| [Background]Hereditary hemorrhagic telangiectasia(HHT)is an autosomal dominantly inherited disease characterized by systemetic abnormal vascular development.The proteins encoded by pathologic genes are associated with transforming growth factor-?(TGF-?)superfamily signaling pathway.HHT gene mutations cause abnormal vascular structure that can occur in specific parts of the pulmonary circulation or systemic circulation,including from microvascular telangiectaia to larger arteriovenous malformations,with the largest diameter up to several centimeters.Clinically,it is characterized by skin and mucosal telangiectasia(especially the tongue,lips,mouth,fingers and nose)with bleeding tendency and arteriovenous malformations(AVMs)in visceral organs such as liver,lung,brain,and gastrointestinal tract.Epistaxis is the most common clinical symptoms.Clinically,according to HHT Cura,cao clinical diagnostic criteria,diagnosis of HHT can be made as long as the patient meets at leaset three of the following four separate manifestations including recurrent spontaneous epistaxis,telangiectasia on skin and mucous membrane(specific location:finger pulp,oral mucosa or tongue),visceral involvement(gastrointestinal tract,lung,liver,brain and spinal artery arteriovenous malformations)and family history(first degree relative involvement).The patients who meet only two diagnostic criteria is suspected to be with HHT,and a diagnosis should not be considered for the patients with only one criteria.Although this clinical diagnostic criteria have been shown to be highly sensitive and specific,its diagnosis effect is limited in young people and children,since symptoms of HHT patients is age-dependent.At this point,genetic diagnosis has become a powerful auxiliary diagnostic tool.However,HHT has genetic heterogeneity and mutations in ENG(Endoglin)and ACVRL1(activin A receptor-like-1)gene in TGF-? signal transduction pathway can lead to HHT1 and HHT2,togather accouting for about 85%of cases.The Small Mothers Against Decapentaplegic 4(SMAD4)gene mutation accounted for about 2%,manifesting as HHT and juvenile polyposis(JP/HHT)syndrome.Chromosomes 5q31 and 7p14 mutations were associated with HHT but no map gene has been targeted.More recently,another gene in the same pathway,the bone morphogenesis-9(BMP9)gene(also known as GDF2,located on chromosome 10q11),was reported to be the cause of a small number of patients who have similar or overlap phenotype with HHT.In spite of this,about 15%patients clinical diagnosed with HHT still did not have a certain pathogenic gene mutation.HHT racial and geographical distribution is broader and distinct.Reported incidence was range from 1/1300 to 1/40,000.Due to the lack of epidemiological investigation,the accurate incidence,clinical and genetic background of the Chinese HHT patient is unclear.Therefore,more research on the genetic background of Chinese HHT patients and the distribution of pathogenic genes is particularly important,so we hope that this study will help health care workers and patients better understand this severe but ignored rare disease and develop more appropriate screening,diagnosis and treatment strategies.Hereditary hemorrhagic telangiectasia can involve the liver diffusely in the formof vascular malformations associated with progressive biliary disease,high-output cardiac failure(HOCF)and portal hypertension(PH),which can occur simultaneously or sequentially.Previous studies showed that 8%-31%HHT patients have liver involvement,but the incidence of liver involment by HHT was recently reported to be as high as 41%-84%in large-scale imaging screening.However,only a small number of liver involvement patients(<8%)were with significant liver-related symptoms,which is emerging and increasing gradually with age,and sometimes can be self-mitigated.Although the patient always has no obvious symptoms or mild symptoms at early stage,but once the severe cardiac output heart failure,portal hypertension and biliary tract necrosis and even liver failure was developed,it can endanger the lives of patients.At present,liver transplantation(LT)is considered to be the gold standard for the treatment of liver HHT patients,but these patients who underwent LT were troubled with more serious complications,and LT was restrcted by the limitation of the liver donor.Except severe hepatobiliary necrosis and hepatic failure,the more severe shunt-related complications,such as high cardiac output heart failure could be presented in the majority of HHT patients,whereas the liver function maintains a normal level and not yet meets the LT score criteria.Hepatic arterial embolization can block the hepatic arteriovenous fistula and reduce the shunt volume,but the hepatic artery embolization itself can also leads to hepatic duct ischemia and necrosis.Moreover,the role of hepatic arterial embolization is temporarily and easy to relapse,necessitating multiple phase embolization,which would undoubtedly increase the risk of hepatobiliary necrosis and liver failure.Hepatic artery ligation has similar principle and complications with hepatic artery embolization.In addition,the presence of widespread collateral circulation can lead to recurrence.Our center has devoted to the diagnosis and treatment of liver HHT for more than ten years and has accumulated a wealth of clinical experiences and case data.Innovative double banding/ligation procedure was scrupulously carried out for selected severe symptomatic liver HHT patients,which significantly improved the prognosis of patients.This article intends to retrospectively analyze the surgical treatment outcome of liver HHT patient to provide a reliable reference for the treatment of the disease.[Objetctives]1.To study the genetic background and the distribution of pathogenic genes in Chinese hepatic HHT patients;2.To analyze clinical features of Chinese hepatic HHT patients;3.To retrospectively analyze the surgical treatment ourcome of hepatic HHT patient.Part I Clinical characteristics and gene mutation study of hepatic hereditary hemorrhagic telangiectasia[Methods]1.Collection of medical information and drawing family pedigree map.Through referring to hospital and/or outpatient medical records and follow-up on the phone and/or on-site,comprehensive medical data was collected and detailed family information was integrated into family pedigree map.2.Clarify the diagnosis of HHT and assess liver involvementThe clinical diagnosis was established according to Curac,ao criteria.Then Doppler color ultrasound,CT and/or MRI were utilized to determine whether patients had hepatic arteriovenous malformations and the type of arteriovenous shunts,and to screen for other affected organs.Cardiac function and liver function were assessed by Cardiac Doppler color ultrasonography and laboratory tests.3.Collection of blood samples and gene mutation screening and analysis3.1 Collection of blood samples and extraction of whole genomic DNABlood samples were collected from the outpatient,hospitalized and follow-up patients and their family members with informed consent from all the individuals participating in the study.Immediately,whole genomic DNA from peripheral blood was extracted using the the TIANamp Blood DNA kit for gene sequencing to find pathogenic gene mutation.3.2 Screening pathogenic gene mutations3.2.1 Application of Sanger Sequencing for mutation screeningNewly proposed molecular testing protocols for HHT based on the suspected clinical diagnosis was referenced.For patients with clinically confirmed HHT as detemined by the Curagao criteria,genetic screening consists of testing of ENG and ACVRL1 by first-generation sequencing method(Sanger Sequencing)with reflex to SMAD4 gene if ENG and ACVRL1 test results are inconclusive.3.2.2 Mutation screening with high-throughput sequencing method For those suspected cases,mLutational analysis inlcudes a five gene(ENG,ACVRL1,SMAD4,GDF2,and RASA1)next generation sequencing(NGS)panel was utilized for pathogenic mutations.The nucleotide sequences of the Single Nucleotide Variants region in the genes should be re-evaluated by individual Sanger sequencing method.3.2.3 Mutation screening by whole exome sequencingFor clinically diagnosed HHT patients in which mutation screening results are inconclusive,whole exome sequencing,such as next generation sequencing,was used to determine whether there is a novel mutation in a potential pathogenic gene.[Results]1.General information and family treeThis study included nine patients from eight families,including one man and eight women,with an average age of 46 ± 10 years and an age range of 35-62 years.Among them,according to clinical diagnostic criteria,six patients meet three or more clinical diagnostic criteria,can be diagnosed as HHT and the remaining three meet two diagnostic criteria as suspected HHT.According to the follow-up information,a detailed family map was drawn.2.Characteristic manifestations of patients2.1 General clinical manifestations of all patientsSix patients had typical telangiectasia on skin and mucous membrane,with the finger pulp and tongue as the most common sites.Seven patients had recurrent epistaxis history.Four patients had severe gastrointestinal bleeding.2.2 Liver-related clinical manifestations2.2.1 Imaging characteristics of the patientsPatients with liver involvement were confirmed by abdominal enhanced CT and CTA,and typical imaging features included extensive intrahepatic telangiectasia,arteriovenous shunt,tortuous expansion of the hepatic artery,and abnormal collateral circulation.In addition,some patients showed atypical cirrhosis,cholestasis and even biloma formation.2.2.2 Pathological characteristics of the patientsPathological manifestations of patients including hepatic artery tortuous expansion,sinusoidal expansion,hepatobiliary necrosis,cholestasis and biloma.2.2.3 Clinical symptoms and signAbdominal pain(7/9,78%)is the most common symptoms.Right upper quadrant vascular bruit was the most common sign during physical examination and presented in 78%paitents.The typical clinical presentations related to liver involvement included high-output heart failure(HCOF),portal hypertension,and biliary disease.Patients can be suffering only from HCOF(patient ?/1 and??/2)or bliary disease(paitent ? and ?),or presented with any two of these features(patient?,HCOF+Portal hypertension;patient ?,HCOF+Biliary disease;patient ?,Portal hypertension + Biliary disease)or a combination of three(patient ?)or none of them(patient ?).Atrial fibrillation was presented in only one patient.2.3 Other organs involvementElectronic gastroscopy and colonoscopy found gastric and/or colon telangiectasia in two patients with.In addition,a patient was found to have a spleen involvement.3.Mutation analysis3.1 We identified a total of 4 ACVRL1 gene mutations in 5 patients.One was splice site mutation(c.626-3C>G).and three were missense mutations(c.925G>A,p.Gly309Ser;c.1038C>G,p.Ile346Met;c.1007T>Q p.Va1336Gly)in exon 7,two of which were novel.3.2 Mutation screening using the next generation.sequencing found no pathogenic mutations.3.3 Two patients underwent whole exome sequencing,and top 20 ranked candidate pathogenic genes were identified.Part ? Efficacy of double banding/ligation of hepatic artery in patients with severe symptomatic hepatic hereditary hemorrhagic telangiectasia[Methods]1.Collection of medical informationDetailed medical informations were collected by referring to medical records,including general information,imaging features,liver and cardiac function,pulmonary arterial systolic pressure,and post-operative complications.2.Comparison of pre and post-operation dataPreoperative and postoperative clinical manifestations,imaging features,liver and cardiac function and pulmonary arterial systolic pressure were compared to evaluated surgical results.3.Evaluation of the quality of lifeQuality of life was evaluated with the Short Form Health Survey questionnaire.[Results]1.Surgical details and surgical-related complicationsFor each patient,the common hepatic artery and one branch of the left and/or right hepatic artery were banded,and other significantly dilated hepatic artery branches were ligated.No patient died after surgery.2.Clinical symptomatic improvement after operation Clinical symptoms were improved in all patients,although ischemic cholangitis was observed in two patients and treated conservatively.3.Cardiac function improment after operationCardiac function,classified per the New York Heart Association(NYHA)cardiac functional grading,improved(NYHA ?-? vs NYHA ?-?),pulmonary artery systolic pressure was significantly reduced(48 ±8 mmHg vs.24 ± 4 mmHg;P<0.05),and and remained in the normal range(26 ± 3 mmHg)at the end of follow-up.4.Changes of laboratory resultsThe levels of y-glutamyl transpeptidase and alkaline phosphatase decreased in 11 patients(144±94 U/L vs 71±34 U/L;P =0.003)and 10 patients(207±71 U/L vs 105±32 U/L;P =0.001),respectively.5.Improvement of quality of life after operationThe average follow-up time was 50 ± 28 months range from 6-11 months.Short Form Health Survey questionnaire showed that all dimensions of quality of life improved in all surviving patients.[Conclusion]1.Liver involvement by HHT can progress to severe cardiac dysfunction or even heart failure and refractory portal hypertension even seriously affecting liver function.Double banding/ligation of hepatic artery was an effective therapy to improve symptoms and quality of life in selected patients with HHT and liver involvement.2.ACVRL1 is the main pathogenic gene for Chinese hepatic HHT patients,with different mutation type and loci in different patients.3.Missense mutation was the main mutation type and there can also be splicing mutation and other types of mutation.4.About half of the patients still have no pathogenic gene mutations,there may be new mutations in potential pathogentic genes. |
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