Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_51_библиотеки_им_акад_М_И_Перельмана
.pdf
This page intentionally left blank
https://t.me/medicina_free
CHAPTER
12
Sepsis and the liver
Richard Moreau
1,2,3
, Javier Fernandez
1,4
,MarioAltieri
5
and Vicente Arroyo
1
1
EF Clif, EASL-CLIF Consortium and Grifols Chair, Barcelona, Spain
2
INSERM et Universite
´
de Paris, Centre de
Recherche sur l’Inflammation (CRI), Paris, France
3
Service d’He
´
patologie, Ho
ˆ
pital Beaujon, AP-HP, Clichy, France
4
Liver Unit, Hospital Clı
´
nic, IDIBAPS and CIBERehd, Barcelona, Spain
5
Service d’He
´
pato-Gastroente
´
rologie et
Nutrition, Unite
´
de Transplantation He
´
patique, Centre Hospitalier Universitaire, Caen, France
Introduction
In the intensive care units (ICUs), organ system function is routinely assessed using the Sequential Organ
Failure Assessment (SOFA), which ranges from 0 (normal) to 4 (most abnormal) for each of six components (liver,
kidney, coagulation, brain, circulation, respiration), with higher scores indicating mo re severe organ dysfunction
(
Table 12.1) [1]. According to the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3),
sepsis is defined as a life-threatening organ system dysfunction caused by a dysregulated host response to infection
[2]. Organ dysfunction is an acute change in the SOFA organ subscore of 2 points or more, which is associated
with an in-hospital mortality of more than 10%
[2]. According to the Third International Consensus Definitions for
Sepsis and Septic Shock (Sepsis-3), the liver is one of the organ systems whose dysfunction can mediate poor out-
come of infection.
Here, we will first summarize knowledge obtained in the general population about pathophysiology of organ
dysfunction during sepsis, with special emphasis on liver dysfunction as a collateral damage caused by the host
immune response to infection. We will also consider the liver as an organ generating protective responses against
infection. Finally, we will describe the specifics of sepsis in patients with cirrhosis (i.e., patients who have a
chronic liver disease when they develop sepsis) and emphasize the management of infections in these patients.
Sepsis in the general population
Pathophysiology of organ dysfunction during the early phase of sepsis
Infections by bacteria or fungi induce an elaborated immune response whose purpose is to recognize the
microbe and ultimate ly kill it to decrease microbial burden
[3]. The first step of the immune response is the detec-
tion of the microbe by the innate immune system (which includes myeloid cells [neutrophils, monocytes, den-
dritic cells] and some epithelial cells)
[3]. Microbes express pathogen-activated molecular patterns (PAMPs) that
are unique molecular structures recognized by pattern-recognition receptors (PRRs) of the innate immune sys-
tem. PRRs include Toll-like receptors (TLRs), C-type lectin receptors, retinoic acid inducible gene 1like recep-
tors, and nucleotide-binding oligomerization domainlike receptors (
Table 12.2) [3,4]. The detection of PAMPs
and virulence factors results in the induction of a battery of inflammatory mediators (cytokines, chemokines,
lipids) indispensable for the orchestration of immune cells involved in host resistance against microbes
[3,4].
Some infected individuals develop an excessive systemic inflammatory response, which is associated with organ
dysfunction(s). The factors explaining this excessive inflammatory response are still poorly understood and prob-
ably involve microbial factors (burden, virulence) and host factors (genetics, age, comorbidities)
[4].
145
Cardio-Hepatology.
DOI:
https://doi.org/10.1016/B978-0-12-817394-7.00008-5 © 2023 Elsevier Inc. All rights reserved.
https://t.me/medicina_free
The development of organ dysfunction involves multiple mechanisms that occur in the microcirculation of
vital organs and are often driven by proinflammatory cytokines
[4]. Indeed, these cytokines activate the endothe-
lium to produce tissue factor that activates the coagulation cascade, while at the same time there is an
impairment of anticoagulant mechanisms and fibrinolytic pathw ays. Together these effects result in the formation
of microvascular thrombosis. In addition, activated neutrophils contributes to the thrombus, probably through
their neutrophil extracellular traps (NETs). Thrombus formation results in tissue hypoperfusion, which may be
aggravated by hypotension or shock (due the induction of arteriolar inducible nitric oxide [NO] synthase, iNOS).
Collectively, thes e disorders of microcirculation result in decreased tissue oxygenation, an effect that may be
accentuated by the cytokine-induced loss of the endothelial barrier function. In sepsis, there is also an
impairment of mitochondrial respiration (i.e., oxygen use) because of damage of mitochondria induced by oxida-
tive stress
[4].
Of note, among patien ts who survive the early “proinflammatory” phase of sepsis, a large proportion develop
protracted immunosuppression
[4,5]. Several mechanisms play a role in immunosu ppression, including T-cell
exhaustion, decreased numbers of lymphocyte subsets, increased numbers of myeloid-derived suppressor cells,
and regulatory T cells. Immunosuppression results in the development of secondary infections in almost one-
third of patients with protracted sepsis. In addition, immunosuppression probably explains the fact that 50% of
patients with protracted sepsis have reactivation of latent viruses
[5].
The liver as a victim of deregulated host response to infection
Liver failure
In the SOFA scoring system, liver function is assessed by measuring serum bilirubin levels
[1]. Liver failure is
defined by a SOFA hepatic subscore of 3 or 4, that is, by serum bilirubin levels of 6 mg/dL or more (
Table 12.1).
Among critically ill patients admitted to the ICU, the prevalence of liver failure is relatively low at presentation
(B3%)
[1,6]. However, in a large series of patients admitted for acute respiratory distress syndrome, higher
SOFA hepatic subscore at presentation was among the independent predictors of 90-day mortality
[7], arguing
that even subtle changes in hepatic function may affect the outcome. Although liver function is altered during
sepsis, the hepatic acute-phase response seems to be preserved as indicated by the increased plasma CRP levels
measured in patients with severe sepsis
[4].
Shock liver
Sepsis-associated liver failure may be a consequence of extensive liver cell necrosis caused by shock
[8].
Features of the shock liver have been detailed in another chapter of this book (
chapter 9). Of note, during sepsis,
TABLE 12.1 Evaluation of organ system functions on the sepsis-related organ failure assessment (SOFA) scale.
a
Scale
Organ system: marker 0 1 2 3 4
Liver: Bilirubin, mg/dL ,1.2 1.21.9 25.9 611.9 12
Renal: Creatinine, mg/dL or
urine output, mL/day
b
,1.2 1.21.9 23.4 3.54.9 or ,500 .5or,200
Coagulation: Platelets, x10
3
/
μl
.150 # 150 # 100 # 50 # 20
Brain: Glasgow coma scale 15 1314 1012 69 ,6
Circulation: Hypotension No MAP
,70 mm
Hg
Dopamine # 5or
dobutamine any dose
c
Dopamine .5, epinephrine
# 0.1 or norepinephrine # 0.1
c
Dopamine .15, epinephrine
.0.1 or norepinephrine .0.1
c
Respiration: PaO
2
/FiO
2
.400 # 400 # 300 # 200 # 100
a
For each organ system, failure is defined by a subscore of 3 or 4.
b
Because urinary-output criteria are often unavailable, some investigators prefer to define kidney failure as acute kidney injury of stage 3.
c
Adrenergic dose: μg/kg.min.
Adapted from Vincent JL, de Mendonc¸a A, Cantraine F, Moreno R, Takala J, Suter PM, et al. Use of the SOFA score to assess the incidence of organ dysfunction/failure in
intensive care units: results of a multicenter, prospective study. Working group on “sepsis-related problems” of the European Society of Intensive Care Medicine. Crit Care
Med. 1998;26:17931800.
146 12. Sepsis and the liver
III. Cardiovascular system in liver failure
https://t.me/medicina_free
TABLE 12.2 Pattern-recognition receptors (PRRs), their cellular localization, and their ligands (pathogen-associated molecular
patterns, PAMPs).
PAMPs
PRRs Localization Nature Origin of the ligand
Toll-like receptors (TLRs)
a
TLR1 Plasma membrane Triacyl lipoprotein Bacteria
TLR2 Plasma membrane Lipoprotein Bacteria, viruses, parasites, self
TLR3 Endolysosome Double-stranded RNA Virus
TLR4 Plasma membrane Lipopolysaccharide Bacteria
TLR5 Plasma membrane Flagellin Bacteria
TLR6 Plasma membrane Diacyl lipoprotein Bacteria, viruses
TLR7 Endolysosome Single-stranded RNA Virus, bacteria, self
TLR8 Endolysosome Single-stranded RNA Virus, bacteria
TLR9 Endolysosome Unmethylated DNA with CpG motifs Virus, bacteria, protozoa, self
TLR10 Endolysosome Unknown Unknown
TLR11
b
Plasma membrane Profilin-like molecule Protozoa
TLR12
b
Endolysosome Profilin Protozoa (Toxoplasma gondii)
TLR13
b
Endolysosome 23 S ribosomal RNA Bacteria
Nucleotide-binding olgomerization
domain (NOD)-like receptors
NOD1 Cytosol γ-D-glutamyl-mesodiaminopimelic acid
(iE-DAP)
Bacteria
NOD2 Cytosol Muramyl dipeptide (MDP) Bacteria
NLRP3 Cytosol RNA (vita-PAMP) Bacteria
NLRC4 (IPAF) Cytosol Flagellin Bacteria
NAIP5 and NAIP6 Cytosol Flagellin Bacteria
Retinoic acid-inducible gene (RIG)-I-
like receptors
RIG-I Cytosol Short double-stranded RNA,
5
0
triphosphate double-stranded RNA
RNA viruses, DNA viruses,
Salmonella typhimurium RNA
MDA5 Cytosol Long double-stranded RNA RNA viruses
LGP2 Cytosol Unknown RNA viruses
C-type lectin receptors
Dectin-1 Plasma membrane β-Glucan Fungi
Dectin-2 (also known as CLEC6A) Plasma membrane β-Glucan Fungi
MINCLE Plasma membrane Unknown Fungi
Miscellaneous
AIM2 Cytosol Double-stranded DNA Bacteria, viruses
IFI16 Cytosol Double-stranded DNA Bacteria, viruses
ZBP1 Cytosol Double-stranded DNA Bacteria, viruses
cGAS Cytosol Double-stranded DNA Bacteria, viruses
(Continued)
147Sepsis in the general population
III. Cardiovascular system in liver failure
https://t.me/medicina_free
shock-induced liver cell necrosis can result in the release in the extracellular milieu of molecules that are nor-
mally strictly intracellular. The presence of these molecules is recognized as a danger by innate PRRs and this
recognition induces an inflammatory response
[4,9]. Molecules released by dead cells are called damage-
associated molecular patterns (DAMPs). Potential DAMPs include high-mobility group protein B1, S100 proteins,
interleukin (IL)-1α, IL-33, mitochondrial DNA, mitochondrial formyl peptides, RNA, DNA, and histones. In the
absence of sepsis, the primary purpose of the DAMP-induced, sterile inflamm atory responses is to repair the
damaged tissue
[9]. However, in the context of sepsis, PRR activation by DAMPs may accentuate or perpetuate
the inflammatory response induced by PAMPs and therefore be deleterious.
Sepsis-induced alterations in hepatic biotransformation, including hepatocellular cholestasis
The normal hepatocyte is the site of biotransformation, that is, the process of enzymatic transformation of lipo-
philic molecules (in particular bile acids) into water-soluble molecules, which are readily excreted in the bile [10].
In the absence of biotransformation, there would be deleterious accumulation of lipophilic molecules. The bio-
transformation of bile acids is a three-step process, including the cytochrome P450-dependent phase I (compris-
ing intramolecular modifications that allow channeling to phase II reactions), phase II (conjugation with various
compounds such as glucuronate, glutathione, amino acids, sulfonates), and phase III (excretion). The phase III of
biotransformation involves two sinusoidal systems for bile-salt uptake in hepatocytes, the sodiumtaurocholate
cotransporter (NTCP), organic-aniontransporting polypeptide (OATP), and several ATP-dependent export
pumps contained in the canalicular membrane, for example, the multidrug resistanceassociated protein 2
(MRP2) and bile salt export pump (BSEP)
[11].
Hepatocellular cholestasis (i.e., impaired bile formation at the hepatocyte level) associated with parallel
accumulation of bile acids are common findings in bacterial infections
[8,12]. Disrupted brush borders with
widened bile canaliculi have been shown using transmission electron microsco py in livers from animals with
sepsis. Sepsis-induced cholestasis is related to alterations in phase III biotransformation (
Fig. 12.1) [8,12].The
mechanisms of these alterations are still incompletely understood and may involve neutrophil infiltration of
the liver driven by the phosphatidylinositol-3-kinase (PI3K) gamma (mostly activated by G-pro tein-coupled
receptors)
[8]. In addition, PI3K activation may contribute to biliary secreto ry failure through sustained inter-
nalization of ATP-dependent canalicular transporters (MRP2 and BSEP), illustrating the role of PI3Ks in the
control of trafficking
[12]. Finally, analysis of the liver transcriptome in animal models of sepsis found a down-
regulation of the gene encoding MRP2, NTCP, and OATP, indicating an extensive reprogramming of genes
involved in phase III biotransformation
[13]. Thus, in these animals, key transcription factors involved in the
induction of hepatic phase III biotransformation were downregulated, including farnesoid X-activated receptor
(also known as FXR, bile acid receptor) among others
[13]. Moreover, these studies performed in livers from
TABLE 12.2 (Continued)
PAMPs
PRRs Localization Nature Origin of the ligand
HMGB proteins Cytosol Double-stranded DNA, single-stranded
DNA
Bacteria
LRRFIP1 Cytosol Double-stranded DNA, single-stranded
DNA
Bacteria
Caspases 4/5 Cytosol Lipopolysaccharide Bacteria
Stimulator of interferon genes protein
(STING)
Endoplasmic
reticulum membrane
c-di-AMP (vita-PAMP) Bacteria
Hexokinase Cytosol MDP Bacteria
a
TLRs form homodimers except TLR2 that heterodimerizes with TLR1 or TLR6.
b
Expressed in mice but not humans.
NAIP, nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family, apoptosis inhibitory protein; NLRC4, NLR family, CARD domain containing
4; NLRP1, NLR family, pyrin domain containing 1; NLRP3, NLR family, pyrin domain containing 3; DDX58, DEAD (Asp-Glu-Ala-Asp) box polypeptide 58; RIG-I,
retinoic acid-inducible gene I; CpG-DNA, DNA containing the unmethylated phosphate-guanine(CpG) dideoxynucleotide motif; AIM2, absent in melanoma 2;
IFI16, interferon, gamma-inducible protein 16; ZBP1, Z-DNA binding protein 1, cGAS, cyclic GMP-AMP synthase; LRRFIP1, leucine rich repeat (in FLII)
interacting protein 1; cyclic-diGMP, cyclic diguanylate monophosphate; cyclic-di-AMP, cyclic diadenosine monophosphate; STING , stimulator of interferon genes
protein; HMBG, high-mobility group box.
148 12. Sepsis and the liver
III. Cardiovascular system in liver failure
https://t.me/medicina_free
animal models of sepsis found an extensive downregulation of genes involved in phase I and phase II of bio-
transformation [13], indicating that sepsis induces a massive reprogramming of all the processes of biotransfor-
mation from functionalization to excretion. Of note, these results were obtained at early stages of sepsis,
indicating that sepsis-induced hepatocyte dysfunction, reflected by blood accumulation of bile acids, develops
during the first hours of sepsis.
Collectively, these findings have several implications. First, because the increases in serum bilirubin are late
features of sepsis-induced liver failure, one should use other biomarkers (e.g., bile acid levels) to detect early
impairment of liver function in this context. Second, a defect in bile aci d secretion may result in hepatocyte accu-
mulation of bile acids, which may cause cell death and therefore contribute to sepsis-induced liver injury. Third,
phases I, II, and III of biotransformation are involved not only in bile acid secretion, but also have a major role in
drug clearance. Accordingly, sepsis-induced downregulation of the process of hepatic biotransformation may
result in altered metabolism of certain drugs used in the context of sepsis and ultimately contribute to the devel-
opment of adverse events.
Sepsis-induced ductular cholestasis
Sepsis-induced cholestasis is characterized by defective bile flow at the level of small or large bile ducts
[8].
The mechanisms by which sepsis induces ductular cholestasis are poorly understood. Cytokines released by cho-
langiocytes may induce periductular infiltration by activated immune cells. Cytokine-induced inhibition of chlo-
ride and bicarbonate fluxes may also play a role in decreased bile flow.
Secondary sclerosing cholangitis
Secondary sclerosing cholangitis (also known as ischemic-like cholangiopathy), which develops in critically ill
patients, is characterized by progressive inflammatory destruction of the bile ducts
[8]. Secondary sclerosing cho-
langitis may rapidly progress to cirrhosis. The extreme vulnerability of biliary epithelial cells to hypoxia, which-
ever is its trigger, is the underlying mechanism explaining the development of secondary sclerosing cholangitis
in critically ill patients. Hypoxia-induced cell death may result in DAMP release causing local inflammation,
resulting in the accentuation of tissue damage.
Infection-induced protective responses originating in the liver
The liver is a component of the innate immune system. Because of its unique anatomical location , the liver
plays an important role in clearing microbes and PAMPs from blood delivered by the portal vein. Kupffer cells
that are hepatic resident macrophages are crucial for the immune surveillance
[8]. Moreover, the liver exerts pro-
tective effects against infections or their consequences through the engagement of different metabolic programs,
which will be described below.
Acute-phase protein synthesis during infection
Master proinflammatory cytokines (IL-6, tumor necrosis factor [TNF-α, IL-1β]) released during infection,
through their cognate receptors engaged at the surface of hepato cytes stimulate classical signaling pathway to
Hepatocyte
NTCP
OATP
Bile
flow
Tight
junction
MDR3
BSEP
MRP2
Biliary excretion -
canalicular export
Basolateral
bile acid
uptake
FIGURE 12.1 Schematic of bile acid metabolism
and biliary transporters in the hepatocyte. BSEP denotes
bile salt export pump, MDR3 multidrug resistance pro-
tein 3, MRP multidrug resistanceassociated protein,
NTCP sodium-taurocholate cotransporting polypeptide;
and OATP, organic anion transporting polypeptide. Red
crosses indicate transporters whose activity may be inhib-
ited in response to infection. Infection may also lead to
disruption of tight junctions.
149Sepsis in the general population
III. Cardiovascular system in liver failure
https://t.me/medicina_free
induce the synthesis of acute-phase proteins (Fig. 12.2) [14,15]. In addition to the engagement of their classical
signaling pathways, proinflammatory cytokines increase the expression of the liver-specific ER membrane-
anchored transcription factor CREBH (for cyclic AMP-responsive element-binding protein 3-like protein 3)
[16].
In response to hepatocyte ER stress (which is caused by PAMPs and cytokines), CREBH is cleaved to produce an
amino-terminal fragment that induces genes encoding the acute-phase proteins C-reactive protein [CRP, a short
pentraxin]
[16] and hepcidin [17].
Acute-phase proteins induced by proinflammatory cytokines (also known as positive acute-phase proteins)
are secretory proteins with multiple roles in the innate immune response of the host (
Table 12.3) [14].For
example, acute-phase proteins including CRP, serum amyloid protein, and mannose-binding protein promote
pathogen clearance through complement activation and phagocytosis. Another example of acute-phase pro-
tein is hepcidin, whose role is to limit vital iron that is needed by invading microbes. Hepcidin accomplishes
this task by triggering degradation of the iron exporter ferroportin, thereby limiting iron egress from e ntero-
cytes and macrophages
[17]. Of note, during infection, there is also repression of the synthesis of a variety of
secretory proteins (called negative acute-phase proteins), including albumin, transferrin, among others
(
Table 12.3) [15].
Synthesis of positive acute-phase proteins requires not only amino acids (building blocks) but also ATP
(energy) and nucleotides, which are necessary to execute the successive steps of gene expression
[15]. During sep-
sis, the activation of the hypothalamicpituitaryadrenal axis stimulates the production of glucocorticoids,
which induce skeletal muscle catabolism. This results in the release in the blood of amino acids, which are then
imported into the liver and used for the synthesis of acute-phase proteins. In contrast to amino acids, nucleotides
have to be produced by hepatocytes through the engagement of cell-intrinsic metabolic processes which are
under control of cytokines.
Although the mechanisms of these metabolic processes are incompletely understood, analysis of the lit-
erature provides likely explanations for cytokine-driven nucleotide synthesis in hepatocytes
[1820].First,
there is evidence for an important role of the activation by cytokines of the PI3K-AKT-mechanistic (for-
merly “mammalian”) target of rapamycin (mTOR) signaling pathway
[18].mTORmayinducetheexpres-
sion of the glucose membrane transporter and some key enzymes of glycolysis (
Fig. 12 .3). As a result,
glucose entry is enhanced and glucose is channeled to aerobic glycolysis and synthesis of pyruvate. Then,
pyruvate is converted to acetyl-CoA and oxidized by mitochondrial Krebs cycle for producing molecules of
Hepatocyte membrane
IL-6
TNF-α
IL-6R
gp130
TNFR1
Hepatocyte membrane
MAPK
Jak1, Jak2
PI3K
AKT
STAT3
Induction of
genes encoding
acute-phase proteins
Induction of
metabolic genes
MAPK
Induction of genes
encoding
acute-phase proteins
NF-κB
FIGURE 12.2 Schematic of signaling pathways used by infection-induced paradigmatic proinflammatory cytokines to induce acute-
phase proteins in hepatocytes. Signaling pathways used by interleukin (IL)-6 and tumor necrosis factor (TNF)-α are illustrated here. These
pathways include (i) the phosphatidylinositol 3 kinase (PI3K)-AKT pathway, which stimulates the induction of genes involved in glycolysis
and (ii) the nucleotide synthesis, which both are required for synthesis of acute-phase proteins (see
Fig. 12.3).
150 12. Sepsis and the liver
III. Cardiovascular system in liver failure
https://t.me/medicina_free
electron-donor NADH. The electrons provided by NADH molecules are then used by the electron transfer
chain for oxidative phosphorylation (OXPHOS) and ATP production. Besides the central carbon metabo-
lism (i.e., glycolysis and Krebs cycle), other metabolic pathways may be engaged (
Fig. 12.3) [19,20].First,
the glycolysis intermediat e 3-phospho -
D-glycerate is metabolized to serine which then gives rise to glycine,
this amino acid playing a major role in several steps of de novo purine biosynthesis. Second, cytokine-
activated AKT phosphorylates a key enzyme of the pentose phosphate pathway (PPP, a branch of glycoly-
sis) resulting in channeling of glucose to produce ribose-5-phosphate and then 5-phosphoribose-1-
pyrophosphate, whic h is a key molecule of purine and pyrimidine synthesis. In ad dition, AKT also
increases NADP
1
synthesis through the direct phosphorylation of NAD kinase, thereby increasing the
availability of cellular NADPH to sustain NADPH-dependent anabolic production of purine nucleotides.
Third, glutamine is used for de novo purine and pyrimidine synthesis. In addition, glutamine via gluta-
mate gives rise to the Krebs cycle intermediate α-ketoglutarate which is oxidized through the Krebs cycle
to produce oxaloacetate that can then be converted to aspartate. The aspartate derived from Krebs cycle is
involved in de novo purine and pyrimidine synthesis and oxidation of α-ketoglutarate is used for mito-
chondrial energy production.
Urea cycle during infection
In the liver, the urea cycle converts excess systemic nitrogen, derived from t he breakdown o f nitrogen-
containing metabolites, such as ammonia and glutamine, into urea, a disposable nitrogenous compound
(
Fig. 12.4). During liver viral infection [21], there is an increased production of type 1 interferons (IFNs) which
has been shown to induce a dysregulation of the urea cy cle characterized by the downregulation of every
enzymes of the cycle, except arginase 1 which is upregulated. Because arginase 1 catalyzes the conversion of
arginine into ornithine and urea, upregulation of this enzyme results in a decrease in systemic arginine level s
resulting in suppressed cytotoxic T-cell responses and decreased immunopathology. In addition, the dysregula-
tion of the urea cycle may have consequences on nucleotide synthesis. For example, in certain cancers, the dys-
regulation of the urea cycle results in the diversion of metabolites that fuel the urea cycle, such as glutamine,
TABLE 12.3 Acute-phase proteins produced by the liver.
Positive acute-phase proteins (whose plasma concentrations increase in response to inflammatory signals)
Complement system
C3, C4, C9, factor B, C1 inhibitor, C4b-binding protein, mannose-binding lectin
Coagulation and fibrinolytic system
Fibrinogen, plasminogen, tissue plasminogen activator, urokinase, protein S, vitronectin, plasminogen-activator inhibitor 1
Antiproteases
α1-Protease inhibitor, α1-antichymotrypsin, pancreatic secretory trypsin inhibitor, inter-α-trypsin inhibitors
Transport proteins
Ceruloplasmin, haptoglobin, hemopexin
Participants in inflammatory responses
Secreted phospholipase A2, lipopolysaccharide-binding protein, interleukin-1receptor antagonist, granulocyte colony-stimulating factor
Short pentraxin
C-reactive protein
Others
Serum amyloid A, α1-acid glycoprotein, fibronectin, ferritin, angiotensinogen
Negative acute-phase proteins (whose plasma concentrations decrease in response to inflammatory signals)
Albumin, transferrin, transthyretin, α2-HS glycoprotein, alpha-fetoprotein, thyroxine-binding globulin, insulin-like growth factor I, factor XII
Adapted from Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999;340:448-454.
151Sepsis in the general population
III. Cardiovascular system in liver failure
https://t.me/medicina_free
carbamoyl-phosphate, and aspartate, toward pyrimidine synthesis (Fig. 12.4) [22]. Little is known abou t the
hepatic urea cycle in acute bacterial infections. However, because of the vigorous induction of type 1 IFNs is a
well-documented effects of bacterial PAMPs
[23], in particular lipopolysaccharide (LPS), hepatic urea cycle
may be dysregulated during these infections and result in potential beneficial effects such as decreased T-cell
cytotoxic responses and immunopathology, and increased nucl eotide availability for synthesis of acute-phase
proteins.
Hepatic catabolic metabolism during infection
Microbe-directed inflammatory responses are energetically expensive, necessitating the reallocation of nutri-
ents (glucose, amino acids, and fatty acids) to fuel immune activation
[24]. Because sepsis induces sickness
behavior of anorexia and asthenia, mobilization of stored fuels is critical for survival
[25]. Peripheral insulin
resistance, which decreases nutrient storage in muscle, fat, and liver, provides one mechanism for prioritization
and reallocation of metabolic fuels for host defense
[24]. The liver plays an important role in the adaptation to
Glycine
Serine
3-Phosphoglycerate
Riboses
Pyruvate Lactate
ATP
NAD
+
NADH
PPP
NADPH
NADP
NAD
+
NADH
OAA
Acetyl-CoA
Citrate
α-KG
Glutamate
Glutamine
Succinate
Fumarate
Malate
Aspartate
NAD
+
NADH
CO
2
CO
2
NADP
NADPH
NAD
+
NADH
CO
2
Dihydroorotate
I
II
III
IV
V
Orotate
Nucleotides
NAD
+
NADH
O
2
H
2
O
O
2
ETC
ATP
ROS
NADP
NADPH
Extrahepatic compartment
Sepsis
IL-6
TNF-α
pituitary-
adrenal axis
Glucocorticoids
Skeletal muscle
catabolism
Glutamine
Acute-phase
protein
synthesis
Glucose-6P
Glucose
Glycolysis
Nucleotides
Hepatocyte
Cytokine
receptor
Amino acids
Hypothalamus-
FIGURE 12.3 Schematic of mechanisms supporting the synthesis of acute-phase proteins stimulated by infection-induced cytokines.
During infection, amino acids released from skeletal muscles are used as building blocks for the synthesis of acute-phase proteins in hepato-
cytes. This synthesis requiring also nucleotides, the central carbon metabolism (glycolysis and Krebs cycle) and the pentose phosphate path-
way are stimulated to fuel the de novo synthesis of nucleotides (both purine and pyrimidine nucleotides). OAA, oxaloacetate; etc, electron
transport chain; αKG, α-ketoglutarate; ROS, reactive oxygen species.
152 12. Sepsis and the liver
III. Cardiovascular system in liver failure
https://t.me/medicina_free
nutrient scarcity related to sepsis-induced sickness behaviors. For example, during sepsis, the sympathetic ner-
vous system is activated resulting in hepatic glycogenolysis
[25]. Moreo ver, there is a substrate shift from
ingested carbohydrates to ketone bodies, witnessed by increased circulating levels of the ketone body beta-
hydroxybutyrate
[24]. Oxidation of fatty acids and amino acids, which are mobilized from adipose tissue and
skeletal muscle, respectively, usually support ketogenesis in the liver. During fasting (a physiological condition
where ketone bodies are the primary source of energy in peripheral organs), peroxisome proliferator-activated
receptor alpha (PPAR-α) induces hepatic genes involved in β-oxidation of fatty acids and ketogenesis.
However, during sepsis, there is a disruption of the normal homeostatic r esponse to fasting because of exten-
sive repression of the expression of PPAR-α-target genes involved in mitochondrial oxidation of fatty acids.
Therefore, in this context, peripheral-organ energy production relies on availability of ketone bodies produced
by catabolism of ketogenic amino acids (including isoleucine, lysine, tryptophan, leucine, tyrosi ne, and
phenylalanine).
During sepsis, hepatic tryptophan is catabolized through the kynurenine pathway not only to produce
ketone bodies but also the electron acceptor nicotinamide adenine dinucleotide (NAD
1
) [26].Thisprocess
called de novo NAD
1
biosynthesis, is crucial for maintenance of the cellular NA D
1
pool. T he existence of an
adequate hepatic NAD
1
pool is important because nutrient oxidation, which is indispensable to nucleotide
synthesis requires NAD
1
availability. Moreover, NADH is a key electron donor which is essential for ATP
production.
Hepatic triglyceride release during infection
Growth and differentiation factor 15 (GDF15), previously known as NSAID-activated gene 1 (NAG-1) and
macrophage inhibitory cytokine 1 (MIC-1), is a divergent transforming growth factor β family member. Infection
induces the cytokine GDF15 in several organs, in particular the liver. GGF15 has been shown to stimulate hepatic
triglyceride export via activation of beta-adrenergic signaling
[27]. The resulting maintenance of triglyceride
levels is cardioprotective.
c
e
t
y
o
t
e
Krebs cycle
Krebs cycle
Urea
NH
3
Purine and
pyrimidine synthesis
Purine and
pyrimidine
synthesis
Pyrimidine
synthesis
Polyamine
synthesis
Carbamoyl-P
F
u
m
a
r
a
t
e
K
r
e
b
s
c
y
c
l
e
U
r
e
a
c
y
c
l
e
N
O
α-Ketoglutarate
Glutamate
Glutamine
Aspartate
Citrulline
Ornithine
Arginine
Proline
Arginine succinate
FIGURE 12.4 Schematic of the urea cycle in the hepatocyte. The figure shows the connections of molecules that fuel the urea cycle with
the synthesis of purine and pyrimidine nucleotides; In addition, it shows that arginine can be diverted from urea synthesis for producing
nitric oxide (NO) and citrulline.
153Sepsis in the general population
III. Cardiovascular system in liver failure
https://t.me/medicina_free
Соседние файлы в папке Библиотека им академика М.И. Перельмана