[Portosinusoidal vascular disorder: A paradigm shift]. / Enfermedad vascular portosinusoidal: un cambio de paradigma.

The term portosinusoidal vascular disorder (PSVD) refers to a clinical-pathological entity that encompasses those patients with intrahepatic vascular damage without cirrhosis at risk of developing severe complications of portal hypertension. Numerous systemic diseases, genetic disorders, and toxic agents have been associated with this pathology, making its diagnosis an important clinical challenge. The recent description of uniform diagnostic criteria and a better understanding of its pathophysiology will allow for better identification of patients, even in early stages of the disease. Although there is currently no effective etiological treatment available, early diagnosis allows for the development of preventive strategies for some severe complications of portal hypertension.

Soluble guanylyl cyclase stimulation and phosphodiesterase-5 inhibition improve portal hypertension and reduce liver fibrosis in bile duct-ligated rats.

BACKGROUND: In cirrhosis, the nitric oxide-soluble guanylyl cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway is impaired, which contributes to increased intrahepatic vascular resistance (IHVR) and fibrogenesis. We investigated if sGC stimulation (riociguat (RIO)), sGC activation (cinaciguat (CINA)) or phosphodiesterase (PDE)-5 inhibition (tadalafil (TADA)) improves portal hypertension (PHT) and liver fibrosis. METHODS: Fifty male Sprague-Dawley rats underwent bile-duct ligation (BDL) or sham operation. RIO (0.5 mg/kg), CINA (1 mg/kg), TADA (1.5 mg/kg) or vehicle (VEH) was administered from weeks 2 to 4 after BDL. At week 4, invasive haemodynamic measurements were performed, and liver fibrosis was assessed by histology (chromotrope-aniline blue (CAB), Picro-Sirius red (PSR)) and hepatic hydroxyproline content. RESULTS: Cirrhotic bile duct-ligated rats presented with PHT (13.1 ± 1.0 mmHg) and increased IHVR (4.9 ± 0.5 mmHg⋅min/mL). Both RIO (10.0 ± 0.7 mmHg, p = 0.021) and TADA (10.3 ± 0.9 mmHg, p = 0.050) decreased portal pressure by reducing IHVR (RIO: -41%, p = 0.005; TADA: -21%, p = 0.199) while not impacting heart rate, mean arterial pressure and portosystemic shunting. Hepatic cGMP levels increased upon RIO (+239%, p = 0.006) and TADA (+32%, p = 0.073) therapy. In contrast, CINA dosed at 1 mg/kg caused weight loss, arterial hypotension and hyperlactataemia in bile duct-ligated rats. Liver fibrosis area was significantly decreased by RIO (CAB: -48%, p = 0.011; PSR: -27%, p = 0.121) and TADA (CAB: -21%, p = 0.342; PSR: -52%, p = 0.013) compared to VEH-treated bile duct-ligated rats. Hepatic hydroxyproline content was reduced by RIO (from 503 ± 20 to 350 ± 30 µg/g, p = 0.003) and TADA (282 ± 50 µg/g, p = 0.003), in line with a reduction of the hepatic stellate cell activation markers smooth-muscle actin and phosphorylated moesin. Liver transaminases decreased under RIO (AST: -36%; ALT: -32%) and TADA (AST: -24%; ALT: -27%) treatment. Hepatic interleukin 6 gene expression was reduced in the RIO group (-56%, p = 0.053). CONCLUSION: In a rodent model of biliary cirrhosis, the sGC stimulator RIO and the PDE-5 inhibitor TADA improved PHT. The decrease of sinusoidal vascular resistance was paralleled by a reduction in liver fibrosis and hepatic inflammation, while systemic haemodynamics were not affected.

Effects of Belapectin, an Inhibitor of Galectin-3, in Patients With Nonalcoholic Steatohepatitis With Cirrhosis and Portal Hypertension.

BACKGROUND & AIMS: Increased levels of galectin 3 have been associated with nonalcoholic steatohepatitis (NASH) and contribute to toxin-induced liver fibrosis in mice. GR-MD-02 (belapectin) is an inhibitor of galectin 3 that reduces liver fibrosis and portal hypertension in rats and was safe and well tolerated in phase 1 studies. We performed a phase 2b, randomized trial of the safety and efficacy of GR-MD-02 in patients with NASH, cirrhosis, and portal hypertension. METHODS: Patients with NASH, cirrhosis, and portal hypertension (hepatic venous pressure gradient [HVPG] ≥ 6 mm Hg) from 36 centers were randomly assigned, in a double-blind manner, to groups that received biweekly infusions of belapectin 2 mg/kg (n = 54), 8 mg/kg (n = 54), or placebo (n = 54) for 52 weeks. The primary endpoint was change in HVPG (Δ HVPG) at the end of the 52-week period compared with baseline. Secondary endpoints included changes in liver histology and development of liver-related outcomes. RESULTS: We found no significant difference in ΔHVPG between the 2 mg/kg belapectin group and placebo group (-0.28 mm HG vs 0.10 mm HG, P = 1.0) or between the 8 mg/kg belapectin and placebo group (-0.25 mm HG vs 0.10 mm HG, P = 1.0). Belapectin had no significant effect on fibrosis or nonalcoholic fatty liver disease activity score, and liver-related outcomes did not differ significantly among groups. In an analysis of a subgroup of patients without esophageal varices at baseline (n = 81), 2 mg/kg belapectin was associated with a reduction in HVPG at 52 weeks compared with baseline (P = .02) and reduced development of new varices (P = .03). Belapectin (2 mg/kg) was well tolerated and produced no safety signals. CONCLUSIONS: In a phase 2b study of 162 patients with NASH, cirrhosis, and portal hypertension, 1 year of biweekly infusion of belapectin was safe but not associated with significant reduction in HVPG or fibrosis compared with placebo. However, in a subgroup analysis of patients without esophageal varices, 2 mg/kg belapectin did reduce HVPG and development of varices. ClinicalTrials.gov number: NCT02462967.

Hepatoportal sclerosis related to the use of herbals and nutritional supplements. Causality or coincidence?

 Introduction and aim. Non-cirrhotic idiopathic portal hypertension (NCIPH), also known as hepatoportal sclerosis (HPS) is a disease of uncertain etiology. However, various pathophysiological mechanisms has been postulated, including chronic or recurrent infections and exposure to drugs or toxins. In this context, it appears to be of multifactorial etiology or resulting from a portal vascular endothelium aggression. It is important to consider whether the use of dietary supplements and herbs can trigger or contribute to the occurance of HPS. We report a possible association of HPS with the consumption of herbals and / or dietary supplements. MATERIAL AND METHODS: We describe two cases of HPS in patients without known etiology causes associated with this disease. RESULTS: Both patients were females who were diagnosed with HPS following the consumption of Herbalife® products and putative anorexigenic agents in the form herbals infusions. Image-based analysis and the assessment of the histopathological alterations found in the livers confirmed the diagnosis. The histopatological analysis of liver samples from both patients showed portal tracts enlarged by fibrosis with disappearance or reduction in the diameter of the portal vein branches. In many portal tracts, portal veins branches were replaced by aberrant thin-walled fendiforme vessels. The bile ducts and branches of the hepatic artery show normal aspects. CONCLUSION: After the exclusion of other etiologic factors and a comprehensive analysis of clinical history, consumption of Herbalife® products and anorexigenic agents was pointed-out as a puttative predisposing factor for the development of the disease.

Modified laparoscopic splenectomy and azygoportal disconnection combined with cell salvage is feasible and might reduce the need for blood transfusion.

AIM: To investigate perioperative outcomes in patients undergoing modified laparoscopic splenectomy and azygoportal disconnection (MLSD) with intraoperative autologous cell salvage. METHODS: We retrospectively evaluated outcomes in 79 patients admitted to the Clinical Medical College of Yangzhou University with cirrhosis, portal hypertensive bleeding and secondary hypersplenism who underwent MLSD without (n = 46) or with intraoperative cell salvage and autologous blood transfusion, including splenic blood and operative hemorrhage (n = 33), between February 2012 and January 2014. Their intraoperative and postoperative variables were compared. These variables mainly included: operation time; estimated intraoperative blood loss; volume of allogeneic blood transfused; visual analog scale for pain on the first postoperative day; time to first oral intake; initial passage of flatus and off-bed activity; perioperative hemoglobin (Hb) concentration; and red blood cell concentration. RESULTS: There were no significant differences between the groups in terms of duration of surgery, estimated intraoperative blood loss and overall perioperative complication rate. In those receiving salvaged autologous blood, Hb concentration increased by an average of 11.2 ± 4.8 g/L (P < 0.05) from preoperative levels by the first postoperative day, but it had fallen by 9.8 ± 6.45 g/L (P < 0.05) in the group in which cell salvage was not used. Preoperative Hb was similar in the two groups (P > 0.05), but Hb on the first postoperative day was significantly higher in the autologous blood transfusion group (118.5 ± 15.8 g/L vs 102.7 ± 15.6 g/L, P < 0.05). The autologous blood transfusion group experienced significantly fewer postoperative days of temperature > 38.0°C (P < 0.05). CONCLUSION: Intraoperative cell salvage during MLSD is feasible and safe and may become the gold standard for liver cirrhosis with portal hypertensive bleeding and hypersplenism.

Approach to a child with upper gastrointestinal bleeding.

Upper gastrointestinal bleeding (UGIB) is a potentially life threatening medical emergency requiring an appropriate diagnostic and therapeutic approach. Therefore, the primary focus in a child with UGIB is resuscitation and stabilization followed by a diagnostic evaluation. The differential diagnosis of UGIB in children is determined by age and severity of bleed. In infants and toddlers mucosal bleed (gastritis and stress ulcers) is a common cause. In children above 2 y variceal bleeding due to Extra-Hepatic Portal Venous Obstruction (EHPVO) is the commonest cause of significant UGIB in developing countries as against peptic ulcer in the developed countries. Upper gastrointestinal endoscopy is the most accurate and useful diagnostic tool to evaluate UGIB in children. Parenteral vitamin K (infants, 1-2 mg/dose; children, 5-10 mg) and parenteral Proton Pump Inhibitors (PPI's), should be administered empirically in case of a major UGIB. Octreotide infusion is useful in control of significant UGIB due to variceal hemorrhage. A temporarily placed, Sengstaken-Blakemore tube can be life saving if pharmacologic/ endoscopic methods fail to control variceal bleeding. Therapy in patients having mucosal bleed is directed at neutralization and/or prevention of gastric acid release; High dose Proton Pump Inhibitors (PPIs, Pantoprazole) are more efficacious than H2 receptor antagonists for this purpose.

Surgical management of portal hypertension in children.

The management of children with portal hypertension has dramatically changed during the past decade, with an improvement in outcome. This has been achieved by improved efficiency of endoscopic variceal control and the success of liver transplantation. Emergency surgical shunt procedures are rarely required, with acute bleeding episodes generally controlled endoscopically or, occasionally in adults, by interventional radiological procedures. Portosystemic shunts may be considered as a bridge to transplant in adults but are rarely used in this context in children. Nontransplant surgery or radiological interventions may still be indicated for noncirrhotic portal hypertension when the primary cause can be cured and to allow normalization of portal pressure before liver parenchyma is damaged by chronic secondary changes in some specific diseases. The meso-Rex bypass shunt is used widely but is limited to those with a favorable anatomy and can even be performed preemptively. Elective portosystemic shunt surgery is reserved for failure to respond to conservative management in the absence of alternative therapies.

Development of a large animal model of cirrhosis and portal hypertension using hepatic transarterial embolization: a study in swine.

PURPOSE: To develop a clinically relevant porcine model of liver cirrhosis with portal hypertension by means of hepatic transarterial embolization. MATERIALS AND METHODS: Institutional animal care and use committee approval was obtained for all experiments. Pigs received transcatheter arterial infusion of a 3:1 mixture of iodized oil and ethanol into the hepatic artery in volumes of 16 mL in group 1 (n = 4), 28 mL in group 2 (n = 4), and 40 mL in group 3 (n = 4) with intent of bilobar distribution. Hepatic venous pressure gradient (HVPG) measurement, liver function tests, and volumetry were performed at baseline, at 2 weeks, and before necropsy. RESULTS: Cirrhosis was successfully induced in three animals that received 16 mL of the embolic mixture and in all four animals that received 28 mL. The animals in the 40-mL group did not recover from the procedure and were euthanized within 48 h. Increases in HVPG after 6-8 weeks versus baseline reached statistical significance (P < .05). Correlation between degree of fibrosis and volume of embolic agent did not reach statistical significance, but there was a trend toward increased fibrosis in the 28-mL group compared with the 16-mL group. CONCLUSIONS: Transcatheter hepatic arterial embolization can be used to create a reliable and reproducible porcine model of liver cirrhosis and portal hypertension.

Portal hypertension associated with sickle cell disease.

We report a 12-year-old girl with sickle cell disease who presented with pain in abdomen, fever, joint pain and hematemesis. On examination she had mild jaundice and splenomegaly. Upper GI endoscopy showed esophageal varices. She was treated with variceal band ligation and is well on folic acid supplements and propranolol.

Vitamin A toxicity: when one a day doesn't keep the doctor away.

Vitamin A toxicity has been reported to cause severe liver disease and, occasionally, liver failure. Herein we present the case of a 60-year-old male with symptoms of muscle soreness, alopecia, nail dystrophy, and ascites. He continued to deteriorate with the development of refractory ascites, renal insufficiency, encephalopathy, and failure to thrive. A liver biopsy demonstrated presence of Ito cells and vacuolated Kupffer cells without the presence of cirrhosis. His clinical history revealed ingestion of large doses of vitamin A. His worsening clinical situation ruled out the possibility of a transjugular intrahepatic portosystemic shunt. The patient underwent orthotopic liver transplantation with resolution of symptoms. Vitamin A toxicity should be considered in the differential diagnosis of noncirrhotic portal hypertension. In conclusion, liver transplantation is a valid option if no improvement occurs in spite of cessation of the medication.

Hepatic hydrothorax: diagnosis and management. Case report and review of the literature.

Current practice standards indicate the need for tube thoracostomy in the management of clinically significant recurrent pleural effusions. The following case presentation and review of the literature illustrate a contraindication to chest tube insertion with pleural effusions associated with portal hypertension (hepatic hydrothorax) and suggest alternative therapies.

Hipertensión portal / Portal hypertension

Esta revisión trata sobre los recientes conocimientos de la anatomía, fisiología, etiología, clínica, exámenes auxiliares y tratamiento del síndrome de hipertensión portal. En fisiopatología se destaca que además de los factores clásicos considerados en la hipertensión portal de origen cirrótico, habría otro, dado por el incremento en la sensibilidad de los receptores S2 de serotonina a nivel de la circulación portal. Se hace una actualización de los métodos diagnósticos no invasivos, y se comentan algunas pruebas de laboratorio de utilidad clínica. En relación al tratamiento se ha puesto énfasis en el uso de fármacos, especialmente vasodilatadores, que actúan modificando la magnitud de la presión portal

Angiographic, hemodynamic, and histologic evaluation of portal hypertension and periportal fibrosis induced in the dog by retrograde biliary injections of sesame oil.

Periportal fibrosis and portal hypertension were induced by periodic retrograde biliary injections of sesame oil for two to three months in 12 cholecystectomized dogs equipped with Thomas cannulas. Stable portal hypertension between 18 and 24 cm of water occurred in four of 12 dogs (baseline: 10.4 +/- 0.5 cm of water); the remaining eight dogs required continuous biliary oil injections to maintain the portal pressure in that range. Portosystemic venous collaterals were first seen three weeks after the initial biliary oil injection and were extensively developed after two months. Hepatopetal portal blood flow decreased 61 +/- 5% during the first six months, with the greatest decrease of 32 +/- 4% occurring in the first month. Hepatic arterial flow did not change in the first month and then began to rise slowly to peak at nine months at 170 +/- 32% of its baseline value. The greatest increase in hepatic arterial flow was found between the sixth and ninth month when the portal flow no longer changed significantly. Hepatic fibrosis originating from the portal triads and around extravasated oil droplets appeared to progress slowly during the entire observation period. Animals with advanced hepatic fibrosis remained in satisfactory general health with liver enzymes usually remaining in the high normal to low pathologic range, allowing extensive follow-up examinations at regular intervals.