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Background: The objectives of this study were to evaluate incidence and to identify the risk factors of occurrence and the predictive factors of symptomatic forms of nodular regenerative hyperplasia (NRH) after liver transplantation (LT)., Methods: To identify risk factors of NRH following LT, we included 1648 patients transplanted from 2004 to 2018 and compared the patients developing NRH after LT to those who did not. To identify predictive factors of symptomatic NRH, we selected 115 biopsies displaying NRH and compared symptomatic to asymptomatic forms. Symptomatic NRH was defined as the presence of ascites, esophageal varices, hepatic encephalopathy, portal thrombosis, retransplantation, or death related to NRH., Results: The incidence of NRH following LT was 5.1%. In multivariate analysis, the independent factor of developing NRH after LT was the donor's age (odds ratio [OR] = 1.02; confidence interval, 1.01-1.03; P = 0.02). Symptomatic forms occurred in 29 (25.2%) patients: 19 (16.5%) patients presented with ascites, 13 (11.3%) with esophageal varices, 4 (3.5%) with hepatic encephalopathy, and 8 (7%) with portal thrombosis. The median period before the onset of symptoms was 8.4 (1.5-11.3) y after LT. The spleen size at diagnosis/before LT ratio (OR = 12.5; 114.17-1.37; P = 0.0252) and thrombectomy during transplantation (OR = 11.17; 1.48-84.11; P = 0.0192) were associated with symptomatic NRH in multivariate analysis., Conclusions: NRH following LT is frequent (5.1%) and leads to symptomatic portal hypertension in 25.2% of patients. Using older grafts increases the risk of developing NRH after LT. Clinicians should screen for signs of portal hypertension, particularly in measuring spleen size., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The occurrence of acute liver failure (ALF) in pregnant women due to an etiology unrelated to pregnancy (pregALF) that leads to liver transplantation (LT) has rarely been reported. The objective was to report the outcome of pregnant women and fetus and propose a strategy for the timing of delivery and of LT in these patients., Methods: Five consecutive pregnant patients with ALF were admitted to our center between 1986 and 2018 and underwent an LT. A systematic review of case reports concerning patients with pregALF who underwent LT was extracted from the literature., Results: Three with gestational ages (GA) at admission of 15, 22, and 31 weeks of gestation (WG) were transplanted after delivery (n = 1) or intrauterine demise (n = 2) and 2 with GA of 16 and 23 WG before delivery. One infant survived in each group. Among the 32 cases published previously, 11 (34%) had been transplanted after delivery (median GA:31 [28-33]); 10 of these 11 infants were alive at birth. The other 21 mothers were transplanted before delivery (GA:21 WG [18-22]). The median GA at delivery was 30 WG [27.75-37]. Twelve of 21 infants were alive at birth. One-year survival among the ALF patients in our series and in the literature was 100%. Overall, the perinatal survival rate was low (64.8%)., Conclusions: In pregnant patients presenting with ALF not related to the pregnancy, the LT lifesaving procedure had an excellent outcome. Overall, 65% of the infants were alive at delivery with major mortality in those fetus <22 WG despite continued pregnancy., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare severe adverse drug-induced reaction with multiorgan involvement. The outcome and prediction of those patients who develop severe acute liver injury (sALI) or acute liver failure (ALF) remain little known., Methods: A multicenter retrospective study of patients admitted with a diagnosis of DRESS-related sALI or ALF. Histological review was performed on liver core biopsies from native livers., Results: Sixteen patients (11 women, 5 men; mean age, 39±17.2 years) were classified as having definite (n=13) or probable (n=3) DRESS. At admission, 3 patients had hepatic encephalopathy; median levels of prothrombin time, INR, and total bilirubin were, respectively, 33% (Q1-Q3, 21-41), 2.74 (1.98-4.50), and 94 μmol/L (Q1-Q3, 39.5-243.5). Nine patients received corticosteroid therapy. Overall, 9 patients improved spontaneously and 7 worsened (liver transplantation [LT] (n=5), deceased (n=2)). Transplantation-free and post-LT survival was 56% and 60%, respectively. After LT, DRESS recurrence was observed in 3 of 5 patients. Systemic corticosteroid therapy was not significantly associated with a clinical improvement. In the multivariate analysis, factor V level less than 40% at day 0 and factor V levels of 40% or greater at admission but decreasing at day 2 were associated with worse outcome. Pathological findings (n=7) revealed atypical lymphoid infiltrates, Kupffer cell hyperplasia with erythrophagocytosis, and an inconstant presence of eosinophils., Conclusions: The spontaneous prognosis of patients with sALI/ALF due to DRESS is poor and was not improved by corticosteroid therapy. Histology is helpful to establish diagnosis. Dynamic variables regarding factor V values are predictive of a poor outcome.

Background Data: In compensated cirrhotics with early hepatocellular carcinoma (HCC-cirr), upfront liver resection (LR) and salvage liver transplantation (SLT) in case of recurrence may have outcomes comparable to primary LT (PLT)., Objective: An intention-to-treat (ITT) analysis comparing PLT and SLT strategies., Methods: Of 130 HCC-cirr patients who underwent upfront LR (group LR), 90 (69%) recurred, 31 could undergo SLT (group SLT). During the same period, 366 patients were listed for LT (group LLT); 26 dropped-out (7.1%), 340 finally underwent PLT (group PLT). We compared survival between groups LR and LLT, LR and PLT, and PLT and SLT., Results: Feasibility of SLT strategy was 34% (31/90). In an ITT analysis, group LLT had better 5-yr/10-yr overall survival (OS) compared with group LR (68%/58% vs. 58%/35%; P = 0.008). Similarly, 5-yr/10-yr OS and disease-free survival (DFS) were better in group PLT versus group LR (OS 73%/63% vs. 58%/35%, P = 0.0007; DFS 69%/61% vs. 27%/21%, P < 0.0001). Upfront resection and microvascular tumor invasion were poor prognostic factors for both OS and DFS, presence of satellite tumor nodules additionally predicted worse DFS. Group SLT had similar postoperative and long-term outcomes compared with group PLT (starting from time of LT) (OS 54%/54% vs. 73%/63%, P = 0.35; DFS 48%/48% vs. 69%/61%, P = 0.18, respectively)., Conclusions: In initially transplantable HCC-cirr patients, ITT survival was better in group PLT compared with group LR. SLT was feasible in only a third of patients who recurred after LR. Post SLT, short and long-term outcomes were comparable with PLT. Better patient selection for the "resection first" approach and early detection of recurrence may improve outcomes of the SLT strategy.

Background: Resection and liver transplantation (LT) are the only curative options for hepatocellular carcinoma in cirrhotic patients (HCC-cirr)., Objective: We tried to define the best primary intention-to-treat strategy in patients undergoing either resection or LT for early single HCC-cirr (≤5 cm)., Methods: From 1990 to 2010, 198 patients with early HCC-cirr underwent either resection (group R, n = 97) or LT (group T, n = 101) as the primary procedure. Our policy was to prioritize Childs A patients with peripheral lesions for resection rather than LT. Patient and tumor characteristics, and outcomes (recurrence-free survival [RFS] and overall survival [OS]), were studied., Results: A longer diagnosis-to-surgery interval, more Child Pugh B/C patients, and more tumor nodules (on histopathological examination) were found in group T patients. The postoperative mortality (4.1% vs 3.0%, P = 0.72) and rate of major complications (19.1% vs 24.7%, P = 0.35) were similar in groups R and T, respectively, whereas tumor recurrence was higher in group R (62% vs 10% in group T, P < 0.0001). The 5-year OS (75% vs 52%, P = 0.0008) and RFS (72% vs 20%, P < 0.0001) were better in group T; similarly, more patients were disease free at last follow-up (27% vs 62%, P < 0.0001). Resection as the surgical procedure, tumor diameter 3 cm or more on histology, and microvascular tumor invasion were poor prognostic factors for OS and RFS. Including dropout patients from LT list in the analysis, the outcomes in group T were still better (70% and 61% vs 51% and 36% at 5 and 10 years, P = 0.01)., Conclusions: On an intention-to-treat basis, LT is associated with the best survival outcomes in patients with early HCC-cirr. Resection may achieve comparable OS in patients with single HCC-cirr of size smaller than 3 cm; however, the RFS still remains lower than that in patients of group T. This study could serve as a guide for HCC-cirr patients who are candidates for either resection or LT.

Background: The role of constrictive remodeling, spasm and proliferation (particularly in the adventitia) in the genesis of chronic lumen narrowing after balloon injury remains under debate. This study analyzed the time course of these components following mild injury in normal arteries., Methods: Iliac injury was induced by balloon overstretch in 32 rabbits, sacrificed at timed intervals from day 3 to 28. Angiographic response to nitrates, morphometric, immunohistochemical and biochemical analysis were performed at each time point., Results: Quantitative angiography showed a decrease in lumen diameter and no change in response to nitrates over time. On morphometric analysis, remodeling was usually constrictive, appeared as early as day 3 and was responsible for 69+/-14% of the histologic lumen area stenosis at day 28. Constrictive remodeling was correlated negatively to intimal hyperplasia (r= 0.51, P< 0.002) and positively to the lumen area stenosis (r= 0.92, P< 0.0001). Macrophages (labeled by anti-RAM 11 antibodies) were very rare at all time points. Immunohistochemistry identified a high rate of proliferating smooth muscle cells in the media (13+/-7%) and intima (49+/-8%) at day 7, which decreased rapidly. Proliferating cells in the adventitia were rare (3+/-2% at day 7). The number of proliferating cells was time-dependent (r= 0.82, P< 0.0001) and related to cyclin A mRNA measured by reverse transcription-polymerase chain reaction (r= 0.84, P< 0.0001)., Conclusions: In this model, luminal loss was mainly caused by constrictive remodeling rather than intimal hyperplasia. Constrictive remodeling appeared early and was not time-dependent. Macrophages, spasm and adventitial proliferation did not contribute to this constrictive remodeling.

We report a 25-year-old patient with a progressive asymmetric peripheral neuropathy of the distal lower limbs. Imaging studies showed enlargement of lumbosacral roots, plexus, and proximal sciatic nerve. Sacral plexus biopsy revealed amyloidosis associated with endoneurial edema. Immunohistochemistry with anti-prealbumin, serum amyloid A, and immunoglobulin light chain antisera failed to label the amyloid.

Spontaneously hypertensive Okamoto-strain rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were actively immunized with mouse renin to investigate the effect on blood pressure of blocking the renin-angiotensinogen reaction. Ten male SHR and 10 male WKY rats were immunized with purified mouse submandibular gland renin. Control rats were immunized with bovine serum albumin. Antirenin antibodies were produced by both SHR and WKY rats, but renin-immunized SHR had higher titers of circulating renin antibodies after three injections. The increase in renin antibody in renin-immunized SHR was associated with a significant drop in blood pressure (tail-cuff method) that became similar to that of the WKY control rats after four injections. The blockade by antirenin immunoglobulins of the renin-angiotensinogen reaction also decreased the blood pressure of normotensive rats. Perfusion of renin-immunized rats with mouse submandibular renin (10 micrograms) in vivo caused no increase in blood pressure. Perfusion of renin-immunized, salt-depleted SHR with converting enzyme inhibitor caused no further decrease in blood pressure but significantly decreased blood pressure in salt-depleted control rats. The presence of circulating renin antibodies was associated with low plasma renin activity (0.31 +/- 0.23 ng angiotensin I [Ang I]/ml/hr). Plasma renin activity was unchanged in control animals (13.1 +/- 3.9 ng Ang I/ml/hr in control SHR, 13.9 +/- 3.2 ng Ang I/ml/hr in control WKY rats). Renin antibody-rich serum produced a dose-dependent inhibition of rat renin enzymatic activity in vitro. The chronic blockade of the renin-angiotensinogen reaction in renin-immunized SHR produced an almost-complete disappearance of Ang II (0.8 %/- 7 fmol/ml; control SHR, 30.6 +/- 15.7 fmol/ml) and a 50% reduction in urinary aldosterone. Renin immunization was never associated with a detectable loss of sodium after either 10 or 24 weeks. The glomerular filtration rate was not decreased 10 weeks after renin immunization, whereas blood pressure was significantly decreased, plasma renin activity was blocked, and renal plasma flow was increased. The ratio of left ventricular weight to body weight after 24 weeks was significantly below control levels in renin-immunized WKY rats and SHR. Histological examination of the kidney of renin-immunized SHR showed a chronic autoimmune interstitial nephritis characterized by the presence of immunoglobulins, mononuclear cell infiltration, and fibrosis around the juxtaglomerular apparatus. These experiments demonstrate that chronic specific blockade of renin decreases blood pressure in a genetic model of hypertension in which the renin-angiotensin system is not directly involved.(ABSTRACT TRUNCATED AT 400 WORDS)

To block the renin-substrate reaction by immunological tools is a long-standing dream. Since 1951 active immunization and the passive transfer of antirenin antisera have been successfully carried out in different species and in different experimental models of hypertension and normotension. These studies indicated that renin is a powerful immunogenic protein, capable of breaking down self-tolerance in different species. In this initial period the most significant results were obtained with hog renin. Passive transfer of antisera raised against hog renin or active immunization with hog renin was able to decrease blood pressure in renovascular or essential hypertension in dogs. Renin was semipurified and injected without adjuvant, however, since there was no method for determining plasma renin activity. Recently, complete purification of murine and human renin has allowed an extension of this approach, using the passive transfer of antirenin polyclonal antisera or monoclonal antibodies. Active immunization against pure human renin was successful in normotensive marmosets. This immunization with a nearly homologous renin in a primate model induced a significant decrease in blood pressure, associated with a complete disappearance of plasma renin activity. Unfortunately this powerful immunization was associated with an autoimmune disease that is specific for the kidney, related to self-recognition of the production site of renin by antibodies and lymphocytes. Similar results were reported with the use of mouse submandibular gland renin as an immunogen in spontaneously hypertensive rats (SHR). This manipulation decreased blood pressure in SHR to a level near that of normotensive Wistar-Kyoto control rats. However, again the animals showed a severe autoimmune disease of the kidney.(ABSTRACT TRUNCATED AT 250 WORDS)