Progressive Portal Hypertension Research Articles

Morphological aspects of the normal versus pathological liver

Introduction. Chronic liver diseases stimulate a degree of hepatocyte injury. This previously mentioned modifications, alters the known liver architecture and finally ends in cirrhosis. Liver pathology as cirrhosis develops after a long period of pathological alterations. In this iddea, inflammation is a great point that results in replacement of the healthy liver parenchyma with fibrotic tissue and regenerative nodules. In addition, progressive portal hypertension, systemic inflammation, and liver failure drive cirrhosis outcomes. The management of this liver pathology, is centred on the treatment of the causes and complications. Liver transplantation can be required in some cases.The aim of this article was to identify the best available evidences analyzing liver samples, normall and pathological.Material and methods. Were made permanent preparations and used two colors. Hematoxylin–Eosin and also Goldner – Szekely trichrome stains stain for observation at optical microscope with x10 and x40 lens magnification. Samples liver collected during necropsy, from healthy patients and from patients diagnosed with cirrhosis.Results and discussion. Normal liver with hepatocytes, Kiernann space, connective septa, observations using lens x10 and samples colored with Goldner Szekely trichrome stains. Beside, for comparisions, ill liver images, classic stain H&E. Inflammation is a great point that results in replacement of the healthy liver parenchyma with fibrotic tissue and regenerative nodules. In addition, progressive portal hypertension, systemic inflammation, and liver failure drive cirrhosis outcomes.Conclusions. Our contribution in the written text, is related to the impact of physical, psychological and physiological factors. All this previously mentioned factors, area great impact on the health-related quality of life of adult patients with liver cirrhosis. The management of this liver pathology, is centred on the treatment of the causes and complications. Liver transplantation can be required in some cases.

SUN-602 Weight Loss After Glucagon-Like Peptide-1 Receptor Agonist Treatment in Childhood Obesity with Diabetes and Cirrhosis Associated with a Homozygous MC4R Mutation

BackgroundMutations in the melanocortin-4 receptor (MC4R) represent the most common cause of monogenic obesity. Treatment options are limited but glucagon-like peptide-1 receptor agonists (GLP-1 RA) may be of use to induce weight loss.MethodsExome of the patient was captured using the Agilent SureSelect QXT Human All Exon V5 kit and sequenced on Illumina.Clinical findings and resultsWe report obesity-associated diabetes and cirrhosis in a 13-year girl born from consanguineous parents of Afghan origin. Past medical history revealed mild mental retardation and excessive weight gain since infancy. Linear growth was normal. Her father was obese and no diabetes was found in the family. The girl was initially investigated for hoarseness and found to have pulmonary hypertension, later accepted to be secondary to cirrhosis and portal hypertension. Physical examination revealed obesity (BMI 34.9kg/m2) and acanthosis nigricans. Blood exams showed leucopenia and thrombocytopenia without anemia, compatible with portal hypertension. Chest CT revealed important dilatation of the pulmonary arteries, a nodular liver and splenomegaly. Liver biopsy confirmed cirrhosis. An extensive workup including whole exome sequencing identified a homozygous MC4R variant [NM_005912.2 (MC4R): c.63_64del, p.(Tyr21*)], classified as pathogenic according to the ACMG guidelines. Both parents were heterozygous for this variant. An endocrinological workup showed insulin resistance with a HOMA-IR index of 7.27 and diabetes with peak blood glucose of 11.5mmol/l. HbA1c was 5.1% (32mmol/mol). Thyroid tests, leptin, proinsulin levels (3.5pmol/l, n <11.0pmol/l) were normal.The mutation being homozygous with a predicted complete loss of function (https://www.mc4r.org.uk/), no treatment with a MC4R agonist was tried. At the age of 15 years (BMI 36.0kg/m2), the patient underwent liver transplantation because of progressive portal hypertension and to halt the progression of pulmonary hypertension. At the age of 16 years (BMI 33.2kg/m2, HbA1c 4.9% (30.0 mmol/mol), HOMA-IR 5.3) a treatment with GLP-1 RA (liraglutide) was started at a dosage of 0.6mg and progressively increased to 3mg, in an attempt to induce weight loss, avoid the accumulation of liver fat and to protect the graft. GLP-1 RA is supposed to exerts its effects on appetite independently of the MC4R pathway. 2 months after liraglutide introduction, no side effects, a weight loss of 4kg and a decrease of appetite were observed (BMI 31.6kg/m2, HbA1c 4.5% (26mmol/mol), HOMA-IR 3.14).ConclusionObesity-associated MCR4 mutations, in homozygous state, may lead to diabetes, liver cirrhosis and porto-pulmonary hypertension. Treatment options are scarce, but GLP-1 RA seem to have a rapid, positive effect on weight and metabolic control. Would earlier treatment have prevented progression to end-stage-liver disease and need for liver transplantation?

Interventions for preventing and managing advanced liver disease in cystic fibrosis

Cystic fibrosis is an autosomal recessive inherited defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene resulting in abnormal regulation of salt and water movement across the membranes. In the liver this leads to focal biliary fibrosis resulting in progressive portal hypertension and end-stage liver disease in some individuals. This can be asymptomatic, but may lead to splenomegaly and hypersplenism, development of varices and variceal bleeding, and ascites; it has negative impact on overall nutritional status and respiratory function in this population. Prognosis is poor once significant portal hypertension is established. The role and outcome of various interventions for managing advanced liver disease (non-malignant end stage disease) in people with cystic fibrosis is currently unidentified. This is an updated version of a previously published review. To review and assess the efficacy of currently available treatment options for preventing and managing advanced liver disease in children and adults with cystic fibrosis. We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. Date of last search: 19 November 2019. We also searched the reference lists of relevant articles and reviews and online trials registries. Date of last search: 01 January 2020. Any published and unpublished randomised controlled trials and quasi-randomised controlled trials of advanced liver disease in cystic fibrosis with cirrhosis or liver failure, portal hypertension or variceal bleeding (or both). Authors independently examined titles and abstracts to identify potentially relevant trials, but none were eligible for inclusion in this review. A comprehensive search of the literature did not identify any published eligible randomised controlled trials. In order to develop the best source of evidence, there is a need to undertake randomised controlled trials of interventions for preventing and managing advanced liver disease in adults and children with cystic fibrosis.

Donor-Derived Genotype 4 Hepatitis E Virus Infection, Hong Kong, China, 2018.

Hepatitis E virus (HEV) genotype 4 (HEV-4) is an emerging cause of acute hepatitis in China. Less is known about the clinical characteristics and natural history of HEV-4 than HEV genotype 3 infections in immunocompromised patients. We report transmission of HEV-4 from a deceased organ donor to 5 transplant recipients. The donor had been viremic but HEV IgM and IgG seronegative, and liver function test results were within reference ranges. After a mean of 52 days after transplantation, hepatitis developed in all 5 recipients; in the liver graft recipient, disease was severe and with progressive portal hypertension. Despite reduced immunosuppression, all HEV-4 infections progressed to persistent hepatitis. Four patients received ribavirin and showed evidence of response after 2 months. This study highlights the role of organ donation in HEV transmission, provides additional data on the natural history of HEV-4 infection, and points out differences between genotype 3 and 4 infections in immunocompromised patients.

Clinical Assessment and Management of Portal Hypertension.

The development of portal hypertension in a patient with cirrhosis portends a poor prognosis. Untreated or progressive portal hypertension has serious clinical outcomes, which are often fatal. It is important to recognize portal hypertension early to delay progression and to treat complications of portal hypertension as they arise. This review will focus on the clinical assessment and management of portal hypertension.

Interventions for preventing and managing advanced liver disease in cystic fibrosis.

Cystic fibrosis is an autosomal recessive inherited defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene resulting in abnormal regulation of salt and water movement across the membranes. In the liver this leads to focal biliary fibrosis resulting in progressive portal hypertension and end-stage liver disease in some individuals. This can be asymptomatic, but may lead to splenomegaly and hypersplenism, development of varices and variceal bleeding, and ascites; it has negative impact on overall nutritional status and respiratory function in this population. Prognosis is poor once significant portal hypertension is established. The role and outcome of various interventions for managing advanced liver disease (non-malignant end stage disease) in people with cystic fibrosis is currently unidentified. To review and assess the efficacy of currently available treatment options for preventing and managing advanced liver disease in children and adults with cystic fibrosis. We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books.Date of last search: 06 April 2017.We also searched the reference lists of relevant articles and reviews and online trials registries. Date of last search: 04 January 2017. Any published and unpublished randomised controlled trials and quasi-randomised controlled trials of advanced liver disease in cystic fibrosis with cirrhosis or liver failure, portal hypertension or variceal bleeding (or both). Authors independently examined titles and abstracts to identify potentially relevant trials, but none were eligible for inclusion in this review. A comprehensive search of the literature did not identify any published eligible randomised controlled trials. In order to develop the best source of evidence, there is a need to undertake randomised controlled trials of interventions for preventing and managing advanced liver disease in adults and children with cystic fibrosis.

Hemodynamics in Normal and Diseased Livers: Application of Image-Based Computational Models

This investigation demonstrates the utility of image-based computational models in portal venous hemodynamics. The long-term objective is to develop methodologies based upon noninvasive imaging and hemodynamic computational models for blood flow in major vessels of the liver that will significantly augment and improve current practices in clinical care. Magnetic resonance imaging (MRI) and computational fluid dynamics (CFD) were used to investigate liver hemodynamics. MRI data were obtained in 7 healthy subjects and 4 patients diagnosed with cirrhosis, and computational models were developed and validated for two healthy subjects and two patients. Additional simulations of post-prandial hemodynamics and portal hypertension were completed. The MRI studies identified several new parameters (portal vein V avg/total liver volume, V var, splenic vein flow rate per total liver volume, and % splenic flow/portal vein flow) that offer statistical differentiation between healthy subjects and patients with liver disease. Computational models were used to calculate the contribution of blood supply to the right and left lobes of the liver derived from the superior mesenteric vein (greater in healthy subjects vs. patients); and simulate post-prandial conditions and progressive portal hypertension. CFD offers a tool to test hypotheses without the acquisition of additional data and elucidate hemodynamic effects as disease progresses. In addition, several new MRI derived parameters have been identified as having promise to distinguish between healthy and patient groups and, potentially, to monitor disease progression.

Spleno-adrenal shunt: A novel alternative for portosystemic decompression in children with portal vein cavernous transformation

PurposeChildren with portal vein cavernous transformation (PVCT) can develop life-threatening variceal hemorrhage from progressive portal hypertension. While spleno-renal shunt±splenectomy is the most common portosystemic decompression surgery performed in children, we have adopted a modified spleno-adrenal (SA) shunt for complicated PVCT. We describe our 10year experience focusing on technique evolution and treatment efficacy. MethodsBetween 2001 and 2011, 15 children (9 girls and 6 boys, ages 3–11years, median: 6years) with PVCT, portal hypertension, and hypersplenism were treated with SA shunt with splenectomy in Shanghai Children's Medical Center. All children in the study had endoscopy proven active esophageal variceal bleeding requiring multiple transfusions (mean: 4.2 units) with failed sclerotherapy (mean: 2.6 times). Greater omental vein pressure (GVP) approximating portal venous pressure was measured pre- and post-SA shunt. Pre- and post-operative ammonia levels were obtained. Follow-up ranged from 6months to 10years (mean: 4.2±2years). ResultsIntra-operative adrenal vein diameter and length ranged from 0.7 to 1.8cm and 2 to 3cm, respectively. Intra-operative GVPs pre-and post-SA shunt were (30±11) and (22±7) mmHg, respectively (p<0.01). On follow-up, there have been no recurrences of GI bleeding. Liver function tests remained normal in all children with the exception of elevated post-operative mean blood ammonia levels [Pre (18±7) mmol/L, post (60±17) mmol/L (p<0.05)] in all children. Ammonia levels normalized in all cases on outpatient follow-up. There have been no cases of hepatic encephalopathy, and all have normal age appropriate neurodevelopment (Bayley's assessment). Barium swallow and/or upper endoscopy showed interval resolution of esophageal varices in all children, and vascular ultrasound showed patent shunt anastomosis without stricture in 14 (93%). ConclusionsThe left adrenal vein is a viable conduit for effective selective portosystemic decompression. Similar to the more traditional spleno-renal shunt, SA appears also to have the advantage of preventing hepatic encephalopathy preserving neurodevelopment, although the rise in post-operative ammonia levels was unexpected. Longer follow-up is needed to look for late signs of encephalopathy assessing neurodevelopment long term.

Interstitial Pneumonia and Nodular Regenerative Hyperplasia of the Liver as Initial Manifestations of Polyarteritis Nodosa

A 65-year-old man was admitted to our hospital because of progressive dyspnea. A laboratory examination and high-resolution computed tomography (HRCT) revealed that he had interstitial pneumonia (IP) with liver dysfunction. Myeloperoxidase-ANCA (MPO-ANCA) was negative. Although his respiratory condition had become stable after initiation of steroid therapy, liver dysfunction had worsened with progressive portal hypertension. He died of hepatic insufficiency about three years after the first medical examination. Autopsy showed that he had vasculitis of medium and small blood vessels of the spleen, lungs, and liver. The final diagnosis was classical polyarteritis nodosa (PAN). Microscopically, non-specific interstitial pneumonia was identified in the autopsied lung. The pathological findings of the liver were consistent with nodular regenerative hyperplasia (NRH). We report a case of PAN with IP and NRH preceding findings of systemic vasculitis.

Kidneys in chronic liver diseases

Acute kidney injury (AKI), defined as an abrupt increase in the serum creatinine level by at least 0.3 mg/dL, occurs in about 20% of patients hospitalized for decompensating liver cirrhosis. Patients with cirrhosis are susceptible to developing AKI because of the progressive vasodilatory state, reduced effective blood volume and stimulation of vasoconstrictor hormones. The most common causes of AKI in cirrhosis are pre-renal azotemia, hepatorenal syndrome and acute tubular necrosis. Differential diagnosis is based on analysis of circumstances of AKI development, natriuresis, urine osmolality, response to withdrawal of diuretics and volume repletion, and rarely on renal biopsy. Chronic glomerulonephritis and obstructive uropathy are rare causes of azotemia in cirrhotic patients. AKI is one of the last events in the natural history of chronic liver disease, therefore, such patients should have an expedited referral for liver transplantation. Hepatorenal syndrome (HRS) is initiated by progressive portal hypertension, and may be prematurely triggered by bacterial infections, nonbacterial systemic inflammatory reactions, excessive diuresis, gastrointestinal hemorrhage, diarrhea or nephrotoxic agents. Each type of renal disease has a specific treatment approach ranging from repletion of the vascular system to renal replacement therapy. The treatment of choice in type 1 hepatorenal syndrome is a combination of vasoconstrictor with albumin infusion, which is effective in about 50% of patients. The second-line treatment of HRS involves a transjugular intrahepatic portosystemic shunt, renal vasoprotection or systems of artificial liver support.

A Case Report of Successful Semi-Emergent Living Donor Liver Transplantation for Biliary Atresia Patient With Acute Liver Failure and Progressive Portal Hypertension : The Indication of Liver Transplantation for Biliary Atresia in Infant Patients

A Case Report of Successful Semi-Emergent Living Donor Liver Transplantation for Biliary Atresia Patient With Acute Liver Failure and Progressive Portal Hypertension : The Indication of Liver Transplantation for Biliary Atresia in Infant Patients

End‐stage Liver Disease and Liver Transplant: Current Situation and Key Issues

The aim of this article is to identify the current challenges in pediatric OLT. It is directed to all physicians who care for pediatric patients from the early prospect of liver transplant to posttransplant life. Besides assessing current information on transplant results, the coauthors of this article have identified a number of issues that they consider as the most important that need to be addressed in 2008. Some are only an update of old questions, and others are newly identified problems. The recommendations from the group are summarized at the end of each specific issue and in the consensus guidelines.

Rapid evolution of congenital hepatic fibrosis after liver transplantation for acute liver failure: The potential role of extrahepatic factors

A 9-year-old male underwent deceased donor liver transplantation for idiopathic fulminant hepatic failure. In the postoperative period, a review of perioperative biopsies of the donor liver revealed mild features of congenital hepatic fibrosis. Over the ensuing year, the recipient developed severe complications of congenital hepatic fibrosis including multiple episodes of cholangitis and progressive portal hypertension. After a second transplant, the patient had no further episodes of cholangitis and/or features of portal hypertension. Examination of the explanted liver revealed remarkable progression of the congenital hepatic fibrosis, suggesting that the phenotype of this disease may be dependent in part on extrahepatic factors.

Severe Venoocclusive Disease after Liver Transplantation Treated with Transjugular Intrahepatic Portosystemic Shunt

Venoocclusive disease (VOD) is due to hepatic sinusoidal lining injury leading to portal hypertension; its incidence after liver transplantation is about 2%. When severe, it does not respond to medical therapy and has a high mortality; retransplantation is the only therapeutic option. However, there are no detailed data regarding the use of transjugular intrahepatic portosystemic shunt for VOD after liver transplantation. We describe two patients who developed severe VOD after liver transplantation, failed defibrotide therapy, and were treated by transjugular intrahepatic portosystemic shunt (TIPS). The portal hypertension resolved completely and one had full histological recovery. We believe that TIPS should be attempted as it may resolve progressive portal hypertension and the hepatic congestion, while allowing the clinician time for listing for further liver transplantation if the patient fails to respond.

Pancreatic Arteriovenous Malformation Involving Adjacent Duodenum with Gastrointestinal Bleeding: Report of a Case

A 54-year-old man was admitted to our hospital with the symptoms of palpitation, dyspnea, and tarry stool. Upper gastroduodenal endoscopy revealed submucosal lesions with vascular ectasia in the second part of the duodenum. Dynamic computed tomography (CT) detected a hypervascular lesion in the pancreatic head and the duodenum. Selective angiography showed proliferation of a vascular network and early filling of the portal vein at the early arterial phase. With a diagnosis of pancreatic arteriovenous malformation (AVM), we performed pylorus-preserving pancreaticoduodenectomy. At laparotomy, localized and meandering vessels were seen on the surface of the head of the pancreas. Histological examination showed dilated tortuous vessels accompanied by severed elastic fibers in the vessel media and blood clot formation. The incidence of pancreatic AVM remains extremely low, and recurrent gastrointestinal bleeding is a frequent complication. To prevent recurrent bleeding and progressive portal hypertension, surgery may be the definitive management of symptomatic AVM.

Chronic liver disease related to 6-thioguanine in children with acute lymphoblastic leukaemia

The United Kingdom (UK) acute lymphoblastic leukaemia (ALL) 97/99 clinical trial compared 6-mercaptopurine (6MP) with 6-thioguanine (6TG) as maintenance therapy for childhood ALL. Review of interim results has led to discontinuation of the 6TG arm. We report six children with ALL, who presented with splenomegaly after a median (range) treatment duration of 12 (6-22) months. All these children were treated in the 6TG-arm. The median (range) age at presentation was 6.6 (3.2-11.5) years. There were five boys. The presenting features were splenomegaly in all and hepatomegaly in four. AST was abnormal in one (80 IU/l, normal range 10-50). Abdominal sonography showed an altered texture of the liver parenchyma and confirmed splenomegaly. Microscopy showed findings within the spectrum of occlusive venopathy and nodular regenerative hyperplasia (NRH). After a median (range) follow-up of 23 (4-36) months splenomegaly and thrombocytopenia, suggestive of progressive portal hypertension, continue to worsen in all children. 6TG is associated with chronic hepatic toxicity and progressive portal hypertension on follow-up. Microscopy showed NRH in all patients with features in keeping with an intrahepatic occlusive venopathy and variable parenchymal atrophy and loss.

P0157 PP LIVER DISEASE RELATED TO 6-THIOGUANINE TREATMENT IN CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKAEMIA.

Introduction: Hepatosplenomegaly after chemotherapy in children with haematologic malignancies is a matter of concern. Common causes are recurrence of the disease, infections or drug toxicity. Review of the interim results of the MRC UK ALL 97/99 protocol comparing 6-Thioguanine (6TG) with 6-Mercaptopurine in the treatment of acute lymphoblastic leukaemia (ALL) has led to the discontinuation of the 6TG-arm because of evidence of hepatotoxicity, although no information is available on liver histology. Methods: We report our experience of 6 children (referred between June 1998 and July 2003), with ALL, who presented with splenomegaly after a median (range) treatment duration of 12 (6–22) months. All these children were treated in the 6TG-arm. Results: The median (range) age at presentation was 6.6 (3.2–11.5) years. There were 5 boys and 1 girl. The presenting features were splenomegaly in all and hepatomegaly in 4 without stigmata of chronic liver disease. None of the patients had a history of gastrointestinal bleeding. Liver function tests (transaminases, prothrombin time, albumin and bilirubin) were abnormal in one patient (AST 80 IU/l). The median (range) platelet count was 95 (74–181) 109/l. Ultrasound of the liver was interpreted as showing fatty changes in all and confirmed splenomegaly. No varices were documented in the 3 children who underwent endoscopy. Microscopy in all patients revealed some distortion of the liver architecture and variable degrees of focal sinusoidal dilatation, perisinusoidal fibrosis and hepatocellular hyperplasia with poorly delineated nodules. Steatosis was found in a single case. These findings lay within the spectrum of nodular regenerative hyperplasia. ‘Lafora-like’ bodies were seen in 2 cases, previous parenchymal loss and reticulin collapse in another 2. All children at a median (range) follow up of 22 (4–36) months continue to have increasing splenomegaly and thrombocytopenia, suggestive of progressive portal hypertension. Conclusion: In conclusion liver disease after 6TG treatment is consistent with parenchymal as well as vascular damage and appears to be progressive. Close follow up is warranted in these patients.

Hepatic manifestations of Jeune syndrome (asphyxiating thoracic dystrophy).

Asphyxiating thoracic dystrophy, or Jeune syndrome, is an autosomal recessive skeletal dysplasia with multiorgan involvement. Most patients develop progressive respiratory insufficiency related to the abnormally small thorax and renal insufficiency. Other clinical manifestations include cystic lesions of the pancreas and retinal abnormalities. Hepatic abnormalities have been described both clinically and at autopsy, but the pathogenesis of the liver disease is not clear. A patient with Jeune syndrome developed complications because of progressive portal hypertension necessitating transplantation. We present a discussion of the gross and histopathologic findings in the explanted liver, along with a review of the pathology of liver disease in Jeune syndrome.

Liver transplantation for hepatic cirrhosis in cystic fibrosis.

About 10% of children with CF develop hepatic cirrhosis and progressive portal hypertension. As the portal hypertension worsens these children are likely to develop serious variceal bleeding and other complications including malnutrition and a decline in respiratory function. Indices of lung function may fall as much as 50% in a year and chest infections may require frequent admissions to hospital. The respiratory symptoms are often attributed to CF related lung disease and affected children may therefore be considered unsuitable for liver transplantation. We propose a simple scoring system which can help to select patients who should be referred for assessment of liver transplantation. After careful assessment and preparation children with lung function indices as low as 30% predicted can have a successful outcome after liver transplantation. With good graft function portal hypertension is relieved and absorption, nutrition and respiratory function all improve. The improved quality of life of these children is remarkable.

Liver Transplantation for Cholesteryl Ester Storage Disease

This case describes a patient with cholesteryl ester storage disease who underwent liver transplantation for progressive cirrhosis, portal hypertension, ascites, and uncontrollable gastrointestinal bleeding. Four and one-half years posttransplant, her growth improved, cholesterol levels have returned to normal, and she is clinically well except for mild hypersplenism and an elevated blood urea nitrogen (BUN) and creatinine. Serum triglycerides remain elevated, but there have been no signs of progressive renal, intestinal, vascular, or pulmonary disease.