Histological abnormalities of the small bowel mucosa in cirrhosis and portal hypertension

AIM： To study the small bowel （SB） mucosa on biopsy in cirrhotic patients with portal hypertension and in non-cirrhotic controls and grade findings according to the Marsh criteria. METHODS： We prospectively enrolled 51 consecutive patients undergoing an upper endoscopy for their routine medical care. Twenty five patients with cirrhosis and portal hypertension were compared to 26 controls. We obtained coeliac serology and multiple upper small bowel biopsies on all 51 patients. A GI pathologist interpreted biopsies and graded findings according to the Marsh criteria. We assessed equivalence in Marsh grade between cirrhotic and non-cirrhotic controls using the Mann-Whitney test for equivalence. RESULTS： Gender, ethnicity and age were similar between both groups. Marsh grades were equivalent between the groups. Grade of 0 was present in 96% and grade of 1 was present in 4% of both groups and there was no villus atrophy or decrease in villus/crypt ratio in patients with portal hypertension. CONCLUSION： This study provides evidence for the lack of villus atrophy in patients with cirrhosis and portal hypertension, and supports the continuous reliance on the Marsh criteria when the diagnosis of coeliac disease is to be made in the presence of cirrhosis.     

Nodular regenerative hyperplasia of the liver and coeliac disease: potential role of IgA anticardiolipin antibody

Nodular regenerative hyperplasia (NRH) of the liver is a rare disorder that is often associated with connective tissue disorders, haematological malignancy, or drugs, and is a cause of non-cirrhotic portal hypertension. We describe two cases of NRH in individuals with adult coeliac disease and IgA anticardiolipin antibodies. We discuss the potential impact of this observation on the understanding of the pathogenesis of NRH.     

Portal hypertension in primary biliary cirrhosis

Evidence of portal hypertension was found in 50 out of 109 patients (47%) with primary biliary cirrhosis, and of these 32 bled from oesophageal varices. In four patients portal hypertension was the initial manifestation of the disease and this complication was recognized in a further 17 within two years of the first symptom of primary biliary cirrhosis. The development of portal hypertension was associated with a poor prognosis and death could frequently be attributed to variceal bleeding; the mean duration of survival from the time that portal hypertension was recognized was 14.9 months. Portal decompression operations may have improved the immediate prognosis in some patients but did not otherwise influence the progression of the disease. In 47 patients the histological findings in wedge biopsy or necropsy material were correlated with the presence or absence of varices. An association between nodular regeneration of the liver and varices was confirmed, but, in the absence of nodules, no other histological cause for portal venous obstruction could be found.     

Orthotopic liver transplantation for idiopathic portal hypertension: indications and outcome

BACKGROUND: Idiopathic portal hypertension is a rare clinical syndrome which may be associated with a spectrum of histological lesions, including nodular regenerative hyperplasia and incomplete septal cirrhosis. Here, we report eight adult patients with idiopathic portal hypertension who experienced an unusually severe clinical evolution characterized by the development of progressive hepatic failure requiring orthotopic liver transplantation. Our aims are: (a) to stress the distinctive clinical presentation of these patients, (b) to describe their biological and histopathological features, and (c) to evaluate the results of orthotopic liver transplantation in this rare indication. METHODS: Complete clinical charts and histological data were available in all patients. All patients were male. Their age at diagnosis ranged from 17 to 59 years. Complications of portal hypertension revealed the disease in all cases. Medical treatment was performed in all patients and portosystemic shunt in three. RESULTS: The development of progressive hepatic failure led to the indication of liver transplantation after a delay ranging from 3 to 10 years. Explanted livers showed pure nodular regenerative hyperplasia in three patients and incomplete septal cirrhosis in five. Recovery was uneventful. All patients are alive, without recurrence of the disease. CONCLUSIONS: This report points to the existence of severe cases of idiopathic portal hypertension occurring without underlying or associated systemic disease and characterized by a poor clinical course and requiring liver transplantation.     

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。     

The histopathology of coeliac disease: time for a standardized report scheme for pathologists.

In this paper, we review the histological features of coeliac disease and propose a standardized report scheme based on the Marsh classification. Furthermore, terms used by pathologists are defined. The most important histological differential diagnoses are given, as well as a definition of the different clinical forms of coeliac disease such as symptomatic, silent, latent, potential, treated and refractory coeliac disease.     

Changes in blood flow, portal pressure and shunting during the development of cirrhosis in response to beta-blockade.

An experimental model of cirrhosis was developed in the rat to assess the effect of disease and pharmacological manipulation on blood flow, shunting and portal pressure. With progression in the severity of histological cirrhosis there was a steady fall in effective liver blood flow as measured with radioisotope labelled colloid. This corresponded to a rise in portal pressure and shunting with a close correlation between the two (r = 0.7, p less than 0.01). In control animals and when portal hypertension was caused by extrahepatic obstruction, beta-blockade with propranolol, but not selective beta 2 blockade, significantly decreased liver blood flow. With cirrhosis there was a variable response to propranolol depending on the histological severity of disease, the height of portal pressure and degree of shunting. There is a possibility therefore that a potential may exist for lowering portal pressure by manipulating intrahepatic shunting.     

Role of liver atrophy, hepatic resection and hepatocyte hyperplasia in the development of portal hypertension in biliary disease.

Portal fibrosis is considered to be pivotal in the pathogenesis of portal hypertension associated with extrahepatic biliary obstruction. The histological features, however, include diffuse hepatocyte hyperplasia as well as portal fibrosis, but not cirrhosis, and it is possible that the contribution of hepatocyte hyperplasia in the initiation of portal hypertension is equally important. If so, we hypothesised that patients with biliary obstruction and a coincident condition such as liver atrophy, or hepatic resection, with the potential of accelerating the hepatocyte proliferation caused by biliary obstruction itself, might be expected to develop portal hypertension earlier than patients with biliary obstruction alone. To examine this concept we studied 10 patients with postcholecystectomy bile duct stricture, portal hypertension and liver atrophy, or hepatic resection (group I) and compared them with nine patients with postcholecystectomy stricture and portal hypertension, but no atrophy or resection (group II). Portal hypertension was diagnosed a mean 28 months (range 18-48 months) after cholecystectomy in group I compared with 62 months (range 36-100 months) for patients in group II (p less than 0.005 Mann-Whitney test). Thus hepatocyte hyperplasia may be an important part of the mechanism underlying the development of portal hypertension in chronic biliary disease.     

Portal hypertension in primary biliary cirrhosis: Relationship with histological features

The prevalence and type of portal hypertension (PH) in primary biliary cirrhosis (PBC) and their relationship with liver lesions have been investigated in 32 patients with the disease. Portal hypertension was considered when oesophageal or gastric varices were observed by endoscopy and/or when hepatic venous pressure gradient measured by hepatic vein catheterization was greater than 6 mmHg. Within 3 days of endoscopy, a liver biopsy was performed for histological staging and semiquantitative grading (0 to 3+) of portal and sinusoidal fibrosis, portal inflammation, piecemeal necrosis, lobular necrosis, cholestasis, as well as the presence of granulomas and Mallory's hyaline. Twenty patients (62.5%) had portal hypertension, five of them showing presinusoidal PH (15.5%) and the remaining 15 (47%) with sinusoidal component. The four patients in stage IV had sinusoidal PH and the only patient in stage I had no PH. The prevalence of portal hypertension was similar in patients in stage II (57%) and stage III (55%), but presinusoidal PH was only observed in patients in stage II. Patients with PH showed significantly higher portal inflammation and piecemeal necrosis than patients without PH. By contrast, there were no differences in portal and sinusoidal fibrosis, nor in the other histologic features. These results indicate that portal hypertension is common in PBC and it may be present in the early stages of the disease. The fact that presinusoidal PH was only observed in patients in stage II suggests that portal hypertension is initially of presinusoidal type, and then as the disease progresses is joined by a sinusoidal component.     

Endomysial antibody production is not related to histological damage after in vitro gluten challenge

OBJECTIVE: To determine whether in vitro induction of endomysial antibodies is an in vitro marker of coeliac toxicity. DESIGN: To determine whether in vitro endomysial antibodies induced by gliadin incubation correlate with histological damage induced by in vitro gliadin challenge. METHODS: Small-bowel organ cultures from seven patients with treated coeliac disease were incubated in an organ culture system with gliadin; histological damage was morphometrically evaluated and endomysial antibodies were measured in the organ culture supernatant by indirect immunofluorescence. RESULTS: Although incubation with gliadin caused histological damage, there was no detectable production of endomysial antibody. CONCLUSIONS: In vitro, endomysial antibody induction cannot be used as a marker of coeliac toxicity. Endomysial antibodies are not necessary for generating the histological lesion of coeliac disease.     

系统性硬化症合并非肝硬化性门静脉高压症一例并文献复习

目的 提高风湿科医生对非肝硬化性门静脉高压症的认识.方法 报告1例系统性硬化症合并非肝硬化性门静脉高压症的认识并复习相关文献.结果 患者为51岁女性,病程较长,以门静脉高压为最突出的临床表现,有脾大,全血细胞减少,门静脉重度曲张.肝脏的生化、病毒学以及形态学指标均正常.腹部增强CT未见门静脉血栓形成.最后,诊断为系统性硬化症合并非肝硬化性门静脉高压症.给予小剂量激素及免疫抑制剂治疗,病情稳定.结论 非肝硬化性门静脉高压症是一种少见病,临床上最突出的表现是门静脉高压,该病与风湿性疾病尤其是系统性硬化症合并鲜有报道,风湿科医生应予以重视.     

Diagnostic methods beyond conventional histology in coeliac disease diagnosis

BackgroundCoeliac disease diagnostic criteria currently require the detection of small bowel mucosal villous atrophy and crypt hyperplasia.AimsTo compare conventional histological examination to the determination of small bowel mucosal intraepithelial lymphocytes (IELs) and to serum and intestinal coeliac autoantibodies in untreated coeliac disease with villous atrophy and in mild enteropathy coeliac disease.Patients and methodsStudy comprised consecutive adult patients with coeliac disease suspicion; villous height–crypt depth ratio (Vh/CrD), the densities of CD3+, γδ+ and villous tip IELs and serum and intestinal transglutaminase 2 (TG2)-targeted autoantibodies were studied. Coeliac disease was diagnosed in 223 and excluded in 608 patients. Further, 66 patients were considered to suffer from mild enteropathy coeliac disease. Control group consisted of 138 patients.ResultsVh/CrD determination detected 77% of untreated coeliac disease patients. Serum coeliac autoantibodies had 84% sensitivity for untreated coeliac disease with villous atrophy and 70% sensitivity for mild enteropathy coeliac disease; the specificity was 100%. Intestinal TG2-targeted autoantibodies had sensitivities of 100% and 93%, and 100% specificity, respectively. γδ+ and villous tip IELs proved more reliable than CD3+ IELs.ConclusionsConventional histological examination as the golden standard in coeliac disease diagnosis is questionable. Serum and especially intestinal TG2-targeted autoantibodies seem promising in future coeliac disease diagnostics.     

Fasting plasma nitric oxide products in coeliac disease

OBJECTIVES: In coeliac disease, inducible nitric oxide synthase activity in the duodenal mucosa is greatly increased, resulting in increased production of nitric oxide. We investigated whether this resulted in increased plasma concentrations of its stable end products (nitrate/nitrite: NOx). METHODS: Fasting plasma NOx was determined in 66 patients attending for upper gastrointestinal endoscopy. Of these, 21 had coeliac disease (nine were on a gluten-free diet). The remainder had a variety of other gastrointestinal disorders. NOx was determined using the Griess reaction. Distal duodenal biopsies for coeliac patients were graded according to the Marsh score. RESULTS: Patients with untreated coeliac disease had a higher fasting NOx concentration (mean 117.5 microM) than either those with coeliac disease taking a gluten-free diet (mean 71.2 microM) or those with other diseases (mean 33.5 microM; one-way analysis of variance, P < 0.001). Coeliac patients with higher fasting NOx concentrations had more marked histological changes (P < 0.05). CONCLUSION: Fasting plasma NOx is significantly elevated in untreated coeliac disease and correlates with histological grade. The potential clinical utility of serial NOx measurements to monitor improvement on a gluten-free diet requires further study.     

Portal hypertension in chronic hepatitis: relationship to morphological changes.

Various anatomical factors were examined which might provide passive resistance to portal venous flow and so cause portal hypertension. Methods included the measurement of portal pressure (WHVPG) in cirrhotic and non-cirrhotic patients, morphological assessment by semiquantitative grading of severity of disease, calculation of hepatocyte size indices, and assessment of volume density of hepatocytes, sinusoids, Disse's space and Disse's space collagen by electron microscopy. The wedged hepatic venous pressure gradient increased with progression of disease and portal hypertension was present before histologically detectable cirrhosis had developed. With increasing progression of disease towards cirrhosis, the relationship between individual and aggregated features and the WHVPG diminished and lost statistical significance. Hepatocyte size increased with progression of histological changes and correlated significantly with increase of WHVPG, both in non-alcoholic and alcoholic patients. Disse's space collagen was increased significantly in non-alcoholic chronic active hepatitis compared with patients with near-normal liver. No significant decrease of sinusoidal space was found. Multiple factors rather than any single feature influence the development of portal hypertension.     

Occurrence of large granular lymphocytes and natural killer cells in the epithelium of the gut distinguishes two different coeliac diseases.

In a longterm study, we have divided coeliac disease into two distinct entities (abortive and permanent) based on the occurrence of large granular lymphocytes and natural killer cells within the epithelium of the gut. The natural killer and large granular lymphocytes cells were characterised by either immunohistochemical or phase contrast microscopical procedures on the initial biopsies from 15 children with coeliac disease. They were compared with seven individuals with partial villus atrophy and eight with normal villous morphology. Although the histological findings were similar in the initial biopsies of all patients with coeliac disease, the patients with permanent coeliac disease had a significantly lower number (0.41(0.61)cells/mm2) of large granular lymphocytes and natural killer cells compared with those patients with abortive coeliac disease (11.93 (6.23) cells/mm2). Those in the permanent group developed a significantly more pronounced flat mucosa after gluten challenge or provocation compared with the abortive group and had to remain on a strict gluten free diet in contrast with those in the abortive group. Thus, the occurrence of intraepithelial large granular lymphocytes and natural killer cells characterises two distinctly different coeliac diseases. Based on our results neither the histological evaluation of the biopsy nor the utilisation of the revised European Society for Paediatric Gastroenterology and Nutrition (ESPGAN) Criteria are adequate in diagnosing the two types of coeliac disease.     

Orthotopic Liver Transplantation for Idiopathic Portal Hypertension: Indications and Outcome

Background: Idiopathic portal hypertension is a rare clinical syndrome which may be associated with a spectrum of histological lesions, including nodular regenerative hyperplasia and incomplete septal cirrhosis. Here, we report eight adult patients with idiopathic portal hypertension who experienced an unusually severe clinical evolution characterized by the development of progressive hepatic failure requiring orthotopic liver transplantation. Our aims are: (a) to stress the distinctive clinical presentation of these patients, (b) to describe their biological and histopathological features, and (c) to evaluate the results of orthotopic liver transplantation in this rare indication. Methods: Complete clinical charts and histological data were available in all patients. All patients were male. Their age at diagnosis ranged from 17 to 59 years. Complications of portal hypertension revealed the disease in all cases. Medical treatment was performed in all patients and portosystemic shunt in three. Results: The development of progressive hepatic failure led to the indication of liver transplantation after a delay ranging from 3 to 10 years. Explanted livers showed pure nodular regenerative hyperplasia in three patients and incomplete septal cirrhosis in five. Recovery was uneventful. All patients are alive, without recurrence of the disease. Conclusions: This report points to the existence of severe cases of idiopathic portal hypertension occurring without underlying or associated systemic disease and characterized by a poor clinical course and requiring liver transplantation.     

Follow up in a case of congenital hepatic fibrosis (author's transl)

A case of congenital hepatic fibrosis (CHF) is described. CHF is characterized by hepatomegaly, portal hypertension, extensive portal fibrosis, ectatic bile ducts, and hypoplasia of terminal portal vein branches. In contrast to the severe portal hypertension liver function tests are largely normal. In our case the disease was first detected when the patient was 7 years old. During the following 9 1/2 years three sequential liver biopsies were performed. Each of them showed the same picture and no progression occurred. The characteristic histological picture of CHF includes mature bile ducts without epithelial proliferation, absence of significant intraportal or interlobular inflammatory infiltrates, and small or hypoplastic distal portal vein branches. On the basis of these features the disease can easily be separated from other forms of liver cirrhosis.     

The occurrence of terminal ileal histological abnormalities in patients with coeliac disease

INTRODUCTION: Coeliac disease causes histological changes throughout the small bowel, but is often a proximal lesion. We wanted to assess whether terminal ileal histological abnormalities occurred more commonly in patients with coeliac disease and if specific assessment of intraepithelial lymphocytes increases the recognition of undiagnosed coeliac disease. METHODS: Terminal ileal biopsies were prospectively examined over a 3-year period (April 2001-May 2004). Patients were included if they were found to have a synchronous duodenal biopsy that gave a new diagnosis of coeliac disease (n=20). Terminal ileal biopsies taken at colonoscopy during the same period were also examined from four groups of patients: coeliac disease established on a gluten-free diet but with persisting symptoms (n=25), inflammatory bowel disease (n=47), chronic diarrhoea (n=44) and polyp surveillance (n=47). All biopsies were graded according to the Marsh criteria and an intraepithelial lymphocytes count per 100 enterocytes was obtained. RESULTS: There was only one patient from all five groups who had villous atrophy of the terminal ileal. This patient had a new diagnosis of coeliac disease. The mean intraepithelial lymphocytes count in the coeliac disease group was 23.7 intraepithelial lymphocytes/100 enterocytes. This was significantly higher than the control groups: coeliac disease on a gluten-free diet=17.5 (p<0.012), inflammatory bowel disease=12.3 (p<0.0001), diarrhoea=12.6 (p<0.0001) and polyp=13.7 (p<0.0002). Validating terminal ileal villous intraepithelial lymphocytes counts as a test for coeliac disease using an intraepithelial lymphocytes/100 enterocytes of >25 gives a sensitivity of 45% and a specificity of 97.8%. CONCLUSION: Routinely quantifying terminal ileal intraepithelial lymphocytes may be of limited clinical value. However, subjective recognition of raised intraepithelial lymphocytes on a terminal ileal biopsy should alert the clinician to the possibility of coeliac disease.     

前列腺素E1间接门脉造影与彩色多普勒在离断术复发出血中的应用

确定贲门周围血管离断术（离断术）后复发消化道大出血的原因是选择正确治疗方法的依据，前列腺素Ｅ１间接门脉数字减影血管造影（ＤＳＡ）、腹腔动脉ＤＳＡ与彩色多普勒勒血流显像（ＣＤＦＩ）结合应用，可详细了解门脉系统有无栓塞、有无海绵样变、胃左静脉（ＬＧＶ）、胃左动脉（ＬＧＡ）是否已离断及门脉系统的血注方向。当上述检查方法均未发现明显致消化道出血原因时，结合内镜检查，门脉高压性胃粘膜病变可能是其出血原因。     

Non-cirrhotic portal fibrosis (idiopathic portal hypertension): experience with 151 patients and a review of the literature

BACKGROUND: Non-cirrhotic portal fibrosis (NCPF), the equivalent of idiopathic portal hypertension in Japan and hepatoportal sclerosis in the United States of America, is a common cause of portal hypertension in India. The clinical features, portographic and histological findings, and management of 151 patients with non-cirrhotic portal fibrosis are presented. METHODS: The disease is diagnosed by the presence of unequivocal evidence of portal hypertension in the definite absence of liver cirrhosis and extrahepatic portal vein obstruction (EHPVO). Retrospective analysis of records of 151 patients with NCPF was analyzed for the clinical presentation, physical findings, laboratory tests, radiological and histological findings, and for the outcome of treatment. RESULTS: The disease is characterized by massive splenomegaly with anemia, preserved liver function and benign prognosis in a majority of patients. Splenoportovenography (SPV) showed massive dilatation of the portal and splenic veins, and the presence of collaterals. Twenty-four (15.9%) patients showed evidence of natural/spontaneous shunts (splenorenal 15, umbilical nine) on SPV; these patients had a lower incidence of variceal bleeding. Liver histology demonstrated maintained lobular architecture, portal fibrosis of variable degree, sclerosis and obliteration of small-sized portal vein radicles, and subcapsular scarring with the collapse of the underlying parenchyma. Piecemeal or hepatocytic necrosis was absent in all histology specimens. Three patients showed nodular transformation along with abnormal liver functions, and may represent late manifestation of NCPF where features are similar to those seen in patients with incomplete septal cirrhosis. In the initial part of the study, surgery (side-to-side lieno-renal shunt) was the preferred modality of treatment, however, endoscopic sclerotherapy or variceal ligation has now become the preferred first line of management of variceal bleeding. CONCLUSIONS: The epidemiological and clinical features of NCPF have more similarity to IPH than has previously been documented. The development of spontaneous shunts tends to protect these patients from variceal bleeding.