ALBUMIN METABOLISM DURING INFLAMMATION

B. Soeters (NL)

ESPEN Congress Copenhagen 2016 ALBUMIN - A MATTER OF NUTRITION

Albumin metabolism during inflammation

Peter B. Soeters, the Netherlands

ESPEN congress Copenhagen 2016

Beans et al

Expert Reviews Mol

Medicine

2003 Vol. 5 March

Stages of wound healing:

Trauma/Damage/Disease

Clotting

Early inflammation

Late inflammation:Growth biomass/cells

Remodeling/strengthening

Beans et al

Expert Reviews Mol Medicine

2003 Vol. 5 March

Under the microscope: what we see is inflammation

Inflammation

=

Cell proliferation Matrix deposition

=

Healing

Plasma albumin and inflammation

• Which situations are associated withhypoalbuminaemia?

• Is hypoalbuminaemia caused by diminishedsynthesis?

• Is hypoalbuminaemia caused by an increase in interstitial space (extravascular extracellularvolume)?

• What are the clinical consequences associatedwith hypoalbuminaemic states?

• Is there a useful purpose served by the state of hypoalbuminaemia?

33 Anorexia nervosa studies with bothBMI and plasma albumin levels assessed

Lee JL, Oh ES, Lee RW, Finucane TE. Serum Albumin and Prealbumin in Calorically Restricted,

Nondiseased Individuals: A Systematic Review. Am J Med 2015;128:1023 e1-22.

This patient gained 15 kg in the last week. Her plasma albuminlevels amount to 16 g/L. She was healthy not malnourished beforebecoming ill. She suffered from severe diverticulitis.

Barac-Nieto, M., et al., Body composition in chronic undernutrition. Am J Clin Nutr, 1978. 31(1): p. 23-40.

Nutritional compromise was analyzedbased on: Weight/Height, Albumin, CHI

Barac-Nieto, M., et al., Body composition in chronic undernutrition. Am J ClinNutr, 1978. 31(1): p. 23-40.

Disproportional decrease in CHI compared to decrease in BMI => Oedema + low Alb??

Barac-Nieto, M., et al., Body composition in chronic undernutrition. Am J Clin Nutr, 1978. 31(1): p. 23-40.

Kwashiorkor Marasmus

Hypoalbuminaemia in Kwashiorkor

Jahoor et al, AmJClinNutr 2005;82:792-800

Jahoor et al, AmJClinNutr2005;82:792-800

Smith, M. I., et al. (2013). "Gut microbiomes of Malawian twin pairs discordant forkwashiorkor." Science 339(6119): 548-554.

Stools from discordant twins (1 kwashiorkor, 1 healthy/marasmus)

Smith, M. I., et al. (2013). "Gut microbiomes of Malawian twin pairs discordant forkwashiorkor." Science 339(6119): 548-554.

Endemic malnutrition in adults and children

• Characterized by– Low height (stunting)– Low muscle mass– Very low plasma albumin, when in severe nutritional

compromisein a proportion of individuals– Oedema significant in this last group

• Infestation with parasites/ bowel infection/ other bacterial or candida infections/ changes in microbiome and metabolites

• In marasmus similar infestation/infection but less oedema and only moderately decreased albumin levels. Potential role for the microbiome.

Levitt DG, Levitt MD. Human

serum albumin homeostasis: a

new look at the roles of

synthesis, catabolism, renal and

gastrointestinal excretion, and

the clinical value of serum

albumin measurements.

International journal of general

medicine 2016;9:229-55.

Albumin levels in pathological

states(Fraction of

normal)

Are “growing states” associated withdecreased albumin levels?

Control group First trimester Second trimester Third trimester

(N=23) (N=34) (N=35) (N=24) pa

Guven S, Alver A, Mentese A, Ilhan FC, Calapoglu M, Unsal MA. The novel

ischemia marker 'ischemia-modified albumin' is increased in normal pregnancies.

Acta obstetricia et gynecologica Scandinavica 2009;88:479-82.

TNF alpha, TGF beta, Interferon gamma:moderately elevated in healthy pregnancystrongly elevated in toxicosis and premature child birth

Breast cancer and hypoalbuminaemia

P F, B S, M K, et al. Evaluation of Glutathione, Albumin and Ascorbic Acid Levels in Breast

Cancer Patients. Int J Clin Med 2013:405-8.

Albumin concentration in plasma

Pre-operative Post-operative

50

40

30

20

10

g/L

Bernadette van Acker, Dept Surgery, Maastricht

FSR Albumin

Pre-operative Post-operative

15

10

5

0

%/day

Bernadette van Acker, Dept Surgery, Maastricht

Albumin synthesis rates increase!!

1. Cayol M, Tauveron I, Rambourdin F, et al. Whole-body protein turnover

and hepatic protein synthesis are increased by vaccination in man. Clin Sci (Colch)

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2. Fearon KC, Falconer JS, Slater C, McMillan DC, Ross JA, Preston T.

Albumin synthesis rates are not decreased in hypoalbuminemic cachectic cancer

patients with an ongoing acute-phase protein response [see comments]. Ann Surg

1998;227(2):249-54.

3. Jahoor F, Wykes L, Del Rosario M, Frazer M, Reeds PJ. Chronic protein

undernutrition and an acute inflammatory stimulus elicit different protein kinetic

responses in plasma but not in muscle of piglets. J Nutr 1999;129(3):693-9.

4. Barle H, Januszkiewicz A, Hallstrom L, et al. Albumin synthesis in humans

increases immediately following the administration of endotoxin. Clin Sci (Lond)

2002;103(5):525-31.

5. Jahoor F, Abramson S, Heird WC. The protein metabolic response to HIV

infection in young children. Am J Clin Nutr 2003;78(1):182-9.

6. Dahn MS, Mitchell RA, Lange MP, Smith S, Jacobs LA. Hepatic metabolic

response to injury and sepsis. Surgery 1995;117(5):520-30.

Albumin synthesis rates(normal values mg/kg/day)

Levitt DG, Levitt MD. Human serum albumin homeostasis: a new look at the roles of

synthesis, catabolism, renal and gastrointestinal excretion, and the clinical value of

serum albumin measurements. International journal of general medicine 2016;9:229-55.

Absolute albumin synthesis ratesin liver disease (fraction of normal)

Levitt DG, Levitt MD. Human serum albumin homeostasis: a new look at the roles of

synthesis, catabolism, renal and gastrointestinal excretion, and the clinical value of

serum albumin measurements. International journal of general medicine 2016;9:229-55.

Levitt DG, Levitt MD. Human

serum albumin homeostasis: a

new look at the roles of

synthesis, catabolism, renal and

gastrointestinal excretion, and

the clinical value of serum

albumin measurements.

International journal of general

medicine 2016;9:229-55.

Albuminsynthesis ratesin pathological

states withhealthy livers(Fraction of

normal)

Albumin kinetics in several disease states

• Decreased absolute synthesis rate /BW in:

– Liver disease (acute and chronic)

– Kwashiorkor (enormous fatty livers)(+ NASH?)

• No decrease but rather normal or increased absolute synthesis rates /BW in:

– Most if not all other disease states

• Levitt: Albumin kinetics cannot explain low plasma levels unless clearance is increased (intestinal, renal) ????

• Levitt and Levitt do not take into account the increase in distribution space, which they only consider to bepresent in “acute” situations.

Levitt DG, Levitt MD. Human serum albumin homeostasis: a new look at the roles of

synthesis, catabolism, renal and gastrointestinal excretion, and the clinical value of serum

albumin measurements. International journal of general medicine 2016;9:229-55.

Fleck A, Raines G, Hawker F, et al. Increased vascular permeability: a major cause of

hypoalbuminaemia in disease and injury. Lancet 1985;1(8432):781-4.

Figure 3. Sequential measurements of excess extracellular water (ECW) in 8 elderly (open circles)and 6 young (solid circles) patients with sepsis. Asterisks indicate

significant changes from the preceding measurement. Adapted from Cheng et al, Arch Surg 1998 133: 745-51

Tipping point:Spontaneousrise of:

albumin, urine production,decrease of:

BW

Hubner M, Mantziari S, Demartines N, Pralong F, Coti-Bertrand P, Schafer M. Postoperative Albumin Drop Is a Marker for

Surgical Stress and a Predictor for Clinical Outcome: A Pilot Study. Gastroenterology research and practice

2016;2016:8743187.

Significance of low plasma albumin• Low plasma albumin is not due to diminished

synthesis• In most disease states absolute synthesis rates

increase• Lower concentrations are due to dilution in a larger

amount of body water outside the cells unless substantial clearance by gut/kidney

• Increases in total body water outside cells are due to increased capillary escape of fluid, albumin, electrolytes as an inevitable consequence of inflammation (compare wound healing)

• Therefore low plasma albumin is a sign of the presence of inflammation

• Its course also may reflect rather precisely recovery or worsening of the disease process

Inflammation (Albumin levels) as predictor of outcome

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disease. Ann Surg 1985;201(4):494-8.

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protein levels in older hospitalized patients: continuing importance of serum albumin. Aging Clin Exp Res 2006;18(4):307-11.

7. Kudsk KA, Tolley EA, DeWitt RC, et al. Preoperative albumin and surgical site identify surgical risk for major

postoperative complications. Journal of Parenteral and Enteral Nutrition 2003;27(1):1-9.

8. Pifer TB, McCullough KP, Port FK, et al. Mortality risk in hemodialysis patients and changes in nutritional indicators:

DOPPS. Kidney International 2002;62(6):2238-45.

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patients. Clin Nutr 2004;23(6):1398-404.

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The I.R.A. Study. Istituto di Riposo per Anziani. Aging (Milano) 1999;11(3):194-9.

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predictors of outcome in male and female ESRD patients. Nephrology, Dialysis, Transplantation 2002;17(7):1266-74.

12. Suttmann U, Ockenga J, Selberg O, Hoogestraat L, Deicher H, Muller MJ. Incidence and prognostic value of

malnutrition and wasting in human immunodeficiency virus-infected outpatients. Journal of Acquired Immune Deficiency Syndrome

and Human Retrovirology 1995;8(3):239-46.

13. Yamamoto T, Allan RN, Keighley MR. Risk factors for intra-abdominal sepsis after surgery in Crohn's disease. Dis

Colon Rectum 2000;43(8):1141-5.

14. Zuliani G, Romagnoni F, Volpato S, et al. Nutritional parameters, body composition, and progression of disability in

older disabled residents living in nursing homes. Journal of Gerontology, Series A: Biological Sciences and Medical Sciences

2001;56(4):M212-6.

Levitt DG, Levitt MD. Human serum albumin homeostasis: a new look at the roles of

synthesis, catabolism, renal and gastrointestinal excretion, and the clinical value of

serum albumin measurements. International journal of general medicine 2016;9:229-55.

Plasma albumin and inflammation• Which clinical situations are associated with hypoalbuminaemia? All inflammatory states (endemic malnutrition, disease, surgery/trauma, infection, growth(not extensively discussed) = all states where. increased immune cell proliferation andtissue synthesis are occurring.Not when exclusively in the presence of a negative nutrient balance).

• Is hypoalbuminema caused by diminished synthesis? No, except partly in liver failure and possibly in Kwashiorkor.

• Is hypoalbuminaemia caused by an increase in interstitial space (extravascularextracellular volume)?

Yes, due to increased membrane permeability and capillary escape of fluid, electrolytes andproteins, leading to increased extravascular, extracellular volume (oedema): the distributionspace of albumin.

• What are the clinical consequences associated with inflammatory/hypoalbuminemicstates?

Diminished capacity to generate an adequate immune/host response to a renewedchallenge (ICU: second hit).Inflammatory state is a risk in itself

• Is there a useful purpose served by increased escape of albumin into the interstitium? Very likely, not discussed: transporter/regulator, extracellular scavenger and others.

Should we inhibit the inflammatory response?

• NSAID’s in acute inflammation– some NSAID’s increase anastomotic leakage after surgery– increase the risk of premature birth/ abortion in pregnancy– aggravate heart failure– induce small bowel lacerations and bleeding– Induce renal failure

• NSAID’s in chronic inflammation– Growth:

• Increases risk of premature birth• Increases risk of cryptorchism in boys• But: delays early recurrence after primary treatment of breast cancer

– Chronic inflammatory disease• Corrects the dysbalance between pro- and anti-inflammatory activity

• Severe protracted inflammation due to treatment failure of primary cause (or due to hyperinflammation):– Kills us