Autoimmune hepatitis

Description:

Autoimmune hepatitis (AIG) represents the chronic immune mediated liver disease which is characterized by development of an inflammation, fibrosis, cirrhosis, in some cases a liver failure.

Allocation of AIG in group of chronic diseases of a liver is caused by existence of chronic hepatitis with bright systemacity of defeat and development of a wide range of serumal autoantibodies. The first description of AIG belongs to 1950. At 6 young women "vascular asterisks", high rates of SOE, good effect of treatment hormonal drugs were noted. In the late sixties - the beginning of the 70th years a number of the researches showing high performance of therapy by hormones and Azathioprinum at AIG are conducted.

Reasons of autoimmune hepatitis:

The etiology of this disease is unknown.

Prevalence. AIG belongs to rare diseases: in Europe and North America incidence makes from 50 to 200 cases on 1 million population. According to the European and North American statics, patients with autoimmune hepatitis make up to 20% of all patients  with chronic hepatitis. In Japan AIG is diagnosed in 85% of all  cases of chronic hepatitis.

Pathogeny:

Women at young age are ill preferential. A ratio of women and men among the diseased 8:1. Close connection with a number of antigens of the main complex of histocompatability is characteristic of autoimmune hepatitis (the Ministry of Taxes and Tax Collection; HLA at the person), participating in immunoregulatory processes. In particular, alleles of HLA DR3, Al, B8, DR4, DQ2, B14, C4AQ0 are associated. There are proofs about value of defect of a transkriptsionny factor (AIRE-1) in development of autoimmune hepatitis (its role in formation and maintenance of unresponsiveness is supposed). Because autoimmune hepatitis develops not at all carriers of the alleles specified yours, the role of the accessory trigger (starting) factors starting autoimmune process among which there are viruses of hepatitis A, B, C, herpes (HHV-6 and HSV-1), Epstein-Barre, reactive metabolites of medicines, etc. is discussed. The essence of pathological process comes down to deficit of immunoregulation. At patients decrease in T-suppressor subpopulation of lymphocytes is, as a rule, observed, later in blood and fabrics anti-nuclear antibodies to unstriated muscles, to a specific lipoproteid of a liver appear. Frequent detection of a LE cellular phenomenon with existence of the expressed systemic (extrahepatic) lesions inherent to a system lupus erythematosus, gave the grounds of J. Mackay to call this disease of "lupoid hepatitis".

Symptoms of autoimmune hepatitis:

Manifestations of AIG vary from a heavy acute hepatitis, chronic hepatitis of varying severity and expressiveness of inflammatory activity in a liver before atypically proceeding observations. At 50% only laboratory symptoms of chronic hepatitis come to light, at 30% of patients at the first inspection cirrhosis, and at 20-40% extrahepatic manifestations comes to light.

The beginning of a disease, as a rule, from nonspecific symptoms: weaknesses, nausea, jaundices, abdominal pains, joint pains. 30-40% of patients show the acute beginning of a disease as acute viral or toxic hepatitis with the expressed jaundice, at untimely treatment the liver failure with need of urgent liver transplantation can develop.

Diagnosis:

In diagnosis of autoimmune hepatitis definition of such markers as antinuclear antibodies (ANA), antibodies to microsomes of a liver and kidneys (anti-LKM), antibodies to smooth muscle cells (SMA), soluble hepatic (SLA) and hepatopancreatic (LP) antigens, an asialo-glycoprotein to receptors (hepatic lectin) and antigens of a plasma membrane of hepatocytes (LM) matters.

The international group on studying of autoimmune hepatitis (1993) published diagnostic criteria of this disease, having selected diagnoses of a certain and probable autoimmune hepatitis.

Statement of a certain diagnosis requires absence in the anamnesis of hemotransfusions, reception of hepatotoxic drugs, alcohol abuses; lack of seromarkers of an active viral infection; levels at - globulins and IgG, more than by 1,5 times exceeding normal; credits of ANA, SMA and LKM-1 1:88 for adults and higher than 1: 20 for children; substantial increase of activity of ASAT, ALAT and less expressed increase in an alkaline phosphatase.

It is known that at 95% of sick PBTs definition of AM A represents the main serological diagnostic marker of a disease. At the rest of patients with characteristic kliniko-biochemical and histologic signs of PBTs AMA do not come to light. At the same time, according to a number of authors, ANA (to 71%), SMA (to 37%) and other autoantibodies quite often are found. So far a consensus which would allow to carry this pathology to this or that nosological form was not created. The most often this syndrome is designated as an autoimmune cholangitis which current is deprived of peculiar features that gives the grounds for the assumption of possible secretion of AMA in prethreshold concentration.

The true cross syndrome or AIG/PBTs is characterized by the mixed picture of both diseases and observed at 9% of total number of sick PBTs. At the patient with the proved PBTs the diagnosis of a cross syndrome is established with not less than two of four following criteria:

ALAT not less than 5 norms,
IgG not less than 2 norms.
SMA in a diagnostic caption (> 1: 40).
Periportal step necroses in a bioptata,
There is an accurate association of a syndrome of AIG/PBTs with HLA B8, DR3 and DR4. In serum various autoantibodies decide on the most typical combination in the form of AMA, ANA and SMA. Frequency of identification of AMA at sick AIG, according to some authors, makes 25%, however their caption usually does not reach diagnostic value. Besides, AMA at AIG, as a rule, have no specificity for PBTs though in 8% of cases development of typical antibodies to antigen of an inner membrane of mitochondrions Sq.m is observed. It should be noted a possibility of lozhnopozitivny result of the analysis on AMA at use of a method of an indirect immuioflyuorestsention in view of a similar fluorescent picture with anti-LKM-l.

While the combination of AIG and PBTs occurs generally At adult patients, the cross syndrome (AIG/PSH) is observed preferential in pediatric practice though cases and at adults are described. The beginning of AIG/PSH is usually shown by kliniko-biochemical signs of AIG with the subsequent accession of symptoms of PSH. The range of serumal autoantibodies is almost similar to AIG-1. In the developed stage along with serological and histologic signs of AIG reveal a biochemical syndrome of a cholestasia and fibrous changes of bilious channels in a liver bioptata. The association with inflammatory diseases of intestines found, however, is characteristic of this state it is rather rare by the time of establishment of the diagnosis. As well as in case of the isolated PSH, as the major diagnostic method serves the hongiografiya (endoscopic retrograde, transdermal chrespechechny or magnetic and resonant) allowing to find multifocal ring-shaped strictures inside - and extrahepatic bilious channels. At the same time the normal holangiografichesky picture has to in case of the isolated defeat of small channels. In this situation crucial diagnostic importance belongs to a liver biopsy. Changes of small intra hepatic channels at an early stage are presented by proliferation and hypostasis in one portal paths and their disappearance to others, is frequent in combination with фиброзирующщ, a pericholangitis. Along with it the picture of periportal hepatitis with step or bridge-like necroses and massive limfomakrofagalny infiltration of portal and periportal areas comes to light.

Refer the following to diagnostic criteria of a cross syndrome of AIG/PSH:

association with ulcer colitis less than at PSH;
the association with a disease Krone is very rare;
increase in ShchF, ALAT, ASAT;
ShchF at 50% within norm;
high concentration of IgG;
identification of ANA, SMA, pANCA in serum;
holangiografichesky picture PSH;
histologic picture PSH, AIG (more rare) or combination of signs.
At autoimmune hepatitis at a histologic research in liver tissue the picture of chronic hepatitis with the expressed activity usually comes to light. Bridge-like necroses of a parenchyma, a large number of plasmocytes in inflammatory infiltrate in portal paths and sites of a necrosis of hepatocytes are typical. Infiltrate lymphocytes quite often form lymphoid follicles in portal paths, and periportal hepatocytes create so-called glandulyarny (zhelezistopodobny) structures. Massive lymphoid infiltration is noted also in the centers of segments with extensive necroses of hepatocytes. Quite often the inflammation of small bilious channels and холангиол portal paths meets at safety of interlobular and septal channels. Changes of hepatocytes are shown by gidropichesky or fatty dystrophy.

At a true cross syndrome histologically reveal step necroses in combination with periduktulyarny infiltration of portal paths and destruction of bilious channels. The SINDROA of AIG/PBTs progresses quicker, than typical PBTs, at the same time speed to progress correlates with expressiveness vospalitelno of necrotic changes of a parenchyma of a liver.

Sometimes as a separate cross syndrome allocate also AIG combination to an autoimmune cholangitis proceeding similar to AIG/PBTs syndrome, but for lack of serumal AMA.

Identification of serumal autoantibodies reflects the most frequent phenomenon of autoimmunization at a HCV infection and is observed at 40-65% of patients. The range of autoantibodies is rather wide and includes ANA (to 28%), SMA (to 11%), anti-LKM-l (to 7%), anti-phospholipidic (to 25%), anti-thyroid (to 12,5%), pANCA (5-12%), a rhematoid factor, AMA, antibodies to an asialoglikoproteinovy receptor (anti-ASGP-R), etc. Most often credits of these antibodies do not reach diagnostic values, indicative for this or that autoimmune pathology. At 89% of patients credits of ANA and SMA do not exceed 1: 80. The Seropozitivnost at the same time on ANA and SMA is noted no more than in 4% of cases. Besides, quite often autoantibodies at a HCV infection are polyclonal while at autoimmune diseases they react with strictly certain epitopes.

The research of antibodies to HCV has to be conducted by means of an enzyme immunoassay (IFA), at least, of the second generation, it is desirable with the subsequent confirmation of results a recombinant immunoblotting. At the beginning of the 90th, at the beginning of studying of hepatitis C, in literature messages that to 40% of patients of AIG-1 and to 80% of patients of AIG-2 are positive on anti-HCV appeared. Afterwards, however, it became clear that use of IFA of the first generation for most of patients yielded the false positive result caused by nonspecific reaction against the background of the expressed hypergammaglobulinemia.

At the same time at 11% of patients who correspond to criteria of the International group on studying of AIG and do not answer immunosuppressive therapy or at which the recurrence after cancellation of corticosteroids develops, the positive take of polymerase chain reaction on HCV RNA is observed that gives the grounds to consider them as patients with a viral hepatitis With with autoimmune manifestations.

Treatment of autoimmune hepatitis:

Absolute crawlings to treatment of autoimmune hepatitis are:

- clinical symptoms;
- progressing of pathological process;
- ALAT> norms;
- ASAT> 5 norms;
- at - globulins> 2 norms;
- histologically in tissue of a liver bridge-like or multilobulyarny necroses are found.

Serve as relative indications:

absence and moderately expressed disease symptomatology;
- ASAT from 3 to 9 norms;
- at - globulins < 2 норм;
- morphological and periportal hepatitis.
Treatment is not carried out in case of the asymptomatic course of a disease of dekompensirovanny cirrhosis with bleeding from gullet veins in the anamnesis, at ASAT < 3 норм выраженной цитопении наличии гистологических признаков портального a target="_blank" href="index-280.htm" tppabs="medicalmeds.eu/gastroenterologiya/gepatit/">of hepatitis, inactive cirrhosis

As pathogenetic therapy use glucocorticosteroids more often. Drugs of this group reduce activity of pathological process in a liver that is caused by immunosuppressive influence on K-cells, increase in activity of T-suppressors, considerable decrease in intensity of the autoimmune reactions directed against hepatocytes.

As drugs of the choice serve Prednisolonum or Methylprednisolonum. The initial daily dose of Prednisolonum makes 60 mg (more rare than 50 mg) within 1 week, 40 mg - within the 2nd week, for the 3rd and 4th weeks - 30 mg, a maintenance dose - 20 mg. The daily dose of drug is reduced slowly (under control of a clinical course of a disease, indicators of activity of process), by 2,5 mg by each 1-2 weeks, to supporting which the patient accepts before achievement of full clinical laboratory and histologic remission. Treatment by maintenance doses of Prednisolonum is carried out is long: from 6 months to 2 years, and at a number of patients - during all life.

At achievement of a maintenance dose in order to avoid oppression of adrenal glands it is reasonable to carry out alternating therapy by Prednisolonum, i.e. to accept drug in a double dose every other day. Use of a corticosteroid of new generation of the budesonid having high affinity to corticosteroid receptors and the minimum local side effects is represented perspective.

Relative contraindications to reception of glucocorticosteroids are diabetes, arterial hypertension, osteoporosis, a postmenopause, a cushingoid syndrome.

Therapy with delagil is begun together with Prednisolonum.

Duration of a course of treatment delagil - from 1,5 to 6 months, at separate manumissions - up to 1,5-2 years. Reception of the specified drugs is foreseen according to the following scheme: Prednisolonum within 1 week is used in a dose of 30 mg, the 2nd week - 20 mg, the 3rd and 4th weeks - 15 mg. The maintenance dose makes 10 mg. Azathioprinum is applied on 5№ by mg constantly after the first week. Contraindications are malignant new growths, pregnancy, a cytopenia, intolerance of Azathioprinum. At insufficient efficiency of the scheme increase in a dose of Azathioprinum to 150 mg a day is reasonable. The maintenance dose of a prediizolon makes 5-10 mg, an azatioirbin - 25-50 mg.

As indications to transplantation of a liver serve inefficiency of primary course of treatment within 4 years, a multiple recurrence, side effects of steroid and cytostatic therapy Mprognoz of transplantation, as a rule, favorable, 5-year survival exceeds 90%. The risk of a recurrence is higher at sick AIG of 1 type, especially HLA DRS positive, increasing in process of increase in term after transplantation. Now there are experimental schemes of treatment of AIG including such drugs as cyclosporine, такролимус, the mikofenolat was mofetit, будесониац, etc. However their use was not beyond clinical tests.

At many patients with true cross syndrome AIG/PKP corticosteroids are effective that at an ambiguity of the diagnosis allowing to recommend trial purpose of Prednisolonum in doses, применяв my for treatment of AIG, for the term of 3-6 months. Most of authors decrees howl on high performance of a combination of Prednisolonum with UDHK which leads to full remission at most of patients after remission induction patients have to receive a maintenance therapy Prednisolonum (10-15 mg) and UDHK (10-15 mg / ki in days) vaguely long time. The question of cancellation of drugs, as well as in case of the isolated AIG, can be put at total disappearance of biochemical, serological and histologic symptoms of a disease.

Insufficient efficiency of Prednisolonum or heavy side effects at its appointment form the basis for connection to therapy of Azathioprinum.

Data on efficiency of immunosuppressors at a syndrome of AIG/PSH are contradictory. While one researchers point to resistance to corticosteroid therapy of most of patients, others provide opposite data on the good response to monotherapy by Prednisolonum or its combination with Azathioprinum. Recently published statistical data demonstrate that against the background of treatment by immunosuppressors die or transplantations of a liver more than 30% of patients (are exposed at the isolated AIG only of 8%). It is necessary to take into account that sick PSH belong to the category of persons with the increased risk of osteoporosis and biliary sepsis that significantly limits possibilities of use at them of corticosteroids and Azathioprinum.

UDHK (урсосан) in a dose not less than 15-20 mg/kg, apparently, can be considered as choice drug at AIG/PSH syndrome. Performing trial therapy of UDHK in a combination with Prednisolonum is advisable, considering preliminary positive takes of clinical trials. In the absence of significant effect Prednisolonum should be cancelled in order to avoid development of side effect of pi to continue treatment by the raised UDHK doses.

Treatment of the verified HCV infection with the expressed autoimmune component presents special difficulties.

Appointment IFN-ss which in itself is the inductor of autoimmune processes can lead to deterioration in a clinical course of a disease up to development by the progressing hepatic cases of a fulminantny liver failure are insufficiently described.

Against the background of use IFN-a for sick HGS with existence of markers of an utoimmunization, at the same time an important serological sign there was an increase of an antiserum capacity to ASGP-R. Anti-ASGP-R not only are characteristic of AIG-1, but also probably play a role in a pathogeny of injury of a liver at this disease. At the same time corticosteroids at a viral hepatitis promote strengthening of replication of a virus due to suppression of mechanisms of natural antiviral resistance.

The clinic of Mayo offers use of corticosteroids at credits of ANA or SMA more than 1: 320, in case of smaller expressiveness of an autoimmune component and identification of serumal HCV RNA appointment IFN-a is recommended. Other authors prefer not to adhere to so strict criteria, pointing to good effect of immunosuppressors (Prednisolonum and Azathioprinum) at a HCV infection with the expressed autoimmune component.

Thus, possible options of tactics of treatment of patients with a HCV infection with an autoimmune component provide orientation to credits of autoantibodies, performing immunosuppressive therapy, suppression by immunosuppressors of an autoimmune component with the subsequent use IFN-a.

In case of making decision on the beginning of an interferonoterapiya patients from risk groups are subject to careful monitoring throughout all course of treatment. It should be noted that therapy IFN-a even At patients without initial autoimmune component can lead to emergence of various autoimmune syndromes. Their expressiveness varies from asymptomatic formation of autoantibodies to the developed clinical picture of a classical autoimmune disease. At least one type of autoantibodies appears against the background of an interferonoterapiya at 33-87% of patients with chronic hepatitis C. aiboly frequent of autoimmune syndromes dysfunction of a thyroid gland in the form of hypo - or a hyper thyroidism, Developing at 2,5-20% of patients is.