Cholestasis Of Sepsis Research Articles

Drug-induced cholestatic liver diseases.

Cholestatic DILI is an important and frequently challenging differential diagnosis in patients presenting with elevated liver tests with predominant elevation in alkaline phosphatase. A number of competing etiologies need to be ruled out, such as hepatobiliary malignancy, choledocholithiasis, cholestatic forms of viral hepatitis, cholestasis of sepsis, primary and secondary cholangitis, and right-sided cardiac failure to name a few. Important advances have occurred in the understanding and knowledge of the clinical phenotypes, new etiological agents, risk factors, pathophysiology, and genetic determinants of drug-induced cholestasis since the last review on drug-induced cholestasis was published in Hepatology in 2011. Secondary sclerosing cholangitis (SSC) due to drugs has been well documented for several different drugs. Checkpoint inhibitors are one of the types of drugs shown to lead to secondary sclerosing cholangitis. Several new herbal and dietary supplements have recently been shown to lead to cholestatic liver injury. A number of genetic risk factors for cholestasis due to drugs have been identified in the last decade, and the pathogenesis behind cholestatic injury is better defined. In this review, the focus is on diagnostic approach and description of new clinical phenotypes such as secondary sclerosing cholangitis and vanishing bile duct syndrome. Furthermore, the review provides an overview of the risk factors, genetic determinants, and the pathophysiology of hepatobiliary transporters leading to cholestasis. Management, areas of uncertainty, and future direction are also presented.

The Pivotal Role of Presepsin in Assessing Sepsis-Induced Cholestasis.

The serum levels of presepsin correlate with parameters indicating cholestasis in sepsis; however, the probability and significance of this association remain uncertain. We aimed to ascertain whether infection, as signaled by presepsin levels, is the primary determinant of elevated biliary parameters in sepsis. A unicenter, retrospective study included 396 COVID-free emergency-admitted patients, in which presepsin level was determined. Presepsin, neutrophil count, leukocyte count, C reactive protein, and fibrinogen evaluated the septic/inflammatory state. The statistically significant factors associated with cholestasis, ALT, and AST were analyzed by Fisher's exact test and Spearman regression with Bonferroni's correction. Presepsin emerged as the most likely variable correlated with all cholestasis markers: alkaline phosphatase (p = 7 × 10-8), gamma-glutamyl transferase (p = 5 × 10-10), and conjugated bilirubin (p = 4 × 10-15). Thrombocyte count, C reactive protein, age, creatinine, urea, lactate, and blood pressure, were associated with only one or two of these markers. In a sepsis setting, the increase in cholestasis-related parameters is associated with presepsin with a higher probability than hemodynamic, inflammatory, or coagulation-related variables. Determining this robust link between sepsis and cholestasis could eliminate unnecessary imaging procedures in critically ill patients, enabling clinicians to focus efforts on addressing the primary infectious cause.

Pathophysiology of sepsis-induced cholestasis: A review.

Sepsis is a critical condition resulting from the excessive activation of the inflammatory/immune system in response to an infection, with high mortality if treatment is not administered promptly. One of the many possible complications of sepsis is liver dysfunction with consequent cholestasis. The aim of this paper is to review the main mechanisms involved in the development of cholestasis in sepsis. Cholestasis in a septic patient must raise the suspicion that it is the consequence of the septic condition and limit the laborious attempts of finding a hepatic or biliary disease. Prompt antibiotic administration when sepsis is suspected is essential and may improve liver enzymes. Cholestasis is a syndrome with a variety of etiologies, among which sepsis is frequently overlooked, despite a number of studies and case reports in the literature demonstrating not only the association between sepsis and cholestasis but also the role of cholestasis as a prognostic factor for sepsis‐induced death.

Reduced Mrp2 surface availability as PI3K\u03b3-mediated hepatocytic dysfunction reflecting a hallmark of cholestasis in sepsis

Sepsis-associated liver dysfunction manifesting as cholestasis is common during multiple organ failure. Three hepatocytic dysfunctions are considered as major hallmarks of cholestasis in sepsis: impairments of microvilli covering canalicular membranes, disruptions of tight junctions sealing bile-collecting canaliculae and disruptions of Mrp2-mediated hepatobiliary transport. PI3Kγ loss-of-function was suggested as beneficial in early sepsis. Yet, the PI3Kγ-regulated cellular processes in hepatocytes remained largely unclear. We analysed all three sepsis hallmarks for responsiveness to massive PI3K/Akt signalling and PI3Kγ loss-of-function, respectively. Surprisingly, neither microvilli nor tight junctions were strongly modulated, as shown by electron microscopical studies of mouse liver samples. Instead, quantitative electron microscopy proved that solely Mrp2 surface availability, i.e. the third hallmark, responded strongly to PI3K/Akt signalling. Mrp2 plasma membrane levels were massively reduced upon PI3K/Akt signalling. Importantly, Mrp2 levels at the plasma membrane of PI3Kγ KO hepatocytes remained unaffected upon PI3K/Akt signalling stimulation. The effect explicitly relied on PI3Kγ’s enzymatic ability, as shown by PI3Kγ kinase-dead mice. Keeping the surface availability of the biliary transporter Mrp2 therefore is a cell biological process that may underlie the observation that PI3Kγ loss-of-function protects from hepatic excretory dysfunction during early sepsis and Mrp2 should thus take center stage in pharmacological interventions.

Potential Treatments for SARS-CoV-2 Infection.

Potential Treatments for SARS-CoV-2 Infection.

Effects of Endotoxin on Type 3 Inositol 1,4,5-Trisphosphate Receptor in Human Cholangiocytes.

Clinical conditions that result in endotoxemia, such as sepsis and alcoholic hepatitis (AH), often are accompanied by cholestasis. Although hepatocellular changes in response to lipopolysaccharide (LPS) have been well characterized, less is known about whether and how cholangiocytes contribute to this form of cholestasis. We examined effects of endotoxin on expression and function of the type 3 inositol trisphosphate receptor (ITPR3), because this is the main intracellular Ca2+ release channel in cholangiocytes, and loss of it impairs ductular bicarbonate secretion. Bile duct cells expressed the LPS receptor, Toll-like receptor 4 (TLR4), which links to activation of nuclear factor-κB (NF-κB). Analysis of the human ITPR3 promoter revealed five putative response elements to NF-κB, and promoter activity was inhibited by p65/p50. Nested 0.5- and 1.0-kilobase (kb) deletion fragments of the ITPR3 promoter were inhibited by NF-κB subunits. Chromatin immunoprecipitation (ChIP) assay showed that NF-κB interacts with the ITPR3 promoter, with an associated increase in H3K9 methylation. LPS decreased ITPR3 mRNA and protein expression and also decreased sensitivity of bile duct cells to calcium agonist stimuli. This reduction was reversed by inhibition of TLR4. ITPR3 expression was decreased or absent in cholangiocytes from patients with cholestasis of sepsis and from those with severe AH. Conclusion: Stimulation of TLR4 by LPS activates NF-κB to down-regulate ITPR3 expression in human cholangiocytes. This may contribute to the cholestasis that can be observed in conditions such as sepsis or AH.

Adenovirus-mediated human aquaporin-1 expression in hepatocytes improves lipopolysaccharide-induced cholestasis.

Lipopolysaccharides (LPS) are known to cause cholestasis in sepsis. There is evidence that a defective expression of canalicular aquaporin water channels contributes to bile secretory failure in LPS-induced cholestasis. Thus, we studied whether the hepatic adenovirus-mediated transfer of human aquaporin-1 gene (haqp1) can improve the cholestasis induced by LPS. Adenoviral vector encoding hAQP1 (AdhAQP1) or control vector was administered to rats by retrograde intrabiliary infusion. Hepatocyte canalicular hAQP1 expression was assessed by liver immunostaining and immunoblotting in purified plasma membranes. LPS reduced bile flow and biliary bile acid excretion by 30% and 45%, respectively. AdhAQP1-treatment normalized both bile flow and biliary bile acid excretion in LPS-induced cholestasis. Moreover, markedly elevated serum bile acid levels in cholestatic rats, were also normalized with the AdhAQP1 hepatic transduction. Bile flow and serum or biliary bile acids in normal rats were not significantly altered by AdhAQP1. AdhAQP1 delivery unaffected the downregulated protein expression of canalicular bile salt export pump (BSEP/ABCB11) in cholestasis, but improved its transport activity restoring reduced canalicular cholesterol content. Our data suggest that the adenovirus-mediated hepatocyte hAQP1 expression improves LPS-induced cholestasis in rats by stimulating the BSEP/ABCB11-mediated biliary bile acid excretion; a finding that might contribute to the understanding and treatment of sepsis-associated cholestatic diseases. © 2017 IUBMB Life, 69(12):978-984, 2017.

An Unusual Cause of Abnormal Liver Enzymes, Leukocytosis, and Right Upper Quadrant Abdominal Pain

n 84-year-old man with history of atrial fibrillaAtion on warfarin, coronary artery disease, and chronic kidney disease presented to our institution with abdominal pain, nausea, and jaundice of 1-week duration. During the preceding few months, he had postprandial right upper quadrant abdominal pain that became constant the week of his presentation. On admission, the patient was afebrile, heart rate was 68 beats per minute, and he was hypotensive with blood pressure of 90/40 mm Hg. He was alert and oriented and had jaundice and scleral icterus. His abdomen was mildly distended, with tenderness to palpation over the right upper quadrant and epigastric area without rebound or guarding. The remainder of his physical examination was unremarkable. Blood work revealed white blood cell count of 18.6 10/L (3.8–10.6), hemoglobin 9.2 g/dL (12.9–16.9), serum creatinine 6.1 mg/dL (0.5–1.4), total bilirubin 9.6 mg/dL (0.3–1.5), direct bilirubin 8.2 mg/dL (0.1–0.5), aspartate aminotransferase 59 IU/L (15–41), alanine aminotransferase 51 IU/L (17–63), alkaline phosphatase 801 IU/L (38–126), and international normalized ratio >16. A noncontrast computed tomography (CT) scan was unremarkable with the exception of cholelithiasis. Because of concern for ascending cholangitis, the patient underwent endoscopic retrograde cholangiopancreatography, which failed to demonstrate biliary dilation or filling defects in the biliary tree. The patient’s abnormal liver enzymes were attributed to cholestasis of sepsis, the etiology of which was unclear. During the next 48 hours, his liver enzymes remained elevated, and despite aggressive fluid hydration and empiric antibiotics for anaerobic and gram-negative rod coverage, the patient clinically deteriorated. Pressor support was initiated for hypotension, and the patient had worsening of his abdominal pain, for which a repeat abdominal CT scan with oral contrast was performed (Figure A, arrow indicates extravasated oral contrast at the mid-jejunum with associated extraluminal free air). Repeat CT scan demonstrated multiple jejunal, distal ileal and sigmoid diverticula. There was infiltration of the jejunal mesentery, presence of jejunal mesenteric gas, and extraluminal contrast suggestive of jejunal diverticulitis complicated by perforation. The patient was emergently taken to the operating room for exploratory laparotomy. Intraoperatively, the patient was found to have bile peritonitis and a small perforation in the midjejunum approximately 40 cm distal to the ligament of Treitz. The patient underwent resection of 8 cm of involved jejunum with end-to-end jejunojejunal anastomosis. The patient’s postoperative course was complicated by respiratory failure, which led to his death 6 days later. Small bowel diverticulosis is a rare condition with a prevalence of 0.06%–1.3% compared with 50%–70% for colonic diverticulosis. Up to 80% of small bowel diverticular disease occurs in the jejunum. Jejunal diverticulosis is an acquired disorder, resulting from herniation of mucosa and submucosa through the muscularis along weak points at the mesenteric border where the vasa recta vessels penetrate the bowel wall. Proposed risk factors include conditions associated with increased intraluminal pressure, such as obesity and constipation, as well as motility disorders, including progressive systemic

Renal failure, hepatitis and myocarditis in a previously healthy man.

1School of Medicine, Queen’s University; 2Department of Medicine; 3Division of Infectious Diseases; 4Division of Nephrology, Kingston General Hospital, Kingston, Ontario Correspondence: Dr Gerald A Evans, Division of Infectious Diseases, Kingston General Hospital, Etherington Hall, Room 3013, 76 Stuart Street, Kingston, Ontario K7L 2V7. Telephone 613-533-6619, fax 613-533-6825, e-mail evansg@queensu.ca CASE PRESENTATION A 32-year-old male migrant worker from St Lucia presented to the emergency department with a one-week history of myalgias, headache and fever. He was previously healthy. He was visiting Canada temporarily and had arrived in Canada 11 days before his presentation. One day after arriving in Canada, he ate commercially prepared hamburger patties, which he reported as “off-tasting”. Five days later, he became fatigued and experienced a bilateral, intermittent headache associated with photophobia and visual aura. He noticed that his eyes were bloodshot. Three days later, he developed loose, nonwatery, nonbloody diarrhea, associated with fever and rigors, which resolved completely in two days. At presentation, he complained of lethargy, lower-extremity myalgias, tea-coloured urine and intermittent epigastric discomfort. On examination, his temperature was 37.2°C, heart rate 87 beats/min, respiratory rate 18 breaths/min and blood pressure 113/72 mmHg. He had scleral icterus with conjunctival edema (Figure 1). He had no hepatosplenomegaly. His leukocyte count was 19.9×109/L, hemoglobin level 124 g/L and platelet count 24×109/L. His electrolyte levels, bicarbonate levels and anion gap were within normal limits; however, his creatinine level was 352 μmol/L and urea level was 18 mmol/L. His aspartate aminotransferase level was 310 U/L, alanine transaminase level 175 U/L, alkaline phosphatase level 79 U/L and total bilirubin level 191 μmol/L. His initial creatine kinase level was 2343 U/L and troponin I level was 1.6 μg/L. An initial electrocardiogram showed sinus rhythm with first-degree atrioventricular block and an incomplete right bundle branch block. He was admitted with an initial, presumptive diagnosis of hemolytic uremic syndrome or thrombotic thrombocytopenic purpura, and received two units of fresh frozen plasma. A hemolysis work-up returned negative: serum lactate dehydrogenase level was 353 U/L, haptoglobin level 2.9 g/L, total bilirubin level 191 μmol/L, indirect bilirubin level 60 μmol/L and direct bilirubin level 131 μmol/L. On a blood film, fragments were only rarely observed. Abdominal ultrasonography revealed hepatic periportal echogenicity, diffuse renal cortical echogenicity and no hydronephrosis. Echocardiography showed mild concentric left ventricular wall thickening and no regional wall motion abnormalities, with a preserved left ventricular ejection fraction (54%). Furthermore, serology for cytomegalovirus, hepatitis A virus, hepatitis B virus, hepatitis C virus and HIV were negative. Blood films failed to show intraerythrocytic trophozoites. Blood cultures were negative. Stool culture for Escherichia coli O157:H7 was also negative. He remained clinically stable and had good urine output with improving kidney function. However, his leukocyte count increased to 37.6×109/L and his direct bilirubin level and erythrocyte sedimentation rate increased to 169 μmol/L and 110 mm/h, respectively, suggesting progression of his hepatopathy and ongoing systemic inflammation. A diagnostic test was performed. DIAGNOSIS Leptospirosis serology was ordered. The present case contains many classic feature of severe icteric leptospirosis. Jaundice, headache, conjunctival suffusion, myalgias and diarrhea are all common symptoms (1). In severe leptospirosis, a peripheral leukocytosis with left shift occurs. There tends to be a direct hyperbilirubinemia with lesser increases in transaminase levels and slight elevation of alkaline phosphatase levels, which appear to be related to the cholestasis of sepsis. Clinical and biochemical rhabdomyolysis is common (2). Electrocardiographic abnormalities are frequent, including first-degree atrioventricular block and widespread T-wave inversion (3). Leptospirosis-associated myocarditis confers a case mortality rate as high as 54% (1). Severe thrombocytopenia can occur, but this is less common and indicates a poorer prognosis (2). After serum was obtained, the patient was started on intravenous benzylpenicillin 3×106 units every 6 h. He quickly improved clinically. Three days later, he was discharged home on ceftriaxone 1000 mg intravenously daily for a total of 14 days. Three weeks postdischarge, the patient was seen in the outpatient clinic and was clinically well. His creatinine level normalized to 92 μmol/L. His leukocyte count was 8.2×109/L, hemoglobin level 109 g/L and platelet count was 441×109/L. His liver enzyme levels remained mildly elevated (alanine transaminase 147 U/L and alkaline phosphatase 200 U/L). Retrospectively, the patient reported wading in fresh water while in St Lucia two weeks before his presentation to the authors’ hospital as well as seeing rodents around his house. The serum was sent to the National Microbiology Laboratory in Winnipeg, Manitoba. Leptospirosis ELISA for immunoglobulin M was found to be positive using the Panbio Leptospira IgM ELISA (Inverness Medical Innovations Australia Pty Ltd, Australia). Interpretation criteria were as follows: 11, positive. ELISA results were confirmed using a microagglutination test beginning at a screening dilution of 1:100. Further testing revealed Leptospira interrogans serovar Autumnalis as the most likely serovar (titre 1:800).

The molecular pathogenesis of cholestasis in sepsis

Sepsis-induced cholestasis is a complication of infection. Infections cause systemic and intrahepatic increase in proinflammatory cytokines which result in impaired bile flow ie. cholestasis. Several other mediators of impairment in bile flow have been identified under conditions of sepsis such as increased nitric oxide production and decreased aquaporin channels. The development of cholestasis may also further worsen inflammation. The molecular basis of normal bile flow and mechanisms of impairment in sepsis are discussed.

LPS induces the TNF-α-mediated downregulation of rat liver aquaporin-8: role in sepsis-associated cholestasis

Although bacterial lipopolysaccharides (LPS) are known to cause cholestasis in sepsis, the molecular mechanisms accounting for this effect are only partially known. Because aquaporin-8 (AQP8) seems to facilitate the canalicular osmotic water movement during hepatocyte bile formation, we studied its gene and functional expression in LPS-induced cholestasis. By subcellular fractionation and immunoblotting analysis, we found that 34-kDa AQP8 was significantly decreased by 70% in plasma (canalicular) and intracellular (vesicular) liver membranes. However, expression and subcellular localization of hepatocyte sinusoidal AQP9 were unaffected. Immunohistochemistry for liver AQPs confirmed these observations. Osmotic water permeability (P(f)) of canalicular membranes, measured by stopped-flow spectrophotometry, was significantly reduced (65 +/- 1 vs. 49 +/- 1 microm/s) by LPS, consistent with defective canalicular AQP8 functional expression. By Northern blot analysis, we found that 1.5-kb AQP8 mRNA expression was increased by 80%, suggesting a posttranscriptional mechanism of protein reduction. The tumor necrosis factor-alpha (TNF-alpha) receptor fusion protein TNFp75:Fc prevented the LPS-induced impairment of AQP8 expression and bile flow, suggesting the cytokine TNF-alpha as a major mediator of LPS effect. Accordingly, studies in hepatocyte primary cultures indicated that recombinant TNF-alpha downregulated AQP8. The effect of TNF-alpha was prevented by the lysosomal protease inhibitors leupeptin or chloroquine or by the proteasome inhibitors MG132 or lactacystin, suggesting a cytokine-induced AQP8 proteolysis. In conclusion, our data suggest that LPS induces the TNF-alpha-mediated posttranscriptional downregulation of AQP8 functional expression in hepatocytes, a mechanism potentially relevant to the molecular pathogenesis of sepsis-associated cholestasis.

Mechanisms of Disease: mechanisms and clinical implications of cholestasis in sepsis

Cholestasis is a common complication in patients with extrahepatic bacterial infection and sepsis. This article gives a comprehensive overview of the molecular and cellular mechanisms of sepsis-associated cholestasis. Recent advances in the understanding of intrahepatic cholestasis have allowed us to delineate the molecular mechanisms that underlie sepsis-associated cholestasis and to describe their potential clinical and therapeutic applications. The mechanisms and clinical presentation of sepsis-associated liver injury vary according to the severity of the bacterial infection. Proinflammatory cytokines and nitric oxide cause cholestasis by impairing hepatocellular and ductal bile formation. Ischemic liver injury and, rarely, progressive sclerosing cholangitis can also be found in patients with septic shock, or major trauma with systemic inflammatory response syndrome. Treatment is mainly focused on eradication of the underlying infection and managing the sepsis. The use of ursodeoxycholic acid or extracorporeal liver support as treatments for sepsis-associated cholestasis is under investigation, but neither can be recommended in routine clinical practice at present. Patients with progressive sclerosing cholangitis should be considered for orthotopic liver transplantation.

Cholestatic syndromes

This review highlights recent developments in the molecular pathogenesis of cholestasis as well new aspects of pathogenesis and management of clinical cholestatic disorders. Highlights include the role of nuclear receptors including FXR ligands as potential therapeutic agents, new genetic defects for pediatric cholestasis and sclerosing cholangitis, and novel infections and environmental agents as etiologies for primary biliary cirrhosis. Important clinical studies have been published in the area of pediatric cholestatic syndromes, intrahepatic cholestasis of pregnancy, primary biliary cirrhosis, primary and secondary sclerosing cholangitis, cholestasis of sepsis, viral cholestatic syndromes, and drug-induced cholestasis. These advances continue to improve understanding of the pathophysiology, diagnosis, and management of cholestatic liver disease.

Cholestasis of sepsis

Cholestasis of sepsis is a form of hepatocellular cholestasis that occurs as a result of sepsis. Usually, prior to the development of cholestasis, the manifestations of sepsis dominate the clinical picture. The occurrence of cholestasis is without direct bacterial involvement of the biliary system and appears to be mediated systemically by pro-inflammatory cytokines. These cytokines are released in response to the vigorous inflammatory reaction mediated by endotoxinaemia and bacterial wall lipopolysaccharides. The principal cytokines involved are the pro-inflammatory tumour necrosis factor-alpha (TNF-α), interleukin (IL) 1-β and IL-6. Interplay between these cytokines and a series of hepatocyte membrane transporters appears to result in the cholestasis. Management principles focus upon the control of sepsis.