Further decompensation in cirrhosis: Results of a large multicenter cohort study supporting Baveno VII statements.

BACKGROUND AND AIMS: The prognostic weight of further decompensation in cirrhosis is still unclear. We investigated the incidence of further decompensation and its effect on mortality in patients with cirrhosis. APPROACH AND RESULTS: Multicenter cohort study. The cumulative incidence of further decompensation (development of a second event or complication of a decompensating event) was assessed using competing risks analysis in 2028 patients. A 4-state model was built: first decompensation, further decompensation, liver transplant, and death. A cause-specific Cox model was used to assess the adjusted effect of further decompensation on mortality. Sensitivity analyses were performed for patients included before or after 1999. In a mean follow-up of 43 months, 1192 patients developed further decompensation and 649 died. Corresponding 5-year cumulative incidences were 52% and 35%, respectively. The cumulative incidences of death and liver transplant after further decompensation were 55% and 9.7%, respectively. The most common further decompensating event was ascites/complications of ascites. Five-year probabilities of state occupation were 24% alive with first decompensation, 21% alive with further decompensation, 7% alive with a liver transplant, 16% dead after first decompensation without further decompensation, 31% dead after further decompensation, and <1% dead after liver transplant. The HR for death after further decompensation, adjusted for known prognostic indicators, was 1.46 (95% CI: 1.23-1.71) ( p <0.001). The significant impact of further decompensation on survival was confirmed in patients included before or after 1999. CONCLUSIONS: In cirrhosis, further decompensation occurs in ~60% of patients, significantly increases mortality, and should be considered a more advanced stage of decompensated cirrhosis.

Exocrine Pancreatic Insufficiency is Undiagnosed in Some Patients with Diarrhea-Predominant Irritable Bowel Syndrome Using the Rome IV Criteria.

BACKGROUND AND AIMS: Irritable bowel syndrome (IBS) is one of the most frequent disorders in clinical practice, with a mean 7.6-10.8% worldwide prevalence. A study showed that 6.1% of patients with diarrhea-predominant IBS (IBS-D) had severe exocrine pancreatic insufficiency (EPI). We aimed to identify the prevalence of EPI based on fecal elastase stool testing (Fel-1) in IBS-D and the clinical characteristics that may predict the diagnosis of EPI. METHODS: Patients aged > 18 years presenting to tertiary hospital outpatient clinics with IBS-D completed validated questionnaires and gave a stool sample where Fel-1 concentration was measured. Patients with Fel-1 < 100 µg/g represented EPI and > 100 to < 200 µg/g underwent testing for pancreatic pathology with laboratory and endoscopic ultrasound (EUS) evaluation. RESULTS: One hundred forty patients (mean age 60 years, females 75.7%) were studied. EPI was found in 5% (95% CI 2.2-10.4), and pancreatic steatosis was the main EUS finding (71%). Dyspepsia was an independent factor associated with EPI (OR 34.7; 95% CI 4.95-366.37, p = 0.0007). After pancreatic enzyme replacement therapy (PERT), patients showed a significant improvement in the Bristol stool scale (p < 0.0001), bowel movements per day (p < 0.005), distension score (0.0009), pain score (0.0277) and IBS severity (0.0034). CONCLUSION: EPI is present in 5% of patients who fulfill Rome IV criteria for D-IBS, and dyspepsia was an independent symptom strongly associated with EPI. Pancreatic steatosis was the main endoscopic ultrasound finding. After PERT therapy, patients had significantly improved stool frequency, stool consistency, abdominal pain, distension and IBS severity score.

Sublingual microcirculatory alterations in cirrhotic patients.

OBJECTIVE: To assess sublingual microcirculation in cirrhotic patients and its relationship to spider angiomas, complications, and outcome. METHODS: Thirty-one cirrhotic patients were prospectively compared to 31 matched controls. Sublingual microcirculation was evaluated by videomicroscopy. We specifically looked for capillaries with increased RBCV, which was defined as a velocity higher than the percentile 100th of controls. RESULTS: Compared to controls, cirrhotic patients showed decreased total and PVD (14.4 ± 2.2 vs 16.0 ± 1.3 and 14.1 ± 2.3 vs 15.9 ± 1.6 mm/mm2 , respectively, P < .001 for both) and increased HFI (0.64 ± 0.39 vs 0.36 ± 0.21, P = .001). They also exhibited high RBCV in 2% of the microvessels (P < .0001). Patients with MELD score ≥10 had higher RBCV than patients with score <10 (1414 ± 290 vs 1206 ± 239 µm/s, P < .05). Patients with spider angiomas showed lower vascular densities. Microcirculation did not differ between survivors and nonsurvivors. CONCLUSIONS: Cirrhosis is associated with microcirculatory alterations that can be easily monitored in the sublingual mucosa. Alterations included decreased density and PPV and hyperdynamic microvessels. The most striking finding, however, was the microvascular heterogeneity. Patients with spider angiomas had more severe alterations. Larger studies should clarify the relationship between microcirculatory abnormalities and outcome.

Metabolic alterations, HFE gene mutations and atherogenic lipoprotein modifications in patients with primary iron overload.

Iron overload (IO) has been associated with glucose metabolism alterations and increased risk of cardiovascular disease (CVD). Primary IO is associated with mutations in the HFE gene. To which extent HFE gene mutations and metabolic alterations contribute to the presence of atherogenic lipoprotein modifications in primary IO remains undetermined. The present study aimed to assess small, dense low-density lipoprotein (LDL) levels, chemical composition of LDL and high-density lipoprotein (HDL) particles, and HDL functionality in IO patients. Eighteen male patients with primary IO and 16 sex- and age-matched controls were recruited. HFE mutations (C282Y, H63D and S65C), measures of insulin sensitivity and secretion (calculated from the oral glucose tolerance test), chemical composition and distribution profile of LDL and HDL subfractions (isolated by gradient density ultracentrifugation) and HDL functionality (as cholesterol efflux and antioxidative activity) were studied. IO patients compared with controls exhibited insulin resistance (HOMA-IR (homoeostasis model assessment-estimated insulin resistance): +93%, P< 0.001). Metabolic profiles differed across HFE genotypes. C282Y homozygotes (n=7) presented a reduced ß-cell function and insulin secretion compared with non-C282Y patients (n=11) (-58% and -73%, respectively, P< 0.05). In addition, C282Y homozygotes featured a predominance of large, buoyant LDL particles (C282Y: 43±5; non-C282Y: 25±8; controls: 32±7%; P< 0.001), whereas non-C282Y patients presented higher amounts of small, dense LDL (C282Y: 23±5; non-C282Y: 39±10; controls: 26±4%; P< 0.01). HDL particles were altered in C282Y homozygotes. However, HDL functionality was conserved. In conclusion, metabolic alterations and HFE gene mutations are involved in the presence of atherogenic lipoprotein modifications in primary IO. To what extent such alterations could account for an increase in CVD risk remains to be determined.

[Usefulness of gastric emptying scintigraphy for the evaluation and management of scleroderma related gastroparesis]. / Utilidad de la medición del vaciamiento gástrico por centellografía con 99mTc para la evaluacion y el manejo de la gastroparesia en la esclerodermia.

Scleroderma is a chronic autoimmune disease of unknown cause characterized by fibrotic skin and multiple organs involvement, including the gastrointestinal tract. It occurs mainly in women between 35 and 65 years of age. It is classified as limited or diffuse based on the extent of skin involvement. Gastrointestinal dysmotility is observed in up to 90% of patients with a diffuse and limited scleroderma. It may involve any segment of the gastrointestinal tract from the esophagus to the anus and is related to collagen deposition at the level of enteric and vascular smooth muscle. Gastroparesis is a condition characterized by abnormal gastric motility, delay gastric emptying, in the absence of a mechanical obstruction to outflow. Gastric scintigraphy with radiolabeled solid food is the gold standard for the diagnosis of gastroparesis. Two cases of patients with systemic scleroderma and severe gastroparesis are presented in order to discuss the diagnostic and therapeutic approach, emphasizing the utility of gastric emptying scintigraphy.

[Prolonged survival after local excision of a rectal leiomyosarcoma]. / Sobrevida prolongada luego de la resección local de un leiomiosarcoma de recto.

Leiomyosarcoma is a stromal tumor, originated from smooth muscle cells. The pathologic diagnosis represents a challenge in terms of differentiation from leiomyomas and gastrointestinal stromal tumors (GIST), defined by immunohistochemistry techniques. Its location in the rectum is extremely rare. So, management is not standardized. However, in the largest published series it was found that the abdominoperineal resection leads to better results in the prevention of local recurrence compared with local excision. We present here the case of a 44-year-old woman, whose first clinical manifestation of the disease was fever of prolonged course. A 5 cm leiomyosarcoma was diagnosed at 4 cm from the anal margin. A local transanal resection was performed. The patient is free of disease after 8 years.

Icteric Variant of Stauffer Syndrome as a Paraneoplastic Manifestation of Type 1 Papillary Renal Cell Carcinoma.

Intrahepatic cholestasis as a paraneoplastic manifestation was first described by Dr. Maurice H. Stauffer in 1961. This paraneoplastic manifestation was primarily associated with renal cell carcinoma characterized by abnormal liver enzymes without hepatic metastasis. Stauffer syndrome is classified into 2 types: classical and jaundice variants. Indeed, the jaundice variant is extremely rare and only described in 13 published cases. We report a case of intrahepatic cholestasis associated with a type 1 papillary renal cell carcinoma with complete resolution after surgical treatment.

Analysis of The Left Atrial Function Using Two-Dimensional Strain in Patients with Recent Diagnosis of Hereditary Hemochromatosis.

Hereditary Hemochromatosis (HH) is a genetic condition associated with a systemic iron overload. Heart failure is an important cause of mortality. It has been demonstrated early stages of systolic and diastolic left ventricular dysfunction in previous studies. The aim of the study is to compare the left atrial (LA) function between asymptomatic HH patients and a control group using 2D speckle tracking. Prospective study. LA strain, LA strain rate and LA volumetric parameters during the reservoir, conduit and contraction phases were studied. The LA Stiffness Index was calculated by the ratio between E/e and LA reservoir strain. 30 patients with HH (90% males, 47 ± 18 years old) and 30 healthy controls (85% males, 45 ± 13 years old) were included. LA volume was similar in both groups. No differences were observed in LA ejection fraction (EF), LA passive EF and LA active ejection fraction between both groups. On the contrary, the HH group had lower LA strain during the reservoir (31.5 ± 6.5% vs 38.3 ± 7.9%; P=0.002), and conduit phases (-18 ± 7% vs -23.3 ± 6.4%; P=0.01) and lower LA conduit strain rate (-1.7 ± 0.7 seg-1 vs -2.1 ± 0.5 seg-1; P=0.02) than controls. The LA stiffness index was significantly higher in the HH group (0.25 ± 0.9 vs 0.19 ± 0.6; P=0.01) Early abnormalities in the LA function could be detected by using 2D speckle tracking study despite no evidence of changes in atrial size or volumetric parameters.

[Liver involvement in hereditary hemorrhagic telangiectasia]. / Compromiso hepático en la telangiectasia hemorrágica hereditaria.

Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease with an autosomal dominant inheritance pattern, characterized by widespread telangiectases that can involve the skin, mucous membranes, lung, brain, gastrointestinal tract and/or liver. It has an estimated prevalence of 1 to 2 cases per 10,000. The prevalence of hepatic involvement in HHT had been estimated in 8% to 31% in retrospective studies but in more recent large prospective series the prevalence is higher, ranging between 41% and 78%. Nevertheless, symptoms occur only in 8% of the patients with HHT and liver involvement. Liver involvement by HHT is characterized by widespread diffuse liver vascular malformations that give rise to three types of shunting: arteriovenous (hepatic artery to hepatic vein), arterioportal (hepatic artery to portal vein), and portovenous (portal vein to hepatic vein). The three most common initial clinical presentations are high-output heart failure, portal hypertension and biliary disease. We describe the case of a patient with diagnosis of HHT and hepatic involvement and we review of the literature. A 58-year-old woman with HHT came to consultation with heart failure symptoms and echographic and endoscopic findings of portal hypertension. The multislice computed tomography of the abdomen revealed the presence of multiple telangiectases in the hepatic parenchyma and a shunt from the hepatic artery to the portal vein. We conclude that the symptomatic involvement of the liver in HHT is an extremely infrequent entity. It must be suspected when clinical manifestations and compatible imagenologic findings exist in patients with antecedents of HHT.

Menetrier's disease. A diagnostic and therapeutic challenge.

We present a rare case of hypertrophic gastropathy associated with protein loss. A 35-year-old man was hospitalized for bowel habit changes, abdominal pain, generalized edema and symptomatic anemia. Pertinent laboratory findings included iron deficiency anemia (Hb 6.7g/dl, ferritin 5 ng/ml) and marked hypoalbuminemia (albumin 2.5 g/dl). Endoscopic biopsy samples of giant gastric folds observed along the greater gastric curvature revealed foveolar hyperplasia and significant parietal cell loss. Endoscopic ultrasonography showed gastric parietal thickening with preserved architecture and normal gastric wall layers. Menetrier disease was diagnosed and the patient treated with cetuximab, a monoclonal antibody that inhibits ligand binding of transforming growth factor alpha (TGFa), preventing gastric mucosa cell proliferation. After twelve months of treatment, the patient referred symptoms improvement, and gastric biopsy levels of the proliferation marker protein Ki-67 had decreased.

Presentamos un caso infrecuente de gastropatía hipertrófica asociada a pérdida de proteínas. Un hombre de 35 años fue hospitalizado por cambios en los hábitos intestinales, dolor abdominal, edema generalizado y anemia sintomática. Los hallazgos de laboratorio pertinentes incluyeron anemia ferropénica (Hb 6.7 g/dl, ferritina 5 ng/ml) e hipoalbuminemia marcada (albúmina 2.5 g/dl). Las muestras de biopsia endoscópica de pliegues gástricos gigantes observados a lo largo de la curvatura mayor gástrica revelaron hiperplasia foveolar y pérdida significativa de células parietales. La ecografía endoscópica mostró engrosamiento parietal gástrico con arquitectura conservada y capas de pared gástrica normales. Se diagnosticó enfermedad de Menetrier y se trató al paciente con cetuximab, un anticuerpo monoclonal que inhibe la unión del ligando del factor de crecimiento transformante alfa (TGFa), evitando la proliferación de células de la mucosa gástrica. Después de doce meses de tratamiento, el paciente refirió mejoría de los síntomas y los niveles de la proteína marcadora de proliferación Ki-67 en biopsia gástrica habían disminuido.

Bezafibrate therapy in primary biliary cholangitis refractory to ursodeoxycholic acid: a longitudinal study of paired liver biopsies at 5 years of follow up.

BACKGROUND: Ursodeoxycholic acid (UDCA) is the first-line therapy for primary biliary cholangitis (PBC). However, nearly 40% of patients have an incomplete response to UDCA. The addition of bezafibrate has shown biochemical benefit in this group of patients. AIM: To evaluate the long-term effects of UDCA in combination with bezafibrate on histological outcomes in patients with UDCA-refractory PBC. METHODS: Fifty-nine patients refractory to UDCA were included. Clinical parameters were monitored and paired liver biopsy (PLB) was performed after 5 years of follow-up. RESULTS: Of the total cohort, 49 subjects were analysed and 31 had PLB at 5 years. Values for serum ALP, AST, ALT and GGT significantly improved with UDCA-bezafibrate. This beneficial effect was observed at 12 months where 86% achieved ALP at normal levels. Analyses of PLB showed a significant decrease in liver damage as reflected by Ludwig (baseline 2.29 ± 1.2, to 1.84 ± 1 at year 5, P = 0.0242) and Ishak (baseline 6.19 ± 2.2 to 4.77 ± 2.2 at year 5, P = 0.0008) scores. Overall, regression of fibrosis was attained in 48% of patients. Furthermore, we observed a significant reduction in the proportion with cirrhosis from 19% at baseline to 3% at 5 years (P < 0.001). These beneficial effects were associated with better predictive risk scores using the GLOBE and UK-PBC prognosis models. CONCLUSIONS: Adding bezafibrate to UDCA in patients with UDCA-refractory PBC showed a significant decrease in fibrosis and inflammatory histological scores at 5 years. These beneficial effects warrant further evaluation in long-term cohort studies and controlled trials.

[Faecal microbiota transplantation for Clostridioides difficile infection]. / Trasplante de microbiota fecal en la infección por Clostridioides difficile.

Clostridiodes difficile infection (CDi) is the most common cause of nosocomial diarrhea. Vancomycin, associated or not to metronidazol, is the treatment of choice. However, the rate of treatment failure has increased over the last years and fecal microbiota transplantation (FMT) has emerged as a therapeutic option. To evaluate safety and efficacy of FMT were enrolled 21 hospitalized patients with refractory or recurrent CDi between 2016 and 2019. Fourteen (66%) patients were men and the average age was 76.5 years (range 33-92). Ten had recurrent and 11 refractory CDi, and 18 presented severe and 3 fulminant clinical forms. In 20 cases the FMT was delivered through a nasojejunal tube and in one patient with ileo via enema infusion. Frozen fecal from a stool bank were administered in 20 and in the remaining was used fresh fecal matter. The rate of resolution was observed in 20 patients (95.2%) and none presented recurrence. The response rate was similar in recurrent or refractory forms (9/10 vs 11/11 respectively). One patient with osteomyelitis and multiple organ failure received 2 FMT without response and died. Seven patients (31%) presented mild and self-limited adverse effects. FMT has shown a high efficacy as rescue treatment in cases with refractory or recurrent CDi regardless of severity, with mild side effects. Availability of a stool banks provide reliable, timely and equitable access to FMT for CDi.

La infección por Clostridioides difficile (iCD) es la causa más frecuente de diarrea nosocomial. La primera línea terapéutica es la vancomicina asociada o no al metronidazol. En los últimos años se incrementó el número de fracasos terapéuticos con una mayor frecuencia de formas refractarias o recurrentes. El trasplante de microbiota fecal (TMF) ha surgido como una opción terapéutica para estos casos. Se evaluó la seguridad y la tasa de resolución empleando el TMF en un estudio observacional abierto y prospectivo de 21 pacientes con iCD recurrentes o refractarias internados entre los años 2016 y 2019. La edad media fue de 76.5 años (33-92). Diez presentaron una forma recurrente y 11 una refractaria, 18 fueron graves y 3 fulminantes. En 20 casos el TMF se administró por la vía digestiva alta y en uno por presentar íleo se utilizó la vía baja. Se empleó TMF de heces frescas en un caso y el resto recibió muestras congeladas de un banco de microbiota. Veinte pacientes (95.2%) tuvieron respuesta terapéutica favorable sin presentar recurrencias. Un caso recurrente, con osteomielitis y falla multiorgánica, no tuvo resolución tras dos TMF. La respuesta fue similar en las formas recurrentes y refractarias. Siete pacientes (31%) tuvieron efectos adversos leves y autolimitados. El TMF ha demostrado una alta eficacia como tratamiento de rescate de las formas graves de iCD, con escasos y leves efectos adversos. Contar con un banco de microbiota fecal resulta fundamental para disponer de este recurso terapéutico oportunamente.

Importance of a Rapid and Accurate Diagnosis in Strongyloides Stercoralis and Human T-Lymphotropic Virus 1 Co-infection: A Case Report and Review of the Literature.

Strongyloides (S.) stercoralis and Human T-Lymphotropic Virus 1 (HTLV-1) share some endemic regions such as Japan, Jamaica, and South America and are mostly diagnosed elsewhere in immigrants from endemic areas. This co-infection has not been documented in Argentina although both pathogens are endemic in the Northwest. We present a case of S. stercoralis and HTLV-1 co-infection with an initial presentation due to gastrointestinal symptoms which presented neither eosinophilia nor the presence of larvae in stool samples in a non-endemic area for these infections. A young Peruvian woman living in Buenos Aires attended several emergency rooms and finally ended up admitted in a gastroenterology ward due to incoercible vomiting, diarrhea, abdominal pain, fever, and weight loss. Gastrointestinal symptoms started 3 months before she returned to Argentina from a trip to Peru. She presented malnutrition and abdominal distension parameters. HIV-1 and other immunodeficiencies were discarded. The serial coproparasitological test was negative. Computed tomography showed diffuse thickening of duodenal and jejunal walls. At the beginning, vasculitis was suspected and corticosteroid therapy was initiated. The patient worsened rapidly. Skin, new enteral biopsies, and a new set of coproparasitological samples revealed S. stercoralis. Then, HTLV-1 was suspected and infection was confirmed. Ivermectin and albendazole were administrated, until the stool sample remained negative for 2 weeks. Larvae were not observed in fresh stool, Ritchie method, and agar culture 1 week post-treatment. Although she required initial support with parenteral nutrition due to oral intolerance she slowly progressed favorably. It has been highly recommended to include a rapid and sensitive PCR strategy in the algorithm to confirm Strongyloides infection, which has demonstrated to improve early diagnosis in patients at-risk of disseminated strongyloidiasis.

New evidence for the therapeutic potential of curcumin to treat nonalcoholic fatty liver disease in humans.

INTRODUCTION: The immune system acts on different metabolic tissues that are implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Leptin and linoleic acid have the ability to potentially affect immune cells, whereas curcumin is a known natural polyphenol with antioxidant and anti-inflammatory properties. AIMS: This study was designed to evaluate the pro-inflammatory and pro-oxidant effects of leptin and linoleic acid on immune cells from patients with NAFLD and to corroborate the modulatory effects of curcumin and its preventive properties against the progression of NAFLD using a high-fat diet (HFD)-induced NAFLD/nonalcoholic steatohepatitis mouse model. RESULTS: The ex vivo experiments showed that linoleic acid increased the production of reactive oxygen species in monocytes and liver macrophages, whereas leptin enhanced tumor necrosis factor-α (TNF-α) production in monocytes and interferon-γ production in circulating CD4+ cells. Conversely, oral administration of curcumin prevented HFD-induced liver injury, metabolic alterations, intrahepatic CD4+ cell accumulation and the linoleic acid- and leptin- induced pro-inflammatory and pro-oxidant effects on mouse liver macrophages. CONCLUSION: Our findings provide new evidence for the therapeutic potential of curcumin to treat human NAFLD. However, the development of a preventive treatment targeting human circulating monocytes and liver macrophages as well as peripheral and hepatic CD4+ cells requires additional research.

Alterations in triglyceride rich lipoproteins are related to endothelial dysfunction in metabolic syndrome.

UNLABELLED: Our aim was to analyze the effect of circulating triglyceride rich lipoprotein (TRL) on endothelial function in metabolic syndrome (MetS). METHODS: We studied 40 patients with MetS (ATPIII), divided into those presenting normal endothelial function (n=19) and those with endothelial dysfunction (n=21) by means of the evaluation of pulse wave velocity, before and after brachial artery ischemia. In fasting serum we measured lipid and lipoprotein profile, insulin and glucose (HOMA-IR). Moreover, isolated TRL (d<1006g/l) were chemically characterized. In parallel, using randomly selected TRL from MetS patients with endothelial dysfunction (n=6) and MetS patients with normal endothelial function (n=6), the ability of TRL to inhibit ACh-induced vasorelaxation (10(-9)-10(-5)mM) on aortic rings previously pre-contracted by noradrenaline (10(-8)mM) was evaluated. RESULTS: Interestingly, TRL isolated from MetS patients presenting endothelial dysfunction showed triglyceride over-enrichment (59.1±4.8 vs. 54.1±4.7%; p=0.04), even after adjusting by potential confounders (p=0.05). In addition, while TRL resulting from both MetS groups significantly inhibited endothelium dependent vasorelaxation (p<0.001), TRL from MetS patients with endothelial dysfunction showed a strong tendency to a greater inhibition of vasorelaxation (p=0.06). Moreover, TRL-triglyceride (%) showed a strong tendency to correlate with the grade of vasorelaxation inhibition exerted by TRL (r=0.60; p=0.05). CONCLUSION: These results, taken together, would allow inferring for the first time that the predominance of triglyceride over-enriched TRL in circulation in MetS would induce endothelial dysfunction, contributing to the inherent cardiovascular risk of MetS.