Coexistence of nodular regenerative hyperplasia of the liver and pulmonary arterial hypertension in patients with connective tissue diseases: report of three cases and review of the literature

Abstract

Nodular regenerative hyperplasia of the liver (NRH) is known to be a rare condition in patients with connective tissue diseases (CTD). In this report, we document three patients with CTD who had both NRH and pulmonary hypertension (PH). All three patients developed PH during their course and thereafter developed NRH. The clinical course of these patients suggests that circulatory disturbance caused by PH might be a trigger for NRH.     

Anti-endothelial cell antibodies in connective tissue diseases associated with pulmonary arterial hypertension

Objective

To investigate the prevalence of anti-endothelial cell antibodies (AECA) in connective tissue diseases (CTD) associated with pulmonary arterial hypertension (PAH) and to corroborate the pathologic function of AECA in PAH-associated CTDs.

Methods

AECA were detected by cellular enzyme-linked immunosorbent assay (ELISA) in sera of 19 PAH-associated CTD patients, 22 CTD patients without PAH involvement, and 20 age- and sex-matched healthy individuals as controls. Using IgG purified from the sera of AECA-positive, AECA-negative, and healthy subjects, the effects of AECA on the expression of ICAM-1 and the chemokine regulated upon activation normal T-cell expressed and secreted (RANTES) in cultured endothelial cells were also evaluated.

Results

A total of 12 of the 19 (63.2%) CTD patients with PAH, 9 of the 22 (40.9%) CTD patients without PAH, and 1 of the 20 (5%) healthy controls were positive for AECA, which were calculated as ELISA ratio (ER) values. ER values in PAH-associated CTD patients were significantly higher than those with CTD without PAH (3.68±2.05 versus 1.67±1.07, P<0.001). IgG purified from AECA-positive sera induced a significantly increased level of ICAM-1 expression after 48 h incubation (795.2±32.5 pg/mL) compared with AECA-negative or healthy control IgG (231.5±27.1 and 192.8±33.4 pg/mL, respectively; P<0.001). In addition, RANTES production by cultured human pulmonary arterial endothelial cells (HPAECs) increased in both a time- and concentration-dependent manner in response to incubation with purified AECA-positive IgG.

Conclusions

AECA could be involved in CTD and might participate in the pathogenesis of PAH-associated CTD.     

Pulmonary arterial hypertension among Filipino patients with connective tissue diseases

We describe the clinical features, therapies, and clinical course of pulmonary arterial hypertension (PAH) in a group of Filipinos with connective tissue diseases (CTDs). We retrospectively reviewed the records of patients diagnosed with PAH by a two-dimensional echocardiogram as a tricuspid regurgitant jet of more than 25 mmHg. All patients had underlying CTDs, defined by the American College of Rheumatology criteria, and were seen at the rheumatology clinics of the University of Santo Tomas Hospital and the St. Luke's Medical Center, Philippines. Of the 33 patients (32 women) included in the analysis, there were 14 patients with systemic lupus erythematosus (SLE), 12 with scleroderma, 5 with mixed connective tissue disease (MCTD), 1 with primary antiphospholipid syndrome (APS), and 1 with dermatomyositis. The average age at PAH diagnosis was 38 ± 14 years (mean ± SD), and the mean duration of illness from CTD to PAH diagnosis was 53 ± 52 months. Twelve patients had died at the time of this report, with a median duration of 15 months (range 1–57 months) from PAH diagnosis to mortality: six of these had scleroderma, five with SLE, and one with APS. The following therapies were used in this group of patients: low molecular weight heparin, warfarin, calcium-channel blockers, aspirin, cyclophosphamide, bosentan, iloprost, and sildenafil. We have described the clinical profile of PAH in a group of Filipino patients with CTDs, most commonly SLE. Various forms of pharmacologic therapies were used among these patients. Mortality remains high, particularly among those with underlying scleroderma. Early recognition and treatment are crucial in order to provide a better outcome for these patients.     

Pulmonary arterial hypertension among Filipino patients with connective tissue diseases

Abstract

We describe the clinical features, therapies, and clinical course of pulmonary arterial hypertension (PAH) in a group of Filipinos with connective tissue diseases (CTDs). We retrospectively reviewed the records of patients diagnosed with PAH by a two-dimensional echocardiogram as a tricuspid regurgitant jet of more than 25?mmHg. All patients had underlying CTDs, defined by the American College of Rheumatology criteria, and were seen at the rheumatology clinics of the University of Santo Tomas Hospital and the St. Luke's Medical Center, Philippines. Of the 33 patients (32 women) included in the analysis, there were 14 patients with systemic lupus erythematosus (SLE), 12 with scleroderma, 5 with mixed connective tissue disease (MCTD), 1 with primary antiphospholipid syndrome (APS), and 1 with dermatomyositis. The average age at PAH diagnosis was 38 ± 14 years (mean ± SD), and the mean duration of illness from CTD to PAH diagnosis was 53 ± 52 months. Twelve patients had died at the time of this report, with a median duration of 15 months (range 1–57 months) from PAH diagnosis to mortality: six of these had scleroderma, five with SLE, and one with APS. The following therapies were used in this group of patients: low molecular weight heparin, warfarin, calcium-channel blockers, aspirin, cyclophosphamide, bosentan, iloprost, and sildenafil. We have described the clinical profile of PAH in a group of Filipino patients with CTDs, most commonly SLE. Various forms of pharmacologic therapies were used among these patients. Mortality remains high, particularly among those with underlying scleroderma. Early recognition and treatment are crucial in order to provide a better outcome for these patients.     

结缔组织病相关性肺动脉高压59例临床分析

目的:了解结缔组织病(connective tissue diseases,CTD)相关的肺动脉高压(pulmonary ar-terial hypertension,PAH)的发生率、临床特点及预后,提高对该病的认识及重视。方法:从715例CTD患者中筛选出伴有PAH的患者59例,对其临床资料进行回顾性分析。结果:合并的PAH的总发生率约为8.3%。59例患者中女性47例,男性12例;年龄23～95岁,平均(57±19)岁;病程1个月～30年。其中白塞病合并PAH发生率最高,为19.2%,系统性红斑狼为13.7%、干燥综合征为13.5%、类风湿关节炎为7.4%、大动脉炎为3.5%(P<0.01)。发病年龄与肺动脉压力呈负相关(相关系数r=-0.490,P<0.01),PAH组与非PAH组比较肺间质病变比例、抗核抗体(ANA)阳性率、类风湿因子(RF)阳性率共存差异有统计学意义(P<0.05)。结论:CTD中PAH是较为常见的并发症,本组研究提示,其中白塞病和系统性红斑狼疮发生率最高;发病年龄越早,PAH越严重;肺间质纤维化、炎性指标的升高、ANA及RF阳性提示CTD患者有更易发生PAH的可能。     

结缔组织病相关肺动脉高压发病机制研究进展

肺动脉高压(pulmonary arterial hypertension,PAH)是结缔组织病(connective tissue disease,CTD)常见且严重的并发症之一,影响CTD患者的预后,目前认为CTD相关PAH的发病机制可能是血管痉挛、血管壁重塑、肺间质病变、内皮损伤、血管活性物质失衡、免疫炎症机制、微血栓形成、基因多态性等多种原因,但具体发病机制尚不明确,本文对结缔组织病相关肺动脉高压( CTD-PAH)的发病机制研究作一综述.     

肝结节性再生性增生1例

肝结节性再生性增生(Noducar regenerative hyperplasia of liver,NRHL)是一种临床少见的肝脏疾病,临床主要表现为非肝硬化性肝源性门静脉高压症,因对其临床病理特征缺乏认识,易引起漏诊或误诊,我院收治1例,现报道如下。     

结缔组织病并发肺动脉高压110例临床分析

目的：评估结缔组织病并发肺动脉高压的发生率、临床特点、诊断及治疗方法。方法：1278例结缔组织病患者中110例伴有肺动脉高压,对其进行回顾性分析。结果：结缔组织病合并肺动脉高压的发生率约为8.6%（110/1278）。110例患者中,女性95例,男性15例,年龄11～79岁,平均（46±17）岁;病程0.5～20年,平均（7±6）年。系统性硬化症（SSc）和混合性结缔组织病（MCTD）合并肺动脉高压发生率最高,分别为40.0%和25.0%,显著高于其他结缔组织病（P〈0.01）。有雷诺现象或雷诺现象合并肺间质病变者肺动脉压力显著升高（P〈0.01和P〈0.05）。且雷诺现象与肺动脉压力呈正相关（r=0.531,P〈0.01）。肺功能异常发生率较高,以弥散量降低最为多见。轻度肺动脉高压患者临床表现少,治疗可逆转;重度肺动脉高压治疗反应差,病死率高。结论：结缔组织病合并肺动脉高压较为常见,其中以SSc和MCTD合并肺动脉高压发生率最高。雷诺现象与肺动脉压力呈正相关,是预测肺动脉高压的良好指标。早期诊断和治疗,可以改善患者预后。     

对肝结节状再生性增生的再认识—附18例临床分析

目的通过对18例肝结节状再生性增生(nodular regenerative hyperplasia of liver,NRH)病例进行总结分析,以提高临床医师对此类疾病的认识。方法对北京协和医院1983年1月~2008年12月住院的18例NRH患者的临床表现、实验室检查、影像学检查及病理学检查等多项资料进行总结和分析。结果NRH临床上可表现为肝脏弥漫性病变和占位性病变,但以前者多见。门脉高压症是NRH常见的临床表现,以脾大、脾亢较为突出,肝功能仅轻度异常。NRH常合并自身免疫或胶原血管性疾病,此类患者常伴有多种自身抗体、ESR增快、Ig增高、γ%增高等异常。病理学检查肝脏内弥漫分布小的无纤维分隔的再生结节,其门静脉分支有不同程度的狭窄或闭塞。结论对临床上难以解释或不明原因的门脉高压症患者,尤其是合并自身免疫性疾病的患者,要警惕NRH的可能性。     

12例肝结节状再生性增生临床分析

目的对肝结节状再生性增生（NRHL）的临床、病理及诊断分析总结，期望提高临床医师对本病的认识。方法从300例因脾功能亢进而行脾切除和肝脏活组织检查病例中选出病理诊断符合NRHL的病例12例，分析其病史、临床症状和体征、实验室检查、诊断及处理等资料，且随访治疗效果。结果12例NRHL中6例明确诊断为系统性红斑狼疮，1例克罗恩病，1例疑诊溃疡性结肠炎。应用肾上腺皮质激素治疗6例，免疫抑制剂3例。11例有门脉高压；所有患者均无病毒性肝炎史；肝功能轻度受损；病理特征为肝实质内结节状再生性增生，门脉周围轻度纤维化和汇管区散在淋巴细胞浸润，门静脉分支狭窄和闭塞，无肝坏死表现；术前均被诊断为肝硬化伴门脉高压；行手术治疗后临床症状明显缓解，随访患者多数病情稳定。结论NRHL可能与免疫和肝脏血液循环障碍有关；以门脉高压为主要表现，应与肝硬化鉴别；诊断依靠肝脏楔形活检；处理门脉高压可使临床状况得到改善。     

结缔组织病相关肺动脉高压79例临床分析

目的探讨结缔组织病相关肺动脉高压的发生率、临床特点及预后,提高对该病的认识。方法收集2005年1月～2008年8月我科收治的1876例弥漫性结缔组织病（CTD）中合并肺动脉高压的79例患者的临床资料及部分患者的随访资料。结果①混合性结缔组织病（MCTD）与系统性硬化症（SSc）肺动脉高压发生率最高（40．0％,30．2％）;②主要的临床表现为雷诺现象（62．0％）,抗SSA抗体与抗U1RNP抗体阳性率最高（51．9％）;③雷诺征发生率、血尿酸水平在轻、中重度肺动脉高压组间比较有统计学差异（P〈0．05）,肺动脉收缩压与雷诺征、心包炎、呼吸困难、血尿酸水平呈正相关（P〈0．05）,与关节炎呈负相关（P〈0．05）;④死亡3例,均为系统性红斑狼疮合并重度肺动脉高压者。结论CTD合并肺动脉高压并不少见,雷诺征与血尿酸水平可作为预测肺动脉高压严重程度的指标。     

结缔组织病相关肺动脉高压抗内皮细胞抗体检测及其靶抗原研究

目的 检测抗内皮细胞抗体(AECA)在结缔组织病(CTD)相关肺动脉高压(PAH)患者中的阳性率,探讨其可能的致病机制.方法 试验组选取68例CTD相关PAH患者,对照组为12例特发性肺动脉高压患者、61例CTD无PAH的患者、20例慢性阻塞性肺疾病合并肺源性心脏病患者及20名健康人.提取EA.hy926内皮细胞株的膜蛋白质,免疫印迹法检测以上各组患者血清中AECA阳性率,采用X2检验确定特异性的条带.进而应用液相色谱-电喷雾离子阱质谱分析,分离和鉴定AECA特定的靶抗原.结果免疫印迹法检测结果显示,AECA-78 000条带的阳性率在CTD相关PAH患者79%(54/68)和CTD合并肾小球病变的患者71%(15/21),明显高于特发性PAH患者8%(1/12)、CTD无内脏受累患者50%(10/20)、CTD单纯合并肺间质纤维化患者15%(3/20)和健康对照组(P<0.05或P<0.01).经蛋白质组学方法 分离鉴定,AECA-78 000的靶抗原成分为膜突蛋白.结论 CTD不同靶器官受累的患者AECA78 000条带的阳性率不同,CTD合并PAH患者和CTD合并肾小球病变的患者可能存在有共同的靶抗原(78 000内皮细胞蛋白质),其成分为膜突蛋白.     

肝结节状再生性增生18例临床分析

我院自1983年至2008年共收治18例肝结节状再生性增生(NRH)患者,现将其临床资料总结分析如下. 一、临床资料 1.一般资料:本组患者男6例,女12例,发病年龄22～70岁(中位年龄39岁),病程1个月～6年.18例患者均无肝脏病史,其中3例因体检发现肝脏占位性病变就诊,15例因门静脉高压症就诊.后者中10例合并自身免疫性疾病,其中确诊系统性红斑狼疮5例,未分化型结缔组织疾病4例,炎症性肠病1例.     

Human immunodeficiency virus and nodular regenerative hyperplasia of liver: A systematic review

AIM: To investigate the diagnosis, pathogenesis, natural history, and management of nodular regenerative hyperplasia(NRH) in patients with human immunodeficiency virus(HIV). METHODS: We performed a systematic review of the medical literature regarding NRH in patients with HIV. Inclusion criteria include reports with biopsy proven NRH. We studied the clinical features of NRH, in particular, related to its presenting manifestation and laboratory values. Combinations of the following keywords were implemented: "nodular regenerative hyperplasia", "human immunodeficiency virus", "noncirrhotic portal hypertension", "idiopathic portal hypertension", "cryptogenic liver disease", "highly active antiretroviral therapy" and "didanosine". The bibliographies of these studies were subsequently searched for any additional relevant publications.RESULTS: The clinical presentation of patients with NRH varies from patients being completely asymptomatic to the development of portal hypertension – namely esophageal variceal bleeding and ascites. Liver associated enzymes are generally normal and synthetic function well preserved. There is a strong association between the occurrence of NRH and the use of antiviral therapies such as didanosine. The management of NRH revolves around treating the manifestations of portal hypertension. The prognosis of NRH is generally good since liver function is preserved. A high index of suspicion is required to make a identify NRH. CONCLUSION: The appropriate management of HIVinfected persons with suspected NRH is yet to be outlined. However, NRH is a clinically subtle condition that is difficult to diagnose, and it is important to be able to manage it according to the best available evidence.     

Human immunodeficiency virus and nodular regenerative hyperplasia of liver:A systematic review简

AIM: To investigate the diagnosis, pathogenesis, natural history, and management of nodular regenerative hyperplasia (NRH) in patients with human immunodeficiency virus (HIV).METHODS: We performed a systematic review of the medical literature regarding NRH in patients with HIV. Inclusion criteria include reports with biopsy proven NRH. We studied the clinical features of NRH, in particular, related to its presenting manifestation and laboratory values. Combinations of the following keywords were implemented: “nodular regenerative hyperplasia”, “human immunodeficiency virus”, “noncirrhotic portal hypertension”, “idiopathic portal hypertension”, “cryptogenic liver disease”, “highly active antiretroviral therapy” and “didanosine”. The bibliographies of these studies were subsequently searched for any additional relevant publications.RESULTS: The clinical presentation of patients with NRH varies from patients being completely asymptomatic to the development of portal hypertension – namely esophageal variceal bleeding and ascites. Liver associated enzymes are generally normal and synthetic function well preserved. There is a strong association between the occurrence of NRH and the use of antiviral therapies such as didanosine. The management of NRH revolves around treating the manifestations of portal hypertension. The prognosis of NRH is generally good since liver function is preserved. A high index of suspicion is required to make a identify NRH.CONCLUSION: The appropriate management of HIV-infected persons with suspected NRH is yet to be outlined. However, NRH is a clinically subtle condition that is difficult to diagnose, and it is important to be able to manage it according to the best available evidence.     

Nodular regenerative hyperplasia of the liver diagnosed by needle biopsy of the liver: Report of a case and review of the literature

The authors report the case of a 45 year old woman in whom the diagnosis of nodular regenerative hyperplasia of the liver was made by needle biopsy of the liver, laparoscopy and hepatic venography. The patient did not have any underlying disorders and had not ingested any of the many drugs and chemicals which may produce the lesion. Clinical manifestations were hepatosplenomegaly, portal hypertension and iron deficiency anaemia, and her condition remains unchanged 5 years after diagnosis.     

Nodular regenerative hyperplasia of the liver: an under-recognized cause of portal hypertension in hematological disorders

Portal hypertension has been described in a wide variety of hematological disorders, especially myeloproliferative and lymphoproliferative disorders. Its clinical manifestations may include bleeding esophageal varices, ascites, or hepatic encephalopathy. In patients with hematological disorders, there are a number of potential causes of portal hypertension, including nodular regenerative hyperplasia of the liver (NRH). This lesion is characterized by diffuse replacement of normal hepatic parenchyma by multiple small nodules composed of regenerating hepatocytes with minimal or no fibrosis. This lack of fibrosis distinguishes NRH from cirrhosis. Unlike cirrhosis, NRH only rarely results in compromised hepatic synthetic function. The major manifestation is portal hypertension related to increased resistance to blood flow within hepatic sinusoids. NRH has been linked to a variety of systemic diseases including collagen vascular diseases, myeloproliferative and lymphoproliferative disorders, as well as various medications. Although NRH is commonly associated with blood dyscrasias, the diagnosis is overlooked because of the complexity and wide differential diagnosis of liver diseases in the setting of hematological malignancy. We review herein nodular regenerative hyperplasia of the liver, including aspects of epidemiology, pathogenesis, differential diagnosis, clinical course, and treatment. We highlight its association with different forms of hematological disease, aiming to increase the awareness of this entity to the internist and the treating hematologist/oncologist.     

Right ventricle Tei-index: a tool to increase the accuracy of non-invasive detection of pulmonary arterial hypertension in connective tissue diseases.

OBJECTIVE: To assess the accuracy of echocardiography for predicting pulmonary arterial hypertension (PAH) in a cohort of patients with systemic sclerosis and other connective tissue diseases, and to evaluate whether addition of the right ventricular (RV) Tei-index contributes to the non-invasive diagnosis of PAH in this patient group. PATIENTS AND METHODS: Ninety-eight patients with systemic sclerosis and other connective tissue diseases in whom an echocardiography was performed in the period from January 1st 2004 to July 1st 2005 were included. Echocardiographic systolic pulmonary arterial pressure (PAP), end-diastolic PAP and RV Tei-index were calculated. In cases with a high suspicion of PAH right heart catheterization was performed and systolic, diastolic and mean PAP as well as pulmonary wedge pressure, cardiac output and pulmonary vascular resistance were obtained. These results were compared to the echocardiographic measurements. RESULTS: The average RV Tei-index of our patients was substantially above normal values. In 35 (36%) patients a right heart catheterization was performed and PAH was confirmed in 28 patients. In 6 of 7 patients without PAH, the RV Tei-index was below the upper limit of normal. A significant correlation was found between the RV Tei-index and the catheterization parameters such as systolic PAP, diastolic PAP and mean PAP. CONCLUSION: The accuracy of echocardiography for the detection of PAH increases when the echocardiographic systolic PAP is combined with an elevated RV Tei-index. As a result, by applying the Tei-index, the number of negative catheterizations can be minimized.     

MRI联合血清GPC3水平鉴别肝脏结节性增生病灶临床应用价值研究*

目的 探究磁共振成像(MRI)联合血清磷脂酰肌醇蛋白聚糖3(GPC3)水平在鉴别诊断肝脏结节性增生(NRH)病灶方面的临床价值。方法 2016年3月～2019年8月我院诊治的NRH患者79例,经手术组织病理学检查结果为局灶性结节性增生(FNH)25例,肝细胞腺瘤(LCA)18例,异型增生结节(DN)20例和肝细胞癌(HCC)16例。采用ELISA法检测血清GPC3水平,使用西门子Avanto 3.0 T超导MRI检查设备和ADW 4.6后处理工作站行MRI检查。应用受试者工作特征曲线(ROC)分析MRI联合血清GPC3对四种病变的鉴别诊断价值。结果 HCC组血清GPC3水平为(2.2±0.4)ng/ml,显著高于FNH组或LCA组【分别为(1.0±0.2)ng/ml和(1.2±0.2)ng/ml,P<0.05】,而与DN组血清GPC3水平【(1.8±0.3)ng/ml,P>0.05】比,无显著性差异;MRI鉴别HCC、DN、FNH与LCA的准确率分别为88.0%(22/25)、88.9%(16/18)、70.0%(14/20)和75.0%(12/16),无显著性差异(P>0.05);MRI联合血清GPC3水平鉴别诊断HCC的AUC为0.760,显著大于诊断其他三种病变(分别为0.610、0.611和0.614,P<0.05)。结论 MRI联合血清GPC3水平检测诊断HCC具有较大的临床应用价值,值得进一步验证。     

Hepatic hemodynamics in 24 patients with nodular regenerative hyperplasia and symptomatic portal hypertension

Background and Aim: To evaluate hepatic hemodynamics in patients with nodular regenerative hyperplasia of the liver (NRH) with portal hypertension (PHT). Methods: We retrospectively reviewed the charts of 24 patients referred for PHT related to biopsy‐proven NRH. Hemodynamic measurements included wedged hepatic vein (WHVP) and inferior vena cava (IVCP), and, in 12 patients, portal vein pressure (PVP). Hepatic vein pressure gradient (HVPG: WHVP–IVCP) and portal vein pressure gradient (PVPG: PVP–IVCP) were calculated. Results: Nodular regenerative hyperplasia was associated in 24 patients with various diseases (oxaliplatin chemotherapy, treatment with purine antagonists, post liver transplantation, hematologic and rheumatologic conditions and HIV infection). Liver function parameters were either completely normal or slightly impaired. Patients were referred for gastroesophageal varices (n = 18), and/or ascites (n = 11), and/or splenomegaly (n = 20). In patients with varices or ascites, HVPG was lower than 10 mmHg (a cut‐off point for the presence of varices and/or ascites) in 15/21, suggesting a pre‐sinusoidal component to their PHT confirmed by a PVP higher than 12 mmHg in 12/12 patients. The mean difference between HVPG and PVPG was 8.7 mmHg in these patients. Ten patients were treated by transjugular intrahepatic portosystemic shunt. None of them re‐bled, and one presented transient hepatic encephalopathy. Conclusions: Presinusoidal PHT associated with NRH is probably related to compression of portal venules by the regenerative nodules. In patients with HTP and a HVPG < 10 mmHg, the diagnosis of NRH must be suspected and PVP measured, which is important in the management of these patients.