Regenerative Nodules In Cirrhotic Liver Research Articles

Comprehensive analysis of genetic aberrations linked to tumorigenesis in regenerative nodules of liver cirrhosis.

Hepatocellular carcinoma (HCC) recurrently develops in cirrhotic liver containing a number of regenerative nodules (RNs). However, the biological tumorigenic potential of RNs is still unclear. To uncover the molecular bases of tumorigenesis in liver cirrhosis, we investigated the genetic aberrations in RNs of cirrhotic tissues using next-generation sequencing. We isolated 205 RNs and 7 HCC tissues from the whole explanted livers of 10 randomly selected patients who had undergone living-donor liver transplantation. Whole-exome sequencing and additional targeted deep sequencing on 30 selected HCC-related genes were conducted to reveal the mutational landscape of RNs and HCCs. Whole-exome sequencing demonstrated that RNs frequently harbored relatively high-abundance genetic alterations, suggesting a clonal structure of each RN in cirrhotic liver. The mutation signature observed in RNs was similar to those determined in HCC, characterized by a predominance of C>T transitions, followed by T>C and C>A mutations. Targeted deep sequencing analyses of RNs identified nonsynonymous low-abundance mutations in various tumor-related genes, including TP53 and ARID1A. In contrast, TERT promoter mutations were not detected in any of the RNs examined. Consistently, TERT expression levels in RNs were comparable to those in normal livers, whereas every HCC tissue demonstrated an elevated level of TERT expression. Analyses of RNs constructing cirrhotic liver indicated that a variety of genetic aberrations accumulate in the cirrhotic liver before the development of clinically and histologically overt HCC. These aberrations in RNs could provide the basis of tumorigenesis in patients with liver cirrhosis.

Multiple infarcted regenerative nodules in liver cirrhosis after decompensation of cirrhosis: a case series

IntroductionLiver cirrhosis is a common disease with many known complications. Cirrhosis represents a clinical spectrum, ranging from asymptomatic liver disease to hepatic decompensation. Manifestations of hepatic decompensation include variceal bleeding, ascites, hepatic encephalopathy, hepatorenal syndrome, hepatopulmonary syndrome, portopulmonary hypertension and hepatocellular carcinoma. There are reports about infarcted regenerative nodules in cirrhotic livers after gastrointestinal hemorrhage.Case presentationWe report three Caucasian patients (one female and two male patients; ages: 52, 54 and 60 years) with decompensated liver cirrhosis, who showed newly infarcted regenerative nodules at necropsy. Two of them suffered from gastric variceal bleeding. Histopathology showed extensive infarction in all three cases.Hemorrhage and inflammatory changes were also observed around the infarcted regenerative nodules.ConclusionThese patients showed focal liver lesions, to be considered in the differential diagnosis of cirrhotic livers. Infarcted regenerative nodules may be underdiagnosed in patients with decompensation of cirrhosis. In order to differentiate these lesions from malignant tumors, serial imaging seems to be helpful. However, the main differential diagnosis should be an abscess. It is important to know the wide spectrum of image appearances of these lesions. Hypotension can lead to a reduction of portal and arterial liver flow. Since variceal bleeding or septic shock can induce hypotension - as observed in our patients - we conclude that this leads to infarction of such nodules.

Mutation of p53 gene in regenerative nodules in cirrhotic liver

Background/Aims: Mutations of p53 gene have been detected in precancerous stages of several cancers, and the possible role in multistep carcinogenesis is suggested. The aim of this study was to examine the mutation profile of p53 gene in regenerative nodules in cirrhotic livers. Methods: Ninety eight tissue specimens of regenerative nodules obtained from 15 cases of cirrhosis were used for analysis. Twenty cases of chronic hepatitis and two cases of fatty liver were used as controls. DNA was extracted from each of manually demarcated regenerative nodules, and nucleotide sequence analysis was performed on p53 gene exon 5. Results: Direct sequencing detected p53 mutations in seven of 98 DNA samples (7.1%) from regenerative nodules in six cases of cirrhosis. Subcloning analysis revealed that mutation sites differed in each subclone and the incidences of the mutation varied from 7.7 to 58.8% depending on individual nodules. The mutation was not detected in any of chronic hepatitis and fatty liver. There were inconsistent p53 sequence with regenerative nodules and accompanied hepatocellular carcinomas in six cases. Conclusions: Mutations of p53 gene were frequently found in cirrhotic livers compared with livers of patients with chronic hepatitis ( P<0.01), suggesting that p53 mutations at the stage of cirrhosis may be a causative factor that may potentially lead to hepatocellular carcinoma.

Regenerative nodules in liver cirrhosis: findings at CT during arterial portography and CT hepatic arteriography with histopathologic correlation.

To determine the appearance of regenerative nodules in patients with liver cirrhosis at computed tomography (CT) during arterial portography (CTAP) and CT hepatic arteriography (CTHA). CTAP and CTHA of the liver were performed in 28 consecutive patients with hepatocellular carcinoma (HCC) who were scheduled to undergo partial resection of the liver. Helical CTAP was performed after contrast material injection into the superior mesenteric artery followed by helical CTHA after contrast material injection into the hepatic artery. CT scans were analyzed for the presence of identifiable nodules and their size; results were correlated with gross and microscopic findings. Resected livers showed cirrhosis in 20 patients, chronic hepatitis in four, and normal liver in four. Among the 20 patients with cirrhosis, regenerative nodules were demonstrated as enhancing 3-10 mm nodules surrounded by lower attenuation fibrous septa 0.8-1.5 mm thick at CTAP in seven patients and nonenhancing nodules of the same size surrounded by enhancing fibrous septa at CTHA in 15 patients. The degree of fibrosis determined the conspicuity of nodules. Regenerative nodules in cirrhotic liver are visualized as enhancing nodules surrounded by lower attenuation thin septa at CTAP and nonenhancing nodules surrounded by enhancing fibrous septa at CTHA. CTHA is more sensitive than CTAP in depicting regenerative nodules (P < .005).

Clonal analysis of regenerative nodules in hepatitis C virus-induced liver cirrhosis

Background/Aims: Based on histological criteria, regenerative nodules in cirrhotic liver have been generally considered to result from hyperplastic proliferation of hepatocytes. Whether these nodules are hyperplastic or neoplastic has not been determined definitively. This study examined the issue by clonal analysis of each nodule. Methods: The method for clonal analysis was based on restriction fragment length polymorphism of the X chromosome-linked phosphoglycerokinase gene and on random inactivation of the gene by methylation. Results: Clonality of hepatocellular carcinoma (n = 7) and regenerative nodules (n = 76) induced by hepatitis C virus infection was analyzed. All carcinomas were monoclonal. Clonal analysis of regenerative nodules showed that 43% (33 of 76) were monoclonal in origin. Adjacent monoclonal nodules showed inactivation of the same allele of phosphoglycerokinase gene. Because the gene allele is inactivated at random, it is unlikely that each nodule happens to inactivate the same allele; it is more likely that monoclonal cell expansion is initiated before the nodule is established by septum formation. Conclusions: Monoclonal cell expansion is seen in a considerable number of regenerative nodules in cirrhotic liver. The results indicate that certain genetic changes, which are required for hepatocarcinogenesis, have already occurred in these nodules.

Hepatocellular carcinoma within siderotic regenerative nodules: appearance as a nodule within a nodule on MR images.

Large regenerative nodules in cirrhotic livers may accumulate iron and develop internal iron-poor foci of hyperplasia or malignancy. Magnetic resonance examinations were performed on 23 patients with biopsy-proved cirrhosis. A "nodule-within-nodule" appearance was noted in two patients. This appearance consisted of markedly low intensity of a large nodule on gradient-echo images, with one or two internal foci that were isointense to the liver. Each of the large nodules was 2 cm in diameter, and each of the internal foci was less than 1 cm. Serum alpha-fetoprotein levels were normal in both patients. Aspiration biopsy performed in one patient failed to show malignancy, but histologic confirmation of hepatocellular carcinoma was obtained eventually in both cases. The nodule-within-nodule sign, which reflects the unique histopathology of hepatocellular carcinoma in large siderotic regenerative nodules, is strongly suggestive of early hepatocellular carcinoma, even if serologic markers and biopsy results do not support this diagnosis.

Significant Reduction of the Echogenicity of the Compressed Cavernous Hemangioma

Eleven hyperreflective hepatic nodules in eight patients were examined by means of intraoperative ultrasonography (US) with the transducer placed on the liver surface. The nodules included four cavernous hemangiomas, four hepatocellular carcinomas, one metastatic tumor, and two regenerative nodules in cirrhotic livers. When the relevant part of the liver was compressed during US observation, the echogenicity was reduced only in the case of cavernous hemangioma. This phenomenon is considered to be unique to cavernous hemangioma.