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ЖИГАР ЦИРРОЗЛАРИДА САРОКПЕНИЯНИНГ AХАМИЯТИ
Холиқова Д.С.
Андижон давлат тиббиёт институти, Андижон, Ўзбекистон
Мақолада жигар циррозларида саркопениянинг учраши, учраш частотаси ва унинг турли
ривожланиш йўллари ифодаланган. Турли этиологияли жигар циррозларида саркопения
ривожланиши тўғрисидаги жаҳон адабиётида келтирилган маълумотлар тахлили
келтирилган. Унга кўра саркопениянинг ривожланиш механизмлари комплекс ва
полиэтиологик бўлиб, улардан энг ахамиятлиси, миостатин, рапамицин 1 комплекси,
убиквитин-протеасома йўли, инсулинга ўхшаш ўсиш омили-1, интерлейкин-6, алкоголни
суиистеъмол қилиш каби ҳолатлар иштирок этиши кўрсатилган.
Калит сўзлар: жигар циррози, сарокпения, миостатин, интерлейкин-6.
ЗНАЧЕНИЕ САРОКОПЕНИИ ПРИ ЦИРРОЗЕ ПЕЧЕНИ
Холикова Д.С.
Андижанский Государственный Медицинский Институт, Андижан, Узбекистан
В статье рассматриваются встречаемость, частота саркопении при циррозе печени и
различные пути её развития. Проанализированы данные мировой литературы о развитии
саркопении при циррозе печени различной этиологии. Установлено, что механизмы развития
саркопении сложны и полиэтиологичны, важнейшими из которых являются участие
миостатина, рапамицинового комплекса 1, убиквитин-протеасомного пути,
инсулиноподобного фактора роста 1, интерлейкина-6 и злоупотребление алкоголем
.Ключевые слова: цирроз печени, саркопения, миостатин, интерлейкин-6.
THE SIGNIFICANCE OF SAROCOPENIA IN LIVER CIRRHOSIS
Kholiko a D.S.
Andijan S a e Medical Ins i u e, Andijan, Uzbekis an
The a icle desc ibes he occu ence, equency o sa copenia in li e ci hosis, and i s a ious
de elopmen pa hways. The da a p esen ed in he wo ld li e a u e on he de elopmen o sa copenia
in li e ci hosis o a ious e iologies a e analyzed. Acco ding o i , he mechanisms o sa copenia
de elopmen a e complex and polye iological, he mos impo an o which a e he in ol emen o
myos a in, apamycin complex 1, ubiqui in-p o easome pa hway, insulin-like g ow h ac o -1,
in e leukin-6, and alcohol abuse.
Key wo ds: li e ci hosis, sa copenia, myos a ine, in e leukin-6.
The e m sa copenia was i s coined in 1989 by I win Rosenbe g in he Ame ican Jou nal o
Clinical Nu i ion in an a icle i led “Epidemiological and Me hodological Issues in he S udy o
Nu i ional S a us in he Elde ly—A B ie Re iew” [34]. O e he yea s, nume ous obse a ional
s udies and me a-analyses ha e been published on sa copenia and i s s udy. Howe e , he
mechanisms o sa copenia de elopmen in a numbe o condi ions associa ed wi h i , pa icula ly in
ch onic diseases, including li e ci hosis (LC), emain poo ly unde s ood [18].
Sa copenia is a synd ome cha ac e ized by a dec ease in muscle mass, s eng h, and/o unc ion [8].
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The p esen a ion “MELD - Sa copenia” published in he Jou nal o he Ame ican College o
Gas oen e ology in 2015 was an impo an impe us o i s wo ldwide s udy. In his p esen a ion, he
au ho s showed ha sa copenia is an impo an p edic o o ea ly dea h in pa ien s wi h li e disease
and hose awai ing o gan ansplan a ion. The e iology o li e disease is impo an in he
de elopmen o sa copenia. The e a e a numbe o ac o s ha can accele a e i s de elopmen .
These include alcohol abuse (because i con ibu es o he b eakdown o skele al muscle p o eins),
choles asis (which con ibu es o he malabso p ion o a and i amin D in p ima y bilia y ac
diseases). Pa hological ac o s such as ch onic in lamma ion, insulin esis ance, and physical
ac i i y limi a ion a e also common o sa copenia and non-alcoholic li e diseases [10].
Tandon P. and Nishikawa e al. epo ed ha sa copenia has a p e alence o 30–70% in pa ien s wi h
ch onic kidney disease, depending on he diagnos ic c i e ia used. A p e ious s udy by his au ho
showed ha he incidence o sa copenia de ec ed by compu ed omog aphy was ela ed o he
se e i y o ch onic kidney disease as assessed by he Child-Pugh sco e[39].
Sa copenia and CVD ha e been s ongly associa ed wi h poo die and ho monal imbalances in
pa ien s wi h ad anced disease. A ecen me a-analysis o 22 s udies including nea ly 7,000 pa ien s
wi h ci hosis ound ha he o e all isk o de eloping sa copenia in pa ien s wi h ci hosis was
37.5% [40]. As men ioned abo e, his s udy also ound an associa ion be ween sa copenia and
highe Child-Pugh sco es. Mo e han hal o he pa ien s in his s udy had sa copenia in class C. In
addi ion, he s udy showed ha sa copenia is an independen isk ac o o mo ali y in pa ien s
wi h CVD [48].
Muscle p o ein u no e is con olled by se e al majo molecula pa hways, including he a ge o
apamycin 1 complex (mTORC1, a complex ha unc ions as a senso o nu ien s, ene gy, and
edox p ocesses and egula es p o ein syn hesis), he mechano ecep o signaling cascade, sa elli e
cell signaling, and he ubiqui in-p o easome pa hway (UPS). mTORC1 is a key se ine/ h eonine
p o ein kinase ha is ac i a ed by many ac o s, including amino acids, g ow h ac o s such as
insulin-like g ow h ac o -1 (IGF-1), ene gy s a us, and mechanical s ess [17]. This p ocess
ul ima ely leads o he phospho yla ion o wo majo e ec o s, eIF4E-binding p o ein 1 (4EBP1, a
nega i e egula o o mRNA ansla ion and a subs a e o mechanis ic a ge o apamycin
(mTOR)) and p o ein S6 kinase 1 (p70S6K1). In addi ion, companion cells play a key ole in he
g ow h, epai , and egene a ion o muscle ibe s and a e egula ed by a numbe o g ow h ac o s,
including in e leukin-6 (IL-6), IL-1, and myos a in [22, 23]. Se e al ac o s con ibu e o muscle
p o ein b eakdown, including in lamma ion, dec eased ac i i y, mi ochond ial dys unc ion, and
myos a in. Myos a in is hough o inhibi muscle p o ein syn hesis by inhibi ing he
PI3K/phosphoinosi ide 3-kinase (PI3K)/p o ein kinase B (Ak )/mTORC1 pa hway and i s
downs eam e ec o s [19, 23, 45]. In addi ion, myos a in has been sugges ed o ac i a e he AMPK,
which p omo es inc eased muscle p o ein b eakdown, esul ing in nega i e p o ein balance [19]. A
he same ime, Ak ac i a ion and inhibi ion o he Fo khead box O (FOXO - a amily o
ansc ip ion ac o s in ol ed in a ious cell unc ions, including su i al, me abolism, cell cycle
con ol, and DNA epai ) ansc ip ion ac o can p e en he ac i a ion o ubiqui in ligases, muscle
RING inge -1 (MuRF-1 - a speci ic ubiqui in ligase ha con ols a ophy p ocesses in ans e se
muscles) and muscle a ophy (MAFbx) [37].
Muscle p o ein in he body is in a cons an s a e o lux, wi h bo h syn hesis and deg ada ion
occu ing simul aneously [5]. This pa e n o muscle p o ein u no e is d i en by a numbe o
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en i onmen al s imuli, including p o ein in ake and physical ac i i y [3]. These changes can lead o
a ne p o ein imbalance, wi h muscle loss, i.e., p o ein b eakdown, occu ing when p o ein syn hesis
exceeds p o ein syn hesis. When p o ein syn hesis exceeds p o ein b eakdown, muscle g ow h
occu s [5]. Al hough p o ein in ake alone is su icien o main ain muscle mass in young, heal hy
indi iduals, combining i wi h exe cise syne gis ically inc eases muscle syn hesis [2].
I is hypo hesized ha pa ien s wi h ch onic li e disease ha e impai ed muscle p o ein u no e ,
which con ibu es o he de elopmen o sa copenia. Indeed, ea ly s udies o muscle p o ein
u no e in pa ien s wi h CKD ha e shown ha p o ein syn hesis is educed compa ed o heal hy
con ols using a e io enous (AV) balance and whole body condi ion moni o ing [41]. Howe e ,
p e ious s udies o whole body p o ein b eakdown (WbPB) ha e yielded con lic ing esul s.
Va ious s udies ha e shown ha muscle p o ein b eakdown is inc eased, dec eased, o e en
unchanged in pa ien s wi h CKD [41, 42]. These indings may be due o a numbe o ac o s,
including di e ences in he es s pe o med, he age o he pa ien s, he se e i y o he disease, and
i s e iology [10].
Howe e , i is known ha sa copenia is associa ed wi h an age- ela ed phenomenon o muscle
“anabolic esis ance,” which is a educed esponse o muscle p o ein syn hesis o amino acid in ake
o exe cise compa ed o younge indi iduals [6]. Muscle anabolic esis ance has also been obse ed
in pa ien s wi h CKD in o he s udies [47]. The lack o such s udies is p obably due o he conce n
abou pe o ming muscle biopsy in his g oup o pa ien s due o he high isk o pla ele
dys unc ion, coagulopa hy, and h ombocy openia. Howe e , i has ecen ly been shown ha muscle
biopsies a e sa e in pa ien s wi h Child-Pugh class A CKD [46]. This may p o ide a be e
unde s anding o he dys egula ion o p o ein u no e ha unde lies muscle loss in pa ien s wi h
ch onic li e disease.
Hype ammonemia, a common pa hological condi ion in pa ien s wi h CKD, is a consequence o
hepa ocellula dys unc ion, po osys emic shun ing, and impai ed u eagenesis, which in u n leads
o inc eased ammonia concen a ions in skele al muscle [27]. I has been sugges ed ha in ch onic
li e disease, ammonia up ake by skele al muscle may be enhanced as a p o ec i e mechanism o
p e en neu o oxici y [32]. Al hough he speci ic mechanism by which ammonia is abso bed is s ill
unknown, he exp ession o i s anspo e s, as well as Rh B (Rhbg) and Rh C glycop o eins (Rhcg),
may also be impo an (66). Such ammonia accumula ion is no wi hou consequences and may lead
o sa copenia, which in u n leads o a dec ease in muscle mass, which is necessa y o p e en
hype ammonemia [11, 32, 33].
In pa ien s wi h CKD, simila o he ISR-like dec ease in mTORC1 signaling obse ed in esponse
o in acellula amino acid dep i a ion, GCN2 ac i a ion and inc eased eIF2a phospho yla ion a e
obse ed [46]. Howe e , hype ammonemia induces a s a e o cellula s ess ha dis up s ISR by
p e en ing ATF4 mRNA exp ession. This ailu e o induce ATF4 mRNA exp ession may lead o
u he educ ions in muscle p o ein syn hesis and inc eased au ophagy due o he cessa ion o ISR
and he inabili y o e u n o no mal le els o p o ein syn hesis [14, 30]. The changes in adap i e
ISR in pa ien s wi h CKD ha e been desc ibed abo e, indica ing ha a second pa hway is ac i a ed
in esponse o inc eased ammonia concen a ions. This second signaling pa hway is media ed by
SLC7A5 (SLC7A5 amily membe 7 membe 5)/LAT1 (la ge neu al amino acid anspo e 1),
which is inc eased in pa ien s wi h CKD. SLC7A5/LAT1 ac s as an amino acid exchange and
inc eases L-leucine up ake [14, 46]. I is hough ha inc eased L-leucine concen a ions a e used o
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u ilize his amino acid o ace yl-CoA o ma ion in mi ochond ia and inc ease ene gy ou pu . Unde
no mal condi ions, leucine anspo elies on i s anspo by he glu amine exchange membe
SLC38A2. Howe e , in hype ammonemia, glu amine is mainly used o ammonia de oxi ica ion
[14, 16]. Taken oge he , he ac i a ion o ISR in pa ien s wi h CKD leads o impai ed mTORC1
signaling and inc eased au ophagy, which may con ibu e o he de elopmen o sa copenia [14, 30].
In addi ion, bo h alcohol abuse and ch onic li e disease a e conside ed o be impo an in he
de elopmen o sa copenia associa ed wi h i [9]. The e o e, i is o en di icul o dis inguish
be ween ch onic li e disease and he speci ic e ec s o alcohol on i . E hanol can be me abolized
no only in he li e and b ain, bu also in pa in skele al muscle [32]. Alcohol-induced li e disease
is o en accompanied by a dec ease in skele al muscle mass, as well as signi ican changes in
p o ein u no e , and e hanol ac s by inhibi ing mTORC1 s imula ion [36]. Excessi e alcohol
consump ion is also associa ed wi h an inc ease in myos a in, which is hough o play a media ing
ole in impai ed muscle p o ein syn hesis [24]. Howe e , ma ke s o CKD emain unchanged in
animal models o alcoholic li e disease and a e educed in humans. I has been shown ha hei
au ophagy may cause an inc ease in he b eakdown o muscle p o eins [40]. Simila o
hype ammonemia, e hanol has been ound o con ibu e o a dec ease in muscle p o ein syn hesis
due o mi ochond ial dys unc ion, esul ing in he o ma ion o CFS and ac i a ion o au ophagy
[4]. In u n, muscle p o ein syn hesis may be impai ed due o he a o emen ioned educ ion in ATF
gene a ion and mRNA ansla ion [9].
In addi ion, some endoc ine diso de s, including low se um es os e one, a e impo an in he
pa hogenesis o sa copenia in ch onic li e disease [35]. Low es os e one le els may be due o
al e a ions in he hypo halamic-pi ui a y-gonadal axis in male pa ien s wi h JC [41]. This has been
shown o lead o dec eased es os e one p oduc ion and inc eased ac i i y o a oma ase, he enzyme
esponsible o i s con e sion o es adiol, as obse ed in olde men and in a s wi h po oca al
anas omosis [12]. Ra s wi h po oca al anas omosis ha e low es os e one le els and a educed
g ow h a e due o educed ood in ake and e iciency (whe e e iciency is measu ed as body weigh
gain pe g am o ood consumed). Inhibi ion o a oma ase in his model esul ed in inc eased
es os e one and imp o ed body weigh along wi h inc eased ood in ake and e iciency [12].
Howe e , i is ad isable o con inue esea ch in his a ea in pa ien s wi h CHD o con i m he
indings.
The abo e da a con i m he complexi y o he mechanism o de elopmen o sa copenia in JTs, he
in ol emen o a la ge numbe o ac o s. Bu a numbe o aspec s o he p oblem ha e no been
s udied in dep h, and i is necessa y o con inue esea ch in his di ec ion. In pa icula , he
occu ence o sa copenia in JTs o di e en e iologies, some o i s speci ic de elopmen
mechanisms ha e no been s udied, besides, i s cou se in u al, u ban and dis ic condi ions has no
been e alua ed.
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