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.     

布-加综合征、肝血窦阻塞综合征与肝硬化的鉴别

布-加综合征是由肝静脉或其开口以上的下腔静脉阻塞性病变引起的以下腔静脉阻塞、门静脉高压为特点的综合征,诊断依靠影像学检查,治疗的关键是解除梗阻。肝血窦阻塞综合征是指肝窦内皮完整性破坏和肝窦内充血阻塞而产生的肝内窦后性门静脉高压症,临床表现类似布-加综合征,诊断依靠肝组织活检。这两种疾病的治疗和预后均与肝实质病变导致的肝硬化不同,所以临床上需要注意这三种疾病的鉴别。     

Decreased hepatic nitric oxide synthesis during liver surgery.

BACKGROUND/AIMS: Liver cells can produce nitric oxide from L-arginine through the action of nitric oxide synthase, but local changes in the concentrations of nitric oxide-related metabolites during liver surgery are not well characterized. We investigated such changes during and after liver surgery. METHODOLOGY: We determined nitrite plus nitrate, L-arginine and L-citrulline concentrations in radial arterial and hepatic venous blood during and after liver surgery in 17 patients. Portal venous blood concentrations were also measured at the end of surgery in 7 patients. RESULTS: Both arterial and hepatic venous nitrite plus nitrate concentrations were significantly decreased during surgery and remained low compared to pre-operative values until post-operative day 2. Arterial and hepatic venous nitrite plus nitrate concentrations were not significantly different. L-arginine concentrations in both arterial and hepatic venous blood were significantly decreased during surgery, but returned to pre-operative levels on post-operative day 1. L-arginine concentrations in hepatic venous blood were significantly lower than in arterial blood. L-citrulline concentrations in both arterial and hepatic venous blood were significantly decreased during surgery compared to pre-operative values, and tend to be decreased until post-operative day 2. L-citrulline concentrations were significantly higher in hepatic venous blood than in arterial blood. CONCLUSIONS: Hepatic nitric oxide production was decreased peri-operatively during liver surgery. The decreases in L-arginine concentrations and in nitric oxide synthase activity may account for the decrease in nitric oxide production.     

吡咯生物碱相关肝窦阻塞综合征发病机制的研究进展

吡咯生物碱诱导的肝窦阻塞综合征主要原因为摄入了含吡咯生物碱的中草药或食品。从药物因素、宿主因素、影响因素三个方面,回顾了近年来吡咯生物碱及其代谢产物参与疾病发生发展机制的研究进展。认为吡咯生物碱相关肝窦阻塞综合征的发病机制复杂、影响因素较多,部分患者预后较差,且发病机制尚未十分明确,有必要进一步深入研究。     

Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease)

The term veno-occlusive disease of the liver refers to a form of toxic liver injury characterized clinically by the development of hepatomegaly, ascites, and jaundice, and histologically by diffuse damage in the centrilobular zone of the liver. The cardinal histologic features of this injury are marked sinusoidal fibrosis, necrosis of pericentral hepatocytes, and narrowing and eventual fibrosis of central veins. Recent studies suggest that the primary site of the toxic injury is sinusoidal endothelial cells, followed by a series of biologic processes that lead to circulatory compromise of centrilobular hepatocytes, fibrosis, and obstruction of liver blood flow. Thus we propose a more appropriate name for this form of liver injury--sinusoidal obstruction syndrome. This review encompasses historical perspectives, clinical manifestations of sinusoidal obstruction syndrome in the setting of hematopoietic cell transplantation, histologic features of centrilobular injury, and a discussion of the pathophysiology of sinusoidal injury, based on both animal and clinical investigations.     

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.     

肝窦阻塞综合征八例临床分析

目的探讨肝窦阻塞综合征（SOS）的临床诊治方法。方法回顾性分析8例SOS的临床资料,并进行随访。结果8例SOS主要临床表现为腹胀（8例）、肝区疼痛（7例）、腹水征（8例）及肝肿大（7例）等。8例的肝功能损害程度大多较轻,血清-腹水白蛋白梯度均大于11．1g／L,血清与腹水CA125均显著升高。超声检查均见肝脏肿大、胆囊壁水肿或增厚、门静脉增宽且流速缓慢、肝静脉变细以及腹腔积液等;MRI表现为门脉期及延迟期肝实质不均匀片状强化,肝叶、段静脉腔内造影剂充盈不良。经皮肝穿刺活检均见肝窦扩张、淤血及肝细胞变性、坏死,3例发现小静脉管腔狭窄、管壁增厚伴纤维组织增生。8例中1例行肝移植术后痊愈,4例经内科治疗后逐渐康复,3例死亡。结论SOS的临床表现以突出的门脉高压症为特点,CA125常显著升高,超声及MRI对本病的诊断与鉴别诊断有重大价值,而经皮肝穿刺活检的价值有限,联合应用影像学方法与病理活检可提高诊断正确率。早期应用抗凝药物是治疗本病的关键,严重病例可行肝移植术。     

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。     

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。     

千里光致肝窦阻塞综合征伴停经1例

肝窦阻塞综合征(hepatic sinusoidal obstruction syndrome,SOS)是一种少见的肝脏血管性疾病,含吡咯烷生物碱的植物为其常见致病因素,严重者可出现致命性多器官功能衰竭。由于SOS早期症状不典型,发病机制复杂,缺乏特效的治疗手段,目前误诊率高、预后较差。本文对1例千里光所致SOS伴停经病例进行报道,并回顾相关文献,为临床防治药物性肝血管损伤提供参考。     

土三七导致肝窦阻塞综合征20例

目的分析土三七导致肝窦阻塞综合征(SOS)患者的临床特点及诊治方法。方法回顾性分析2011年11月至2015年12月收治的20例服用土三七所致肝窦阻塞综合征患者的临床诊治资料。结果 20例患者中以老年人居多,大多数在服药的4个月内发病,均以腹胀为首发表现,所有患者肝脏CT或MRI检查均有"地图样"改变,肝静脉变细或不显示,1例患者出现肝肿大且无腹水,余19例均有腹水,有饮酒史和无饮酒史患者的肝损伤未见显著差异。20例患者中,1例治愈,7例好转,其中有2例是行TIPS治疗后好转。结论土三七可导致SOS的发生,肝脏CT或MRI检查有特征性的表现,早期抗凝、改善微循环治疗有一定疗效,应重视土三七的肝毒性。     

Superoxide contributes to development of salt sensitivity and hypertension induced by nitric oxide deficiency

This study was performed to examine the role of superoxide (O2-) in the development of salt sensitivity and hypertension induced by inhibition of nitric oxide (NO) generation. Male Sprague-Dawley rats were fed with diet containing either normal salt (NS) (0.4% NaCl) or high salt (HS) (4% NaCl). These rats were treated with or without an NO synthase inhibitor, nitro-L-arginine methylester (L-NAME) (15 mg/kg/d) and O2- scavenger, tempol (30 mg/kg per day) in the drinking water for 4 weeks. Systolic blood pressure (SBP) was measured by tail-cuff plethysmography and urine collection was performed during the course of experimental periods. At the end of 4 weeks, L-NAME treatment resulted in greater increases in SBP in HS rats (127+/-2 to 172+/-3 mm Hg; n=8) than in NS rats (130+/-2 to 156+/-2 mm Hg; n=9). Co-administration of tempol with L-NAME markedly attenuated these SBP responses to a similar level in both HS (128+/-3 to 147+/-2 mm Hg; n=8) and NS rats (126+/-2 to 142+/-3 mm Hg; n=8). Urinary 8-isoprostane excretion (UIsoV) increased in response to L-NAME treatment that was higher in HS (10.6+/-0.5 to 21.5+/-0.8 ng/d) than in NS rats (10.8+/-0.7 to 16.9+/-0.6 ng/d). Co-treatment with tempol completely abolished these UIsoV responses to L-NAME in both HS and NS rats but did not alter urinary H2O2 excretion rate. The decreases in urinary nitrate/nitrite excretion in response to L-NAME treatment were not altered by co-administration of tempol in both HS and NS rats. These data suggest that enhancement of O2- activity during NO inhibition contributes to the development of salt sensitivity that is associated with NO-deficient hypertension.     

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.     

The changes of hepatic sinusoidal microcirculation and effects of nitric oxide synthase inhibitor during sepsis

BACKGROUND/AIMS: Sepsis may cause changes in liver blood flow, which may result in liver injury. Microcirculation in organ undergoes moderate alteration during sepsis or septic shock. The changes in hepatic microcirculation corresponding to liver functions and the effects of nitric oxide synthase inhibitor on the liver during sepsis were studied. METHODOLOGY: Sepsis was produced by CLP (cecal ligation and two-hole puncture). In part I, the leukocyte adherence, leukocyte rolling numbers, and velocity of sinusoidal microcirculation of liver were compared with in vivo microscopy among early septic, late septic and control rats. In part II, the rats were randomly divided into two groups after CLP procedure, group A was given L-NAME (NG-nitro-L-arginine-methylester hydrochloride), 10 mg/kg BW, and group B was given normal saline as a control. The hepatic microcirculation, measured with a Laser-Doppler Flowmeter, was performed at 0, 2, 4, 6, and 8 hours after the CLP procedure. Their liver functions were also examined and compared with the microcirculation. RESULTS: The results showed that the adherent and rolling numbers of leukocytes in the sinusoidal capillary significantly increased in early and late septic rats; and the centralized velocity of flow significantly decreased in late septic rats. For rats without L-NAME, their sinusoidal flux of the liver increased 2 and 4 hours after CLP, and then decreased gradually. Their GOT levels progressively increased after CLP, but the albumin levels decreased. For rats with L-NAME (group A), their sinusoidal flux levels at 2, 4 and 6 hours after CLP were significantly lower than those in rats without L-NAME (group B), but their GOT levels were higher since the 4th hour after CLP. CONCLUSIONS: Our conclusions are that hepatic microcirculation initially increased then decreased and the liver functions deteriorated gradually after sepsis was induced. These changes were aggravated when the nitric oxide synthesis was inhibited.     

Inducible nitric oxide synthase contributes to ventilator-induced lung injury

RATIONALE: Inducible nitric oxide synthase (iNOS) has been implicated in the development of acute lung injury. Recent studies indicate a role for mechanical stress in iNOS and endothelial NOS (eNOS) regulation. OBJECTIVES: This study investigated changes in lung NOS expression and activity in a mouse model of ventilator-induced lung injury. METHODS: C57BL/6J (wild-type [WT]) and iNOS-deficient (iNOS(-/-)) mice received spontaneous ventilation (control) or mechanical ventilation (MV; VT of 7 and 20 ml/kg) for 2 hours, after which NOS gene expression and activity were determined and pulmonary capillary leakage assessed by the Evans blue albumin assay. RESULTS: iNOS mRNA and protein expression was absent in iNOS(-/-) mice, minimal in WT control mice, but significantly upregulated in response to 2 hours of MV. In contrast, eNOS protein was decreased in WT mice, and nonsignificantly increased in iNOS(-/-) mice, as compared with control animals. iNOS and eNOS activities followed similar patterns in WT and iNOS(-/-) mice. MV caused acute lung injury as suggested by cell infiltration and nitrotyrosine accumulation in the lung, and a significant increase in bronchoalveolar lavage cell count in WT mice, findings that were reduced in iNOS(-/-) mice. Finally, Evans blue albumin accumulation in lungs of WT mice was significant (50 vs. 15% increase in iNOS(-/-) mice compared with control animals) in response to MV and was prevented by treatment of the animals with the iNOS inhibitor aminoguanidine. CONCLUSION: Taken together, our results indicate that iNOS gene expression and activity are significantly upregulated and contribute to lung edema in ventilator-induced lung injury.     

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.     

Interleukin-2-activated rat natural killer cells express inducible nitric oxide synthase that contributes to cytotoxic function and interferon-gamma production.

Natural killer (NK) cells are large granular lymphocytes capable of destroying cells infected by virus or bacteria and susceptible tumor cells without prior sensitization and restriction by major histocompatability complex (MHC) antigens. Their cytotoxic activity could be strongly enhanced by interleukin-2 (IL-2). Previous findings, even if obtained with indirect experimental approaches, have suggested a possible involvement of the inducible nitric oxide (iNOS) pathway in the NK-mediated target cell killing. The aim of the present study was first to directly examine the induction of iNOS in IL-2-activated rat NK cells isolated from peripheral blood (PB-NK) or spleen (S-NK), and second to investigate the involvement of the iNOS-derived NO in the cytotoxic function of these cells. Our findings clearly indicate the induction of iNOS expression in IL-2-activated PB-NK and S-NK cells, as evaluated either at mRNA and protein levels. Accordingly, significantly high levels of iNOS activity were shown, as detected by the L-arginine to L-citrulline conversion in appropriate assay conditions. The consequent NO generation appears to partially account for NK cell-mediated DNA fragmentation and lysis of sensitive tumor target cells. In fact, functional inhibition of iNOS through specific inhibitors, as well as the almost complete abrogation of its expression through a specific iNOS mRNA oligodeoxynucleotide antisense, significantly reduced the lytic activity of IL-2-activated NK cells. Moreover, IL-2-induced interferon-gamma production appears also to be dependent, at least in part, on iNOS induction.