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 chronicization of HDV infection is 60-70%.

The hepatitis D virus has a cytopathogenic effect on hepatocytes, constantly maintains the activity of the inflammatory process in the liver and, therefore, contributes to the progression of the disease.

Since active replication of HDV is regulated by the presence of HBV, chronic hepatitis D does not usually develop as a result of manifest coinfection with hepatitis D and B viruses. Chronic hepatitis D occurs as a result of latent coinfection and is especially common in HDV superinfection with chronic HBV infection.

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Epidemiology of chronic hepatitis D

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

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Pathomorphology of chronic hepatitis D

No specific morphological changes characteristic of chronic delta infection have been established. In some cases, inflammation is limited to the portal zones, and the disease is classified as benign chronic hepatitis of minimal and low activity. Most patients with chronic hepatitis B and D have periportal infiltration, combined with molar, confluent or bridging necrosis of parenchymatous cells. Intralobular infiltration may be pronounced.

Three histological types of chronic hepatitis B are identified in the presence of delta infection:

• chronic hepatitis of high activity with predominantly periportal changes and moderate diffuse inflammation in the lobule (in 70% of patients);
• chronic hepatitis with bridging necrosis and localized hepatocyte damage and fibrosis in the bridging zone (in 20% of patients);
• chronic lobular hepatitis with intense lobular damage associated with the accumulation of macrophages and lymphocytes in the sinusoids and in areas of focal hepatocyte necrosis (in 10% of patients).

As a rule, eosinophilic granular degeneration of individual hepatocytes or groups of parenchymatous cells is noted in delta infection. A complex of histological signs in the form of eosinophilic degeneration of fine-drop steatosis of hepatocytes 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 severity of parenchymal damage in chronic hepatitis B and D is significantly greater than that in “pure” CHB.

Statistically more significant mononuclear hyperplasia and infiltration in the portal zone area and inside the lobules in liver biopsies of patients with chronic hepatitis B than in patients with CHB without markers of delta infection are emphasized. Morphological changes in chronic hepatitis of high activity caused by delta infection are characterized by the advantage of connective tissue proliferation processes over the inflammatory reaction in the liver. In a morphological study of the liver in adult patients with CHD using the method of K. Ishak et al. (1995), it was found that moderate or high activity of the pathological process was observed in almost 90% of cases, and the stage of liver cirrhosis - in 65%. These data are consistent with the results of other researchers who have shown a significant degree of severity of liver damage in CHB.

Therefore, the available publications with the analysis of the pathomorphology of delta infection do not allow us to make a final conclusion about any specificity and isolation from HB-virus liver damage associated with the hepatitis delta virus. There are isolated reports of chronic hepatitis D in childhood.

In the children with chronic hepatitis B and the presence of serological markers of the delta virus that we observed, there was a wide range of liver damage - from chronic hepatitis of minimal and low activity to chronic hepatitis of high activity with transition to cirrhosis; chronic lobular hepatitis was not noted. However, when comparing morphological changes in the liver taking into account the presence or absence of markers of the delta virus, a predominance of a more severe inflammatory process was documented in patients with chronic hepatitis D, compared with that in patients who had only CHB. The proportion of chronic hepatitis of low activity in the absence of anti-delta in the blood serum ("pure" CHB) was documented in 32.2% of cases. Thus, in the group of patients with delta infection, among the morphological variants of chronic hepatitis, a pathological process with a cirrhosis-prone nature developed with a higher frequency (40%) than in the group of patients without delta markers (14.9%) (p<0.05).

Symptoms of Chronic Hepatitis D

There are two types of chronic delta infection: combined chronic hepatitis D and CHB; CHB associated with HBV carriage.

In the first variant, chronic hepatitis D occurs under conditions of ongoing active replication of HBV, which is documented by the presence of the corresponding markers of 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 full-fledged HBV replication. According to clinical observations, 52% of patients had a high probability of having the second variant of chronic delta infection, since none of them had HBeAg in their blood serum, but had anti-HBE.

As for total anti-HBc, they were detected in all blood serum samples from patients with both types of chronic delta infection.

Serological marker profiles in chronic delta infection

Serological marker	Combined CHB and CHB	CHB against the background of HBV carriage
HBsAg	+	+
HBeAg	+	-
Anti-NVE	-	+
Anti-HBC IgM	+	-
HBV DNA	+	-
HDV RNA	+	+
Anti-HV IgM	+	+
Anti-HDV total	+	+

In patients with low-activity chronic hepatitis D, the leading clinical signs are an enlarged liver, sometimes a larger spleen, and possible symptoms of intoxication in the form of fatigue and irritability. Some patients have "bruises" on the extremities, extrahepatic signs in the form of telangiectasias or palmar erythema. Among functional liver tests, the leading ones are moderate hyperenzymemia and some decrease in the prothrombin index. Patients with high-activity chronic hepatitis D are characterized by symptoms of intoxication and dyspoitic phenomena. Almost half of the patients have increased fatigue, emotional instability, and aggressiveness in relationships with relatives and peers. While maintaining appetite, most patients have signs of discomfort from the gastrointestinal tract in the form of nausea, a feeling of heaviness in the epigastric region and right hypochondrium, and flatulence. Icterus and subicterus of the sclera are rarely registered. An enlarged liver is noted in all patients. Half of the patients have an enlarged spleen, hemorrhagic syndrome in the form of "bruises" on the limbs, trunk, short-term nosebleeds and limited petechial rash. Telangiectasias in the form of small elements are often encountered, mainly on the face, neck, hands, palmar erythema, and pronounced dysproteinemia is characteristic.

Clinical and laboratory manifestations of chronic hepatitis D with transition to cirrhosis were mainly represented by pronounced symptoms of intoxication, dyspeptic phenomena, icterus of the skin and sclera, significant enlargement and compaction of the liver, which was always consistent with the high echogenicity of the organ during ultrasound. Constant symptoms were a significant enlargement of the spleen and hemorrhagic manifestations with a high frequency of nosebleeds and petechial rashes. Palmar erythema is detected in almost all patients. Along with pronounced clinical symptoms, these children have high activity of liver-cell enzymes, a sharp decrease in the prothrombin index and sublimate titer, an increase in the content of y-globulins in the blood serum.

According to observations of D. T. Abdurakhmanov (2004), YF Liaw (1995), V. E. Syutkin (1999), the combined course of chronic hepatitis D and CHB in adult patients is rare - 10-16% of cases. Basically, suppression of the hepatitis B virus replication by the hepatitis D virus is noted. At the same time, the clinical picture of CHD does not differ significantly from that of CHB. Complaints of an asthenic nature (weakness, increased fatigue, sleep disturbance), weight loss, pain and heaviness in the right hypochondrium predominate. Jaundice is observed in some patients. A biochemical blood test records an increase in ALT and AST activity by 3-10 times, in some cases there is an increase in bilirubin content due to the conjugated fraction with a simultaneous increase in the GGTP level, as well as a moderate increase in the concentration of y-globulins.

The course and outcome of chronic hepatitis D

In case of superinfection with the hepatitis delta virus in patients with CHB, in addition to the risk of developing fulminant hepatitis, as in HBV carriers, there is an extremely high probability of progression of the pathological process in the liver and rapid development of liver cirrhosis.

In this case, three main variants of the course of chronic hepatitis D are distinguished:

• rapidly progressive course with the development of decompensation and liver failure within a period of several months to 2 years (in 5-10% of patients, mainly consumers of psychotropic drugs);
• relatively calm and non-progressive course (in 15% of patients);
• development of severe fibrosis and cirrhosis of the liver over several years with a stable condition and development of decompensation after 10-30 years - in 70-80% of patients.

In recent years, when assessing the course and prognosis of outcomes of chronic hepatitis D, more and more attention has been paid to the genotype of the hepatitis D virus. It has been established that genotype I is characterized by a spectrum of different course options; genotype II is characterized by a mild, mainly non-progressive course, and genotype III is the most severe, rapidly progressing course with an early outcome in liver cirrhosis.

Chronic hepatitis D is characterized by long-term persistence of activity. Over an observation period of 2 to 10 years, only 24% of patients experience persistent remission.

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

As observations show, with CHB and CHD, gradual seroconversion of HBeAg to anti-HB occurs, and HBV DNA disappears with continued replication of the hepatitis delta virus (preservation of delta antigen in liver cells and anti-delta in the blood serum in high titers). Apparently, full-fledged HBV replication ceases over time, and the activity of the pathological process in the liver is maintained due to the reproduction of the hepatitis delta virus. This fundamental issue requires further study.

Diagnosis of chronic hepatitis D

Superinfection with hepatitis delta virus against the background of chronic HB-virus infection manifests itself with clinical symptoms of acute hepatitis. Of decisive importance is the detection of previously absent anti-delta IgM in the blood serum. Diagnostic significance is given to the decrease in the concentration of HBsAg at the time of superinfection with hepatitis delta virus. Among other diagnostic criteria of delta superinfection, a decrease in anti-HBc titers or their complete disappearance is characteristic.

It is important to note that M. Rizzettо (2000) points out that in the presence of a clear clinical picture of delta superinfection, the only marker of the virus may be delta antigen in liver tissue. Diagnostic difficulties with delta superinfection are especially characteristic when it occurs in hepatitis B virus carriers or in patients with sluggish chronic hepatitis B who are unaware of their carriage or disease. In these cases, detection of HBsAg in the clinical picture of typical hepatitis clearly orients the physician only to viral hepatitis B, and only detection of delta virus markers and continued persistence of HB5A§ allow the correct diagnosis to be made.

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

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Treatment of chronic hepatitis D

Considering the presence of persistent immunological disorders (deficiency and imbalance of T-system immune parameters, macrophage depression) in patients with chronic hepatitis D, most clinicians believe it is reasonable to use immunomodulatory drugs to correct the immune status. Levami zol (Decaris), BCG vaccine, and the thymus drug taktivin were used as immunocorrectors.

Under the influence of taktivin in children with chronic hepatitis D, the level of T-lymphocytes, which was reduced before the start of treatment, increased by 20-30% and the ratio of T-helpers/T-suppressors was leveled - from 10±2.4 to 4.7-0.62 (p 0.05). At the end of taktivin therapy, clinical and biochemical remission lasting from 6 months to 1 year was observed in 1 of 6 patients.

Thus, immunocorrective therapy for chronic hepatitis D leads to positive changes in immunological parameters, but does not have a significant effect on the replication of the pathogen; remission has been observed only in individual patients.

In adult patients with chronic hepatitis D, the use of thymosin, ribavirin and lamivudine was ineffective (Garripoli A. et al. 1994; Lau DT et. al., 2000).

Currently, the only drug for treating patients with chronic hepatitis D is interferon alpha, prescribed in high doses - from 5 to 10 million IU per day for 12 months or longer. A persistent response is observed in only 10-15% of patients. According to domestic clinicians, the frequency of a persistent response after a 12-month course of interferon alpha in patients with chronic hepatitis D 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 therapy for chronic hepatitis D is made by other clinicians. Thus, F. Rosma et al. (1991) showed in a randomized study that the use of interferon alpha in the generally accepted daily dose of 3 million IU for 6-12 months in adult patients does not lead to remission in patients with chronic hepatitis D. True, the prescription of very high doses (9-10 million IU per day) of interferon alpha to adult patients contributes to the onset of remission in 15-25% of cases of chronic hepatitis D. However, it is known that increasing the dose of interferon is fraught with an increase in the frequency of serious side effects of the drug.