Post-COVID-19 Secondary Sclerosing Cholangitis: A Rare but Severe Condition with no Treatment Besides Liver Transplantation.

BACKGROUND The incidence of abnormal liver function, mainly aspartate aminotransferase and alanine aminotransferase elevations, in patients with COVID-19 is not uncommon, but persistent liver damage after the acute phase of the disease is uncommon and has been recently recognized as a new entity named post-COVID-19 cholangiopathy. CASE REPORT We report a clinical case with progressive cholestatic disease following severe COVID-19. AST and ALT peaked at hospital admission and while its serum concentration went down, bilirubin and cholestatic liver enzymes started to increase, reaching the maximum at day 122. Magnetic resonance imaging (MRI) revealed a diffuse irregularity of intra- and extrahepatic bile ducts, with multiple focal strictures alternating with mild focal dilations of the biliary tree, suggesting a sclerosing cholangiopathy. A transjugular liver biopsy showed a prominent bile ductular reaction, cholangiocyte injury, inflammatory infiltrate rich in neutrophils, biliary infarctions, marked cholestasis, and portal fibrosis, suggesting the diagnosis of post-Covid-19 secondary sclerosing cholangitis. The patient evolved with a continuous deterioration of liver functions, but liver transplantation was not performed due to his poor clinical condition. CONCLUSIONS Post-COVID-19 SSC is a severe disease with no effective clinical treatment and has liver transplantation as the only treatment for a few selected patients.

Diazoxide reduces local and remote organ damage in a rat model of intestinal ischemia reperfusion.

BACKGROUND: Intestinal ischemia reperfusion is a common clinical condition that causes functional impairment. Once tight junctions are damaged, barrier function is compromised, and the intestines become a source for entry of bacterial and inflammatory mediators into the circulation, leading to systemic inflammatory response syndrome, multiple organ failure, and death. It is possible that diazoxide could protect the intestines against ischemia reperfusion. The aim of this study is to determine whether diazoxide can provide protection in a rat model of intestinal ischemia reperfusion. METHODS: A total of 32 adult male specific pathogen-free Wistar rats were randomized into three groups: a control group, n = 6; a saline group, n = 13; and a diazoxide group, n = 13. The saline and diazoxide groups underwent clamping of the superior mesenteric artery for 1 h, with samples in all the groups being collected 12 h later. RESULTS: Intestinal histology showed greater damage in the intestinal ischemia reperfusion groups. mRNA expression of zonula occludens-1 and occludin (tight junction proteins) and interleukin-6 and cyclooxygenase-2 was the highest in the Saline group. The Diazoxide group showed a reduction in aspartate aminotransferase serum levels compared with the other groups. CONCLUSIONS: Increased expression of zonula occludens-1, occludin, and cyclooxygenase-2 suggested a greater regenerative effort because of more severe lesions in the saline group. In addition, increased expression of interleukin-6 in the saline group was suggestive of inflammation, indicating that diazoxide had protective effects in the diazoxide group. Reduced aspartate aminotransferase in the diazoxide group suggested liver protection. Diazoxide protects the intestines and liver from intestinal ischemia reperfusion lesions in rats.

Intestinal Barrier Dysfunction in Human Pathology and Aging.

BACKGROUND: The intestinal barrier is a layer that constitutes the most important barrier against the external environment. It can be partially disrupted in several frequent scenarios, leading to autoimmune and inflammatory diseases. Translocation of intestinal luminal contents into the intestinal mucosa may induce inflammatory disorders and therefore tissue injuries. Disruption of the intestinal barrier may induce local and systemic injuries and may play a role in inflammatory bowel disease, liver diseases, the aging process and in the systemic inflammatory response syndrome, including lung, heart and brain dysfunctions. CONCLUSION: Here, we discuss how the maintenance of it selectively permeability is crucial to adequate absorption of nutrients, electrolytes and water while maintaining effective host defense properties in order to avoid intestinal injury, systemic inflammation and distant organ damage.

Personalized Medicine for Sepsis.

Sepsis is a complex syndrome triggered by infection and characterized by systemic deregulation of immune and inflammatory pathways. It is a major cause of death worldwide and results in the widespread use of antibiotics and substantial health care costs. In a vicious circle, sepsis treatment promotes the emergence of highly virulent and resistant pathogens and devastating nosocomial infections. Sepsis is a heterogeneous disease affecting many people worldwide. Because individual patients have different inflammatory responses and unique profiles of immune activation against pathogens, the most effective way to advance the treatment of sepsis is probably through a tailored approach. The advent of high-throughput technologies and the remarkable progress in the field of bioinformatics has allowed the subclassification of many pathological conditions. This has potential to provide better understanding of life-threatening infections in people. The study of host factors, however, needs to be integrated with studies on bacterial signaling in both symbiotic and pathogenic bacteria. Sepsis is certainly the sum of multiple host-microbial interactions and the metagenome should be extensively investigated. Personalized medicine is probably the only strategy able to deconstruct and reassemble our knowledge about sepsis, and its use should allow us to understand and manipulate sepsis as a wide, interconnected phenomenon with myriad variables and peculiarities. In this study, the recent advances in this area, the major challenges that remain, and the reasons why the septic patient should be approached as a superorganism are discussed.

Cathelicidin LL-37 bloodstream surveillance is down regulated during septic shock.

Host defense peptides are ancient weapons of the innate immunity. The human cathelicidin LL-37 protects the epithelial barrier against infection and is constitutively secreted in the bloodstream by immune cells. Current knowledge claims that LL-37 is up regulated upon infection. LL-37 can protect against bacterial infections and possesses many immunomodulatory properties. Here, we show that the human host defense peptide LL-37 is down regulated during septic shock. Furthermore, we show that these effects are not related to vitamin D serum levels, a potent inducer of LL-37 gene expression, pointing out the complex regulation of cathelicidins during septic shock.

Marginal grafts increase early mortality in liver transplantation.

CONTEXT AND OBJECTIVE: Expanded donor criteria (marginal) grafts are an important solution for organ shortage. Nevertheless, they raise an ethical dilemma because they may increase the risk of transplant failure. This study compares the outcomes from marginal and non-marginal graft transplantation in 103 cases of liver transplantation due to chronic hepatic failure. DESIGN AND SETTING: One hundred and three consecutive liver transplantations to treat chronic liver disease performed in the Liver Transplantation Service of Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo between January 2001 and March 2006 were retrospectively analyzed. METHODS: We estimated graft quality according to a validated scoring system. We assessed the pre-transplantation liver disease category using the Model for End-Stage Liver Disease (MELD), as low MELD (< 20) or high MELD (>or= 20). The parameters for marginal and non-marginal graft comparison were the one-week, one-month and one-year recipient survival rates, serum liver enzyme peak, post-transplantation hospital stay and incidence of surgical complications and retransplantation. The significance level was 0.05. RESULTS: There were no differences between the groups regarding post-transplantation hospital stay, serum liver enzyme levels and surgical complications. In contrast, marginal grafts decreased overall recipient survival one month after transplantation. Furthermore, low-MELD recipients of non-marginal grafts showed better one-week and one-month survival than did high-MELD recipients of marginal livers. After the first month, patient survival was comparable in all groups up to one year. CONCLUSION: The use of marginal graft increases early mortality in liver transplantation, particularly among high-MELD recipients.

Kras mutation analysis of fine needle aspirate under EUS guidance facilitates risk stratification of patients with pancreatic mass.

OBJECTIVES: The accuracy of endoscopic ultrasound-fine needle aspiration cytology (EUS-FNAC) for the diagnosis of pancreatic cancer is suboptimal. Mutational activation of the kras oncogene is almost universally present in pancreatic cancer tissue. We, therefore, investigated if analysis for mutant kras gene in the EUS-FNAC aspirates supplements cytopathology for the diagnosis of pancreatic adenocarcinoma (PAC). METHODS: EUS-FNAC specimens obtained from 74 patients with pancreatic masses were analyzed for the presence of kras mutation on codon 12 using polymerase chain reaction-restriction fragment length polymorphism and MvaI restriction enzyme. Definitive diagnosis was based on surgical pathology or long-term follow-up (median 27.8 mo); 57 patients had PAC, 11 patient's chronic pancreatitis, and 9 patient's nonfunctioning neuroendocrine tumors. RESULTS: Analysis of mutant kras gene in addition to cytopathology allowed the detection of PAC in 4 additional patients as compared with cytopathology alone. Cytopathology and kras mutant analysis were negative for PAC in 17 patients of whom 6 patients (35%) had PAC. The respective sensitivity (90.9% vs. 82.5%), specificity (47.6% vs. 97.9%), positive predictive value (89.5% vs. 83.8%), negative predictive value (98.1% vs. 94.1%), accuracy (89.2% vs. 58.8%) of cytopathology plus kras mutation versus cytopathology were numerically superior but did not reach statistical significance. CONCLUSIONS: Analysis for the presence of mutant kras gene supplements conventional cytopathology for the diagnosis of PAC even without a cytopathologist in attendance and using only 3 needle passes. Among patients with negative cytopathology, the presence of kras mutation represents pancreatic cancer while the absence of kras mutation increases the possibility of benign lesion.