Definitive diagnosis of hepatic sinusoidal obstruction syndrome induced by pyrrolizidine alkaloids

OBJECTIVE: Hepatic sinusoidal obstruction syndrome (HSOS) induced by a Chinese medicinal herb Tusanqi is increasingly being reported in recent years. The aim of the study was to investigate the possibility of using blood pyrrole‐protein adducts test as a confirmatory diagnostic method. METHODS: Patients with HSOS according to international diagnostic criteria associated with Tusanqi from January 2006 to August 2010 in Zhongshan Hospital Fudan University were included and clinical features were collected. Pyrrole‐protein adducts in blood sample were determined with ultra performance liquid chromatography‐mass spectrometry (UPLC‐MS) while pyrrolizidine alkaloids (PAs) in available herbal preparations were analyzed by high performance liquid chromatography‐ultraviolet (HPLC‐UV). RESULTS: Five patients (age 41–72 years, median age 54 years, all women) were included. Ascites (5/5), jaundice (5/5) and hepatomegaly (4/5) were common manifestations. The imaging features were diffused, patchy hepatic enhancement, periportal edema and ascites. Pathology ascertained that blood flow was obstructive at the site of sinusoid. PAs (Seneionine and seneciphylline) were identified in all the three available herbal preparations ingested by the HSOS patients. Pyrrole‐protein adducts were unequivocally found in all the five blood samples. Two patients recovered, two developed chronic illness and one died due to liver failure and hepatic encephalopathy. CONCLUSIONS: The detection of blood pyrrole‐protein adducts using a UPLC‐MS approach is a specific, reliable, unambiguous and confirmatory test for HSOS induced by PA, and should be used together with the conventional HSOS clinical diagnostic criteria for the definitive diagnosis of PA‐induced HSOS.     

Expert consensus on the clinical management of pyrrolizidine alkaloid‐induced hepatic sinusoidal obstruction syndrome

Hepatic sinusoidal obstruction syndrome (HSOS) is a hepatic vascular disease presenting with abdominal distension, pain in the hepatic region, ascites, jaundice, and hepatomegaly. In China, this disease is often associated with the oral intake of plants that contain pyrrolidine alkaloids. The existing guidelines are limited to HSOS associated with hematopoietic stem cell transplantation in Western countries. The Hepatobiliary Diseases Committee of the Chinese Society of Gastroenterology convened an expert consensus conference on the diagnosis and treatment of PA–HSOS to evaluate current research in China and abroad. The “Nanjing criteria” developed by the committee to diagnose PA–HSOS include a confirmed history of PA‐containing plant use and (i) abdominal distention and/or pain in the hepatic region, hepatomegaly, and ascites; (ii) elevation of serum total bilirubin or abnormal laboratory liver tests; (iii) evidence on enhanced computed tomography or magnetic resonance imaging; or (iv) pathological evidence that rules out other known causes of liver injury. Supportive symptomatic treatment, anticoagulant therapy, and placement of a transjugular intrahepatic portosystemic shunt for patients who do not respond to medical treatment are effective for the treatment of PA–HSOS. The benefits of glucocorticoids and prostaglandin E1 in PA–HSOS are not clear.     

Validation of the Nanjing Criteria for Diagnosing Pyrrolizidine Alkaloids-induced Hepatic Sinusoidal Obstruction Syndrome

Background and AimsHepatic sinusoidal obstruction syndrome (HSOS) is caused by toxic injury to sinusoidal endothelial cells in the liver. The intake of pyrrolizidine alkaloids (PAs) in some Chinese herbal remedies/plants remains the major etiology for HSOS in China. Recently, new diagnostic criteria for PA-induced HSOS (i.e. PA-HSOS) have been developed; however, the efficacy has not been clinically validated. This study aimed to assess the performance of the Nanjing criteria for PA-HSOS.MethodsData obtained from consecutive patients in multiple hospitals, which included 86 PA-HSOS patients and 327 patients with other liver diseases, were retrospectively analyzed. Then, the diagnostic performance of the Nanjing criteria and simplified Nanjing criteria were evaluated and validated. The study is registered in www.chictr.org.cn (ID: ChiCTR1900020784).ResultsThe Nanjing criteria have a sensitivity and specificity of 95.35% and 100%, respectively, while the simplified Nanjing criteria have a sensitivity and specificity of 96.51% and 96.33%, respectively, for the diagnosis of PA-HSOS. Notably, a proportion of patients with Budd-Chiari syndrome (11/49) was misdiagnosed as PA-HSOS on the basis of the simplified Nanjing criteria, and this was mainly due to the overlapping features in the enhanced computed tomography/magnetic resonance imaging examinations. Furthermore, most of these patients (10/11) had occlusion or thrombosis of the hepatic vein, and communicating vessels in the liver were found in 8/11 patients, which were absent in PA-HSOS patients.ConclusionsThe Nanjing criteria and simplified Nanjing criteria exhibit excellent performance in diagnosing PA-HSOS. Thus, both could be valuable diagnostic tools in clinical practice.     

CT动态增强扫描诊断肝窦阻塞综合征的临床价值及意义

目的探讨CT动态增强扫描对肝窦阻塞综合征(HSOS)的诊断价值。方法纳入经活组织检查及影像学确诊的HSOS、布-加综合征(BCS)及肝硬化患者51例,分别利用CT动态增强扫描结果、巴尔的摩标准再次诊断HSOS,对比两者诊断效果。结果 HSOS的典型CT表现包括CT平扫呈肝大、密度减低;增强扫描动脉期可见肝动脉血管增粗扭曲;门静脉期呈"地图状"改变、肝静脉不清、下腔静脉及门静脉呈"晕征"或"轨道征"、下腔静脉肝段扁平等;延迟期强化范围增大。CT对HSOS的诊断敏感性0.857,优于巴尔的摩标性0.500,CT对HSOS诊断特异性0.811,差于巴尔的摩标准0.946。CT与巴尔的摩标准对HSOS的诊断准确率接近,差异无统计学意义(P0.05)。结论早期诊断HSOS时,CT动态增强扫描是巴尔的摩标准的有力补充。     

26例肝窦阻塞综合征临床及影像分析

目的了解肝窦阻塞综合征患者的临床特点及影像特征。方法回顾性分析2010年11月至2019年2月在解放军总医院第五医学中心住院诊治的26例肝窦阻塞综合征患者的临床资料,归纳总结其主诉、临床表现、实验室检查、影像学特征及病因。结果26例肝窦阻塞综合征患者以腹胀、乏力、纳差、腹水为主要症状,1例为肝移植术后患者,1例为肾移植术后患者,均有明确的化学治疗史,1例患者病因不明,23例患者有明确的中草药服用史,其中21例服用土三七。ALT升高17例,AST升高20例,糖类抗原CA125升高23例。CT及MR影像学显示,脾脏增大11例,腹水24例,肝脏密度及信号不均21例,增强扫描强化不均匀23例,肝静脉变细或显示不清11例。结论肝窦阻塞综合征的病因以服用土三七为主,临床表现为腹胀、乏力、纳差,可有肝功能异常及CA125升高,影像学表现以肝脾肿大、腹水、肝脏密度及信号不均,增强扫描强化不均及肝静脉变细或显示不清为主。     

Tusanqi and hepatic sinusoidal obstruction syndrome

Hepatic sinusoidal obstruction syndrome (HSOS), characterized by hepatomegaly, ascites and hyperbilirubinemia, is caused by toxic injury to hepatic sinusoidal endothelial cells. One major etiology of HSOS in China is the intake of products containing pyrrolizidine alkaloids (PA) such as Tusanqi. The manifestations of patients with HSOS are usually non‐specific, presenting with abnormal liver function and portal hypertension. Diagnosis of the disease depends mostly on liver histopathology when clinical and imaging data are not sufficient. A history of Tusanqi intake is mostly important for the diagnosis. Due to a lack of effective, evidence‐based treatments for HSOS, avoiding the mistaken use of PA‐containing products including Tusanqi is important for the prevention of HSOS.     

16例吡咯烷生物碱相关肝窦阻塞综合征的临床病理分析

目的观察吡咯烷生物碱(PA)植物致肝窦阻塞综合征(HSOS)患者的肝穿刺活体组织检查(简称活检)病理学表现。方法选取2012年至2017年诊断为PA-HSOS患者,收集患者一般情况、肝功能指标、服药史、肝穿刺活检时间、肝穿刺病理组织切片、起病6个月后的临床预后等资料。用临床资料进行临床分期;观察不同临床分期患者的病理组织学表现。对数据采用Wilcoxin符号秩和检验、非配对t检验、一元线性回归分析。结果收集到16例患者,起病、随访6个月后丙氨酸转氨酶水平分别为59.25 U/L和25.50 U/L、天冬氨酸转氨酶分别为108 U/L和45 U/L,差异均有统计学意义。而总胆汁酸分别为35μmol/L和36.15μmol/L,白蛋白分别为32.45 g/L和31 g/L,差异无统计学意义。将PA-HSOS病理发展过程分为早期、中期、晚期。早期小叶中心带窦内皮完整性受损,红细胞进入窦内皮与肝细胞之间的窦周间隙。中期出血带内红细胞溶解,网状纤维塌陷密集,胶原纤维沉积,尚有血流的腔隙充血扩张,其腔内覆有窦内皮细胞;出血带周围肝板出现再生现象,部分肝窦代偿性扩张。晚期出血带内胶原沉积形成大面积纤维瘢痕,其内多数有血流的扩张腔隙内覆血管内皮;边缘带肝细胞呈双排再生,插入纤维间隔。肝穿刺组织内重度出血损伤的肝小叶比例和患者预后无关。结论PA-HSOS早期小叶中心带红细胞通过受损的窦内皮进入窦周间隙,表现为肝板出血性坏死。至中晚期出现肝板再生和血管改造,故大部分患者临床病程呈自限性。病理分期和肝穿刺活检时间具有明显相关性,但无法根据标本出血损伤程度判断患者预后。     

层黏连蛋白及其整合素受体在肝窦毛细血管化时的协调表达

目的：探讨层黏连蛋白（LN）及其整合素受体在肝窦毛血管化时的协调表达。方法：皮下注射四氯化碳制备大鼠肝纤维化模型,取肝组织用扫描电镜、特殊染色等进行病理组织形态学观察;层黏连蛋白及其整合素受体α6斑点免疫印迹研究。结果：动态观察了肝纤维化的特征病理变化;肝窦毛细血管化,即窗孔消失,基底膜形成及表型改变。LN在肝纤维化各期窦周阳性着色面积分别为0、1．902％、6．02％、9．68％、14．14％,其差异有显著性（P＜0．001）;正常时α6在肝窦内皮细胞（SEC）上无表达,肝窦毛细血管化时SEC出现α6表达与LN在窦周沉积一致,α6在纤维化时组织中含量明显高于正常（P＜0．05）。结论：LN于肝纤维经时在肝组织中不断沉积,并沿肝窦壁形成基底膜,使肝窦毛细血管化,且SEC出现LN整合素受体的诱导表达。提示LN及其整合素受体的协调表达在肝窦毛细血管化及肝纤维化的发病机制中有着重要的作用。     

整合素α6在肝窦毛细血管化中的表达

目的探讨整合素α6在肝窦毛细血管化时的表达情况. 方法皮下注射四氯化碳制备大鼠肝纤维化模型,进行层粘连蛋白(LN)及其整合素受体α6免疫组织化学检测及整合素α6斑点免疫印迹研究. 结果动态观察了LN在肝纤维化时沿肝窦在Disse间隙沉积形成肝窦毛细血管化;正常时整合素α6局限于汇管区血管内皮和胆管内皮细胞膜上,窦内皮细胞(SEC)上无表达,肝窦毛细血管化时,SEC出现整合素α6阳性表达沿肝窦连续分布,整合素α6在纤维化时组织中含量明显高于正常(P＜0.05). 结论肝窦毛细血管化时SEC出现整合素α6亚基的诱导表达.     

Liver transplantation for benign liver tumors

Benign liver tumors are common lesions that are usually asymptomatic and are often found incidentally due to recent advances in imaging techniques and their widespread use. Although most of these tumors can be managed conservatively or treated by surgical resection, liver transplantation(LT) is the only treatment option in selected patients. LT is usually indicated in patients that present with life-threatening complications, when the lesions are diffuse in the hepatic parenchyma or when malignant transformation cannot be ruled out. However, due to the significant postoperative morbidity of the procedure, scarcity of available donor liver grafts, and the benign course of the disease, the indications for LT are still not standardized. Hepatic adenoma and adenomatosis, hepatic hemangioma, and hepatic epithelioid hemangioendothelioma are among the most common benign liver tumors treated by LT. This article reviews the role of LT in patients with benign liver tumors. The indications for LT and long-term outcomes of LT are presented.     

Ultrasound liver elastography beyond liver fibrosis assessment

Several guidelines have indicated that liver stiffness(LS) assessed by means of shear wave elastography(SWE) can safely replace liver biopsy in several clinical scenarios, particularly in patients with chronic viral hepatitis. However, an increase of LS may be due to some other clinical conditions not related to fibrosis,such as liver inflammation, acute hepatitis, obstructive cholestasis, liver congestion, infiltrative liver diseases. This review analyzes the role that SWE can play in cases of liver congestion due to right-sided heart failure, congenital heart diseases or valvular diseases. In patients with heart failure LS seems directly influenced by central venous pressure and can be used as a prognostic marker to predict cardiac events. The potential role of LS in evaluating liver disease beyond the stage of liver fibrosis has been investigated also in the hepatic sinusoidal obstruction syndrome(SOS) and in the Budd-Chiari syndrome. In the hepatic SOS, an increase of LS is observed some days before the clinical manifestations;therefore, it could allow an early diagnosis to timely start an effective treatment.Moreover, it has been reported that patients that were successfully treated showed a LS decrease, that reached pre-transplantation value within two to four weeks. It has been reported that, in patients with Budd-Chiari syndrome, LS values can be used to monitor short and long-term outcome after angioplasty.     

肝移植术后并发急性侵袭性真菌性鼻窦炎1例

肝移植术后真菌感染在临床比较常见,但急性侵袭性真菌性鼻窦炎在肝移植术后患者中极为少见,在耳鼻喉科也较为少见,该类患者病情凶险,预后极差。本文通过总结分析我院收治的1例肝移植术后并发急性侵袭性真菌性鼻窦炎患者的病史、临床表现、影像学特征及治疗经验,探讨肝移植术后急性侵袭性真菌性鼻窦炎的临床特点、诊断标准、治疗原则。     

肝窦内皮细胞调控肝脏微环境影响肝纤维化的研究进展

肝窦内皮细胞不仅是血液和肝细胞进行物质交换的重要中介细胞,也是慢性肝损伤因素导致肝纤维化和肝硬化的重要肝非实质细胞。它主要通过与肝星状细胞、肝细胞、Kupffer细胞的相互作用和介导肝脏硬度、肝脏血管再生从而调控肝脏微循环,参与肝纤维化的发展。阐明这些机制,有助于探索肝纤维化治疗的新靶点和方案。     

肝窦内皮细胞损伤在大鼠肝纤维化形成中的作用

目的 研究肝窦内皮细胞损伤在二甲基亚硝胺大鼠肝纤维化形成中的作用。方法 采用二甲基亚硝胺(dimethylnitrosamine,DMN)4周12次腹腔注射制备大鼠肝纤维化模型,应用电镜技术、免疫组织化学及图像分析方法结合血清生化测定,24周动态观察肝纤维化形成过程中肝窦内皮细胞损伤及其表型的改变。结果 造模2d后肝结构未见明显改变,肝窦内皮细胞(sinusoidal endothelial cell,SEC)远侧胞浆窗孔数减少、造模1周SEC失窗孔更明显,肝组织内未见明显变性坏死及纤维间隔形成,造模4周时见肝组织内大片出血坏死,有大量假小叶形成,内皮下出现SEC窗孔减少。SEC失窗孔早于肝细胞发生较为严重的坏死、肝纤维化的形成以及肝窦内皮下基底膜的形成。造模4周HA(ng/ml)和肝羟脯氨酸(ug/g)平均含量分别为231.30±143.80和223.04±37.09,对照组分别为56.50±18.10和61.55±20.85,t值在3.14～8.28,P<0.05。结论 DMN引起大鼠肝窦内皮细胞损伤及其表型改变可能是其诱导肝纤维化重要的始动机制之一。     

Liver stiffness and perfusion changes for hepatic sinusoidal obstruction syndrome in rabbit model

BACKGROUND Hepatic sinusoidal obstruction syndrome(SOS)is caused by damage to hepatic sinusoidal endothelial cells that results in fibrous obliteration of intrahepatic venules and necrosis of hepatocytes.Currently the diagnosis is primarily based on nonspecific clinical features and invasive liver biopsy.Therefore,noninvasive imaging methods are required for the early diagnosis and severity assessment of hepatic SOS.AIM To determine the effectiveness of supersonic shear wave imaging(SSI)and dual energy computed tomography(DECT)for diagnosing hepatic SOS using a rabbit model.METHODS Among nine New Zealand white rabbits(3-4 kg,male),three in control group ingested normal saline for 20 d and six in the SOS group ingested 6-thioguanine(5 mg/kg/d)for 20 d.Liver stiffness was measured using SSI on days 0,3,10,and 20.On the same days,liver perfusion was evaluated from virtual monochromatic images of 55 keV and iodine map using DECT.Morphologic changes in the liver were assessed using CT.Final pathology scores were compared between the two groups.Liver stiffness and perfusion parameters were compared according to the groups,days,and pathology scores.RESULTS Final pathology scores were significantly higher in the SOS than the control group(median 22 vs 2,P=0.024).No gross morphologic changes were seen in livers.Liver stiffness,Hounsfield Unit values,and iodine concentrations were higher in the SOS compared to the control group on days 10 and 20(all,P≤0.007).Compared to day 0,liver stiffness and perfusion parameters were higher on day 20 in the SOS group(all,P≤0.001).Correlation coefficients for liver stiffness(r=0.635),Hounsfield Unit values(r=0.587),and iodine concentration(r=0.611)with final pathology scores were positive without significance(all,P>0.05).CONCLUSION Liver stiffness and perfusion parameters were significantly increased in the livers of a rabbit SOS model.SSI and DECT might aid in early diagnosis of hepatic SOS.     

四氯化碳诱导的肝纤维化大鼠肝窦毛细血管化的形成

目的：观察四氯化碳（CCl4）诱导的大鼠肝纤维化过程中肝窦毛细血管化的形成过程,探讨其与肝纤维化的关系。方法32只清洁级雄性SD大鼠,随机分为正常对照组,肝纤维化模型组,正常对照组大鼠腹腔注射0．9％氯化钠溶液2 mL/kg ,模型组大鼠腹腔注射50％ CCl4-蓖麻油混合液2 mL/kg ,每周2次,共8周;分别于造模第2、4、6、8周处死大鼠,观察肝组织炎症及纤维化程度,放射免疫法检测血清中透明质酸（HA）的含量,透射电镜观察肝窦窦壁结构,S-P 免疫组织化学检测各组大鼠肝组织CD31、层黏连蛋白（LN）、IV型胶原（Col-IV）的表达。结果肝脏组织学证实CCl4诱导的大鼠肝纤维化模型构建成功,6周可见纤维间隔形成;透射电镜显示,CCl4诱导2周时,部分肝窦内皮细胞（liver sinusoidal endothelial cells ,LSEC）窗孔减少,内皮下未见基底膜（Basement membrane,BM）,随着造模的进程,LSEC 窗孔进一步减少,部分甚至消失,第6、8周时局部肝窦内皮下形成连续的BM。同时,随着肝纤维化的进程,HA浓度逐渐升高,肝窦内皮细胞表面标志物CD31及基底膜主要成分Col-IV、LN表达逐渐增强。结论在CCl4诱导大鼠肝纤维化过程中,肝窦毛细血管化是逐渐形成的,LSEC失窗孔早于纤维间隔的形成,而肝窦内皮下基底膜出现在纤维间隔形成以后。     

Liver injury in COVID-19: Clinical features,potential mechanisms,risk factors and clinical treatments

The coronavirus disease 2019 (COVID-19) pandemic has been a serious threat to global health for nearly 3 years. In addition to pulmonary complications, liver injury is not uncommon in patients with novel COVID-19. Although the prevalence of liver injury varies widely among COVID-19 patients, its incidence is significantly increased in severe cases. Hence, there is an urgent need to understand liver injury caused by COVID-19. Clinical features of liver injury include detectable liver function abnormalities and liver imaging changes. Liver function tests, computed tomography scans, and ultrasound can help evaluate liver injury. Risk factors for liver injury in patients with COVID-19 include male sex, preexisting liver disease including liver transplantation and chronic liver disease, diabetes, obesity, and hypertension. To date, the mechanism of COVID-19-related liver injury is not fully understood. Its pathophysiological basis can generally be explained by systemic inflammatory response, hypoxic damage, ischemia-reperfusion injury, and drug side effects. In this review, we systematically summarize the existing literature on liver injury caused by COVID-19, including clinical features, underlying mechanisms, and potential risk factors. Finally, we discuss clinical management and provide recommendations for the care of patients with liver injury.     

Pathophysiology,epidemiology, classification and treatment options for polycystic liver diseases

Polycystic liver diseases(PLD)represent a group of genetic disorders in which cysts occur in the liver(autosomal dominant polycystic liver disease)or in combination with cysts in the kidneys(autosomal dominant polycystic kidney disease).Regardless of the genetic mutations,the natural history of these disorders is alike.The natural history of PLD is characterized by a continuous increase in the volume and the number of cysts.Both genders are affected;however,women have a higher prevalence.Most patients with PLD are asymptomatic and can be managed conservatively.Severe symptoms can affect 20%of patients who develop massive hepatomegaly with compression of the surrounding organs.Rrarely,patients with PLD suffer from acutecomplications caused by the torsion of hepatic cysts,intraluminal cystic hemorrhage and infections.The most common methods for the diagnosis of PLD are cross sectional imaging studies.Abdominal ultrasound and computerized tomography are the two most frequently used investigations.Magnetic resonance imaging is more sensitive and specific,and it is a valuable test for patients with intravenous contrast allergies or renal dysfunction.Different treatment modalities are available to physicians caring for these patients.Medical treatment has been ineffective.Percutaneous sclerotherapy,transarterial embolization,cyst fenestration,hepatic resection and liver transplantation are indicated to specific groups of patients and have to be tailored according to the extent of disease.This review outlines the current knowledge of the pathophysiology,clinical course,diagnosis and treatment strategies of PLD.     

Liver transplantation and atrial fibrillation: A meta-analysis

AIM To assess prevalence of pre-existing atrial fibrillation(AF) and/or incidence of AF following liver transplantation, and the trends of patient's outcomes overtime; to evaluate impact of pre-existing AF and post-operative AF on patient outcomes following liver transplantation. METHODS A literature search was conducted utilizing MEDLINE, EMBASE and Cochrane Database from inception throughMarch 2018. We included studies that reported:(1) prevalence of pre-existing AF or incidence of AF following liver transplantation; or(2) outcomes of liver transplant recipients with AF. Effect estimates from the individual study were extracted and combined utilizing randomeffect, generic inverse variance method of DerSimonian and Laird. The protocol for this meta-analysis is registered with PROSPERO(International Prospective Register of Systematic Reviews, No. CRD42018093644). RESULTS Twelve observational studies with a total of 38586 liver transplant patients were enrolled. Overall, the pooled estimated prevalence of pre-existing AF in patients undergoing liver transplantation was 5.4%(95%CI: 4.9%-5.9%) and pooled estimated incidence of AF following liver transplantation was 8.5%(95%CI: 5.2%-13.6%). Meta-regression analyses were performed and showed no significant correlations between year of study and either prevalence of pre-existing AF(P = 0.08) or post-operative AF after liver transplantation(P = 0.54). The pooled OR of mortality among liver transplant recipients with pre-existing AF was 2.34(2 studies; 95%CI: 1.10-5.00). In addition, pre-existing AF is associated with postoperative cardiovascular complications among liver transplant recipients(3 studies; OR: 5.15, 95%CI: 2.67-9.92, I2 = 64%). With limited studies, two studies suggested significant association between new-onset AF and poor clinical outcomes including mortality, cerebrovascular events, post-transplant acute kidney injury, and increased risk of graft failure among liver transplant recipients(P 0.05).CONCLUSION The overall estimated prevalence of pre-existing AF and incidence of AF following liver transplantation are 5.4% and 8.5%, respectively. Incidence of AF following liver transplant does not seem to decrease overtime. Preexisting AF and new-onset AF are potentially associated with poor clinical outcomes post liver transplantation.