Chronic Hepatitis - Classification

In 1968, De Groot et al. published a classification of chronic hepatitis in the Lancet journal, which was approved by the European Association for the Study of the Liver. The classification is based on the identification of morphological variants of chronic hepatitis. The authors proposed identifying the following morphological variants of chronic hepatitis.

1. Chronic persistent hepatitis is characterized by pronounced infiltration of the portal fields by lymphoid cells (portal hepatitis). These infiltrates do not penetrate the liver lobule and do not cause damage to the integrity of the border plate (the layer of hepatocytes separating the portal field from the liver lobule). Dystrophic changes may be observed in hepatocytes. Proliferation of Kupffer cells and development of portal fibrosis are possible.
2. Chronic aggressive hepatitis (later the term aggressive was replaced by active hepatitis for deontological reasons).

In this variant of chronic hepatitis, the inflammatory infiltrate captures the portal tracts and then, destroying the border plate, invades the liver lobule, an inflammatory reaction from moderate to severe is noted. Depending on this, chronic hepatitis with moderate and severe activity was subsequently distinguished.

Chronic hepatitis with moderate activity is characterized by stepwise small-focal necrosis of hepatocytes in the parenchyma adjacent to the portal fields. As a rule, inflammatory infiltrates and stepwise necrosis penetrate no further than the middle of the lobules.

In chronic hepatitis with pronounced activity, multilobular, bridging portocentral (connecting portal fields with the central zone of the hepatocyte) and portoportal (connecting adjacent portal fields) necrosis develop. All prerequisites are created for disruption of the architectonics of the liver lobules and the subsequent development of liver cirrhosis.

Subsequently, many authors identified the so-called necrotizing form of chronic hepatitis.

In 1971 Popper and Schaarner demonstrated the existence of a lobular form of chronic hepatitis. It is characterized by small necroses in the second or third zones of the acini and intralobular lymphocyte infiltration, which is expressed significantly more than the infiltration of the portal tracts (a pronounced predominance of intralobular lesions over portal and periportal ones).

In 1974, in Acapulco (Mexico), an international classification of chronic liver diseases was adopted. This classification retained the same morphological principle of dividing chronic hepatitis into persistent and active. However, it was claimed that the etiology of chronic hepatitis is a history of acute viral hepatitis B or A, other etiological factors were considered unproven.

In 1994, the World Congress of Gastroenterologists in Los Angeles adopted the recommendations of the International Working Group on New Nomenclature and Terminology of Chronic Hepatitis and Liver Cirrhosis. It is recommended to include the etiologic component in the diagnosis of chronic hepatitis and liver cirrhosis in all possible cases.

Nomenclature and definition of chronic hepatitis
(World Congress of Gastroenterology, Los Angeles, 1994)

1. Chronic hepatitis B is an inflammatory liver disease caused by the hepatitis B virus (HBV) that lasts 6 months or more and may lead to cirrhosis or be associated with cirrhosis.

The expression to be associated with cirrhosis most likely means the following possibilities:

• chronic hepatitis B joins existing cirrhosis of another etiology;
• Chronic hepatitis B occurs in parallel with cirrhosis of the same nature and determines the degree of activity of the process.

2. Chronic hepatitis D is an inflammatory liver disease caused by hepatitis D virus (HDV) in combination with HBV infection, lasting 6 months or more and which may lead to cirrhosis or be associated with cirrhosis.
3. Chronic hepatitis C is an inflammatory liver disease caused by the hepatitis C virus that lasts 6 months or more and can lead to cirrhosis or be associated with cirrhosis.
4. Chronic viral hepatitis, not otherwise specified, is an inflammatory disease of the liver that lasts 6 months or more and is caused by an unidentified or unknown virus.
5. Autoimmune hepatitis is a non-resolving, predominantly periportal hepatitis (usually with hypergamma globulinemia and tissue autoantibodies) that in most cases responds to immunosuppressive therapy.
6. Chronic hepatitis not classified as viral or autoimmune is an inflammatory liver disease lasting 6 months or more that has features of viral and/or autoimmune hepatitis, but the viral or autoimmune etiologic factor cannot be clearly established.
7. Chronic drug-induced hepatitis is an inflammatory liver disease that lasts for 6 months or more and is caused by a side effect of a drug. The side effect of a drug may be due to:

• direct toxic effect of the drug or its metabolites;
• idiosyncratic reaction to a drug or its metabolite.

8. Alpha2-antitrypsin deficiency liver disease is a chronic liver disease associated with or caused by an autosomal recessive disorder of protein metabolism, typically characterized by abnormally low serum alpha-antitrypsin (serum alpha-protease inhibitor) levels. The liver disease may lead to or be associated with chronic hepatitis or cirrhosis.
9. Primary biliary cirrhosis.
10. Primary sclerosing cholangitis.
11. Wilson-Konovalov liver disease.

Terms that are outdated and which are not advisable to use are:

• chronic persistent hepatitis;
• chronic active hepatitis;
• chronic non-purulent destructive cholangitis;
• pericholangitis;
• portal cirrhosis of the liver;
• postnecrotic liver cirrhosis;
• posthepatitis cirrhosis of the liver;
• Laennec's cirrhosis of the liver;
• nugritive cirrhosis.

The recommendation not to use the terms chronic persistent hepatitis, chronic active hepatitis, and chronic lobular hepatitis is explained by the fact that these categories essentially represent a system for assessing the degree of activity of the inflammatory process in the liver. Morphological variants of chronic hepatitis correlate with its degree of activity.

Desmet, Gerber, Hoofiiagle. Manus, Schneuer in 1995 proposed a classification of chronic hepatitis, which, in their opinion, allows for the implementation of all available clinical, etiological and histological information. The classification is divided into three main sections: etiology, degree of activity and stage of the disease.

The authors identify the following etiological forms of chronic hepatitis: chronic hepatitis B, chronic hepatitis C, chronic hepatitis D, autoimmune hepatitis (types 1, 2, 3), drug-induced chronic hepatitis, chronic hepatitis of unknown etiology (cryptogenic hepatitis).

The degree of activity of chronic hepatitis is determined by the severity, expression and depth of the necrotic and inflammatory processes.

To determine the degree of activity of chronic hepatitis, the authors propose using the Knodell histological index (HAI index).

Etiology of chronic hepatitis

• Chronic hepatitis B
• Chronic hepatitis D
• Chronic hepatitis E
• Chronic hepatitis G
• Autoimmune hepatitis
  • type 1
  • type 2
  • type Z
• Drug-induced hepatitis
• Cryptogenic hepatitis

[ 1 ], [ 2 ], [ 3 ], [ 4 ], [ 5 ], [ 6 ], [ 7 ]

Components of the histological activity index (Knodell, 1981)

Components	Digital rating range
1. Periportal necrosis with or without bridging necrosis	0-10
2. Intralobular degeneration and focal necrosis	0-4
3. Portal necrosis	0-4
4. Fibrosis	0-4

Note:

1. The degree of activity is reflected by the first three components, the fourth - the stage of the process.
2. The histological activity index is obtained by summing the numbers for the first three components.

Depending on the histological index, 4 degrees of activity can be distinguished: minimal, mild, moderate, severe, and a correlation can be made with forms of chronic hepatitis according to the old terminology.

To assess the degree of activity of chronic hepatitis, the blood level of ALT and clinical data are also used.

• Mild course of the process - ALT activity less than 3 norms.
• Moderate course - ALT activity from 3 to 10 norms.
• Severe course - more than 10 norms.

The clinical course is assessed based on three main methods:

• using a questionnaire with a list of symptoms (fatigue, nausea, abdominal pain, poor appetite), the patient indicates the degree of influence of these symptoms on him: no influence (0) or influence slightly (1), moderately (2), quite significantly (3), extremely (4);
• use of a 10 cm long analogue scale, graduated from “absent” to “I have not experienced a more severe condition”, on which the patient makes a mark at the point corresponding to the severity of each symptom;
• the use of the Karnofsky scale, which asks patients to rate their symptoms based on how they cope with the challenges of everyday life, i.e. the impact of disease symptoms on quality of life is assessed.

Stages of chronic hepatitis

Stages of chronic hepatitis are distinguished based on the degree of expression and prevalence of fibrosis and development of cirrhosis. In chronic hepatitis, fibrous tissue forms inside and around the portal tracts, combined with a periportal necrosis process. Stepwise necrosis can spread to adjacent portal tracts (porto-portal septa) or penetrate into the liver lobules and reach the central hepatic veins (porto-central septa).

Liver cirrhosis is characterized by parenchymal regenerative nodules surrounded by fibrous septa, which leads to architectural disturbances, impaired blood flow and portal hypertension.

Thus, taking into account the above recommendations of the World Congress of Gastroenterologists in Los Angeles (1994), the proposals of Desmet et al. (1995), the modern classification of chronic hepatitis can be presented as follows:

Serological markers and variants of chronic hepatitis

Chronic hepatitis B

• Replication phase (HBeAg-positive chronic hepatitis) - serological markers: HBeAg, HBcAbIgM, pre-S antigens, DNA polymerase, DNA-HBV
• Integration phase (HBeAg-negative chronic hepatitis) - serological markers: HBsAg, HBcAblgG, HBeAb
• HBeAg-negative chronic hepatitis with preserved viral replication (mutant HBVe variant) - serological markers: DNA
  polymerase, DNA-HBV, HBcAgM, pre-S antigens, HBeAb

Chronic hepatitis D

• Serological markers of the replication phase. HDV-RNA, antibodies to D-antigen IgM and IgG

Chronic hepatitis C

• Serological markers of the replication phase: HCV-RNA, HCVcoreAblgM and IgG

Chronic hepatitis G

• HGV-PHK

Autoimmune hepatitis (type 1)

• Antibodies to nuclear antigens or smooth muscle

Autoimmune hepatitis (type 2)

• Antibodies to liver-renal microsome type I, directed against cytochrome P-450 11 D6

Autoimmune hepatitis (type 3)

• Antibodies to solubilized liver antigen

Drug-induced hepatitis

• In some cases, antinuclear antibodies and antibodies to liver-renal microsomes

Degree of activity of chronic hepatitis

• Chronic hepatitis with minimal activity
• Mild chronic hepatitis
• Moderate chronic hepatitis
• Severe chronic hepatitis

[ 8 ], [ 9 ], [ 10 ]

Degree (stage) of fibrosis

• No fibrosis
• Weakly expressed
• Moderate fibrosis
• Severe fibrosis
• Cirrhosis

[ 11 ], [ 12 ], [ 13 ]