Plasmapheresis for chronic hepatitis

Chronic hepatitis B is one of the most severe types of autoimmune diseases. It is known that after the acute hepatitis B chronicity occurs in 5-10% of patients, and according to U.S. statistics in the U.S. the number of patients with chronic hepatitis B was 1.25 million people. At the same time, deaths from chronic hepatitis B in 5 to 10 times higher than from acute, entering the top ten causes of death, 50 times greater than the frequency of deaths of HIV infection [31].
On the scale of the Earth are infected with hepatitis B virus more than one third of the population (approximately 1 billion people) and about ¼ of them will develop chronic hepatitis, cirrhosis and primary liver cancer. Thus 2.1 million people die annually. In Europe, each year 1 million people are infected, of which about 90,000 will be chronically ill and 22,000 will die from cirrhosis or cancer [129].

Chronic forms of hepatitis C in the United States affects about 4.5 million people [63, 80], and in Russia, even their number reaches 10 million people. In St. Petersburg, there are such patients, about 200,000 people (ie, 4-4.5% of the total population) [90].  Its effects are more severe because the hepatitis C virus (HCV) has the highest chronicity potential being the main reason for the formation of the whole group of chronic liver disease – chronic hepatitis, cirrhosis and hepatocellular carcinoma [85, 108]. From liver disease caused by hepatitis C virus in the United States die each year more than 8,000 people [92]. Across the Earth by patients with hepatitis C (170 million people), there are much higher than in AIDS patients (40 million people), despite the fact that this hepatitis is the same incurable disease [37].

The examination of 20 people 18 years after their accidental exposure to HCV donor plasmapheresis center in the city of Salzburg, it was found that 90% had evidence of chronic HCV infection, 50% had progressive chronic hepatitis and 20% –   cirrhosis [25].
Hepatitis D virus also always leads to chronic [109]. Unfortunately and frequency transformation in hepatic carcinoma, although in 20-30 years from the onset of the disease is close to 100% [104].
Hepatitis G virus still poorly understood. It occurs in 1.6% of blood donors, and 20% of drug addicts and patients after multiple blood transfusions [16].

What are the causes of such chronic viral hepatitis? There is much evidence that viral infection, no matter how difficult or, alternatively, it may easily course, causing a cascade of immune-pathogenicity reactions, leading eventually to the formation of autoimmune hepatitis [45, 62]. Confirming the autoimmune nature of chronic hepatitis (especially infection with the hepatitis C virus) is almost regular its combination with other types of autoimmune disease – vasculitis, glomerulonephritis, cryoglobulinemia, polymyositis, pulmonary fibrosis, porphyria, uveitis,  keratitis, thrombocytopenia, etc. [20, 22, 87, 93, 117, 122]. In particular, in the genesis of renal lesions leading consider circulating immune complexes containing antigen C [98]. Even after liver transplantation when immunosuppressive therapy helps build-level viremia HCV, symptoms may recur and nephrotic syndrome also [82].

HCV infection is often accompanied and cutaneous manifestations also, such as pruritus, urticaria, porphyria, lichen planus. In addition, these dermatoses long time can be the only manifestations of the underlying disease [38]. In patients with hypertrophic cardiomyopathy symptoms HCV-infection detected much more frequently than in the control groups (15.7% vs. 2,4%) [65]. Since HCV is lymphotropic, it can be a trigger of clonal B-cell proliferation. Indeed, markers of hepatitis C are often found in non-Hodgkin B-cell lymphoma. On the other hand, the toxic effects of chemotherapy at this type of lymphoma are also the most severe with concomitant chronic hepatitis C [118].

Patients with chronic hepatitis C is often found autoantibodies – rheumatoid factor, an antithyroid immunoglobulin, antinuclear and other mitochondrial antibodies [7, 9, 21, 35, 49, 68,  124]. Cryoglobulinemia accompanies chronic hepatitis C in 36-45%. It has been suggested that this viral infection "starts" and mechanisms of autoimmune hepatitis also [119]. One-third of such patients show autoantibodies to specific human hepatic lipoprotein [28].

HCV viral infection is involved in the pathogenesis and mixed cryoglobulinemia, both through direct formation of immune complexes, leading to vasculitis and exciting lymph-proliferative processes underlying this disease. This is associated with a particular lymph-tropism HCV and may also be responsible for the transformation of mixed cryoglobulinemia in malignant lymphoma. HCV-infection apparently also involved in the pathogenesis of idiopathic B-cell non-Hodgkin's lymphoma in the same pathogenic mechanisms [128]. At the same time, cryoglobulinemic vasculitis may be accompanied by multiple fingers necrosis and in the treatment of this complication plasmapheresis finds its application [72].

Anti-HCV antibodies can be detected in 72% of patients with "autoimmune" hepatitis, 50% of patients with alcoholic hepatitis, 66% of drug addicts and in 2.4% of healthy individuals. In addition, 21.3% for HBsAg positive patients with chronic hepatitis were positive and HCV-viruses, which means more significant than you might think, the spread of this kind of viral infection [95].
By the way, the development of autoimmune mechanisms, only a lesser severity, described also in some other viral infections (hepatitis B and D, herpes simplex-1, Epstein-Barr virus), but only hepatitis C acquire self-progressive malignant nature [108].

It was established that interferon is widely used in the treatment of viral infections may even induce autoimmune processes and cause exacerbations in 4-19% of patients [58, 59, 87, 123]. On the background of interferon in these patients showed a twofold increase in the frequency of formation of autoantibodies to human hepatic lipoprotein, antinuclear and mitochondrial autoantibodies [43]. Interferon possesses cardiotoxicity and can trigger the development of pericarditis [86]. Interferon may contribute to ischemic retinopathy, retinal hemorrhages, optic neuritis, keratoconjunctivitis, uveitis, sometimes with loss of vision [23, 73, 75, 78, 97, 100, 127].

Moreover, in patients with autoimmune predisposition interferoncan trigger the development of autoimmune thyroiditis [71], the defeat of the eye muscles, chronic inflammatory demyelinating polyneuropathy and multiple sclerosis [24, 64, 66, 77, 87, 113]. Y. Kato-Motozaki et al. [48] described the formation of heavy polyradiculopathy with the advent of anti-ganglioside antibodies in the treatment of hepatitis B using interferon-alpha, which was stoped only after a course of cascade plasmapheresis. In the experiment on mice application of g-interferon animal skin causes the formation of antinuclear (anti-DNA) autoantibodies, which were postponed in the vessels of the glomeruli of the kidneys and lead to severe proliferative glomerulonephritis [99]. K.-P. Meyer [69] explicitly states that the use of interferon in patients with autoimmune hepatitis may lead to severe course and even death.

Among the factors that trigger the formation of autoantibodies, are cytokines IL-1b and  TNF-a that often present in the formulations of interferon-a and can stimulate an autoimmune disorder with interferon. Their level increases even when vaccination against viral hepatitis A and B, as well as against staph, proteus and Pseudomonasinfection. There are also reports of no effect of interferon-a in concomitant HCV- and HBV-infection [128]. Many patients can not tolerate interferon therapy because of the large number of side effects [92]. In particular, reported a significant increase in levels of total cholesterol, triglycerides, very low density lipoproteins, while reducing high-density lipoprotein in the treatment of interferon-a [32, 94,  126]. Other side effects of interferon describe cutaneous manifestations (skin dryness and itching, erythema, seals, reversible alopecia, psoriasis and provocation Herpes labialis) [30].

S. Kiefersauer et al. [51] reported that the HCV-infection, at least 50% of patients remain chronically infected. IFN-a therapy was effective in only 25% of patients with HCV. Assuming that the CD8+ T-cells prevented the therapeutic effect, they have involved the incorporation of monoclonal antibodies to CD8+, leading to a high ratio CD4+ / CD8+ from 1.6 to 3.0 during treatment with a gradual decline to 2.3 after 1 year following the last infusion of monoclonal antibodies. In these patients gradually decreased ALT and clinical improvement occurred, which a, b and g could not be achieved by interferon.  HCV have multiple genotypes, with genotype 1b is the most chronicity and it is more resistant to interferon [10]. Even more modern concomitant therapy with INF-alpha-2a and ribavirin does not always lead to success, especially in elderly patients [44, 125]. More than half of patients with chronic hepatitis C are insensitive to interferon [42]. And in general, P.L. Almasio et al. [6] believed too exaggerated the positive effect of such treatment in viral hepatitis C.

On the other hand, should take into account the enormous cost of an intensive course of treatment with interferon, which can reach $ 10,000 [11, 52] and in UK hospitals – up to £ 3,000 with a total maintenance cost £ 93,000 [41] Based only on clinical and laboratory criteria for chronic hepatitis C is virtually indistinguishable from autoimmune hepatitis [110]. It must be borne in mind that the absence of antinuclear or antibodies to smooth muscle does not exclude the presence of autoimmune hepatitis. That is why we must be careful in appointing interferon for hepatitis C patients who have not excluded autoimmune hepatitis [15]. At the same time, as in chronic hepatitis C can never exclude its autoimmune character, it becomes clear high risk of interferon in such cases.
However, the classical approach to the treatment of such patients as having autoimmune pathology with chronic hepatitis C may result in an increase in virus replication with the risk of deterioration of the clinical course [8, 19] .

There is a serious clinical dilemma – both interferon and corticosteroids almost impossible to use. However, only plasmapheresis is a decent alternative antiviral therapy for hepatitis C [87]. Removing autoantibodies plasmapheresis helps restore reparative possibilities of hepatocytes, and, on the other hand, removing the "toxic press" from the immune system should stimulate its normalization.
In recent years, more widespread acquire liver transplantation for chronic hepatitis, cirrhosis and liver tumors. However, even after such operations HCV persists, leading to relapse of chronic hepatitis in 50-60% of patients. Three-month course of ribavirin promotes normalization of aminotransferase levels and histological improvement, but after the cessation of such therapy biochemical signs of hepatitis return again, indicating that the inability even of ribavirin prevent the progression of fibrosis in patients with autoimmune hepatitis C [13, 18]. Intrigue HCV-infection is prolonged "light gap" from infection to clinical manifestations of liver disease – up to 10-20 years. However, such "asymptomatic" is quite relative. Indeed, may not hyperbilirubinemia and signs of portal hypertension. However, careful analysis of these patients reveals a less optimistic picture. In such patients, a significant fatigue observed in 78%, depression in 53%, joint pain – in 53%, weakness – 51%, a sleep disorder in 51%, abdominal discomfort – 51%, weight loss in 43%, headaches – 39%, itching in 39%,  ikterus in 20% cases. This suggests that these patients have a significant deterioration in the quality of life, which contradicts the common opinion that chronic hepatitis is virtually asymptomatic until signs of cirrhosis [3]. It is possible that such practices contribute to the above other autoimmune related diseases, are also still in the subclinical phase.

Nevertheless, we must not forget that in the coming years, millions of carriers of hepatitis C virus become seriously ill with a sharp increase in mortality from chronic hepatitis and cirrhosis.
All the above facts convincingly prove autoimmune nature of chronic hepatitis, almost naturally developing after suffering the viral hepatitis B, C and D, and if so, it only plasmapheresis helps to mitigate its manifestations and postpone the inevitable outcome. This raises the question of the appointment of preventive courses of plasmapheresis in the very early rehabilitation period after acute viral hepatitis (especially C and D), as there is no guarantee that will avoid chronic process. Because the occurrence of autoantibodies is provoked both the viral infection, and the changes in the antigenic structure of hepatocytes, which occurred at the height of the disease. "Random" HCV detection must also raise the question of holding such preventive courses of plasmapheresis. Given the same factual incurable viral infection of this kind, even when 10-20 years asymptomatic develop signs of chronic hepatitis B, it is necessary to repeat such courses of plasmapheresis at least once a year for the rest of life [121].

E.G.Kirillova et al. [53] reported positive results of the use of plasmapheresis in the treatment of patients with chronic hepatitis. On the background of improving overall observed decrease in the levels of bilirubin, ALT, circulating immune complexes, alkaline phosphatase, middle weight molecules. Repeated courses of plasmapheresis provide more long-term remission. 

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