Incidence, predictive factors and clinical significance of development of portal vein thrombosis in cirrhosis: A prospective study.

BACKGROUND AND AIMS: The role of portal vein thrombosis (PVT) in the natural history of cirrhosis is controversial. There are few prospective studies validating risk factors for development of PVT. We analysed the incidence, factors associated with PVT development and its influence on cirrhosis decompensations and orthotopic liver transplant (OLT)-free survival. METHODS: In this prospective observational study between January 2014 and March 2019, 445 consecutive patients with chronic liver disease were screened and finally 241 with cirrhosis included. Factors associated with PVT development and its influence on cirrhosis decompensations and OLT-free survival by time dependent covariate coding were analysed. RESULTS: Majority of patients belonged to Child-Pugh class A 184 (76.3%) and the average MELD score was 10 ± 5. Previous cirrhosis decompensations occurred in 125 (52.1%), 63 (26.1%) were on NSBB and 59 (27.2%) had undergone banding for bleeding prophylaxis. Median follow-up was 29 (1-58) months. Cumulative incidence of PVT was 3.7% and 7.6% at 1 and 3 years. Previous decompensation of cirrhosis and low platelet counts but not NSBB independently predicted the development of PVT. During follow-up, 82/236 (34.7%) patients developed cirrhosis decompensations. OLT-free survival was 100% and 82.8% at 3 years, with and without PVT respectively. MELD score, but not PVT, independently predicted cirrhosis decompensations (HR 1.14; 95%CI:1.09-1.19) and OLT-free survival (HR 1.16;95%CI:1.11-1.21). CONCLUSION: Previous decompensations of cirrhosis and thrombocytopenia predict PVT development in cirrhosis suggesting a pathophysiologic role for severity of portal hypertension. PVT development did not independently predict cirrhosis decompensations or lower OLT-free survival.

Anticoagulation in Cirrhosis and Portal Vein Thrombosis Is Safe and Improves Prognosis in Advanced Cirrhosis.

BACKGROUND: The role of portal vein thrombosis (PVT) in the natural history of cirrhosis is controversial. AIMS: We analyzed the safety and effect of anticoagulant therapy (AT) on PVT recanalization and orthotopic liver transplant (OLT)-free survival. METHODS: Eighty consecutive patients from a prospective registry of cirrhosis and non-tumoral PVT at a tertiary center were analyzed. AT effect on PVT recanalization and OLT-free survival was determined by time-dependent Cox regression analysis. RESULTS: Average MELD score was 15 ± 7. Portal hypertension-related complications at PVT diagnosis were present in 65 (81.3%) patients. Isolated portal vein trunk/branch thrombosis was present in 53 (66.3%) patients. AT was started in 37 patients. AT was stopped in 17 (45.9%) patients, in 4 (10.8%) due to bleeding events. No variceal bleeding occurred while on AT. Anticoagulation was restarted in 6/17 (35.2%) patients due to rethrombosis. In 67 patients with adequate follow-up imaging, AT significantly increased the rate of PVT recanalization compared with those who did not receive anticoagulation [51.4% (18/35) vs 6/32 (18.8%), p = 0.005]. OLT-free survival after a median follow-up of 25 (1-146) months was 32 (40%). Although there was no significant effect of AT on overall OLT-free survival, OLT-free survival was higher among patients with MELD ≥ 15 receiving AT compared to those who did not (p = 0.011). Baseline MELD at PVT detection independently predicted PVT recanalization (HR 1.11, 95% CI 1.01-1.21, p = 0.027) and mortality/OLT (HR 1.12, 95% CI 1.05-1.19, p < 0.001). CONCLUSIONS: Although AT did not improve overall OLT-free survival, it was associated with higher survival in advanced cirrhosis. Anticoagulation increased PVT recanalization and should be maintained after PVT recanalization to avoid rethrombosis.

Intrahepatic clear cell cholangiocarcinoma - An uncommon histologic subtype: case report and literature review.

Clear-cell cholangiocarcinoma is a very uncommon variant of cholangiocarcinoma with a largely unknown natural history and prognosis. We report a case of a 51-year-old previously healthy woman presenting with a large liver nodule found on routine imaging. Needle biopsy of the lesion suggested a non-hepatocellular carcinoma. After extensive workup for other primary neoplasms, the patient underwent a partial hepatectomy. Histopathology was compatible with a moderately differentiated clear-cell cholangiocarcinoma. There was no evidence of liver disease in the remaining tissue. The patient underwent chemotherapy and remains in clinical remission after two years.

Ascitic Calprotectin is a Novel and Accurate Marker for Spontaneous Bacterial Peritonitis.

BACKGROUND: Spontaneous bacterial peritonitis (SBP) is a known complication of advanced cirrhosis and presents a high mortality rate. A polymorphonuclear (PMN) cell count >250/µl in the ascitic fluid is the current gold standard for diagnosing SBP. AIM: We evaluated the accuracy of a point-of-care test (POCT) for ascitic calprotectin in diagnosing patients with SBP. METHODS: Eighty-eight patients admitted with decompensation of liver cirrhosis were studied including 41 patients (46.6%) with SBP. Ascitic calprotectin was measured using a quantitative POCT developed by Bühlmann® . RESULTS: Calprotectin levels correlated with PMN cell count and other inflammatory markers and were significantly higher in patients with SBP. An optimal cutoff of calprotectin above 1.57 µg/ml presented high sensitivity (87.8%), specificity (97.9%), and positive (97.3%) and negative (90.2%) predictive values for diagnosing SBP. Using calprotectin selectively in patients with a serum albumin-ascites gradient above 11 g/l further increased the sensitivity and negative predictive values of the test. CONCLUSION: Ascitic calprotectin appears to be a reliable method for diagnosing SBP in patients with liver cirrhosis. It may present an alternative to other conventional diagnostic methods.

The use of a segmental endoscopic score may improve the prediction of clinical outcomes in acute severe ulcerative colitis.

BACKGROUND: Acute severe colitis (ASC) remains a challenging complication of ulcerative colitis. The early identification of patients who will not respond to optimal therapy is warranted. Increasing evidence suggests that endoscopy may play a role in predicting important outcomes in acute severe colitis. METHODS: The endoscopic activity of consecutive patients with acute severe colitis was evaluated using the Mayo endoscopic sub-score (Mayo) and the ulcerative colitis endoscopic index of severity (UCEIS). Two segmental indexes were also produced by summing the scores of the rectum and sigmoid (seg-Mayo and seg-UCEIS, respectively). Endpoints included the need for salvage therapy with infliximab or cyclosporine, refractoriness to corticosteroids, and colectomy. RESULTS: Of one hundred and eight patients enrolled in the study, 60 (55.6%) were male; with a median age of 34.5 years (range 15-80). All patients received intravenous steroids. Fifty-nine patients (55.6%) showed an incomplete or absent response to steroids, 35 patients (34.3%) received salvage therapy with infliximab or cyclosporine and 38 patients (33.3%) were colectomized during the index hospitalization or within the first year of follow-up. All scores were able to predict the need for surgery, but only the seg-UCEIS significantly predicted refractoriness to steroids. CONCLUSIONS: There was a strong correlation between endoscopic severity and unfavorable outcomes. The UCEIS outperformed the Mayo endoscopic sub-score in all important outcomes. Segmental scoring further improved the performance of the UCEIS.

The soluble form of HFE protein regulates hephaestin mRNA expression in the duodenum through an endocytosis-dependent mechanism.

Dietary iron absorption regulation is one of the key steps for the maintenance of the body iron homeostasis. HFE gene expression undergoes a complex post-transcriptional alternative splicing mechanism through which two alternative transcripts are originated and translated to a soluble HFE protein isoform (sHFE). The first purpose of this study was to determine if sHFE transcript levels respond to different iron conditions in duodenal and macrophage cell models. In addition, we aimed to determine the functional effect of the sHFE protein on the expression of iron metabolism-related genes in a duodenal cell model as well as, in vivo, in duodenum biopsy samples. Levels of sHFE transcripts were measured in HuTu-80, Caco-2, HT-29 and activated THP1 cells, after holo-Tf stimulus, and in total RNA from duodenum biopsies of functional dyspepsia patients. Also, the expression of several iron metabolism-related genes was determined after endogenous and exogenous overexpression of sHFE protein in a duodenal cell model. sHFE endocytosis mechanism was studied using endocytosis inhibitors. Our results showed that sHFE transcript expression was up-regulated after holo-Tf stimuli. Hephaestin and duodenal cytochrome b expressions were down-regulated by both endogenous HFE and sHFE proteins in a duodenal cell model. Exogenous sHFE was able to down-regulate hephaestin mRNA levels by a clathrin-independent, dynamin-mediated, and RhoA-regulated endocytosis mechanism. Moreover, HEPH levels negatively correlated with sHFE levels in the duodenum of functional dyspepsia patients. Thus, sHFE seems to be an important iron metabolism regulator playing a role in the control of dietary iron absorption in the duodenum.

Human Herpesvirus 6 Reactivation Associated With Intestinal Pseudo-Obstruction in a Renal Transplant Recipient.

Human herpesvirus 6 infection is common after organ transplant. Generally, infection is asymptomatic or is associated with a mild illness. However, human herpesvirus 6 infection in these patients may as well be life threatening as a result of severe end-stage organ disease. Here, we have reported a case of a severe human herpesvirus 6 infection with cerebral, hepatic, and gastrointestinal involvement, which presented as intestinal pseudo-obstruction. The patient was a renal transplant recipient who was successfully treated with ganciclovir. We also reviewed the literature on human herpesvirus 6 diagnosis and the associated colitis and encephalitis with its infection in solid-organ transplant recipients.

Proactive therapeutic drug monitoring is more effective than conventional management in inducing fecal calprotectin remission in inflammatory bowel disease.

BACKGROUND: Proactive therapeutic drug monitoring (pTDM) may improve treatment outcomes in inflammatory bowel disease. AIMS AND METHODS: We compared 135 patients following a prospective pTDM protocol aiming at an infliximab trough level (IFXTL) between 5 and 10 µg/ml with sequential measurements of Fc, with 108 patients from a retrospective group under conventional management. We evaluated the rates of Fc remission (<250 µg/g) and other clinical outcomes at 2-year of follow-up. RESULTS: pTDM associated with higher rates of Fc remission (69.6% vs. 50.0%; P = 0.002), and steroid-free clinical remission (78.4% vs. 55.2%, P = 0.028) with a trend for clinical remission (79.3% vs. 68.5%, P = 0.075). There was no difference in treatment discontinuation (P = 0.195), hospitalization (P = 0.156), and surgery (P = 0.110). Higher IFXTL associated with Fc remission at week 14 (6.59 vs. 2.96 µg/ml, P < 0.001), and at the end of follow-up (8.10 vs. 5.03 µg/ml, P = 0.001). In patients reaching Fc remission after week 14, IFXTL increased from week 14 to the end of follow-up (2.71 vs. 8.54 µg/ml, P < 0.001). Fc remission associated with higher rates of clinical (85.8% vs. 56.8% P < 0.001) and steroid-free clinical remission (86.9% vs. 50.0% P < 0.001), lower IFX discontinuation (8.8% vs. 36.8%, P < 0.001), and hospitalization (13.5% vs. 33.7%, P < 0.001), without significance for surgery (6.1% vs. 12.6%, P = 0.101). CONCLUSION: pTDM was more effective than conventional management in inducing Fc remission which was associated with improved outcomes.

Diagnosis and treatment of iron-deficiency anemia in gastrointestinal bleeding: A systematic review.

BACKGROUND: Anemia is considered a public health issue and is often caused by iron deficiency. Iron-deficiency anemia (IDA) often originates from blood loss from lesions in the gastrointestinal tract in men and postmenopausal women, and its prevalence among patients with gastrointestinal bleeding has been estimated to be 61%. However, few guidelines regarding the appropriate investigation of patients with IDA due to gastrointestinal bleeding have been published. AIM: To review current evidence and guidelines concerning IDA management in gastrointestinal bleeding patients to develop recommendations for its diagnosis and therapy. METHODS: Five gastroenterology experts formed the Digestive Bleeding and Anemia Workgroup and conducted a systematic literature search in PubMed and professional association websites. MEDLINE (via PubMed) searches combined medical subject headings (MeSH) terms and the keywords "gastrointestinal bleeding" with "iron-deficiency anemia" and "diagnosis" or "treatment" or "management" or "prognosis" or "prevalence" or "safety" or "iron" or "transfusion" or "quality of life", or other terms to identify relevant articles reporting the management of IDA in patients over the age of 18 years with gastrointestinal bleeding; retrieved studies were published in English between January 2003 and April 2019. Worldwide professional association websites were searched for clinical practice guidelines. Reference lists from guidelines were reviewed to identify additional relevant articles. The recommendations were developed by consensus during two meetings and were supported by the published literature identified during the systematic search. RESULTS: From 494 Literature citations found during the initial literature search, 17 original articles, one meta-analysis, and 13 clinical practice guidelines were analyzed. Based on the published evidence and clinical experience, the workgroup developed the following ten recommendations for the management of IDA in patients with gastrointestinal bleeding: (1) Evaluation of hemoglobin and iron status; (2) Laboratory testing; (3) Target treatment population identification; (4) Indications for erythrocyte transfusion; (5) Treatment targets for erythrocyte transfusion; (6) Indications for intravenous iron; (7) Dosages; (8) Monitoring; (9) Indications for intravenous ferric carboxymaltose treatment; and (10) Treatment targets and monitoring of patients. The workgroup also proposed a summary algorithm for the diagnosis and treatment of IDA in patients with acute or chronic gastrointestinal bleeding, which should be implemented during the hospital stay and follow-up visits after patient discharge. CONCLUSION: These recommendations may serve as a starting point for clinicians to better diagnose and treat IDA in patients with gastrointestinal bleeding, which ultimately may improve health outcomes in these patients.

Interventional Algorithm in Gastrointestinal Bleeding-An Expert Consensus Multimodal Approach Based on a Multidisciplinary Team.

The approach to the patient with gastrointestinal bleeding (GIB) can be very complex. A multidisciplinary panel of physicians with expertise in Gastroenterology, Anesthesiology, and Transfusion Medicine worked together to provide the best knowledge and guide clinical practitioners in the real setting of health institutions, characterized by disparate availability of human and technical resources. The authors propose a global and personalized approach according to different clinical scenarios to improve the outcomes of patients with GIB, for whom the reduction of inappropriate transfusions is crucial. The goal of this document is to provide clear and objective guidance through interventional algorithms toward a goal-directed approach according to the clinical situation and supported by the latest available scientific data on GIB management in different settings.

Proactive Infliximab Drug Monitoring Is Superior to Conventional Management in Inflammatory Bowel Disease.

BACKGROUND: Increasing evidence supports the use of reactive therapeutic drug monitoring (TDM) in Crohn's disease (CD) and ulcerative colitis (UC) following secondary loss of response. It is still unknown if proactive TDM can improve clinical outcomes. METHODS: Consecutive patients completing infliximab (IFX) induction therapy were prospectively allocated into a proactive TDM protocol (pTDM). Before the fourth infusion and every 2 infusions, IFX trough levels and antidrug antibodies were measured using a drug-sensitive assay (Theradiag, Lisa Tracker). Treatment was proactively escalated aiming at an IFX trough level between 3 and 7 ug/mL (CD) and 5 and 10 ug/mL (UC). A retrospective cohort treated with IFX but without TDM served as the reference group. End points included the need for surgery, hospitalization, treatment discontinuation, and mucosal healing at 2 years of follow-up. RESULTS: Two hundred five patients were included, 56 in the proactive regimen. Treatment escalation was more common in pTDM patients (76.8% vs 25.5%; P < 0.001), who also required less surgery (8.9% vs 20.8%; P = 0.032) and presented higher rates of mucosal healing (73.2% vs 38.9%; P < 0.0001). Proactive TDM significantly decreased the odds of reaching any unfavorable outcome (odds ratio, 0.358; 95% confidence interval, 0.188-0.683; P = 0.002). CONCLUSIONS: Proactive TDM is associated with fewer surgeries and higher rates of mucosal healing than conventional non-TDM-based management.

Predicting the Course of Disease in Hospitalized Patients With Acute Severe Ulcerative Colitis.

BACKGROUND: Up to one-third of patients with acute severe ulcerative colitis (ASUC) will fail intravenous steroid (IVS) treatment, requiring rescue therapy with cyclosporin (Cys), infliximab (IFX), or colectomy. Although several scores for predicting response to IVS exist, formal comparison is lacking. METHODS: We performed a single-center retrospective analysis including 489 patients with ulcerative colitis. In patients with ASUC, the Mayo endoscopic subscore and the Oxford, Edinburgh, and Lindgren scores were assessed. Outcomes included IVS failure, need for rescue medical therapy, and surgery. RESULTS: One hundred twelve patients presented with ASUC. Forty-two percent showed an incomplete or absent response to IVS, 28.6% received rescue therapy (22 with IFX, 10 with Cys, and 1 with sequential treatment), and 26.8% required surgery. The Lindgren score showed the highest performance in predicting IVS failure (are under the curve [AUC], 0.856; 95% confidence interval [CI], 0.784-0.928), need for medical rescue therapy (AUC, 0.826; 95% CI, 0.749-0.902), and surgery (AUC, 0.836; 95% CI, 0.712-0.960; all P < 0.01). CONCLUSIONS: In our series, the Lindgren score was superior to the Mayo, Oxford, and Edinburgh scores in predicting major clinical outcomes in ASUC.

Transmural Healing Is Associated with Improved Long-term Outcomes of Patients with Crohn's Disease.

BACKGROUND: Mucosal healing (MH) is currently accepted as one of the best treatment targets in Crohn's disease. However, even in patients with sustained MH, residual bowel wall inflammation can still be detected by cross-sectional imaging. The long-term benefits of obtaining transmural healing (TH) have not been previously assessed. METHODS: We performed an observational study including 214 patients with Crohn's disease with a magnetic resonance enterography (MRE) and colonoscopy performed within a 6-month interval. Patients were classified as having TH (inactive MRE and colonoscopy), MH (active MRE with inactive colonoscopy), or no healing (active colonoscopy). Need for surgery, hospital admission, and therapy escalation were evaluated at 12 months of follow-up. RESULTS: Patients with TH presented lower rates of hospital admission, therapy escalation, and surgery than patients with MH or no healing. In logistic regression analysis, endoscopic remission (odds ratio 0.331 95% confidence interval [0.178-0.614], P < 0.001) and MRE remission (odds ratio 0.270 95% confidence interval [0.130-0.564], P < 0.001) were independently associated with a lower likelihood of reaching any unfavorable outcome. CONCLUSIONS: TH is associated with improved long-term outcomes in Crohn's disease and may be a more suitable target than MH.

Case of acute hepatitis E with concomitant signs of autoimmunity.

Sporadic cases of acute viral hepatitis E have been described in developed countries, despite the more common occurrence in endemic areas and developing countries. We present the case of a 58 years old Portuguese female, with no epidemiological relevant factors, admitted with acute hepatitis with positive anti-nuclear antibodies, anti-smooth muscle antibody and high serum gamma globulin (> 1.5 fold increase). Serologies for hepatitis A virus, hepatitis B virus, hepatitis C virus, Epstein-Barr virus, cytomegalovirus, hereditary sensory neuropathy and varicella zoster virus were negative. Liver biopsy histology revealed changes compatible with autoimmune hepatitis. Prednisolone and azathioprine was started. She tested positive for immunoglobulin M anti hepatitis E virus (HEV) with detectable viremia by reverse transcription polymerase chain reaction (RT-PCR) technique. HEV-RNA was confirmed through RT-PCR in a liver specimen, establishing the diagnosis of acute hepatitis E. Immunosuppression was stopped. She clinically improved, with resolution of laboratory abnormalities. Therefore, we confirmed acute hepatitis E as the diagnosis. We review the literature to elucidate about HEV infection and its autoimmune effects.

Severe intrahepatic cholestasis, erythrocytosis and hypoglycemia: unusual presenting features of systemic AL amyloidosis.

We report the case of a 68-year-old African woman who presented with jaundice, hepatomegaly and anasarca. Clinical investigation disclosed severe intrahepatic cholestasis, nephrotic syndrome, erythrocytosis and hypoglycemia. Diagnosis of systemic AL amyloidosis was established by percutaneous liver biopsy. Bone marrow biopsy showed 32% of myeloma cells. The patient started treatment with melphalan and prednisolone, but liver function deteriorated and she died in hepatic failure complicated by septic shock three weeks after the diagnosis. We present possible explanations for the unusual clinical and laboratory findings, which required a multidisciplinary approach and posed challenging problems in differential diagnosis and management.