• Hepatic encephalopathy
• Hereditary hemorrhagic telangiectasia
• Portosystemic malformations
• Rare diseases

• Humans
• Male
• Female
• Telangiectasia, Hereditary Hemorrhagic/complications
• Telangiectasia, Hereditary Hemorrhagic/physiopathology
• Cross-Sectional Studies
• Middle Aged
• Adult
• Hepatic Encephalopathy
• Aged
• Vascular Malformations/physiopathology
• Neuropsychological Tests
• Quality of Life

• PI20/00592 Instituto de Salud Carlos III
• PI23/00164 Instituto de Salud Carlos III

• Osler–Weber–Rendu disease
• outflow obstruction syndrome
• portal vein thrombosis
• porto-sinusoidal vascular disorder
• vascular liver diseases
• vascular malformations

• Humans
• Elasticity Imaging Techniques/methods
• Hepatic Artery/diagnostic imaging
• Liver/diagnostic imaging
• Liver/blood supply
• Liver Diseases/diagnostic imaging
• Portal Vein/diagnostic imaging
• Ultrasonography, Doppler, Color/methods
• Vascular Diseases/diagnostic imaging
• Vascular Diseases/diagnosis
• Vascular Diseases/physiopathology
• Diagnostic Imaging

• SMAD4 mutation
• Colectomy
• Digestive cancer
• Gastrectomy
• Gastrointestinal cancer
• Osler weber rendu
• Polyps

• Humans
• Telangiectasia, Hereditary Hemorrhagic/genetics
• Telangiectasia, Hereditary Hemorrhagic/complications
• Female
• Adult
• Male
• Middle Aged
• Smad4 Protein/genetics
• Neoplastic Syndromes, Hereditary/genetics
• Intestinal Polyposis/genetics
• Intestinal Polyposis/congenital
• Intestinal Polyposis/complications
• Follow-Up Studies
• Aged
• Cross-Sectional Studies
• Mutation
• Phenotype

• hereditary hemorrhagic telangiectasia
• interventional radiology
• vascular malformations

Hereditary hemorrhagic teleangiectasia (HHT), also known as Rendu-Osler-Weber syndrome, is the most common cause of hepatic vascular malformations in adults. Different vascular shunts (arteriovenous, arterioportal or portovenous) lead to different clinical manifestations. Even though no hepatic-related symptoms are reported in the majority of cases, the severity of liver disease could lead to refractory medical conditions, in some cases requiring liver transplantation. The aim of this manuscript is to provide an updated overview of the current evidence regarding the diagnosis and treatment of HHT liver involvement and liver-related complications.

• Hereditary hemorrhagic teleangiectasia
• Rendu-Osler-Weber syndrome
• Hepatic vascular malformations
• Liver

The aim was to describe three patients with hemorrhagic hereditary telangiectasia (HHT) requiring liver transplantation (LT) and to perform a systematic review focusing on surgical complications and long-term follow-up. Unrestricted searches of the Medline and Embase databases were performed through February 2022. Forty-five studies were selected including 80 patients plus the three new reported patients, 68 (81.9%) were female and mean age was 50 (27–72) years. Main indications for LT were high-output cardiac failure (n = 40; 48.2%), ischemic cholangitis (n = 19; 22.9%), and a combination of both conditions (n = 13;15.6%). Mean cold ischemic time and red blood cell units transfused during LT were 554 (300–941) minutes and 11.4 (0–88) units, respectively. Complications within 30 days were described in 28 (33.7%) patients, mainly bleeding complications in 13 patients, hepatic artery (HA) thrombosis in four and hepatic vein thrombosis in one. Mean follow-up was 76.4 (1–288) months, and during it, four new patients developed thrombotic complications in HA, HA aneurysm, celiac artery, and the portal–splenic–mesenteric vein. HHT relapse in the transplant allograft was detected in 13 (17.1%) patients after 1–19 years (including two fatal recurrences). Overall mortality was 12%. In conclusion, previous assessment of HA anatomy and hyperdynamic circulatory state could reduce LT complications. The risk of relapse in the hepatic graft supports a multidisciplinary follow-up for HHT patients with LT.

Hereditary hemorrhagic telangiectasia is an inherited disease related to an alteration in angiogenesis, manifesting as cutaneous telangiectasias and epistaxis. As complications, it presents vascular malformations in organs such as the lung, liver, digestive tract, and brain. Currently, diagnosis can be made using the Curaçao criteria or by identifying the affected gene. In recent years, there has been an advance in the understanding of the pathophysiology of the disease, which has allowed the use of new therapeutic strategies to improve the quality of life of patients. This article reviews some of the main and most current evidence on the pathophysiology, clinical manifestations, diagnostic approach, screening for complications, and therapeutic options, both pharmacological and surgical.

• VEGF
• angiogenesis
• arteriovenous malformations
• epistaxis
• hereditary hemorrhagic telangiectasias
• telangiectasias

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disease characterized by the formation of cutaneous and visceral telangiectasias and arteriovenous malformations (AVM). Multiple organs may be affected, including the nasal mucosa, skin, lungs, gastrointestinal tract, and brain. The following case highlights a unique manifestation of HHT in a patient with a gastrointestinal hemorrhage and epistaxis, resulting in hyperammonemia and diffuse cerebral edema and herniation. Clinicians should be aware of this potential complication in such patients and initiate ammonia-reducing agents early to avoid this devastating consequence.

Arteriovenous malformations (AVMs) are abnormal communications between arteries and veins that lack intervening capillary beds. They have been described in almost every organ in the body, emerging sporadically or as part of well-described syndromes. Hereditary hemorrhagic telangiectasia (HHT) is a rare, progressive, and lifelong disease characterized by AVMs and recurrent hemorrhaging. In the last 2 decades, significant advances have been made in understanding the pathogenesis of this condition. The accumulation of knowledge has led to a natural evolution of therapy, from open surgery to endovascular procedures, and now to a role for medications in certain AVMs. Here, we review a case of HHT and describe the most up-to-date clinical practice, including diagnosis of HHT, subtypes of HHT, and medical therapy.

• Arteriovenous malformation
• case report
• hereditary hemorrhagic telangiectasia
• transforming growth factor-β signaling

Arterioportal fistulas (APFs) are uncommon vascular abnormalities with a heterogeneous etiology. In pediatric orthotopic liver transplantation (OLT), APFs are frequently iatrogenic, following percutaneous liver interventions. The aim of this study was to report the 10-year experience of a tertiary referral center for pediatric OLT in the interventional radiological (IR) and conservative management of acquired APFs. A retrospective search was performed to retrieve pediatric patients (<18 years old) with a diagnosis of APF at color Doppler ultrasound (CDUS) or computed tomography angiography (CTA) from 2010 to 2020. Criteria for IR treatment were the presence of hemodynamic alterations at CDUS (resistive index <0.5; portal flow reversal) or clinical manifestations (bleeding; portal hypertension). Conservatively managed patients served as a control population. Clinical and imaging follow-up was analyzed. Twenty-three pediatric patients (median age, 4 years; interquartile range = 11 years; 15 males) with 24 APFs were retrieved. Twenty patients were OLT recipients with acquired APFs (16 iatrogenic). Twelve out of twenty-three patients were managed conservatively. The remaining 11 underwent angiography with confirmation of a shunt in 10, who underwent a total of 16 embolization procedures (14 endovascular; 2 transhepatic). Technical success was reached in 12/16 (75%) procedures. Clinical success was achieved in 8/11 (73%) patients; three clinical failures resulted in one death and two OLTs. After a median follow-up time of 42 months (range 1–107), successfully treated patients showed an improvement in hemodynamic parameters at CDUS. Conservatively managed patients showed a stable persistence of the shunts in six cases, spontaneous resolution in four, reduction in one and mild shunt increase in one. In pediatric patients undergoing liver interventions, APFs should be investigated. Although asymptomatic in most cases, IR treatment of APFs should be considered whenever hemodynamic changes are found at CDUS.

• arterioportal fistula
• embolization
• endovascular
• shunt
• transhepatic

• Adrenomedullin
• Angiogenesis
• Hereditary hemorrhagic telangiectasia
• Rare diseases

• Adrenomedullin/genetics
• Biomarkers
• Endothelial Cells
• Female
• Humans
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Telangiectasia, Hereditary Hemorrhagic/genetics

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized by multiple telangiectases and caused by germline disease-causing variants in the ENG (HHT1), ACVRL1 (HHT2) and, to a lesser extent MADH4 and GDF2, which encode proteins involved in the TGF-β/BMP9 signaling pathway. Common visceral complications of HHT are caused by pulmonary, cerebral, or hepatic arteriovenous malformations (HAVMs). There is large intrafamilial variability in the severity of visceral involvement, suggesting a role for modifier genes. The objective of the present study was to investigate the potential role of ENG, ACVRL1, and of other candidate genes belonging to the same biological pathway in the development of HAVMs.

We selected 354 patients from the French HHT patient database who had one disease causing variant in either ENG or ACVRL1 and who underwent hepatic exploration. We first compared the distribution of the different types of variants with the occurrence of HAVMs. Then, we genotyped 51 Tag-SNPs from the Hap Map database located in 8 genes that encode proteins belonging to the TGF-β/BMP9 pathway (ACVRL1, ENG, GDF2, MADH4, SMAD1, SMAD5, TGFB1, TGFBR1), as well as in two additional candidate genes (PTPN14 and ADAM17). We addressed the question of a possible genetic association with the occurrence of HAVMs.

The proportion of patients with germline ACVRL1 variants and the proportion of women were significantly higher in HHT patients with HAVMs. In the HHT2 group, HAVMs were more frequent in patients with truncating variants. Six SNPs (3 in ACVRL1, 1 in ENG, 1 in SMAD5, and 1 in ADAM17) were significantly associated with HAVMs. After correction for multiple testing, only one remained significantly associated (rs2277383).

In this large association study, we confirmed the strong relationship between ACVRL1 and the development of HAVMs. Common polymorphisms of ACVRL1 may also play a role in the development of HAVMs, as a modifying factor, independently of the disease-causing variants.

• ACVRL1
• HHT, Rendu-Osler
• Hepatic arteriovenous malformation
• Modifier gene

• Doppler US
• Hereditary hemorrhagic telangiectasia (HHT)
• Intrahepatic shunts
• Liver
• Superb microvascular imaging (SMI)
• Ultrasonography

• Female
• Humans
• Liver/blood supply
• Liver/diagnostic imaging
• Liver Diseases/diagnostic imaging
• Male
• Telangiectasia, Hereditary Hemorrhagic/diagnostic imaging
• Ultrasonography/methods

• Genetic test
• Genotype
• Hereditary hemorrhagic telangiectasia
• Phenotype
• Rare diseases

Gender differences in organ involvement and clinical severity have been poorly described in hereditary hemorrhagic telangiectasia (HHT). The aim of this study was to describe differences in the severity of HHT manifestations according to gender.

Severity was measured according to Epistaxis Severity Score (ESS), Simple Clinical Scoring Index for hepatic involvement, a general HHT-score, needing for invasive treatment (pulmonary or brain arteriovenous malformations -AVMs- embolization, liver transplantation or Young’s surgery) or the presence of adverse outcomes (severe anemia, emergency department -ED- or hospital admissions and mortality).

One hundred forty-two (58.7%) women and 100 (41.3%) men were included with a mean age of 48.9 ± 16.6 and 49 ± 16.5 years, respectively. Women presented hepatic manifestations (7.1% vs 0%) and hepatic involvement (59.8% vs 47%), hepatic AVMs (28.2% vs 13%) and bile duct dilatation (4.9% vs 0%) at abdominal CT, and pulmonary AVMs at thoracic CT (35.2% vs 23%) more often than men. The Simple Clinical Scoring Index was higher in women (3.38 ± 1.2 vs 2.03 ± 1.2), and more men were considered at low risk of harboring clinically significant liver disease than women (61% vs 25.3%). These differences were mantained when considering HHT1 and HHT2 patients separetely. Duodenal telangiectasia were more frequent in men than women (21% vs 9.8%). Invasive treatments were more frequently needed in women (28.2% vs 16%) but men needed attention at the ED more often than women (48% vs 28.2%), with no differences in ESS, HHT-score, anemia hospital admissions or mortality.

HHT women showed more severe hepatic involvement than men, also among HHT1 and HHT2 patients. Women had higher prevalence of pulmonary AVMs and needed invasive procedures more frequently, while men needed attention at the ED more often. These data might help physicians to individualize HHT patients follow-up.

• Arteriovenous malformations
• Gender
• Hereditary hemorrhagic telangiectasia
• Rare diseases

Hemorrhagic hereditary telangiectasia (HHT) type 2 patients have increased activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway in telangiectasia. The main objective is to evaluate the activation of the PI3K pathway in cutaneous telangiectasia of HHT1 patients. A cutaneous biopsy of a digital hand telangiectasia was performed in seven HHT1 and eight HHT2 patients and compared with six controls. The study was approved by the Clinical Research Ethics Committee of our center. A histopathological pattern with more dilated and superficial vessels that pushed up the epidermis was identified in HHT patients regardless of the type of mutation and was associated with older age, as opposed to the common telangiectasia pattern. The mean proliferation index (Ki-67) was statistically higher in endothelial cells (EC) from HHT1 than in controls. The percentage of positive EC for pNDRG1, pAKT, and pS6 in HHT1 patients versus controls resulted in higher values, statistically significant for pNDRG1 and pS6. In conclusion, we detected an increase in EC proliferation linked to overactivation of the PI3K pathway in cutaneous telangiectasia biopsies from HHT1 patients. Our results suggest that PI3K inhibitors could be used as novel therapeutic agents for HHT.

• Smad pathway
• hemorrhagic hereditary telangiectasia
• mTOR inhibitors
• phosphatidylinositol 3-kinase
• rare diseases
• telangiectasia
• transforming growth factor-beta (TGF-β)

• Activin Receptors, Type II/genetics
• Adult
• Aged
• Biopsy
• Case-Control Studies
• Cell Cycle Proteins/metabolism
• Cell Proliferation
• Endoglin/genetics
• Endothelial Cells/cytology
• Endothelial Cells/metabolism
• Endothelial Cells/pathology
• Female
• Humans
• Intracellular Signaling Peptides and Proteins/metabolism
• Male
• Middle Aged
• Mutation
• Phosphatidylinositol 3-Kinase/metabolism
• Phosphorylation
• Proto-Oncogene Proteins c-akt/metabolism
• Ribosomal Protein S6 Kinases/metabolism
• Signal Transduction
• Telangiectasia, Hereditary Hemorrhagic/genetics
• Telangiectasia, Hereditary Hemorrhagic/metabolism
• Telangiectasia, Hereditary Hemorrhagic/pathology

• Enfermedades Minoritarias
• Haemorrhagic hereditary telangiectasia
• Rare diseases
• Telangiectasia hemorrágica hereditaria
• Vascular malformation
• malformación vascular

• alveolar-arterial gradient
• hepatopulmonary syndrome
• hereditary hemorrhagic telangiectasia
• pulmonary arteriovenous malformation
• pulmonary circulation

• Hepatopulmonary Syndrome/congenital
• Humans
• Male
• Middle Aged
• Telangiectasia, Hereditary Hemorrhagic/complications

Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is a rare genetic blood disorder that leads to abnormal bleeding due to absent capillaries and multiple abnormal blood vessels known as arteriovenous malformations. A feature of HHT is high-output heart failure due to multiple arteriovenous malformations. High-output heart failure can lead to recurrent epistaxis Kiesselbach area syndrome (REKAS), further exacerbating heart failure through increased blood loss and resultant anemia. We report a patient with HHT who presented with high-output heart failure contributing to REKAS. In patients with REKAS, we propose if anemia is present, REKAS can be avoided by correcting the anemia by increasing the hemoglobin level to greater than 9 to 10 g/dL. This decreases hyperdynamic circulation and reduces pressure in the blood vessels of the nose.

• anemia
• epistaxis
• hereditary hemorrhagic telangiectasia
• high-output heart failure
• recurrent epistaxis Kiesselbach area syndrome

• BCS, Budd–Chiari syndrome
• Budd–Chiari syndrome
• LMWH, low-molecular-weight heparin
• MPD, myeloproliferative disorders
• PVT, portal vein thrombosis
• VKA, vitamin K antagonists
• non-cirrhotic portal hypertension
• portal vein thrombosis
• pregnancy

• Capillarization
• endotheliopathy
• portal hypertension

• Aged, 80 and over
• Diagnosis, Differential
• Epistaxis/etiology
• Female
• Hemoperitoneum/complications
• Hemoperitoneum/diagnosis
• Hemoperitoneum/surgery
• Humans
• Interdisciplinary Communication
• Liver/blood supply
• Telangiectasia, Hereditary Hemorrhagic/complications
• Telangiectasia, Hereditary Hemorrhagic/diagnosis
• Telangiectasia, Hereditary Hemorrhagic/surgery
• Telangiectasis/diagnosis
• Telangiectasis/etiology
• Vascular Malformations/etiology

• Hereditary hemorrhagic telangiectasia
• Liver
• Rendu-Osler-Weber syndrome
• Ultrasonography

Accompanying rapid developments in hepatic surgery, the number of surgeries and identifications of histological types of primary hepatic space-occupying lesions (PHSOLs) have increased dramatically. This has led to many changes in the surgicopathological spectrum of PHSOLs, and has contributed to a theoretical basis for modern hepatic surgery and oncological pathology. Between 1982 and 2009 at the Eastern Hepatobiliary Surgery Hospital (EHBH) in Shanghai, 31 901 patients underwent surgery and were diagnosed as having a PHSOL. In this paper, we present an analysis of the PHSOL cases at the EHBH for this time period, along with results from a systematic literature review. We describe a surgicopathological spectrum comprising more than 100 types of PHSOLs that can be stratified into three types: tumor-like, benign, and malignant. We also stratified the PHSOLs into six subtypes derived from hepatocytes; cholangiocytes; vascular, lymphoid and hemopoietic tissues; muscular, fibrous and adipose tissues; neural and neuroendocrine tissues; and miscellaneous tissues. The present study provides a new classification system that can be used as a current reference for clinicians and pathologists to make correct diagnoses and differential diagnoses among various PHSOLs.

• Liver tumors
• Tumor-like lesions
• Pathology
• Immunohistochemistry
• Classification

• hereditary hemorrhagic telangiectasia
• liver vascular malformations
• heart failure
• portal hypertension
• gastrointestinal bleeding
• liver transplantation

This guideline has been approved by the American Association for the Study of Liver Diseases (AASLD) and represents the position of the association.

• Budd-Chiari Syndrome/diagnosis
• Budd-Chiari Syndrome/etiology
• Budd-Chiari Syndrome/therapy
• Child
• Hepatic Veno-Occlusive Disease/chemically induced
• Hepatic Veno-Occlusive Disease/diagnosis
• Hepatic Veno-Occlusive Disease/therapy
• Humans
• Liver Cirrhosis/complications
• Liver Transplantation
• Portal Vein
• Telangiectasia, Hereditary Hemorrhagic/diagnosis
• Telangiectasia, Hereditary Hemorrhagic/etiology
• Telangiectasia, Hereditary Hemorrhagic/therapy
• Venous Thrombosis/diagnosis
• Venous Thrombosis/etiology
• Venous Thrombosis/therapy

• R01 DK046357 NIDDK NIH HHS

• Arteriovenous shunt
• Gd-EOB-DTPA-enhanced magnetic resonance imaging
• Hereditary hemorrhagic telangiectasia
• Nodular regenerative hyperplasia