Hepatic metabolic response to injury and sepsis

doi:10.1016/S0039-6060(05)80251-X

Surgery

Volume 117, Issue 5, May 1995, Pages 520-530

https://doi.org/10.1016/S0039-6060(05)80251-X Get rights and content

Background. Experimental reports have indicated that hepatic oxidative and synthetic metabolism may become depressed in sepsis. Because the mechanism of infection-related liver dysfunction has not been established, further study of these functional alterations could contribute to the therapeutic management of septic organ failure syndromes. However, recently controversy has arisen over the existence of these derangements that must be reconciled before further progress in this field can be made.

Methods. Splanchnic balance studies for the measurement of glucose output and oxygen consumption were used to assess hepatic function in fasted normal volunteers (n=18), injured patients (n=10), and patients with sepsis (n=18). The liver's contribution to splanchnic metabolism was estimated from a comparison of splanchnic oxygen utilization in response to increases in the liver-specific process of glucogenesis. In addition, in vivo liver albumin production was determined by using the [¹⁴C] carbonate technique.

Results. Glucose output after injury and sepsis was increased by 12.8% and 76.6%, respectively, compared with controls. On the basis of substrate balance studies, gluconeogenesis was estimated to account for 46%, 87%, and 93%, respectively, of splanchnic glucose output in each of the three groups. In patients with sepsis glucose output was also noted to be linearly related to regional oxygen consumption, indicating that these processes were coupled and increases in the respiratory activity of the splanchnic cellular mass could be accounted for by increases in new glucose output and gluconeogenic substrate clearance. The mean albumin synthetic rate increased during injury and sepsis by 22% and 29%, respectively, compared with normal volunteers.

Conclusions. These studies cast doubt on the commonly held notion that tissue respiratory dysfunction may occur during sepsis. On the contrary, hepatic function is accelerated during hyperdynamic sepsis, and evidence indicating oxidative or synthetic functional depression is lacking.

References (77)

LongCL et al.
Nonsuppressibility of gluconeogenesis by glucose in septic patients
Metabolism
(1976)
SchreiberG et al.
The acute phase response of plasma protein synthesis during experimental inflammation
J Biol Chem
(1982)
SaxHC et al.
Increased synthesis of secreted hepatic proteins during abdominal sepsis
J Surg Res
(1988)
RohMS et al.
Stimulatory effect of interleukin-1 upon hepatic metabolism
Metabolism
(1986)
von AllmenD et al.
Hepatic protein synthesis in a modified septic rat model
J Surg Res
(1990)
FlaimKE et al.
The role of amino acids in the regulation of protein synthesis in perfused rat liver
J Biol Chem
(1982)
KnausWA et al.
The APACHE III prognostic system: risk prediction of hospital mortality for critically ill hospitalized adults
Chest
(1991)
LongCL et al.
Metabolism and recycling of urea in man
Am J Clin Nutr
(1978)
ShoemakerWC et al.
Prospective trial of supranormal values of survivors as therapeutic goals in high-risk surgical patients
Chest
(1988)
HamptonWA et al.
Effective hepatic blood flow and hepatic bioenergy status in murine peritonitis
J Surg Res
(1987)

BakkerJ et al.

Blood lactate levels are superior to oxygen-derived variables in predicting outcome in human septic shock

Chest

(1991)

PeliasME et al.

In vivo [³¹P] NMR assessment of early hepatocellular dysfunction during endotoxemia

J Surg Res

(1992)

HolmanJM et al.

Effect of bacterial sepsis on gluconeogenic capacity in the rat

J Surg Res

(1988)

LangCH et al.

Carbohydrate dynamics in the hypermetabolic septic rat

Metabolism

(1984)

TanakaA et al.

A possible role of inorganic phosphate as a regulator of oxidative phosphorylation in combined urea synthesis and gluconeogenesis in perfused rat liver

J Biol Chem

(1989)

WilliamsonJR et al.

Energy costs of gluconeogenesis in rat liver

Metabolism

(1971)

CastellJV et al.

Interleukin-6 is the major regulator of acute phase protein synthesis in adult human hepatocytes

FEBS Lett

(1989)

GersovitzM et al.

Dynamic aspects of whole body glycine metabolism: influence of protein intake in young adult and elderly males

Metabolism

(1980)

GersovitzM et al.

Albumin synthesis in young and elderly subjects using a new stable isotope methodology: response to level of protein intake

Metabolism

(1980)

FryDE et al.

Multiple system organ failure: the role of uncontrolled infection

Arch Surg

(1980)

CerraF

Hypermetabolism, organ failure and metabolic support

Surgery

(1987)

LongCL et al.

Carbohydrate metabolism in man: effect of elective operations and major injury

J Appl Physiol

(1971)

DietzeG et al.

On gluconeogenesis of human liver

Diabetologia

(1976)

LundhomK et al.

Gluconeogenesis in human liver tissue

Scand J Clin Lab Invest

(1976)

IlesRA et al.

The effect of reduction of perfusion rate on lactate and oxygen uptake, glucose output and energy supply in the isolated perfused liver of starved rats

Biochem J

(1979)

DeFranzoRA et al.

Synergistic interactions of counterregulatory hormones: a mechanism for stress hyperglycemia

Acta Chir Scand Suppl

(1980)

VasconcelosPRL et al.

Time course in hepatic metabolism in response to sepsis in the rat: impairment of gluconeogenesis and ketogenesis in vitro

Clin Sci

(1987)

ClemensMG et al.

Regulation of glucose production from lactate in experimental sepsis

Am J Physiol

(1983)

GuillemJG et al.

Hepatic gluconeogenic capability is depressed before changes in oxidative capability

J Trauma

(1982)

MelaL et al.

Defective oxidative metabolism of rat mitochondrials in hemorrhage and endotoxin shock

Am J Physiol

(1971)

AstizM et al.

Early impairment of oxidative metabolism and energy production in severe sepsis

Circ Shock

(1988)

LiaoWS et al.

Changes in plasma albumin concentration, synthesis rate and mRNA level during acute inflammation

Am J Physiol

(1986)

KlasigKC et al.

Changes in protein synthesis due to an inflammatory challenge

Proc Soc Exp Biol Med

(1984)

SganzaG et al.

Reprioritization of hepatic plasma protein release in trauma and sepsis

Arch Surg

(1985)

PetersonVM et al.

Total enteral nutrition versus total parenteral nutrition after major torso injury: attenuation of hepatic reprioritization

Surgery

(1988)

HotchkissRS et al.

Reevaluation of the role of cellular hypoxia and bioenergetics failure in sepsis

JAMA

(1992)

TowsendMC et al.

Alterations of hepatic mitochondrial function in a model of peritonitis in immature rats

J Pediatr Surg

(1986)

HiyamaDT et al.

Synthesis of albumin and acute phase proteins in perfused liver after burn injury in rats

J Burn Care Rehabil

(1991)

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Hepatic metabolic response to injury and sepsis

Metabolism

J Biol Chem

J Surg Res

Metabolism

J Surg Res

J Biol Chem

Chest

Am J Clin Nutr

Chest

J Surg Res

Chest

J Surg Res

J Surg Res

Metabolism

J Biol Chem

Metabolism

FEBS Lett

Metabolism

Metabolism

Multiple system organ failure: the role of uncontrolled infection

Arch Surg

Hypermetabolism, organ failure and metabolic support

Surgery

Carbohydrate metabolism in man: effect of elective operations and major injury

J Appl Physiol

On gluconeogenesis of human liver

Diabetologia

Gluconeogenesis in human liver tissue

Scand J Clin Lab Invest

The effect of reduction of perfusion rate on lactate and oxygen uptake, glucose output and energy supply in the isolated perfused liver of starved rats

Biochem J

Synergistic interactions of counterregulatory hormones: a mechanism for stress hyperglycemia

Acta Chir Scand Suppl

Time course in hepatic metabolism in response to sepsis in the rat: impairment of gluconeogenesis and ketogenesis in vitro

Clin Sci

Regulation of glucose production from lactate in experimental sepsis

Am J Physiol

Hepatic gluconeogenic capability is depressed before changes in oxidative capability

J Trauma

Defective oxidative metabolism of rat mitochondrials in hemorrhage and endotoxin shock

Am J Physiol

Early impairment of oxidative metabolism and energy production in severe sepsis

Circ Shock

Changes in plasma albumin concentration, synthesis rate and mRNA level during acute inflammation

Am J Physiol

Changes in protein synthesis due to an inflammatory challenge

Proc Soc Exp Biol Med

Reprioritization of hepatic plasma protein release in trauma and sepsis

Arch Surg

Total enteral nutrition versus total parenteral nutrition after major torso injury: attenuation of hepatic reprioritization

Surgery

Reevaluation of the role of cellular hypoxia and bioenergetics failure in sepsis

JAMA

Alterations of hepatic mitochondrial function in a model of peritonitis in immature rats

J Pediatr Surg

Synthesis of albumin and acute phase proteins in perfused liver after burn injury in rats

J Burn Care Rehabil