Basic Principles of Disease

ESPEN Congress Prague 2007

B. Soeters

Nutrition in Severe Sepsis

Basic Principles of Disease

Peter B. Soeters

Basic Principles of Disease• Wound Healing• Effects of Wound Healing on metabolism in

other tissues– Appropriate– Not appropriate?

• Inflammation and the Gut– MOF– Liver Disease– Gut Function

Basic Principles of Disease• Wound Healing• Effects of Wound Healing on metabolism in

other tissues– Appropriate– Not appropriate?

• Inflammation and the Gut– MOF– Liver Disease– Gut Function

Beans et alExpert Reviews Mol Medicine2003 Vol. 5 March

Singer et al, NEJM 1999 341: 738-46

Permeability integral part of Inflammation = Healing

• Wound swelling = oedema, due to increased permeability, promoted by cytokines etc.

• Increased permeability is necessary to allow cells and proteins to get access to the places where healing is necessary

• Permeability therefore part of inflammation and not the cause of inflammation

• Inflammation is part of the healing process

Basic Principles of Disease• Wound Healing• Effects of Wound Healing on metabolism in

other tissues– Appropriate– Not appropriate?

• Inflammation and the Gut– MOF– Liver Disease– Gut Function

Role Neutrophil (and Macrophage)

Local Trauma has generalized effects on the whole organism

• Metabolic effects after Trauma induced by:– Systemic neuro-endocrine changes– Including systemic cytokine cascade (cytokines

immune cells etc appear in the systemic circulation)

– Have influences on other tissues (muscle, liver, immune system, other organs)

• Neuro-endocrine and cytokine effects in principle adaptive and useful. (Leakiness?)

CONTROL

24-h ENDOTOXEMIA

PS PB PS PB

PS PB PS PB

Protein kinetics Maastricht Metabolic

group

Protein export

But also stimulation Immune system, generation immune cells

Distant organs react appropriately to local wounds

• Muscle– Increases protein breakdown (also net protein

breakdown = difference between synthesis and breakdown) leads to release of amino acids

– Increased production alanine and glutamine– Increased Cori-cycling (Glucose/Lactate)

• Supplies liver, wound, immune system with necessary building blocks

Distant organs react appropriately to local wounds/infection

• Liver– Produces protein

• Fibrinogen• Albumin• Globulins, Complement etc

– Increased Cori-cycling (Lactate/Glucose)– Becomes Glutamine consumer

• These are all necessary and useful adaptations to allow wound healing/host defence

Distant organs react to wounds

• Spleen/Immunesystem– Produce Immune cells and take up substrate to do

this (amino acids/fatty acids)– Increase Cori-cycling (Glucose/Lactate)– Become Glutamine consumers– Supply Immune cells for wound

• These are all necessary and useful adaptations to allow wound healing/host defence

Basic Principles of Disease• Wound Healing• Effects of Wound Healing on metabolism in

other tissues– Appropriate– Not appropriate?

• Inflammation and the Gut– MOF– Liver Disease– Gut Function

Fink et al, Clin Care Clin 2005 21: 177-96

• Endotoxin/proinflammatory cytokines open up tight junctions in:– Kidney– Lung– Liver – Intestine– Other organs?

• Severely: interferes with function

MOF patients• Generalized inflammatory response

– Generalized oedema due to increased permeability in all organs, also in organs that do not play major roles in host response (lung, heart, kidney).

– In principle adaptive but overshoot (negative side of the coin)

– Diminished function• Generally in the presence of persisting infection

(interferes with adequate wound healing; perpetuates pro-inflammatory response)

• Some people react stronger than others (……)

Basic Principles of Disease• Wound Healing• Effects of Wound Healing on metabolism in

other tissues– Appropriate– Not appropriate?

• Inflammation and the Gut– MOF– Liver Disease– Gut Function

MOF and Gut permeability• Any infectious focus can cause MOF,

including the gut• No good correlation between mesenteric

node bacteria and cause of sepsis• Sepsis insidious in extra-intestinal locations

(brain, kidney, gallbladder etc)• Bacteria can be easily cleared• Permeability the result of MOF, not the

cause

Basic Principles of Disease• Wound Healing• Effects of Wound Healing on metabolism in

other tissues– Appropriate– Not appropriate?

• Inflammation and the Gut– MOF– Liver Disease– Gut Function

Delicate balance between gut and liver necessary for their health

• Bacterial overgrowth in the intestine• Disturbed entero-hepatic cycling

– Altered bile acid composition– Diminished pool size– In short bowel, high output

fistulae/stomata/bypass/cholestasis• Intestinal inflammation/increased permeability

– Celiac disease, IBD, Malnutrition associated inflammation

• Sepsis

Are all significantly more often

Associated withLiver Disease:

CholestasisSteatosis/Steatohepatis/Cirrhosis

PBC???PSC???

Soeters et al, Clin Opinion Clin Nutr Metabolic Care 2007 10: 632-638

Basic Principles of Disease• Wound Healing• Effects of Wound Healing on metabolism in

other tissues– Appropriate– Not appropriate?

• Inflammation and the Gut– MOF– Liver Disease– Gut Function

Slatzle et al J GI Surg 2004 8: 645-52

Cullen et alJ Surg Res 1995 58:90-5

Cullen et al, J Surg Res 1995 58:90-5

•Paralysis complete bowel•Gas in all segments•Abnormal gas pattern in ileocecal region

Medical PhysiologyBoron, BoulpaepSaunders

Medical PhysiologyBoron, BoulpaepSaunders

Slatzle et al J GI Surg 2004 8: 645-52

Effect TNF-alpha on Na/K pump

FieldJCI 2006116:2580-82

Inflammation includes Increased Permeability

• Decreases motility• Decreases enzyme secretion (not shown/not

well investigated)• Decreases:

– Absorption Electrolytes/Water, Glucose, Amino Acids, Fat, etc

– Decreases uphill gradients (Glutamine/Glutathione/Amino Acids etc)

Conclusions I• Inflammation is in principle the necessary

mechanism to heal wounds/clear infection • An obligatory functional part of inflammation is

increased permeability• Local trauma/infection has useful effects on the

remainder of the organism• Ongoing inflammation/infection perpetuates the

proinflammatory part of the healing response and continues to induce inflammatory activity in the whole organism

Conclusions II• Increased intestinal permeability is part of the

generalized inflammatory activity induced by (unresolved) trauma/infection

• The site of trauma /infection does not have to be located in the gut itself.

• Increased intestinal permeability is therefore more often than not the sequel rather than the cause of MOF

• Chronic inflammatory activity in the intestine is associated with increased rates of pluriform aspecific liver diseases compared to individuals with healthy guts

Conclusions III• It is attractive to speculate that the specific genetic

built-up of the individual predisposes to develop liver disease in the presence of intestinal inflammation

• The inflammatory state of the intestine, at least in part mediated by TNF-α, leads to:– Decreased motility– Decreased Sodium linked transport = absorption of

glucose, amino acids, short chain fatty acids– This causes mixed osmotic/secretory diarrea – Possibly decreased digestion (not very well

investigated)• In disease artificial nutrition should be carefully

monitored