characteristics of HCV infection

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inflammatory infiltrate, piecemeal necrosis, lobular necrotico-inflammatory lesions, and fibrosis. The histo- logical activity of chronic hepatitis is usually assessed.
Nephrol Dial Transplant (1996) 11 [Suppl 4]: 12-15

Nephrology Dialysis Transplantation

Current anatomico-pathological classification of hepatitis: characteristics of HCV infection Jean-Francois Mosnier Department of Pathology, Hopital de Bellevue, Boulevard Pasteur 42055, Saint-Etienne Cedex 2, France chronic hepatitis associated intra-portal inflammatory infiltrates with piecemeal necrosis lesions and intralobular hepatocyte necrosis. To the authors of that classification, persistent or aggressive chronic hepatitis corresponded to different stages of severity of the same disease. A better understanding of the natural history, of the pathogeny and causes of chronic hepatitis has made that classification obsolete. Natural history

A number of authors considered persistent chronic hepatitis and active chronic hepatitis as two set (frozen) but different expressions of chronic hepatitis. The evolution of histological lesions in a virus B-linked chronic hepatitis according to viral replication variations has attested to the contrary. Chronic hepatitis linked to B virus begins with an intense replication phase during which the HBe antigen and the B virus DNA are present in serum. During that phase, the histological aspect is variable: active chronic hepatitis, or persistent chronic hepatitis, or lobular chronic hepatitis characterized by a marked intra-lobular inflammatory infiltrate. When seroconversion from HBe antigen into anti-HBe antibody occurs, reflecting the decrease in viral replication, intra-lobular chronic hepatitis begins. During the low replication phase which follows, histology reveals an aspect of persistent chronic hepatitis. If viral replication is then reactivated, it will be histologically characterized by the onset of Anatomico-clinical classification of chronic intra-lobular chronic hepatitis. So, the histological hepatitis characteristics of chronic hepatitis will vary along with the viral replication steps. These various steps may be Chronic hepatitis is an clinico-pathological syndrome associated with the formation of increasingly mutilatwith multiple possible causes. A hepatitis is considered ing fibrosis whose outcome is cirrhosis. During the low chronic when it has persisted for more than 6 months replication phases, cirrhosis cannot be associated with with no improvement. Histologically, chronic hepatitis any other chronic hepatitis lesion. Such a cirrhosis is is characterized by the association of portal and lobular said to be inactive or cold and could be mistaken for inflammation and hepatocyte necrosis. The first classi- cryptogenetic cirrhosis because viral serological fication of chronic hepatitis was proposed in 1968. It markers can be undetectable [1]. distinguished between persistent and active chronic hepatitis. Persistent chronic hepatitis were histologically characterized by intra-portal inflammatory infilt- Aetiology rate isolated without piecemeal necrosis or intra- Since 1968, the causes for chronic hepatitis have been lobular hepatocyte necrosis. Active or aggressive partially clarified. Chronic hepatitis causes can be viral © 1996 European Renal Association-European Dialysis and Transplant Association

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Abstract. Better knowledge of the natural history and aetiology of chronic hepatitis and the introduction of effective treatments have lead to revising the histopathological classification of chronic hepatitis. The basic lesions observed in chronic hepatitis are intra-portal inflammatory infiltrate, piecemeal necrosis, lobular necrotico-inflammatory lesions, andfibrosis.The histological activity of chronic hepatitis is usually assessed by apply KnodelTs score or histological activity index (HAI). This score includes inflammatory lesions and fibrosis. Butfibrosisis in fact the consequence of portal and lobular inflammation. The current classifications, including that proposed at the 1994 world conference on gastroenterology, propose discriminating between activity, or grade, and fibrosis, or stage. The classification of chronic hepatitis has also been revised because it was ill-adapted to assessing the C virus-linked chronic hepatitis. Histologically, these are little active chronic hepatitis associated with intra-sinusoidal inflammatory infiltrates of the leukaemia type, intralobular microgranulomas, intraportal lymphoid aggregates, and lesions of the small biliary tracts. Although non-specific, these lesions are evocative enough to histologically back-up diagnosis. Liver biopsy confirms chronic hepatitis diagnosis, determines its grade and stage, sometimes its cause. Liver biopsy also permits assessing treatment response.

Current anatomico-pathological classification of hepatitis

Basic lesions of chronic hepatitis Certain histological lesions are common to all forms of chronic hepatitis, regardless of aetiology. These are intra-portal inflammatory infiltrate, hepatocyte necrosis of the 'border blade' or piecemeal necrosis, hepatocyte necrosis and intra-lobular inflammatory infiltrate. The intra-portal inflammatory infiltrate is composed

of lymphocytes, plasmocytes and very few polymorphonuclear cells (PMN). The proportions of these elements can vary according to the aetiology. Plasmocytes are in greater number in auto-immune hepatitis. The infiltrate is sometimes inflammatory and associated with a more or less formed lymphoid follicle, sometimes with a germinal centre reconstituting an activated follicle of secondary lymphoid organs [5]. Piecemeal necrosis is defined as a necrosis of the hepatocytes localized at the interface between hepatic lobule and connective tissue of a portal space or fibrous septum. Intra-lobular hepatocyte lesions are the hepatocyte balloonization (increase in size and clarification of hepatocytes] and eosinophil necrosis (leading to Councilman body formation]. These lesions are focal, affecting an isolated hepatocyte or a small cluster of hepatocytes. Necrosis can be confluent, reflecting death of a number of adjacent hepatocytes replaced by inflammatory elements and cellular debris. The connective pattern is abnormally visible. When that confluent necrosis links portal spaces and/or centra-lobular veins, it is called 'bridging necrosis'. Bridging necrosis between a portal space and a centra-lobular vein has pejorative prognostic value. The intensity, composition and localization of the inflammatory infiltrate and of hepatocyte necrosis vary according to patient, development or aetiology of chronic hepatitis. Fibrosis is the consequence of the above lesions. Its extent is variable. Fibrosis can be periportal, moderate without architectural modifications of the liver lobule. It can be bridging, either between portal spaces or between portal spaces and centra-lobular veins, accompanied by local lobular architectural changes. In the worst situation, cirrhosis is constituted: annular mutilating fibrosis delimitates regeneration nodules. Grades and stages of chronic hepatitis The grade of chronic hepatitis defines the intensity of the necrotic-inflammatory process at the time of liver

Table 1. (From Ludwig) Causes

Grades

Stages

• Chronic hepatitis chronic hepatitis B chronic hepatitis B & D

1 - minimal activity 2 - mild activity 3 - moderate activity

chronic hepatitis C viral chronic hepatitis unspecified undetermined chronic hepatitis: viral or autoimmune or cryptogenetic viral and autoimmune chronic hepatitis drug-related chronic hepatitis •Autoimmune hepatitis • Primary biliary cirrhosis • Hepatitis associated with primary sclerosing cholangitis •Wilson's disease • Hepatitis associated with al anti-trypsin deficiency

4 - severe activity

1 - No fibrosis 2 - Periportal fibrosis 3 - Septal fibrosis Without cirrhosis 4 - Cirrhosis

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(B, C, and D viruses), autoimmune (type 1: antinuclear and anti- smooth tissue autoantibody; type 2: anti-LKM 1 antibody directed against cytochrome P450 II D6; type 3: other antibodies) or drug-related, in certain cases to be related to autoimmune hepatitis (presence of anti-cytochrome P450 antibody induced by drug treatment). Certain chronic hepatitis are still of undetermined causes after comprehensive clinical and biological investigation: these chronic hepatitis are called cryptogenetic. Primary biliary cirrhosis, primary sclerosing cholangitis. Wilson's disease and a-1 antitrypsin deficiency often exhibit identical morphology to that of chronic hepatitis. Effectively, these pathologies can also share clinical and serological diagnostic criteria with chronic hepatitis. That is the case in particular with primary biliary cirrhosis with anti-nuclear antibodies, called primary autoimmune choliangites. The breaking down of chronic hepatitis aetiologies permitted the development of adapted therapeutics, such as corticoids for autoimmune hepatitis and interferon a for chronic hepatitis linked to viruses B and C. A new classification for chronic hepatitis was presented before the World Conference of GastroEnterology in Los Angeles in 1994. That classification takes the clinical, serological (viral, autoantibody serology) and morphological (stage of severity of necroticinflammatory lesions, fibrosis stage or extent) data into account. It was mostly based on Ludwig's [3] and Desmet et al.'s [4] proposals. The classification is detailed in Table 1.

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Histological lesions of chronic hepatitis linked to the C virus The introduction of serological screening tests for C virus infection revealed that 60 to 90% of patients with non-A non-B chronic hepatitis had anti-HCV antibodies. The remaining 10 to 30% are patients with antiHCV or anti-HBV antibody levels too low to be detectable or patients with chronic hepatitis linked to unknown viruses. The identification of histological lesions characteristic of C virus infection presents multiple advantages. It distinguishes between patients cured of their viral infection but presenting positive HCV serology and normal transaminase, from those with C virus chrome hepatitis despite a normal transaminase. It also permits diagnosing chronic hepatitis linked to C virus in patients with negative or undetermined HCV serology and undetectable viraemia. Lastly, it provides diagnosis for chronic hepatitis C associated with another liver disease, of alcoholic origin in particular. Unfortunately, there are no specifically recognizable lesions of chronic infection by HCV. Nevertheless, the association of certain histological signs has been sufficiently standardized or stereotyped to secure diagnosis in a large number of cases. The characteristic pathological aspects of chronic HCV hepatitis associate clinical hepatitis with minimal or mild activity, a few piecemeal necrosis lesions, intraportal lymphoid folhcles, lesions in the interlobular biliary channels, macrovacuolar stenosis and a 'leukaemia-like' intralobular lymphocyte inflammatory

infiltrate [1,6]. Intra-lobular hepatocyte necrosis is generally punctual and eosinophilic. Hepatocytes in eosinophilic necrosis are isolated or surrounded by a microgranuloma composed of Kuppfer cells, macrophages and lymphocytes. More unusual lesions have been reported, such as Mallory bodies or epithelioid and giant cell granulomas [7]. None of the above described signs is specific to HCV chronic hepatitis. Intra-portal lymphoid follicles, the most evocative lesion of HCV infection observed in 49-78% of cases according to series [6,7] are also more frequent in primary binary cirrhoses, autoimmune chronic hepatitis and HBV chronic hepatitis. The biliary channel lesions observed in 31 to 90% of HCV chronic hepatitis, according to series [7,8], are also found in primary biliary cirrhosis, drug-related hepatitis (Chlorpromazine) and liver graft rejection. Lymphoid follicles and biliary channel lesions are generally associated with viraemia. Lastly, chronic hepatitis with severe activity may by linked to the C virus. Histology also varies according to the mode of contamination and to the size of the inoculum [9]. Several studies have reported that patients infected during blood transfusion presented with chronic hepatitis histologically more active than drug-abuser patients with negative HIV serology [9]. So far, no specific and distinctive histological signs have been described according to the various HCV genotypes. Infection by HCV genotype lb and high viraemia are signs of poor response to interferon a treatment. The HAI, not correlated to viraemia, is a poor predictor of treatment response. In responder patients, interferon a induced a regression of the intra-portal inflammatory infiltrate, of piecemeal necrosis and intra-lobular inflammatory infiltrate. The hepatocyte necrosis disappears. These histological lesions recur in the event of a relapse. Immunohistochemistry, in situ hybridization and in situ polymerase chain reaction have shown that there were few viral particles in the liver. The virus infects hepatocytes as well as macrophages and lymphocytes [10]. These techniques are not part of the HCV screening routine techniques because of their poor sensitivity or complexity. However, they should contribute to a better understanding of the lesions induced by HCV. At the moment, intra-lobular lymphocyte necrosis, piecemeal necrosis and biliary lesions are thought to be induced by the host's immune reaction. Mallory bodies and steatosis are thought to be linked to the directly cytopathogenic action of HCV, a member of the Flavivirus family. Intra-portal lymphoid follicles could be part of the autoimmune lesions associated with HCV chronic hepatitis [5,7]. Thyroiditis, Sjogren's syndrome and high anti-LKM-1 or antiGOR antibody titres are other manifestations which reflect the occurrence of autoimmune phenomena linked to HCV chronic infection. Conclusion Liver biopsy sampling is of diagnostic and prognostic value. It provides a diagnosis of HCV chronic hepatitis,

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biopsy. The stage of chronic hepatitis defines the extent of liver mutilation by fibrosis. The stage of chronic hepatitis is linked to the duration of disease. Various scoring tools are currently used to assess the grades and stages of chronic hepatitis. The tool most widely used is Knodell's score, or Histological Activity Index (HAI]. The basic lesions which determine that score are the intensity of the intra-portal inflammatory infiltrate, rated 0-4, the intensity of piecemeal necrosis and bridging necrosis, rated 0-10, the intensity of intra-lobular hepatocyte necrosis, rated 0-4 and the extent of fibrosis, rated 0-4. A number of pathologists now discriminate the first three data which constitute the grade of the fourth one, which constitutes the stage. So, the maximum grade score can be 18: a 1-3 score describes chronic hepatitis with minimal activity, 4-8 describes chronic hepatitis with mild activity, 9-12 is a chronic hepatitis with moderate activity and a 13-18 score describes a highly active and severe chronic hepatitis. The persistent chronic hepatitis of the former classification would score 1-5. The stage is rated 0-4. A score of 4 reflects cirrhosis. The poor correlation between histological activity, as assessed by HAI, and biological activity measured by serum transaminase level, may be due to the size of a biopsy specimen being too small, but also to slower evolution of histological lesions in relation to the transaminase variations.

Current anatomico-pathological classification of hepatitis

is References

Fig. 1. Histological aspect of HCV chronic hepatitis with moderate activity and extendedfibrosis:the intra-portal inflammatory infiltrate is important and associated with an intra-portal lymphoid nodule. Piecemeal necrosis lesions are also present (haematein-eosine x 200).

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it permits detecting or ruling out another pathology, assessing the grade and stage of chronic hepatitis and the effectiveness of interferon a treatment. Lastly, systematic liver biopsy contributes to the understanding of the mechanisms which lead to hepatocyte necrosis during HCV chronic hepatitis.

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