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Chronic lymphocytic leukemia/small lymphocytic lymphoma. Clinical recommendations

The article is published based on the results of the Russian Consensus on the diagnosis and treatment of primary sclerosing cholangitis (PSC), discussed at the 44th annual Scientific Session of the CNIIG "Personalized Medicine in the Era of Standards" (March 1, 2018). The aim of the review is to highlight the current issues of classification of diagnosis and treatment of patients with PSC, which causes the greatest interest of specialists. The urgency of the problem is determined by the multivariate nature of the clinical manifestations, by often asymptomatic flow, severe prognosis, complexity of diagnosis and insufficient study of PSC, the natural course of which in some cases can be considered as a function with many variables in terms of the nature and speed of progression with numerous possible clinical outcomes. In addition to progression to portal hypertension, cirrhosis and its complications, PSC can be accompanied by clinical manifestations of obstructive jaundice, bacterial cholangitis, cholangiocarcinoma and colorectal cancer. Magnetic resonance cholangiography is the main method of radial diagnostics of PSC, which allows to obtain an image of bile ducts in an un-invasive way. The use of liver biopsy is best justified when there is a suspicion of small-diameter PSC, autoimmune cross-syndrome PSC-AIG, IgG4-sclerosing cholangitis. Currently, a drug registered to treat primary sclerosing cholangitis which can significantly change the course and prognosis of the disease does not exist. There is no unified view on the effectiveness and usefulness of ursodeoxycholic acid and its dosage in PSC. Early diagnosis and determination of the phenotype of PSC is of clinical importance. It allows to determine the tactics of treatment, detection and prevention of complications

Heart injury is one of the extrahepatic manifestations of chronic hepatitis C (CHC). The paper gives Russian and foreign authors' data on a relationship between CHC and myocardial injury. It discusses different pathogenetic components (the direct effect of the virus, immunological components), through which hepatitis C virus can induce myocarditis and cardiomyopathies in patients with CHC.Поражение сердца - одно из внепеченочных проявлений хронического гепатита С (ХГС). Представлены данные отечественных и зарубежных авторов о взаимосвязи ХГС и поражения миокарда. Обсуждаются различные патогенетические звенья (прямое воздействие вируса, иммунологические), через которые вирус гепатита С может индуцировать развитие миокардита и кардиомиопатий у больных ХГС.

Hepatic encephalopathy (PE) requires from physician to know all the aspects of its clinical manifestations and special psychometric methods for its diagnosis. Hepatic encephalopathy significantly reduces the quality of life in patients with chronic diffuse liver diseases. The article tells about early prescription of pathogenetic therapy to eliminate minor PE which is most common in patients with liver cirrhosis in order to prevent marked PE and improve the quality of life of patients and their survival.

Two clinical observations of the variant form of hepatic lesion: autoimmune hepatitis--primary biliary cirrhosis with systemic manifestations are presented in patients with long-standing Sjogren's syndrome, one at the stage of lever cirrhosis, the other at stage F2 of fibrosis. Difficulties encountered in diagnostics and the necessity of changing the entire spectrum of autoimmune markers characteristic of Sjogren's syndrome, autoimmune hepatitis and primary biliary cirrhosis are discussed. The possibility of different forms of hepatic lesions in autoimmune hepatitis--primary biliary cirrhosis is emphasized.

The presented clinical case gave rise to discussion of the main mechanisms and factors behind the progress of chronic hepatitis C. Special emphasis is laid on the currently available possibilities of antiviral therapy and its future prospects. The efficacy of personalized treatment and approaches to its improvement are considered based on the proper preventive measures and correction of factors responsible for poor responsiveness to the treatment, in the first place metabolic disorders (obesity, hepatic steatosis).

Studies of hepatitis C virus (HCV) genotype and subtype structure in patients with chronic hepatitis C in 3 regions of the Central federal district of Russia.Hepatitis C virus genotype and subtype structure was determined in patients with chronic HCV infection in Moscow (1993 - 1995 and 2005), Moscow region (2008) and Vladimir region (1993 -1995, 2005-2007). HCV genotype was determined by using A. Widell et al. (1994) technique, PCR (AmpliSens diagnostic kits), Genotype C test system.In all studied regions and during all the time periods the first position in rating belonged to HCV 1b subtype. In 1993 - 1995 and 2005 - 2007 period changes in HCV genotype and subtype structure were registered that consisted of relative weight of 1b subtype decrease and 3a subtype increase. Subtype 1b in females with chronic hepatitis C was registered more often than in males. In Vladimir region 3a subtype in males was detected more often than in females. In males older than 30 years the first rating position belongs to 1b subtype and in males younger than 30 years--subtype 3a. In females older than 30 years in Moscow region and Vladimir region, as well as in females younger than 30 years in Vladimir region subtype 1b was detected more often, while in Moscow region HCV subtypes 1b and 3a were detected with the same rate of 47.6%.Currently there is an urgent need to include mandatory monitoring of hepatitis C virus genetic variants into the system of hepatitis C epidemiologic control in Russia. This approach will allow for a significant increase in quality of hepatitis C serological diagnostics, and can be used in the prognosis of evolution of the epidemic process of this disease.

Primary biliary cirrhosis (PBC) is characterized by high frequency of systemic extrahepatic manifestations (EHM), which often precede the development of full clinical picture of PBC and play the leading part in the clinical course of the disease, sometimes determining its prognosis. The examination of 145 PBC patients (including two men) found a frequency of EHM of 72. 4%. The majority of EHM were caused by delayed-type hypersensitivity reactions, such as Sjogren syndrome, fibrosing alveolitis, autoimmune thyroiditis, tubulointerstitial nephritis, pulmonary granulomatosis/sarcoidosis, systemic scleroderma, rheumatoid arthritis, and ulcerative colitis; immunocomplex pathology including vasculites involving blood vessels of different caliber and localization and polyneuropathy was rarer. In 24.1% of PBC patients, system EHM manifestations were the first clinical signs of the disease. In 62.8% of patients with EHM their different combinations were registered. The most frequent one was a combination of Sjogren syndrome, fibrosing alveolitis, and tubulointerstitial nephritis, which was found in 16.2% of the patients. 6 7% of the patients had a combination of four EHM - Sjogren syndrome, fibrosing alveolitis, tubulointerstitial nephritis, and autoimmune thyroiditis. A long duration of PBC (more than five years from the debut), stage IV of the disease, and the presence of the rheumatoid factor in blood serum, were risk factors of the development of system PBC manifestations. In 20% of EHM patients their symptoms prevailed in the clinical picture, thus determining the severity of the condition. Three patients died of system EHM of PBC (systemic scleroderma, pulmonary granulomatosis). Thus, PBC diagnostics must be performed with taking into account system EHM found in this category of patients.

To study the incidence and prognostic significance of extrahepatic manifestations of chronic HCV-infection with low activity of hepatic process and to specify treatment policy.Sixty-two patients with low-active chronic hepatitis C (CHC) entered the study. Blood samples from all the patients were studied clinically, biochemically, immunologically and virusologically. In 58 patients the diagnosis was confirmed morphologically (liver tissue).Systemic manifestations of CHC were observed in 23 (37.1%) patients, in 12 of them they were associated with cryoglobulinemia. Most frequent was cryoglobulinemic vasculitis with skin (12.9%) and joint (9.7%) involvement, cryoglobulinemic glomerulonephritis (11.3%), arthralgia without association with cryoglobulinemia (11.3%). Independent risk factors for development of systemic disorders in CHC of low activity comprised female gender, age over 45, the disease duration and presence of cryoglobulinemia.CHC of low activity is characterized by high occurrence of systemic manifestations primarily associated with cryoglobulinemia. Renal affection with development of cryoglobulinemic glomerulonephritis is most prognostically significant.

The trial enrolled 38 patients with chronic HCV-infection and Sjogren's syndrome (mean age 44.3 +/- 13.7 years). Biopsy of the minor salivary glands (MSG) was made in 20 patients. Polymerase chain reaction was used to study 20 MSG biopsies, 38 samples of native saliva for HCV-RNA. Saliva samples were also studied for Herpes virus DNA (EBV, CMV, HHV-VI type). All the patients with VHC appeared to have signs of xerostomia, 24 (63.2%) patients had xerophthalmia. MSG pathohistological changes were found in 19 (95%) patients. In the majority of cases (86.9%) they were characterized by mild infiltration and advanced fibrosis. HCV-RNA was found in the saliva of 23 (57.5%) patients, in MSG tissue--in 9 (39.1%) patients. HCV-RNA detection in the saliva did not depend on the degree of viremia, viral RNA in MSG correlated with viral load. EBV and HHV-VI, HHV-VI only and EBV were detected only in 7 (18.4%), 10 (26.3%) and 6 (15.8%) patients, respectively. Xerostomia occurred with the same rate (26.1 and 31.3%) in patients with and without herpes viruses in the saliva. Detection rate for HCV-RNA in the saliva was not related with viremia degree. Sjogren's disease symptoms in CHC patients did not depend on the presence or absence of DNA of herpes viruses in the saliva.

The necessity of the search for new drugs to treat chronic hepatitis B (CHB) is explained by the necessity to prevent hepatic cirrhosis (HC) and hepatocellular carcinoma. Treatment of HBeAg-negative CHB rests on the same principles as of HBeAg-positive one. Efficacy of nucleoside analogue lamivudin is well studied in HBeAg-positive CHB. The aim of this study was to evaluate lamivudine efficacy in therapy of HBeAg-negative CHB. Lamivudine (epivir--150 mg/day or zeffix--100 mg/day) was given for 1 year to 10 patients (5 males, 5 females, mean age 49.5 +/- 13.5). Their blood serum contained no HBeAg but contained HBeAb and HBVDNA. Chronic hepatitis was verified morphologically in 9 patients of whom 2 had HC and 2 developing HC. Moderate activity of the disease was in 4 patients, low--in 5. All the patients had a high ALT level (150 +/- 140 U/l, 60-528 U/l, high normal value 40 U/l). ALT and HBV DNA in the serum were examined by polymerase chain reaction in the course of treatment and for 6 months after its end. To the end of the treatment a complete response (absence of HBVDNA and normalization of ALT) was achieved in 8 (80%) patients. 5 (63%) of them 2-4 months after the end of the treatment had the exacerbation with appearance of HBVDNA in the serum and elevation of ALT level. A persistent response (6 months after lamivudin treatment) was in 3 (30%) patients, in 2 of them HBsAg was not detected. Lamivudin therapy is effective in HBeAg-negative CHB. In this study a high baseline level of ALT was the factor predisposing to a lasting response to treatment.

To determine factors affecting overall survival and risk to develop hepatocellular carcinoma (HCC) in patients with hepatic cirrhosis (HC) of mixed (viral, alcoholic) etiology.Mono- and multi-variance analysis of prognostic effects of such factors as age of the patients, mixed infection VHB/VHC, markers of HBV replication, antibodies to nuclear antigen of HBV (HBcAb) without HBs-system in the serum ("isolated" HBcAb), duration of viral infection, alcohol intake and abuse, dilatation of the esophageal veins, some laboratory parameters were studied in 55 HC patients having at least one marker of hepatitis B virus (HBV) and/or hepatitis C virus (HCV), long history of alcohol abuse.It was found that risk of HCC was associated with duration of alcohol abuse and infection, mixed HBV/HCV infection, age 60 and older. Of independent significance was only duration of alcohol abuse. Lethal outcomes in HC patients in the mixed infection were due to development of HCC (36%) and HC complications (64%). Survival of the patients was less in severe dilatation of the esophageal veins, high clinicolaboratory index, low level of serum albumin, presence of "isolated" BcAb and mixed viral infection.Of the greatest prognostic efficacy in respect of survival was the model combining "isolated" HBcAb, the degree of esophageal veins dilatation and hepatitis activity.

In order to determine the differences in histological grade of activity and the stage of fibrosis in patients with chronic liver diseases due to multiple hepatitis virus infection and single infection of HBV and HCV we assessed the 68 liver biopsies samples according to Knodell and Scheuer scoring systems. Retrospectively, 216 liver biopsies reports from consecutive patients with chronic viral hepatitis were analysed. Histological activity index (HAI) in HBV/HCV coinfection was higher than in a single HCV infection; it did not differ in groups of HBV/HBC and HBV. The difference was due to the interface hepatitis; lobular activity and portal inflammation were the same. In HDV superinfection HAI was high due to both portal-periportal and lobular hepatitis. HAI depended mainly upon the presence of HBV replication; in patients with chronic hepatitis C with HBV-DNA HAI was also higher than in single HCV group. No difference in HAI between triple and dual hepatitis virus infection was found. In patients with HBV/HCV coinfection and especially with HDV superinfection the advanced stages occurred more than often than in patients with single infections.

Upon analysis of 550 cases of different chronic diffuse pulmonary diseases included in a group of interstitial diseases of the lungs (IDL) the authors came to the conclusion that IDL incorporate such variants as alveolitis, pulmonary vasculitis and pulmonary hemorrhages; granulomatosis covers exogenic allergic alveolitis, alveolitis in chronic active hepatitis; vasculitis group includes such rare diseases as necrotizing sarcoid granulomatosis vasculitis and lymphoid granulomatosis; fibrosing alveolitis--secondary alveolitis in sclerodermia systematica, rheumatoid arthritis, Sjogren's disease, chronic active hepatitis. Knowledge of IDL etiology (environmental, occupational, induced by radionuclides, drugs, viruses, fungi) with focus on drug affection of the lungs is thought of value. Biopsy and bronchial lavage findings are compared clinically and morphologically. Mechanisms of pulmonary fibrosis and approaches to inhibition of pulmonary fibrosis progression are outlined.

Various profiles of serum HBV markers (HbsAg) were identified in 16 patients, markers of active replication in 4 patients (HbeAg, 2 cases; HBcAb IgM, 1 case; HBcAb IgM and HbsAg IgM, 1 case) out of 22 patients with Sjögren disease (SD) having serum HBV markers and systemic manifestations. Of these 3 had a history of acute viral hepatitis, 12 were previously at risk to be infected with hepatitis viruses, 7 had neither the disease nor its risk factors, none of them had chronic active hepatitis or hepatic cirrhosis, 7 exhibited clinical signs of pseudolymphoma, 1 had serum monoclonal IgM kappa in the presence of HBV active replication markers (HBsAg IgM, HbcAb IgM). The present and previous data (on association of SS with chronic active hepatitis and hepatic cirrhosis due to HBV) suggest the involvement of the virus in SD etiology.

The authors describe pulmonary granulomatosis in a male patient with chronic active hepatitis of viral etiology with persistence of hepatitis B virus in blood serum and liver tissue. The presence of active virus infection with proven hepatitis B virus replication, evidenced by demonstration of HBeAg and HBcAb in blood serum, suggests an importance of universal etiological factor in the development of liver and lung lesions in the given patient, which is confirmed indirectly by demonstration of HBsAg in the cells of lavage fluid.

Myocarditis attended chronic active hepatitis in 22 patients (in 13 of them the outcome of hepatitis was liver cirrhosis). Twelve patients recovered, postmyocarditis cardiosclerosis developed in 6 and 4 patients died. Chronic myocarditis in the stage of aggravation was revealed in 3 cases at autopsy and severe postmyocarditis cardiosclerosis with manifested dilatation of the heart cavities in 1 case.

Thirty biopsies of the lower lip mucosa from patients with clinical and subclinical manifestations of Sjögren syndrome were studied. The results indicate characteristic morphological changes in small salivary glands. The dynamics of these changes consists in progressive lymphoid infiltration of the gland tissue and includes 4 stages: I--weak lymphoid infiltration, II--focal lymphoid infiltration, III--focal-extensive lymphoid infiltration, IV--diffuse lymphoid infiltration, that is, lymphomatosis. In parallel with the progressive lymphoid infiltration there occur sclerosis of the stroma, atrophy and loss of parenchyma of the salivary glands in which the chemical composition of the secrete is changes as confirmed by tests done for mucus. The results obtained and data from literature permit a conclusion that Sjögren syndrome is a generalized autoimmune disease underlain by the disturbance of immunological homeostasis.

Sixty patients with Sjogren's disease (SD) were examined. In all the patients--women aged 23 to 70, apart from the generalized "dry syndrome", there were signs of involvement of other organs and systems. Biopsy and autopsy material was studied histologically and histochemically, in some cases immunofluorescent and electron-microscopical study was performed. The most pronounced morphological and clinical manifestations of SD were linked with the damage to exocrine glands. Their alterations were represented by delayed type hypersensitivity and were similar in all exocrine glands, hence the exocrine tissue might be regarded as a target tissue in SD. One of the mechanisms of the exocrine tissue damage is connected with a mutual duct antigen of exocrine glands represented by the serum component IgA. The involvement of certain organs and systems with the development of chronic persistent hepatitis, fibrosing alveolitis, mesangioproliferative and tubulointerstitial nephritis, pronounced hyperplasia of lymphoid tissue with its plasmatization and generalized affection of the microcirculatory system of the immunocomplex nature, is noted in SD with various frequency.

Different patterns of serum HBV markers (HBsAg, HBsAb, HBeAg, HBeAb, HBcAb) were identified in 82 patients (12 with chronic active hepatitis, 67 with hepato-cirrhosis developing in the outcome of chronic active hepatitis, and in 3 with primary biliary cirrhosis) of 105 (78%) patients with chronic liver diseases. Besides, IgM HBcAb were identified in 9 of 47 patients (19.1%), HBsAg IgM in 4 of 9 patients (44.4%), antibodies to the delta-agent in 8 of 23 (34.8%) suffering from chronic liver diseases with the presence of serum HBV markers. Chronic liver diseases with the presence of HBsAg and/or other serum HBV markers were characterized by a variety of clinico-laboratory manifestations determined by the involvement of some organs and systems in a process. A degree of activity of chronic liver diseases was not correlated with a replication phase, an integration phase, and an immunological resolution phase in 49 patients with identified phases of development of HBV-infection. More frequent identification of serum HBV markers including those of a replication phase was not noticed among patients on prolonged immunosuppressant therapy.

Virus infection of organs and tissues in chronic active hepatitis (CAH) is generalized, therefore CAH may be considered to be a generalized viral infection in which liver involvement is only one but most important manifestation thereof. The involvement of both liver and other internal organs in CAH is underlain by delayed type hypersensitivity reaction supported by immune complexes containing hepatitis B virus antigens. The intensity of hypersensitivity reaction (immune inflammation) and autoimmunization is mediated genetically.