Nicolas M. Intagliata

Excess mortality on the liver transplant waiting list: Unintended policy consequences and model for End‐Stage Liver Disease (MELD) inflation

The Model for End‐Stage Liver Disease (MELD) allocation system for liver transplantation provides “exceptions” for diseases such as hepatocellular carcinoma (HCC). It was the aim of this study to assess equipoise between exception candidates and nonexception candidates on the waiting list and to assess if the exception system contributes to steadily increasing regional MELD at transplant. In all, 78,595 adult liver transplant candidates between January 2005 and December 2012 were analyzed. Yearly trends in waiting list characteristics and transplantation rates were analyzed for statistical association with MELD exceptions. Regional variations in these associations and the effect of exceptions on regional MELD scores at transplant were also analyzed. 27.29% of the waiting list was occupied by candidates with exceptions. Candidates with exceptions fared much better on the waiting list compared to those without exceptions in mean days waiting (HCC 237 versus non‐HCC 426), transplantation rates (HCC 79.05% versus non‐HCC 40.60%), and waiting list death rates (HCC 4.49% versus non‐HCC 24.63%). Strong regional variation in exception use occurred but exceptions were highly correlated with waiting list death rates, transplantation rates, and MELD score at removal in all regions. In a multivariate model predicting MELD score at transplant within regions, the percentage of HCC MELD exceptions was the strongest independent predictor of regional MELD score at transplant. Conclusion: Liver transplant candidates with MELD exceptions have superior outcomes compared to nonexception candidates and the current MELD exception system is largely responsible for steadily increasing MELD scores at transplant independent of geography. (Hepatology 2015;61:285–291)

Prophylactic anticoagulation for venous thromboembolism in hospitalized cirrhosis patients is not associated with high rates of gastrointestinal bleeding

Hospitalized patients with cirrhosis are at risk to develop venous thromboembolism. Although current guidelines support the routine administration of thromboprophylaxis to hospitalized patients, there is limited data regarding the safety or efficacy of this practice in hospitalized cirrhosis patients.

Hepatic Decompensation Likely Attributable to Simeprevir in Patients with Advanced Cirrhosis

BackgroundHyperbilirubinemia is a common side effect of protease inhibitors used to treat chronic hepatitis C (HCV), and most patients do not experience without clinically overt hepatotoxicity. The safety of second-wave protease inhibitors, including simeprevir, has not been well studied in patients with advanced cirrhosis.Materials & MethodsWe report two cases of suspected drug-induced liver injury leading to hepatic decompensation in patients with advanced HCV cirrhosis treated with the combination of simeprevir and sofosbuvir on a compassionate basis. Both patients developed marked hyperbilirubinemia out of proportion to their aminotransferases, despite clearance of hepatitis C RNA. RUCAM scoring was probable and possible, respectively. While other factors may have contributed to the liver injury, including infection and concurrent administration of other medications, we believe that the potentially deleterious hepatic effects of simeprevir on transporters or other key functional components were the main reason for their decompensation.ConclusionsProtease inhibitors should be used with caution, if at all, in patients with cirrhosis, especially in those with the most advanced disease. We await newer, safer, direct-acting antiviral therapies for such patients, especially those on our transplant list.

Procoagulant therapeutics in liver disease: a critique and clinical rationale

The complex nature of haemostasis in patients with liver disease can result in bleeding and/or thrombosis. These opposing outcomes, which have multiple contributing factors, can pose diagnostic and therapeutic dilemmas for physicians. With the high rate of haemorrhagic complications in patients with cirrhosis, we examine the various procoagulants available for use in this population. In this Review, we describe the clinical and current rationale for using each of the currently available procoagulants—vitamin K, fresh frozen plasma (FFP), cryoprecipitate, platelets, recombinant factor VIIa (rFVIIa), antifibrinolytics, prothrombin concentrate complexes (PCC), desmopressin and red blood cells. By examining the evidence and use of these agents in liver disease, we provide a framework for targeted, goal-directed therapy with procoagulants.

Direct Oral Anticoagulants in Cirrhosis

Opinion statementThe risk of thrombosis in patients with chronic liver disease is increasingly recognized. As patients with cirrhosis develop indications for anticoagulation therapy (e.g., venous thromboembolism, portal vein thrombosis, or atrial fibrillation), providers are left to make difficult decisions when selecting therapeutics with little evidence to rely on. Current practice supports the use of low molecular weight heparin or vitamin K antagonists in select patients with cirrhosis requiring anticoagulation. While traditional anticoagulants may be safe and effective in select patients with compensated cirrhosis, the use of direct oral anticoagulants (DOAC) is more controversial. DOAC are desirable as they do not require routine monitoring and can be taken orally. Unfortunately, patients with chronic liver disease were excluded from clinical trials that demonstrated efficacy and safety when compared to traditional anticoagulation. Data are now emerging that support the use of DOAC in well-compensated cirrhosis patients. However, further study is needed with all (traditional and DOAC) anticoagulation medications in patients with cirrhosis to better ensure safety and further understand pharmacologic properties in this challenging population.

Anticoagulation in cirrhosis patients: What don't we know?

Patients admitted to the hospital are at high risk for developing venous thrombosis when compared with the general population (1, 2). Prophylaxis with unfractionated heparin or low-molecular-weight heparin (LMWH) decreases the risk of development of venous thrombosis in hospitalized medical patients (3). Current guidelines recommend venous thrombosis prophylaxis for hospitalized medical patients who will be confined to a bed (4). Hospitalized patients with cirrhosis are also known to be at risk to develop deep venous thrombosis (5–9). They are often rendered immobile because of complications like encephalopathy, ascites, oedema or muscle wasting. As it is well established that prophylaxis decreases the risk of venous thrombosis in hospitalized patients, it is currently unclear if a similar benefit would extend to patients with cirrhosis. The article in this issue of Liver International by Bechmann et al. (10) provides one of the first studies to specifically examine the effects of venous thrombosis prophylaxis in this unique population. This study evaluates the efficacy of using anti-Xa values to monitor and guide dosing of LMWH in cirrhotic patients receiving both prophylactic and therapeutic doses of LMWH. Using anti-Xa levels to measure effect in prophylactic or therapeutic dosing of LMWH is only routinely indicated in special patient populations, such as those with renal failure or advanced age. However, cirrhotic patients have not been well studied and pharmacodynamic data regarding LMWH in patients with cirrhosis are scarce. Patients admitted with cirrhosis who met inclusion criteria (prolonged immobilization, advanced age, low levels of protein C and protein S, malignancy, known thrombophilia, stroke, shock, prior thrombotic events) were enrolled. Patients with a recent major bleeding event, creatinine clearance o 30 ml/min or history of heparin-induced thrombocytopenia were excluded. A smaller cohort of nine patients that needed full dose therapeutic LMWH for known thrombosis was also followed. Although not powered to evaluate for safety of LMWH, there were no reported deaths and no thrombotic events in either group. The authors cite bleeding events that were similar to previous studies in hospitalized patients with cirrhosis. By measuring levels of anti-Xa activity, they found that only 11 out of 75 patients in the prophylaxis group and zero out of nine in the therapeutic group achieved therapeutic dosing levels using standard weight-based regimens of LMWH, regardless of dose adjustments. Interestingly, a negative correlation was found between levels of anti-Xa and severity of liver disease as defined by Childs–Pugh– Turcotte, model for end-stage liver disease and the presence of ascites. A positive correlation was found between levels of antithrombin (AT) and anti-Xa. Because cirrhotic patients are deficient in AT, the authors argue that these findings may indicate that current dosing guidelines are not effective for cirrhotic patients. The authors conclude that either current assays measuring anti-Xa are inaccurate in cirrhotic patients, or that the acquired deficiency of AT inherent in cirrhosis may lead to reduced efficacy of LMWH. Anti-Xa levels may not be an accurate way to assess the degree of anticoagulation provided by standard dosing of LMWH in cirrhotic patients. Coagulopathy of liver disease is a complex interplay between proand anticoagulant factors that are not accurately assessed by currently available biochemical indices (11–14). The apparent propensity to bleed or alternatively to develop clot presents a challenging clinical paradox to physicians that care for this patient population. This study re-inforces the evolving notion among hepatologists that current laboratory tests to evaluate coagulopathy cannot be extrapolated and applied to cirrhotic patients. For example, the commonly held misconception that an elevated INR provides a ‘protective’ barrier to developing thrombosis remains unfortunately pervasive in the medical community. While coagulation parameters can often be abnormal in patients with cirrhosis, the values per se have little predictive value on bleeding risk (15, 16). In this study, the authors found that the majority of patients did not achieve therapeutic effect as measured by anti-Xa levels with current standard-dose regimens of LMWH. This apparent decreased efficacy of LMWH in cirrhotic patients is an important finding. This study is the first, to our knowledge, to report this in the cirrhosis patient population. While decreased efficacy may indeed argue for altering dosing patterns in cirrhotic patients, the authors also suggest that inaccuracies inherent in classical anti-Xa assays may lead to false conclusions. It is becoming increasingly apparent that cirrhotic patients are prone to developing venous thrombosis. This study shows us that future investigation aimed at evaluation of safety, dosing and monitoring of these medications are desperately needed before definitive recommendations for prophylaxis and treatment of thrombosis can be developed. While they did not specifically state their dosing adjustment methods in this study, it is an

Prediction of bleeding in cirrhosis patients: Is the forecast any clearer?

We read with great interest the article by De Pietri and colleagues evaluating the use of viscoelastic testing (thromboelastography [TEG]) as a guide to prophylactic blood product transfusion prior to procedures in patients with cirrhosis. This provocative study is timely as the dogma of coagulation in cirrhosis has undergone significant revision in the last several years. Evidence clearly indicates that conventional coagulation tests such as prothrombin time/international normalized ratio do not reliably predict bleeding in patients with cirrhosis. The authors should be commended for approaching such a clinically important and relevant topic with such rigor. Prophylactic transfusion to prevent bleeding before a procedure has been a common practice in patients with liver disease yet lacks supportive evidence. In fact, liver transplantation can be performed without the requirement of any blood products in some patients, despite prolonged conventional coagulation tests. The authors demonstrated that using TEG parameters resulted in significantly fewer transfusions. This is a clinically very important result. However, the question remains whether a transfusion prompt based on TEG results is comparable to that commonly used for conventional coagulations tests, such as prothrombin time/international normalized ratio. In other words, did TEG testing simply result in a higher transfusion threshold compared to conventional coagulation tests, and does that explain this observed benefit? Moreover, it must also be noted that use of TEG parameters presupposes the test’s ability to accurately define risk and guide intervention. To our knowledge, TEG has never been shown to predict bleeding in patients with cirrhosis. The primary clinical use of viscoelastic testing in cirrhosis has been in patients undergoing liver transplantation as a point of care guide to intraoperative transfusion therapy. The question thus remains, are prophylactic transfusions, irrespective of “normal” or “abnormal” preprocedural testing, necessary at all for most procedures? Recent advances in understanding the coagulopathy of liver disease raise the question of the need for a third cohort in which no prophylactic transfusions of platelets or fresh frozen plasma are given prior to procedures. An alternative approach to patients undergoing low-risk to moderate-risk procedures may be to consider “rescue” therapy in the event of bleeding, rather than prophylactic therapy aimed at an unproven predictive marker. This approach would certainly minimize the use of unnecessary transfusion even further and is well supported by experience in liver transplant. TEG, in this case, represents a reference point to calibrate prophylactic transfusion goals that ipso facto do not change the inherent risk of bleeding. While the use of TEG reduced transfusion overall, it is not clear that reliance on this measure, without a proven ability to predict bleeding in cirrhosis, gains us any further insight into an authentic need for prophylactic transfusions. The one significant bleeding event in this study was hemoperitoneum after paracentesis. As the authors note, it is likely this bleeding would have occurred irrespective of transfusion because of a mechanical injury to a blood vessel. We commend the authors for efforts at a more rational and “physiologic” approach to determining bleeding risk in this challenging population. TEG may help to decrease the practice of unnecessary and harmful transfusion prophylaxis in this population; however, we question if the widespread use of this testing would gain us any significant predictive advantage over the current clinically available tests. Future studies should include patients who do not receive prophylactic transfusions, with a carefully constructed rescue plan should bleeding occur.

Decreased Portal Vein Velocity is Predictive of the Development of Portal Vein Thrombosis: a Matched Case-Control Study

Portal vein thrombosis (PVT) in cirrhosis may lead to hepatic decompensation and increased mortality. We aimed to investigate if decreased portal vein (PV) velocity is associated with future PVT.

Dismantling the myth of "autoanticoagulation" in cirrhosis: an old dogma dies hard.

Autophagy is a cellular catabolic process that relies on the cooperation of autophagosomes and lysosomes. During starvation, the cell expands both compartments to enhance degradation processes. We found that starvation activates a transcriptional program that controls major steps of the autophagic pathway, including autophagosome formation, autophagosomelysosome fusion, and substrate degradation. The transcription factor EB (TFEB), a master gene for lysosomal biogenesis, coordinated this program by driving expression of autophagy and lysosomal genes. Nuclear localization and activity of TFEB were regulated by serine phosphorylation mediated by the extracellular signal-regulated kinase 2, whose activity was tuned by the levels of extracellular nutrients. Thus, a mitogen-activated protein kinase-dependent mechanism regulates autophagy by controlling the biogenesis and partnership of two distinct cellular organelles.

Thrombosis of the Portal Venous System in Cirrhotic vs.Non-Cirrhotic Patients

INTRODUCTION AND AIM Thrombosis is a vascular disorder of the liver often associated with significant morbidity and mortality. Cirrhosis is a predisposing factor for portal venous system thrombosis. The aim of this study is to determine differences between cirrhotics and non-cirrhotics that develop thrombosis in portal venous system and to evaluate if cirrhosis severity is related to the development of portal venous system thrombosis. MATERIAL AND METHODS We studied patients diagnosed with portal venous system thrombosis using contrast-enhanced computed tomography scan and doppler ultrasound at Medica Sur Hospital from 2012 to 2017. They were categorized into two groups; cirrhotics and non-cirrhotics. We assessed the hepatic function by Child-Pugh score and model for end-stage liver disease. RESULTS 67 patients with portal venous system thrombosis (25 with non-cirrhotic liver and 42 with cirrhosis) were included. The mean age (± SD) was 65 ± 9.5 years in cirrhotic group and 57 ± 13.2 years (p = 0.009) in noncirrhotic group. Comparing non-cirrhotics and cirrhotics, 8 non-cirrhotic patients showed evidence of extra-hepatic inflammatory conditions, while in the cirrhotic group no inflammatory conditions were found (p < 0.001). 27 (64.29%) cirrhotic patients had thrombosis in the portal vein, while only 9 cases (36%) were found in non-cirrhotics (p = 0.02). CONCLUSIONS In cirrhotic patients, hepatocellular carcinoma and cirrhosis were the strongest risk factors to develop portal venous system thrombosis. In contrast, extrahepatic inflammatory conditions were main risk factors associated in non-cirrhotics. Moreover, the portal vein was the most frequent site of thrombosis in both groups.INTRODUCTION AND AIM Thrombosis is a vascular disorder of the liver often associated with significant morbidity and mortality. Cirrhosis is a predisposing factor for portal venous system thrombosis. The aim of this study is to determine differences between cirrhotics and non-cirrhotics that develop thrombosis in portal venous system and to evaluate if cirrhosis severity is related to the development of portal venous system thrombosis. MATERIAL AND METHODS We studied patients diagnosed with portal venous system thrombosis using contrast-enhanced computed tomography scan and doppler ultrasound at Medica Sur Hospital from 2012 to 2017. They were categorized into two groups; cirrhotics and non-cirrhotics. We assessed the hepatic function by Child-Pugh score and model for end-stage liver disease. RESULTS 67 patients with portal venous system thrombosis (25 with non-cirrhotic liver and 42 with cirrhosis) were included. The mean age (± SD) was 65 ± 9.5 years in cirrhotic group and 57 ± 13.2 years (p = 0.009) in non-cirrhotic group. Comparing non-cirrhotics and cirrhotics, 8 non-cirrhotic patients showed evidence of extra-hepatic inflammatory conditions, while in the cirrhotic group no inflammatory conditions were found (p < 0.001). 27 (64.29%) cirrhotic patients had thrombosis in the portal vein, while only 9 cases (36%) were found in non-cirrhotics (p = 0.02). CONCLUSIONS In cirrhotic patients, hepatocellular carcinoma and cirrhosis were the strongest risk factors to develop portal venous system thrombosis. In contrast, extrahepatic inflammatory conditions were main risk factors associated in non-cirrhotics. Moreover, the portal vein was the most frequent site of thrombosis in both groups.