Chronic hepatitis D

Chronic hepatitis D is the outcome of acute viral hepatitis D, occurring as a superinfection in chronic carriers of HBV markers. The frequency of chronic HDV infection is 60-70%.

The hepatitis D virus exerts a cytopathogenic effect on hepatocytes, constantly supports the activity of the inflammatory process in the liver and, consequently, promotes the progression of the disease.

Due to the fact that active replication of HDV is regulated by the presence of HBV, the formation of chronic hepatitis D in the outcome of the manifest co-infection with hepatitis viruses D and B. As a rule does not occur. Chronic hepatitis D occurs in the outcome of latent coinfection and, especially, in the superinfection of HDV with chronic HBV infection.

[1], [2], [3], [4]

Epidemiology of chronic hepatitis D

The prevalence of chronic hepatitis D has undergone significant changes. If before 1990 the share of hepatitis D in children reached 30% in the structure of all chronic hepatitis D, after 5 years - up to 10, now it is only 2.6%, which can be explained by a sharp decrease in the number of sick children in Moscow clinics, hospitalized from the areas of Central Asia, Transcaucasia and Moldova, which are known to be endemic for hepatitis D.

Currently, the incidence of chronic hepatitis D in Russia is 1%, while in the countries of Central Asia, and in particular in Turkmenistan, the proportion of chronic hepatitis D among chronic viral hepatitis is 8%.

[5], [6], [7], [8], [9], [10],

Pathomorphology of chronic hepatitis D

There are no specific morphological changes characteristic of chronic delta infection. In some cases, inflammation is limited to the limits of portal areas, and the disease is classified as benign chronic hepatitis of minimal and low activity. The majority of patients with chronic hepatitis B and D experience periportal infiltration, which is combined with moth, drain or bridge necrosis of parenchymal cells. Expressed may be intra-lobular infiltration.

Identify three histological types of chronic hepatitis B in the presence of delta infection:

• chronic high-activity hepatitis with predominant peri-portal changes and moderate diffuse inflammation in the lobule (in 70% of patients);
• chronic hepatitis with bridge necrosis and localized in the bridge area by hepatocyte damage and fibrosis (in 20% of patients);
• chronic lobular hepatitis with an intense lobular lesion associated with the accumulation of macrophages and lymphocytes in sinusoids and in zones of focal necrosis of hepatocytes (in 10% of patients).

As a rule, in the delta infection, eosinophilic granular degeneration of individual hepatocytes or groups of parenchymal cells is noted. A complex of histological signs in the form of eosinophilic degeneration of small-droplet hematocyte steatosis in combination with a pronounced macrophage reaction is regarded as a possible manifestation of the cytopathic effect of the hepatitis delta virus.

It is indicated that the parenchymal lesion is significantly more pronounced in cases of chronic hepatitis B and D, in comparison with that for "pure" CHB.

Statically more significant mononuclear hyperplasia and infiltration in the portal zones and within the lobules in liver biopsy specimens in patients with chronic hepatitis B are emphasized, than in patients with chronic hepatitis B without delta infection markers. Morphological changes in chronic hepatitis of high activity due to delta infection are characterized by the advantage of the processes of proliferation of connective tissue over the inflammatory response in the liver. In the morphological study of the liver in adult patients with HGD by the method of K. Ishak et al. (1995) found that moderate or high activity of the pathological process was observed in almost 90% of cases, and the stage of cirrhosis of the liver - in 65%. These data are consistent with the results of other researchers who showed a significant degree of severity of liver damage in CHB.

Consequently, the available publications with the analysis of the pathomorphology of delta infection do not allow us to draw a definitive conclusion about any specificity and isolation from HBV-virus liver damage associated with the hepatitis delta virus. There is a single information about chronic hepatitis D in childhood.

The children we observed with chronic hepatitis B and the presence of serological markers of the delta virus had liver damage in a wide range - from chronic hepatitis of minimal and low activity to chronic hepatitis of high activity with transition to cirrhosis; chronic lobular hepatitis was not observed. However, when comparing morphological changes in the liver, taking into account the presence or absence of delta virus markers, the prevalence of a more severe inflammatory process in patients with chronic hepatitis D was documented, compared with that in patients with only CHB. The proportion of chronic low-activity hepatitis in the absence of anti-delta in the serum ("pure" CHB) is documented in 32.2% of cases. Thus, in the group of patients with delta infection among the morphological variants of chronic hepatitis with a greater frequency (40%) than in the group of patients without delta markers (in 14.9%), a pathological process with a cirrhotogenic orientation (p <0, 05).

Symptoms of chronic hepatitis D

There are two variants of chronic delta infection: joint chronic hepatitis D and CHB; HGD on the background of carriage of HBV virus.

In the first variant, chronic hepatitis D occurs under conditions of continued active replication of HBV, which is documented by the presence of the appropriate markers HBV and HDV in the blood serum.

A distinctive feature of the second variant of chronic delta infection is the absence of serological indicators of high-grade replication of HBV. According to the data of clinical observations, 52% of patients could be more likely to talk about the presence of a second variant of chronic delta infection, since all of them did not show HBeAg in the serum, but there were anti-HBE.

As for anti-HBc total, they were found in all serum samples in patients with both variants of chronic delta-infection.

Serological marker profiles for chronic delta infection

Serological marker	Joint CGB and HBV	HBV on the background of carrier HBV
HBsAg	+	+
HBeAg	+	-
Anti-HBe	-	+
Anti-HBs IgM	+	-
HBV DNA	+	-
RNA NDV	+	+
Anti-HV IgM	+	+
Anti-HDV total	+	+

In patients with low-activity CGD, leading clinical signs are increased liver size, sometimes - the spleen, symptoms of intoxication in the form of fatigue, irritability are possible. In some patients "bruises" are found on the limbs, extrahepatic signs in the form of telangiectasias or palmar erythema. Of the functional tests of the liver, there are moderate hyperfermentemia and a slight decrease in the prothrombin index. Patients with chronic hepatitis D of high activity are characterized by symptoms of intoxication and dyspitic phenomena. Almost half of patients experience increased fatigue, emotional instability, aggressiveness in relations with relatives and peers. With the preservation of appetite, most patients have signs of gastrointestinal discomfort in the form of nausea, a feeling of heaviness in the epigastric region and right hypochondrium, flatulence. The icterity and subcyteric sclera are rarely recombined. Liver enlargement is noted in all patients. A half spleen increases, hemorrhagic syndrome in the form of "bruises" on the limbs, trunk, short-term nosebleeds and limited petechial rash is revealed. Telangiectasias are often found in the form of small elements. Mainly on the face, neck, hands, palmar erythema, characterized by pronounced manifestations of dysproteinemia.

Clinical and laboratory manifestations of chronic hepatitis D with transition to cirrhosis were mainly expressed by symptoms of intoxication, dyspeptic phenomena, skin ichthyosis and sclera, significant enlargement and compaction of the liver, which was always in accordance with the high echogenicity of the organ with ultrasound. Constant symptoms were a significant increase in the spleen and hemorrhagic manifestations with a high incidence of nasal bleeding and petechial rashes. Almost all patients have palmar erythema. Along with the marked clinical symptoms, these children have high rates of hepatic-cell enzyme activity, the prothrombin index and the sulfate titer drop sharply, and the serum γ-globulin content increases.

According to D.T. Abdurakhmanova (2004), YF Liaw (1995), V.E. Syutkin (1999), the joint course of chronic hepatitis D and CHB in adult patients is rare - in 10-16% of cases. In general, hepatitis D virus is suppressed by hepatitis D virus replication of hepatitis B virus. Moreover, the clinical picture of XGD does not differ significantly from that of CHB. Asthenic complaints predominate (weakness, fatigue, sleep disturbance), weight loss, pain and heaviness in the right upper quadrant. Jaundice is observed in individual patients. In the biochemical analysis of blood, an increase in ALT and ACT activity is observed in 3-10 times, in some cases there is an increase in bilirubin content due to the conjugated fraction with simultaneous increase in GGTP level, and a moderate increase in the concentration of y-globulins.

The course and outcome of chronic hepatitis D

At superinfection with hepatitis delta virus in patients with CHB, in addition to the danger of occurrence, as in carriers of HBV fulminant hepatitis, the probability of progression of the pathological process in the liver and rapid development of liver cirrhosis is extremely high.

In this case, three main variants of the course of HGD are distinguished:

• rapidly progressing with the development of decompensation and liver failure in the period from several months to 2 years (in 5-10% of patients, mainly consumers of psychotropic drugs);
• Relatively calm and not progressing course (in 15% of patients);
• the development of severe fibrosis and cirrhosis of the liver for several years with a stable state and development of decompensation after 10-30 years - in 70-80% of patients.

In recent years, when evaluating the course and prognosis of the outcomes of chronic hepatitis D, the genotype of the hepatitis D virus is increasingly being addressed. It has been established that the I genotype is characterized by a spectrum of different variants of the course; II genotype - a mild, mainly non-progressive course, and the third genotype is the most severe, rapidly progressing course with an early outcome in cirrhosis of the liver.

Chronic hepatitis D is characterized by a prolonged persistence of activity. During the observation period from 2 to 10 years, only 24% of patients noted the onset of persistent remission.

The relationship between HBV and hepatitis D virus in the process of chronic hepatitis B and D is ambiguous. Many researchers emphasize the inhibitory effect of the hepatitis delta virus on HBV activity. At the same time, according to the data of other authors, CHB and CGD can proceed for a long time at signs of replicative activity of both pathogens.

Observations show that with HBV and HGD gradual seroconversion of HBeAg to anti-HB occurs, and the disappearance of HBV DNA with continuing replication of the hepatitis virus delta (preservation of the delta antigen in the liver cells and anti-delta in the serum in high titres). Apparently, with the passage of time, the complete replication of HBV ceases, and the activity of the pathological process in the liver is maintained through the reproduction of the hepatitis delta virus. This fundamental question needs further study.

Diagnosis of chronic hepatitis D

With uber infection with the hepatitis delta virus against the background of chronic HBV-viral infection is manifested clinical symptoms of acute hepatitis. Of decisive importance is the detection in the serum of previously absent anti-delta IgM. The diagnostic value is given to the drop in the concentration of HBsAg at the time of superinfection with the hepatitis delta virus. Of the other diagnostic criteria for superinfection, the delta is characterized by a drop in the anti-HBc titers or their complete disappearance.

It is important to point out to M. Rizzetto (2000) that in the presence of a vivid clinical picture of superinfection, the delta antigen in the liver tissue can be the only marker of the virus. Diagnostic difficulties with respect to superinfection of the delta are especially characteristic when it occurs in carriers of the hepatitis Vili virus in patients with slow CVD who are unaware of their carrier or illness. In these cases, the detection of HBsAg in the clinical picture of a typical hepatitis unambiguously guides the doctor only to viral hepatitis B, and only the detection of delta virus markers and the persistent HB5Ag persistence allow ultimately to make the correct diagnosis.

The third situation is also possible, when the onset of delta infection in the current CHB is unknown and is diagnosed by the entry of another clinical or follow-up examination. The main criteria for delta infection in these cases are the detected anti-delta IgM and general anti-delga in permanently high titres. In the subclinical course of CHB, the presence of delta infection can be established based on the detection of anti-delta in elevated titers.

[11], [12], [13]

Treatment of chronic hepatitis D

Considering the presence of persistent immunological disorders (deficiency and imbalance of T-system immunity indices, macrophage depression) in patients with chronic hepatitis D, most clinicians believe that the use of immunomodulatory medications to correct the immune status is justified. As immunocorrectors, left ashes (decaris), BCG vaccine, thymus drug-tactivin were used.

Under the influence of tactin in children with chronic hepatitis D, the level of T-lymphocytes decreased by 20-30% before the start of treatment and the T-helper / T suppressor ratio was equalized from 10 ± 2.4 to 4.7-0.62 (p 0, 05). After the end of tactinotherapy, clinical-biochemical remission lasting from 6 months to 1 year was observed in 1 out of 6 patients.

Thus, immunocorrective therapy with XGD leads to positive shifts in immunological parameters, but does not significantly affect the replication of the pathogen; remission was noted only in individual patients.

In adults with chronic hepatitis D, thymosin, ribavirin, and lamivudine were ineffective (Garripoli A. Et al 1994, Lau DT et al., 2000).

Currently, the only drug for the treatment of patients with chronic hepatitis D is interferon alfa, prescribed in high doses, from 5 to 10 million IU per day for 12 months and longer. A stable response is observed only in 10-15% of patients. According to domestic clinicians, the frequency of a stable response after a 12-month course of interferon alfa in patients with XGD was 16.6%.

Summarizing the results, it should be emphasized that the effectiveness of immunomodulatory therapy and interferon therapy for chronic hepatitis D in children is low and unstable, which coincides with the data of Di Marco et al. (1996).

The same conclusion regarding the therapy for XGD is made by other clinicians. Thus, F. Rosma et al. (1991) in a randomized trial showed that the use of interferon alfa in a conventional daily dose of 3 million IU for 6-12 months in adult patients does not lead to remission in patients with CHD. However, the appointment of very high doses (9-10 million ME per day) of interferon alfa to adult patients contributes to the onset of remission in 15-25% of cases with chronic hepatitis D. However, it is known that an increase in the doses of interferon is fraught with an increase in the frequency of serious side effects of the drug.