Pathological aspects of diffuse nodular hyperplasia of the liver

The microscopical features in specimens of liver tissue from 14 patients considered to be suffering from Diffuse Nodular Hyperplasia (DNH) were compared with the changes found in livers from five other groups of patients. The diagnoses in these groups were macronodular cirrhosis, hepatic venous occlusion, congestive cardiac failure, compensatory hyperplasia after destruction of part of the liver and chronic biliary disease respectively. In all these groups the formation of thick hepatocyte plates, thought to represent cell proliferation, was a constant and striking feature. Such plate thickening in the periportal regions was associated with congestive cardiac failure and with hepatic venous occlusion. The diffuse involvement of almost all plates formed part of the changes in DNH, cirrhosis, compensatory hyperplasia and chronic biliary disease. Normal vascular relations were retained in the patients with compensatory hyperplasia and chronic biliary disease and lost in cirrhosis and, in some parts, in DNH. The nodules were small in DNH and larger in cirrhosis, where they were surrounded by fibrous tissue. DNH appeared to be recognizable in needle biopsy specimens.     

Liver changes associated with cholecystitis.

AIMS--To investigate the histopathological changes in the livers of patients undergoing cholecystectomy and to relate these changes to the underlying biliary tract pathology. METHODS--Liver changes in 67 patients undergoing cholecystectomy were investigated. Sixty three had gall stones, one cholesterolosis only, and there were three cases of acute acalculous cholecystitis. RESULTS--Only 34% of the patients had completely normal liver biopsy specimens. The most clinically important pathology was found in 11 of the 14 patients with choledocholithiasis: three of these had cholangitis and eight had features of large bile duct obstruction (four also had chronic cholestasis and portal-portal linking fibrosis). Non-specific reactive hepatitis was the most common abnormality in the remaining 53 patients with cholecystitis alone, and was found in 18. A further four patients had chronic cholestasis without fibrosis and early primary biliary cirrhosis was a coincidental finding in another. Clinical symptoms were poorly correlated with gall bladder and liver pathology apart from an association between jaundice and choledocholithiasis. Liver function tests of obstructive pattern were noted in 23 of 58 patients, most of whom had choledocholithiasis or non-specific reactive hepatitis. Bile cultures were positive in 10 of 42 patients, predominantly in cases of cholangitis and acute cholecystitis. CONCLUSIONS--Cholangitis and extensive fibrosis associated with large bile duct obstruction are common findings in patients with choledocholithiasis. The liver disease may progress to secondary biliary cirrhosis if the obstruction is not relieved, emphasising the need for early surgery. A peroperative liver biopsy may be useful to exclude cirrhosis in these patients, but is unlikely to be informative in those with cholecystitis alone.     

FLORID DUCT LESIONS AND EXTENSIVE BILE DUCT LOSS OF THE INTRAHEPATIC BILIARY TREE IN CHRONIC LIVER DISEASES OTHER THAN PRIMARY BILIARY CIRRHOSIS

Intrahepatic biliary tree with either florid duct lesions or a moderate to severe degree of the duct loss in four livers with chronic hepatic diseases other than primary biliary cirrhosis were studied with histometric and serial section observations. Florid duct lesions, distributed segmentally in the liver, were found in one case with incomplete septal cirrhosis and one case with idiopathic portal hypertension. The florid duct lesions including marked plasma cell infiltration and occasional periductal granulomas, were not associated with any bile duct loss in the two cases. The duct lesions were reversible in one case during a long clinical course. On the other hand, a moderate to severe bile duct loss with biliary epithelial degeneration and necrosis was associated with no or little periductal inflammatory cell infiltration in one other case with chronic intrahepatic cholestasis, probably drug-induced, and in one case with idiopathic portal hypertension. Although florid duct lesions and bile duct loss were important diagnostic features of primary biliary cirrhosis, one of them was observed to develop independently in severely diseased livers, not consistent with a diagnosis of primary biliary cirrhosis, sclerosing cholangitis or intrahepatic bile duct paucity syndrome.     

Regression of liver fibrosis after biliary drainage in patients with chronic pancreatitis and stenosis of the common bile duct

BACKGROUND: Chronic obstruction of the common bile duct may cause hepatic fibrosis and secondary biliary cirrhosis. METHODS: We studied liver-biopsy specimens from 11 patients with chronic stenosis of the common bile duct due to chronic pancreatitis; all the patients had undergone liver biopsy before or at the time of surgical biliary decompression and underwent a subsequent liver biopsy for various clinical reasons. The patients were followed as part of a prospective study of 501 patients who had been treated for chronic pancreatitis. Two pathologists, who were unaware of the sequence of specimens, graded fibrosis on a scale of 0 (none) to 3 (cirrhosis). RESULTS: The 11 patients were all men. Chronic pancreatitis was due to alcohol abuse in 10 of the men; 1 had idiopathic disease. The median age at diagnosis was 38 years. The median interval between the first and second liver biopsies was 2.5 years (range, 0.3 to 9.0). The two patients who had restenosis of the biliary anastomosis were excluded from the analysis of fibrosis. In the group of nine patients without restenosis, the second specimen showed significant improvement in fibrosis (P=0.01). The fibrosis improved by two grades in two patients and by one grade in four patients; in three patients, the grade did not change. The pathologists agreed on the grading of specimens from 10 of the 11 patients. CONCLUSIONS: In patients with chronic pancreatitis and stenosis of the common bile duct, liver fibrosis may regress after biliary drainage.     

Histologic changes mimicking biliary disease in liver biopsies with venous outflow impairment.

Impairment of venous outflow from the liver manifests as zone 3 sinusoidal dilatation and congestion (SDC) in liver biopsy. The spectrum of histologic changes in portal tracts has not been described. We studied liver biopsies from 34 patients with a confirmed diagnosis of venous outflow impairment (VOI). Liver transplant recipients and biopsies with cirrhosis and hepatic neoplasms were excluded. Clinical records were reviewed for laboratory tests and radiographic findings. In all, 19 patients had right heart disease, 13 had classic Budd-Chiari syndrome and two had veno-occlusive disease. Liver chemistry tests showed elevated liver transaminases (n=21; 61.8%), elevated alkaline phosphatase (n=31; 91.2%) and GGT (all 13 cases tested). The elevation in ALT and AST was mild (below 200 U/l in all cases), while alkaline phosphatase (ALP) was elevated above 500 U/l in nine (26.5%) patients and above 1000 U/l in three cases. On biopsy, all cases showed SDC. The portal tracts showed (a) portal expansion with bile ductular proliferation (n=16; 47.1%) accompanied by lymphoplasmacytic infiltrate (n=10), lymphocytic cholangitis (n=3) and portal or periportal fibrosis (n=11), (b) Portal and/or periportal fibrosis without ductular proliferation (n=3; 8.8%) or (c) Normal portal tracts (n=15; 44.1%). The combination of elevated ALP and bile ductular changes on biopsy suggested chronic bile duct disease. Ultrasound/CT scan evaluation of bile ducts in 26 patients showed no biliary tree abnormality. Antimitochondrial antibody testing in eight cases also yielded negative results. In conclusion, bile ductular proliferation, portal inflammation and portal-based fibrosis are commonly seen in liver biopsies of patients with VOI even in the absence of bile duct disease. These changes are often accompanied by elevated ALP and GGT and can lead to the suspicion of chronic biliary disease. In the absence of demonstrable abnormalities in the biliary tree, these changes can be attributed to venous outflow impairment.     

Relationship between Tetrahydrobiopterin and Portal Hypertension in Patients with Chronic Liver Disease

Tetrahydrobiopterin (BH4) is an essential cofactor in NO synthesis by endothelial nitric oxide synthase (eNOS) enzymes. It has been previously suggested that reduced intrahepatic BH4 results in a decrease in intrahepatic NO and contributes to increased hepatic vascular resistance and portal pressure in animal models of cirrhosis. The main aim of the present study was to evaluate the relationship between BH4 and portal hypertension (PHT). One hundred ninety-three consecutive patients with chronic liver disease were included in the study. Liver biopsy, measurement of BH4 and hepatic venous pressure gradient (HVPG) were performed. Hepatic fibrosis was classified using the Laennec fibrosis scoring system. BH4 levels were determined in homogenized liver tissues of patients using a high performance liquid chromatography (HPLC) system. Statistical analysis was performed to evaluate the relationship between BH4 and HVPG, grade of hepatic fibrosis, clinical stage of cirrhosis, Child-Pugh class. A positive relationship between HVPG and hepatic fibrosis grade, clinical stage of cirrhosis and Child-Pugh class was observed. However, the BH4 level showed no significant correlation with HVPG or clinical features of cirrhosis. BH4 concentration in liver tissue has little relation to the severity of portal hypertension in patients with chronic liver disease.

Graphical Abstract

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Nonselective inhibition of prostaglandin-endoperoxide synthases by naproxen ameliorates acute or chronic liver injury in animals

The rising prevalence of hepatic injury due to toxins, metabolites, viruses, etc., necessitates development of further mechanisms for protecting the liver and for treating acute or chronic liver diseases. To examine whether inhibition of inflammation is directed by cyclo-oxygenase pathways, we performed animal studies with naproxen, which inhibits prostaglandin-endoperoxide synthases 1 and 2 and is in extensive clinical use. We administered carbon tetrachloride to induce acute liver injury and ligated the common bile duct to induce chronic liver injury in adult rats. These experimental manipulations produced abnormalities in liver tests, tissue necrosis, compensatory hepatocyte or biliary proliferation, and onset of fibrosis, particularly after bile duct ligation. After carbon tetrachloride-induced acute injury, naproxen decreased liver test abnormalities, tissue necrosis and compensatory hepatocellular proliferation. After bile duct ligation-induced chronic injury, naproxen decreased liver test abnormalities, tissue injury and compensatory biliary hyperplasia. Moreover, after bile duct ligation, naproxen-treated rats showed more periductular oval liver cells, which have been classified as hepatic progenitor cells. In naproxen-treated rats, we found greater expression in hepatic stellate cells and mononuclear cells of cytoprotective factors, such as vascular endothelial growth factor. The ability of naproxen to induce expression of vascular endothelial growth factor was verified in cell culture studies with CFSC-8B clone of rat hepatic stellate cells. Whereas assays for carbon tetrachloride toxicity using cultured primary hepatocytes established that naproxen was not directly cytoprotective, we found conditioned medium containing vascular endothelial growth factor from naproxen-treated CFSC-8B cells protected hepatocytes from carbon tetrachloride toxicity. Therefore, naproxen was capable of ameliorating toxic liver injury, which involved naproxen-induced release of physiological cytoprotective factors in nonparenchymal liver cells. Such drug-induced release of endogenous cytoprotectants will advance therapeutic development for hepatic injury.     

The role of liver biopsy in evaluating acute allograft dysfunction following liver transplantation: a clinical histologic correlation of 34 liver transplants

One hundred six liver biopsy specimens from 34 orthotopic liver transplant (OLT) patients were examined and the histologic findings correlated with the clinical course of the patients to determine if specific morphologic patterns were associated with specific causes of acute allograft dysfunction. The principle causes of allograft injury in these patients appeared to be acute rejection and ischemic injury, with rarer cases of viral infection and biliary obstruction. Graft rejection causing transient liver dysfunction was associated with a mixed inflammatory infiltrate in the portal tracts and involving the interlobular bile ducts. Rejection resulting in severe, persistent dysfunction was associated with destruction and loss of the interlobular bile ducts or portal inflammation, followed by acute centrilobular hepatocyte necrosis. Ischemic liver injury was characterized by hepatocyte ballooning and/or hepatocyte necrosis. Ischemic injury causing transient graft dysfunction demonstrated focal, limited areas of hepatocyte necrosis or transient centrilobular hepatocyte ballooning. Severe ischemic injury resulting in persistent dysfunction caused diffuse hepatocyte necrosis or centrilobular ballooning followed by centrilobular hepatocyte loss and severe cholestasis with evidence of bile duct epithelial injury. The histologic patterns observed were not pathognomonic; radiologic studies, bile cultures, and other laboratory tests were necessary to rule out biliary or vascular obstruction and bacterial cholangitis. However, liver biopsies, especially serial biopsies, were helpful in suggesting the probable cause of liver dysfunction and in predicting subsequent allograft recovery or failure.     

Growth inhibition and apoptosis in liver myofibroblasts promoted by hepatocyte growth factor leads to resolution from liver cirrhosis

Liver cirrhosis is characterized by hepatic dysfunction with extensive accumulation of fibrous tissue in the liver. In response to chronic hepatic injury, hepatic portal myofibroblasts and activated hepatic stellate cells (HSCs) play a role in liver fibrosis. Although administration or gene expression of hepatocyte growth factor (HGF) leads to improvement in hepatic fibrosis/cirrhosis, the related mechanisms are not fully understood. We investigated mechanisms involved in resolution from liver cirrhosis by HGF, focusing on growth regulation and apoptosis in portal myofibroblasts. Cultured rat HSCs could not proliferate, were withdrawn after passage, and were replaced by proliferating portal myofibroblasts during the passages. In quiescent HSCs, c-Met receptor expression was undetected whereas c-Met receptor expression was detected in activated HSCs and liver myofibroblasts expressing alpha-smooth muscle actin (alpha-SMA), suggesting that activated HSCs and portal myofibroblasts are targets of HGF. For cultured rat portal myofibroblasts, HGF counteracted phosphorylation of extracellular signal-regulated kinase (Erk) 1/2 and mitogenic stimulus induced by platelet-derived growth factor, induced c-jun N-terminal kinase (JNK) 1 phosphorylation, and promoted apoptotic cell death. In the dimethylnitrosamine rat model of liver cirrhosis, administration of HGF suppressed proliferation while promoting apoptosis of alpha-SMA-positive cells in the liver, events that were associated with reduced hepatic expressions of alpha-SMA and histological resolution from liver cirrhosis. Growth inhibition and enhanced apoptosis in portal myofibroblasts by HGF are newly identified mechanisms aiding resolution from liver fibrosis/cirrhosis by HGF.     

Vinyl-chloride-induced liver disease. From idiopathic portal hypertension (Banti's syndrome) to Angiosarcomas.

Histologic examination of liver tissue (eight autopsy and 18 biopsy specimens) and five spleens from 20 workers with vinyl chloride polymerization showed hepatic angiosarcomas in 15. In addition, a peculiar pattern of progressive portal-tract, inconspicuous intralobular and conspicuous capsular fibrosis was observed in the five workers without angiosarconma, in all the seven patients with angiosarcoma from whom tumor-free portions of the liver were available, and in two tumor-free biopsies from patients subsequently found to have angiosarcoma. The fibrosis was accompanied by splenomegaly. Hypertrophy and hyperplasia of both hepatocytes and hepatic and splenic mesenchymal cells were also seen. The histologic similarity to chronic inorganic arsenical poisoning, in which angiosarcomas also occur, and to idiopathic portal hypertension (Banti's syndrome) suggests that the latter syndrome at times results from unknown toxic, possible environmental, chemicals.     

单一庚型肝炎病毒感染的临床和病理与免疫组化的相关性探讨

目的 探讨单由庚型肝炎病毒（ＨＧＶ）感染对肝脏的致病性。方法 用酶联免疫吸附法检测３６例血清抗－ＨＧＶ，用ＨＧＶ的ＮＳ５片段单克隆抗体（ＭｃＡｂ）对２０例临床和病理确诊为单一庚型肝炎者行肝组织免疫组化，其中急性肝炎１０例，慢性肝炎７例，亚急性重型肝炎１例，慢性重型肝炎２例。结果 ①临床表现：急性肝炎呈急性起病，表现为发热、乏力、恶心、厌油等症状，个别有呕吐现象；慢性肝炎起病缓慢，症状轻；重型肝炎呈急性起病，有高度乏力、严重消化道症状，重者发生肝昏迷。②ＡＬＴ和ＡＳＴ改变：急性肝炎和重型肝炎呈中度升高，慢性肝炎呈轻度升高，重型肝炎可出现“酶胆分离”现象。③肝组织的病理损害：急性肝炎以肝细胞肿胀和汇管区炎症细胞浸润为主。慢性肝炎以肝细胞肿胀、小叶内碎屑样或灶状坏死、汇管区轻度炎症细胞浸润和／或纤维组织轻度增生为主。     

Comparative pathological study of hepatic changes induced by Fasciola gigantica and Gigantocotyle explanatum in Javanese thin-tailed sheep.

Pathological changes in the liver induced by Fasciola gigantica and Gigantocotyle explanatum were readily distinguishable from each other. Lesions associated with the migration of immature flukes through the parenchyma were a prominent feature of infection with Fasciola gigantica, whereas lesions induced by Gigantocotyle explanatum were confined to the large bile ducts. The size of the hepatic lesions increased during the course of infection with Fasciola gigantica and was associated with the formation of progressively larger areas of scar tissue in the parenchymal migration tracts as the flukes grew. This was also as a result of the progressively increasing cellular infiltration, proliferation of bile ductules and fibrosis which occurred in adjacent portal triads and interlobular septa. The absence of signs of migration through the hepatic parenchyma by Gigantocotyle explanatum, was regarded as evidence that these flukes gain entry to the bile ducts from the intestine via the common bile duct. In bile ducts infected with Fasciola gigantica there was more extensive desquamation of the epithelium, more intense mucosal infiltration with lymphoid cells and fewer eosinophils, less severe glandular hyperplasia, more free blood in the lumen and a thicker duct wall than in bile ducts infected with Gigantocotyle explanatum.     

Apoptosis in the human liver during allograft rejection and end-stage liver disease

The contribution of apoptosis (programmed cell death) to cellular damage in human liver disease is unknown. Using the in situ DNA end labelling method (ISEL), evidence was sought of programmed cell death (PCD) in liver tissue from patients with various liver diseases. In particular, the study aimed to determine whether PCD is involved in either the loss of interlobular bile ducts (vanishing bile duct syndrome—VBDS) or the perivenular hepatocyte drop-out, both of which are characteristic of irreversible graft rejection. Large numbers of apoptotic hepatocytes were found in pervenular areas in tissues taken from patients with chronic graft rejection. Significant hepatocyte apoptosis, was not seen in long-term stable allografts, primary biliary cirrhosis, cholestasis, paracetamol-induced fulminant hepatic failure, or fulminant hepatic failure of indeterminate origin (non-A, non-B, non-C hepatitis). Bile ducts rarely stained positively, but mononuclear cells present in the post-transplant tissues were frequently positive, showing nuclear or cytoplasmic staining. The presence of cytoplasmic staining suggested that some mononuclear cells had ingested apoptotic DNA from other cellular sources. PCD may thus contribute to the perivenular hepatocyte loss in chronic rejection. The absence of ductular epithelial cell staining suggests that PCD is not involved significantly in the bile duct loss of VBDS. Furthermore, apoptosis of monomuclear cells implies that PCD may be involved in regulating the inflammatory cell infiltration of graft rejection.     

Pathological aspects of cholangiocarcinoma

Tissue specimens resected from liver and bile-ducts were examined in an attempt to distinguish features of cholangiocarcinoma from those of other tumours and from reactions to duct obstruction and changes in the tumour-bearing liver. Macroscopical and microscopical features were compared and certain changes were found only in cases of cholangiocarcinoma. The type of tumour correlated moderately well with the level of bile duct involved and some microscopical findings were noted only in patients suffering from cholangiocarcinoma. Mucin was demonstrable in all 33 cholangiocarcinomas. Other striking features included heterogeneity of epithelial cells within the same acinus and a tendency to spread between hepatocyte plates, along duct walls and in relation to nerves. Reactive hyperplasia of ductal subepithelial mucous glands was found in association with duct obstruction with and without cholangiocarcinoma. Sclerosis, a common accompaniment of cholangiocarcinoma was noted in other tumours.     

Pathology and pathogenesis of idiopathic portal hypertension with an emphasis on the liver

Idiopathic portal hypertension (IPH) is characterized by a long-standing presinusoidal portal hypertension of unknown etiology in adults. Some unidentified agent(s) affect(s) the intrahepatic small portal veins or portal tracts. Immunological disturbance, thromboembolism, infectious etiology and/or increased fibrogenesis in portal tracts are suspected as being candidates for the primary agent(s). During the long clinical course of IPH, several pathological changes may occur, including subcapsular parenchymal atrophy, atrophy of the liver, portal and parenchymal fibrosis, and portal venous phlebosclerosis and thrombosis. The last-named of these lesions is mostly found in patients with a history of splenectomy. Subcapsular parenchymal and hepatic atrophy may result from a hepatocellular dropout via apoptosis or necrosis because of intrahepatic hemodynamic disturbances, particularly chronic portal venous blood insufficiency. Pericellular fibrosis and thin fibrous septa are also frequently found and associated with activated perisinusoidal cells positive for smooth muscle actin. At the same time, vague nodular hyperplasia of hepatocytes not surrounded by fibrous septa is not infrequently seen. It may resemble nodular regenerative hyperplasia, partial nodular transformation, or focal nodular hyperplasia. However, liver cirrhosis does not occur even at the terminal stage. Taking these findings into consideration, a new staging of IPH with a combination of hepatic parenchymal atrophy and portal venous thrombosis was proposed: non-atrophic liver without subcapsular parenchymal atrophy (stage I), non-atrophic liver with subcapsular parenchymal atrophy (stage II), atrophic liver with subcapsular parenchymal atrophy (stage III), and portal venous occlusive thrombosis (stage IV). IPH livers are likely to progress from stage I to stage III. Stage IV, which occurs relatively late, has a poor prognosis. This staging is applicable to clinical and autopsy cases without any histological data.     

Adenomatous hyperplasia of the liver resembling focal nodular hyperplasia in patients with chronic liver disease

Two nodules of hepatic adenomatous hyperplasia (AH) resembling focal nodular hyperplasia were found in two patients with cirrhosis or chronic active hepatitis. Imaging techniques suggested that the nodules were hepatocellular carcinoma. Pathological examination showed that the nodules (approximately 1.0 cm in diameter) were clearly demarcated from the surrounding liver tissue, and contained foci of scar-like fibrosis in the centre of the nodules. Microscopically, they contained portal tracts and fulfilled the criteria of AH. A large number of arteries were present in the central scarlike fibrosis as well as in the parenchyma of the nodules. There were foci of mildly atypical hepatocytes in one nodule but no cellular atypia in the other. Morphometric analysis showed that the cumulative luminal area of arteries per unit area was much greater in the nodules than in the extranodular liver tissues, while the cumulative luminal area of portal veins per unit area was much less in the nodules than in the extranodular liver tissues. Although the pathogenesis is unclear, these nodules might have developed through localized vascular changes associated with chronic liver disease, may have arisen from pre-existing arterial malformation, or may represent the early stages of angiogenesis in hepatocarcinogenesis.     

Apoptosis of bile duct epithelial cells in hepatic allograft rejection

Liver biopsy remains the 'gold standard' for monitoring rejection in liver transplant patients. Portal inflammation, bile duct damage and endothelialitis are recognized features of hepatic allograft rejection. The pathogenesis of the bile duct injury during rejection, however, remains unclear. To define the mechanism of bile duct damage, we studied the light- and electronmicroscopic appearance of hepatic tissue from selected patients in whom allograft failure was solely due to rejection. Of the 25 orthotopic liver transplant rejection cases examined, 17 were mild, seven were moderate and one was severe rejection. Light microscopy examination of the damaged bile duct epithelium revealed evidence of apoptosis which was confirmed by electronmicroscopy. Furthermore, there appeared to be a positive correlation between the grade of rejection and the number of apoptotic cells. Also included in the study were 13 cases of chronic active hepatitis and 10 normal livers which showed the least apoptotic cells. We conclude that the identification of apoptotic cells in damaged bile ducts in allograft biopsies might be helpful in the diagnosis of rejection and in assessment of the severity of rejection.     

Liver disease and common-bile-duct stenosis in cystic fibrosis

To determine the incidence of common-bile-duct lesions and their relation to liver disease in cystic fibrosis, we performed hepatobiliary scanning in 50 of 61 patients with cystic fibrosis who had hepatomegaly, abnormal liver function, or both and in 31 of 92 patients with cystic fibrosis who did not have hepatomegaly or abnormal liver function. Ninety-six percent of the patients with liver disease had evidence of biliary tract obstruction, which was defined cholangiographically as a stricture of the distal common bile duct in the majority of cases. All the patients without liver disease had normal intrahepatic and common-duct excretion of tracer. Abdominal pain was significantly more common in patients with common-duct obstruction (P less than 0.001), and enlarged gallbladders occurred only in such patients. Since fasting levels of serum bile acids were elevated in nearly half these patients, irrespective of the severity of their liver disease, serum bile acids may be markers of the severity of the common-duct lesion. We conclude that strictures of the distal common bile duct are common in patients with cystic fibrosis and liver disease. This association requires further study, since surgical relief of common-duct obstruction may prevent or ameliorate the hepatic complications of cystic fibrosis.