Pathology of chronic hepatitis

2021-01-27 12:00 AM

Intense mononuclear inflammatory cell infiltrates in the portal space extends into the hepatic lobule (in plasmocyte autoimmune hepatitis).


Chronic hepatitis (VGM) is a manifestation of many types of liver damage caused by various causes, including inflammation and hepatocellular necrosis lasting> 6 months. A mild form is a form that does not progress or progress very slowly and does not lead to cirrhosis or liver cancer while the severe form is a form of severe necrotizing fasciitis or multiple progression attacks on liver cells that eventually lead to fibrosis and oncology. Chronic hepatitis caused by a variety of causes is most common after hepatitis, especially B, C, and B combined with D and more recently, chronic hepatitis G; autoimmune hepatitis, drug-induced chronic hepatitis.


Lesions are often a combination of inflammatory laxative, necrotic and fibrosis. Inflammatory cell laxative is mainly in the portal space, causing the portal space to expand, inflammation also occurs around the liver lobules, with liver cells becoming necrotic. Laxative inflammatory cells are mainly mononuclear inflammatory cells especially lymphocytes and plasmocytes and monocytes

Hepatocellular necrosis is usually severe and widespread, especially cluster necrosis of several or three cells at the site of access to the portal, this necrosis called termite necrosis, very characteristic of chronic hepatitis work. Another common type of necrosis is bridged necrosis, connecting the portal space and the central vein of the lobule.

Neoplastic fibers and nodules change more or less depending on the stage of disease progression, in the post-fibrosis predominates and causes the liver structure to completely turn upside down and the appearance of neoplastic nodules. The inflammation is reduced gradually to the image of the disease stage as in cirrhosis and eventually cancer may be developed.

Classification of chronic hepatitis

Currently, it is classified based on a combination of clinical, serological and histological changes giving more information values. The classification of chronic hepatitis is based on the following factors


Histological activity is also known as degree.

Progression is called stage.

Sort by cause

Clinical and serum diagnosis allows the diagnosis of chronic hepatitis caused by viruses, mainly viruses B, C, combination D, other viruses; Chronic autoimmune inflammation includes subgroups: type 1, type 2 and type 3; chronic drug-induced hepatitis; Chronic hepatitis of an unexplained hepatitis is called Cryptogenic chronic hepatitis.

Sorted by degrees

Gradation is based on histological evaluation of necrotic activity during liver biopsy. The evaluation of histological severity included perioral necrosis and disruption of the perioral hepatocyte layer by necrotic inflammatory cells called termite necrosis. The connection of these necrosis forms bridging necrosis, connecting the portal space and central blood vessels, or the portal spaces together. Many systems score this level of necrosis, but the most popular today is a hepatitis activity index (HAI) based on the work of Schnell and Ishak. HAI is a measure of degree, which also measures the fibrosis level that is currently used to segment the disease. It is also used to measure disease activity before and after treatment. Clinical VGM divided into 3 degrees mild, moderate and severe.

Classification by stage

This category reflects the stage of the disease progression, based on the degree of cirrhosis of the liver.

Lint free.

Mild fibers.

Medium fiber.

Heavy fibers include bridging fibers.

True cirrhosis of the liver.

Classification associated with histology

Chronic hepatitis exists:

Diffuse mononucleosis cell laxative but confined to the portal space, the portal boundary intact and there is no invasion of necrotizing fasciitis into the hepatic lobe, or with only a little fibrosis around door without cirrhosis. Usually asymptomatic or very mild patient such as fatigue, loss of appetite, nausea. Very poor entity may only have a slightly large or normal liver. The enzyme transaminases increased only slightly and had no or very little involvement with cirrhosis.

Small lobe chronic hepatitis:

In addition to portal inflammation, histological examination has focal necrosis and inflammation in the lobules. Morphologically, chronic lobular hepatitis is similar to the slow progression of acute hepatitis. The boundary around the portal space remains intact, with no cirrhosis around the portal or limited, the lobe structure is retained and seldom converted to active chronic hepatitis and cirrhosis. Therefore, sub-lobe chronic hepatitis is considered as a form of chronic hepatitis that exists. Sometimes the clinical activity of chronic lobe hepatitis is spontaneously increased, the transaminase activity is similar to that in acute hepatitis and has transient hepatic histological damage. The current term for chronic lobe hepatitis is to correspond to a mild or moderate form and the stage with no minimal fibrosis or fibrosis.

Chronic active hepatitis:

Clinical features are characterized by persistent portal necrosis, periosteal, hepatic lobe inflammation and fibrosis, ranging from mild to severe. Chronic active hepatitis is known as the process of liver damage that leads to cirrhosis, failure, and death. Morphological features of the active chronic liver tablets include:

Intense mononuclear inflammatory cell infiltrate in the portal space extends into the hepatic lobule (in plasmocyte autoimmune hepatitis).

Destruction of hepatocytes around the lobule disrupting the hepatocellular barrier around the portal space (termite-style necrosis).

The fibrous wall surrounds the portal space and extends from the central opening, isolating the parenchymal cells into a cluster and enveloping bile ducts.

There is a regeneration of the liver parenchyma to form a rose, and a thickening and regeneration of the liver parenchyma (neutrophil).



The onset of symptoms may manifest as flare-ups like in acute hepatitis (one third of the cases), with the remainder often unnoticeable by the majority of patients, often manifested only by functional symptoms common is fatigue, feeling of heaviness in the right lower rib region, sometimes there is muscle pain, joint pain or sometimes only general aches and pains. During episodes, symptoms are often richer and more intense with fever, jaundice, yellow or dark urine, muscle and joint pain, and especially liver pain and itching. Examination found that the liver is medium-large, tight, painful, jaundice, erythematous and star-shaped vasodilation. There may be 30% enlarged spleen especially in the presence of portal hypertension, accompanied by groin; lymph nodes 15-20% are usually axillary and cervical.

Extra-hepatic manifestations may be seen: skin rash, Hashimoto autoimmune thyroiditis, vasculitis, glomerulonephritis, Sjogren's syndrome, bleeding ulcerative colitis, anaemia, thrombocytopenic bleeding.

In the post-cirrhosis period, inflammatory manifestations usually subside instead that of cirrhosis and liver failure is prominent; or symptoms of liver cancer with a very large, stiff liver with lumpy tumours.


CTM: BC and HC usually decrease, can decrease both TC, VS often increases.

Liver function: Very variable.

Bilirubin increases both direct and indirect.

The transaminase enzyme usually increases> 5 times normal.

Gamma globulin increased but albumin decreased, A / G ratio was very low.

The prothrombin ratio decreased; factor V decreased.

The alkaline phosphatase increased.


HBsAg (+), viral DNA, DNA polymerase and HBeAg (+) in chronic active hepatitis B.

Anti HVC and HVC-RNA (+) in chronic hepatitis C virus.

KT- anti-nuclear, KT-smooth muscle resistance, KT- mitochondrial resistance (+) in autoimmune hepatitis.

Liver biopsy:

L à a necessary test to help diagnose the cause and stage, severity of chronic hepatitis images necrotic inflammatory infiltration of liver necrosis termites gnaws, necrotic bridging necrosis array interspersed with highly developed fibrous organization in the portal lobule infiltration and neo-nodular nodules in later stages.

Diagnose the cause


Chronic hepatitis B:

During the recovery period, about 1-10% of patients still carry the virus, the risk of chronic disease is facilitated by a previous immunodeficiency state. Infection from the new-born is usually silent but up to a 90% risk of becoming chronic, while infection in adolescents is already immune, the clinical manifestations of acute hepatitis are more pronounced, but only 1 % becomes chronic. The degree of liver damage varies from mild, moderate and severe; The degree of tissue damage is related to the severity of the disease. A 5-year follow-up study showed 97% survival in survival of VGM, 55% in active chronic hepatitis.

In addition to histological damage, viral replication is also important in prognosis. Chronic hepatitis is divided into two phases based on viral replication index (HBeAg, HBV-DNA), and presence of intracellular nucleocapsid antigen (HBcAg). In the less viral replication phase, there was no presence of

HBeAg and HBV-DNA but anti-HBe, absence of intracellular HBcAg, this phase is very infectious, and less liver damage. Viral nuclear phase tends to be severe, while in patients with no viral replication phase it is usually mild or moderate hepatitis or healthy carriers. The spontaneous shift from chronic nuclear hepatitis to an annual non-nuclear hepatitis is between 10-15%.

Liver damage due to chronic B virus infection is not caused directly by the virus, but is related to an immune response against hepatocytes due to their antigens, especially HBcAg.

The clinical course of chronic hepatitis B varies from asymptomatic infection to very severe and even fatal liver failure. The onset is usually silent, with only a few presenting as acute hepatitis. The common symptoms are fatigue, intermittent jaundice, with anorexia, later on appearing symptoms of cirrhosis and portal hypertension such as oedema, groin, bleeding, especially from venous enlargement of the oesophagus, disorder bleeding clotting, liver encephalopathy, large spleen. the symptoms of the liver are almost identical to those of acute viral hepatitis due to deposition of Ag-Ab immune complexes such as arthralgia, arthritis, skin rash, glomerulonephritis, vasculitis.


Enzyme transaminase increased from 100 to 1000 units in which SGPT increased more, but when cirrhosis, SGOT prevailed.

The alkaline phosphatase increased moderately. Bilirubin increased 3 to 5 times normal.

Albumin blood reduction.

The decrease in prothrombin ratio especially in the severe period is also a prognostic factor.

The markers are HBeAg and anti HBe, HBV-DNA, HBsAg, anti-HBc often (+).

Chronic hepatitis D (Delta):

Discovered in 1977, this is a special virus that can only develop in the presence of B virus.

The clinical picture of chronic hepatitis D is similar to that of chronic hepatitis B, if co-infection, the clinical picture will be very severe but does not seem to increase the progression to chronic, and superinfection in hepatitis B patients. Chronic damage to the liver is very severe.

Diagnosis is based on the presence of HDV Ag and anti HDV both types IgG and IgM. The presence of HDV Ag in the liver and serum HDV-RNA indicate viral replication. The presence of circulating antibodies against the liver-kidney microsome (anti LKM) is an important factor in the diagnosis of chronic hepatitis D, which is a different type of LKM3 from LKM1 in autoimmune hepatitis.

Chronic hepatitis C:

Formerly called 0A0B (not A not B). The chronic progression after hepatitis C is 50-70%. In addition, chronic hepatitis 10 years after blood transfusion leads to cirrhosis. Even for mild to moderate and asymptomatic forms with only a slight increase in transaminases, liver biopsy has only mild to moderate damage. The rate of chronic hepatitis C is compensated leading to cirrhosis is 50%. In patients with anti-HVC although asymptomatic and normal transaminases. In liver biopsy there is also chronic hepatitis and can detect HCV-RNA circulating in the blood. VGM C's progress is often slow and quiet. The degree of progression depends on the HCV-RNA concentration and duration of infection.

Clinical manifestations of VGM. C is similar to B: fatigue is most common, jaundice is rare. Extra-hepatic manifestations due to immune complexes are less common than B with the exception of cryogenic globulin complex. However, it is often combined with Sjogren's syndrome, Lichen planar, skin porphyrin.

The tests are similar to VGM B, but the enzyme transaminase is less erratic and less likely. Sometimes there are autoantibodies.

Anti - LKM1 usually (+) like the autoimmune type 2 VGM.

Anti - C100, Anti C22 / 33 (+).

Chronic autoimmune hepatitis

It is also a chronic disease in which the liver is continuously inflamed, necrotic, and fibrosis eventually leading to cirrhosis, accounting for 10-20% of VGM. The disease is caused by an autoimmune reaction against the Antigens that is currently not fully identified, three quarters of the cases are encountered in young women. Extra-hepatic autoimmune manifestations as well as serum immunological abnormalities reinforce this disease.

The process of liver damage is cellular-mediated against liver cells, on the basis of a genetic predisposition by chemicals and viruses. The evidence supports autoimmune VGM:

Histological damage to the liver is mainly toxic T cells and cytoplasm.

The circulating autoantibodies: antinuclear, anti-smooth muscle, anti-thyroid ... factor, rheumatoid factor, increased blood globulin. - Together with other autoimmune diseases: thyroiditis, rheumatoid arthritis, autoimmune haemolysis, ulcerative colitis, proliferative glomerulonephritis, diabetes, Sjogren's syndrome.

Organizational harmony factor: HLA-B1 (Human leucocyte antigen), - B8, - Drw3 and - Drw4.

The disease responded well to corticosteroids and immunosuppressants.

The clinical picture is similar to chronic viral hepatitis. Onset can be gradual or sudden with fatigue, loss of appetite, amenorrhea, acne, joint pain, skin rash, colitis, pleural effusion, pericardium, anaemia, conjunctivitis, dry eyes enlarged spleen, oedema.

Laboratory tests: in addition to biological disorders as in chronic viral hepatitis, here Gamma globulin> 2, 5g%, Low factor (+). Antinuclear antibodies, anti-mitochondria (+).

Diagnosis: Based on the following factors:

There is no known etiology.

Often combined with other immune disorders: Lupus, PCE, Hashimoto, haemolytic anaemia, Sjogren's syndrome ...

Presence in the serum of autoantibodies.

Depending on the types of antibodies, it is divided into 3 antibodies:

Type 1: usually occurs in young women, increased gamma globulin, antinuclear antibodies and smooth muscle.

Type 2: typically occurs in Mediterranean children, LKM1 antibodies.

Type 3: has antibodies to the liver soluble antigen.

Chronic drug-induced hepatitis

Some drugs, especially when used for> 6 months, can cause VGM, the most common are: Clometacin, Tiénilique acide, (-méthyldopa,

Nitrofurantoin, Papaverine, Oxyphenacetin, Isoniaside, Amiodarone, Aspirin, Acetaminophen, Vitamin A, Methotrexate, PTU.

Drug-induced lesions are usually very severe and cirrhosis is usually present before disease is discovered.

Diagnosis should be based on the following factors:

Long history of hepatotoxic drugs.

Going well when stopping the drug.

Other causes could not be found.

Some tests are quite specific for each drug: Liver biopsy with hepatocellular lipide-phospo infection in Amiodarone-induced chronic hepatitis, KT antimitochondrial anti-M6 in chronic hepatitis caused by Isoniaside, Anti LKM3 in hepatitis caused by tiénilique, anti-LM in dihydralazine-induced chronic hepatitis ...

Diagnose the form of the disease

Chronic hepatitis persists


Mechanical function: usually very quiet and gentle, with no symptoms or just slight fatigue, loss of appetite, discomfort in the epigastric region or lower right rib; sometimes mild irritation in the liver.


Jaundice: absent or very discreet.

Erythema and spider nodules are absent.

Liver: Not large or slightly grown by a few centimetres, soft, mild, but painless.

Nodes have no. Spleen is not large. There is no door booster.



Yeast transaminase did not increase or only increased slightly 2-3 times.

The alkaline phosphatase, Bilirubin, and gamma globulin did not increase or only slightly.

No viral replication activity.

Histology: Mild inflammation of the portal space with mononuclear inflammatory cells, but never beyond the portal space. Liver damage is normal or very little changed. The liver structure is intact.


Well, with little or no lead to cirrhosis and liver cancer.

Chronic active hepatitis


Mechanical function: The most obvious manifestations are exacerbations with moderate fever, fatigue, loss of appetite, joint pain, muscle pain, and especially pain in the right lower rib. Dark, itchy urine, and jaundice.


The naked eye is most yellow in progression.

Erythema and spider nodules are increasing at most when there is cirrhosis of the liver.

The liver is 3-4cm large below the ribs, the pain becomes tight and then becomes firm, sharp.

Large lymph nodes rate of 20%.

Large spleen 30%.

Gate hypertension: usually appears after cirrhosis has occurred.



Yeast transaminases usually increase> 5 times normal.

The basic alkaline phosphatase and blood bilirubin are usually 3 to 5 times higher than normal.

Globulin increased> 25%.

The ratio of prothrombin and factor 5 decreased.

The viral replication activity is clear: viral DNA, DNA polymerase (+).


Inflammation beyond the portal lobes of the liver.

Broken cabinets in the form of rodents, broken bridge cabinets.

Gangrene or plaque.

Fibrous proliferation, invading hepatic lobule.

The liver structure is reversed.

Prognosis: X infancy, eventually leading to cirrhosis and liver cancer.


Treatment of chronic hepatitis B virus

The aim of treatment of chronic viral hepatitis: to stop viral replication and to halt biological and histological inactivation. There are 3 levels of response:

Type 1 Response: Discontinue viral replication marked by disappearance of viral DNA in serum.

Type 2 response: When viral replication is prolonged by HBe seroconversion (anti-HBe antibodies).

Category 3 response: complete discontinuation of viral replication and HBs seroconversion (anti HBs).


Lamivudine: (Didéoxythiacytidine, Zefflix * from Glaxowellcome) antiviral Herpes and Retrovirus are effective in inhibiting viral replication by inhibiting replication of viral DNA and DNA polymerase. 100mg tablet, 1 tablet a day, for 3 months, the effect of making (-) viral DNA in HT is 100%, but after stopping the drug, 64% turned positive again. It also reduces HBeAg and HBsAg but more slowly.

The 1-year course also resulted in HBeAg negative only in 39% of patients. Lamivudine has also been used in the prevention of re-infection with B virus in liver transplantation by combination with anti-HBsAg immunoglobulin. In hepatitis B combined with HIV infection, the dose of 300mg / ng is very effective.

Famciclovir: dose of 1500mg / ng divided 3 times over 16 weeks significantly reduced the rate of viral DNA and transaminase activity after 1 week. Use of 2nd dose: 750mg / ng for another 16 weeks also significantly increases anti-HBe seroconversion. It is also used in the prophylaxis of liver transplantation, or in case of suppression of treatment with interferon.

Adefovir: (Hepsera) 10mg tablet / day 1 tablet for 6 months to 1 year, kidney function should be monitored.

Interferon: Interferon alpha acts through two mechanisms: one is to inhibit viral RNA and increase the activity of antiviral enzymes. The other is to increase the cellular immune response by increasing the expression of type 1 cell fusion antigens and stimulating the activity of helper T lymphocytes and T killers. Dose of 5 million units daily subcutaneous injection or 10 million units subcutaneously or intramuscularly 3 times a week, used for 4-6 months. Meet type 2 about 40%. The response was better in patients with HBV DNA <200 pg / mL and in patients with transaminases> 100-200 unit


Side effects:

Like a cold with fever, headache, fatigue.

Anaemia, neutropenia, thrombocytopenia.

More severe but less common and site dependent side effects are: psychosis, epilepsy, failure or hyperthyroidism.

Long-acting interferon: Peginterferon 2a (Pegasys), only once a week, dose 90-180mcg.

Corticosteroids: Given interferon for 4 weeks, because when stopped abruptly, there will be an immune response to an increase in viral-infected cell destruction, which will help Interferon work better, but in cirrhotic patients there is risk of severe liver failure.

Liver transplant: Indicated for severe liver failure, but also cannot avoid recurrent hepatitis on transplant liver (80%). Interferon treatment prior to transplantation helps slow this inflammatory process.

Treatment of chronic hepatitis D

Only Interferon is effective in the treatment of VGM D, but it is often more difficult to evaluate since this patient is often combined with HIV infection and VGM.C. With interferon alpha, the inhibitory response to viral replication is 50%, often accompanied by a decrease in transaminases, and a decrease in histological activity, but is rarely achieved a complete discontinuation of viral replication, since Withdrawal of therapy will result in re-emergence of antigens and viral RNA, as well as an increase in transaminase return. Interferon dose is 10 million higher than 10 million v (3 times / week and lasting 6-12 months.

Liver transplantation is also performed for severe liver failure and there is also a risk of hepatitis on the transplanted liver.

Treatment of chronic hepatitis C

Corticoids to no avail.

Interferon alpha is the most effective treatment available today. It disappeared the increase in transaminases after 1-2 months of treatment. Many studies show that interferon normalizes the transaminase enzyme in 50% of cases, as well as reduces histological activity. Dose 3 million units a week 3 times subcutaneously within 6 months. Care should be taken to use interferon in case of severe liver failure, because when treatment is discontinued, there will be a rebound reaction, in terms of chronic hepatitis activity will make the liver worse.

The long-term efficacy of interferon therapy is not fully known. Because after stopping treatment 3 - 6 months, nearly 1 half has phenomenon of relapse. Currently, there are long-acting interferon: Peginterferon 2a (Pegasys), injected only once a week, at a dose of 90-180mcg, better effects and less side effects, but the price is still high.

Ribavirin: A broad-spectrum nucléotide agonist, can be used as monotherapy against virus C, it improves histology and liver enzymes in 30 to 50% of patients. However, it did not significantly reduce the viral load and the biological response was not maintained after discontinuation of the drug. Dosage is 1000-1200mg / ng, used for 6 months.

Liver transplant treatment is similar to VGM B.

Treatment of autoimmune hepatitis

Mainly taking corticoids and immunosuppressants.

Corticoids: Use alone, the dose of 30-60mg / ng for adults within 2-3 weeks, then reduce the dose gradually, to maintain the transaminase enzyme at normal level, with the usual dose of 10-20mg / ng.

If corticosteroids are ineffective, combine with Azathioprine at a dose of 50mg / ng. This dose is effective in 80% of cases. whether alone or in combination with Azathioprine should last for at least 2 years. If after this time the enzyme is normal and there is no more hepatocellular necrosis, discontinue treatment and follow up. If there is a relapse, it must be treated as from the beginning. Usually, the recurrence rate is about 60-90% of the cases, so sometimes it takes lifelong treatment.

Cyclosporine: A highly promising drug currently being used to treat cases that are resistant to corticoids. Dose 5-6mg / kg, lasting 1-2 years.