Journal of Pathology and Translational Medicine

Review

A review of liver fibrosis and cirrhosis regression: Michael J. Lee; J Pathol Transl Med. 2023;57(4):189-195. Published online June 20, 2023; DOI: https://doi.org/10.4132/jptm.2023.05.24

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Cirrhosis has traditionally been considered an irreversible process of end-stage liver disease. With new treatments for chronic liver disease, there is regression of fibrosis and cirrhosis, improvement in clinical parameters (i.e. liver function and hemodynamic markers, hepatic venous pressure gradient), and survival rates, demonstrating that fibrosis and fibrolysis are a dynamic process moving in two directions. Microscopically, hepatocytes push into thinning fibrous septa with eventual perforation leaving behind delicate periportal spikes in the portal tracts and loss of portal veins. Obliterated portal veins during progressive fibrosis and cirrhosis due to parenchymal extinction, vascular remodeling and thrombosis often leave behind a bile duct and hepatic artery within the portal tract. Traditional staging classification systems focused on a linear, progressive process; however, the Beijing classification system incorporates both the bidirectional nature for the progression and regression of fibrosis. However, even with regression, vascular lesions/remodeling, parenchymal extinction and a cumulative mutational burden place patients at an increased risk for developing hepatocellular carcinoma and should continue to undergo active clinical surveillance. It is more appropriate to consider cirrhosis as another stage in the evolution of chronic liver disease as a bidirectional process rather than an end-stage, irreversible state.

Citations

Citations to this article as recorded by

Emerging advanced approaches for diagnosis and inhibition of liver fibrogenesis
Tamer A. Addissouky, Majeed M. A. Ali, Ibrahim El Tantawy El Sayed, Yuliang Wang
The Egyptian Journal of Internal Medicine.2024;[Epub] CrossRef
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Original Articles

The Morphologic Changes of the Sinusoidal Endothelial Cells in N-diethylnitrosamine Induced Cirrhotic Rat Liver.: Ok Ji Paik, Hee Kyung Park, Jong Min Chae, Jyung Sik Kwak, Tae Joong Sohn; Korean J Pathol. 1996;30(7):604-615.

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Abstract PDF: The purpose of this study is to investigate the morphologic changes of the sinusoidal endothelial cells and the associated structures of the cirrhotic rat liver induced by repeat intraperitoneal injections of N-diethylnitrosamine (DEN) (100 mg/kg/week). One day to 6 weeks later, rat livers were observed under the light, transmission and scanning electron microscopy, and immunostained with laminin antibody. Two weeks after DEN treatment, the fibrillar material in Disse's space was noted, and then a basement membrane-like structure was found at 4 weeks after treatment. Laminin was detected in perisinusoidal areas after 4 weeks. Laminin was strongly positive on the fibrous septum and in the sinusoidal wall of cirrhotic nodules after 6 weeks of treatment. The diameters and numbers of sinusoidal endothelial fenestrations did not change significantly until 2 weeks. They decreased within 4 weeks, and then the sinusoidal endothelium was poorly fenestrated at 6 weeks after DEN treatment. These results suggest that as fibrosis develops in cirrhosis, the deposit of extracellular matrix such as laminin within Disse's space is a major contributing factor in the structural alteration of sinusoidal endothelial cells, and the capillarization of the sinusoidal endothelial cells may be a contributor to impairment of the hepatic function in cirrhosis.

Primary Biliary Cirrhosis-Autoimmune Hepatitis Overlap Syndrome.: Jong Yup Bae, Young Nyun Park, Chanil Park; Korean J Pathol. 1997;31(1):87-90.

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Abstract PDF: Cases sharing features of both primary biliary cirrhosis and autoimmune hepatitis have been reported as a mixed type, overlap syndrome, immunocholangitis and autoimmune cholangiopathy. A primary biliary cirrhosis- autoimmune hepatitis overlap syndrome is unusual and characterized by overlapping features; cholestasis, high titer of alkaline phosphatase, bile duct damage and granulomas in the liver biopsy, high antinuclear antibody, increased IgG and IgM and intra-acinar hepatitis with piecemeal necrosis. Autoimmune mechanisms are thought to play a major role in the pathogenesis of the overlapping syndrome and the bases of immunosuppressive therapy. A 58-year-old female patient shows overlapping clinical and laboratory findings, chronic active hepatitis in initial liver biopsy which transits to primary biliary cirrhosis with cholangitis and granulomas. This is a case of hepatobiliary lesion showing overlapping features of both primary biliary cirrhosis and autoimmune hepatitis over 3-year period.

Clonality of Large Regenerative Nodule Accompanied by Hepatocellular Carcinoma.: Zhe Piao, Bong Kyun Chun, Woo Jung Lee, Young Nyun Park, Ho guen Kim, Chanil Park; Korean J Pathol. 1997;31(9):884-890.

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Abstract PDF: In order to clarify the preneoplastic nature of large regenerative nodules without dysplastic change, we analysed the clonality of hepatocellular carcinomas (HCCs) and large nodules, diameter > or =0.5 cm, of cirrhotic liver by X-linked human androgen receptor (HUMARA) gene assay, using the principle of random X chromosome methylation and inactivation in female. Ten cases of HCC and 5 cases of large nodules without dysplasia from 9 female patients were selected. All the tumors, large nodules and paired normal control cells were selectively microdissected from deparaffinized hematoxylin and eosin stained slides. Genomic DNA was isolated and digested with HhaI. Polymerase chain reaction(PCR) amplication of the HUMARA locus was performed using 32P-a-dCTP containing PCR mixtures. The PCR amplified products were separated by gel electrophoresis and analysed by autoradiography. Nine HCCs from 8 patients were monoclonal and 1 case was polyclonal and the remaining 1 case was not polymorphic at the HUMARA locus. The HCC case which showed polyclonality contained many inflammatory cells. All the large nodules were polyclonal by HUMARA assay. These results suggest that all or most of the cells composing the large regenerative nodules without dysplasia are polyclonal. This assay may be informative for the differentiation between regenerative and preneoplastic nodules in cirrhotic liver and the size of nodule may be not important in hepatocarcinogenesis.

Clinicopathologic Comparison between Autoimmune Cholangitis and Primary Biliary Cirrhosis.: Gyeong Hoon Kang, So Dug Lim, Eun Sil Yu, On Ja Kim, Geun Chan Lee, Neung Hwa Park, Dong Jin Suh; Korean J Pathol. 1998;32(2):115-124.

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Abstract PDF: Primary biliary cirrhosis (PBC) is characterized by histological findings of an immunoinflammatory destruction of small- and medium-sized bile ducts with progressive portal fibrosis, and the presence of anti-mitochondrial antibody (AMA) with a laboratory evidence of chronic cholestasis. The term "autoimmune cholangitis" (AIC) is used for a disease with the clinical and pathologic features of primary biliary cirrhosis (PBC) but with negative AMA and positive anti-nuclear antibody (ANA) tests. Eight cases of AIC and ten cases of PBC were reviewed in order to determine whether there was any difference between two diseases in clinico-pathologic aspects. All of the patients were female and the mean ages of AIC and PBC patients were 48 and 47 years, respectively. ANA test was positive in six of ten PBC paients and their mean titer was lower than that of AIC patients. IgM level was significantly higher in PBC group than in AIC group. No significant difference was found between two groups with respect to biochemical and histopathological features. Since the only consistently distinguishing features between these two conditions are the autoantibody profile (AMA vs ANA) and immunoglobulin level (IgM), these two conditions might be part of a spectrum. PBC can be considered to be the same as AMA-positive AIC or alternatively AIC to be the same as AMA-negative PBC.

Differential Expression of Promyelocytic Leukemia Protein in Autoimmune Liver Diseases.: Hyun Jung Kim, Jung Sun Kim, Yong Sang Lee, Young Hwa Chung, Han Joo Lee, Dong Jin Suh, Chong Jai Kim, Eunsil Yu; Korean J Pathol. 2004;38(6):357-363.

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Abstract PDF: BACKGROUND
Promyelocytic leukemia protein (PML) is a primary biliary cirrhosis (PBC)-specific autoantigen. Anti-PML antibody is analyzed using cultured cells with patient sera, however, PML expression has rarely been examined in liver tissues.
METHODS
In the present study, PML expression was examined immunohistochemically in paraffin embedded liver needle biopsy specimens obtained from 20 cases of PBC, 10 cases of autoimmune cholangitis, 36 cases of autoimmune hepatitis and from 5 cases of noninflammatory livers.
RESULTS
Variable PML immunopositivity was detected in the bile duct epithelial cells of 18 (90.0%) of 20 PBC cases and in all 10 cases (100.0%) of autoimmune cholangitis, whereas it was only present in 6 (16.7%) of 36 cases of autoimmune hepatitis (p<0.001). In contrast, hepatocyte PML immunopositivity was higher in autoimmune hepatitis (33/36 cases, 90.8%), than in PBC (10/20 cases, 50.0%) or autoimmune cholangitis (3/10 cases, 30.0%) (p<0.05).
CONCLUSION
Our data indicate that the differential expression of PML is closely related to autoimmune liver diseases type, and suggest that the overexpression of PML protein in bile duct cells is associated with the development of autoantibodies in patients with PBC or autoimmune cholangitis. Furthermore, PML immunoreactivity may be useful for the diagnosis of autoimmune cholangitis and overlap syndrome.

Morphological Changes of Hepatic Microcirculation in N-diethylnitrosamine Induced Cirrhotic Rat Liver.: Sang Han Lee, Ji Hwa Kim, Ik Su Kim, Jong Min Chae; Korean J Pathol. 1995;29(2):197-204.

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Abstract PDF: Morphological changes of hepatic microcirculation, especially in the peribiliary plexus, in cirrhotic livers of rats induced by repeated intraperitoneal injections of N-diethyinitrosamine (DEN) (100mg/kg/week) were studied by scanning electron microscopy. Control rats were treated with saline. The livers were perfused with saline and injected with methyl-methacrylated resin (Mercox CL-2B) through the thoracic aorta. Diffuse nodular changes mimicking human cirrhosis were seen in the livers six weeks after injections of DEN. The cirrhotic livers showed an increase of vascular channels composed mainly of venous branches around the regenerating nodules and increased arterioloportal anastonloses. Peribiliary plexi of the cirrhotic livers had more vessels than those of the controls. Many dilated veins and ramificating portal vein branches were also Present. Direct connections between peribiliary plexi and sinusoids or between peribiliary plexi and portal veins were increased in the cirrhotic liver. These results suggest that the peribiliary plexi in experimentally induced cirrhotic liver might play a role in a collateral circulation under a state of portal hypertension.

Case Report

Methotrexate Induced Chronic Active Hepatitis: A report of two cases.: Jee Young Han, Young Nyun Park, Chan Il Park, Chae Yoon Chon; Korean J Pathol. 1994;28(2):168-172.

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Abstract PDF: Although methotrexate(MTX) has been known to have many side effects, especially toxicity on the hemopoietic cells and the liver, it has been used as a potent anticancer drug and for the treatment of psoriasis or rheumatoid arthritis. The severity of hepatotoxicity varies from mild fatty change to chronic active hepatitis(CAH) and cirrhosis. We experienced two cases of MTXinduced CAH in patients with psoriasis, which prompted us to report in view of the absence of biopsy proven MTX hepatotoxicity in the Korean literature. Microscopically, the liver showed a distorted lobular architecture with portal fibrous expansion, piecemeal necrosis and bridging necrosis/fibrosis. The hepatic lobules revealed fatty changes of hepatocyte, focal hepatocytolysis, delicate collagen deposits along the space of Disse and the characteristically marked polyploid nuclear change of hepatocytes.

Original Articles

The Tissue Expression of HBsAg and HBcAg in Hepatocellular Carcinoma and Peritumoral Liver.: Jee Young Han, Woo Hee Jung, Chae Yoon Chon, Chan Il Park; Korean J Pathol. 1993;27(4):371-378.

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Abstract PDF: To evaluate the tissue expression rate and pattenr of HBsAg and HBcAg in tumors and peritumoral livers, an immunohistochemical study was undertaken on 47 surgically resected hepatocellular carcinomas(HCCs). The results are as follows. 1. Patient's sera were positive for HBsAg in 40 cases(85.1%). In the remaining 7 cases, the tumor and peritumoral liver expressed neither HBcAg nor HbSaG, suggesting that they were caused by other etiologies than hepatitis B virus. 2. The peritumoral liver had HBsAg and HBcAg in 95.0% and 27.5% among the 40 cases, respectively. But the tumor expressed HBsAg in 50.0% and HBcAg in none. 3. The expression of HBsAg within the tumor and both HBsAg and HBcAg in the peritumoral liver tended to be more frequent in the pretreated cases before surgery. 4. Edmondson-Steiner grade IV tumors revealed a lower expression rate of HBsAg than the low grade tumors(p<0.05). Incases with cirrhosis at peritumoral tissues, HBcAg was less frequently found than in those without cirrhosis. The majority of tissue HBsAg and HBcAg was represented as groups of positive cells. These results suggest that, during the development and progression of HCCs, the HBcAg containing cells are repeatedly removed and the HBcAg negative cells are selected, because cellular expression of HBcAg is the target of host immune response.

Morphometric Analysis of Cirrhotic Nodules in Hepatocellular Carcinoma-bearing Livers.: Gyeong Hoon Kang, Yong Il Kim; Korean J Pathol. 1991;25(4):338-345.

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Abstract PDF: It has been well known that liver cirrhosis, regardless of its etiology, is an important predisposing factor in hepatocarcinogenesis. However, the type of cirrhosis in hepatocellular carcinoma(HCC)-bearing liver varies not only by geographic areas but also with the cirteria applied for morphological classification of cirrhosis. To elucidate the relationship between the nodule size of HCC-bearing cirrhotic liver and clinicopathologic features, we measured cirrhotic nodule areas of 49 surgically resected HCC cases using image analyzer. The morphological type of cirrhosis was predominantly macronodular(49%), and followed by mixed(37%) and micronodular(14%). Seventy percent of the cases showed seropositivity for HBsAg. The average area of cirrhotic nodules was significantly larger in HBsAg-positive cases(mean: 6.14 mm2) than that of HBsAg-negative cases(mean: 2.5 mm2)(p<0.05), and their size was bigger in cases with grossly expansile pattern of HCC than those cases with infiltrative ones(p<0.05). Based on the above findings, we assume that seropositivity of HBsAg may influence on the regenerative activity of cirrhotic nodules and also subsequent increase of risk for further development of HCC. The presence of cirrhohsis and nodule size seem to be the important contributing factors to determine the growing patterns of HCC.

Primary Biliary Cirrhosis: A Clinicopathologic Analysis of Four Cases.: Mi Kyung Kim, Yong Il Kim, Hyo Suck Lee, Chung Yong Kim; Korean J Pathol. 1991;25(4):318-326.

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Abstract PDF: Primary biliary cirrhosis, a chronic, progressive, and often fatal cholestatic liver disease, is characterized by destruction of intrahepatic bile ducts, portal inflammation and scarring, and the eventual development of cirrhosis and liver failure. We reviewed four cases of primary biliary cirrhosis primarily suspected with peritoneoscopic liver biopsy specimens. All patients were female and their age ranged from 29 to 50 years(median age: 43.8 years). Presenting symptoms were typically pruritus and/or upper abdominal discomfort. On physical examination, interus was presented in 3; hepatomegaly in 3; chronic liver disease stigmata in one. Co-existing autoimmune diseases such as Hashimoto' thyroiditis and Sjoegren' syndrome were found in 2 cases. Biochemical tests of liver function revealed a cholestatic pattern. An antimitochondrial-antibody test was positive in 2 out of 3 patients(75%). Increase levels of serum immunoglobulins, especially of IgM, were evident in 3 cases. Histologic staging(Ludwig et al.) disclosed stage I lesion in one, stage III in two, and stage IV in the remaining one.

Gross Anatomical Typing of Hepatocellular Carcinoma: Classification of 49 lobectomized hepatocellular carcinomas.: Young Nyun Park, Eun Kyung Han, Chan Il Park; Korean J Pathol. 1991;25(2):83-92.

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Abstract PDF: Forty-nine lobectomized hepatocellular carcinomas(HCC) were classified according to the gross anatomical features. Because the presence of cirrhosis in the remaining liver has a good clinico-pathological implication, cases of HCC were divided into non-cirrhotic(non-LC) and cirrhotic(LC) groups. In both groups, the tumors themselves belonged to either expanding, focal spreading, spreading or mixed type. Another special type, which has been called a "diffuse type" is added in the LC group with the name of "cirrhotomimetic type" Among 49 cases, 21 belonged to the non-LC group and 28 to the LC group. Most common was expanding type(20 cases, 40.8%), which was followed by spreading(32.7%), focal spreading(16.3%), mixed(6.1%) and cirrhotomimetic(4.1%) types. Expanding type of the LC group was the single most common type(13 cases, 26.5%). The accordance rate of gross typing was 0.94. Tumor masses of the LC group showed a greater tendency of having a fibrous capsule(60.7%) and a lobulated cut surface(82.1%), in contrast to those of the non-LC group (28.6% and 42.9% respectively). The patient's age and the HBsAg seropositivity were not different between the groups and between the types. Increased serum level of AFP was particularly frequent in the spreading type(81.3%) of both groups and in the cirrhotomimetic type(100%).

Liver Cirrhosis: Etiological diagnosis and morphological characteristics of 369 biopsy-proven cases.: Eun Kyung Han, Chanil Park, Sang In Lee; Korean J Pathol. 1990;24(4):412-422.

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Abstract PDF: To pursue a desirable format for the pathological diagnosis of liver cirrhosis, the authors attempted to classify 369 biopsy-proven cirrhosis on the basis of etiology and made effort to find out the morphological characteristics of each category. About 735 of total cases were HBsAg seropositive postnecrotic cirrhosis. Alcholic cirrhosis ws the second most frequent type, although accounted only 6.8%. In about 15%, the etiology was not known. Excluding the congenital biliary atresia, chronic biliary obstruction appeared to be a rare cause of cirrhosis among these biopsied cases. Of the HBsAg positive postnecrotic cirrhosis, the eAg seropositive cases tended to be micronodular and to show a higher necroinflammatory activity, in contrast to eAg seronegative cases and those complicated by hepatocellular carcinoma (HCC), suggesting that the loss of eAg is followed by a decrease of the destructive activity, active regeneration of hepatocytes and finally the development of HCC. alcoholic cirrhosis was micronodular in 64% and revealed histologic evidences of alcoholic liver disease in most cases. The results indicate that etiological diagnosis can be made in most cases of cirrhosis by the morphological characteristics and the precise clinical informations, including those on the NANB virus and the inborn error of metabolism, and that the pathological diagnosis should be more comprehensive, implicating the etiology, the nodular size and the necroinflammatory activity.

The Effect of Common Bile Duct Ligation on Liver Morphology and Coper Metabolism in Rat.: Kyoung Sook Kim, Chanil Park, Jang Whan Cho, In Joon Choi, Yoo Bock Lee; Korean J Pathol. 1990;24(4):402-411.

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Abstract PDF: To clarity the effect of biliary obliteration on copper metabolism of rat liver and on the hepatic morphology, 0.5% cuppuric sulfate was administered intraperitoneally for 42 days following ligation of the common bile duct (CBD) of Sprague-Dawley rats. The blood copper concentration, the hepatic copper content and the accumulation patterns of copper and copper binding protein in the liver were examined and compared with those of the simple CBD ligation group and the simple copper over loaded group. CBD ligation induced marked proliferation of bile ductular structures which, after expanding the portal tracts, invaded and divided the hepatic lobules. There was, however, no excess fibosis beyond what needed to support the new ductules. The blood copper concentration and the hepatic copper content were increased by copper overload with or without CBD ligation, particularly incases with CBD ligation. Liver cell necrosis did not occur by the overloaded copper alone in rats. The hepatic copper and copper binding protein were accumulated at periportal liver cells in the group of coppe overload after CBD ligatio, whereas they began to appear at perivenular hepatocytes in the simple copper overloaded group. In conclusion, it is suggested that CBD ligation does not induce excess fibrosis or liver cirrhosis in rat as far as during our experimental period, but affect significantly on copper metabolism by intrahepatic redistribution of the copper and the copper binding proteins.

Alcoholic Type Cirrhosis Following Side to Side Ileo-Transverse Colon Anastomosis.: Kwang Hwa Park, Kwang Hyup Han, Chan Il Park; Korean J Pathol. 1990;24(2):148-152.

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Abstract PDF: A case of micronodular cirrhosis of the alcoholic type developed following an intestianl bypass surgery in a 47 year-old nonalcoholic male patient is presented. The patient denied any drug use of a long duration and had no diabetes mellitus. Five years before, a side to side ileo-transverse colon anastomosis had been performed for perforated intestinal tuberculosis at 1 m proximal to the ileocecal valve, bypassing a short segment of ileum (about 1.5 m) and transverse colon. The ileum distal to the perforated site had been found completely stenosed. He was severely lean with evidences of nutritional deficiency such as low serum levels of the albumin and vitamin B12. The liver biopsy showed a fatty change, Mallory bodies and perihepatocellular collagenosis within the cirrhotic nodules. The present case suggests that, when there are blind loop formation and nutritional deficiency, hepatic changes identical to those following jejunoileal bypass could develop even by reduction of a shore segment of the small intestine.

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