10 Nutrition and ulcerative colitis

10

Nutrition and ulcerative colitis

ANN BURKE MB, BCh, BAO Fellow in Gastroenterology Department of Medicine, Division of Gastroenterolog)

GARY R. LICHTENSTEIN MD

Assistant Professor of Medicine, Director of IBD Program Department of Medicine, Divisiun of Gastroenterology

JOHN L. ROMBEAU” MD Professor of Surgery Department qf Surgery

Director Harrison Surgical Nutrition Research Laboratoq

Hospital of the Universiv of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA

The role of diet in the aetiology and pathogenesis of ulcerative colitis (UC) remains uncertain. Impaired utilization by colonocytes of butyrate, a product of bacterial fermentation of dietary carbohydrates escaping digestion, ma9 be important. Sulphur-fermenting bacteria may be involved in this impaired utilization. Oxidative stress probably mediates tissue injury but is probably not of causative importance. Patients with UC are prone to malnutrition and its detrimental effects. However, there is no role for total parenteral nutrition and bowel rest as primary therapy for UC. The maintenance of adequate nutrition is very important, particularly in the peri-operative patient. In the absence of massive bleeding, perforation, toxic megacolon or obstruction, enteral rather than parenteral nutrition should be the mode of choice. Nutrients may be beneficial as adjuvant therapy. Butyrate enemas have improved patients with otherwise recalcitrant distal colitis in small studies. Non-cellulose fibre supplements are of benefit in rats with experimental colitis. Eicosapentaenoic acid in fish oil has a steroid-sparing effect which, although modest, is important, particularly in terms of reducing the risk of osteoporosis, but it seems to have no role in the patient with inactive disease. y-Linolenic acid and anti-oxidants also are showing promise. Nutrients may also modify the increased risk of colorectal carcinoma. Oxidative stress can damage tissue DNA but there are no data published at present on possible protection from oral anti-oxidants. Butyrate protects against experimental carcinogenesis in rats with experimental colitis. Folate supplementation is weakly associated with decreased incidence of cancer in UC patients when assessed retro- spectively. Vigilance should be maintained for increased micronutrient requirements and

* Corresponding author

BaiWre k Clinical Gastroenterolopy- 153 -. Vol. 11, No. 1, March 1997

ISBN O-702&23 10-8 0950-3528/97/010153+22 $12.00/00

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154 A. BURKE ET AL

supplements given as appropriate. Calcium and low-dose vitamin D should be given to patients on long-term steroids and folate to those on sulphasalazine.

Key words: ulcerative colitis; butyrate; fish oil; anti-oxidants.

The aim of this review is to analyse critically the role of nutrition in ulcerative colitis (UC). The roles for diet in the aetiology of UC and in its treatment and in the maintenance of nutrition in the patient, as well as the possibility of using nutrition as a therapy, will be addressed. The roles of nutrition in colorectal cancer, micronutrients and interaction of drugs and nutrition as they pertain to UC will also be discussed.

ROLE OF NUTRITION IN THE PATHOGENESIS OF UC

The aetiology of idiopathic inflammatory bowel disease by definition remains unknown. Because it is an enteric condition it is logical to consider diet as a possible aetiological factor. Several studies on the relationship of diet and inflammatory bowel disease have been undertaken but have not been particularly conclusive. The relevant diet may have occurred years prior to the onset of disease, and information from recalled dietary intake is unreliable. Whether dietary factors are aetiological, consequential or coincidental to inflammatory bowel disease is unknown (Sandler, 1993) Anumber of possible effects of diet on the pathogenesis of UC will be explored (Figure 1).

Butyrate

One of the many theories is that of the ‘starving colonocyte’ as proposed by Roediger (1990). Butyrate is the main fuel of the colonocyte (Roediger, 1980b) just as glutamine is the main oxidizable substrate of the enterocyte. Unlike other organs, the intestine receives its nutrients from both luminal as well as vascular sources. Indeed, 70% of the fuel requirements of the colonic mucosa are derived from butyrate and other short-chain fatty acids (SCFAs) which are the products of fermentation of dietary fibre and undigested starch by the anaerobic intestinal flora (Roediger, 1990). Concentrations of butyrate in the serum are negligible (Cummings et al, 1987) suggesting the colonocytes must obtain butyrate primarily from the lumen. The distal colon is less able than the proximal colon to utilize other fuels, a finding in keep- ing with the distribution of UC affecting distal bowel first and extending proximally. In isolated human colonocytes cultured in the presence of adequate butyrate, the percentage of oxygen consumption attributable to the utilization of n-butyrate was 73% for ascending colon and 75% for descend- ing colon (Roediger, 1980b). In the absence of butyrate but in the presence of glucose, the percentage oxygen consumption attributable to the utilization of glucose was 80% for ascending colon colonocytes and 30% for descend- ing colon colonocytes. In the presence of adequate glucose and 10mM butyrate, these decreased to 41% and 16%, respectively.

Diversion colitis, which occurs in some patients in the colonic segments

NUTRITION AND ULCERATIVE COLITIS 155

Normal colonocyte Plentiful fibre is fermented by colonic microflora to yield adequate amounts of butyrate. N-3 fatty acids modulate the potency of inflammatory cytakines. Less chemotaxis leads to less neutrophll activity. Antiwdants limit damage from free radicals.

Diseased colonocyte Scant flbre yields smaller amounts of butyrate. Its utilization is impaired by the effects of sulphate reducing bacteria. N-6 fany acids are convertad into potent cytokines. Activated neutrophils release free radicals which are not neutralized due to the lack of free radical scavengers.

Figure 1. Possible nutrient mediated mechanism in the pathogenesis of ulcerative colitis.

diverted from the faecal stream by surgery, when extensive, has an endo- scopic appearance indistinguishable from UC. Other than the absence of crypt abscesses its histological appearance is also quite similar (Komorowski, 1990). SCFA enemas instilled twice daily into the colon over a 6-week period, in open-label studies, improved diversion colitis in four patients (Harig et al, 1989). However, a 2-week trial in a double-blind study did not demonstrate efficacy (Guillemot et al, 1991), perhaps because the duration of the treatment was too short (Roediger, 1992). Colonocytes cultured from patients with quiescent UC demonstrate impaired utilization of butyrate. By measuring the rate of CO, production, Chapman et al (1994) demonstrated butyrate utilization in normal specimens to be almost double that in UC specimens obtained at endoscopy from normal-appearing colon in asympto- matic patients with quiescent colitis. The rates of utilization of glutamine and glucose were the same in normal and patient specimens and were much lower than that of butyrate. This confirmed the earlier work of Roediger (1980a), which had been called into question because of doubt about the viability of the cell suspensions. However, another study of a similar design failed to show differences in butyrate utilization in UC (Florin et al, 1991).

156 A. BURKE ET AL

Sulphides

Removal of oxygen to achieve an anaerobic environment within the colonic lumen is facilitated by the presence of reducing agents most of which contain sulphur, mercaptides, such as hydrogen sulphide (H,S), methanethiol and mercaptoacetate. Sulphur for fermentation in the colon is derived from transmural extraction mainly as sulphated mucopoly- saccharides, or from dietary sources including amino acids and crnciferous vegetables (Roediger et al, 1993a).

Limited attention has been given to the injurious nature of H,S to colonocytes. The colon contains levels of H,S that would be highly toxic to lung or brain (Roediger et al, 1993b). Colonocytes contain the highest activity of S-methyltransferase of all bodily tissues (Weiseger et al, 1990). This enzyme acts on S-adenosyl-L-methionine (SAM) to methylate sulphide to methanethiol, which is six times less toxic than sulphide to colonocytes (Roediger et al, 1993b). Exogenous methionine strongly increases SAM levels (Eloranta, 1977). Mercaptides inhibit butyrate but not glucose oxidation by colonocytes at concentrations of 5 mmol/l, which is a level found in the colonic lumen. This effect was more marked in colonocytes taken from the distal colon than from the proximal colon (Roediger et al, 1993a). It confirmed studies done earlier in animals (Roediger and Nance, 1990). The mechanism whereby sulphides impair butyrate utilization is unclear but may be via the interaction with coenzyme-A to form a coenzyme-A-persulphite complex, which inhibits SCFA dehydrogenases and impairs ketogenesis from butyrate. Cell membranes of colonocytes in UC show structural abnormalities which are specific to the disease and which suggest impaired lipogenesis in colonocytes. Lipogenesis from butyrate, by cultured colonocytes, is stimulated by the presence of glucose, an effect which is reversed by mercaptoacetate. This in turn was reversed by 5-amino salicylic acid (5-ASA). The mechanism by which this is achieved is unclear. Altered cell membranes may lead to altered barrier function, a feature of UC (Roediger et al, 1992).

Luminal levels of sulphides are significantly higher in patients with UC compared with controls (Florin et al, 1990; Gibson et al, 1991). The increasing sensitivity of more distal than proximal mucosa to the effects of mercaptides and the impaired utilization of butyrate caused by mercaptides, an effect which is reversible, are all compatible with the clinical observations of UC and suggest that mercaptides may play a role in the pathogenesis of UC (Roediger et al, 1993a). Sulphate-reducing bacteria were detected in the faeces from 96% of UC patients studied compared to 75% of controls (P= 0.02) (Velazquez et al, 1996a). Dietary intake and intestinal absorption are the main factors which affect the amount of sulphate entering the colon (Florin et al, 199 1). There are no published data on manipulating dietary intake of sulphates in UC.

Oxidant injury

Various studies have showed evidence of oxidative stress in the colon in UC


(Ahnfelt-Ronne et al, 1990; Yamada and Grisham, 1993; Grisham, 1994) as well as an impaired ability to counteract this oxidative injury (Bhaskar et al, 1995; Buffington and Doe, 1995). Yet the evidence for a direct causative role of oxidative stress in inflammatory bowel disease remains circumstantial. Other than one anecdotal report of remission with high doses of vitamin E in conjunction with iron (Bennet, 1986) and relapse on discontinuing it, there are no published data on the effects of dietary pro- or antioxidants on UC. In this case report, it was proposed that the iron complexed with the vitamin E to produce a-tocopherylquinone (a-TQ) and it is likely that the a-TQ was functioning as an anti-oxidant (Guthy, 1986). Whereas it is possible that oxidative stress is involved in mediating the injury of UC (and will be discussed later in this regard) it is less likely that it is of direct aetiological importance.

Pantothenic acid

In pigs, pantothenic acid deficiency produces a colitis resembling human UC. With supplementation, symptoms resolve rapidly, although histological changes are slower to improve (Wintrobe et al, 1943). The colitis is associated with low tissue levels of coenzyme-A. This is the active form of pantothenic acid (Nelson, 1968) and is involved in ketogenesis from butyrate by the colonocyte. Low tissue levels of coenzyme A have been found in the mucosa of UC patients despite normal serum and tissue levels of pantothenic acid (Ellestad-Sayed et al, 1976).

NUTRITION AS PRIMARY THERAPY FOR UC

The development of total parenteral nutrition (TPN) has permitted provision of long-term nutrients to a patient with a non-functioning bowel or to bypass the bowel to allow it to rest. Two early studies showed a potential benefit from TPN as primary therapy in ulcerative colitis but they had only five patients each and were retrospective, uncontrolled studies (Dean et al, 1976; Fazio et al, 1976). Subsequent, larger retrospective studies were less promising, with over half of the patients requiring surgery during the initial hospitalization and many of the others relapsing after discharge (Fischer et al, 1973; Reilly et al, 1976; Harford and Fazio, 1978; Mullen et al, 1978; Hanauer et al, 1984). (Table 1). These have been reviewed and summarized many times (Afonso and Rombeau, 1990; Bartels et al, 1995; Gassull et al, 1995). The randomized prospective studies by Dickson (Dickson et al, 1980) and McIntyre (McIntyre et al, 1986) finally laid to rest any question of TPN and bowel rest as primary therapy for UC. They showed no significant differences in remission or surgery rates in 36 and 27 acute UC patients respectively, compared to controls. They concluded that TPN is not indicated as primary therapy for UC. Dickson’s study (Dickson et al, 1980) did indicate that TPN provided a nutritional benefit to the study patients. This occurred at a cost of significant complications in three of 20 patients receiving TPN (one haemothorax, one pneumothorax and one catheter-related sepsis).

Table

1.

Total

pa

rente

ral

nutri

tion

for

ulcer

ative

co

litis.

Refer

ence

St

udy

type

UC

Total

no

. of

patie

nts

Contr

ols

Mean

fo

llow

Comp

licati

ons

of G

IBD

patie

nts

with

TP

N for

TPN

St

eroid

s up

per

iod

Outco

me

TPN

(all

patie

nts)*

Go

Dean

et a

l (19

76)

Mulle

n et

al (1

978)

Re

trosp

ectiv

e

Reilly

et

al (1

976)

Re

trosp

ectiv

e

Fisch

er et

al (1

973)

Re

trosp

ectiv

e

Hana

uer

et al

(198

4)

Retro

spec

tive

Fazio

et

al (1

976)

; se

e Ha

rford

an

d Fa

zlo

( 197

8)

Retro

spec

tive

Harfo

rd

and

Fazio

(1

978)

Fo

llow-

up

of fiv

e su

cces

ses

in ab

ove

study

Elso

n et

al (1

980)

Pr

ospe

ctive

no

n-ra

ndom

Dick

son

et al

(I 98

0)

Pros

pecti

ve

rand

omize

d

Retro

spec

tive

McInt

yre

et al

(198

6)

Pros

pecti

ve

rand

omize

d

16

5 NO

llfZ

74

24

34

II

13

4

38

38

71

s

5 s

30

IO

36

13

47

IS

None

None

None

None

None

None

NOlIe

14

I2

‘As

Indica

ted’

Hosp

ital

stay

‘Ofte

n’

‘Mos

t’ ?A

ll

All

N/A

N/A

N/A

All

All

All

6-12

0 mo

nths

Hosp

ital

stay

>6 m

onths

27 m

onths

Hosp

ital

stay

741

month

s

I surg

ery

I che

st tub

e

IS s

urgery

5

relap

ses

IO s

urgery

3 su

rgery

I9 su

rgery

4 re

lapse

d+su

rger

y

I surg

ery

(add

itiona

l pa

tient

on

adju

vant

TPN

impr

oved

en

ough

to

avoid

op

)

2 su

rgery

3 re

lapse

s no

surg

ery

Up t

o 43

mon

ths

6 su

rgery

3 re

lapse

s (I

surge

ry)

I.311

ye

ars

TPN

7 su

rgery

5 re

lapse

(2

surge

ry)

Contr

ol 6

surge

ry (I

died)

; 3

relap

se

(2 su

rgery)

43

TPN

9 su

rgery

(I die

d)

4 re

lapse

Co

ntrol

5 su

rgery

(2 die

d)

4 re

lapse

?

I pne

umoth

orax

I c

andid

a se

psisA

ied

3 pn

eumo

thora

x 3

line

infec

tion

2 pn

eumo

thora

x 6

line

infec

tion-

l die

d I s

uhcla

vian

vein

thr.

I pne

umoth

orax

2

line

infec

tion

N/A

2 pn

eumo

thora

x I e

xtrav

asati

on

1 sub

clavia

n ve

in thr

. 1 d

eath

(C

NS

embo

lus)

none

4 lin

e inf

ectio

n I a

ir em

bolus

I

PE

I pne

umoth

orax

I h

aemo

thora

x I l

ine s

epsis

> I p

neum

othor

ax

z i m N/

A No

t av

ailab

le.

* No

t inc

luding

me

taboh

c co

mplic

ation

s. t

Four

of eig

ht

requ

ired

surge

ry.

4 k r


NUTRITION AS ADJUVANT THERAPY FOR UC

Indications for total parenteral or enteral nutrition in UC

Malnutrition is common in UC even though it may not be as severe or as frequent as with Crohn’s disease (Seidman, 1989). Weight loss occurs in 18-62% of adults. Ten per cent of children with UC experience growth failure and 20% pubertal delay. UC patients tend to present relatively acutely while still in a state of adequate nutrition which deteriorates if nutrition, sufficient to meet the increased needs of the patient, is not provided (Gassull et al, 1996). Nutrient .intake is often decreased in UC patients because they restrict food to avoid diarrhoea or are required to fast for various investigative studies. Every day of fasting produces a negative nitrogen balance for which 3-5 days of optimal nutrition are needed to repair (ASPEN Board of Directors, 1986). Acute attacks are associated with increased protein loss from the gastrointestinal tract (Stuart Welch et al, 1937; Powell-Tuck, 1986) while at the same time the increased circulating levels of inflammatory mediators interfere with appetite and protein intake (Powell-Tuck, 1986). It is because of this that enteral supplements can be effective where oral nutrition fails (Gassull et al, 1996).

Most previously healthy adults can tolerate weight loss of 5-10% with little functional consequence (Burress Welbom and Moldawer, 1997). Losses of body weight in excess of 25-30% are associated with significant morbidity. Nutrition-associated complications include death, sepsis, abscess formation and other infections, poor wound healing and respiratory failure. The risk of complications increases with the degree of malnutrition (Detsky et al, 1994). Energy expenditure is increased in active UC (Klein et al, 1988) at a time when intake tends to be reduced. A Subjective Global Assessment using nutrition has been devised by Detsky et al (1987). It is reproducible and correlates well with indicators of hospital morbidity (Baker et al, 1982; Jeejeebhoy et al, 1990). Using a subjective scale comparing multiple indices, a grading of well-nourished, moderate or severe malnutrition can be applied to each individual (Table 2). Patients who are moderately or severely malnourished should receive nutritional support. The assistance of a dietitian is invaluable in formulating appropriate nutritional support. Patients who present with acute severe colitis have a high rate of early surgery. Recognition of malnutrition-related complications and the reduced morbidity associated with the delivery of parenteral nutrition has led to extensive use of nutritional support in the peri-operative period. Despite this, no definite conclusions can be ascertained from the existing data on peri-operative nutrition (Poret and Kudsk, 1990). The American Society for Parenteral and Enteral Nutrition has published guidelines (ASPEN Board of Directors, 1986) which suggest that nutritional support be given if 7-10 days of post-operative starvation is expected in a previously healthy patient, or 5-7 days in a previously malnourished patient, which includes many patients with active UC (Poret and Kudsk, 1990). Patients with severe acute colitis undergoing or likely to undergo colectomy have a high metabolic stress. This occurs in the face of

160 A. BURKE ET AL

protein and blood loss from an inflamed gastrointestinal tract and decreased intake from the anorexia associated with significant inflammation. They are in a group who should receive TPN within l-3 days of fasting. Minimal stress in a well-nourished patient where gastrointestinal function is expected to return within 10 days, such as in a patient with a mild to moderate flare of brief duration, is not an indication for TPN (ASPEN Board of Directors, 1986).

Table 2. Subjective global assessment of nutritional status

Well Moderate Severe Criterion nourished malnutrition malnutrition

Weight loss measured as a percentage of body <5% 5-10% >lO% weight; recent stabilization of weight or recovery of weight lost is also important

Dietary intake is assessed as a percentage of nutritional requirements

100% 70-90% < 70%

GI symptoms

Functional capacity

Loss of subcutaneous fat, assessed at triceps and costal margin in mid-axillary line

None Intermittent Daily, > 2 weeks

At baseline Some limitations Bedridden

None Slight Marked

Loss of muscle bulk, at quadriceps and deltoids None Slight Marked

Peripheral oedema None Slight Marked

Ascites None Slight Marked

Finally, based on the above information but without using any formal scoring system, the patient is assigned a nutritional state of well nourished, moderately malnourished or severely malnourished- the subjective global assessment

Reproduced from Rombeau and Afonso (1992, Inflammatory Bowel Disease, MacDermott RP & Stenson W (eds), pp 525-553, New York: Elsevier) with permission.

Total enteral nutrition or total parenteral nutrition?

Despite studies indicating its lack of efficacy, the temptation remains to use the parenteral rather than the enteral route for alimentation in the UC patient. There is a concern that total enteral nutrition (TEN) will only exacerbate the patient’s diarrhoea and inflammation even though it has already been shown that oral diet is as well tolerated as TPN in acute colitis patients (Dickson et al, 1980; McIntyre et al, 1986). Rats with experimental colitis gained a protective effect when pectin was added to their enteral feed compared to fibre-free enteral nutrition or the same diet given parenterally (Rolandelli et al, 1988). Non-cellulosic fibres are completely fermented in the colon providing short-chain fatty acids without adding bulk. Rao et al (1987) showed that active UC patients have normal fat and xylose absorption and that the diarrhoea is secretory. The introduction of total enteral nutrition (TEN) after 24 hours of fasting was associated with a slight but insignificant increase in diarrhoea and was very well tolerated. The diarrhoea settled as the corticosteroids took effect. They achieved improved nutritional status comparable to that of Dickson’s study. Gonzalez-Huix et


al (1993) also demonstrated equal nutritional improvement with TPN and TEN in inflammatory bowel disease patients with fewer complications in the TEN group. TEN is also considerably less expensive than TPN. Currently, most commercially available enteral supplements contain little or no fibre. Absolute contra-indications to TEN in inflammatory bowel disease are massive haemorrhage, bowel perforation, toxic megacolon and intestinal obstruction (Gassull et al, 1996).

Oral nutrition

Not to be forgotten is the well-balanced healthy diet for the patient with mild to moderate disease who is being managed as an outpatient. It is important to avoid unnecessary dietary restrictions. Many patients put themselves on very restrictive diets to avoid diarrhoea. Lactose intolerance occurs at the same rate in UC patients as in the general population and so lactose need not be restricted routinely. Its prevalence is dependent on race: Northern Europeans 5-15%, African-Americans 45-80%, Asians 90- 100% (Lloyd and Olsen, 1995). There have been no studies demonstrating advantage of soluble or insoluble fibre in UC. In quiescent or mild UC there is probably no reason to avoid fibre and possibly several beneficial effects to support its use. These include the trophic (Fleming and Arce, 1986; Chapman et al, 1994) and anti-inflammatory (Rolandelli et al, 1988) effects that fibre has been shown to have on the colon in rats. In addition, butyrate was demonstrated to inhibit the development of colon cancer in rats (D’Argenio et al, 1996) and to promote the differentiation of several human colon and other cancer cell lines in vitro (Kim et al, 1982; Dexter et al, 1984; Kruh et al, 1991; Young, 1991; Hague et al, 1993). In a double-blind placebo-controlled cross-over study, patients with ulcerative colitis in remission reported improved gastrointestinal symptoms on ispaghula husk compared to controls (Hallert et al, 1991). At the very least, over the 2-month study period no adverse effects were noted. However, more in vivo studies are needed in this area.

SPECIFIC NUTRIENTS AS ADJUVANT THERAPY FOR ULCERATIVE COLITIS

Butyrate

Following its success in the treatment of diversion colitis, several small trials have been performed to assess the impact on UC of butyrate given by enema. The mixed results are reviewed in Chapter 7. Larger prospective trials need to be done to assess its true efficacy. In a rat model, the administration of an enteral diet supplemented with indigestible oligo- saccharide (a putative butyrate precursor) was associated with anti-inflammatory activity that was similar in efficacy to sulphasalazine (Grisham et al, 1996).

162 A. BURKE ET AL

Eicosapentaenoic acid and gamma linolenic acid

A primer in lipids and injlammation

Fatty acids are identified by the number of carbons (C20) followed by the number of double bonds, (C20:4), followed by the identification of the position of the first double bond, (C20:4 n-6).

The two essential fatty acids are linoleic acid (C 18:2 n-6) and a-linolenic acid (C18:3 n-3) of which the daily requirements are approximately 2.5-5 g of linoleic and 2-3 g of a-linolenic acid per day. By a series of desaturation and elongation steps, linoleic acid is converted to y-linolenic acid (GLA) to dihomo-y-linolenic acid (DHLA) to arachidonic acid (C20:4 n-6), and a- linolenic acid is converted to stearidonic and to eicosapentanoic acid (EPA) (C20:5 n-3) via a C20:4 n-6 intermediary (Rolandelli and Ullrich, 1997) (Figure 2).

Evening Primrose Oil I Fish 011

Li lolipase

pG~~~~ PGI,‘antl-inflammatory PGI,‘anti-inflammatory ver;potent LTBS

TXA, prwnflammatory TXA, pro-Mammatory chemoattractant weak chemo- attractant

Figure 2. Modification of eicosanoids in ulcerative colitis. Phospholipase releases arachidonic acid from the cell membrane. It is converted to prostaglandins of the 2 series by cycle-oxygenase and to leukotrienes of the 4 series by S’lipoxygenase. Supplementing the diet with evening primrose or fish oils enriches the membrane lipid content of GLA and EPA respectively which, in turn, are converted to 1 and 3 series prostaglandins and the EPA is converted to 5 series leukotrienes. PGEI can inhibit the action of phospholipase, so decreasing the release of arachidonic acid, the rate limiting step in PG synthesis. AA = arachidonic acid, DHLA = dihomo-gamma linolenic acid, EPA = eicosapentaenoic acid; GLA = gamma hnolenic acid; LT = leukotriene; PG = prostaglandin; TX = thromboxane.

Arachidonic acid, an o-6 fatty acid, is the substrate of the cyclooxygenase 1 and 2 enzymes which synthesize prostaglandins (PG) of the 2 series e.g. PGE,, PGF,, PGI, and the 5’-lipoxygenase enzymes which synthesize leukotrienes (LT) of the 4 series e.g. LTB, the main neutrophil chemo-attractant in UC (Lobos et al, 1987). These derivatives of arachidonic acid are collectively known as eicosanoids and are important mediators of inflammation. The release of arachidonic acid from membrane phospholipids by phospholipase A, is the rate-limiting step in eicosanoid synthesis. Glucocorticoids generate a membrane-bound protein called


lipocortin which reduces arachidonic acid release and thus reduces the production of all eicosanoids (Schumert et al, 1988). Fish oil is high in the w-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic (DHA) (C22:5 n-3) acid. EPA can act as an alternative substrate for these enzymes to yield LTB,, which is 30 times less potent than LTB, in stimulating neutrophil chemotaxis (Terano et al, 1984; Lee et al, 1985). Moreover, PGI, is synthesized in favour of PGI,. They have approximately the same anti- inflammatory activity, and thromboxane A, (TXA,) is synthesized in preference to the more pro-inflammatory TXA, (Greenfield et al, 1993).

Evening primrose oil and borage oil are high in GLA (C18:3 n-6). GLA is rapidly converted to DHLA (C20:3 n-6) and competes with arachidonic acid for the cycle-oxygenase enzymes yielding prostaglandin PGE, in preference to PGE,. PGE, raises intracellular CAMP which inhibits phospholipase and the release of arachidonic acid from cell membranes (Greenfield et al, 1993). DHLA is converted to its 15-lipoxygenase product which is also anti-inflammatory in that it inhibits the actions of 5-lipoxygenase which is responsible for the synthesis of LTB,.

Fish oil

With improved understanding of the role of eicosanoids in the pathogenesis of inflammation has come an interest in trying to alter this inflammatory response by modifying tissue fatty acid and phospholipid content. A low incidence of UC is noted in Japan where fish consumption is high (Sandler, 1993), but no studies assessing fish consumption in UC have been published. UC is associated with a marked neutrophilic infiltrate in the diseased colon. LTB, is a potent neutrophil chemotactic agent and is the main neutrophil chemo-attractant in UC (Lobos et al, 1987). In patients with UC, concentrations of LTB, and PGE, in rectal dialysates are increased, and the levels correlate with disease activity (Lauritsen et al, 1986). Fish oil increases the concentration of the less potent pro-inflammatory agent LTB, in lieu of LTB, (Terano et al, 1984; Lee et al, 1985). Modulating plasma lipids alters their physical properties. It is possible that EPA could have a beneficial effect independent of leukotrienes. Marotta et al (1995) showed a protective effect of EPA on experimental colitis induced by dextran sulphate in rats. In their study dextran sulphate altered membrane lipids when compared to controls but this alteration did not occur when EPA was given at the same time. Eicosanoid levels were not assessed in this study.

Several studies have been performed to investigate the effects of fish oil supplementation on membrane lipid composition, inflammatory mediators and UC. A case report using intravenous fish oil supplements demonstrated marked increase in tissue EPA and DHA until they exceeded the levels of arachidonic acid. This was associated with LTB, levels greater than LTB, levels, and TXB, levels greater than TXB, levels. This enrichment was maintained only to a minor extent with oral supplements. Colitis activity was decreased during periods of parenteral but not enteral supplementation (Grimminger et al, 1993). Several studies have investigated oral EPA

164 A.BURKE ETAL

supplements, in the form of fish oil capsules, for the treatment of UC (McCall et al, 1989; Salomon et al, 1990; Aslan and Triadafilopoulos, 1992; Hawthorne et al, 1992; Stenson et al, 1992; Greenfield et al, 1993) (Table 3). The results of early open label studies were very promising (McCall et al, 1989; Salomon et al, 1990). Larger, more controlled trials have shown more modest but consistent results. It would seem that in active disease, fish oil supplements have a steroid-sparing effect (Aslan and Triadafilopoulos, 1992; Hawthorne et al, 1992; Stenson et al, 1992), but have no prophylactic effect on quiescent disease to maintain remission (Hawthorne et al, 1992; Greenfield et al, 1993).

Gamma linolenic acid

GLA is present in large quantities in evening primrose oil and borage oil. It has become popular as a ‘health food supplement’ and has been used in small studies in rheumatoid arthritis (Leventhal et al, 1994; DeLuca et al, 199.5). By promoting PGE, in favour of PGE, production, it inhibits arachidonic acid release and eicosanoid synthesis. In 19 patients with mild or quiescent colitis, compared to eight controls, GLA administration led to increased tissue levels of DHLA and improvement in stool consistency in eight patients (Greenfield et al, 1993). This effect was maintained 3 months after discontinuation of GLA. GLA has not been studied in more active disease. GLA improves P-oxidation of fatty acids in the liver in rats (Takada et al, 1994); however, whether it enhances colonocyte P-oxidation of butyrate and other fatty acids is unknown. The possibility also exists that prolonged administration could eventually lead to increased tissue arachidonic acid counteracting its original inhibitory effect (Phinney, 1994). At present, there is no clear evidence to advocate the use of GLA supplementation in UC.

Anti-oxidants

A primer in oxidative stress

A free radical is any chemical species capable of independent existence and containing one or more unpaired electrons (Gutteridge, 1995). Reactive oxygen species are free radicals which contain oxygen, e.g. superoxide anion O,‘-, which is produced during the respiratory burst in the activated neutrophil, and hydroxyl radical *OH, which is many times more potent than the superoxide anion. Reactive oxygen species mediate the injury of inflammation. They are produced enzymatically by activated neutrophils and macrophages and non-enzymatically by the Fenton or Haber-Weiss reaction (Grisham and Granger, 1988; Schumert et al, 1988):

Together

O,‘- + Fe3+ -+ 0, + Fe*+ H,O, + Fe2+ + *OH + OH- + Fe3+

O;- + H,O, + *OH + OH- + 0,

Refer

ence

Ty

pe

of stu

dy

Table

3.

Fish

oil

and

even

ing

prim

rose

oi

l for

ulc

erati

ve

coliti

s.

Numb

er

Wee

ks

of Do

se

of EP

A +

of pa

tients

Pa

tients

on

PO

Dise

ase

study

/trea

tmen

t DH

A (g/

day)

(stud

y/con

trol)

stero

ids/S

-ASA

ac

tivity

Ou

tcome

McCa

ll et

al (1

989)

Op

en

label

12/1

2

Salom

on

et al

(199

0)

Open

lab

el 8/8

Aslan

an

d Do

uble

blind

48

/12

Triad

afilop

oulos

Cr

oss-o

ver

(199

2)

*

Sten

son

et al

(I 99

2)

Doub

le bli

nd

36/l

6 Cr

oss-o

ver

Hawt

horn

e et

al (1

992)

Do

uble

blind

52

/.52

Rand

omize

d Co

ntro

lled

Gree

nfield

et

al (1

993)

Ra

ndom

ized

4314

3 Co

ntro

lled

3-4

+ N/

A

2.7+

1.8

2.7+

I.8

Plac

ebo’1

3.24+

1.2

6 Pl

aceb

oi

4.8 +

I .2

Pl

aceb

o6

l.13+

1.2

2 GL

A 0.2

4 Pl

aceb

o’j

6/6+

I o/o

I l/C

ross-o

ver

24iC

ross-o

ver

46lS

O

1618

I9

on e

venin

g pr

imro

se

oil

04

O/3

Activ

e

S/8

Activ

e

2/l

I Mi

ld-mo

dera

te

6112

Ac

tive

EPA

N/A/

38

Activ

e 56

pla

cebo

N/

A 30

Re

miss

ion

40

media

n pr

ed.

IO m

g in

both

grou

ps

EPA

l/l 1

Mode

rate

1 GL

A l/1

7 Mi

ld 29

co

ntrol

O/4

Remi

ssion

I3

6/6

symp

tomati

c im

prov

e-

ment

at

4 we

eks;

616

in re

miss

ion

at 12

wee

ks

71 IO

sym

ptoma

tic

and

endo

- sc

opic

impr

ovem

ent;

4/5

decre

ased

ste

roid

dose

Daily

ac

tivity

ind

ex

decre

ased

56

%

in EP

A ve

rsus

4%

in co

ntrols

; 8/

l I

decre

ased

or

elimi

- na

ted

other

me

dicati

ons

Impr

oved

his

tolog

y an

d re

ctal

LTB4

co

mpar

ed

to pla

cebo

; 53

%

decre

ase

in ste

roid

requ

ireme

nts

on

EPA

(P =

NS)

Activ

e dis

ease

; me

dian

pred

nison

e do

se

at 2

month

s 0

mg (

EPA)

5

mg

(contr

ol)

(P =

0.01

) re

miss

ion:

no e

ffect

EPA

no e

ffect

GLA

impr

oved

sto

ol co

nsist

ency

* Co

ntrols

we

re

healt

hy

volun

teers

given

EP

A.

i- Pl

aceb

o ole

ic ac

id IO

.3 g,

palm

itic

acid

2. I

g, lin

oleic

acid

I .8

g da

ily.

$ Pl

aceb

o (ve

getab

le oil

) ole

ic ac

id 12

.36

g, pa

lmitic

ac

id 2.5

2 g,

linole

ic ac

id 2.

I6 g

daily

. 8

Plac

ebo

(oliv

e oil

) ole

ic ac

id 72

%,

palm

itic

acid

l2%,

linole

ic ac

id I I

%.

¶ Fis

h oi

l (E

PA

2.25

g/day

+

DHA

I .4S

g/da

y for

I

mont

h,

then

EPA

I. I3

g/day

+

DHA

I .22

g/da

y for

5

month

s).

Even

ing

prim

rose

oi

l (G

LA

0.47

g/day

for

I

mont

h the

n 0.2

4 g/d

ay

for

S mo

nths).

Ol

ive

oil

(plac

ebo)

(o

leic

acid

8.28

g/day

, pa

lmitic

ac

id I .

64 g

/day,

linole

ic ac

id I .

45 g

/day

for

I mo

nth,

the

n 4.1

4, I.3

2 an

d I .

22 g

/day

resp

ectiv

ely,

for

5 mo

nths).

166 A. BURKE ET AL

The identity and availability of in vivo compounds that catalyse the Fenton reaction remain unknown (Grisham and Granger, 1988). However, haem proteins can release chelatable iron that can participate in Fenton chemistry (Gutteridge, 1995). The hydroxyl radical produced by the Fenton reaction is probably the chemical entity which initiates lipid (LH) peroxidation (Gutteridge, 1995):

LH + *OH + L* + H,O

This lipid radical can, in turn, react with molecular oxygen to form a hydroperoxide radical which can attack the next lipid (L’H) and a chain reaction has been set up (Kappus, 1985):

L* + o2 * LOO* LOO* + L’ + L’. + LOOH

Anti-oxidants such as vitamin E (TH), break the chain by forming stable intermediaries which can be further metabolized enzymatically to less harmful products (Kappus, 1985):

L’* + TH -+ LOOH + T*

or by enzymatically removing free radicals (Grisham and Granger, 1988; Kehrer and Lund, 1994):

2 o;- + 2H’

2H20, catalase ) O1 + H,O 2~s~ + H,O, glutathione peroxidz GSSG + 0 ‘7)

2

GSSG + NADPH + II+ glutathione reducta; 2GSH + NADP

Oxidative stress and UC

A direct role for oxidative stress as a pathogenic factor in chronic gut inflammation remains to be defined (Grisham, 1994) but indirect evidence abounds. In UC, activated neutrophils come in contact with chelate iron in stool, ideal for the Fenton reaction (Babbs, 1992). Several studies suggest a role for oxidative stress in UC. Ahnfelt-Ronne, in an elegant paper, demonstrated increased concentration of lipid peroxides in pre-treatment biopsies and normalization with treatment with 5-ASA in 15 patients with UC or Crohn’s colitis (the numbers with each diagnosis were not given) in conjunction with clinical improvement in disease activity (Ahnfelt-Ronne et al, 1990). He also showed that metabolites of 5-ASA formed in vitro by exposure to oxygen free radicals could be demonstrated in the faeces of patients with ulcerative or Crohn’s colitis treated with 5-ASA but not in rheumatoid arthritis patients with normal bowel function. The concentrations of 5-ASA found in normal colonic mucosa (0.1-0.2 mmoV1) are much lower than that required to inhibit cycle-oxygenase and S’lipoxygenase (I-10 mmol/l). Diseased mucosa from patients with UC can achieve levels five-fold normal, which is within the range required to scavenge free


radicals (0.01-0.4 mmol/l). Hydroxyl radicals require higher concentrations of .5-ASA but are largely derived from superoxide radicals which are readily scavenged at 0.01-0.02 mmol/l (Grisham, 1994). Increased lipid peroxidation has also been demonstrated by Sedghi et al (1994). Bhaskar et al (1995) failed to show a significant increase in lipid peroxidation even though the patient levels were twice that of controls, but they used an assay less sensitive than that of Sedghi. Depletion of different colonic antioxidant defences in UC patients has been demonstrated in various studies (Mulder et al, 1991; Fields et al, 1994; Buffington and Doe, 1995). Salim used allopurinol, which is a potent scavenger of hydroxyl radicals and inhibits xanthine oxidase which forms superoxide radicals, and dimethyl sulphoxide (DMSO), which also scavenges hydroxyl radicals in a double- blind randomized controlled study (Salim, 1992). Patients received sulphasalazine alone (51), sulphasalazine and allopurinol (50) or sulphasalazine, a,llopurinol and DMSO for 1 year. The treated groups, compared with controls, had improved remission (84% versus 5 1%) and relapse rates (5% versus 25%). Few studies have been done assessing the role of dietary anti- oxidants in UC. The use of high-dose a-tocopherylquinone (a-TQ), a likely product of vitamin E and iron interaction in vivo, is reported as a personal experience (Bennet, 1986). The author notes marked improvement with a-TQ and relapse within 2-3 days of stopping it. The mechanism of action is unclear but a-TQ does have potent anti-oxidant properties (Guthy, 1986). A study using vitamin C as a single agent in six patients with inactive to moderately active disease showed no effect on clinical parameters or neutrophil chemotaxis over a 6-month period (Hermanowicz et al, 1985). The role of other dietary anti-oxidant manipulations remains to be seen.

UC AND MALIGNANCY

The increased risk of colonic neoplasm with long-standing UC is well known. To date, there is no dietary intervention to alter this risk but a number of interesting possibilities warrant further exploration.

Butyrate

It is over 20 years since Burkitt suggested an association between colorectal cancer and a diet low in fibre (Burkitt, 1973). Some of this effect is possibly mediated by butyrate. Butyrate, although trophic to normal colonic mucosa, has an inhibitory effect on the replication of colon cancer cells in vitro, promoting apoptosis or differentiation (Kim et al, 1982; Dexter et al, 1984; Fleming and Arce, 1986; Kruh et al, 199 1; Young, 199 1; Hague et al, 1993). In an experimental model where colon cancer was induced in colitic rats, butyrate restored depressed transglutaminase levels and decreased the number and surface area of tumours compared with controls (D’Argenio et al, 1996). Transglutaminase is involved in apoptosis and reactions between extracellular matrix proteins. Butyrate alters the gene expression for several proteins, including those inducing transglutamine activity. In another study,

168 A. BURKE ET AL

butyrate decreased the amount of crypt surface proliferation, which, in comparison to crypt base proliferation, is a biomarker of colon cancer risk and increased c-&n expression (Velazquez et al, 1996b). c-&n is the key component of the AP-1 complex which mediates terminal differentiation- a state which, in turn, is associated with growth arrest. Intravenous infusion of butyrate reduced seeding and growth of malignant colorectal cells in vivo in mice (Velazquez et al, 1996a). No studies of sufficient duration have been done to assess possible similar protective effects in humans.

Anti-oxidants

Free radicals are known to mediate carcinogenesis. Indeed, the malignant effect of radiation is via free radical production. No studies have been published assessing a possible anticarcinogenic effect of anti-oxidants in UC.

Folate

In a retrospective study, folate supplementation was associated with a lower incidence of neoplasia in patients with UC (Lashner et al, 1989). A more recent cohort study of 98 patients, although failing to reach statistical significance, supports this, with a relative risk of 0.72 for neoplasia in UC patients taking folate supplements (Lashner et al, 1997). To date, no prospective, published data exist. However, because sulphasalazine impairs folate absorption by > 30%, it is probably wise to provide folate supplements routinely.

Fish oils

It is interesting to note increased levels of cycle-oxygenase-2 (the inducible form) in rat colonic tumours compared to areas of normal tissue in the same animals (DuBois et al, 1996). NSAIDs seem to exert a protective effect in colorectal cancer. The mechanism of this effect is unknown but it would seem not to be due to cycle-oxygenase inhibition (Alberts et al, 1995). That EPA or GLA might exert a similar effect is purely speculative.

MICRONUTRIENTS

The status of various micronutrients in UC is difficult to assess. There are relatively few studies examining this and most do not separate Crohn’s disease, with its small-bowel involvement, from UC. Malnutrition is common in UC, and iron deficiency occurs in two-thirds of patients (Seidman, 1989). Overt manifestations of micronutrient deficiency, other than iron, are rare in UC. Malitolli et al (1988) report a patient with severe UC who, despite several days of peri-operative TPN, including thiamine 3.2 mg/day, developed Wemicke’s encephalopathy. Deficiencies are more likely to occur during periods of increased disease activity when demands and losses are increased and intake decreased. Serum copper levels tend to


be increased in UC patients (Femandez-Banares et al, 1990; Ringstad et al, 1993). Serum levels of zinc have been reported to be decreased with an associated decreased vitamin A level (Femandez-Banares et al, 1990; Mulder et al, 1994), normal (Ainley et al, 1988) with normal absorption (Valberg et al, 1986), or increased (Ringstad et al, 1993). It is of interest that Mulder et al noted decreased copper and zinc metallothionein, which are free radical scavengers, in patients with UC compared to controls, and in inflamed mucosa compared to non-inflamed mucosa in UC patients. Tissue zinc is one of the many factors regulating metallothionein synthesis (Mulder et al, 1991). It is probably wise to measure Zn and Mg levels in the plasma in acutely ill patients and those with very long-term disease and supplement as needed. Likewise, low plasma levels of fat-soluble vitamins with low vitamin B, and elevated vitamin B, have also been reported in a study involving 12 UC and three Crohn’s colitis patients (Femandez- Banares et al, 1989). The significance of these findings in such a small group of patients is difficult to ascertain but, again, water and fat-soluble vitamins should be supplemented on an ‘as needed’ basis. Iron should be monitored in the ‘well’ patient also and supplemented as needed.

NUTRITIONAL IMPLICATION OF DRUG THERAPY

The two main drugs in the treatment of UC are glucocorticoids and 5-ASA compounds. Glucocorticoids, when given in pharmacological doses for extended durations, are associated with the development of osteoporosis. Part of this is due to steroid-mediated impaired intestinal absorption and renal resorbtion of calcium leading to secondary hyperparathyroidism and bone resorption (Nesbitt, 1995). Oral calcium supplementation decreases bone resorption (Reid and Ibbertson, 1986). Glucocorticoids also influence osteoblast function and bone turnover, so calcium supplementation alone will not prevent bone loss (Adler and Rosen, 1994). Vitamin D supplementation in unselected patients with glucocorticoid-induced osteoporosis simply led to hypercalcaemia. In patients on long-term or frequent steroids, calcium supplementation of l-l.5 g/day with the vitamin D supplementation available in fortified dairy products or a simple multivitamin pill is probably worthwhile. Higher doses of vitamin D are warranted only in patients with proven vitamin D deficiency. As mentioned previously, patients taking sulphasalazine should also take folate supplements.

THE FUTURE

The low incidence of UC in Japan has been attributed in part to dietary factors. The Japanese diet, compared to the Western diet, is very high in soy bean products. Soy beans are known to contain protease inhibitors. One of these protease inhibitors which has received much attention is the Bowman-Birk inhibitor (BBI). It is possible that these protease inhibitors have an anti-inflammatory effect. Indeed, BBI prevents the production of

170 A. BURKE ET AL

the superoxide radical by stimulated neutrophils (Frenkel et al, 1987). Trials assessing its use in UC are in progress.

Due to its rapid absorption, butyrate is currently used only as an enema for the treatment of distal colitis. The development of butyrate precursors, e.g. fructo-oligosaccharides and xylo-oligosaccharides (Grisham et al, 1996), and formulations whereby the oral butyrate reaches the colon will allow the assessment of this treatment modality in more extensive colitis.

Finally, the definitive role for butyrate, fish oil, evening primrose oil and anti-oxidants remains to be clarified. Further studies will need to be done in this area.

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172 A. BURKE ET AL

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10 Nutrition and ulcerative colitis