Nodular regenerative hyperplasia and primary biliary cirrhosis]

We report two cases of nodular regenerative hyperplasia of the liver associated with primary biliary cirrhosis. Cholestasis and presence of antimitochondrial antibodies were noted in both patients. In one patient, the diagnosis of nodular regenerative hyperplasia was supported by the demonstration of disseminated small hepatic nodules without perinodular fibrosis. Twelve years later, the histopathological picture was one of primary biliary cirrhosis. The other patient presented an histological picture of regenerative hyperplasia of the liver and primary biliary cirrhosis. The association of regenerative hyperplasia of the liver and primary biliary cirrhosis is discussed.     

Nodular regenerative hyperplasia of the liver and primary biliary cirrhosis. A fortuitous association?

We report here in a case of primary biliary cirrhosis associated with nodular regenerative hyperplasia of the liver in a white woman revealed by digestive hemorrhage due to ruptured esophageal varices. The diagnosis of primary biliary cirrhosis was based on the following: elevated serum IgM, high titer of antimitochondrial antibody (anti M2), typical histopathological picture of stage I/II disease. The diagnosis of nodular regenerative hyperplasia was supported by the demonstration of disseminated small hepatic nodules without perinodular fibrosis. This association may be a supplementary argument in favor of a possible autoimmune origin of nodular regenerative hyperplasia of the liver.     

Nodular regenerative hyperplasia of the liver,CREST syndrome and primary biliary cirrhosis: an overlap syndrome?

Nodular regenerative hyperplasia of the liver (NRHL) has been found in association with collagen vascular diseases, after drug therapy, with autoimmune disease, and with a variety of haematological disorders. The association of NRHL with the syndrome of Calcinosis cutis, Raynaud's phenomenon, oesophageal dysfunction, sclerodactyly and telangiectasia (CREST syndrome) has only been reported on two previous occasions. The liver disease usually associated with CREST syndrome is primary biliary cirrhosis (PBC) and recently nodular hyperplasia of the liver has been reported in patients with early stage PBC. We present a case of NRHL with CREST syndrome and serological and biochemical features of PBC, a newly recognised overlap syndrome.     

Increased uptake of bromodeoxyuridine by hepatocytes from early stage of primary biliary cirrhosis

The relationship between DNA synthesis activities of hepatocytes in biopsied specimens and liver volume was studied in various stages of primary biliary cirrhosis using an in vitro bromodeoxyuridine (a thymidine analogue)-anti-bromodeoxyuridine reaction and computed tomography. The mean bromodeoxyuridine (+/- SE) labeling index for 10 patients in an early histological stage (stage I, 4, and stage II, 6, 3.4% +/- 0.4%) of primary biliary cirrhosis was 17 times that for 6 control subjects (0.2% +/- 0.1%, P less than 0.001), and was significantly higher than that for 19 female patients with chronic aggressive hepatitis (0.9% +/- 0.2%, P less than 0.001), 14 compensated cirrhotic patients of viral origin (all female, 1.1% +/- 0.3%, P less than 0.01), and 5 patients with stage III primary biliary cirrhosis (0.5% +/- 0.1%, P less than 0.001). The mean (+/- SE) liver volume in the early stage of primary biliary cirrhosis (1225 +/- 40 cm3) was about 1.5 times that in control subjects (835 +/- 42 cm3, P less than 0.001). These results suggest that liver volume has already become large in the early stage of primary biliary cirrhosis perhaps because of markedly increased DNA synthesis in hepatocytes.     

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.     

Differential expression of MHC class II subregion products on bile duct epithelial cells and hepatocytes in patients with primary biliary cirrhosis

To study the expression of MHC Class II subregion gene products on biliary epithelial cells in primary biliary cirrhosis, frozen sections from liver biopsies of 15 patients with primary biliary cirrhosis were studied immunohistochemically using HLA-D subregion specific monoclonal antibodies L243 (HLA-DR), Leu10 (HLA-DQ) and B7/21 (HLA-DP). Patients with early stages of primary biliary cirrhosis showed expression of HLA-DP, HLA-DR and HLA-DQ subregion gene products on bile duct epithelial cells. In advanced stages of disease, no MHC Class II antigens or only HLA-DR and HLA-DP were expressed on bile duct cells. While normal hepatocytes did not express detectable amounts of MHC Class II antigens, hepatocytes from liver biopsies of four patients with primary biliary cirrhosis showed a distinct staining exclusively with monoclonal antibodies specific for HLA-DR. The expression of MHC Class II antigens on parenchymal cells was independent of a lymphocytic infiltration into the tissue. This study demonstrates that bile ductular cells, but not hepatocytes, express a full set of MHC Class II molecules at least during the early stages of primary biliary cirrhosis. We propose, therefore, that the expression of both HLA-DR and HLA-DQ subregion products on bile duct epithelial cells may be a necessary, although not sufficient, condition for the initiation of an autoimmune process leading to the destruction of intrahepatic bile ducts in primary biliary cirrhosis.     

Cholestatic features in focal nodular hyperplasia of the liver

Twenty specimens of focal nodular hyperplasia were studied with special attention to the histological features of chronic cholestasis (grouped under the headings of cholestasis, cholate-stasis and signs of ductular reabsorption). In all specimens, evidence was found for one or more features of cholestasis and cholate-stasis. Signs of ductular reabsorption were less constant, and apparently varied according to the developmental stage of the lesion. The cholestatic features emphasize the bile secretory capacity of the lesional parenchyma, and are apparently due to the lack of real bile ducts in the portal tract equivalents of the lesional tissue. Evidence is presented that the "ductular component" in FNH is not due to proliferation of pre-existing ductules, but rather derives from ductular metaplasia of liver cell plates in zone 1 equivalents. This metaplastic development of a ductular network may serve the function of reabsorbing the biliary constituents produced by the lesional parenchyma, leading to periductular inflammation and progressive fibrosis, thus producing an equivalent of biliary fibrosis and biliary cirrhosis.     

Bone mass in women with primary biliary cirrhosis: the relation with histological stage and use of glucocorticoids

To assess the impact of primary biliary cirrhosis on bone mass in general and the relative importance of the stage of the liver disease and of treatment with glucocorticoids for the possible development of osteoporosis, bone mineral mass was measured by single and dual photon absorptiometry in 55 unselected female patients with longstanding primary biliary cirrhosis. Although most of the patients had a bone mineral density within the normal range, the bone mineral densities of the lumbar spine and distal and proximal forearm were 8% (P less than 0.004), 8% (P less than 0.03), and 5% (NS) respectively, lower than in age-matched healthy women. Multiple regression analysis showed that the histological stage of the liver disease (early stage vs. late stage) was an independent determinant of axial bone mineral density, whereas the use of glucocorticoids resulted in only a moderate and not significant bone loss. Serum calcium proved to be significantly lower in the patients with late-stage primary biliary cirrhosis than in those with early-stage disease, whereas no significant differences were found in these groups with regard to several biochemical parameters of bone metabolism. In conclusion, in patients with primary biliary cirrhosis, bone loss was only moderate and related to the histological stage. The effect of low-dose glucocorticoids on bone mass seemed not significant.     

Antibodies to a human liver membrane lipoprotein (LSP) in primary biliary cirrhosis.

Antibodies reacting with a human liver-specific membrane lipoprotein (LSP) have been detected using a sensitive and specific radioimmunoassay in 19 (51%) of 37 patients with primary biliary cirrhosis. The anti-LSP antibodies were found only in the later stages of the disease as judged by histological criteria, being present in 73% of those in stage IV, 44% of those in stage III, and none of those in stage I or II. Although there was no relationship between percentage binding and standard liver function tests, there was a close correlation between percentage binding of 125I-LSP by serum and the extent of piecemeal necrosis of periportal hepatocytes on liver biopsy. The timing of the anti-LSP response makes it very unlikely that it is involved in the pathogenesis of the early bile duct damage but the results of this and other studies suggest that antibodies to this hepatocyte membrane lipoprotein may be an important cause of periportal liver cell necrosis in both primary biliary cirrhosis and chronic active hepatitis and could be one of the factors determining progression to cirrhosis in both these conditions.     

Hepatic manifestations of autoimmune rheumatic diseases

Hepatic manifestations in autoimmune disease include chronic active hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, and nodular regenerative hyperplasia. These diseases are rare and may occur concomitantly or serially. Clinicians must be aware of the possibility of liver disease so that it can be treated as soon as possible.     

Clinical significance of the serum levels of the 7S domain of type IV collagen in patients with primary biliary cirrhosis

The serum levels of the 7S domain of type IV collagen were measured with a radio-immunoassay in 42 patients with primary biliary cirrhosis (asymptomatic: n = 28; symptomatic: n = 14), 10 patients with chronic active hepatitis, 10 patients with liver cirrhosis and 10 healthy female controls. Serum levels of the 7S domain of type IV collagen were: 4.28 ng/mL (3.88-4.72 ng/mL; mean and range of mean +/- s.d.) in healthy controls; 5.97 ng/mL (5.07-7.02 ng/mL) in patients with chronic active hepatitis; 8.23 ng/mL (6.40-10.58 ng/mL) in patients with liver cirrhosis; and 6.79 ng/mL (4.76-9.67 ng/mL) in patients with primary biliary cirrhosis. Patients with liver cirrhosis and primary biliary cirrhosis had higher levels of serum 7S domain of type IV collagen than healthy controls (P < 0.001, respectively). Serum levels of the 7S domain of type IV collagen in patients with asymptomatic primary biliary cirrhosis, 5.83 ng/mL (4.55-7.48 ng/mL) were significantly lower than those in symptomatic primary biliary cirrhosis, 9.18 ng/mL (6.53-12.91 ng/mL; P < 0.001). Serum levels of the 7S domain of type IV collagen increased significantly along with advancement of the histological stages of primary biliary cirrhosis. Serum levels of the 7S domain of type IV collagen in the paired sera of eight patients with asymptomatic primary biliary cirrhosis (mean interval 30 months, range 12-48 months) showed significant rises during the intervals (P < 0.05), while serum levels of albumin and total bilirubin did not change significantly during these intervals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evidence of increased intestinal synthesis and extracellular deposition of IgM in primary biliary cirrhosis. An immunofluorescence study of liver and small-intestinal biopsy specimens

Direct immunofluorescence showed intense extracellular granular deposition of IgM and C3 in liver and small-intestinal biopsy specimens from patients with primary biliary cirrhosis. In contrast, IgM deposits were not observed in liver tissue from patients with other liver diseases, whereas small-intestinal IgM deposits were seen also in 2 of 17 patients with various intestinal disorders. The tissue deposition of IgM did not vary with plasma IgM levels, degree of cholestasis, or histological stage of the disease but seemed to reflect an abnormal property of the IgM molecule. The number of IgM-positive mononuclear cells in intestinal mucosa from patients with primary biliary cirrhosis was markedly increased, suggesting increased local synthesis of IgM. Deposition of IgM with complement-activating ability might contribute to the development of tissue damage in primary biliary cirrhosis. In addition, the apparent specificity of these IgM deposits in liver for primary biliary cirrhosis might be of diagnostic value when histological classification is difficult.     

不同组织学分期原发性胆汁性肝硬化患者临床特征分析

目的比较不同组织学分期原发性胆汁性肝硬化（PBC）患者的临床特征。方法回顾性分析39例组织学分期为早期和55例为进展期的PBC患者的人口学、实验室检查、影像学检查和预后指标（Mayo 风险评分、MELD评分、Child-Pugh评分）,比较两组患者之间的差异。结果早期与进展期患者年龄构成比无显著性差异,但均以40～59岁居多;两组患者平均年龄、ALB、CHE、TBIL、PT、PLT、TC、IgG、MRS、MELD评分、Child-Pugh评分均具有显著性差异;腹水、食道或胃底静脉曲张发生率亦具有显著性差异（P〈0.05）;在早期患者仍可出现门脉高压的表现,出现腹水及食道静脉曲张的比例为7.7%;早期与进展期PBC患者乏力和瘙痒的发生率在两者之间无显著性差异（P〉0.05）;病理分期与MRS、MELD及Child-Pugh评分均具有相关性。结论早期PBC患者的预后优于进展期患者,但在PBC早期仍可出现门脉高压的表现,临床医生应予以重视。     

Advances in hepatobiliary pathology: update for 2010

Recent publications on hepatology and hepatic pathology provide a wealth of new information on wideranging topics. Morphologic aspects of liver disease associated with hepatitis B and C viruses, autoimmune hepatitis, and HIV infection were addressed, as was the prevalent problem of nonalcoholic fatty liver disease. Advances in diagnosis and pathogenesis of primary biliary cirrhosis, primary sclerosing cholangitis, and the increasingly complex spectrum of IgG4 hepatobiliary diseases were also reported. The histologic and immunohistochemical features of the rare "calcifying nested stromal-epithelial tumor" of the liver were described in a 9-case series. For benign and malignant liver tumors, immunohistochemistry plays a major diagnostic role, and several recent studies demonstrate the value of immunostains in distinguishing between liver-cell adenoma and focal nodular hyperplasia.     

Recurrence of primary biliary cirrhosis after orthotopic liver transplantation

BACKGROUND/AIMS: The incidence of graft failure due to recurrence of primary biliary cirrhosis after liver transplantation and the clinical value of histological and serological parameters indicating a recurrence are still discussed controversially in the literature. METHODOLOGY: In a retrospective study 18 patients who had received orthotopic liver grafts for primary biliary cirrhosis were investigated for recurrence of disease. Histological findings, the appearance of primary biliary cirrhosis associated autoimmune diseases, the course of antimitochondrial antibodies, serological parameters of liver function and HLA status were evaluated. RESULTS: During a median follow-up period of 114 months, 6 of 18 patients developed a recurrence of primary biliary cirrhosis as indicated by liver biopsies, one patient developed clinical graft failure together with histological recurrence. Twelve patients developed autoimmune diseases. Antimitochondrial antibodies were present in all patients within a period of 12 months after transplantation. Serological parameters were elevated in 16 of 18 patients. Histological findings, serological parameters and associated diseases did not correlate with each other and with clinical symptoms of primary biliary cirrhosis recurrence. CONCLUSIONS: Graft failure due to recurrent disease can occur, but, despite a follow-up period of nearly 10 years, it is not possible to define predictive factors on the basis of histology or serology.     

Detection of mitochondria in bile canaliculi in early stage primary biliary cirrhosis cases

Biopsy specimens of liver obtained from patients with early stages of primary biliary cirrhosis were examined by electron microscopy with special attention being paid to changes in bile canaliculi, as well as bile ducts and hepatocytes. Ultrastructural alterations of hepatocytes were minimal and non-specific. In bile canaliculi mitochondria were noted to be normal or slightly lack uniformity. These findings varied according to each case. This alteration was strongly considered to be specific in early stage primary biliary cirrhosis cases.     

Long-term prospective study of the effect of ursodeoxycholic acid on cystic fibrosis-related liver disease

GOALS: To evaluate the efficacy of UDCA in arresting the progression of the early multifocal hepatic lesion to overt CF-related NBC. BACKGROUND: Focal biliary cirrhosis is an early hepatic pathologic change related to the ion transport defect in cystic fibrosis. The factors involved in the progression of focal to nodular biliary cirrhosis are not clear. Ursodeoxycholic--a hydrophilic, nontoxic, choleretic, and hepatoprotective exogenous bile acid--has been reported to be effective in the management of cholestatic liver disease. STUDY: For 10 years at 6-month intervals, 70 individuals with cystic fibrosis (38 men and 32 women; age range, 2--29 years) were examined using hepatosplenomegaly, liver function tests, and ultrasound liver scan. Patients demonstrating evidence of liver involvement at the onset or during the study received ursodeoxycholic acid 20 mg/kg body weight. RESULTS: After the administration of ursodeoxycholic acid, the progression of nodular biliary cirrhosis ultrasound changes was arrested, hepatic function was preserved, and no variceal bleeding was observed. No case of focal biliary cirrhosis progressed to nodular biliary cirrhosis. Furthermore, the multifocal, multilobular changes suggestive of focal biliary cirrhosis on ultrasound scan were reversed to normal. CONCLUSION: Ursodeoxycholic acid is effective in improving cholestasis and hepatic dysfunction in nodular biliary cirrhosis and, also, in reversing the early sonography findings suggestive of focal biliary cirrhosis. It is speculated that ursodeoxycholic acid may prove to affect the natural history of cystic fibrosis-related liver disease.     

Long-term response of primary biliary cirrhosis (stage I) to therapy with ursodeoxycholic acid

We report about a 56-year-old asymptomatic female patient, who was examined in April 1991 for an increase of biochemical parameters of the liver. Based on the biochemical and serological results (abnormal cholestatic liver function tests, positive antimitochondrial antibodies) as well as liver biopsy primary biliary cirrhosis stage I was diagnosed. Therapy with ursodeoxycholic acid (12mg/kg body-weight/die) was started. Follow-up examinations indicated that cholestatic parameters had normalized and antimitochondrial antibodies became negative. In a further biopsy of the liver nearly regular liver parenchyma was demonstrated. Thus, therapy with ursodeoxycholic acid was stopped. However, in November 1992 cholestatic parameters increased again and, antimitochondrial antibodies recurred (subtype anti-M9: positive) without any clinical symptoms. Ursodeoxycholic acid therapy was reintroduced again. Within 3 months cholestatic parameters returned to normal and antimitochondrial antibodies were eliminated again. Since then ursodeoxycholic acid has been given continuously and a long-term remission as defined by clinical, serological and histological criteria could be maintained until today. This case report indicates a serological remission and a marked histological improvement in a female patient with an early stage of primary biliary cirrhosis (stage I) during therapy under ursodeoxycholic acid. It has to be discussed whether certain early stages of primary biliary cirrhosis with benign antimitochondrial antibody-profile (anti-M9: positive) respond well to long-term treatment with ursodeoxycholic acid.     

Small bowel motility in primary biliary cirrhosis

Objective: Previous studies have shown small bowel motor activity abnormalities in patients with liver cirrhosis of different etiologies, but motility has not been studied in patients with primary biliary cirrhosis. Our aim was to investigate proximal small bowel motility in these patients.
Methods: Twenty-five female patients presenting clinical, biochemical, serological, and histological findings compatible with primary biliary cirrhosis, 10 female patients with nonalcoholic liver cirrhosis, and 10 normal female controls were studied. Motility of the upper small bowel was measured in the fasted state by means of perfused manometric catheters, connected to external transducers and positioned in the small bowel under fluoroscopy.
Results: The average amplitude of contractions was significantly decreased in patients with primary biliary cirrhosis compared with other liver cirrhosis (20.2 ± 1.0 vs 32 ± 2.9 mm Hg). Also, a significantly increased frequency of cluster of contractions and an increased duration of phase II of the migrating motor complex as seen in liver cirrhosis was observed when compared with normals.
Conclusions: We conclude that primary biliary cirrhosis patients present motor abnormalities of the small intestine similar to those of patients with liver cirrhosis of other etiologies. In addition, a decrease in the amplitude of small bowel contractions was also found in these patients, suggesting a myogenic involvement.     

自身免疫性肝病活检组织病理学特征分析109例

目的:分析比较自身免疫性肝炎(AIH)、原发性胆汁性肝硬化(PBC)、原发性硬化性胆管炎(PSC)及其重叠综合征的组织病理学变化,提高对自身免疫性肝病(AILD)的认识.方法:对27例AIH、67例PBC、4例PSC、1例AIH-PSC重叠综合征和10例AIH-PBC重叠综合征患者的肝穿组织病理资料进行回顾性分析.结果:AILD患者多发于中年女性(73.3%),肝组织病理变化以界面性肝炎为主(77.7%),在重度患者则出现重度界面性肝炎、桥样坏死等.PBC患者早期(Ⅰ、Ⅱ)占28.3%,而晚期(Ⅲ、Ⅳ)占71.7%,肝组织病理变化以小胆管减少甚至消失为主(62.6%).AIH-PBC重叠综合征患者并非罕见,他的肝组织病理学具有AIH和PBC的双重特征.结论:AILD是非病毒性肝病的重要组成部分,其诊断需综合临床表现、生化、免疫指标和组织学变化.