Inflammatory diseases

1
Inflammatory diseases nutrition

• Christian A. Drevon
• Department of nutrition, Institute of Basic
  Medical Sciences, University of Oslo

2
Inflammatory diseases

• Arthritis
• Rheumatoid
• Uric acid
• Bowel diseases
• Crohns disease
• Ulcerative colitis
• Celiac disease
• Skin diseases - atopic dermatitis psoriasis
• Allergies
• Obesity
• Diabetes type 1 and 2?
• Atherosclerosis

3
Chronic inflammation
Diffuse chronic inflammation in the wall of an
abscess of bone, with numerous dilated blood
vessels (bv) surrounded by a mixture of
inflammatory cells including neutrophils,
macrophages and lymphocytes Diffuse chronic
inflammation in the synovial membrane in
rheumatoid arthritis several lymphocytes and
plasma cells (abundant dark pink cytoplasm)
beneath the layer of synovial cells (sc)
4
Chronic inflammation
The role of chemokines, generated at a site of
inflammation, in promoting leucocyte activation
and recruitment
5
Rhematoid arthritis (RA) American College of
Rheumatology, 1987
1 Morning stiffness lasting for gt 1 h for gt 6
weeks 2 Arthritis in three areas for gt 6 weeks
3 Arthritis of the hands or wrists for gt 6
weeks 4 Symmetrical arthritis for gt 6 weeks 5
Rheumatoid nodules 6 Positive test result for
rheumatoid factor 7 Radiographical changes in
the wrists/hands Four criteria are required for
the diagnosis of RA Affects 1 of the
population
6
Rhematoid arthritis (RA) Wordsworth P,
http//www.ELS.net
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Rhematoid arthritis (RA) Wordsworth P,
http//www.ELS.net
Typical rheumatoid joint deformities. Wasting of
the small muscles, swelling of the
metacarpophalangeal joints and a small
subcutaneous nodule on the little finger. The
fingernail clubbing is characteristic of the
pulmonary fibrosis from which this patient also
suffered.
8
Extra-articular manifestations of rhematoid
arthritis Wordsworth P, http//www.ELS.net
Cumulative frequency () Lymph node
enlargement 50 Splenic enlargement 25
Pleurisy 30 Lung fibrosis 10
Pericarditis 1020 Osteoporosis 4 60
Skin nodules 25 Sjögren syndrome 15
Major vasculitis (males) 10 Amyloidosis
520
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Organ-affections with RA

• Joints muscles
• Normochrome anemia
• Cardiovascular diseases - vasculitis, etc
• Sclerodermia malacia
• Peripheral neuropathy
• Osteoporosis
• Infections
• Failure of internal organs

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Dietary prevention/treatment of RA

• Little food
• Energy deficiency --gt inflammation
• Vegetarian diet J Kjeldsen- Kragh
• Vitamin D Cantorna MT, Mahon BD. Mounting
  evidence for vitamin D as an environmental factor
  affecting autoimmune disease prevalence.Exp Biol
  Med (Maywood), 20042291136-42
• N-3 fatty acids Berbert AA et al.
  Supplementation of fish oil and olive oil in
  patients with rheumatoid arthritis. Nutrition.
  200521131-6

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Kjeldsen-Kragh J et al. Controlled trial of
fasting and one-year vegetarian diet in
rheumatoid arthritis. Lancet 1991338(8772)899-9
02

• Fasting is an effective treatment for rheumatoid
  arthritis, but most patients relapse on
  reintroduction of food
• Fasting followed by one year of vegetarian diet
  was assessed in a randomised, single-blind
  controlled trial
• 27 patients stayed four-week at a health farm.
  After initial 7-10 days subtotal fast, they were
  put on an individually adjusted gluten-free vegan
  diet for 3.5 months. The food was then gradually
  changed to a lactovegetarian diet for the
  remainder of the study
• 26 control patients stayed for four weeks at a
  convalescent home, but had ordinary diet the
  whole study period
• After four weeks the diet group showed
  significant improvement in number of tender
  joints, Ritchie's articular index, number of
  swollen joints, pain score, duration of morning
  stiffness, grip strength, erythrocyte
  sedimentation rate, CRP, white blood cell count,
  and a health assessment questionnaire score. In
  the control group, only pain score improved
  significantly
• The benefits in the diet group were still present
  after one year, and evaluation of the whole
  course showed significant advantages for the diet
  group in all measured indices

14
Cantorna MT, Mahon BD. Mounting evidence for
vitamin D as an environmental factor affecting
autoimmune disease prevalence.Exp Biol Med
(Maywood), 20042291136-42

• Low vitamin D status has been implicated in the
  etiology of autoimmune diseases such as multiple
  sclerosis, rheumatoid arthritis,
  insulin-dependent diabetes mellitus, and
  inflammatory bowel disease
• The optimal level of vitamin D intake required to
  support optimal immune function is not known but
  is likely to be at least that required for
  healthy bones
• Experimentally, vitamin D deficiency results in
  increased incidence of autoimmune disease
• Mechanistically, data point to a role for vitamin
  D in the development of self-toleranc
• 1,25-dihydroxy vitamin D3 regulates T helper cell
  (Th1) and dendritic cell function while inducing
  regulatory T-cell function. The net result is
  decreased Th1-driven autoimmune response and
  reduced severity of symptoms.

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Inflammatory diseases

• Arthritis
• Rheumatoid
• Uric acid
• Bowel diseases
• Crohns disease
• Ulcerative colitis
• Celiac disease
• Skin diseases - atopic dermatitis psoriasis
• Allergies
• Obesity
• Diabetes type 1 and 2?
• Atherosclerosis

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Urinsyregikt

• Klinisk syndrom som skyldes vevsdeponering av
  Na-urat monohydrat
• Kan deponeres i
• ledd --gt inflammasjon ødelegger ledd
• bløtdeler (tofi etter ca 10 år) uten inflammasjon
• Plutselig smerte i et ledd uex (1.tås gr ledd)
• Komplette remisjon, men nye anfall gradvis
  hyppigere

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Urinsyregikt 2

• Tofi i brusk, sener bursae
• Diagnose v/uratkrystaller i leddvæske
• Av og til affeksjon av mange ledd. Da må man se
  uratkrystaller i leddvæske
• Ingen andre sikre effekter av hyperurikemi enn
  gikt
• pH lt 5.7 --gt urinsyre (lite løselig), ellers urat

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Årlig insidens av urinsyregikt
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Behandling

• Kolchisin
• Diaré, langsom ulik tid til effekt inntrår
• NSAIDS Cox2-hemmere
• Brukes mye og har god smertelindrende effekt
• Kortikosteroider
• God effekt, men kjente bivirkninger ved langvarig
  bruk
• Kostendring/profylakse

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Kolchisin hemmer

• Nøytrofile granulocytters fagocytose av urat ved
  å danne en dimer med tubulin --gt urat kommer ikke
  til lysosomene
• Frigjøring av kjemotaktiske faktorer Mobilitet
  adhesjon av polymorfnukleære granulocytter
• Tyrosin fosforylering
• Dannelse av LTB4

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NSAIDs/Cox2 hemmere steroider

• Meget effektive i å redusere smerten (innen 2 -4
  t)
• Tas raskt etter de første symptomene
• Kortikosteroider
• Meget effektivt v/njiseksjon i leddene
• Brukes når kolchisin Cox2 hemmere er uvirksomme
  eller kontraindisert

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Risiko for hyperuricemi

• Økt nedbrytning av ATP --gt AMP --gt adenosin
  inosin
• --gt urat
• Inntak av sukrose, alkohol, hard fysisk aktivitet
  hypoksi --gt urat dannelse
• Fedme alkohol-inntak --gt Redusert renal
  ekskresjon
• Øl, innmat, kjøtt, sjømat, sauser, (gjær, sopp,
  spinat, aspargis, blomkål, linser, erter
  bønner) inneholder mye puriner som --gt urat, men
  ikke nødvendigvis fører til økt plasma
  konsentrasjon

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Risiko for hyperuricemi 2

• Redusert ekskresjon av urat
• Nyresvikt
• Tiazider, lav-dose salisylat
• Melkesyre, ketonlegemer, angiotensin
  vasopressin
• Mann gt 35 år, drikker alkohol, er fet, evt. meget
  fysisk aktiv

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Urinsyregikt er assosiert med..

• Fedme
• Diabetes type 2
• Hypertensjon
• Høyt inntak av kjøtt sjømat
• Ikke med totalt protein
• Omvendt assosiert med inntak av melkeprodukter
  Choi HK et al. Arthritis Rheum. 200552283-9

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Profylakse

• Kan forebygge akutte attakker v/små doser av
  kolchisin eller Cox2 hemmere
• Serum urat-nivå lt 360 uM kan forebygge
  urinsyregikt
• Serum urat-nivå lt 300 uM kan bidra til
  resorpsjon av tofi
• Mutasjoner i gener som koder for proteiner av
  betydning for urat-stoffskiftet

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Indikasjon for å senke serum urat-nivået

• Årsaken til hyperurikemi kan ofte ikke fjernes
• Kausal terapi fører ikke serum urat-nivå lt 420 uM
• Pasienten har hatt 2 - 3 anfall av leddsmerter
  eller tofi
• Medikamenter - oftest livslang behandling
• Urikosurika (probenesid sulfopyrazol) --gt økt
  utskillelse av urat (obs. steiner) er best ved
  lav urat-clearance
• Xantin-oksidase (obs allergi) hemmere best v/høy
  urat-produksjon, (men også ved lav
  urat-clearance)
• Kan presipitere nye anfall i ledd nyrer

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Kostbehandling av urinsyregikt

• Tradisjonelt viktig
• Relativt effektive medikamenter har betydd svært
  mye og har tatt over mye av kost-behandlingen
• Følg generelle råd om sunt kosthold
• Urat-innholdet fra ca 1 g/d --gt 100 - 150 mg/d

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Generelle kostråd

• Hold vekten
• Mer av
• grønnsaker
• frukt
• korn
• poteter
• Fisk?
• vann

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Generelle kostråd 2

• Mindre av
• Fete melkeprodukter
• helmelk, smør, fløte, ost
• Fete kjøtt-produkter
• burgere/kjøttkaer
• pølser
• fett kjøtt
• Margariner/oljer
• Pomme frites, kaker (wienerbrød)

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Purin-fattig kost?

• Kjedelig begrenset betydning
• Kan medføre endringer av av serum urat-nivået på
  ca 15
• Kan være nødvendig
• Spar på alkohol (særlig øl?) Choi et al. Alcohol
  intake and risk of incident gout in men a
  prospective study. Lancet. 2004363(9417)1277-81
• Spar på kjøtt sjømat
• Meieri-produkter kan være gynstig Choi et al.
  Purine-rich foods, dairy and protein intake, and
  the risk of gout in men. N Engl J Med.
  20043501093-103
• Høyt væske-inntak

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Diet gout (Medline)http//www.ncbi.nlm.nih.gov/
PubMed/
Choi HK. Dietary risk factors for rheumatic
diseases. Curr Opin Rheumatol. 200517141-6. Pero
nato G. Purine metabolism and hyperuricemic
states. 'The point of view of the
rheumatologist'. Contrib Nephrol. 20051471-21.
Johnson RJ et al. Uric acid, evolution and
primitive cultures. Semin Nephrol. 2005253-8.
Choi HK et al. Purine-rich foods, dairy and
protein intake, and the risk of gout in men. N
Engl J Med. 20043501093-103 Choi HK et al.
Alcohol intake and risk of incident gout in men
a prospective study. Lancet. 2004363(9417)1277-8
1 Lyu LC et al. A case-control study of the
association of diet and obesity with gout in
Taiwan. Am J Clin Nutr. 200378690-701 Harris MD
et al. Gout and hyperuricemia. Am Fam Physician.
199959925-34. Simmonds HA et al. When to
investigate for purine and pyrimidine disorders.
Introduction and review of clinical and
laboratory indications. J Inherit Metab Dis.
199720214-26. Pak CY. Southwestern Internal
Medicine Conference medical management of
nephrolithiasis-a new, simplified approach for
general practice. Am J Med Sci. 1997313215-9.
Emmerson BT. The management of gout. N Engl J
Med. 1996334445-51.
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Some antioxidants in Bing sweet cherries Jacob
et al. Consumption of cherries lowers plasma
urate in healthy women. J Nutr 20031331826-9
Substance measured Concentration (mg/100 g
fresh weight) Hydroxycinnamates 67.9
4.0 Procyanidins 21.7 2.5 Flavanols 34.8
3.9 Anthocyanins 38.0 3.6 Total phenolics
163 9 Vitamin C 18.4 2.3 Antioxidant
capacity (TEAC) µmol TE 211 8 Antioxidant
capacity (FRAP) µmol 170 2 Means SEM TEAC,
Trolox equivalent antioxidant capacity FRAP,
ferric reducing ability of plasma
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Biomarkers in healthy women before after cherry
consumption Jacob et al. Consumption of cherries
lowers plasma urate in healthy women. J Nutr
20031331826-9
Biomarker Baseline 1.5 h 3 h 5 h Plasma urate
µM Cherries 214 13 221 22 203
13 183 15 Grapes 278 25 263 26
257 23 260 21 Strawberries 286 25
280 20 277 25 262 29 Kiwifruit 285
28 256 21 257 23 281 19 Urinary urate
µmol/mmol creatinine 202 13 278 29 350
33 260 17 Plasma CRP mg/L 4.3
2.2 ND 3.1 1.3 3.6 1.6 Nitric oxide
µM 37.4 5.2 ND 31 2.9 32 2.1 ORAC
µmol TE/L 531 37 628 37 681 24 711
27 FRAP µM 454 23 432 21 403 14
414 21 Ascorbic acid µM 65.4 5.6 74.5
5.6 71.8 6.0 68.2 5.2 Different from
baseline, P lt 0.05 Significant decrease over
time, P lt 0.05 ND, no data ORAC, oxygen radical
absorbing capacity (lipophilic) FRAP, ferric
reducing ability of plasma TE, Trolox
equivalents/L
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Mechanisms of action for polyunsaturated fatty
acids
Platelets
W blood cell
Chemotactic agent


n-3
n-3
1) Eicosanoids

2) Substrate for enzymes
COOH
CH3
COOH
CH3


3) Peroxidation
Red blood cells


4) Membrane- flexibility
more flexible



5) Acylation of proteins
FA
Protein
membrane

FA


6) Transcription factors
Nucleus
DNA
Promoter
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Synthesis of essential fatty acids
n-3 fatty acids
n-6 fatty acids
Enzymes
??
Linoleic 182
?-Linolenic 183 ?
6-desaturase ?-Linolenic 183
Octadecatetraenoic 184
elongase Dihomo-?-linolenic 203
Eicosatetraenoic 204 ?
5-desaturase Arachidonic 204
Eicosapentaenoic 205
elongase Adrenic 224
Docosapentaenoic 225
elongase Tetracosatetraenoic 244
Tetracosapentaenoic 245
? 6-desaturase Tetracosapentaenoic 245
Tetracosahexaenoic 246
?-oxidation Docosapentaenoic 225
Docosahexaenoic 226
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Synthesis of eicosanoids

AA (EPA) in phospholipid /diacylglycerol
5- lipoxygenase
12- lipoxygenase
12-OH-acids


Arachidonic acid (EPA)
Leucotriene LTA4 (LTA5)
cyclooxygenase
Leucotriene
Cyclic endoperoxides
LTB4(LTB5) LTC4(LTC5)

different enzymes
LTD4(LTD5)
Prostaglandine Prostacycline Thromboxane
LTE4(LTE5)
PGE2(PGE3) PGI2(PGI3) TXA2(TXA3)
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Biological effects of eicosanoids
Fatty acid AA EPA AA EPA AA EPA Enzyme Cell
type Eicosanoids TXA2 TXA3 PGI2 PGI3 LTB4 LTB
5
Lipoxigenase
Cyclooxigenase
Endotelial cells
Platelets
Leucocytes
BIOLOGIC EFFECT Aggregation
Antiaggregation Vasoconstriction
Vasodilatation Chemotaxis

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Inflammation n-3 fatty acids

• Cell culture biochemical studies
• Little epidemiology
• Inuits have little inflammatory diseases
• Clinical trials
• Rheumatoid arthritis
• Psoriasis
• Atopic dermatitis
• Crohns disease
• IgA nephropathy

39
Skin inflammations n-3 FA

• Psoriasis - most likely no effect of n-3 FA
• Søyland et al. N Engl J Med. 1993 328 1812-1816
• Atopic dermatitis - perhaps an effect of n-3 FA
• Bjørneboe et al. Br J Dermatol 1987 117 463-469
• Søyland et al. Br J Dermatol 1994 130 757-764

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Effect of dietary supplementation with
eicosapenta-enoic acid in the treatment of atopic
dermatitisBjørneboe A et al. Br J Dermatol.
1987, 117463-9

• The effects of a dietary supplement of n-3 fatty
  acids in patients with atopic dermatitis were
  investigated in a 12-week, double-blind study
• The experimental group(16) received 10 g of fish
  oil daily, of which about 1.8 g was
  eicosapentaenoic acid. This amount of
  eicosapentaenoic acid can be obtained from a
  daily intake of fat fish. The controls (15)
  received an iso-energetic placebo supplement
  containing olive oil. Compliance was monitored by
  gas-chromatographic analysis of the fatty acid
  pattern in serum phospholipids
• Results favoured the experimental group with
  regard to scale (P less than 0.05), itch (P less
  than 0.05) and overall subjective severity (P
  less than 0.02) as compared to the controls

41
Dietary supplementation with very long-chain n-3
fatty acids in patients with atopic dermatitis. A
double-blind, multicentre study Søyland E et
al. Br J Dermatol. 1994, 130757-64

• Lasting 4 months, during wintertime, 145 patients
  with moderate to severe atopic dermatitis were
  assigned to receive either 6 g/day of
  concentrated n-3 fatty acids, or an isoenergetic
  amount of corn oil. As local treatment, only an
  emollient cream or hydrocortisone cream was
  allowed.
• The overall clinical score, as evaluated by the
  physicians, improved during the trial by 30 in
  the fish oil (P lt 0.001) and 24 in the corn oil
  group (P lt 0.001). This was also consistent with
  the results from a selected skin area, and it was
  further confirmed by the total subjective
  clinical score reported by the patients
• No significant differences in the clinical scores
  between the two groups at baseline, and at the
  end of the study
• In the fish oil group, the amount of n-3 fatty
  acids in serum phospholipids was significantly
  increased at the end of the trial, compared with
  pretreatment values (P lt 0.001), whereas the
  level of n-6 fatty acids was decreased (P lt 0.001)

42
Effect of dietary supplementation with
very-long-chain n-3 fatty acids in patients with
psoriasis Søyland E et al. N Engl J Med. 1993,
3281812-6

• 4 m double-blind, multicenter trial, with 145
  patients (moderate-to-severe psoriasis) received
  either highly purified ethyl esters of n-3 FA
  containing 5 g of EPA and DHA acid) or an
  isoenergetic amount of corn oil containing mainly
  n-6 fatty acids. All patients were advised to
  reduce their intake of saturated fatty acids
• In the fish-oil group, n-3 fatty acids were
  increased in serum PL (P lt 0.001), the ratio of
  AA to EPA acid decreased (P lt 0.001), and the
  level of n-6 fatty acids decreased (P lt 0.001).
  In the corn-oil group, only DHA increased (P lt
  0.05)
• Psoriasis Area and Severity Index (physicians) or
  subjective score did not change during the trial
  in either group There was no difference in
  clinical manifestations between groups
• Among patients in the fish-oil group, increased
  concentration of n-3 FA in serum PL not
  accompanied by clinical improvement, whereas in
  the corn-oil group there was significant
  correlation between clinical improvement and
  increase in EPA and total n-3 FA
• Dietary supplementation with marine n-3 FA was no
  better than corn-oil supplementation. Clinical
  improvement was not correlated with increase in
  concentration of n-3 FA in serum PL among the
  patients in the fish-oil group, whereas there was
  a significant correlation between clinical
  improvement and an increase in EPA and total n-3
  FA in the corn-oil group

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A double-blind, randomized, placebo-controlled
trial of n-3 versus n-6 fatty acid-based lipid
infusion in atopic dermatitisMayser P et al. J
Parenter Enteral Nutr. 2002, 26151-8

• In a 10-day double-blind, randomized,
  placebo-controlled trial, 22 patients
  hospitalized for moderate-to-severe atopic
  dermatitis were randomly assigned to receive
  daily infusions of either n-3 fatty acid-based
  lipid emulsion (fish oil, 10 200 mL/d) or a
  n-6-lipid emulsion (soybean oil, 10 200 mL/d)
• 20 patients completed the trial
• Marked improvement from baseline in both groups
• On days 6, 7, 8, and 10, disease severity
  score-defined as the sum of all scores-was more
  pronounced (p lt .05) in the n-3 group than the
  n-6 group
• Free AA in plasma did not change in any group,
  whereas EPA, and the membrane EPA/AA ratio
  markedly increased due to n-3-lipid infusion
• EPA-derived lipid mediators appeared, whereas
  lymphocyte functions were unaffected
• In the post-treatment period (2/4 weeks), relapse
  was observed in some patients after n-3
  psoralene-ultraviolet A (PUVA) infusion, whereas
  there was a marked long-term improvement in the
  n-6 group
• CONCLUSIONS Iv n-3-fatty acid acutely improves
  the severity of atopic dermatitis. The long-term
  beneficial effects of iv n-6 fatty acids should
  be evaluated further

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Gamma-linolenic acid supplementation for
prophylaxis of atopic dermatitis-a randomized
controlled trial in infants at high familial risk
(van Gool CJ et alAm J Clin Nutr. 2003, 77943-51)

• Double-blind, randomized, placebo-controlled
  trial, formula-fed infants (n 118) with a
  maternal history of atopic disease received
  borage oil supplement (containing 100 mg GLA) or
  sunflower oil supplement as a placebo daily for
  the first 6 mo of life.
• The intention-to-treat analysis showed a
  favorable trend for severity of atopic dermatitis
  associated with GLA supplementation ( x/- SD
  SCORAD 6.32 /- 5.32) in the GLA-supplemented
  group as compared with 8.28 /- 6.54 in the
  placebo group (P 0.09 P 0.06 after
  adjustment for total serum IgE at baseline, age 1
  wk), but no significant effects on the other
  atopic outcomes.
• The increase in GLA concentrations in plasma
  phospholipids between baseline and 3 m was
  negatively associated with the severity of atopic
  dermatitis at 1 y (Spearman's correlation
  coefficient -0.233, P 0.013)
• CONCLUSION Early supplementation with GLA in
  children at high familial risk does not prevent
  the expression of atopy as reflected by total
  serum IgE, but it tends to alleviate the severity
  of atopic dermatitis in later infancy in these
  children

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IgA nephropathy

• Most common glomerulonephritis
• Affects mostly young adults
• 20-40 gets chronic renal failure
• Two studies showed that treatment stabilized
  renal function, and two reported a decline in
  renal function
• A meta-analysis of these 4 randomized trials plus
  a small, nonrandomized study showed that the
  probability of a minor beneficial effect on the
  preservation of renal function was 75 (Dillon
  JJ. Fish oil therapy for IgA nephropathy
  efficacy and interstudy variability. J Am Soc
  Nephrol 199781739-1744)

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Intestinal inflammations

• Crohns disease, ulcerous necrotising colitis
• In two studies Crohn patients in remission
  received n-3 fatty acids or control treatment for
  up to 1 year. In one study a significant positive
  effect of n-3 fatty acids was observed by reduced
  rate of relapse. No significant effect in the
  other study
• Controversial, but positive conclusion
• Belluzzi A. N-3 fatty acids for the treatment
  of inflammatory bowel diseases. Proc Nutr Soc.
  2002 61391-395 .. studies suggest the
  effectiveness of these new therapeutic
  approaches, not only when conventional treatment
  fails or when it is not possible to treat
  chronically, but also, in some instances, as
  first choice

47
Transplantations

• Heart
• Holm et al. Eur Heart J 200122428-36. 3.4 g/d
  n-3 fatty acids may reduce the long-term
  continuous rise in blood pressure retain renal
  function 1-12 y after heart transplantation
• Holm et al. Transplantation 2001, 2772706-113.4
  g/d n-3 fatty acids in HTx recipients increased
  plasma TNFa reduced IL-10 in an inflammatory
  direction, possibly related to prooxidative
  effects of these fatty acids
• Kidney
• Busnach et al. J Nephrol 19981187-93. After 12
  m 6 g/d of n-3 FA --gt lower creatinine than
  controls (1.26 /- 0.06 vs. 1.88 /- 0.2 mg/dl, p
  lt 0.05), comparable Cyclosporin A dosage, and a
  larger CyA area under the curve (n.s.), with a
  higher blood peak level (Cmax) (p lt 0.04) and
  less variance in time to peak (n.s.)

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49
Obesity, diabetes and immunity

• Christian A. Drevon
• Department of nutrition, Institute of Basic
  Medical Sciences, University of Oslo

50
Metabolsk syndrom, syndrom X, tromboaterogent
syndrom

• Meget vanlig, økende forekomst
• Karakterisert ved ikke optimal livsstil
• Overvekt, abdominal
• BT
• Dyslipidemi
• Redusert insulinfølsomhet
• (Lav fysisk aktivitet)
• (Røyking)
• (Inflammasjon - lavgradig)

51
Inflammation energy metabolism

• Energy surplus --gt inflammation CRP, TNF-alpha,
  IL-6 and sICAM-1 (soluble intercellular
  cell-adhesion molecule-1
• Adipokines include several inflammatory molecules
• Fasting --gt reduced inflammation Sharman
  Volek. Weight loss leads to reductions in
  inflammatory biomarkers after a
  very-low-carbohydrate diet and a low-fat diet in
  overweight men. Clin Sci (Lond). 2004107365-9
  longevity
• Leptin is important for the immune response
• Diabetes type 1 is inflammation in b-cells
  (autoimmune?)
• Diabetes type 2 - low degree of inflammation due
  to energy surplus

52
Adipose tissue functions

• Energy store (fatty acids) - large efficient
• Storage of cholesterol, vitamin D E
• Insulation - thermic, mechanical electrical
• Metabolic control - brown adipocyte (heat)
• Immune function -TH2 cells, cross-talk with
  immune cells
• Endocrine organ - adipokines

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Adipokines - bioactive proteins from white
adipocytes

• TNFa - FFA release,glucose-transport
• Leptin - food intake, FA-oxydation, growth factor
• Resistin - diabetes? Inflammasjon?
• Adiponectin - diabetes, fettsyre-oksidasjon
• Adipsin - fettvevslagring clearance av TAG fra
  plasma?
• Komplement C3- TAG syntese glukose transport
• Angiotensin - blodtrykksregulering
• IL-6 KO --gt fedme
• Plasminogen aktivator inhibitor (PAI)-1
• Metalloproteiner - Zn-homeostase,
  tungmetall-detox, antiox, angiogenese
• Retinol bindende protein (RBP)

54
galanin receptors
IL-1, IL-1Ra
Lafontan M. Annu Rev Pharmacol Toxicol. 2004 Sep
7 Epub
55
Leptin levels are associated with immune response
in malnourished infants Palacio A et al. J Clin
Endocrinol Metab. 2002873040-6

• Circulating leptin levels, proinflammatory and T
  helper cells type 1 (Th1), Th2 cytokine
  production, and lymphoproliferative response were
  measured in 15 infants with primary moderate
  malnutrition on admission and after recovery of
  10 of weight
• 16 healthy, well nourished infants of comparable
  age served as controls
• Deficit in the z-score of weight for age, weight
  for height, body mass index, and circulating
  leptin and growth factors in malnourished infants
  on admission compared with controls (P lt 0.05),
  associated with suppression of the
  lymphoproliferative response, Th1, and
  proinflammatory cytokine production (P lt 0.05)
• After a 10 weight gain, --gt increased
  circulating leptin levels parallel with increased
  Th1 activity,and enhancement in interferon-gamma
  and suppression of IL-4 production
• The lymphoproliferative response became similar
  to that detected in control infants
• Significant increase in IL-1 and TNFalpha
  production compared with that at admission
• These findings suggest an association between the
  increase in leptin and the immunological recovery
  observed following refeeding of malnourished
  infants

56
Omega-3 fatty acids - mechanisms of action for
lowering of
postprandial plasma triacylglycerol (TAG) and
free fatty acids
L
i
v
e
r
5
Oxidation
FFA
Omega-3 FA
TAG
TG
Intestine
FFA
4
8
Adipose tissue
TAG
VLDL
2
TAG
MG
Lipolysis
TAG

3
1
FFA
FFA
CM
7
FFA
Oxidation
Excretion
M
u
s
c
l
e
Oxidation of glucose
B
l
o
o
d
6
57
Development of atherosclerosis and interaction
with omega-3 fatty acids
Monocytes
Blood
Platelets
HDL
LDL
Endothelium
0
Intima
Intima
Smooth muscle cells
Macrophages with cholesterol (foam cells)
58
Influence of omega-3 fatty acids on modification
of LDL
Uptake by macrophages (foam cells)
Omega-3 fatty acids
4
Chemotactic
White blood cells
2
Reactive oxygen species
3
3
Oxidized LDL
Pro-oxidants

Cytotoxic
Modulates cytokines, growth factors and
eicosanoids
1
Antioxidants
-
Native LDL
59
Fatty acids plasma cholesterol
?cholesterol mM 120 0.03 140
0.12 160 0.05 TransMarin 0.035 TransVeg
0.026 181 - 0.003 182/3 - 0.015
?LDLcholesterol mM 0.03 0.14 0.04
0.04 0.037 - 0.006 - 0.015
60
Dietary lipids
61
Dietary advice 1

• Keep energy balance
• High intake of
• vegetables
• fruits
• grain
• potatoes
• fish
• water

62
Dietary advice 2

• Low intake
• Margarines/oils
• French fries
• Fatty milk products
• whole milk, butter, cream, cheese
• Fatty meat products
• burgers
• sausages
• fatty meat