The incidence of new mental health disorders after acute pancreatitis: A large, propensity-matched, observational study.

INTRODUCTION: The prevalence of acute pancreatitis (AP) and mental health disorders (MHDs) are rising. While the association between chronic pancreatitis (CP) and MHDs is established, it is unknown whether there is a risk of MHDs after an index episode of AP. The aim of this study was to evaluate the incidence of MHDs and pharmacotherapy use after an episode of AP. METHODS: This was a large observational study using the TriNetX research network, an electronic health record dataset containing inpatient and outpatient data from more than 50 healthcare organizations. Patients with AP from 2015-2020 were identified. Four cohorts were created: acute necrotizing pancreatitis (ANP), acute pancreatitis without necrosis (AP-WON), acute appendicitis, and healthy controls without pancreatitis. The cohorts were matched by age, sex, race, ethnicity, and nicotine and alcohol use. The primary outcome was new composite MHDs at one-year. Secondary outcomes included stratified MHDs, psychiatric medication use, opioid analgesic use, and all-cause mortality. RESULTS: The ANP, AP-WON, appendicitis, and healthy control cohorts contained 11,806, 177,266, 27,187, and 561,833 patients, respectively. Patients with AP-WON had significantly higher rates of composite MHDs compared with those hospitalized for appendicitis (9.7% vs 4.7%, HR 1.9, 95% CI 1.7-1.9). This association was augmented when comparing ANP to appendicitis (12.8% vs 5.2%, HR 2.4, 95% CI 2.1-2.7). All secondary outcomes were observed at significantly higher rates in the AP-WON cohort when compared to appendicitis. Again, these associations were augmented comparing ANP to appendicitis. CONCLUSION: Compared with controls, patients with AP had significantly higher rates of new MHDs and their associated pharmacotherapies at one-year, suggesting that a single episode of AP may independently place patients at risk for developing MHDs irrespective of whether they go on to develop CP.

Risk Factors and Outcomes of Intracardiac Thrombosis During Orthotopic Liver Transplantation.

BACKGROUND: Intracardiac thrombosis incidence during orthotopic liver transplantation is estimated at 0.36% to 6.2% with mortality up to 68%. We aimed to evaluate risk factors and outcomes related to intracardiac thrombosis during orthotopic liver transplantation. MATERIALS AND METHODS: A comprehensive retrospective data review of 388 patients who underwent orthotopic liver transplantation at an urban transplant center from January 2013 to October 2016 was obtained. RESULTS: Six patients were found to have documented intracardiac thrombosis; 4 cases were recognized during the reperfusion stage and 1 during pre-anhepatic stage. All allografts were procured from decreased donors with a median donor age of 44 years (interquartile range, 35.25-49.75) and the cause of death was listed as cerebrovascular accident in 5 donors. Preoperative demographic, clinical, laboratory, and historical risk factors did not differ in patients with thrombosis. None had a prior history of trans-jugular intrahepatic portosystemic shunt or gastrointestinal bleeding. Three patients had renal injury, but no intraoperative hemodialysis was performed. Transesophageal echocardiographic findings included elevated pulmonary artery pressure (1/6), right ventricular strain (1/6), and pulmonary artery thrombus (1/6). Three patients died intraoperatively. Tissue plasminogen activator alone was given to 1 patient who did not survive, intravenous heparin only to 1 patient with resolution, and a combination of both was used in 2 patients with clot resolution achieved. CONCLUSION: Cardiac thrombosis should be considered in patients having hemodynamic compromise during liver transplantation. Transesophageal echocardiography is a useful diagnostic tool. Intracardiac thrombosis treatment remains challenging; however, using both thrombolytics and heparin could achieve better results.

Management of Direct-Acting Antiviral Failures.

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Novel Therapies in Hepatic Encephalopathy.

Despite widespread use of lactulose and rifaximin for the treatment of hepatic encephalopathy, this complication of advanced liver disease remains a major burden on the health care system in the United States and continues to predispose to high morbidity and mortality. Several agents have surfaced over recent years with promise to treat hepatic encephalopathy and mitigate the cognitive impairment associated with this disease process. The purpose of this article is to highlight the leading emerging therapies in hepatic encephalopathy as well as their therapeutic targets.

Acute Kidney Injury in Patients Undergoing Chronic Hepatitis C Virus Treatment With Ledipasvir/Sofosbuvir.

Ledipasvir-sofosbuvir, a once-a-day, oral combination pill, was approved in 2014 for the treatment of chronic hepatitis C infection. Initial trials did not comment on nephrotoxicity; however, recent data suggest a risk of acute kidney injury (AKI) with the use of the medication. We assessed the rates of AKI in patients undergoing ledipasvir-sofosbuvir in a large, urban tertiary care center. This single-center retrospective observation study included all patients undergoing therapy from October 1, 2014, to October 1, 2015. Rates of AKI, defined by more than a 0.3 mg/dL increase in serum creatinine level, were calculated. Patients were followed 12 weeks after therapy to assess for sustained viral response as well as to assess for improvement of AKI after completion of therapy, defined by less than 0.2 mg/dL above baseline serum creatinine. In total, 197 patients were included in the final analysis who had completed ledipasvir-sofosbuvir therapy and completed laboratory values. Among the patients treated, 38 (19%) had AKI during therapy. An additional 4 (2%) had AKI at the end of therapy. Of the 38 patients who experienced AKI, 20 (53%) had improvement in serum creatinine to less than 0.2 mg/dL above their baseline. When comparing for chronic kidney disease (CKD) stage, those with CKD I or II experienced AKI 17% of the time compared with 47% of the time in CKD III or worse (P = 0.005). Conclusion: AKI was seen in nearly one-fifth of our patients, and patients with CKD stage III or worse are at increased risk. Although ledipasvir-sofosbuvir is generally safe in the general population, close monitoring of renal function is recommended.

A Perplexing Case of Abdominal Pain That Led to the Diagnosis of Zollinger-Ellison Syndrome.

Zollinger-Ellison syndrome (ZES) is a rare clinical disorder, characterized by hypersecretion of gastric acid and multiple ulcers distal to the duodenal bulb. This occurs via the release of gastrin by neuroendocrine tumors known as gastrinomas. Patients with ZES present with nonspecific GI symptoms, which often leads to a delay in diagnosis. Our patient is a 55-year-old female with chronic abdominal pain, nausea, and diarrhea. She underwent EGD, EUS, MRCP, CT scans, and cholecystectomy, which did not reveal the cause of her symptoms. Repeat EGD showed a cratered ulcer in the second portion of the duodenum, suspicious for ZES. Serum gastrin was initially only moderately elevated while on PPI therapy, but chromogranin A was also elevated. Repeat gastrin level after stopping PPI therapy was 1639 pg/mL. Somatostatin receptor scintigraphy was obtained, which showed two small lesions in the gastrinoma triangle. She subsequently underwent a Whipple pancreaticoduodenectomy and pathology was positive for four microscopic foci of a neuroendocrine tumor. She reported improvement in her symptoms after surgery. This case highlights the need for increased awareness of ZES in patients with unexplained GI complaints and emphasizes the use of multiple modalities in the diagnosis of ZES.

Predictors of delayed failure of structural kyphoplasty for pathological compression fractures in cancer patients.

OBJECT Pathological compression fractures in cancer patients cause significant pain and disability. Spinal metastases affect quality of life near the end of life and may require multiple procedures, including medical palliative care and open surgical decompression and fixation. An increasingly popular minimally invasive technique to treat metastatic instabilities is kyphoplasty. Even though it may alleviate pain due to pathological fractures, it may fail. However, delayed kyphoplasty failures with retropulsed cement and neural element compression have not been well reported. Such failures necessitate open surgical decompression and stabilization, and cement inserted during the kyphoplasty complicates salvage surgeries in patients with a disease-burdened spine. The authors sought to examine the incidence of delayed failure of structural kyphoplasty in a series of cement augmentations for pathological compression fractures. The goal was to identify risk predictors by analyzing patient and disease characteristics to reduce kyphoplasty failure and to prevent excessive surgical procedures at the end of life. METHODS The authors retrospectively reviewed the records of all patients with metastatic cancer from 2010 to 2013 who had undergone a procedure involving cement augmentation for a pathological compression fracture at their institution. The authors examined the characteristics of the patients, diseases, and radiographic fractures. RESULTS In total, 37 patients underwent cement augmentation in 75 spinal levels during 45 surgeries. Four patients had delayed structural kyphoplasty failure necessitating surgical decompression and fusion. The mean time to kyphoplasty failure was 2.88 ± 1.24 months. The mean loss of vertebral body height was 16% in the patients in whom kyphoplasty failed and 32% in patients in whom kyphoplasty did not fail. No posterior intraoperative cement extravasation was observed in the patients in whom kyphoplasty had failed. The mean spinal instability neoplastic score was 10.8 in the patients in whom kyphoplasty failed and 10.1 in those in whom kyphoplasty did not fail. Approximately 50% of the kyphoplasty failures occurred at junctional spinal levels. All the patients in whom kyphoplasty failed had fractures in 3 or more cortical walls before treatment, whereas 46% of patients in the nonfailure group had fractures with breaching of 3 or more walls. CONCLUSIONS Although rare, delayed failures of structural augmentation with cement during kyphoplasty do occur and can lead to additional surgeries. A possible predictive index may include wall integrity of the vertebral body, competency of the posterior tension band, and location of the kyphoplasty at a junctional spinal level. Additional studies are required to confirm these findings.

Increased estrogen receptor alpha in experimental aortic aneurysms in females compared with males.

BACKGROUND: Estrogen receptor alpha (ERα) has been identified in the vessel wall, offering vasoprotective effects when upregulated. Estrogens are known to mediate the inflammatory milieu, and inflammation has long been associated with abdominal aortic aneurysm (AAA) formation. Therefore, it is theorized that increased estrogen receptor in females contributes to their relative resistance to AAAs. The objective of this study was to determine gender differences in ERα levels during experimental AAA formation. METHODS: Infrarenal aortas of male and female C57 mice (n = 18 and n = 16, respectively) were infused with 0.4% elastase. Diameters were measured at days 0 and 14. Aortic messenger RNA expression of ERα was determined on day 3 by reverse transcription-polymerase chain reaction, whereas ERα protein levels were measured via Western blot. Immunohistochemistry using rabbit antibody for ERα was performed on day 14 samples and quantified. Zymography was done for matrix metalloproteinases (MMP)2 and 9 activity levels. Samples of human AAAs were collected and Western blot performed. Data were compared for significance using a student t-test. RESULTS: Infrarenal aortic diameter increased in elastase-perfused males (ME) by 80% at 14 days after perfusion, whereas females (FE) increased by only 35% (P = 0.0012). FE had ×10 greater ERα messenger RNA expression compared with ME at day 3 (P = 0.003). Similarly, ERα protein levels were 100% higher in FE compared with those in ME on day 14 (P = 0.035). ERα protein levels were 80% higher in female human patients with AAA than those in their male counterparts (P = 0.029). ERα visualized via immunohistochemistry was 1.5 fold higher in FE than ME (P = 0.029). MMP2 and 9 activity levels were decreased in female compared with male aortas. CONCLUSIONS: This study demonstrates an increase in aortic wall ERα in females compared with males that correlates inversely with MMP activity and AAA formation. These findings, coupled with observations that exogenous estrogen inhibits AAA formation in males, further suggest that estrogen supplementation may be important to prevent AAA formation and growth.

Phosphorylation of AKT and abdominal aortic aneurysm formation.

It is hypothesized that differential AKT phosphorylation between sexes is important in abdominal aortic aneurysm (AAA) formation. Male C57BL/6 mice undergoing elastase treatment showed a typical AAA phenotype (80% over baseline, P < 0.001) and significantly increased phosphorylated AKT-308 (p308) and total-AKT (T-AKT) at day 14 compared with female mice. Elastase-treated Raw cells produced increased p308 and significant amounts of matrix metalloproteinase 9 (MMP-9), and these effects were suppressed by LY294002 treatment, a known AKT inhibitor. Male and female rat aortic smooth muscle cells treated with elastase for 1, 6, or 24 hours demonstrated that the p308/T-AKT and AKT-Ser-473/T-AKT ratios peaked at 6 hours and were significantly higher in the elastase-treated cells compared with controls. Similarly, male cells had higher phosphorylated AKT/T-AKT levels than female cells. LY294002 also inhibited elastase-induced p308 formation more in female smooth muscle cells than in males, and the corresponding cell media had less pro-MMP-9. AKT siRNA significantly decreased secretion of pro-MMP-9, as well as pro-MMP-2 and active MMP-2 from elastase-treated male rat aortic smooth muscle cells. IHC of male mice AAA aortas showed increased p308, AKT-Ser-473, and T-AKT compared with female mice. Aortas from male AAA patients had a significantly higher p308/T-AKT ratio than female AAA tissues. These data suggest that AKT phosphorylation is important in the upstream regulation of MMP activity, and that differential phosphorylation may be important in sex differences in AAA.

The role of extracellular signal-related kinase during abdominal aortic aneurysm formation.

BACKGROUND: It is hypothesized that activation of extracellular signal-related kinase (ERK) is critical in activating matrix metalloproteinases (MMPs) during abdominal aortic aneurysm (AAA) formation. STUDY DESIGN: C57BL/6 male mice underwent either elastase or heat-inactivated elastase aortic perfusion (n = 9 per group). Mouse aortic smooth muscle cells were transfected with ERK-1 and 2 siRNA along with or without elastase treatment. Mouse and human aortic tissue were analyzed by Western blots, zymograms, and immunohistochemistry, and statistical analysis was done using Graphpad and Image J softwares. RESULTS: Western blot and immunohistochemistry documented increased phospho-mitogen-activated protein kinase kinase-1/2 (pMEK-1/2; 153%, p = 0.270 by Western) and pERK (171%, p = 0.004 by Western blot) in the elastase perfused aortas. Male ERK-1(-/-) mice underwent elastase perfusion, and aortic diameter was determined at day 14. ERK-1(-/-) mice failed to develop AAA, and histologic analysis depicted intact collagen and elastin fibers in the aortas. Zymography of aortas of elastase-treated ERK-1(-/-) mice showed lower levels of proMMP2 (p < 0.005) and active MMP2 (p < 0.0001), as well as proMMP9 (p = 0.037) compared with C57BL/6 mice. siRNA transfection of ERK-1 and -2 significantly reduced formation of pro- and active MMP2 (p < 0.01 for both isoforms) in aortic smooth muscle cells treated with elastase in vitro. Human AAA tissue had significantly elevated levels of pMEK-1/2 (150%, p = 0.014) and pERK (159%, p = 0.013) compared with control tissues. CONCLUSIONS: The MAPK (mitogen-activated protein kinase)/ERK pathway is an important modulator of MMPs during AAA formation. Targeting the ERK pathway by reagents that inhibit either the expression or phosphorylation of ERK isoforms could be a potential therapy to prevent AAA formation.

Increased PAI-1 in females compared with males is protective for abdominal aortic aneurysm formation in a rodent model.

The serine proteases, along with their inhibitor plasmin activator inhibitor-1 (PAI-1), have been shown to play a role in abdominal aortic aneurysm (AAA) formation. The aim of this study is to determine if PAI-1 may be a protective factor for AAA formation and partially responsible for the gender difference observed in AAAs. Male and female wild-type (WT) C57BL/6 and PAI-1(-/-) mice 8-12 wk of age underwent aortic perfusion with porcine pancreatic elastase. Animals were harvested 14 days following perfusion and analyzed for phenotype, PAI-1 protein levels, and matrix metalloproteinase (MMP)-9 and -2 activity. WT males had an average increase in aortic diameter of 80%, whereas females only increased 32% (P < 0.001). PAI-1(-/-) males increased 204% and females 161%, significantly more than their WT counterparts (P < 0.001). Western blot revealed 61% higher PAI-1 protein levels in the WT females compared with the WT males (P = 0.01). Zymography revealed higher levels of pro-MMP-2 and active MMP-2 in the PAI-1(-/-) males and females compared with their WT counterparts. PAI-1(-/-) females had significantly higher serum plasmin levels compared with WT females (P = 0.003). In conclusion, WT female mice are protected from aneurysm formation and have higher levels of PAI-1 compared with males during experimental aneurysm formation. Additionally, both male and female PAI-1(-/-) animals develop significantly larger aneurysms than WT animals, correlating with higher pro- and active MMP-2 levels. These findings suggest that PAI-1 is protective for aneurysm formation in the elastase model of AAA and plays a role in the gender differences seen in AAA formation.

Increased JNK in males compared with females in a rodent model of abdominal aortic aneurysm.

BACKGROUND: In humans, there is a 4:1 male:female ratio in the incidence of abdominal aortic aneurysms (AAAs). c-Jun-N-terminal kinase (JNK) is an important upstream regulator of several enzymes involved in AAA formation, including the matrix metalloproteinases (MMPs). The purpose of this study was to determine if there is a gender difference between males and females in JNK during AAA formation. MATERIALS AND METHODS: Male and female C57/B6 mice underwent aortic perfusion with elastase or heat inactivated elastase with aortas harvested at d 3 and 14 for phenotype determination, RT-PCR, Western blot, and zymography. Additionally, in vitro experiments using siRNA were conducted to define JNK regulation of matrix metalloproteinases (MMPs). A t-test was used to compare between groups. RESULTS: Males formed larger AAAs at d 14 compared with females (P < 0.001), with significantly higher levels of JNK1 protein, proMMP9, proMMP2, and active MMP2. At d 3, males had more JNK1 mRNA, protein, and MMP activity. Knockdown of JNK 1 or 2 in vitro decreased MMP activity, while knockdown of JNK 1 and 2 together blocked all MMP activity. CONCLUSION: Alterations in JNK between genders is partially responsible for the differential rates of experimental AAA formation, likely through differential regulation of MMPs.