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Inoyatova Flora Ilyasovna, MD, Professor, Academician of the Academy of Sciences Republic of Uzbekistan Head of Hepatology Department of Republican Specialized Scientific Practical Medical Center of Pediatrics, Tashkent, Uzbekistan E-mail: hepar.child@yandex.ru Inogamova Gulnoza Zaxidjanovna, Ph D. Senior Researcher of Hepatology Department of Republican Specialized Scientific Practical Medical Center of Pediatrics, Tashkent, Uzbekistan E-mail: igz.science@yandex.ru
LIVER CIRRHOSIS IN CHILDREN: ETIOLOGY, CLINICAL ASPECTS, AND PROGRESSION MARKERS
Abstract. Examination of202 sick children in the age from 7 to 15 provided definition of etiological structure of LC, where viral infection (73.3%) prevailed with a greater part of hepatotropic viruses (90.6%), the accent among which was put on B+C+D(32.2%), B+D(21.4%) and B+C(l6.1%)mixed infections. Mixed infection is considered to be a predictor of the pathology progression, especially in case of accretion with autoimmune hepatitis. In other cases LC is formed as an outcome of autoimmune (4.9%), hereditary "exchange" (6.9%), and combined (9.9%) hepatitis. Peculiarities of clinical progress and development of complications were determined dependently on the etiology. Self-descriptiveness of PINP and PICP terminal peptides was determined in the progression of liver cirrhosis in children.
Keywords: liver cirrhosis, etiology, clinical symptoms, complications, markers of fibrosis, children.
Liver cirrhosis (LC) is a chronic polyetiological damage factors in the progression of the disease predetermines the
of liver, characterized by disorder of hepatic architectonics, necessity to study nodular aspects of this pathology with a
formation of fibrous septa, nodular regeneration, and growth perspective of further development of differential approaches
of connective tissue, leading to hepatic failure. LC predeter- in the performance of diagnostic and therapeutic activities. mines unfavorable vital prognosis and high lethality rate, es- The objective: To determine the peculiarities of etiologi-
pecially among children [2; 5]. Real prevalence of LC is not cal structure, clinical progress of LC, and self-descriptiveness
studied well. It is obvious that in more than 50% of patients of serum tests for liver fibrosis in children. manifestation of the disease occurs at the decompensation Materials and methods. 202 children with LC diagnosis
stage, testifying unfavorable prognosis of the pathology and in the age from 7 to 15 years old were examined while they
decreasing survival rate among the patients [1; 10; 11]. In had "D" registration at the RSSPMC of Pediatrics of the MH
70% cases the only method of treatment is considered to be of the RUz. 57.9% of them were boys, and 42.1% girls. The
liver transplantation, the performance of which is quite lim- term of the disease was 5.3+0.2 years. According to Child-
ited [12; 13]. According to WHO among the reasons of death Pugh, dependently on the severity of LC the patients were
LC takes the eighth place, while in economically developed classified to: class A - 35.6%, class B - 34.2%, class C - 30.2%
countries of the world it is included to the number of six ba- [7]. LC diagnosis was based on the data of history, clinical,
sic dangerous diseases [7; 8]. At the same time, taking into biochemical (ALT, AST, total bilirubin\fractions, alkali
account that LC can be a terminal stage of the development phosphotase, y-glutamyl transferase (GGTP), thymol test,
of both progressing and latent forms of chronic hepatic pa- y-globulin, prothrombin time and platelets, creatinine), and
thologies, and in 70-90% cases of liver cirrhosis there is risk of instrumental tests (US and elastometering on HD3Toshiba
liver cancer development [14], it is not difficult to imagine the scanner with Doppler of portal system vessels; MRI, EGDS).
colossal economical and social damage caused by this pathol- PCR and EIA methods were used to verify HBV HCV, HDV
ogy to society and states. Increase of the number of etiological (with Bio-Red reactants, USA); Herpesviridae viruses such
as Herpes Simplex Virus (HSV), cytomegalovirus (CMV), Epstein-Barr Virus (EBV), Toxoplasma gondi, Chlamydia trachomatis, Ureaplazma urealiticum, Micoplazma; definition of auto antibodies ANA, SMA, anti-LKM-1 (Orgentec reactants, Germany), terminal N-propeptides (PINP) and C-teplopeptides (PICP) of the I type collagen in blood serum (Cloud-Clone Corporation reactants, USA), ceruloplasmin in urine (AssayPro reactants, USA). Statistical processing was performed by means of variation statistics using Student's t-criterion on special Excel-2012 software.
73,3*
Results and discussion. The study of the etiological structure of LC (Fig.1) provided the definition of the prevailing of viral persistence (73.3%), 90.6% of which was due to hepatotropic viruses (p < 0.001) with the accent of mixed infection prevalence (HBV+HCV+HDV-35.5%, HBV+HDV-24.7% and HBV+HCV-17.7%). In the rest cases (9.4%) we detected TORCH-infections with dominant CMV-infection (78.5%), among which there were 42.9% cases of CMV combined with Herpes virus. Rarely (p < 0.001) we revealed EBV(l4.3%) and Toxoplasma (7.1%).
m viral
Li autoimmune
4,4
h hereditary y combined cryptogenic
Figure 1. Etiological structure of liver cirrhosis in the examined children (%)
* - reliability of the difference to the studied groups (p < 0.001)
The part of LC in the outcome of autoimmune hepatitis was 4.9% with prevailing of the I type (70%), where there was characteristic reveal of high titers (1:43-1:67) of ANA (85.7%) and SMA (57.2%) markers. One third of the children was diagnosed with the II type with anti-LKM-1 titers in 1:53-1:88 range. LC with hereditary character was revealed in 6.9% cases with diseases such as Wilson's (42.8%), glycogenosis (28.6%), sclerozing cholangitis (14.3%), and hemochromatosis (14.3%). From the total number of children 9.9% of LC cases had a combined etiology, where together with 20% cases of autoimmune hepatitis, 35% cases ofWilson's disease, and 45% of glycogenosis there was viral infection (HBV- 60%, HCV- 30% and HDV-10%). In 4.4% cases, due to some reasons, the etiology was not determined.
History analysis of the tempo of the disease progression dependent on the etiology (Fig.2), showed that the most early formation of LC at the moment of infection was noted among the patients with mixed infection (4.6 ± 0.3 years), especially in the cases of triple B+C+D infection (3.2 ± 0.2 years), autoimmune etiology (3.4 ± 0.5 year) and combined forms with HBV/HCV or HDV infections (3.0 ± 0.3 years). In cases of viral mono infections the speed of progression was average 7.9 ± 0.3 years for HBV infection and 9.9 ± 0.5 years for HCV Development of LC as the outcome of hereditary syndromes took average 6.7 ± 0.3 years. When there was overlapping with viral infection the terms of LC development shortened up to 4.9 ± 0.3 years. Thus, a significant factor in the progression of the disease was the number of viruses and their long-lasting replication.
Assessment of LC severity according to Child-Pugh scale confirmed the importance of viral mixed infection in the progression of the pathology, where the majority of the children had clinical decompensation stage (class C), especially with HBV+HDV and triple infection (50% and 70.8%, respectively, p < 0.05). In contrast, most of the children with mono infection had compensation stage of LC (class A), corresponding to 66.6% in case of HBV and 80% in case of HCV infection (p < 0.01). The same pattern was observed with TORCH infections, where 71.4% had LC class A. LC analysis in the outcome of autoimmune process demonstrated, that the most severe forms were registered in cases of the II type (66.6%, p < 0.05). LC conditioned by hereditary pathologies ofsubstance exchange, as well as combined etiology, was characterized by sub-compensation progressing (class B) in more than a half of the children 57.2% and 55% (p < 0.05), respectively. Compensated progression was noted only in children with LC as the outcome of Wilson's disease with HCV infection (60%) and glycogenosis with HCV(33.3%), and HBV infection (16.6%). The most severe progress of LC was characteristic for overlapping of HDV with autoimmune process (100%, p < 0.001). Independently of the etiology, LC was characterized by a wide range of clinical syndromes, but reliable differences were achieved only for individual parameters. So, LC as an outcome of autoimmune hepatitis was characterized by (p < 0.05-0.01) prevailing of cholestatic syndrome including icteric skin, sclera and itching (90%), and long-lasting fever (70%). At the same time, LC as an outcome of genetically determined disorders of exchange processes was char-
acterized by prevalence of enlargement (above 5 cm) of liver (85.7%) and dyspeptic syndrome including nausea, vomiting, stomachache, and flatulence (100%, p < 0.05-0.001). In case of viral etiology of LC it is possible to isolate hemorrhagic syndrome in the form of episodic nasal, gingival, esophageal bleedings and hemorrhages (83.8%), and less in case of autoimmune LC (70%, p < 0.01 to the III group of children).
Frequent complications of LC, deteriorating the progression and prognosis ofthe disease, were hepatic encephalopathy (HE), bleeding from varicose widened veins (BVWV) with development of hepatic coma, hepatorenal syndrome (HRS) (HRS), and joining of bacterial infection (BI) [9; 15; 16]. The frequency of the listed complications differed among the examined children dependently on the etiology (Tab.1). Hepatocellular failure with the development of HE the most often was formed in the patients with autoimmune (80%) and exchange LC (78.5%, p < 0.001). in cases of viral etiol-
ogy of LC only in 34.8% of the children, among which in 18.7% of the cases HE did not develop as a result of portal failure. BVWV of esophagus and stomach occurred in the majority of the patients with autoimmune (90%, p < 0.01) and viral (69.7%) LC; in 42.8% cases in children with hereditary LC. Mostly these were class B and class C patients. It occurred only in 8% cases of class A LC children with viral etiology. Endocopically determined stage of esophageal nodes correlated with sonographically determined one for portal hypertension, while the probability of bleeding was high in case of portal hypertension III stage and III-IV stages of esophageal VWV. Besides the size of VWV, the risk of bleeding (2-3 folds) depended on the presence of red color sings and severity of the disease. After bleeding the Child-Pugh score reliably increased (p < 0.05). Recurrent bleedings within a year were observed in 45.2% of class B and class C patients.
Table 1. - Development of LC complications dependently on the etiology
Value LC etiology P,-2 P!-3 P2-3
Viral (I) Autoimmune (II) Hereditary (III)
HE 34.8± 3.9 80.0±12.6 78.5±10.9 < 0.001 < 0.001 > 0.05
BVWV 69.7±3.7 90.0±9.4 42.8±13.2 < 0.05 > 0.05 < 0.001
HRS 7.3±2.1 40.0±15.4 14.2±9.3 < 0.05 > 0.05 > 0.05
BI 67.7±3.8 70.0±14.4 57.1±13.2 > 0.05 > 0.05 > 0.05
P - reliability of the difference between the studied groups.
Among the other complications, HRS was revealed in 12.8% cases, with a greater frequency than in cases of autoimmune LC, especially when there was overlapping with hepato-tropic viruses (70%, p < 0.05). Frequency of BI (pneumonia, pleuritis, myocarditis, etc.) did not depend on the etiology. The most perceptive for bacterial infections were the patients with LC class B (77.1%), especially class C (97%).
It is known that, various collagens (type I, III, IV, V, VI) are considered to be serum markers of tissue fibrosis, among which in case of liver pathology collagen type I and IV deserve a special attention as components of basal membrane of hepa-tocytes. While the level of collagen type IV reflects current hepatocellular damages at the initial stages and the processes of hepatic lobular structure regeneration [6], at the late stages of the pathological process in liver there is accumulation of ECM febrile type collagen, particularly type I, which participates in
Table 2.- Values of terminal peptides of collage type I in children with LC with various etiologies
the formation of bridge-like fibrosis and cirrhosis [3]. Then, the diagnostic criteria of fibrogenesis are PINP, and criteria of fibrolysis are PICP [1; 4]. The study of these markers revealed that (tab. 2) independently of the etiology of LC the amount of PINP reliably increased compared to the control values (p < 0.001), with greater expression in children with viral genesis of LC, indicating more intensive process of fibrogenesis in liver. At the same time, amount of other biomarker PICP did not exceed control values (p > 0.05). The exclusion were children with LC with viral genesis, where the level reliably decreased compared to the control one (p < 0.05), indicating prevailing of fibrogenesis over fibrolysis and, as a whole, progression of pathological process in liver. In the children of the other groups functional activity of these systems was in tension, confirming partial preserving of compensatory mechanisms of extra cellular matrix.
Collages type I values LC etiology Control
Viral (I) Autoimmune (II) Hereditary (III)
PINP, pg/ml 4.016 ± 0.28* a 2.961 ± 0.44* 2.103 ± 0.57* b 1.265 ± 0.26
PICP, pg/ml 0.291 ± 0.14* 0.477 ± 0.18 0.394 ± 0.10 0.767 ± 0.43
Difference reliability * - to control;a -1 and II;b -1 and IIIgroups (p < 0.001)
It means that these fibrosis markers can be considered to be indicators of compensation and progression of pathological (cirrhotic) process in liver.
Conclusions
1. In the etiological structure of LC there is prevailing of viral infection (73.3%), where the greater part is taken by hepatotropic viruses (90.6%) with an accent of mixed infection by B+C+D (32.2%), B+D (214%) and B+C infections (16.1%). In the rest cases LC is formed as an outcome of autoimmune (4.9%), hereditary exchange (6.9%) and combined (9.9%) hepatitis.
2. The severity of the LC progression with viral genesis in children depends on the kind of infection - the more persisting viruses are there, the more severe the pathology proceeds - especially in cases of overlapping by HDV where the frequency of class C LC clinical stages was revealed in the most cases (60%).
Peculiarities of clinical progression of LC in children dependently on the etiology were stage prevailing of hemor-
rhagic syndrome and splenomegaly as an outcome of viral hepatitis, cholestatic syndrome and long-lasting fever as an outcome of autoimmune one, and dyspeptic syndrome and hepatomegaly as an outcome of hereditary exchange hepatitis.
3. Various amounts of N-terminal peptides and C-terminal teplopeptides of collage type I in children with LC with different etiology reflect not only the degree of hepatic cellular damage, but also can serve to be markers of the compensation and the pathology progression degree. The most expressed destructive alterations were characteristic for LC with viral genesis.
4. Frequency and expression of nosologic complications of LC in children were determined by etiological factors. The most frequent complications with the layout of all kinds of manifestations were characteristic for LC with autoimmune genesis. LC with viral genesis was characterized by the development of BVWV, and hereditary one by development of HE. Development of complications deteriorated progression and prognosis of LC in children requiring the search for new prevention measures and effective therapeutic methods.
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