Introduction Chronic
liver diseases are a fairly broad group of diseases that combine viral liver damage and other infectious and toxic damage to the liver, autoimmune and metabolic disorders, which can evolve into liver cirrhosis and even hepatocellular cancer. Most of them are difficult to treat with drugs and are a leading cause of mortality. This manual explains the need for apheresis therapy, mainly plasmapheresis, in such liver diseases.
Viral hepatitisChronic hepatitis B is one of the most serious types of autoimmune diseases. It is known that, after acute hepatitis B, chronicity occurs in 5-10% of patients, and according to statistics from the USA, the number of patients with chronic hepatitis B in that country was 1.25 million people, and in the world, it reaches between 180 and 350 million people. Viral hepatitis B is the leading cause of death, reaching 786,000 deaths per year due to complications such as cirrhosis, liver failure, and hepatocellular carcinoma. At the same time, deaths from chronic hepatitis B are 5 to 10 times higher than those from acute hepatitis, ranking among the top ten causes of death, 50 times more frequent than deaths from HIV infection. Despite the introduction of vaccination, hepatitis B remains a major problem, as many patients are not even aware of their condition
of its existence. However, quality of life in chronic hepatitis B is significantly reduced.
Globally, more than one-third of the population is infected with the hepatitis B virus (approximately 1 billion people) and about 1/4 of them will develop chronic hepatitis, cirrhosis and primary liver cancer. Thus, between 1 and 2 million people die annually. In Europe, every year 1 million people become infected, of which around 90,000 will become chronically ill and 22,000 will die due to cirrhosis or cancer. Unfortunately, hepatitis B has no cure with current medicine.
Approximately 15 million patients with hepatitis B (HBV) have developed a hepatitis delta (HDV) infection in addition to their HBV infection. Patients superinfected with this satellite virus suffer a more severe development of the disease. Chronic HDV infection commonly results in the most rapid and progressive form of viral hepatitis; It is the chronic viral infection that is most likely to lead to cirrhosis, and is associated with an increased risk of hepatocellular carcinoma. HDV infection is the only chronic human hepatitis virus infection without a therapy approved by the U.S. Food and Drug Administration. Peginterferon alfa is the only recommended therapy, but it produces unsatisfactory results.
Plasmapheresis in the Treatment of Chronic Liver Diseases
Chronic forms of hepatitis C affect approximately 4.6 million people in the United States [4]. Its effects are more severe because the hepatitis C virus (HCV) has the greatest potential for chronicity, being the main cause of the formation of the entire group of chronic liver diseases: chronic hepatitis, cirrhosis and hepatocellular carcinoma. Mortality from hepatitis C is 3 times higher than from hepatitis B. Globally, the number of patients with hepatitis C is much higher than that of AIDS patients (40 million people), despite the fact that hepatitis is the same incurable disease. Globally, HCV infection imposes a very high economic burden. It has been estimated that the treatment of viral hepatitis C cost 6.5 billion dollars in 2012 and will reach 9.1 billion dollars by 2024.
There are cases of chronic hepatitis E development, especially in people with immune disorders. Its manifestations may include jaundice, weakness, and low-grade fever
Both acute and chronic hepatitis can also be caused by herpes viruses (cytomegalovirus, Epstein-Barr virus and herpesvirus-6) with the same consequences, up to fulminant forms.
What are the causes of these chronic viral hepatitis? It has been suggested that this viral infection also "triggers" the mechanisms of autoimmune hepatitis. There is much evidence that viral infection, no matter how severe or mild its course, causes a cascade of immuno-pathogenic reactions, which ultimately lead to the formation of autoimmune hepatitis. Confirmation of the autoimmune nature of chronic hepatitis (especially in hepatitis C virus infection) is almost regular in combination with other types of autoimmune diseases: vasculitis, glomerulonephritis, cryoglobulinemia, polymyositis, pulmonary fibrosis, porphyria, uveitis, cataracts, keratitis, thrombocytopenia, etc
In particular, in the genesis of kidney lesions are circulating immune complexes containing the C antigen. Hepatitis C often triggers the formation of membranoproliferative glomerulonephritis, which is accompanied by the development and progression of kidney failure. At the same time, severe manifestations of kidney failure may develop, requiring hemodialysis. Even after a liver transplant, when immunosuppressive therapy helps reduce HCV viremia levels, symptoms may recur and so can nephrotic syndrome. However, severe membranoproliferative glomerulonephritis with rapidly progressive renal failure can also develop in the context of hepatitis B.
However, severe membranoproliferative glomerulonephritis with rapidly progressive renal failure can also develop in hepatitis B, requiring intensive courses of plasmapheresis
HCV infection is often accompanied by skin manifestations, such as pruritus, hives, porphyria, lichen planus, and even ulcers. In addition, these dermatoses may be the only manifestations of the underlying disease for a long time. In patients with chronic hepatitis C, autoantibodies such as rheumatoid factor, antithyroid immunoglobulin, autoantibodies to specific human hepatic lipoproteins, antinuclear antibodies, and other mitochondrial antibodies are frequently found.
Brain metabolic disorders are also common. In patients with hypertrophic cardiomyopathy, signs of HCV infection are found much more frequently than in control groups. Signs of atherosclerosis are also revealed, with increased thickness of the carotid artery intima and epicardial fat. HCV infection can also promote lymphoproliferation, up to the development of non-Hodgkin's lymphoma. Since HCV is lymphotropic, it can be a trigger for clonal proliferation of B cells. In fact, markers of hepatitis C are frequently found in B-cell non-Hodgkin lymphoma. HCV may play a direct role in cell transformation, particularly in de novo large B-cell lymphoma. On the other hand, the toxic effects of chemotherapy in this type of lymphoma are also the most serious when there is concomitant chronic hepatitis C
It is also quite common to observe cases of hepatitis C virus infection in patients on chronic hemodialysis. Thus, the risk of a fatal outcome increases considerably, and antiviral therapy in such cases is associated with serious secondary complications.
HCV viral infection is involved in the pathogenesis of mixed cryoglobulinemia, both by the direct formation of immune complexes, leading to vasculitis, and by the stimulation of lymphoproliferative processes underlying this disease. Cryoglobulinemia accompanies chronic hepatitis C in 36-45%. This is associated with the particular lymphotropism of HCV and may also be responsible for the transformation of mixed cryoglobulinemia into malignant lymphoma. HCV infection is also apparently involved in the pathogenesis of idiopathic B-cell non-Hodgkin lymphoma through the same pathogenic mechanisms. At the same time, cryoglobulinemic vasculitis can be accompanied by multiple necrosis in the fingers, in addition, in chronic hepatitis C, both arterial and venous thrombosis develop.
Therefore, in the treatment of this complication, plasmapheresis also finds its application. Plasma exchange is also indicated in the case of the development of Waldenström's macroglobulinemia
Anti-HCV antibodies can be detected in 72% of patients with "autoimmune" hepatitis, 50% of patients with alcoholic hepatitis, 66% of drug addicts, and 2.4% of healthy individuals. In addition, 21.3% of HBsAg-positive patients with chronic hepatitis were also positive for the HCV virus, which means that the spread of this type of viral infection is more significant than it might seem.
Treatment of viral hepatitisIt has been established that interferon, widely used in the treatment of viral infections, can even induce autoimmune processes and cause exacerbations in 4-19% of patients. In these patients, during treatment with interferon, a twofold increase in the frequency of formation of autoantibodies against human hepatic lipoprotein, antinuclear and mitochondrial autoantibodies was observed. Interferon has cardiotoxicity and can trigger the development of pericarditis. In addition, interferon may contribute to ischemic retinopathy, retinal hemorrhages, optic neuritis, keratoconjunctivitis, uveitis, and occasionally, vision loss. In addition, in patients with an autoimmune predisposition, interferon can trigger the development of autoimmune thyroiditis, eye muscle damage, chronic demyelinating inflammatory polyneuropathy, and multiple sclerosis. The formation of severe polyradiculopathy with the appearance of anti-ganglioside antibodies has been described during the treatment of hepatitis B with interferon-alpha, which only stopped after a course of cascading plasmapheresis.
In the mouse experiment, the application of γ-interferon to the skin of the animals causes the formation of antinuclear autoantibodies (anti-DNA), which are deposited in the vessels of the renal glomeruli and lead to severe proliferative glomerulonephritis. Explicitly states that the use of interferon in patients with autoimmune hepatitis can lead to a severe course and even death.
Among the factors that trigger the formation of autoantibodies are the cytokines IL-1β and TNF-α, which are often present in the formation of autoimmune diseases.
Interferon-α formulations may stimulate an interferon-associated autoimmune disorder. Its level increases even with vaccination against viral hepatitis A and B, as well as against staphylococci, proteus and Pseudomonas infections. There are also reports that interferon-α has no effect on concomitant HCV and HBV infections.
Many patients cannot tolerate interferon therapy because of the large number of side effects. In particular, a significant increase in levels of total cholesterol, triglycerides, and very low-density lipoproteins has been reported, while decreasing high-density cholesterol during interferon-α treatment. Other side effects of interferon include skin manifestations, such as dry and itchy skin, erythema, seals, reversible alopecia, psoriasis, and cold sore provocation.
Interferon therapy may contribute to the development of ischemic retinopathy, retinal hemorrhages, optic neuritis, keratoconjunctivitis, uveitis, sometimes with vision loss. In addition, vasculitis, glomerulonephritis, cryoglobulinemia, thyroiditis, and other autoimmune diseases can also develop.
At least 50% of patients remain chronically infected. IFN-α therapy was effective in only 25% of HCV patients. Assuming that CD8+ T cells impeded the therapeutic effect, the incorporation of monoclonal antibodies to CD8+ has been involved, resulting in a high CD4+/CD8+ ratio of 1.6 to 3.0 during treatment, with a gradual decrease to 2.3 after 1 year after the last monoclonal antibody infusion. In these patients, ALT gradually decreased and clinical improvement occurred, which could not be achieved with interferon α, β, and γ.
HCV has multiple genotypes, with genotype 1b being the one with the highest chronicity and greater resistance to interferon. Even the most modern concomitant therapy with INF-alfa-2a and ribavirin does not always lead to success, especially in older patients. More than half of patients with chronic hepatitis C are insensitive to interferon. On the other hand, the huge cost of an intensive course of interferon treatment, which can reach between £30,000 and £100,000, must be taken into account.
Based solely on clinical and laboratory criteria, chronic hepatitis C is virtually indistinguishable from autoimmune hepatitis. It should be noted that the absence of antinuclear antibodies or other autoantibodies
Smooth muscle antibodies do not exclude the presence of autoimmune hepatitis. Therefore, we should be cautious about prescribing interferon for patients with hepatitis C who have not ruled out autoimmune hepatitis. At the same time, since in chronic hepatitis C its autoimmune character can never be excluded, the high risk of interferon in such cases is understood.
However, the classic approach to the treatment of such patients, considering them with autoimmune pathology and chronic hepatitis C, may result in an increase in viral replication, with the risk of worsening the clinical course. In addition, there is no evidence to show that interferon therapy reduces the risk of the subsequent development of hepatocellular carcinoma.
There is a serious clinical dilemma: both interferon and corticosteroids are almost impossible to use. However, only plasmapheresis is a suitable alternative to antiviral therapy for hepatitis C. By eliminating autoantibodies, plasmapheresis helps restore the reparative abilities of hepatocytes and, on the other hand, by removing the "toxic pressure" of the immune system, it should stimulate their normalization.
In recent years, liver transplantation has become more common to treat chronic hepatitis, cirrhosis, and liver tumors. However, even after these operations, HCV persists, leading to a relapse of chronic hepatitis in 50-60% of patients. A three-month course of ribavirin promotes normalization of aminotransferase levels and histological improvement, but after discontinuation of such therapy, biochemical signs of hepatitis return, indicating that ribavirin is not able to prevent the progression of fibrosis in patients with autoimmune hepatitis C.
HCV infection has a prolonged "gap" from infection to clinical manifestations of liver disease, which can last from 10 to 20 years until the development of cirrhosis or hepatocellular carcinoma. However, this "asymptomatism" is quite relative. In fact, hyperbilirubinemia and signs of portal hypertension may not appear. However, a close analysis of these patients reveals a less optimistic picture. In these patients, significant fatigue is seen in 78%, depression in 53%, joint pain in 53%, weakness in 51%, sleep disturbances in 51%, abdominal discomfort in 51%, weight loss in 43%, headaches in 39%, itching in 39%, and jaundice in 20% of cases. This suggests that these patients experience a significant deterioration in quality of life, which contradicts the common view that chronic hepatitis is virtually asymptomatic until signs of cirrhosis occur. It is possible that such practices contribute to other related autoimmune diseases that are also in a subclinical phase.
However, we must not forget that in the coming years millions of carriers of the hepatitis C virus will become seriously ill, with a sharp increase in mortality due to chronic hepatitis and cirrhosis. In recent years, hepatitis C treatment has been actively implemented with direct-acting antiviral therapy (DAA), based on a combination of drugs such as sofosbuvir, ledipasvir, simeprevir, paritaprevir, and dasabuvir. This has increased the effectiveness of drug therapy from less than 50% to more than 90%. However, full recovery of liver function is quite illusory. Levels of urea, nitric oxide, methionine, and cyclic polyamines remain elevated. Often, after viral eradication, tests remain indicating continuous alterations in the liver. There is another limitation in the use of DAA therapy: in the presence of concomitant membranoproliferative glomerulonephritis, some direct-acting drugs, such as sofosbuvir, are contraindicated due to their nephrotoxic effect. Therefore, such therapy should be combined with plasmapheresis, corticosteroids, and rituximab.
However, in hepatitis C, there are multiple concomitant extrahepatic diseases associated with the development of systemic immune disorders, such as diabetes, cryoglobulinemia, vasculitis with kidney damage, cardiovascular and neuropsychiatric disorders, not to mention the liver lesions themselves, such as fibrosis, cirrhosis, fatty hepatosis, and hepatocellular carcinoma. It is not yet clear how much viral eradication will contribute to the reverse development of the disorders that have already occurred. These patients are still at risk of developing hepatocellular carcinoma, which requires constant monitoring, alpha-fetoprotein control, and elastography, especially in cases of advanced fibrosis and in older people. In addition, with an existing hepatocellular carcinoma, hepatitis C treatment is less successful.
There are observations suggesting a reactivation of hepatitis B and autoimmune hepatitis in the context of such DAA therapy
Fibrosis and fatty hepatosis also remain. In the treatment of hepatitis C with pegylated interferon-alpha, rhabdomyolysis may develop with increased creatine kinase levels.
Therefore, even modern direct-acting antiviral therapy does not fully guarantee recovery from liver lesions that have already occurred nor does it eliminate the risk of hepatocellular carcinoma.
All of the facts mentioned above convincingly demonstrate the autoimmune nature of chronic hepatitis, which almost naturally develops after having suffered from viral hepatitis B, C, and D. In this case, plasmapheresis is the only thing that can help mitigate its manifestations and delay the inevitable outcome. This raises the question of the implementation of preventive courses for plasmapheresis in the period of early rehabilitation after acute viral hepatitis (especially C and D), as there is no guarantee of avoiding the chronic process.
The emergence of autoantibodies is caused both by viral infection and by changes in the antigenic structure of hepatocytes that occur at the peak of the disease. The "random discovery" of HCV must also raise the question of conducting such preventive courses of plasmapheresis. Since this viral infection is incurable, even when after 10-20 years of being asymptomatic they develop signs of chronic hepatitis, it is necessary to repeat these courses of plasmapheresis at least once a year for the rest of life.
Based on the improvement in overall condition, a decrease in the levels of bilirubin, ALT, ESR, circulating immune complexes, alkaline phosphatase, and medium-sized molecules was observed. Plasmapheresis sessions were combined with extracorporeal laser irradiation (HeNe) of the blood and external radiation of the hepatic area. Repeated courses of plasmapheresis provided longer remission. In cases of exacerbation of chronic hepatitis, the results of the use of plasma exchange were better than those of pharmacological treatment with entecavir.
In cases of chronic advanced hepatitis C with the development of hepatic encephalopathy, plasmapheresis also contributed to the improvement of general health status and the elimination of symptoms of poisoning, with decreased bilirubin and transaminase levels almost returning to normal.
As a further illustration, we give an example from our own clinical practice:
Patient V., 80 years old. 33 years ago, in 1985, a 10-fold increase in ALT level was incidentally revealed, and ultrasonographic investigation showed an increase and consolidation of the liver with symptoms of portal hypertension and an increase in portal vein diameter to 15 mm. It was only in 1993 that the etiology was clarified: antibodies against hepatitis C were found. However, since 1985 a plasma exchange course was held with 4 sessions, with elimination of up to 1-1.5 liters of plasma each time, on an annual basis. ALT levels remained at normal or subnormal levels throughout this time, and ultrasonographic investigation in 2012 showed normalization of liver size and structure, with a reduction of portal vein diameter to 12 mm. There were no signs of HCV viremia, although the HCV test was consistently positive. Throughout this period, health was satisfactory. No special drug therapy was given.
The example given confirms our concept of conducting preventive plasma exchange courses immediately after detection of viral hepatitis C.
However, in liver transplant patients with chronic hepatitis C, the chances of damage to the donor's liver are not eliminated. In addition, the development of cirrhosis in the transplanted liver is often more intense than before the transplant. In such cases, the cascade plasmapheresis method was used, where not only were autoantibodies selectively removed, but complex therapy for HCV (interferon, ribavirin, including cascade plasmapheresis) was also performed. HCV RNA was reduced to 8.2% and 0.7% on the 5th and 30th day of treatment, respectively. In three patients who underwent this therapy as a preventive measure, they showed no recurrence of the disease even one year after treatment. The patient who had already developed signs of fibrous cholestatic hepatitis showed rapid reverse dynamics in the lesions of the transplanted liver. There was a drastic decrease in the amount of hepatitis C virus in the blood (and without the additional use of antiviral drugs) through the use of cascading plasmapheresis. Cascade plasma exchange was used even in the presence of acute renal failure, in the context of hemodialysis, which also promoted the decrease in the level of viremia.
Cascade plasmapheresis was used for the purpose of viral decontamination in patients who had previously received interferon therapy or its combination with ribavirin, without success.
but if at least a part of them remains, it does not prevent a new exacerbation of the disease
Chronic alcoholic hepatitis and liver cirrhosis occur as a result of the formation of free radicals due to the action of ethanol, which causes damage to cell membranes and organelles. The oxidation product of alcohol, acetaldehyde, also generates free radicals. In addition, alcohol promotes the release of cytotoxic cytokines (IL-1, IL-6, IL-8, TNF-α). The number of cytotoxic T cells in the liver also increases, contributing to the development of necrosis, fibrosis, and subsequently cirrhosis. In addition, alcohol contributes to the progression of other forms of chronic hepatitis
We must also point out the main role of chronic alcohol poisoning in the development of both primary chronic hepatitis and alcoholic cirrhosis. In addition, there is evidence that chronic alcoholism develops immunosuppression, supplementing the ability to fight hepatitis, which contributes to a more severe course of the disease and chronicity. Consumption of more than 90 g of alcohol per day has been found to significantly increase the severity of chronic hepatitis. This underscores the need to abstain from any type of alcoholic beverage in patients with already developed chronic liver disease, and even in those cases where a high probability of such a process can be expected to occur in HCV-infected individuals.
In chronic hepatitis of alcoholic genesis, plasma exchange courses also contribute to stabilization of status, with decreased levels of bilirubin, ALT, erythrocyte sedimentation rate (ESR), alkaline phosphatase, and reduced liver size according to ultrasound. In the future, with the use of liver treatment and diet (elimination of alcohol), it is possible to achieve a fairly persistent and prolonged remission.
Hepatosis grasa (steatosis) is a growing health problem in many countries around the world, associated with increased morbidity and mortality. It is also defined as non-alcoholic fatty hepatosis. It occurs in 30% of the total population and in 40% to 70% of obese people. It often accompanies other metabolic disorders, such as obesity and diabetes. With insufficient sugar control in diabetes, excessive accumulation of glycogen in hepatocytes (glycogenic liver disease) is possible. It can also be related to the consequences of Helicobacter pylori infection and inflammatory bowel diseases (such as Crohn's disease, ulcerative colitis).
necrotizing colitis), when, due to the increased porosity of the intestinal wall, toxic metabolites reach the liver. The development of fatty hepatosis has also been described as a result of general irradiation of the body in children during tumor treatment. At the same time, insulin resistance and dyslipidemia develop, also affecting the liver.
Fatty hepatosis is accompanied by fibrosis with hepatocyte apoptosis, leading to endothelial dysfunction with elevated ALT and AST levels, followed by the development of cirrhosis. In the near future, it is expected to be the main indication for liver transplantation. But even after transplantation, there is a high risk of reappearance of fatty hepatosis in the graft if its root causes are not removed. The frequency of hepatocellular carcinoma associated with fat hepatosis is also increasing. Fatty hepatosis also contributes to the development of atherosclerosis and cardiovascular disease. Since there are no specific methods of treatment or prevention for fatty hepatosis, preventive plasmapheresis is justified at the first signs of this pathology.
Liver cirrhosisA serious complication of viral hepatitis is the development of liver cirrhosis with imminent portal hypertension and profuse bleeding from esophageal and gastric varices. But, in the context of developing cirrhosis with severe chronic liver failure, courses of plasmapheresis and cryoplasmassorption also contribute to a certain stabilization of the patient's condition. Thus, in these patients, as a result of the treatment of liver failure, the encephalopathy phenomenon was stopped, ascites was reduced, the level of cholestasis decreased, and the prothrombin index increased by more than 60%. Partial plasma replacement after cryogenic treatment helped stabilize the level of total protein in the blood. Plasmapheresis also helps relieve itching, which frequently accompanies cirrhosis, for up to 6 months.
In liver cirrhosis complicated by diuretic-resistant ascites, plasmapheresis was performed, and ascitic fluid obtained by paracentesis was used as a replacement solution, which was subjected to ultrafiltration and cryoplasmosorption. This restored circulating blood volume, reduced protein loss, decreased bilirubin and transaminase levels. In cases of extremely severe hepatic impairment, positive results were obtained using the MARS system, where plasma obtained by membrane plasmapheresis is subsequently passed through a special column, in which the plasma is used.
the albumin adsorbed related toxins are then removed by dialy-sis, and then returned to the patient a purified.
Exogenous toxic hepatitis
Exogenous toxic hepatitis often develops when receiving a drug such as isoniazid, used to treat tuberculosis. Especially dangerous is the combination of this drug with rifampicin. It evolves with hepatocyte necrosis and the associated mortality is ten times higher than in viral hepatitis. Although rare (1 in 10,000 anesthesia), serious liver damage can also develop as a result of halothane inhalation. Even a "harmless" drug such as paracetamol, in doses greater than 10 g, can cause fatal liver necrosis. The development of severe acute hepatitis has also been described by the use of omeprazole in the treatment of gastritis due to acid hypersensitivity. Cholestasis can also develop due to regular contraceptive administration. The plasmapheresis course, with up to 9 sessions, allowed this pathology to be normalized.
The development of acute liver damage with fulminant liver failure after the ingestion of paracetamol (acetaminophen), already mentioned above, is common and, in some cases, has even required a liver transplant. The timely use of plasmapheresis courses in such cases favors the restoration of liver functions.
These data also underline the desirability of early excretion of these hepatotoxic drugs by plasmapheresis to reduce the magnitude of damage and prevent the progression of pathological liver disorders. All this makes it necessary to resort to extracorporeal detoxification methods once again.
Primary biliary cirrhosis
It is a chronic and progressive autoimmune disease of the cholestatic type. It occurs mainly in middle-aged women with a frequency of 3.9 to 15 per 1 million inhabitants. In this disease, the small intralobular bile ducts degrade, with a transition to fibrosis and cirrhosis with the development of portal hypertension. It is manifested by jaundice of the skin, weakness, persistent pruritus, osteoporosis, hypercholesterolemia with xanthomas and xanthelasma. Laboratory monitoring reveals marked cholestasis with elevated levels of bilirubin, transaminases, immunoglobulin M, and the presence of antibodies against mitochondria.
Oxidative stress plays an important role in pathogenesis, with significant accumulation of free radicals, malondialdehyde, and 8-isoprostane due to lower antioxidant activity, vitamin A, and selenium.
The common first-line treatment is ursodeoxycholic acid, although it does not always produce the right effect. However, 95% of patients have highly specific antimitochondrial autoantibodies. Since the main etiological factor of the disease is also the accumulation of autoantibodies, plasmapheresis can provide substantial help to patients. In fact, as a result of the course of plasmapheresis, total bilirubin decreased by 25-30%, ALT and AST by 12-15%, and levels of CIC and medium-sized molecules were normalized, which helped reduce pruritus and asthenic-neurotoxic manifestations. According to ASFA recommendations, in some cases, reducing persistent pruritus requires a course of plasmapheresis 2-3 times per week for approximately four weeks.
A similar liver disease is primary sclerosing cholangitis, a chronic cholestatic liver disease of unknown etiology. Like patients with autoimmune hepatitis, those with primary biliary cirrhosis and primary sclerosing cholangitis may present with anti-mitochondrial antibodies (AMAs), cytoplasmic anti-neutrophils (ANCAs), intestinal antibodies, and anti-ribosomal antibodies (ARBs). Sclerosing cholangitis is usually accompanied by IgG4 antibodies with T lymphocyte infiltration and the concomitant development of cholecystitis, retroperitoneal fibrosis, tubulointerstitial nephritis, interstitial pneumonia, prostatitis, and lymphadenopathy.
Autoimmune hepatitis often develops and combines with primary biliary cirrhosis and primary sclerosing cholangitis, and sometimes also with ulcerative colitis and Crohn's disease. In particular, inflammatory bowel diseases are found in 75% of patients with primary sclerosing cholangitis. At the same time, most of the drugs prescribed for ulcerative colitis and Crohn's disease (in particular, methotrexate and thiopurines) are highly toxic to the liver
In all these cases, therapeutic apheresis also helps to soften the overall toxic effect, both in the development of acute hepatitis and in chronic exposure to hepatotropic toxicants.
Budd-Chiari syndrome
Budd-Chiari syndrome occurs most often in antiphospholipid syndrome and is characterized by progressive obstruction of the hepatic veins from the lobular vein to the confluence of the inferior vena cava in the right atrium. It manifests with hepatomegaly, abdominal pain, and ascites. It can occur acutely and malignantly, but usually has a chronic, asymptomatic course. In the latter case, there is a negligible increase in
Budd-Chiari syndrome
Budd-Chiari syndrome occurs most often in antiphospholipid syndrome and is characterized by progressive obstruction of the hepatic veins from the lobular vein to the confluence of the inferior vena cava in the right atrium. It manifests with hepatomegaly, abdominal pain, and ascites. It can occur acutely and malignantly, but usually has a chronic, asymptomatic course. In the latter case, there is a negligible increase in basal activity of transaminases and alkaline phosphatase in conjunction with hypoalbuminemia. However, this chronic metabolic disorder of liver cells leads to fibrosis and cirrhosis.
The autoimmune nature of the disease involves the use of plasmapheresis to remove both antibodies and vasoactive and pathological metabolites. In the intensive course of plasmapheresis in the treatment of acute Budd-Chiari syndrome, with obstruction of blood flow in the hepatic veins and rapid progression of ascites and oliguria due to high levels of AST, ALT, LDH and bilirubinemia, a positive treatment dynamic was observed: reduction in liver size and ascites with incomplete recanalization of the hepatic veins.
Crigler-Najjar syndrome
This syndrome is characterized by an acute increase in the level of unconjugated bilirubin, up to the development of encephalopathy, due to the congenital lack of enzymes that promote the elimination of bilirubin (uridine diphosphate glucuronosyltransferases). Plasmapheresis in such cases also helped to alleviate severe manifestations of the disease.
Thus, the picture of homeostasis disorders, which lead to an increase in organic disorders, is becoming clearer and clearer. The materials presented indicate a variety of causes of liver damage, but all are related to common pathogenic mechanisms associated with the accumulation of a number of toxic products that damage the liver parenchyma. In this case, many of these pathological products accumulate, and the size of their molecules prevents their excretion through the kidneys, while the liver is also unable to destroy them. On the other hand, the fact that these products accumulate suggests that no medication can help them leave the body.
Conclusion
To date, significant progress has been made in the treatment of viral infections, but these drugs themselves are not safe and are not always able to interrupt already existing liver pathological disorders, which still require the use of plasmapheresis. Therefore, in all these cases, plasmapheresis is a method of treatment and prevention of the progression of liver damage, justifiably pathogenic.
In such cases, it is sufficient to remove up to 1 liter of plasma, replacing it only with crystalline solutions during 4 plasmapheresis sessions, performed every two days, which can be carried out even in an outpatient setting. In the future, it will be necessary to regularly repeat these courses up to twice a year. Thus, it is possible to effectively interrupt the progression of the disease and prevent the transition to the development of irreversible liver damage in cirrhosis and hepatocellular carcinoma. But even in advanced processes, plasmapheresis can significantly improve the condition of patients.
liver diseases are a fairly broad group of diseases that combine viral liver damage and other infectious and toxic damage to the liver, autoimmune and metabolic disorders, which can evolve into liver cirrhosis and even hepatocellular cancer. Most of them are difficult to treat with drugs and are a leading cause of mortality. This manual explains the need for apheresis therapy, mainly plasmapheresis, in such liver diseases.
Viral hepatitisChronic hepatitis B is one of the most serious types of autoimmune diseases. It is known that, after acute hepatitis B, chronicity occurs in 5-10% of patients, and according to statistics from the USA, the number of patients with chronic hepatitis B in that country was 1.25 million people, and in the world, it reaches between 180 and 350 million people. Viral hepatitis B is the leading cause of death, reaching 786,000 deaths per year due to complications such as cirrhosis, liver failure, and hepatocellular carcinoma. At the same time, deaths from chronic hepatitis B are 5 to 10 times higher than those from acute hepatitis, ranking among the top ten causes of death, 50 times more frequent than deaths from HIV infection. Despite the introduction of vaccination, hepatitis B remains a major problem, as many patients are not even aware of their condition
of its existence. However, quality of life in chronic hepatitis B is significantly reduced.
Globally, more than one-third of the population is infected with the hepatitis B virus (approximately 1 billion people) and about 1/4 of them will develop chronic hepatitis, cirrhosis and primary liver cancer. Thus, between 1 and 2 million people die annually. In Europe, every year 1 million people become infected, of which around 90,000 will become chronically ill and 22,000 will die due to cirrhosis or cancer. Unfortunately, hepatitis B has no cure with current medicine.
Approximately 15 million patients with hepatitis B (HBV) have developed a hepatitis delta (HDV) infection in addition to their HBV infection. Patients superinfected with this satellite virus suffer a more severe development of the disease. Chronic HDV infection commonly results in the most rapid and progressive form of viral hepatitis; It is the chronic viral infection that is most likely to lead to cirrhosis, and is associated with an increased risk of hepatocellular carcinoma. HDV infection is the only chronic human hepatitis virus infection without a therapy approved by the U.S. Food and Drug Administration. Peginterferon alfa is the only recommended therapy, but it produces unsatisfactory results.
Plasmapheresis in the Treatment of Chronic Liver Diseases
Chronic forms of hepatitis C affect approximately 4.6 million people in the United States [4]. Its effects are more severe because the hepatitis C virus (HCV) has the greatest potential for chronicity, being the main cause of the formation of the entire group of chronic liver diseases: chronic hepatitis, cirrhosis and hepatocellular carcinoma. Mortality from hepatitis C is 3 times higher than from hepatitis B. Globally, the number of patients with hepatitis C is much higher than that of AIDS patients (40 million people), despite the fact that hepatitis is the same incurable disease. Globally, HCV infection imposes a very high economic burden. It has been estimated that the treatment of viral hepatitis C cost 6.5 billion dollars in 2012 and will reach 9.1 billion dollars by 2024.
There are cases of chronic hepatitis E development, especially in people with immune disorders. Its manifestations may include jaundice, weakness, and low-grade fever
Both acute and chronic hepatitis can also be caused by herpes viruses (cytomegalovirus, Epstein-Barr virus and herpesvirus-6) with the same consequences, up to fulminant forms.
What are the causes of these chronic viral hepatitis? It has been suggested that this viral infection also "triggers" the mechanisms of autoimmune hepatitis. There is much evidence that viral infection, no matter how severe or mild its course, causes a cascade of immuno-pathogenic reactions, which ultimately lead to the formation of autoimmune hepatitis. Confirmation of the autoimmune nature of chronic hepatitis (especially in hepatitis C virus infection) is almost regular in combination with other types of autoimmune diseases: vasculitis, glomerulonephritis, cryoglobulinemia, polymyositis, pulmonary fibrosis, porphyria, uveitis, cataracts, keratitis, thrombocytopenia, etc
In particular, in the genesis of kidney lesions are circulating immune complexes containing the C antigen. Hepatitis C often triggers the formation of membranoproliferative glomerulonephritis, which is accompanied by the development and progression of kidney failure. At the same time, severe manifestations of kidney failure may develop, requiring hemodialysis. Even after a liver transplant, when immunosuppressive therapy helps reduce HCV viremia levels, symptoms may recur and so can nephrotic syndrome. However, severe membranoproliferative glomerulonephritis with rapidly progressive renal failure can also develop in the context of hepatitis B.
However, severe membranoproliferative glomerulonephritis with rapidly progressive renal failure can also develop in hepatitis B, requiring intensive courses of plasmapheresis
HCV infection is often accompanied by skin manifestations, such as pruritus, hives, porphyria, lichen planus, and even ulcers. In addition, these dermatoses may be the only manifestations of the underlying disease for a long time. In patients with chronic hepatitis C, autoantibodies such as rheumatoid factor, antithyroid immunoglobulin, autoantibodies to specific human hepatic lipoproteins, antinuclear antibodies, and other mitochondrial antibodies are frequently found.
Brain metabolic disorders are also common. In patients with hypertrophic cardiomyopathy, signs of HCV infection are found much more frequently than in control groups. Signs of atherosclerosis are also revealed, with increased thickness of the carotid artery intima and epicardial fat. HCV infection can also promote lymphoproliferation, up to the development of non-Hodgkin's lymphoma. Since HCV is lymphotropic, it can be a trigger for clonal proliferation of B cells. In fact, markers of hepatitis C are frequently found in B-cell non-Hodgkin lymphoma. HCV may play a direct role in cell transformation, particularly in de novo large B-cell lymphoma. On the other hand, the toxic effects of chemotherapy in this type of lymphoma are also the most serious when there is concomitant chronic hepatitis C
It is also quite common to observe cases of hepatitis C virus infection in patients on chronic hemodialysis. Thus, the risk of a fatal outcome increases considerably, and antiviral therapy in such cases is associated with serious secondary complications.
HCV viral infection is involved in the pathogenesis of mixed cryoglobulinemia, both by the direct formation of immune complexes, leading to vasculitis, and by the stimulation of lymphoproliferative processes underlying this disease. Cryoglobulinemia accompanies chronic hepatitis C in 36-45%. This is associated with the particular lymphotropism of HCV and may also be responsible for the transformation of mixed cryoglobulinemia into malignant lymphoma. HCV infection is also apparently involved in the pathogenesis of idiopathic B-cell non-Hodgkin lymphoma through the same pathogenic mechanisms. At the same time, cryoglobulinemic vasculitis can be accompanied by multiple necrosis in the fingers, in addition, in chronic hepatitis C, both arterial and venous thrombosis develop.
Therefore, in the treatment of this complication, plasmapheresis also finds its application. Plasma exchange is also indicated in the case of the development of Waldenström's macroglobulinemia
Anti-HCV antibodies can be detected in 72% of patients with "autoimmune" hepatitis, 50% of patients with alcoholic hepatitis, 66% of drug addicts, and 2.4% of healthy individuals. In addition, 21.3% of HBsAg-positive patients with chronic hepatitis were also positive for the HCV virus, which means that the spread of this type of viral infection is more significant than it might seem.
Treatment of viral hepatitisIt has been established that interferon, widely used in the treatment of viral infections, can even induce autoimmune processes and cause exacerbations in 4-19% of patients. In these patients, during treatment with interferon, a twofold increase in the frequency of formation of autoantibodies against human hepatic lipoprotein, antinuclear and mitochondrial autoantibodies was observed. Interferon has cardiotoxicity and can trigger the development of pericarditis. In addition, interferon may contribute to ischemic retinopathy, retinal hemorrhages, optic neuritis, keratoconjunctivitis, uveitis, and occasionally, vision loss. In addition, in patients with an autoimmune predisposition, interferon can trigger the development of autoimmune thyroiditis, eye muscle damage, chronic demyelinating inflammatory polyneuropathy, and multiple sclerosis. The formation of severe polyradiculopathy with the appearance of anti-ganglioside antibodies has been described during the treatment of hepatitis B with interferon-alpha, which only stopped after a course of cascading plasmapheresis.
In the mouse experiment, the application of γ-interferon to the skin of the animals causes the formation of antinuclear autoantibodies (anti-DNA), which are deposited in the vessels of the renal glomeruli and lead to severe proliferative glomerulonephritis. Explicitly states that the use of interferon in patients with autoimmune hepatitis can lead to a severe course and even death.
Among the factors that trigger the formation of autoantibodies are the cytokines IL-1β and TNF-α, which are often present in the formation of autoimmune diseases.
Interferon-α formulations may stimulate an interferon-associated autoimmune disorder. Its level increases even with vaccination against viral hepatitis A and B, as well as against staphylococci, proteus and Pseudomonas infections. There are also reports that interferon-α has no effect on concomitant HCV and HBV infections.
Many patients cannot tolerate interferon therapy because of the large number of side effects. In particular, a significant increase in levels of total cholesterol, triglycerides, and very low-density lipoproteins has been reported, while decreasing high-density cholesterol during interferon-α treatment. Other side effects of interferon include skin manifestations, such as dry and itchy skin, erythema, seals, reversible alopecia, psoriasis, and cold sore provocation.
Interferon therapy may contribute to the development of ischemic retinopathy, retinal hemorrhages, optic neuritis, keratoconjunctivitis, uveitis, sometimes with vision loss. In addition, vasculitis, glomerulonephritis, cryoglobulinemia, thyroiditis, and other autoimmune diseases can also develop.
At least 50% of patients remain chronically infected. IFN-α therapy was effective in only 25% of HCV patients. Assuming that CD8+ T cells impeded the therapeutic effect, the incorporation of monoclonal antibodies to CD8+ has been involved, resulting in a high CD4+/CD8+ ratio of 1.6 to 3.0 during treatment, with a gradual decrease to 2.3 after 1 year after the last monoclonal antibody infusion. In these patients, ALT gradually decreased and clinical improvement occurred, which could not be achieved with interferon α, β, and γ.
HCV has multiple genotypes, with genotype 1b being the one with the highest chronicity and greater resistance to interferon. Even the most modern concomitant therapy with INF-alfa-2a and ribavirin does not always lead to success, especially in older patients. More than half of patients with chronic hepatitis C are insensitive to interferon. On the other hand, the huge cost of an intensive course of interferon treatment, which can reach between £30,000 and £100,000, must be taken into account.
Based solely on clinical and laboratory criteria, chronic hepatitis C is virtually indistinguishable from autoimmune hepatitis. It should be noted that the absence of antinuclear antibodies or other autoantibodies
Smooth muscle antibodies do not exclude the presence of autoimmune hepatitis. Therefore, we should be cautious about prescribing interferon for patients with hepatitis C who have not ruled out autoimmune hepatitis. At the same time, since in chronic hepatitis C its autoimmune character can never be excluded, the high risk of interferon in such cases is understood.
However, the classic approach to the treatment of such patients, considering them with autoimmune pathology and chronic hepatitis C, may result in an increase in viral replication, with the risk of worsening the clinical course. In addition, there is no evidence to show that interferon therapy reduces the risk of the subsequent development of hepatocellular carcinoma.
There is a serious clinical dilemma: both interferon and corticosteroids are almost impossible to use. However, only plasmapheresis is a suitable alternative to antiviral therapy for hepatitis C. By eliminating autoantibodies, plasmapheresis helps restore the reparative abilities of hepatocytes and, on the other hand, by removing the "toxic pressure" of the immune system, it should stimulate their normalization.
In recent years, liver transplantation has become more common to treat chronic hepatitis, cirrhosis, and liver tumors. However, even after these operations, HCV persists, leading to a relapse of chronic hepatitis in 50-60% of patients. A three-month course of ribavirin promotes normalization of aminotransferase levels and histological improvement, but after discontinuation of such therapy, biochemical signs of hepatitis return, indicating that ribavirin is not able to prevent the progression of fibrosis in patients with autoimmune hepatitis C.
HCV infection has a prolonged "gap" from infection to clinical manifestations of liver disease, which can last from 10 to 20 years until the development of cirrhosis or hepatocellular carcinoma. However, this "asymptomatism" is quite relative. In fact, hyperbilirubinemia and signs of portal hypertension may not appear. However, a close analysis of these patients reveals a less optimistic picture. In these patients, significant fatigue is seen in 78%, depression in 53%, joint pain in 53%, weakness in 51%, sleep disturbances in 51%, abdominal discomfort in 51%, weight loss in 43%, headaches in 39%, itching in 39%, and jaundice in 20% of cases. This suggests that these patients experience a significant deterioration in quality of life, which contradicts the common view that chronic hepatitis is virtually asymptomatic until signs of cirrhosis occur. It is possible that such practices contribute to other related autoimmune diseases that are also in a subclinical phase.
However, we must not forget that in the coming years millions of carriers of the hepatitis C virus will become seriously ill, with a sharp increase in mortality due to chronic hepatitis and cirrhosis. In recent years, hepatitis C treatment has been actively implemented with direct-acting antiviral therapy (DAA), based on a combination of drugs such as sofosbuvir, ledipasvir, simeprevir, paritaprevir, and dasabuvir. This has increased the effectiveness of drug therapy from less than 50% to more than 90%. However, full recovery of liver function is quite illusory. Levels of urea, nitric oxide, methionine, and cyclic polyamines remain elevated. Often, after viral eradication, tests remain indicating continuous alterations in the liver. There is another limitation in the use of DAA therapy: in the presence of concomitant membranoproliferative glomerulonephritis, some direct-acting drugs, such as sofosbuvir, are contraindicated due to their nephrotoxic effect. Therefore, such therapy should be combined with plasmapheresis, corticosteroids, and rituximab.
However, in hepatitis C, there are multiple concomitant extrahepatic diseases associated with the development of systemic immune disorders, such as diabetes, cryoglobulinemia, vasculitis with kidney damage, cardiovascular and neuropsychiatric disorders, not to mention the liver lesions themselves, such as fibrosis, cirrhosis, fatty hepatosis, and hepatocellular carcinoma. It is not yet clear how much viral eradication will contribute to the reverse development of the disorders that have already occurred. These patients are still at risk of developing hepatocellular carcinoma, which requires constant monitoring, alpha-fetoprotein control, and elastography, especially in cases of advanced fibrosis and in older people. In addition, with an existing hepatocellular carcinoma, hepatitis C treatment is less successful.
There are observations suggesting a reactivation of hepatitis B and autoimmune hepatitis in the context of such DAA therapy
Fibrosis and fatty hepatosis also remain. In the treatment of hepatitis C with pegylated interferon-alpha, rhabdomyolysis may develop with increased creatine kinase levels.
Therefore, even modern direct-acting antiviral therapy does not fully guarantee recovery from liver lesions that have already occurred nor does it eliminate the risk of hepatocellular carcinoma.
All of the facts mentioned above convincingly demonstrate the autoimmune nature of chronic hepatitis, which almost naturally develops after having suffered from viral hepatitis B, C, and D. In this case, plasmapheresis is the only thing that can help mitigate its manifestations and delay the inevitable outcome. This raises the question of the implementation of preventive courses for plasmapheresis in the period of early rehabilitation after acute viral hepatitis (especially C and D), as there is no guarantee of avoiding the chronic process.
The emergence of autoantibodies is caused both by viral infection and by changes in the antigenic structure of hepatocytes that occur at the peak of the disease. The "random discovery" of HCV must also raise the question of conducting such preventive courses of plasmapheresis. Since this viral infection is incurable, even when after 10-20 years of being asymptomatic they develop signs of chronic hepatitis, it is necessary to repeat these courses of plasmapheresis at least once a year for the rest of life.
Based on the improvement in overall condition, a decrease in the levels of bilirubin, ALT, ESR, circulating immune complexes, alkaline phosphatase, and medium-sized molecules was observed. Plasmapheresis sessions were combined with extracorporeal laser irradiation (HeNe) of the blood and external radiation of the hepatic area. Repeated courses of plasmapheresis provided longer remission. In cases of exacerbation of chronic hepatitis, the results of the use of plasma exchange were better than those of pharmacological treatment with entecavir.
In cases of chronic advanced hepatitis C with the development of hepatic encephalopathy, plasmapheresis also contributed to the improvement of general health status and the elimination of symptoms of poisoning, with decreased bilirubin and transaminase levels almost returning to normal.
As a further illustration, we give an example from our own clinical practice:
Patient V., 80 years old. 33 years ago, in 1985, a 10-fold increase in ALT level was incidentally revealed, and ultrasonographic investigation showed an increase and consolidation of the liver with symptoms of portal hypertension and an increase in portal vein diameter to 15 mm. It was only in 1993 that the etiology was clarified: antibodies against hepatitis C were found. However, since 1985 a plasma exchange course was held with 4 sessions, with elimination of up to 1-1.5 liters of plasma each time, on an annual basis. ALT levels remained at normal or subnormal levels throughout this time, and ultrasonographic investigation in 2012 showed normalization of liver size and structure, with a reduction of portal vein diameter to 12 mm. There were no signs of HCV viremia, although the HCV test was consistently positive. Throughout this period, health was satisfactory. No special drug therapy was given.
The example given confirms our concept of conducting preventive plasma exchange courses immediately after detection of viral hepatitis C.
However, in liver transplant patients with chronic hepatitis C, the chances of damage to the donor's liver are not eliminated. In addition, the development of cirrhosis in the transplanted liver is often more intense than before the transplant. In such cases, the cascade plasmapheresis method was used, where not only were autoantibodies selectively removed, but complex therapy for HCV (interferon, ribavirin, including cascade plasmapheresis) was also performed. HCV RNA was reduced to 8.2% and 0.7% on the 5th and 30th day of treatment, respectively. In three patients who underwent this therapy as a preventive measure, they showed no recurrence of the disease even one year after treatment. The patient who had already developed signs of fibrous cholestatic hepatitis showed rapid reverse dynamics in the lesions of the transplanted liver. There was a drastic decrease in the amount of hepatitis C virus in the blood (and without the additional use of antiviral drugs) through the use of cascading plasmapheresis. Cascade plasma exchange was used even in the presence of acute renal failure, in the context of hemodialysis, which also promoted the decrease in the level of viremia.
Cascade plasmapheresis was used for the purpose of viral decontamination in patients who had previously received interferon therapy or its combination with ribavirin, without success.
but if at least a part of them remains, it does not prevent a new exacerbation of the disease
Chronic alcoholic hepatitis and liver cirrhosis occur as a result of the formation of free radicals due to the action of ethanol, which causes damage to cell membranes and organelles. The oxidation product of alcohol, acetaldehyde, also generates free radicals. In addition, alcohol promotes the release of cytotoxic cytokines (IL-1, IL-6, IL-8, TNF-α). The number of cytotoxic T cells in the liver also increases, contributing to the development of necrosis, fibrosis, and subsequently cirrhosis. In addition, alcohol contributes to the progression of other forms of chronic hepatitis
We must also point out the main role of chronic alcohol poisoning in the development of both primary chronic hepatitis and alcoholic cirrhosis. In addition, there is evidence that chronic alcoholism develops immunosuppression, supplementing the ability to fight hepatitis, which contributes to a more severe course of the disease and chronicity. Consumption of more than 90 g of alcohol per day has been found to significantly increase the severity of chronic hepatitis. This underscores the need to abstain from any type of alcoholic beverage in patients with already developed chronic liver disease, and even in those cases where a high probability of such a process can be expected to occur in HCV-infected individuals.
In chronic hepatitis of alcoholic genesis, plasma exchange courses also contribute to stabilization of status, with decreased levels of bilirubin, ALT, erythrocyte sedimentation rate (ESR), alkaline phosphatase, and reduced liver size according to ultrasound. In the future, with the use of liver treatment and diet (elimination of alcohol), it is possible to achieve a fairly persistent and prolonged remission.
Hepatosis grasa (steatosis) is a growing health problem in many countries around the world, associated with increased morbidity and mortality. It is also defined as non-alcoholic fatty hepatosis. It occurs in 30% of the total population and in 40% to 70% of obese people. It often accompanies other metabolic disorders, such as obesity and diabetes. With insufficient sugar control in diabetes, excessive accumulation of glycogen in hepatocytes (glycogenic liver disease) is possible. It can also be related to the consequences of Helicobacter pylori infection and inflammatory bowel diseases (such as Crohn's disease, ulcerative colitis).
necrotizing colitis), when, due to the increased porosity of the intestinal wall, toxic metabolites reach the liver. The development of fatty hepatosis has also been described as a result of general irradiation of the body in children during tumor treatment. At the same time, insulin resistance and dyslipidemia develop, also affecting the liver.
Fatty hepatosis is accompanied by fibrosis with hepatocyte apoptosis, leading to endothelial dysfunction with elevated ALT and AST levels, followed by the development of cirrhosis. In the near future, it is expected to be the main indication for liver transplantation. But even after transplantation, there is a high risk of reappearance of fatty hepatosis in the graft if its root causes are not removed. The frequency of hepatocellular carcinoma associated with fat hepatosis is also increasing. Fatty hepatosis also contributes to the development of atherosclerosis and cardiovascular disease. Since there are no specific methods of treatment or prevention for fatty hepatosis, preventive plasmapheresis is justified at the first signs of this pathology.
Liver cirrhosisA serious complication of viral hepatitis is the development of liver cirrhosis with imminent portal hypertension and profuse bleeding from esophageal and gastric varices. But, in the context of developing cirrhosis with severe chronic liver failure, courses of plasmapheresis and cryoplasmassorption also contribute to a certain stabilization of the patient's condition. Thus, in these patients, as a result of the treatment of liver failure, the encephalopathy phenomenon was stopped, ascites was reduced, the level of cholestasis decreased, and the prothrombin index increased by more than 60%. Partial plasma replacement after cryogenic treatment helped stabilize the level of total protein in the blood. Plasmapheresis also helps relieve itching, which frequently accompanies cirrhosis, for up to 6 months.
In liver cirrhosis complicated by diuretic-resistant ascites, plasmapheresis was performed, and ascitic fluid obtained by paracentesis was used as a replacement solution, which was subjected to ultrafiltration and cryoplasmosorption. This restored circulating blood volume, reduced protein loss, decreased bilirubin and transaminase levels. In cases of extremely severe hepatic impairment, positive results were obtained using the MARS system, where plasma obtained by membrane plasmapheresis is subsequently passed through a special column, in which the plasma is used.
the albumin adsorbed related toxins are then removed by dialy-sis, and then returned to the patient a purified.
Exogenous toxic hepatitis
Exogenous toxic hepatitis often develops when receiving a drug such as isoniazid, used to treat tuberculosis. Especially dangerous is the combination of this drug with rifampicin. It evolves with hepatocyte necrosis and the associated mortality is ten times higher than in viral hepatitis. Although rare (1 in 10,000 anesthesia), serious liver damage can also develop as a result of halothane inhalation. Even a "harmless" drug such as paracetamol, in doses greater than 10 g, can cause fatal liver necrosis. The development of severe acute hepatitis has also been described by the use of omeprazole in the treatment of gastritis due to acid hypersensitivity. Cholestasis can also develop due to regular contraceptive administration. The plasmapheresis course, with up to 9 sessions, allowed this pathology to be normalized.
The development of acute liver damage with fulminant liver failure after the ingestion of paracetamol (acetaminophen), already mentioned above, is common and, in some cases, has even required a liver transplant. The timely use of plasmapheresis courses in such cases favors the restoration of liver functions.
These data also underline the desirability of early excretion of these hepatotoxic drugs by plasmapheresis to reduce the magnitude of damage and prevent the progression of pathological liver disorders. All this makes it necessary to resort to extracorporeal detoxification methods once again.
Primary biliary cirrhosis
It is a chronic and progressive autoimmune disease of the cholestatic type. It occurs mainly in middle-aged women with a frequency of 3.9 to 15 per 1 million inhabitants. In this disease, the small intralobular bile ducts degrade, with a transition to fibrosis and cirrhosis with the development of portal hypertension. It is manifested by jaundice of the skin, weakness, persistent pruritus, osteoporosis, hypercholesterolemia with xanthomas and xanthelasma. Laboratory monitoring reveals marked cholestasis with elevated levels of bilirubin, transaminases, immunoglobulin M, and the presence of antibodies against mitochondria.
Oxidative stress plays an important role in pathogenesis, with significant accumulation of free radicals, malondialdehyde, and 8-isoprostane due to lower antioxidant activity, vitamin A, and selenium.
The common first-line treatment is ursodeoxycholic acid, although it does not always produce the right effect. However, 95% of patients have highly specific antimitochondrial autoantibodies. Since the main etiological factor of the disease is also the accumulation of autoantibodies, plasmapheresis can provide substantial help to patients. In fact, as a result of the course of plasmapheresis, total bilirubin decreased by 25-30%, ALT and AST by 12-15%, and levels of CIC and medium-sized molecules were normalized, which helped reduce pruritus and asthenic-neurotoxic manifestations. According to ASFA recommendations, in some cases, reducing persistent pruritus requires a course of plasmapheresis 2-3 times per week for approximately four weeks.
A similar liver disease is primary sclerosing cholangitis, a chronic cholestatic liver disease of unknown etiology. Like patients with autoimmune hepatitis, those with primary biliary cirrhosis and primary sclerosing cholangitis may present with anti-mitochondrial antibodies (AMAs), cytoplasmic anti-neutrophils (ANCAs), intestinal antibodies, and anti-ribosomal antibodies (ARBs). Sclerosing cholangitis is usually accompanied by IgG4 antibodies with T lymphocyte infiltration and the concomitant development of cholecystitis, retroperitoneal fibrosis, tubulointerstitial nephritis, interstitial pneumonia, prostatitis, and lymphadenopathy.
Autoimmune hepatitis often develops and combines with primary biliary cirrhosis and primary sclerosing cholangitis, and sometimes also with ulcerative colitis and Crohn's disease. In particular, inflammatory bowel diseases are found in 75% of patients with primary sclerosing cholangitis. At the same time, most of the drugs prescribed for ulcerative colitis and Crohn's disease (in particular, methotrexate and thiopurines) are highly toxic to the liver
In all these cases, therapeutic apheresis also helps to soften the overall toxic effect, both in the development of acute hepatitis and in chronic exposure to hepatotropic toxicants.
Budd-Chiari syndrome
Budd-Chiari syndrome occurs most often in antiphospholipid syndrome and is characterized by progressive obstruction of the hepatic veins from the lobular vein to the confluence of the inferior vena cava in the right atrium. It manifests with hepatomegaly, abdominal pain, and ascites. It can occur acutely and malignantly, but usually has a chronic, asymptomatic course. In the latter case, there is a negligible increase in
Budd-Chiari syndrome
Budd-Chiari syndrome occurs most often in antiphospholipid syndrome and is characterized by progressive obstruction of the hepatic veins from the lobular vein to the confluence of the inferior vena cava in the right atrium. It manifests with hepatomegaly, abdominal pain, and ascites. It can occur acutely and malignantly, but usually has a chronic, asymptomatic course. In the latter case, there is a negligible increase in basal activity of transaminases and alkaline phosphatase in conjunction with hypoalbuminemia. However, this chronic metabolic disorder of liver cells leads to fibrosis and cirrhosis.
The autoimmune nature of the disease involves the use of plasmapheresis to remove both antibodies and vasoactive and pathological metabolites. In the intensive course of plasmapheresis in the treatment of acute Budd-Chiari syndrome, with obstruction of blood flow in the hepatic veins and rapid progression of ascites and oliguria due to high levels of AST, ALT, LDH and bilirubinemia, a positive treatment dynamic was observed: reduction in liver size and ascites with incomplete recanalization of the hepatic veins.
Crigler-Najjar syndrome
This syndrome is characterized by an acute increase in the level of unconjugated bilirubin, up to the development of encephalopathy, due to the congenital lack of enzymes that promote the elimination of bilirubin (uridine diphosphate glucuronosyltransferases). Plasmapheresis in such cases also helped to alleviate severe manifestations of the disease.
Thus, the picture of homeostasis disorders, which lead to an increase in organic disorders, is becoming clearer and clearer. The materials presented indicate a variety of causes of liver damage, but all are related to common pathogenic mechanisms associated with the accumulation of a number of toxic products that damage the liver parenchyma. In this case, many of these pathological products accumulate, and the size of their molecules prevents their excretion through the kidneys, while the liver is also unable to destroy them. On the other hand, the fact that these products accumulate suggests that no medication can help them leave the body.
Conclusion
To date, significant progress has been made in the treatment of viral infections, but these drugs themselves are not safe and are not always able to interrupt already existing liver pathological disorders, which still require the use of plasmapheresis. Therefore, in all these cases, plasmapheresis is a method of treatment and prevention of the progression of liver damage, justifiably pathogenic.
In such cases, it is sufficient to remove up to 1 liter of plasma, replacing it only with crystalline solutions during 4 plasmapheresis sessions, performed every two days, which can be carried out even in an outpatient setting. In the future, it will be necessary to regularly repeat these courses up to twice a year. Thus, it is possible to effectively interrupt the progression of the disease and prevent the transition to the development of irreversible liver damage in cirrhosis and hepatocellular carcinoma. But even in advanced processes, plasmapheresis can significantly improve the condition of patients.
