2024Hypertriglyceridemia (HTG) is a common dyslipidemia associated with an increased risk of cardiovascular disease and pancreatitis. It is well stablished that the severe...
Hypertriglyceridemia (HTG) is a common dyslipidemia associated with an increased risk of cardiovascular disease and pancreatitis. It is well stablished that the severe cases of disease often present with an underlying genetic cause. In this study, we determined the frequency and variation spectrum of genes involved in the triglyceride metabolism in a series of Brazilian patients with severe HTG. A total of 212 patients with very high HTG, defined with fasting triglycerides (TG) ≥ 880 mg/ dL, that underwent a multi-gene panel testing were included in this research. Germline deleterious variants (i.e. Pathogenic/Likely Pathogenic (P/LP) variants) were identified in 28 out of 212 patients, reflecting an overall diagnostic yield of 13% in our cohort. Variants of unknown significance (VUS) were identified in 87 patients, and represent 80% of detected variants in this dataset. We confirm the as the most frequently mutated gene in patients with severe HTG, and we had only one suspected case of familial chylomicronemia syndrome, caused by a homozygous variant in in our cohort. Notably, we report 16 distinct and novel variants (P/LP and VUS), each of them representing a single case, not previously reported in any public databases or other studies. Our data expand our knowledge of genetic variation spectrum in patients with severe HTG in the Brazilian population, often underrepresented in public genomic databases, being also a valuable clinical resource for genetic counseling and healthcare programs in the country.
PubMed: 38933898
DOI: 10.1016/j.ymgmr.2024.101100 -
Journal of Diabetes and Metabolic... Jun 2024In recent years, new hypoglycaemic drugs that affect the incretin system have become increasingly popular in the treatment of type 2 diabetes mellitus (T2DM):... (Review)
Review
OBJECTIVES
In recent years, new hypoglycaemic drugs that affect the incretin system have become increasingly popular in the treatment of type 2 diabetes mellitus (T2DM): glucagon-like receptor 1 agonists (GLP1RAs), dipeptidyl peptidase 4 inhibitors (DPP4is) and the recently developed dual glucagon-like receptor 1 agonist and glucose-dependent insulinotropic polypeptide (tirzepatide). Their main role of these drugs is to normalise blood glucose levels. In addition, GLP1RAs are approved for the treatment of excessive body weight. The efficacy of drugs affecting the incretin system is well described in the literature, however, there are still only few reports about their safety. This review aims to summarize the results of current research and meta-analyses on risk of acute pancreatitis (AP) during incretin-affecting drugs treatment.
METHODS
A narrative review was performed using present literature in an attempt to identify the relationship between AP and incretin-affecting drugs. The following keywords were used: acute pancreatitis, glucagon-like receptor 1 agonists, dipeptidyl peptidase 4 inhibitors and tirzepatide.
RESULTS
It was demonstrated that the use of DPP4is is safe for the majority of patients with T2DM, whereas a risk of AP should be noted in case of GLP1RAs therapy. To date, most studies found no significant association between tirzepatide therapy and the increased risk of AP.
CONCLUSION
The majority of studies have shown that DPP4is, GLP1RAs and tirzepatide are effective and safe in most T2DM patients. However, the follow-up time for patients treated with tirzepatide is short, therefore more studies are required to confirm the safety of this drug.
PubMed: 38932809
DOI: 10.1007/s40200-024-01430-6 -
Journal of Clinical Medicine Jun 2024: Acute pancreatitis (AP) is characterized by pancreatic gland inflammation, and its clinical course ranges from mild to severe. Predicting the severity of AP early and...
Comparison of Controlling Nutritional Status Score with Bedside Index for Severity in Acute Pancreatitis Score and Atlanta Classification for Mortality in Patients with Acute Pancreatitis.
: Acute pancreatitis (AP) is characterized by pancreatic gland inflammation, and its clinical course ranges from mild to severe. Predicting the severity of AP early and reliably is important. In this study, we investigate the potential use of the Controlling Nutritional Status (CONUT) score as a prognostic marker in acute pancreatitis. : We examined 336 patients who had been hospitalized with an AP diagnosis in the internal medicine clinic. The patients included in the study were followed up for 5 years. The study analyzed the specific variables of age, gender, and AP etiology as recorded biochemical parameters for all study participants and calculated the effects of age, sex, Bedside Index of Severity in AP (BISAP), the revised Atlanta classification, and the CONUT score on mortality. : When compared with surviving patients, non-surviving patients had higher scores for BISAP, CONUT, and the Atlanta Classification ( 0.001). In the non-surviving group, hemoglobin, lymphocyte, and albumin levels were significantly lower and creatinine, uric acid, and procalcitonin levels were significantly higher compared to the surviving group ( ˂ 0.001, 0.003, ˂0.001, ˂0.001, 0.005, ˂0.001, respectively). The multivariate analysis showed a significant association of mortality with age, CONUT, and BISAP scores ( ˂ 0.003, 0.001, 0.012 respectively). The CONUT score was separated into two groups based on the median value. The predicted survival time in the group with a CONUT score > 2 (53.8 months) was significantly lower than in the group with a CONUT score ≤ 2 (63.8 months). The cumulative incidence of all-cause mortality was significantly higher in the patients with higher CONUT scores. : This study has assigned the CONUT score as an independent risk factor for mortality in AP.
PubMed: 38929944
DOI: 10.3390/jcm13123416