François Durand

Acute-on-Chronic Liver Failure Is a Distinct Syndrome That Develops in Patients With Acute Decompensation of Cirrhosis

BACKGROUND & AIMS Patients with cirrhosis hospitalized for an acute decompensation (AD) and organ failure are at risk for imminent death and considered to have acute-on-chronic liver failure (ACLF). However, there are no established diagnostic criteria for ACLF, so little is known about its development and progression. We aimed to identify diagnostic criteria of ACLF and describe the development of this syndrome in European patients with AD. METHODS We collected data from 1343 hospitalized patients with cirrhosis and AD from February to September 2011 at 29 liver units in 8 European countries. We used the organ failure and mortality data to define ACLF grades, assess mortality, and identify differences between ACLF and AD. We established diagnostic criteria for ACLF based on analyses of patients with organ failure (defined by the chronic liver failure-sequential organ failure assessment [CLIF-SOFA] score) and high 28-day mortality rate (>15%). RESULTS Of the patients assessed, 303 had ACLF when the study began, 112 developed ACLF, and 928 did not have ACLF. The 28-day mortality rate among patients who had ACLF when the study began was 33.9%, among those who developed ACLF was 29.7%, and among those who did not have ACLF was 1.9%. Patients with ACLF were younger and more frequently alcoholic, had more associated bacterial infections, and had higher numbers of leukocytes and higher plasma levels of C-reactive protein than patients without ACLF (P < .001). Higher CLIF-SOFA scores and leukocyte counts were independent predictors of mortality in patients with ACLF. In patients without a prior history of AD, ACLF was unexpectedly characterized by higher numbers of organ failures, leukocyte count, and mortality compared with ACLF in patients with a prior history of AD. CONCLUSIONS We analyzed data from patients with cirrhosis and AD to establish diagnostic criteria for ACLF and showed that it is distinct from AD, based not only on the presence of organ failure(s) and high mortality rate but also on age, precipitating events, and systemic inflammation. ACLF mortality is associated with loss of organ function and high leukocyte counts. ACLF is especially severe in patients with no prior history of AD.

Assessment of the benefits and risks of percutaneous biopsy before surgical resection of hepatocellular carcinoma

BACKGROUND/AIMS Because of a potential risk of needle tract seeding, the use of ultrasound (US)-guided biopsy for the diagnosis of hepatocellular carcinoma (HCC) is controversial. This study was aimed at determining the usefulness, accuracy and safety of this technique as well as the incidence of needle tract seeding. METHODS From 1986 to 1996, 137 patients who underwent resection or transplantation for suspected HCC had US-guided biopsy before surgery. The analysis of the resected liver was compared to the results of biopsy. Patients were assessed with a mean follow up of 38 months. RESULTS The diagnosis of HCC was established by biopsy in 122 patients (89%). Thirteen of the 15 patients with negative biopsy were shown to have HCC after surgery. The remaining two patients had non-malignant nodules. Sensitivity and accuracy of US-guided biopsy were 90 and 91%, respectively. Accuracy was significantly influenced by the location of the nodule but not by its size. Needle tract seeding occurred in two patients (1.6%). CONCLUSIONS In this series, the incidence of needle tract seeding was less than 2% and no recurrence was observed after local excision. This risk should be balanced with the risk of deciding an aggressive treatment in a patient without malignancy. Patients with negative biopsy should undergo a second biopsy and/or repeated investigations by imaging techniques.

Aiming at minimal invasiveness as a therapeutic strategy for Budd‐Chiari syndrome

The 1‐year spontaneous mortality rate in patients with Budd‐Chiari syndrome (BCS) approaches 70%. No prospective assessment of indications and impact on survival of current therapeutic procedures has been performed. We evaluated a therapeutic strategy uniformly applied during the last 8 years in a single referral center. Fifty‐one consecutive patients first received anticoagulation and were treated for associated diseases. Symptomatic patients were considered for hepatic vein recanalization; then for transjugular intrahepatic portosystemic shunt (TIPS), and finally for liver transplantation. The absence of a complete response led to the next procedure. Assessment was according to the strategy, whether procedures were technically applicable and successful. At entry, median (range) Child‐Pugh score and Clichy prognostic index were 8 (5–12), and 5.4 (3.1–7.7), respectively. A complete response was achieved on medical therapy alone in 9 patients; after recanalization in 6, TIPS in 20, liver transplantation in 9, and retransplantation in 1. Of the 41 patients considered for recanalization, the procedure was not feasible in 27 and technically unsuccessful in 3. Of the 34 patients considered for TIPS, the procedure was considered not feasible in 9 and technically unsuccessful in 4. At 1 year of follow‐up, a complete response to TIPS was achieved in 84%. One‐ and 5‐year survival from starting anticoagulation were 96% (95% CI, 90–100) and 89% (95% CI, 79–100), respectively. In conclusion, excellent survival can be achieved in BCS patients when therapeutic procedures are introduced by order of increasing invasiveness, based on the response to previous therapy rather than on the severity of the patients condition. (HEPATOLOGY 2006;44:1308–1316.)

Portal vein thrombosis, cirrhosis, and liver transplantation

Portal vein thrombosis is not uncommon in candidates for transplantation. Partial thrombosis is more common than complete thrombosis. Despite careful screening at evaluation, a number of patients are still found with previously unrecognized thrombosis per-operatively. The objective is to recanalize the portal vein or, if recanalization is not achievable, to prevent the extension of the thrombus so that a splanchnic vein can be used as the inflow vessel to restore physiological blood flow to the allograft. Anticoagulation during waiting time and transjugular intrahepatic portosystemic shunt (TIPS) are two options to achieve these goals. TIPS may achieve recanalization in patients with complete portal vein thrombosis. However, a marked impairment in liver function, which is a characteristic feature of most candidates for transplantation, may be a contraindication for TIPS. Importantly, the MELD score is artificially increased by the administration of vitamin K antagonists due to prolonged INR. When patency of the portal vein and/or superior mesenteric vein is not achieved, only non-anatomical techniques (renoportal anastomosis or cavoportal hemitransposition) can be performed. These techniques, which do not fully reverse portal hypertension, are associated with higher morbidity and mortality risks. Multivisceral transplantation including the liver and small bowel needs to be evaluated. In the absence of prothrombotic states that may persist after transplantation, there is no evidence that pre-transplant portal vein thrombosis justifies long term anticoagulation post-transplantation, provided portal flow has been restored through conventional end-to-end portal anastomosis.

Acute liver cell damage in patients with anorexia nervosa: a possible role of starvation-induced hepatocyte autophagy.

BACKGROUND & AIMS Acute liver insufficiency is a rare complication of anorexia nervosa. The mechanisms for this complication are unclear. The aim of this study was to describe patient characteristics and clarify the mechanisms involved. METHODS Liver specimens from 12 patients (median age, 24 years; median body mass index, 11.3 kg/m(2)), with a prothrombin index <50% and/or an International Normalized Ratio >1.7 and anorexia nervosa as the only cause for acute liver injury were analyzed. A detailed pathologic examination was performed, including under electron microscopy. RESULTS Liver cell glycogen depletion was a constant finding. There was a contrast between the increase in serum alanine aminotransferase (56 times normal on average; 1,904 IU/L) and the absence of significant hepatocyte necrosis on histology. Centrilobular changes (trabecular atrophy and/or sinusoidal fibrosis) were observed in 6 patients. There were rare or no (<5%) terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive hepatocytes, suggesting that apoptosis was not the primary mechanism. Hepatocytes from 4 patients showed numerous autophagosomes, a morphologic hallmark of autophagy, on electron microscopy. In contrast, the mitochondria, endoplasmic reticulum, and nuclei were normal in most cells. These features were absent in 11 control patients. The outcome was favorable in all patients, with a rapid return to normal liver function. CONCLUSIONS Anorexia nervosa with extremely poor nutritional status should be added to the list of conditions causing acute liver insufficiency. Our findings show that starvation-induced autophagy in the human liver may be involved in liver cell death during anorexia nervosa, even though other mechanisms of liver cell damage could also play a role.

Management of the critically ill patient with cirrhosis: A multidisciplinary perspective.

a r Management of the critically ill patient with cirrhosis: A multidisciplinary perspective Mitra K. Nadim1,⇑, Francois Durand, John A. Kellum, Josh Levitsky, Jacqueline G. O’Leary, Constantine J. Karvellas, Jasmohan S. Bajaj, Andrew Davenport, Rajiv Jalan, Paolo Angeli, Stephen H. Caldwell, Javier Fernández, Claire Francoz, Guadalupe Garcia-Tsao, Pere Ginès, Michael G. Ison, David J. Kramer, Ravindra L. Mehta, Richard Moreau, David Mulligan, Jody C. Olson, Elizabeth A. Pomfret, Marco Senzolo, Randolph H. Steadman, Ram M. Subramanian, Jean-Louis Vincent, Yuri S. Genyk

Systemic inflammation in decompensated cirrhosis: Characterization and role in acute-on-chronic liver failure

Acute‐on‐chronic liver failure (ACLF) in cirrhosis is characterized by acute decompensation (AD), organ failure(s), and high short‐term mortality. Recently, we have proposed (systemic inflammation [SI] hypothesis) that ACLF is the expression of an acute exacerbation of the SI already present in decompensated cirrhosis. This study was aimed at testing this hypothesis and included 522 patients with decompensated cirrhosis (237 with ACLF) and 40 healthy subjects. SI was assessed by measuring 29 cytokines and the redox state of circulating albumin (HNA2), a marker of systemic oxidative stress. Systemic circulatory dysfunction (SCD) was estimated by plasma renin (PRC) and copeptin (PCC) concentrations. Measurements were performed at enrollment (baseline) in all patients and sequentially during hospitalization in 255. The main findings of this study were: (1) Patients with AD without ACLF showed very high baseline levels of inflammatory cytokines, HNA2, PRC, and PCC. Patients with ACLF showed significantly higher levels of these markers than those without ACLF; (2) different cytokine profiles were identified according to the type of ACLF precipitating event (active alcoholism/acute alcoholic hepatitis, bacterial infection, and others); (3) severity of SI and frequency and severity of ACLF at enrollment were strongly associated. The course of SI and the course of ACLF (improvement, no change, or worsening) during hospitalization and short‐term mortality were also strongly associated; and (4) the strength of association of ACLF with SI was higher than with SCD. Conclusion: These data support SI as the primary driver of ACLF in cirrhosis. (Hepatology 2016;64:1249‐1264).

Harvesting the middle hepatic vein with a right hepatectomy does not increase the risk for the donor

The harvesting of the middle hepatic vein (MHV) with a right hepatectomy for living‐donor liver transplantation allows an optimal venous drainage for the recipient but can also have adverse effects for the donor. This study compares morbidity, early liver function, and volume regeneration in 2 groups of donors who underwent right hepatectomy with (MHV+, n = 21) or without (MHV−, n = 20) MHV harvesting during 2 successive periods. The operative time was 401 ± 60 minutes in the MHV+ group compared with 392 ± 63 minutes in the MHV− group, and the transection time was 152 ± 53 minutes in the MHV+ group compared with 131 ± 30 minutes in the MHV− group (not significant). Blood loss in the MHV+ group was 773 ± 343 mL compared with 613 ± 361 mL in the MHV− group (not significant). The graft weight and remnant liver volume ratio were similar in the MHV+ and MHV− groups (763 ± 200 gm vs. 832 ± 156 gm and 42% ± 9.5% vs. 43% ± 8.3%, respectively). Postoperative biologic liver function tests showed that prothrombin time (PT) ratio on postoperative days 1 and 3 were significantly lower in the MHV+ group compared with the MHV− group (53% vs. 65% and 63% vs. 72%, respectively, P < .05). There were no differences in postoperative alanine aminotransferase and aspartate aminotransferase peak levels between the MHV+ and MHV− groups (319 ± 198 IU /L vs. 310 ± 110 IU /L and 317 ± 226 IU /L vs. 296 ± 125 IU /L, respectively). Bilirubin maximal blood level was similar in the 2 groups (32 ± 17 μmol/L in the MHV+ group vs. 43 ± 16 μmol/L in the MHV− group, P < .05). No donor died. The overall morbidity was lower in the MHV+ group compared with the MHV− group (36% vs. 55%; P > .05, not significant). The donors remnant liver volume regeneration, evaluated by computed tomography (CT) volumetric study on day 7, was similar in the 2 groups (97% ± 29% in the MHV+ group and 103% ± 39% in the MHV− group, P > .05). The results of this comparative study show that right hepatectomy with the MHV neither affects morbidity nor impairs early liver function and regeneration in donors. (Liver Transpl 2004;10:71–76.)

Respiratory complications: a major concern after right hepatectomy in living liver donors.

Background. One of the main concerns after living donor liver transplantation is the risk of morbidity and/or mortality that it imposes on the donors. Respiratory postoperative complications in living liver donors have already been reported but their frequency seems to be underestimated. We designed a prospective study to evaluate the rate and the nature of postoperative pulmonary complications in 112 consecutive donors. Methods. The medical records of the 112 living liver donors operated on at our center from 1998 to 2003 were reviewed and all the cases of respiratory complications were retrieved. Moreover, since 2000, all patients had a computed tomography angiography of the thorax at day 7 on a prospective basis. Results. In all, 112 hepatectomies (44 right and 68 left) for adult-to-adult or adult-to-child liver donation were performed in our center. No postoperative mortality was recorded. Fourteen major respiratory complications developed in of 11 of 112 donors (9.8%), in all cases after right hepatectomy, and included nonsevere pulmonary embolism (n=7), right pleural empyema (n=3), and bacterial pneumonia (n=3). Minor respiratory complications (7.1% of the donors) included iatrogenic pneumothorax (n=3) and pleural effusion requiring thoracocentesis (n=5). Abdominal complications (mainly biliary leak) developed in 10 donors (8.9%), who in the vast majority remained free of pulmonary complications. Conclusions. In our series, pulmonary complications are frequent in living liver donors. These complications are mainly observed after right hepatectomy. The particular prevalence of pulmonary embolism should lead to focus on its early diagnosis and prevention.

Fipexide-induced fulminant hepatitis : report of three cases with emergency liver transplantation

Fipexide belongs to a new class of cognition activators and is noted for its lack of amphetamin-like side effects. We describe three patients who developed fulminant hepatic failure less than 2 months after beginning fipexide administration. The mean interval from the onset of jaundice to the onset of encephalopathy was 8 days. Emergency liver transplantation was undertaken when factor V was 20% of normal or less and coma developed. All patients were transplanted less than 1 week after the onset of encephalopathy. Two survived and one died immediately after transplantation. Histologic examination of the livers revealed massive liver cell necrosis, predominantly centrilobular, and a moderate inflammatory infiltrate within the portal spaces. We conclude that fipexide can induce massive liver cell necrosis and fulminant liver failure. As a result of this life-threatening complication, reconsideration of the indications for this drug is warranted.