Liver transplantation for acute liver failure in a SARS-CoV-2 PCR-positive patient

Current guidelines recommend deferring liver transplantation (LT) in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection until clinical improvement occurs and two PCR tests collected at least 24 hours apart are negative. We report a case of an 18-year-old, previously healthy African-American woman diagnosed with COVID-19, who presents with acute liver failure (ALF) requiring urgent LT in the context of SARS-CoV-2 polymerase chain reaction (PCR) positivity. The patient was thought to have acute Wilsonian crisis on the basis of hemolytic anemia, alkaline phosphatase:bilirubin ratio <4, AST:ALT ratio >2.2, elevated serum copper, and low uric acid, although an unusual presentation of COVID-19 causing ALF could not be excluded. After meeting criteria for status 1a listing, the patient underwent successful LT, despite ongoing SARS-CoV-2 PCR positivity. Remdesivir was given immediately posttransplant, and mycophenolate mofetil was withheld initially and the SARS-CoV-2 PCR test eventually became negative. Three months following transplantation, the patient has made a near-complete recovery. This case highlights that COVID-19 with SARS-CoV-2 PCR positivity may not be an absolute contraindication for transplantation in ALF. Criteria for patient selection and timing of LT amid the COVID-19 pandemic need to be validated in future studies.     

Renal Replacement Therapy for Acute Kidney Injury in Severe Alcohol-Associated Hepatitis as a Bridge to Transplant or Recovery

Digestive Diseases and Sciences - Acute kidney injury is seen in approximately 30% of patients with severe alcohol-associated hepatitis (AH) and is associated with increased mortality. Controversy...     

Possible Anandamide and Palmitoylethanolamide involvement in human stroke

Background  

Endocannabinoids (eCBs) are ubiquitous lipid mediators that act on specific (CB1, CB2) and non-specific (TRPV1, PPAR) receptors. Despite many experimental animal studies proved eCB involvement in the pathogenesis of stroke, such evidence is still lacking in human patients. Our aim was to determine eCB peripheral levels in acute stroke patients and evaluate their relationship with clinical disability and stroke volume.     

Unilateral headache with bilateral internal ophthalmoplegia

We describe the case of a young woman suffering from migraine. After some years, the headache started to be accompanied by internal ophthalmoplegia. Mydriasis was unilateral and after a few months became bilateral. The ophthalmoplegic migraine is a rare type of headache and it is characterized by paresis of one or more of the third, fourth or sixth cranial nerves. Migraine attacks associated with mydriasis (internal ophthalmoplegia) are extremely rare. Triptan therapy resolved mydriasis, but not the headache.     

Albumin administration in patients with cirrhosis: Current role and novel perspectives

Mortality in cirrhosis is mostly associated with the development of clinical decompensation, characterized by ascites, hepatic encephalopathy, variceal bleeding, or jaundice. Therefore, it is important to prevent and manage such complications. Traditionally, the pathophysiology of decompensated cirrhosis was explained by the peripheral arterial vasodilation hypothesis, but it is currently understood that decompensation might also be driven by a systemic inflammatory state (the systemic inflammation hypothesis). Considering its oncotic and nononcotic properties, albumin has been thoroughly evaluated in the prevention and management of several of these decompensating events. There are formal evidence-based recommendations from international medical societies proposing that albumin be administered in individuals with cirrhosis undergoing large-volume paracentesis, patients with spontaneous bacterial peritonitis, those with acute kidney injury (even before the etiological diagnosis), and those with hepatorenal syndrome. Moreover, there are a few randomized controlled trials and meta-analyses suggesting a possible role for albumin infusion in patients with cirrhosis and ascites (long-term albumin administration), individuals with hepatic encephalopathy, and those with acute-on-chronic liver failure undergoing modest-volume paracentesis. Further studies are necessary to elucidate whether albumin administration also benefits patients with cirrhosis and other complications, such as individuals with extraperitoneal infections, those hospitalized with decompensated cirrhosis and hypoalbuminemia, and patients with hyponatremia.     

Portal Hypertension and Related Complications: Diagnosis and Management

Portal hypertension is a major complication of cirrhosis, and its consequences, including ascites, esophageal varices, hepatic encephalopathy, and hepatorenal syndrome, lead to substantial morbidity and mortality. The past several decades have seen major improvements in the clinical management of complications of portal hypertension, resulting in substantial gains in patient outcomes. However, important challenges remain. This review focuses on the pathophysiology and diagnosis of portal hypertension and discusses general approaches in the management of patients with ascites as a result of portal hypertension.     

Sphingosine-1-Phosphate Mediates a Reciprocal Signaling Pathway between Stellate Cells and Cancer Cells that Promotes Pancreatic Cancer Growth

Sphingosine-1-phosphate (S1P) is produced by sphingosine kinase 1 and is implicated in tumor growth, although the mechanisms remain incompletely understood. Pancreatic stellate cells (PSCs) reside within the tumor microenvironment and may regulate tumor progression. We hypothesized that S1P activates PSCs to release paracrine factors, which, in turn, increase cancer cell invasion and growth. We used a combination of human tissue, in vitro, and in vivo studies to mechanistically evaluate this concept. Sphingosine kinase 1 was overexpressed in human pancreatic tissue, especially within tumor cells. S1P activated PSCs in vitro and conditioned medium from S1P-stimulated PSCs, increased pancreatic cancer cell migration, and invasion, which was dependent on S1P2, ABL1 (alias c-Abl) kinase, and matrix metalloproteinase-9. In vivo studies showed that pancreatic cancer cells co-implanted with S1P2 receptor knockdown PSCs led to less cancer growth and metastasis in s.c. and orthotopic pancreatic cancer models compared with control PSCs. Pancreatic cancer cell–derived S1P activates PSCs to release paracrine factors, including matrix metalloproteinase-9, which reciprocally promotes tumor cell migration and invasion in vitro and cancer growth in vivo.Sphingosine-1-phosphate (S1P) is a lipid-signaling molecule that governs growth, survival, and migration of epithelial cells.^1,2 S1P is converted from sphingosine through a reaction that is catalyzed by sphingosine kinase (SK), which exists in two isoforms: SK1 and SK2. S1P is produced intracellularly and then exported out, where it binds its receptors S1P1 and S1P2, which couple to distinct G proteins and signaling pathways.² Accumulating evidence indicates that excessive S1P signaling correlates with cancer phenotype, including up-regulation of S1P and/or SK1 in several cancer types³ and correlation of the levels of these molecules with patient prognosis. However, the mechanistic relationship of the S1P pathway with cancer growth remains incompletely developed.Additional lines of evidence link S1P signaling with fibrosis. Indeed, S1P induces extracellular matrix synthesis and profibrotic marker gene expression. Mice genetically deficient in S1P2 are resistant to liver fibrosis.^4,5 These observations are relevant to pancreatic cancer, in which the tumor microenvironment is characterized by dense fibrotic stroma owing to enhanced matrix production by activated pancreatic stellate cells (PSCs).^6–8 Indeed, the activation phenotype of PSCs, characterized by increased proliferation, migration, synthesis of matrix proteins, and secretion of growth factors and cytokines, is thought to occur in response to tumor cell–derived cues and, in turn, contribute to tumor growth through multiple postulated mechanisms.^6,9,10 This led us to explore whether S1P may mediate reciprocal interactions between tumor cells and PSCs that could sanction tumor growth.Herein, we found that SK1 is up-regulated in pancreatic cancer. S1P activates PSCs to produce matrix metalloproteinase-9 (MMP-9) through an S1P2-, c-Abl–, and NF-κB–dependent pathway. In turn, PSC-derived MMP-9 stimulates pancreatic cancer cell migration and invasion. Both s.c. and orthotopic pancreatic cancer models indicate that this molecular pathway regulates tumor growth in vivo. These studies highlight the importance of S1P signaling as a mechanism that links the tumor with its microenvironment to achieve tumor growth in pancreas.