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Much has evolved over the past 25 years regarding our understanding of the coagulopathy of liver disease. Paradoxically, this form of coagulopathy is relatively hypercoagulability despite the common clinical impression of a hemorrhagic tendency. The latter is largely driven by portal-mesenteric venous pressure (ie, portal hypertension) and has little to do with hemostatic pathways. It cannot be emphasized enough that the INR does not offer a meaningful measure in this situation and may lead to interventions such as fresh frozen plasma that can actually worsen portal pressure and hence pressure-driven bleeding. With regard to procedure-related bleeding, we point out substantial differences in the definition of high-risk procedures and propose a new operational definition dependent on the applicability of local hemostatic measures, although this requires further investigation. The common occurrence of venous thrombosis in these patients requires careful consideration of hemostatic pathways and overall risk and benefit of intervention. The decision regarding anticoagulation therapy needs to be driven not only by a global assessment including history of non–portal hypertensive–related bleeding, but also by fall risk which can result in head trauma in patients prone to encephalopathy. This is probably best estimated by frailty but has yet to be adequately investigated. In the background of these concerns, several superimposed and complex conditions including infections and renal dysfunction should be taken into account. Inherited forms of thrombophilia in the setting of cirrhosis perhaps do not outweigh the thrombophilia inherent to liver disease but warrant further consideration. [ABSTRACT FROM AUTHOR]

Much has evolved over the past 25 years regarding our understanding of the coagulopathy of liver disease. Paradoxically, this form of coagulopathy is relatively hypercoagulability despite the common clinical impression of a hemorrhagic tendency. The latter is largely driven by portal-mesenteric venous pressure (ie, portal hypertension) and has little to do with hemostatic pathways. It cannot be emphasized enough that the INR does not offer a meaningful measure in this situation and may lead to interventions such as fresh frozen plasma that can actually worsen portal pressure and hence pressure-driven bleeding. With regard to procedure-related bleeding, we point out substantial differences in the definition of high-risk procedures and propose a new operational definition dependent on the applicability of local hemostatic measures, although this requires further investigation. The common occurrence of venous thrombosis in these patients requires careful consideration of hemostatic pathways and overall risk and benefit of intervention. The decision regarding anticoagulation therapy needs to be driven not only by a global assessment including history of non–portal hypertensive–related bleeding, but also by fall risk which can result in head trauma in patients prone to encephalopathy. This is probably best estimated by frailty but has yet to be adequately investigated. In the background of these concerns, several superimposed and complex conditions including infections and renal dysfunction should be taken into account. Inherited forms of thrombophilia in the setting of cirrhosis perhaps do not outweigh the thrombophilia inherent to liver disease but warrant further consideration. [ABSTRACT FROM AUTHOR]

The coagulation system is known to be rebalanced but fragile in stable cirrhosis. Acute kidney injury (AKI) is common in these patients and associated with an increased bleeding risk. We aimed to assess coagulation parameters in this population. We prospectively enrolled 43 hospitalized patients with decompensated cirrhosis with (n = 22) or without (n = 21) AKI. Coagulation factor levels, viscoelastic coagulation assay, and thrombin generation assay were performed and compared between these groups and a healthy reference group. Conventional markers of coagulation were not statistically different between patients with and without AKI. Factor XIII was significantly reduced in all patients with cirrhosis compared to healthy controls (p = <0.0001). In patients with AKI, factor XIII was significantly lower compared to patients without AKI (AKI 38% vs. non-AKI 60% p = 0.002). In patients with cirrhosis, factor XIII had a significantly positive correlation with EXTEM maximal clot firmness (r = 0.5440, p = 0.0002) and FIBTEM maximal clot firmness (r = 0.7397, p = <0.0001) and a negative correlation with EXTEM clot formation time (−0.413, p = 0.0065). Factor XIII was significantly reduced in decompensated cirrhosis patients with AKI compared to decompensated patients without AKI. These findings suggest that exacerbation of factor XIII deficiency in AKI in decompensated cirrhosis may affect bleeding risk and warrants further study. [ABSTRACT FROM AUTHOR]

Ectopic varices (ECV) are a heterogeneous group of portosystemic shunts that occur in the presence of portal hypertension. The shunts occur throughout the abdomen and pelvis, including the gallbladder, the genitourinary system, and the retroperitoneal space, but they are most common within the bowel (small intestine and colon) and at the mucocutaneous junction of a stoma. Bleeding rates vary depending on the location, but overall, ECV account for 1%-5% of all variceal bleeding and can lead to significant morbidity and mortality. Management of these shunts can be very difficult owing to complex underlying vascular anatomy. Although there is a role for endoscopic intervention in these cases, definitive therapy by this modality is often unachievable, necessitating complex endovascular procedures to ultimately occlude the shunt. Understanding the anatomy, the reported success rates with various procedural interventions, and the complications of those interventions is of the utmost importance in the management of ECV and will be reviewed here in detail. [ABSTRACT FROM AUTHOR]

Primary sclerosing cholangitis (PSC) is a major unmet medical need in clinical hepatology. Cilofexor is a nonsteroidal farnesoid X receptor agonist being evaluated for the treatment of PSC. Here, we describe the safety and preliminary efficacy of cilofexor in a 96-week, open-label extension (OLE) of a phase II trial. Noncirrhotic subjects with large-duct PSC who completed the 12-week, blinded phase of a phase II study (NCT02943460) were eligible, after a 4-week washout period, for a 96-week OLE with cilofexor 100 mg daily. Safety, liver biochemistry, and serum markers of fibrosis, cellular injury, and pharmacodynamic effects of cilofexor (fibroblast growth factor 19, C4, and bile acids [BAs]) were evaluated. Among 52 subjects enrolled in the phase II study, 47 (90%) continued in the OLE phase (median age, 44 years; 60% male patients, 60% with inflammatory bowel disease, and 45% on ursodeoxycholic acid [UDCA]). At OLE baseline (BL), the median serum alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) were 368 U/L (interquartile range [IQR], 277–468 U/L) and 417 U/L (IQR, 196–801 U/L), respectively. Of the 47 subjects enrolled, 15 (32%) discontinued treatment prematurely (pruritus [n = 5], other adverse events [n = 5], subject decision/investigator discretion [n = 5]). At week 96, reductions in liver biochemistry parameters occurred, including serum ALP (median, −8.3% [IQR, −25.9% to 11.0%]; P =.066), GGT (−29.8% [IQR, −42.3% to −13.9%]; P <.001), alanine aminotransaminase (ALT) (−29.8% [IQR, −43.7% to −6.6%]; P =.002), and aspartate aminotransaminase (AST) (−16.7% [IQR, −35.3% to 1.0%]; P =.010), and rebounded after 4 weeks of untreated follow-up. ALP response (≥20% reduction from BL to week 96) was similar in the presence or absence of UDCA therapy (29% vs 39%; P =.71). At week 96, cilofexor treatment was associated with a significant reduction in serum 7α-hydroxy-4-cholesten-3-one (C4) (−29.8% [IQR, −64.3% to −8.5%]; P =.001). In subjects with detectable serum BAs at BL (n = 40), BAs decreased −23.9% (IQR, −44.4% to −0.6%; P =.006) at week 48 (n = 28) and −25.7% (IQR, −35.9% to 53.7%; P =.91) at week 96 (n = 26). Serum cytokeratin 18 (CK18) M30 and M65 were reduced throughout the OLE; significant reductions were observed at week 72 (CK18 M30, −17.3% [IQR, −39.3% to 8.8%]; P =.018; CK18 M65, −43.5% [IQR, −54.9% to 15.3%]; P =.096). At week 96, a small, but statistically significant absolute increase of 0.15 units in Enhanced Liver Fibrosis score was observed compared with BL (median, 9.34 vs 9.53; P =.028). In this 96-week OLE of a phase II study of PSC, cilofexor was safe and improved liver biochemistry and biomarkers of cholestasis and cellular injury. ClinicalTrials.gov identifier: NCT02943460 [ABSTRACT FROM AUTHOR]

The coagulopathy of liver disease is distinctly different from therapeutic anticoagulation in a patient. Despite stable elevated standard clot-based coagulation assays, nearly all patients with stable chronic liver disease (CLD) have normal or increased clotting. Common unfamiliarity with the limitations of these assays in CLD may lead to inappropriate and sometimes harmful interventions, including blood product transfusions before a procedure. Knowledge of the distinct hemostatic alterations in CLD can allow identification of the small subset of patients with clinically significant coagulopathy who can benefit from hematologic optimization before invasive procedures. [ABSTRACT FROM AUTHOR]

An improved understanding of non-alcoholic fatty liver disease epidemiology would lead to identification of individuals at high risk of developing chronic liver disease and extra-hepatic complications, thus contributing to more effective case finding of non-alcoholic fatty liver disease among selected groups. We aimed to illustrate the epidemiology of non-alcoholic fatty liver disease in high-risk groups, which were identified based on existing literature. To this end, PubMed was searched to retrieve original articles published until May 2015 using relevant and pertinent keywords “nonalcoholic fatty liver disease” and “diabetes”, “obesity”, “hyperlipidaemia”, “familial heterozygous hypobetalipoproteinaemia”, “hypertension”, “metabolic syndrome”, “ethnicity”, “family history” or “genetic polymorphisms”. We found that age, sex and ethnicity are major physiological modifiers of the risk of non-alcoholic fatty liver disease, along with belonging to “non-alcoholic fatty liver disease families” and carrying risk alleles for selected genetic polymorphisms. Metabolic syndrome, diabetes, obesity, mixed hyperlipidaemia and hypocholesterolaemia due to familial hypobetalipoproteinaemia are the major metabolic modifiers of non-alcoholic fatty liver disease risk. Compared with these metabolic conditions, however, arterial hypertension appears to carry a relatively more modest risk of non-alcoholic fatty liver disease. A better understanding of the epidemiology of non-alcoholic fatty liver disease may result in a more liberal policy of case finding among high-risk groups. [ABSTRACT FROM AUTHOR]

Two patients presented with bleeding duodenal varices secondary to mesenteric and portal vein chronic occlusion. After a failed transhepatic recanalization, a combined transmesenteric and transhepatic approach was used to recanalize the chronic portal and mesenteric venous obstruction. The occluded segment was treated with transmesenteric stent placement in one patient and stent placement and coil embolization of varices in the second patient. Follow-up imaging and endoscopy showed decompression of the duodenal varices in both patients and absence of further bleeding episodes. [ABSTRACT FROM AUTHOR]

Abstract: Lipid deposition in the liver is associated with metabolic disorders including fatty liver disease, type II diabetes, and hepatocellular cancer. The enzymes acetyl-CoA carboxylase 1 (ACC1) and ACC2 are powerful regulators of hepatic fat storage; therefore, their inhibition is expected to prevent the development of fatty liver. In this study we generated liver-specific ACC1 and ACC2 double knockout (LDKO) mice to determine how the loss of ACC activity affects liver fat metabolism and whole-body physiology. Characterization of LDKO mice revealed unexpected phenotypes of increased hepatic triglyceride and decreased fat oxidation. We also observed that chronic ACC inhibition led to hyper-acetylation of proteins in the extra-mitochondrial space. In sum, these data reveal the existence of a compensatory pathway that protects hepatic fat stores when ACC enzymes are inhibited. Furthermore, we identified an important role for ACC enzymes in the regulation of protein acetylation in the extra-mitochondrial space. [Copyright &y& Elsevier]

Abstract: Purpose: To assess the short-term rebleeding rate associated with the use of a transjugular intrahepatic portosystemic shunt (TIPS) compared with balloon-occluded retrograde transvenous obliteration (BRTO) for management of gastric varices (GV). Materials and Methods: A single-center retrospective comparison of 50 patients with bleeding from GV treated with a TIPS or BRTO was performed. Of 50 patients, 27 (17 men and 10 women; median age, 55 y; range, 31–79 y) received a TIPS with covered stents, and 23 (12 men and 11 women; median age, 52 y; range, 23–83 y) underwent a BRTO procedure with a foam sclerosant. All study subjects had clinical and endoscopic evidence of isolated bleeding GV and were hemodynamically stable at the time of the procedure. Clinical and endoscopic follow-up was performed. Kaplan-Meier analysis was used to evaluate rebleeding rates from the GV. Results: The technical success rate was 100% in the TIPS group and 91% in the BRTO group (P = .21). Major complications occurred in 4% of the patients receiving TIPS and 9% of patients the undergoing BRTO (P = .344). Encephalopathy was reported in 4 of 27 (15%) patients in the TIPS group and in none of the patients in the BRTO group (0%; P = .12). At 12 months, the incidence of rebleeding from a GV source was 11% in the TIPS group and 0% in the BRTO group (P = .25). Conclusions: BRTO appears to be equivalent to TIPS in the short-term for management of bleeding GV. Further comparative studies are warranted to determine optimal management strategies in individual patients. [Copyright &y& Elsevier]

The human hemostasis system is complex and poorly understood after decades of intense scientific study. Despite multiple defects in routine coagulation laboratory studies in patients with chronic liver disease, there is growing evidence that these patients are effectively “rebalanced” with regard to procoagulant and anticoagulant activity and that most of these patients remain in a tenuous but balanced state of hemostasis. A major difficulty in the assessment of these patients is that there are no established laboratory tests that accurately reflect the changes in both the procoagulant and anticoagulant systems; therefore, routine laboratory testing is misleading to the clinician and may prompt inappropriate or risky therapies with little real benefit to the patient. The international normalized ratio is an example of this type of misleading test. Although the international normalized ratio is inextricably linked to prognosis and severity of protein synthetic dysfunction in acute and chronic liver disease, it is a very poor marker for bleeding risk and should not be used in isolation for this purpose. Coagulation disorders are critical in the management of frequent clinical scenarios such as esophageal variceal bleeding, invasive and percutaneous procedures, portal vein thrombosis, venous thromboembolism, and acute liver failure. This article summarizes the pathophysiology of hemostasis in liver disease, describes the strengths and weaknesses of various laboratory tests in assessment of these patients, and outlines the optimal management of hemostasis for some common clinical scenarios. Further research is needed for proper understanding of hemostasis in liver disease to optimally and safely manage these complex patients. [Copyright &y& Elsevier]

Patients with gastric variceal bleeding require a multidisciplinary team approach, which includes hepatologists, endoscopists, diagnostic radiologists, and interventional radiologists. Upper gastrointestinal endoscopy is the first-line diagnosis and management tool for bleeding gastric varices (GVs) as it is with all upper gastrointestinal bleeding scenarios. Traditionally, in the United States, when endoscopy fails to control gastric variceal bleeding, a transjugular intrahepatic portosystemic shunt (TIPS) is performed along the classic teachings of decompressing the portal circulation. However, TIPS has shown inconsistent effectiveness in controlling gastric variceal bleeding. Conversely, the balloon-occluded retrograde transvenous obliteration (BRTO) procedure has become common practice in Asia for the management of GVs. The BRTO procedure is gaining popularity in the United States. BRTO has shown to be effective in controlling gastric variceal bleeding with low gastric variceal rebleed rates. Regardless of the endovascular management (TIPS vs BRTO vs both), a multidisciplinary team with adequate preprocedural clinical assessment and management and endoscopic and imaging evaluation is required before and after the endovascular procedure. The article discusses the pre- and post-BRTO clinical evaluation and management, as well as endoscopic and imaging evaluation. Moreover, the article proposes indications, contraindications, and management protocols for the management of GVs. [ABSTRACT FROM AUTHOR]

Abstract: Bleeding complications, particularly in the gastro-intestinal tract, may complicate the clinical course of liver cirrhosis. Coexistence of abnormal global tests exploring the platelet and clotting systems generated the hypothesis that cirrhotic patients have “coagulopathy” predisposing to bleeding complications. Using more sophisticated laboratory methods this hypothesis has been partly confuted as cirrhotic patients actually disclose an ongoing prothrombotic state in the portal and systemic circulation that could predispose to thrombosis. Recent data of the literature support this hypothesis as portal vein thrombosis and peripheral thrombosis are frequent features of cirrhosis. We reviewed the literature data to assess the prevalence of bleeding and thrombotic complication in cirrhosis and the role of clotting activation in precipitating them. Whilst it appears scarcely relevant the interplay between the so called “coagulopathy” and bleeding, the interplay between clotting activation and thrombosis seems to be relevant but needs more accurate investigation in larger study populations. [Copyright &y& Elsevier]

Abstract: Purpose: Balloon-occluded retrograde transvenous obliteration (BRTO) of bleeding gastric varices (GV) is well described in the literature. Using Ethanolamine oleate as the sclerosing agent in BRTO, but it is not readily available in the United States in the desired concentrations. The authors'' aim is to describe their initial experience with BRTO using sodium tetradecyl sulfate (STS) foam as an alternative sclerosing agent. Materials and Methods: The authors performed a retrospective review of their initial series in which STS foam was used to treat bleeding GV using BRTO. All study subjects had endoscopic evidence of gastric variceal bleeding. STS foam was made using a combination of agents with a 3:2:1 ratio of gas: 3% STS: Lipiodol (Ethiodol; Savage Laboratories, Melville, New York). Mean values and ranges were calculated for each variable, and clinical and imaging outcomes were assessed. Results: The authors performed BRTO in 22 cirrhotic patients (11 men and 11 women) with a mean age of 52 years (range, 23–83 years). Technical success was achieved in 20 of 22 (91%) patients. Complications occurred in three of 22 (14%) patients. The overall mean dose of STS used was 300 mg (range, 30–600 mg) with mean total volume of sclerosant mixture of 34.1 mL (range, 10–65 mL). Follow-up imaging was available for 18 of 20 (90%) technically successful procedures with a mean period of 89 days (range, 1–359 days). Complete obliteration of GV was achieved in 16 of 18 (89%) patients. There were no cases of recurrent variceal bleeding with a mean clinical follow-up period of 130 days (range, 1–510). Conclusions: BRTO utilizing STS foam appears effective in obliterating bleeding GVs with good short-term outcomes. [Copyright &y& Elsevier]

Background and Objectives: Gastric variceal hemorrhage treatment remains a difficult issue for clinicians. There is controversy regarding whether first-line treatment should be endoscopic therapy with cyanoacrylate glue or placement of a transjugular intrahepatic portosystemic shunt (TIPS). We compared these methods on the basis of rebleeding, survival, and complications. Design, Setting, Patients, and Interventions: This was a retrospective cohort analysis of cirrhotic patients with gastric variceal hemorrhage treated with endoscopic cyanoacrylate therapy or TIPS placement at a single U.S. center from 1997 to 2007. The groups were compared for rebleeding at 72 hours, 3 months, and 1 year; survival rates at 3 months and 1 year; and acute and extended complications and morbidity. Main Outcome Measurements and Results: A total of 105 patients were included. There were no significant pretreatment differences between the 2 groups in age, sex, MELD (Model for End-Stage Liver Disease) score at the time of admission, or cause of liver disease. There were no significant differences in rebleeding at 72 hours, 3 months, and 1 year; survival at 3 months and 1 year; and aggregate long-term survival or acute complications. However, the TIPS group had a higher rate of long-term morbidity requiring hospitalization (41% with a TIPS and 1.6% in the cyanoacrylate arm, P < .0001). Limitations: Retrospective and uncontrolled samples. Conclusion: In patients with similar characteristics, cyanoacrylate therapy performed as well as a TIPS in controlling and preventing gastric variceal hemorrhage with no significant differences in survival. Patients receiving cyanoacrylate therapy experienced significantly less long-term morbidity related to therapy than patients who received a TIPS. Cyanoacrylate therapy appears to be safe and effective and compares favorably with TIPS therapy. [Copyright &y& Elsevier]

Gastric varices are found in a significant number of patients with portal hypertension. There are several endoscopic treatment options for gastric varices, but none have gained widespread use among endoscopists. Rubber band ligation of gastric varices has been used with success in several small case series of patients. Detachable snare ligation has also been used, but experience with this technique is limited. Thrombin injection offers a potential treatment option, but it too requires further investigation. Adhesive injection therapy shows much promise in providing successful variceal obliteration in a cost effective manner. Complications, as described with each of these endoscopic methods, require that great care be taken even in the hands of the most experienced endoscopist when treating gastric varices. [Copyright &y& Elsevier]

This expert review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership. The intent is to evaluate the current data on mechanism of altered coagulation in patients with cirrhosis, provide guidance on the use of currently available testing of the coagulation cascade, and help practitioners use anticoagulation and pro-coagulants appropriately in patients with cirrhosis. This review is framed around the best practice points, which were derived from the most impactful publications in the area of coagulation in cirrhosis and agreed to by all authors. Global tests of clot formation, such as rotational thromboelastometry, thromboelastography, sonorheometry, and thrombin generation, may eventually have a role in the evaluation of clotting in patients with cirrhosis, but currently lack validated target levels. In general, clinicians should not routinely correct thrombocytopenia and coagulopathy before low-risk therapeutic paracentesis, thoracentesis, and routine upper endoscopy for variceal ligation in patients with hepatic synthetic dysfunction–induced coagulation abnormalities. Blood products should be used sparingly because they increase portal pressure and carry a risk of transfusion-associated circulatory overload, transfusion-related acute lung injury, infection transmission, alloimmunization, and/or transfusion reactions. The following transfusion thresholds for management of active bleeding or high-risk procedures may optimize clot formation in advanced liver disease: hematocrit ≥25%, platelet count >50,000, and fibrinogen >120 mg/dL. Commonly utilized thresholds for international normalized ratio correction are not supported by evidence. Thrombopoietin agonists are a good alternative to platelet transfusion, but require time (about 10 days) to elevate platelet levels. The large volume of fresh frozen plasma required to reach an arbitrary international normalized ratio target, limitations of the usual target, minimal effect on thrombin generation, and adverse effects on portal pressure limit the utility of this agent significantly. The 4-factor prothrombin complex concentrate contains both pro- and anticoagulant factors that offer an attractive low-volume therapeutic to rebalance a disturbed hemostatic system. However, dosage is, in part, based on international normalized ratio, which is problematic in cirrhosis, and published experience in liver disease is limited. Anti-fibrinolytic therapy may be considered in patients with persistent bleeding from mucosal oozing or puncture wound bleeding consistent with impaired clot integrity. Both ε-aminocaproic acid and tranexamic acid inhibit clot dissolution. Neither is believed to generate a hypercoagulable state, although both may exacerbate pre-existing thrombi. Desmopressin releases von Willebrand factor as its primary hemostatic mechanism. As this factor is usually elevated in cirrhosis, the agent lacks a sound evidence-based foundation, but may be useful in patients with concomitant renal failure. Systemic heparin infusion is recommended for symptomatic deep vein thrombosis and portal and mesenteric vein thrombosis, but there are unresolved issues regarding monitoring with both the anti-Xa assay and the partial thromboplastin time due to cirrhosis-related antithrombin deficiency (heparin cofactor). Treatment of incidental portal and mesenteric vein thrombosis depends on estimated impact on transplantation surgical complexity vs risks of bleeding and falls. Therapy with low-molecular-weight heparin, vitamin K antagonists, and direct-acting anticoagulants improve portal vein repermeation vs observation alone. Direct-acting anticoagulants, such as the factor Xa and thrombin inhibitors, are relatively safe and effective in stable cirrhotic patients, but are in need of further study in patients with more advanced liver disease. [ABSTRACT FROM AUTHOR]

Portal vein thrombosis unrelated to solid malignancy is common in patients with cirrhosis, but less frequently observed in patients without cirrhosis. Prompt diagnosis and management of acute symptomatic portal vein thrombosis are essential. Failure to detect and treat thromboses can result in mesenteric ischemia, chronic cavernous transformation, and complications of portal hypertension. In patients with cirrhosis, development of portal vein thrombosis is often insidious and remains undetected until its incidental detection. Management of portal vein thrombosis in patients with cirrhosis is more controversial. However, there are data to support treatment of specific patients with anticoagulation agents. We review the common and distinct features of portal vein thromboses in patients without liver tumors, with and without cirrhosis. [ABSTRACT FROM AUTHOR]