gastrointestinal complications associated with anorexia ... · anorexia nervosa (an) is a...

SYNTHESIS AND REVIEW (CE ACTIVITY)

Gastrointestinal Complications Associated with AnorexiaNervosa: A Systematic Review

Mark L. Norris, MD1,2*Megan E. Harrison, MD1,2

Leanna Isserlin, MD3

Amy Robinson, MD1

Stephen Feder, MD1,2

Margaret Sampson, PhD4

ABSTRACTObjective: A systematic review identify-ing gastrointestinal (GI) complicationsattributable to anorexia nervosa (AN) wascompleted.

Method: Studies of any design exploringthe pathogenesis of complications andtreatment strategies were included. Thereview was completed in accordancewith PRISMA standards.

Results: A total of 123 articles wereretained, including one randomized con-trol trial. The majority of included studieswere case reports and case series. Con-trolled studies demonstrated thatpatients with AN were more likely tohave delays in gastric motility, gastricemptying and intestinal transit than com-parator groups although results were notuniform across all studies. Publishedreports suggest that complications canoccur at any segment of the GI tract.These issues may derive as a conse-quence of severe malnourishment, fromeating disorder related symptoms such as

self-induced purging or from the refeed-ing process itself. Multiple studies notedthat patients with AN report high rates ofGI symptoms although in the few caseswhere medical testing was undertaken,correlations between self-reported symp-toms and measurable pathology werenot demonstrated.

Discussion: GI complications may occurthroughout the entire GI tract in patientswith AN. It is recommended that clini-cians use careful judgment when pursu-ing targeted investigation or introducingsymptom specific treatments in responseto GI complaints. Evidence suggests thatmost GI complications resolve withrefeeding and cessation of ED symptoms.

Keywords: systematic; review; gas-trointestinal; anorexia nervosa; gas-tric emptying; gastric motility;constipation; transit; gastric dilata-tion; superior mesenteric arterysyndrome

ResumenObjetivo: Se complet�o una revisi�on sis-tem�atica para identificar complicaciones

gastrointestinales (GI) atribuibles a la ano-

rexia nervosa (AN).

M�etodo: Se incluyeron estudios de cual-quier dise~no, que exploraran la patog�e-

nesis de las complicaciones y lasestrategias de tratamiento. La revisi�on

fue completada de acuerdo a los est�an-dares PRISMA.

Resultados: un total de 123 art�ıculosfueron revisados incluyendo un estudio

aleatorio controlado. La mayor�ıa de losestudios incluidos fueron reportes de

casos y series de casos. Los estudios con-trolados demostraron que los pacientes

con AN fueron m�as propensos a tener

motilidad g�astrica, vaciamiento g�astrico y

tr�ansito intestinal retardados en compa-

raci�on con el grupo control, aunque los

resultados no fueron uniformes en los

diferentes estudios. Los reportes publica-

dos sugieren que las complicaciones pue-

den ocurrir en cualquier segmento del

tracto GI. Estos problemas pueden ser

consecuencia de la severa desnutrici�on,

de s�ıntomas relacionados con el tras-

torno alimentario tales como conductas

purgativas o del proceso de real-

imentaci�on por s�ı mismo. M�ultiples estu-

dios reportaron que los pacientes con AN

presentan altos �ındices de s�ıntomas GI,

aunque en los pocos casos donde se

practicaron estudios m�edicos, no se

demostr�o correlaci�on entre s�ıntomas

auto-reportados y patolog�ıa medible.

Accepted 17 August 2015

This article was published online on 26 September 2015. An error was subsequently identified. This notice is included in the online

and print versions to indicate that both have been corrected on 18 January 2016.

*Correspondence to: Dr. Mark Norris, MD, FRCPC, Pediatrics & Adolescent Medicine, Department of Pediatrics, Children’s Hospital of

Eastern Ontario, 401 Smyth Road, Ottawa, ON, Canada K1H 8L1. E-mail: [email protected] Department of Pediatrics, Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada2 Children’s Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada3 Department of Psychiatry, Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada4 Library and Media Services, Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada

Published online 26 September 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/eat.22462VC 2015 Wiley Periodicals, Inc.

216 International Journal of Eating Disorders 49:3 216–237 2016

Discusi�on: Las complicaciones GI

pueden ocurrir a cualquier nivel del

tracto GI en pacientes con AN. Se

recomienda que los m�edicos sean

muy cuidadosos en su diagn�ostico y

estudio o al implementar tratamien-

tos espec�ıficos para los s�ıntomas en

respuesta a las quejas GI. La eviden-

cia sugiere que la mayor�ıa de las

complicaciones GI se resuelven con

la realimentaci�on e interrupci�on de

los s�ıntomas de trastorno de la con-

ducta alimentaria. VC 2015 WileyPeriodicals, Inc.

(Int J Eat Disord 2016; 49:216–237).

Introduction

Anorexia nervosa (AN) is a psychiatric disturbancethat can result in serious and potentially deadlymedical complications.1 The gastrointestinal tractis susceptible to complications that are directlyand indirectly attributed to weight loss and purgingbehaviours. Scientific study as well as clinical prac-tice suggests that eating disorder patients com-monly report symptoms related to the GI tract,although it can sometimes be challenging to differ-entiate complaints that represent functional issuesas opposed to recognizable pathology.2 To datethere has not been a systematic review on the topicwhich has utilized internationally recognized andaccepted search criteria such as that outlined byPRISMA guidelines.3

This systematic review addresses the followingobjectives:

To identify gastrointestinal complications attrib-utable to anorexia nervosa

To review studies exploring the pathogenesis ofthese complications

To describe treatment strategies intended toaddress GI complications related to AN.

In accordance with PRISMA guidelines, our sys-tematic review protocol was registered with theInternational Prospective Register of SystematicReviews (PROSPERO) on 24 March 2015 (registra-tion number CRD42015017854).

Search Strategy

The following databases were searched focusing ongastrointestinal disease and AN: MEDLINE includ-ing In-Process & Other Non-Indexed Citations(1946 to Mar 5 2015) and Embase (1980 to 2015Week 09). All were searched using the Ovid inter-face. The MEDLINE search strategy was developedby a librarian experienced in systematic reviewsearches (MS). No language or study design limitswere applied. The search strategies are presentedin the Appendix.

Non-English articles were included assumingthey could be translated sufficiently, using GoogleTranslate, for evaluation.4 Bibliographies of rele-vant manuscripts were also searched to ensure anypotentially relevant articles were included in theinitial screen.

Eligibility Criteria

Studies were selected according to the criteria out-lined below:

Studies

Studies of any design, including published casereports, were included.

Participants

Studies were included that involved pediatricand adult patients with AN. In cases where studiesincluded both adults and children, or cohorts withAN and bulimia nervosa (BN), data was aggregatedseparately where possible.

Intervention or Exposure

Publications were targeted that examined theprevalence of GI complications and that reportedon interventions implemented in patients with AN.

Outcomes

Primary endpoints were publications that increasedknowledge and influence clinical practice. Pertinentendpoints addressed the myriad of GI complicationsincluding but not limited to: esophageal complica-tions such as gastro-oesophageal reflux (GER); gas-tric complications such as dilatation, perforation;hepatic and pancreatic complications; intestinalcomplications such as ileus, obstruction, constipa-tion; anorectal issues including prolapse. Outcomeshave been presented where feasible in tabularformat.

GASTROINTESTINAL COMPLICATIONS IN ANOREXIA NERVOSA

International Journal of Eating Disorders 49:3 216–237 2016 217

Setting

Studies conducted in hospital or outpatient clinicalsettings were included.

Abstract and Article Selection

Titles and (where available) abstracts of studiesobtained using the search strategy were reviewedindependently by two researchers using the out-lined inclusion criteria. In cases where agreementwas not reached, a third reviewer helped determinesuitability. The full text of potentially eligible stud-ies was retrieved and assessed for eligibility by tworeview team members, with input from a third

reviewer as required. We recorded and tracked rea-sons for excluding trials (Fig. 1). Reviewers werenot blinded to study authors or institutions duringthe review. Articles were excluded if they could notbe obtained during the search time frame (March15-April 30th, 2015).

Results

Database searching identified 717 records, with 631retained for screening after duplicates wereremoved. Reference lists identified 40 additionalreports that were assessed for eligibility. A total of123 articles met criteria for the review and were

FIGURE 1. Flow Diagram.

NORRIS ET AL.


retained (Fig. 1). Figure 2 illustrates a breakdownof study designs of the 123 included papers. In anattempt to provide as concise a review as possible,the authors have chosen to only present complica-tions primarily observed in AN, as opposed tothose more frequently observed in bulimia nervosa(BN) but also co-occurring in AN.

Gastro-Esophageal Complications

Tables 1 and 2 summarize reports that focusedon gastric findings and complications. Studies thatfocused on sialadenosis, which is characterized bynoninflammatory salivary gland enlargement,51–62

esophageal perforation,63–67 and rumination syn-drome,68–71 will not be discussed as part of theresults given these complications are more fre-quently observed in BN (although pertinent refer-ences have been made available).51–71

Esophageal Motility and Achalasia/Dysphagia. Twostudies using esophageal manometry to investigatemotility in patients diagnosed with AN39,72 pro-duced conflicting results. Benini et al.72 reported ahigh frequency of esophageal-related symptoms inAN patients but almost all (23/24) had normalesophageal manometry. Stacher39 identified a highrate of primary esophageal motility disorders in50% of the study sample (15/30), including sevenwho were subsequently diagnosed with achalasia.In this case series of 30 women (age range of 14–43years old) with a presumed diagnosis of AN, 10 of15 patients with esophageal motility disordersrequired medical interventions (mechanical dilata-tion for achalasia; fundoplication for patient withsevere GERD and esophagitis; nifedipine to treatabnormal esophageal contractions and spasms) toaddress the esophageal abnormalities, highlightingthe importance of the medical history and work-upof patients with AN. There is potential for selectionbias in Stacher’s39 group given all study AN patients

were selected from individuals who were referredto a tertiary care site for esophageal disorders.

There is scant research exploring achalasia anddysphagia in AN; we identified two studies whichare described here. Of note, a large number of caseswere identified in which patients had improperlybeen diagnosed with AN, and were later found afterundergoing more intensive medical investigationto have achalasia. Given the reality that dysphagiaimpacts a patient’s ability to be successfully refeed,it is imperative that the initial clinical assessmentinclude questions pertaining to swallowing andthat appropriate investigations be undertaken incases where difficulties are identified. Oro-pharyngeal dysphagia symptoms were the present-ing symptoms described in a case series of threefemale patients ages 24–33 years with severe AN[body mass index (BMI) range 9.6–12.7 kg/m2].73

During bedside swallowing tests (video-fluoro-scopic swallowing study scales), all the threepatients were found to have dysphagia (mild tomoderate in two patients; severe in one patient),abnormal oro-pharyngeal swallowing function,and signs of aspiration. Authors described signifi-cant improvements in the dysphagia symptomsand swallowing function score tests for all threepatients following dysphagia therapy using 6–9 ses-sions of neuromuscular electrical stimulation(NMES) and swallowing therapy (includingstrengthening exercises). Additionally, patients dis-played no further signs of aspiration, tolerated oraldiets, and gained weight (0.4–3 kg).73 Authors spec-ulate that patients with AN may suffer from dys-phagia because of the weakening of smooth andskeletal musculature secondary to starvation medi-ated atrophy, as well as damage caused by poten-tially long-standing GERD and recurrentvomiting.73 In a case-control prospective studythat aimed to evaluate the frequency of esophagealmotility abnormalities and related symptoms in asmall group of female patients with AN (11 patientswith AN-R, mean age 19.9 years, mean body massindex (BMI) 13.2 kg/m2; 12 patients with AN-binge/purge (AN-BP), mean age 25.4, mean BMI15.5 kg/m2), Benini et al.72 found a relatively lowrate of dysphagia with no difference between ANsubtypes (3/11 patients with ANR, 1/12 patientswith AN-BP); of note the rate of dysphagia in ANwas higher than the rate seen in the matched con-trol group. Patients in the latter study72 had rela-tively higher BMIs than those described in theformer case series.73 The small sample sizes inboth studies described make it difficult to specu-late an overall rate and nature of dysphagia in

FIGURE 2. Study designs of 123 articles included in the review.



TABLE 1. Gastric complications in patients with AN

Author Gender (F/M)Age

(years)BMI, If

Noted (kg/m2)Imaging

(If Completed) Complication Described Outcome

Gastric ComplicationsRussell5 (1966) F 16 NR Physical exam Gastric dilatation Conservative*Evans6 (1968) F 20 NR Gastric dilatation, necro-

sis and perforationGastrectomy and

pyloroplastyJennings7 (1974) 2 cases (F) 14, 25 NR xray Gastric dilatation Conservative*Bessingham8 (1977) 2 cases (F) 16, 19 NR Gastric dilatation Conservative*Brook9 (1977) F 17 NR xray Gastric dilatation Conservative*Browning10 (1977) 2 cases (F) 19 NR laparotomy Gastric dilatation Necro-

sis/gangrene; esopha-gogastric fistula withsubphrenic abcess

Surgical (subtotal gas-trectomy, esophago-gastrostomy, feedingjejunostomy)

16 Gastric perforation DeathKeane11 (1978) F 16 NR xray, exploratory

laparotomyGastric dilatation Duode-

nal ileusConservative*, then sur-

gical for duodenalileus (duodenojejunalanastomosis)

Lebriquir12 (1978) F 23 11 Gastric dilatation, necro-sis and perforation

Death

F 20 11.5 As above DeathKline13 (1979) 15 12.4 Gastric perforation

(thought to be second-ary to gastric ulcer)

Death

Saul14 (1981) F 22 NR Gastric dilatation, necro-sis and perforation

Total gastrectomy, thendeveloped smallbowel and large intes-tine infarctions

DeathBackett15 (1985) F 17 NR xray Gastric dilatation and

acute pancreatitisConservative*

Abdu16 (1987) 2 cases (F) 14 NR laparotomy Gastric dilatation, Necro-sis, stricture

Surgery

17 Gastric dilatation, Necro-sis, limb ischemia

Surgery, DEATH

Coste17 (1992) F 19 13.1 xray Gastric dilatation Gastricnecrosis

Surgical (totalgastrectomy)

Van Dijk18 (1994) 31 13.5 Gastric dilatation andperforation

Death

De Caprio19 (2000) M 16 13.7 xray, CT scan,endoscopy

Gastric dilatation Conservative*

Nakao20 (2000) F 17 16.6 Gastric dilatation, necro-sis and perforation

Gastric resection andreconstruction

Lo21 (2004) F 26 NR CT scan,enteroscope

Gastric dilatationNecrosis

Conservative* and sur-gery (duodenojejunos-tomy for SMAsyndrome)

Mathevon22 (2004) F 25 15.4 xray, CT scan Gastric dilatation Conservative*Sinicina23 (2005) F 19 17.9 Gastric dilatation, necro-

sis and perforationDeath

Barad24 (2006) F 24 NR CT scan Gastric dilatation Conservative*Birmingham25 (2007) F 19 NR Gastric Bezoar Unremarkable; No fur-

ther gastriccomplications

Arie26 (2008) F 16 11.3 Gastric necrosis andperforation

Total gastrectomy

Watanabe27 (2008) F 31 16.2 Autopsy Gastric dilatationnecrosis

Death

Cardiac output impair-ment circulatorycollapse

Choirat28 (2010) F 19 12 CT scan Gastric dilatation Conservative*Morse29 (2010) F 18 NR Gastric dilatation, necro-

sis and perforation.Tension pneumo-thorax, tensionpneumo peritoneum,ruptured diaphragm,compartment syn-drome of theabdomen.

Complete gastrectomy,right hemicolectomy,repair of the ruptureddiaphragm, and place-ment of an esopha-geal drain andcolostomy; subse-quent distal ileumresection

NORRIS ET AL.


patients with AN but suggest that targeted therapy

helps alleviate symptoms.

Gastric Complications

Gastroesophageal Reflux (GER) and Related Com-

plaints. Symptoms of GER or, regurgitation andheart burn occur in patients in AN,72,74–77 althoughperhaps more commonly in those with BN.78,79 Ina case control trial, Winstead et al.75 found thatpatients with eating disorders (including 34patients with AN) self-reported significantly higherrates of GER symptoms per week as compared withcontrols. Unfortunately, authors did not inquireabout purging in the study sample and did notspecify the type of AN patients were diagnosedwith (i.e., AN-R vs AN-BP). Benini et al.72 found ahigh rate of esophageal complaints includingregurgitation and heart burn as compared to con-trols. Interestingly, at the end of a 22 week rehabili-tation program, there was significant improvementin gastric and colonic symptoms but no improve-ment seen in esophageal related complaints.Symptoms of regurgitation and heartburn did notimprove with weight gain, nor did they correlatewith improvements in patients’ psychopathologicscores.72 Similarly Waldholtz et al.74 prospectivelyidentified no statistical improvement in heartburncomplaints following a hospital-based program ofrefeeding and psychiatric care. This was despitefinding significant improvement, compared tonon-age matched controls, in the number andseverity of GI complaints overall. In contrast, San-tolicola et al.80 did not find elevated rates of epigas-tric pain or burning in a sample of 20 patients withAN compared with constitutionally thin women,

obese women, or healthy controls using standar-dized questionnaires.

Gastric Dilatation and Perforation. Acute gastric dil-atation was first described in 1833 and has beenwell documented in the literature since then.81 Inaddition to eating disorders, gastric dilatation hasbeen reported to result from superior mesentericartery (SMA) syndrome, volvulus of hiatal hernias,trauma resuscitation, medications, and other con-ditions.81–84 Although symptoms of gastric dilata-tion can be vague, patients often present withemesis and gradual abdominal distention withpain.81

Patients with AN are at an increased risk of acutegastric dilatation after an episode of severe binge-ing/overeating14,18,20,29,75 because of decreasedgastric motility, increased gastric capacity, anddecreased gastric emptying.72,85 A total of 30 cases(Table 1) describing acute gastric dilatation inpatients with AN were included in this review.Patients were managed conservatively (gastricdecompression, fluid and nutritional support) inapproximately one-third of thecases,5,7–9,15,19,22,24,28,33,86 while others underwentsurgical intervention as a result of compromisedclinical status.10,17,30,34 Three cases were managedmedically initially, but then required surgical inter-vention for complications.11,21,31 Eight cases of gas-tric dilatation led to perforation.6,12,14,16,18,20,23,29

Gastric necrosis was commonly noted in the casesof dilatation.6,10,12,14,16,17,20,23,26,27,29 Less com-monly, gastric dilatation was associated with: duo-denal ileus,11 acute pancreatitis,15 acute cardiacoutput impairment,27,33 superior mesenteric arterysyndrome,86 acute renal failure,33 and legischemia.34

TABLE 1. (Continued)

Author Gender (F/M)Age

(years)BMI, If

Noted (kg/m2)Imaging

(If Completed) Complication Described Outcome

Tweed-Kent30 (2010) F 26 18.75 AXR, CT scan,laparotomy

Gastric dilatation Surgical (gastrotomy,surgicaldecompression)

Hausler31 (2011) F 21 14.1 CT scan,gastroscopy

Gastric dilatation Chroniclung aspiration, necro-sis, haemothorax,ECMO/ICU prolongedstay, cholecystitis

Conservative* for dilata-tion, but surgical forother complications(intubation, chesttube, cholecystectomy)

Darji32 (2012) M 11 NR Gastric perforation Suture repairRepesse33 (2013) F 18 11.4 CT scan Gastric dilatation Acute

cardiac output impair-ment, Acute renalfailure

Conservative*

Van Eetvelde34 (2014) F 19 NR CT scan,gastroscopy

Gastric dilatation Legischemia; post-opstenosis

Surgical x 2 (decompres-sion, sleevegastrectomy)

Abbreviations: BMI - Body Mass Index; NR - Not Reported; CXR - Chest X-ray; CT - Computerized Tomography; AXR - Abdominal X-ray.



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alre

sult

sG

astr

icem

pty

ing

ofliq

uid

slo

nge

rin

AN,b

ut

not

sign

ifica

nt

NORRIS ET AL.


TAB

LE2.

(Co

nti

nu

ed

)

Auth

or(s

)St

ud

yD

esig

nAg

ein

Year

s(M

ean

,Ran

ge)

Gen

der

Sam

ple

Size

Pts

wit

hAN

Mea

n%

HB

Wor

BM

I(k

g/m

2)

GI

Com

plic

atio

nM

easu

res/

Inte

rven

tion

Ou

tcom

e

Szm

uck

ler4

4(1

990)

Case

Seri

es22

.8Al

lfem

ale

2222

BM

I14

.7G

astr

icm

otili

tyG

astr

icsc

inti

grap

hy

q2

min

for

90m

in,m

easu

red

atb

asel

ine,

1m

o,an

d2-

3m

op

ost-

mea

l

Del

ayed

gast

ric

emp

tyin

gim

pro

ved

rap

idly

(wit

hin

3m

o)of

refe

edin

gp

roce

ssEm

pty

ing

tim

en

egat

ivel

yco

rrel

ated

toB

MI

Lag

tim

esi

glo

wer

inAN

-B/P

than

AN-R

Stac

her

45

(199

2)Ca

seco

ntr

ol22

.5(1

4-36

)Al

lfem

ale

6753

63.9

%H

BW

Gas

tric

mot

ility

Gam

ma

cam

era

over

50m

inp

ost-

mea

lG

astr

icem

pty

ing

sign

ifica

ntl

yd

elay

edan

dan

tral

mot

orac

tivi

tysi

gnifi

-ca

ntl

ylo

wer

inp

atie

nts

vsco

ntr

ols

Effe

ctof

cisa

pri

de

8m

g30

min

pre

-m

eal

Cisa

pri

de

sign

ifica

ntl

yin

crea

sed

rate

ofga

stri

cem

pty

ing

inp

atie

nts

Rav

elli4

6(1

993)

Case

Con

trol

13.6

(11-

15)

5F1M

146

Not

reco

rded

Gas

tric

antr

alac

tivi

tyEG

Gp

rean

dp

ost-

mea

lN

oco

nsi

sten

tab

nor

mal

ity

ofga

stri

can

tral

acti

vity

orga

stri

cem

pty

ing

Stac

her

47

(199

3)R

CT22

.5(1

9-34

)Al

lfem

ale

12N

/A62

.4%

Gas

tric

mot

ility

Effe

ctof

cisa

pri

de

10m

gTI

Dvs

pla

-ce

bo

for

6w

eeks

in1 =

2p

atie

nts

,th

enal

lpat

ien

tsre

ceiv

edci

psa

pr-

ide

for

anot

her

6w

eeks

&ga

stri

cem

pty

ing

afte

rm

eal

Cisa

pri

de

for

6an

d12

wee

kssi

gnifi

-ca

ntl

yac

cele

rate

dga

stri

cem

pty

ing

inp

atie

nts

vsp

lace

bo

and

over

tim

e

Ben

ini4

8(2

004)

Case

con

trol

22.6

(19-

32)

Allf

emal

es47

23N

otre

por

ted

Gas

tric

mot

ility

Ult

raso

un

dm

easu

reof

gast

ric

emp

ty-

ing

pos

t-m

eal

Antr

ald

iste

nsi

ongr

eate

rfo

rA

N-B

/Pth

anAN

-Ror

con

trol

sat

bas

elin

ean

d30

min

pos

t-m

eal

Bow

elSy

mp

tom

Qu

esti

onn

aire

Gas

tric

emp

tyin

gsl

ower

inp

atie

nts

than

inco

ntr

ols

Gas

tric

emp

tyin

gim

pro

ves

wit

hre

feed

ing

over

22w

eeks

no

sign

ifica

nt

corr

elat

ion

bet

wee

nra

teof

gast

ric

emp

tyin

gan

dfe

el-

ings

ofh

un

ger

and

sati

ety

Oga

wa4

9(2

004)

Case

Con

trol

Mea

nn

otre

por

ted

(16-

30)

Allf

emal

e38

15N

otre

por

ted

Gas

tric

mot

ility

Elec

tro-

gast

rogr

aph

y(E

GG

)bef

ore

and

afte

r25

0mlw

ater

Bra

dyg

astr

iasi

gm

ore

com

mon

inp

atie

nts

vsco

ntr

ols

Deg

ree

ofEG

Gab

nor

mal

ity

pos

itiv

ely

corr

elat

edw

ith

du

rati

onof

illn

ess

No

dif

fere

nce

by

sub

typ

eof

AN

Pere

z50

(201

3)Ca

seCo

ntr

ol15

.5(1

0-22

)Al

lfem

ale

3816

BM

I5

17.3

Gas

tric

mot

ility

Ult

raso

un

dga

stri

cre

sid

ual

volu

me

and

pos

t-m

eala

ntr

ald

iam

eter

atb

asel

ine

and

afte

r12

-16

wks

refe

edin

g

Pati

ents

sig

had

imp

aire

dga

stri

cac

com

mod

atio

nat

bas

elin

eco

m-

par

edto

con

trol

Gas

tric

acco

mm

odat

ion

Gas

tric

acco

mm

odat

ion

imp

rove

dsi

gw

ith

refe

edin

gN

od

iffe

ren

cein

resi

du

alga

stri

cvo

l-u

me

bet

wee

np

atie

nts

and

con

trol

sat

bas

elin

eor

afte

rre

feed

ing

Abb

revi

atio

ns:

AN-R

5an

orex

ian

ervo

sa,r

estr

icti

ng

sub

typ

eAN

-B/P

5an

orex

ian

ervo

sa,b

inge

-pu

rge

sub

typ

e;H

BW

–h

ealt

hy

bod

yw

eigh

t;B

MI

–b

ody

mas

sin

dex

.



There are a total of 13 reported cases of gastricperforation.6,10,12–14,16,18,20,23,26,29,32 In these cases,intra-gastric pressure is hypothesized to haveexceeded gastric venous pressure producing ische-mia, necrosis and ultimately perforation of the gas-tric wall.6,14,16,20 Of the patients that presented withgastric rupture, four (31%) occurred in the contextof an episode of over-eating/bingeing,14,18,20,29

seven (54%) presented with severe abdominalpain,6,10,12,14,16,18,20,26,29 and/or abdominal disten-tion,6,10,12,16,18,26 and six (46%) showed signs ofshock at initial presentation.6,14,18,20,29,32 Diagnosisof gastric rupture was confirmed by abdominalX-ray,6,12,14,18,20,26 CT of the abdomen,20,26 and/orduring emergency laparotomy.6,14,18,29,32 In twocases, the diagnosis of gastric perforation was con-firmed on post mortem examinations.13,23 Themortality rate associated with gastric perforation isreportedly as high as 80%.7 In this current review,gastric perforation was fatal in 8 of 13 patients withAN (62% death rate). Table 2 summarizes thereported cases.

Gastric Motor Function, Gastric Motility, and Gastric

Emptying. Few studies investigated gastric electri-cal activity and antral phase pressure activity inpatients with AN. Abell et al.87 completed a casecontrol prospective study and found that allpatients with AN had increased episodes of gastricdysrhythymia as well as impaired antral contractil-ity as compared with matched controls.87 This isclinically significant as the antrum is the part of thestomach most involved with grinding and process-ing of solid meals.88 Dysrhythymias were noted preand post meals and were postulated to be interfer-ing with antral contractility. Five of eight patients(63%) underwent retesting after at least 4 monthsof treatment and continued to exhibit gastric dys-rhythymias and impaired antral contractility. Itshould be noted that 4/5 of these patients contin-ued to have extremely low levels of body fat at thetime of retesting and 2/5 patients had gained 3 kgor less in the 4 months since initiating treatment.Similarly, Benini et al.48 found AN patients hadmore antral distension than controls using anultrasonographic gastric emptying test during atest meal and that maximal dilatation was reachedmuch more quickly.48

Evidence from case control,35,36,38–40,42,43,45,48,49,87

case series,41,44 and case report37 studies would sug-gest that gastric emptying is significantly delayed inpatients with AN (Table 2). There is a paucity ofdata that examines the threshold for weight loss inwhich gastroparesis is likely to occur, as well as howlong it is likely to persist after nutritional rehabilita-

tion and weight gain begins. Illness factors identi-fied as being associated with gastric emptyingabnormality include longer duration of illness49 andseverity of malnutrition.44,48

Delayed gastric emptying is present at baselinein the fasting state, as well as after ingestion of250 mL of water49 or test meal.35–41,43–45,47,48,50,87

Abell et al.87 noted that the delay was occurring asa result of slowing of the “emptying phase” as thelag time between meal ingestion and onset of emp-tying was normal in patients.87 Mixed results havebeen noted when examining solid versus liquid testmeals. Significantly delayed emptying occurredwith both liquid and solid meal components inthree studies.36,41,87 In other studies, a significantdelay in gastric emptying was noted after a solidmeal but no difference between patients with ANand controls after ingestion of a liquidmeal.36,38,41,43

It is unclear whether rate of gastric emptying dif-fers among AN subtypes. Results from studies thathave examined correlates of body weight and gas-tric emptying are inconsistent.40,43 There was nosignificant difference found in gastric emptyingrate based between subtypes of AN in 3 stud-ies.44,45,49 Benini et al.48 concluded that onlypatients with AN-R had significantly delayed gas-tric emptying compared to controls and that theantral region of the stomach was more hypotonicin patients with AN-binge/purge subtype48 butother researchers could not replicate this finding.45

Individuals with early onset AN (mean age 513.6years)46 or who are early in the course of their ill-ness (mean age 15.5 years)50 have not been shownto demonstrate delayed gastric emptying althoughthe pathophysiology remains unexplained in thesecases. A short duration of illness may confer someprotection but further research is warranted.

Measured gastric emptying delay was mapped tofeelings of hunger and satiety in two studies andgastric symptoms in another.42,43,48 Robinsonet al.42 found no difference in feelings of hunger(measured with the Garfinkel Questionnaire89)between patients and controls, and that patientswith AN were significantly more likely to reportfeeling bloated and having a full stomach immedi-ately after eating than controls and display signifi-cantly lower correlations between gastric contentand urge to eat. Also of note, patients were morelikely to report nausea, urge to be sick, sadness, fat-ness, and tension, with some scores continuing torise at the 100 minute post meal mark. Beniniet al.48 found no significant correlation betweenrate of gastric emptying and feelings of hunger and

NORRIS ET AL.


satiety and Hutson failed to correlate gastric symp-toms and emptying times.43

Patients’ gastric emptying parameters improvedthrough refeeding and weight restoration in severalstudies. Benini et al.48 showed that 4 weeks intorefeeding, the time for full gastric emptying meas-ured by ultrasound decreased significantly by 33.4minutes, and by 22 weeks gastric emptyingdecreased by another 41.2 minutes (p< 0.03). Simi-larly, Dubois et al.35 and Rigaud40 demonstratednormalization of the delayed gastric emptying ofliquid and solid meal components on admissionwhen remeasured after 10 weeks of refeeding orafter return to being fully renourished, respectively.One cross sectional study90 found that patientswho are low weight and actively restricting theirintake have a slower gastric emptying than thosewho were similarly underweight but consumingsufficiently to achieve weight restoration. Using acase series design, Szmuckler et al.44 confirmedthat whereas many patients are found to havedelayed gastric emptying upon admission to hospi-tal for treatment of their anorexia nervosa (meanhalf-emptying time 51761/269 minutes), thatwhen re-tested one month later (n 5 12), gastricemptying rates had improved (mean half-emptyingtime 5121 6 68 minutes). Eight of twelve patients(67%) had gastric emptying rates within the normalrange after one month of refeeding. The remainingfour achieved normal gastric emptying within 2–3months of having initiated refeeding (mean half-emptying time 64 6 10 minutes).

Five studies tested the effect of pro-kinetic medi-cation in improving gastric emptying.35,37,39,45,47

Dubois et al.35 observed gastric emptying beforeand after injections of bethanechol chloride0.06 mg/kg. They found a three-fold increase ingastric emptying rate 60 minutes after bethanecholinjection. Stacher and Bergmann45 provided eithercisapride 8 mg or placebo to 22 patients withknown delayed gastric emptying and noted a sig-nificant improvement in the rate of gastric empty-ing (p< 0.001) in the experimental group. Using arandomized control design Stacher et al.47 pre-scribed cisapride 10 mg or placebo three timesdaily for 6 weeks, followed by both groups receivingcisapride for an additional 6 weeks. In the firstphase after six weeks those receiving cisapride sub-stantially reduced their median gastric emptying(195.6 minutes to 76 minutes) compared to pla-cebo (173.8 minutes to 150.2 minutes). During thesecond phase (weeks 7 – 12) when all patientsreceived cisapride the entire group manifested asignificant decrease in their median gastric empty-ing time from baseline to 12 weeks (184.0 minutes

to 93.3 minutes) (p< 0.001). Russell et al.37

described a case report of a patient with AN whosegastric emptying rate, measured as half-emptyingtime, decreased from 119 minutes to 75 minutesafter 14 days of Domperidone 10 mg three timesdaily before meals. Similarly Stacher39 identifiedthat Domperidone 10 mg intravenous significantlyshortened half-emptying time compared to pla-cebo in patients with AN and known delay in gas-tric emptying. In the most recent clinicalguidelines by the American College of Gastroenter-ology,91 metoclopramide is suggested as the firstline prokinetic therapy that should be consideredfor the treatment of gastroparesis symptoms, inaddition to dietary therapy. Caution should be usedwith its administration due to the risk of sideeffects, including tardive dyskinesia and prolonga-tion of the corrected QT (QTc) interval.91 Recentstudies have also examined the dual use of erythro-mycin and metochlopramide,92 although cliniciansshould again be aware of the potential for QTc pro-longation, especially in patients with AN.

Liver Abnormalities

Multiple studies have demonstrated the presence ofelevated transaminases, hypoglycemia, and impairedcoagulation in AN in the absence of other liver pathol-ogy (Table 3).94–96,98,102,105,107–110,113,115,117–119 Moresevere descriptions of serious hepatic complica-tions such as severe hypoglycemia, encephalop-athy,97,111,117 and death from liver failure have beenreported in patients severely malnourished as aresult of AN.103,111,113

While many of the studies looking at liver dys-function in AN examined low weight hospitalizedpatients, others have identified that between 6.7and 52% of patients presenting for outpatientassessment or treatment, and who have no con-founding liver pathologies, also demonstrate ele-vated transaminases.95,108 In the outpatient setting,the state of malnutrition (as measured by BMI) pre-dicts the likelihood of having elevated transami-nases that indicate liver involvement. No differencewas noted between patients with AN-R and AN-B/P subtypes.108

In the inpatient setting, where patients are oftenmore severely medically compromised, estimatesof the percentage of patients with elevated transa-minases range from 26% to 45%.94,104,113,120 Riskfactors associated with the likelihood of liver injuryin hospitalized patients with AN include: youngerage, lower BMI, lower % body fat, AN-R, male sex,and aggressive refeeding.104,113,120



TA

BLE

3.

Liv

er

co

mp

licati

on

sin

AN

Auth

or(s

)St

ud

yD

esig

nM

ean

Age

inYr

s(R

ange

)G

end

erSa

mp

leSi

zeTr

eatm

ent

Sett

ing

Mea

n%

HB

Wor

BM

I(k

g/m

2)

Hep

atic

Com

plic

atio

nO

utc

ome

Har

ris9

3(1

983)

Case

rep

orts

27Al

lfem

ale

2H

osp

ital

10.6

Tran

sam

init

isTr

ansa

min

itis

can

occu

rin

pat

ien

tsw

ith

ANR

esol

ves

wit

hre

feed

ing

Miln

er9

4(1

985)

Ret

rosp

ecti

veco

hor

t14

47F

4M

51H

osp

ital

NR

Tran

sam

init

is2

45%

ofAN

pat

ien

tsex

per

ien

ced

elev

ated

tran

sam

inas

es

Mic

kley

95

(199

6)R

etro

spec

tive

coh

ort

22.5

(11–

57)

278

F4

M28

2O

utp

tcl

inic

NR

Tran

sam

init

is6.

7%of

ANp

atie

nts

exp

erie

nce

del

evat

edtr

ansa

min

ases

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uta

96

(199

8)Ca

sere

por

t21

Fem

ale

1H

osp

ital

12.6

Tran

sam

init

isTr

ansa

min

itis

can

occu

rin

pat

ien

tsw

ith

ANFu

ruta

97

(199

9)Ca

sere

por

t20

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ale

1H

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ital

11H

epat

icfa

ilure

Hyp

ogly

cem

iaEn

cep

hal

opat

hy

Mu

ltio

rgan

failu

re,b

ut

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vere

dw

ith

ICU

man

agem

ent

Jon

es9

8(1

999)

Case

seri

esN

R(1

7–37

)Al

lfem

ale

20H

osp

ital

and

outp

tcl

inic

NR

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sam

init

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lin

pts

had

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ated

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sam

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olve

dw

ith

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edin

gR

iver

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eive

s99

(200

0)Ca

seR

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t23

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ale

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osp

ital

10.6

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sam

init

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ansa

min

itis

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pat

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min

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ked

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DiP

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li10

0(2

004)

Case

rep

ort

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mal

e1

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pit

al10

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atic

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NR

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ved

wit

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Cap

rio1

01

(200

6)Ca

sere

por

ts24

Fem

ale

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ital

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atic

failu

reH

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ilure

can

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rin

pat

ien

tsw

ith

AN

Res

olve

dw

ith

refe

edin

gPo

ssib

lem

ech

anis

mis

hyp

oper

fusi

onR

ivie

re1

02

(200

6)Ca

sere

por

t43

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ital

11.0

Tran

sam

init

isTr

ansa

min

itis

can

occu

rin

pat

ien

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ith

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kad

a10

3(2

006)

Case

rep

ort

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mal

e1

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pit

al7.

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min

itis

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thd

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toh

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ogly

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ng1

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ries

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emal

e53

Ou

tpt

clin

ic18

Tran

sam

init

is26

%of

ANp

atie

nts

exp

erie

nce

del

evat

edtr

ansa

min

ases

ALT

and

GG

Tle

vels

inve

rsel

yco

rrel

ated

wit

h%

bod

yfa

tD

owm

an1

05

(201

0)Ca

sere

por

t32

Fem

ale

1H

osp

ital

9H

epat

icfa

ilure

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atic

failu

rean

dco

agu

lop

ath

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cur

inp

atie

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Coag

ulo

pat

hy

Res

olve

dw

ith

refe

edin

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ssib

lem

ech

anis

mis

hyp

oper

fusi

onR

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u1

06

(200

8)Ca

sese

ries

2420

F2M

12H

osp

ital

11.3

Tran

sam

init

isAc

ute

liver

insu

ffici

ency

and

coag

ulo

pat

hy

can

occu

rw

ith

ANCo

agu

lop

ath

yIm

pro

vem

ent

seen

atD

ay5

ofre

feed

ing

Poss

ible

mec

han

ism

isau

top

hag

ySa

ito1

07

(200

8)Ca

sere

por

ts23

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ital

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atic

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can

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rin

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ith

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kam

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08

(200

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etro

spec

tive

coh

ort

27Al

lfem

ale

25O

utp

tcl

inic

15.2

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sam

init

is2

52%

ofAN

pat

ien

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per

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ceel

evat

edtr

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min

ases

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erB

MI

asso

ciat

edw

ith

liver

inju

ryG

iord

ano1

09

(201

0)Ca

sere

por

t23

Fem

ale

1H

osp

ital

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atic

failu

reSe

vere

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atic

failu

reca

noc

cur

inp

atie

nts

wit

hA

NR

esol

ved

wit

hre

feed

ing

Poss

ible

mec

han

ism

ish

ypop

erfu

sion

du

eto

deh

ydra

tion

,h

ypot

ensi

onan

db

rad

ycar

dia

Nar

ayan

a11

0(2

010)

Case

rep

orts

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mal

e2

Hos

pit

al10

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min

itis

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sam

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atie

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Res

olve

dw

ith

refe

edin

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ansa

min

ases

pea

ked

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ay5

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feed

ing

Saku

rai-

Chin

11

1(2

010)

Case

rep

ort

33Fe

mal

e1

Hos

pit

al12

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lyce

mia

Hep

atic

failu

reR

ecov

ery

wit

hco

nse

rvat

ive

refe

edin

g

Yosh

iuch

i11

2(2

010)

Case

rep

ort

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mal

e1

Hos

pit

al13

.7Tr

ansa

min

itis

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sam

init

isan

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agu

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atie

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ulo

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hy

Res

olve

dw

ith

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NORRIS ET AL.


In the vast majority of patients with AN and ele-vated transaminases, the only treatment necessaryis gradual refeeding and hydration, which leads tocomplete normalization of liver enzymes overtime.100,101,105,106,110,113,114 The time course to peaktransaminase levels during refeeding appears to be2 to 5 days after which transaminase level thenstart to recede and normalize between Day 20 andDay 40 of the refeeding process.99,106,110

Published studies have not presented a consist-ent pattern with regards to the elevation of liverenzymes. Several studies reported elevations in ala-nine transaminase (ALT) greater than aspartatetransaminase (AST) 101–103,113,117–119 and othershave shown thereverse.94,96,97,100,101,104,106,109,111,114–116 Similarly anumber of studies noted elevated alkaline phos-phatase (ALP)94,96,101,109,114,116 and biliru-bin94,96,97,102,111 while others have not. Severalstudies noted the patients developed severe hypo-glycemia,97,102,111,114 all of which then requiredtransfer to the ICU at some point during their treat-ment, suggesting that significant hypoglycemiamay be a marker for imminent severe liver failure.This pattern may differ from what is most oftenobserved clinically, and it should be noted thatmost studies did not consistently report on all liverfunction parameters, making it difficult to drawmeaningful conclusions. The noted discrepanciescould also reflect the fact that most of the availablestudies are either case reports or case seriesdesigns, which focus on reporting abnormalresults, or very severe cases.

Several studies have observed impaired coagula-tion secondary to impaired liver function as evi-denced by elevated INR in patients withAN.93,105,106,112 Similar to elevated transaminases,abnormalities in coagulation appear to resolvewith refeeding and improvement in overall liverfunction.

Hypotheses regarding the mechanism of liverdamage during the course of AN include autophagybased on the presence of autophagomes identifiedon liver biopsy,106,114,116 acute hypoperfu-sion,101,109,116 or possibly oxidative stress second-ary to iron deposits in the liver.121

Three studies have described fatal outcomes dur-ing treatment in patients initially presenting withelevated transaminases.103,113,117 These deathswere attributed to the sequelae of severe liver fail-ure. In an attempt to try and better understand ifthere were any factors that may have contributedto these deaths, or provide insight into factors thatdifferentiate poorer outcomes associated with liverTA

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dysfunction, we offer a brief summary of the infor-mation provided regarding the three deaths. Hana-chi provided details on two patients thatexperienced severe liver-related complications,both of which were eventually transferred to theintensive care unit, one of which died.113 It wasnoted by authors that both patients had initiatedrefeeding in a psychiatric unit and had not receivedearly phosphate, vitamins, or trace elements. Upontransfer to the medical team, they were noted tohave severe hypophosphatemia and hypoglycemia.It was also felt that refeeding had proceeded tooquickly given their very severe state of malnutrition(the noted BMI for one of the two patients was9.2 kg/m2). In Sakada’s case report, their patientwas noted to be very severely malnourished with aBMI on admission of 7.3 kg/m2 although other per-tinent medical case details were not reported.103

Saito also reported 1 death (BMI on admission9.9 kg/m2) related to hepatic failure in a case seriesof 9 patients.117 This patient was also managed ona psychiatric floor and although no mention wasgiven of phosphate/vitamins supplementation,authors did note that the patient failed to receiveadequate fluid resuscitation and refused all butoral nutrition, thus limiting their ability to refeedcautiously. As noted above, the literature relevantto liver dysfunction in AN derives primarily fromcase reports and retrospective chart reviews. Thelargest of these studies included 356 patients,118

but most included only relatively small numbers ofpatients.94,98,104,106,108,117 While important, theselimited data preclude any clear conclusions andfurther study is warranted.

Pancreas Complications

Whereas an elevated amylase is often associatedwith pancreatic injury, in asymptomatic patients,usually with BN, the elevated total amylase, whenassociated with a normal lipase or pancreatic isoa-mylase, derives from the salivary glands ratherthan the pancreas.54,56,58 This section summarizesliterature that describes pancreatic injury associ-ated with AN.

A review of the endocrine function of the pan-creas, including insulin and gastrointestinal hor-mones, in AN is outside the scope of this paper.The nature of pancreatic insult in the context of ANranges in severity from asymptomatic to life-threatening. Two case reports describe low gradeabdominal pain which one to three months later, atthe time of admission, was diagnosed as pancreati-tis.122,123 In a consecutive series of 10 patients withANR,124 40% had abdominal symptoms without

biochemical or ultrasound confirmation of pancre-atitis. Sixty percent, including two who wereasymptomatic had either an elevation of serumamylase or amylase creatinine clearance ratioabnormalities; three of the ten had ultrasoundabnormalities. This is consistent with the non-inflammatory fibrotic pancreatic abnormalitiesthat are associated with protein calorie malnutri-tion and marked by acinar cell atrophy and stellatecell activation (reviewed in Morris125). Low gradechronic injury is thought to explain the pseudocystformation reported in two case reports126,127 andthe elevation of elastase-1.96,128 A study that exam-ined pancreatic function based on fecal elastasemeasurements in nine severely malnourishedpatients with AN (7 restrictors; 3 binge- purge), atthe time of admission and then when weightrestored, could find no evidence of pancreatic dys-function through measurement of fecal elastaseand digestion of 13C-labelled triglycerides.129 Thesestudies report conflicting evidence as to the preva-lence of baseline pancreatic dysfunction in thecontext of severe wasting because of AN, whichmight predispose the compromised pancreas tomore severe injury if challenged by other factors.Such decompensated patients present as severelyill with profound cachexia, hemodynamic instabil-ity and possibly a surgical abdomen. Several patho-genetic mechanisms, perhaps mediated by trypsinactivation125 have been hypothesized: hypoperfu-sion causing multiple organ damage including thepancreas100; pancreatic atrophy resulting in areduced capacity to defend against oxidants gener-ated in severe anorexia127,130; and reflux into thepancreatic duct caused by SMA syndrome associ-ated with marked proximal dilatation of the duode-num and stomach.11,15,131 Such dilatation may beaugmented by overzealous refeeding. While limitedin scope, this literature recommends the following:a normal lipase or pancreatic isoamylase rules outpancreatitis and suggests purging as the source ofhigh amylase; the pancreas must be assessed in thecontext of persistent abdominal pain in a severelymalnourished patient; over aggressive refeedingshould be avoided in patients who are severelymalnourished.131

A case report on a 15 year old adolescent withAN-purging and a BMI of 13 identified whose ele-vated sweat chloride and impaired exocrine func-tion (based on measurements of para-aminobenzoic acide excretion) at the time of admissionresolved with renourishment.132 Pancreaticenzymes and amino acid supplementation wereused in treatment. Whereas this report cautionedagainst over diagnosis of cystic fibrosis, based on

NORRIS ET AL.


sweat electrolytes, in the face of severe malnutri-tion, it also questioned the potential role of pancre-atic enzymes in the context of severe cachexia.132

Intestinal Complications

Relatively few studies of AN patients have inves-tigated or reported on complications associatedwith the small and large intestine. We haveincluded superior mesenteric artery (SMA) syn-drome in this section, a rare complication of ANthat occurs when the duodenum is compressedbetween the SMA anteriorly and the aorta and ver-tebral column posteriorly. This occurs because ofthe loss of the retroperitoneal fat pad that separatesthe transverse portion of the duodenum and theSMA.133 This compression leads to complete orpartial duodenal obstruction. Case reports of SMAsyndrome are described in Table 4; all other casereports of intestinal complications can be found inTable 5. We have omitted any discussion on colo-nic pneumatosis intestinalis, as our search identi-fied just two cases.155,156

Superior Mesenteric Artery (SMA) Syndrome. Wereport 15 cases which involved AN and SMA syn-drome, ranging from 11 – 47 years old (Table4).86,134–147 All but two139,142 of the cases were diag-nosed with radiological imaging. Both upper GI(UGI) series and CT scanning are useful for diagno-sis. CT scan is used to assess the angle between theaorta and the SMA, which is narrow in those withSMA syndrome. CT scanning can also assess duo-denal distension, as well as intra-abdominal andretroperitoneal fat. UGI series with contrast candiagnose the partial or complete duodenal obstruc-tion that is seen in SMA syndrome by showing dila-tation of the proximal duodenum and an abruptnarrowing with failure of contrast passage beyondthe third portion of the duodenum.157,158 Mostcases of SMA syndrome can be treated conserva-tively with gastric decompression, electrolyte cor-rection and nutritional support, with surgeryreserved only as an absolute last resort in thosethat fail conservative management given the lackof data to support such measures. A recent caseseries suggested that a minimally invasive surgicalapproach offers advantages to an open procedurein those that fail supportive measurementsalthough case descriptions of patients that under-went the procedure were not provided.159 Of thecases we describe, 11 (73%) were treated conserva-tively, and 4 (29%) underwent surgical interventionreinforcing the importance of conservative man-agement whenever possible.

Intestinal Absorption and Permeability. The smallintestine has the capacity for active and passiveabsorption. It has been hypothesized that starva-tion may compromise the integrity of the intestinalmucosa thereby permitting increased absorption ofnutrients at a time of need.160 Such compromise ofthe anatomo-functional barrier would theoreticallyalso potentially increase the risk that noxiousagents, including pathogenic bacteria, could gainaccess into the bloodstream. Controlled studies inpatients with AN however have demonstrated oth-erwise. In a study of 14 patients with AN (10 restric-tors; 4 binge/purge) having a mean BMI of 16.97,investigators found through measurement of lactu-lose and mannitol absorption, that intestinal per-meability was decreased.160 The maintainedefficacy of intestinal mucosal absorption was dem-onstrated by measurement of xylose absorption inanorexics at low weight and then again at recovery.This finding supports the clinical observation thatsepsis is in fact an uncommon occurrence inpatients with AN. This contrast between starvationbecause of AN, compared with other etiologies, sug-gests the presence of, as yet unidentified factors.129

Whereas impaired functionality has not been dem-onstrated, a controlled study (21 ANR; 15 AN-BP; 20controls) found that diamine oxidase, a marker forintestinal villi integrity and maturity, was signifi-cantly reduced in patients with ANR. Whereas thisreflects the importance of food exposure to thehealth of the intestinal villi, the lack of functionalmeasures precluded correlations of diamine oxi-dase levels with intestinal permeability as had beensuggested in other animal and human studies.161

Intestinal transit times/constipation. In a descriptivestudy of radiologic findings in 50 patients with AN,Haller et al.162 noted transient non-obstructivemild jejunal dilatation in one-third of the cases andthat small bowel transit ranged from normal tooccasionally delayed although no case-specificinformation was included. Only four controlledstudies were identified that measured intestinaltransit times or focused on measures of constipa-tion as a primary outcome163–166 Hirakawa et al.165

compared gastro-cecal transit times using a lactu-lose hydrogen breath test in 10 patients with ANand 11 healthy controls. Each of the patients (whoranged in age between 13 and 28 with a mean of 19years) was considerably malnourished (18%–52%(mean 32% 6 9 SD) below their target body weight)and complained of numerous GI symptoms. Inves-tigators found that the small bowel transit time aswell as the overall transit time was significantlyprolonged in patients with AN compared with con-trols (117 minutes 6 31 so vs. 81 minute 6 33 SD,



p< 0.02). In a study that investigated the same pri-mary outcomes, Kamal et al.166 compared wholegut and mouth to cecum transit times of tenpatients with AN and 18 in-patients with BN to 10healthy controls. All patients with AN (90% female;mean age 26 years 6 8.8; mean BMI 15.1 6 2.2 kg/m2) complained of constipation. Whole gut transitwas significantly delayed in all AN patients.Although mouth to cecum transit times were alsolonger in the AN group, no significant differenceswere observed between groups (although theauthors noted they failed to control for conditionsknown to influence test results). Chun et al.164 pro-spectively studied colonic transit times (CTTs) in13 female patients with AN admitted to an inpa-tient treatment unit and compared them to 20matched controls. They showed that four of sixpatients tested within 3 weeks of admission hadslow CTT but that all patients had normal transittimes after three weeks of treatment. Chiarioniet al.163 tested CTTs in twelve women (19–29 years,BMI 13.1 kg/m2 1/2 1.6) that complained of

chronic constipation and found significantlyslowed CTT in 8/12 (67%) patients whereas all con-trol patient’s results were normal. In the latterstudy, CTT normalized after a 4 week refeedingprogram. We were unable to identify any controlledstudy that investigated the use or looked at out-comes associated with prescribed laxatives in theearly course of refeeding.

Ano-Rectal Complications

Anorectal Manometry. In an attempt to betterunderstand factors that may impact constipation inpatients with AN, two studies were completedwhich compared results of anorectal manometry inpatients with AN to those of matched con-trols.163,164 Anorectal manometry measures pres-sures of the anal sphincter muscles, the sensationin the rectum, and neural reflexes required for nor-mal bowel movements. In both studies, patientswere low weight and reported constipation. Rectalsensation, internal anal sphincter relaxation thresh-old, rectal compliance, sphincter pressures, and

TABLE 4. Summary of case reports describing superior mesenteric artery syndrome in patients with AN

Author(s)Sex

(F/M)Age

(years)BMI

(kg/m2)

Imaging(if completed/

noted)DiagnosisModality Treatment

Pentlow134 (1981) F 21 NR AXR, barium study Imaging *ConservativeSours135 (1981) F 17 NR AXR, gastroscopy,

abdominalultrasound

Imaging *Conservative

Kalouche136 (1991) F 20 16.7 Barium study Imaging Surgical -duodenojejunostomy

Elbadaway137 (1992) F 18 12.4 Barium study Imaging *Conservative x 2months, then sur-gery –gastrojejunostomy

Stheneur138 (1995) F 14 14.3 AXR,esophagogastrography Imaging *Conservative

Adson139 (1997) F 35 NR Barium study, CTscan abdomen

Laparotomy (due toconcern forappendicitis)

*Conservative

De Silva140 (1998) F 28 NR Barium study Imaging *ConservativeSchmidt-Troschke141 (1998) F 11 14.5 Barium study Imaging *ConservativeJordaan142 (2000) F 13 NR Laparotomy Surgical -

duodenojejunostomyGwee143 (2010) F 17 16.4 AXR, barium study,

CT scan abdomenImaging *Conservative

Listernick144 (2010) M 15 14.8 Barium study Imaging *ConservativeFernandez145 (2011) F 31 16.7 Barium study and

arteriographyImaging Surgical -

duodenojejunostomyRehman146 (2011) F 15 NR Barium study, CT

scan abdomen,gastroscopy

Imaging *Conservative treat-ment failed,required surgery

Mearelli147 (2014) M 47 NR Esophagogastroduo-denoscopy, CTscan abdomen

Imaging *Conservative,required surgicalmobilization of lig-ament of Treitz

Mascolo86 (2015) F 47 10.6 AXR, CT scanabdomen

Imaging *Conservative

*NG tube insertion 1/- gastric decompression, fluid hydration 1/- total parental nutrition.Abbreviations: BMI - Body Mass Index; NR - Not Recorded; CT - Computerized Tomography; AXR - Abdominal X-ray.

NORRIS ET AL.


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expulsion pattern were measured and normal inthe 13 patients with AN in Chun et al.’s study.164

Chiarioni et al.’s study demonstrated conflictingresults as patients with AN were significantly morelikely to have anorectal dysfunction similar to thatdescribed in severe chronic idiopathic constipation,and the blunted rectal sensation did not improvewith refeeding.163

Rectal Prolapse. Rectal prolapse, the full thicknessprotrusion of the rectal wall through the anal canal,can be a rare complication of AN. Five cases of rec-tal prolapse and AN are described in the literature,from ages 16–40 years.167–169 Four of the five casesrequired surgical correction, although one patientrefused the recommendation. Conservative man-agement with fiber supplementation, polyethyleneglycol (PEG) 3350, and pelvic floor strengtheningexercises was successful in the remaining case.170

Functional Complaints

Digestive symptoms and functional GI disorders(FGIDs) are frequently reported by patients withAN.170 Although some studies identified the fre-quency of GI complaints by AN patients,74,166,170

few investigated such complaints (and instead werelimited to self-report), making it difficult to con-clude what proportion of patient complaints arefunctional as compared to those that occurred as aresult of measurable GI dysfunction or disease. Sal-violi170 administered digestive symptom question-naires that were completed at baseline, discharge,at 1 and 6 months’ followup in 48 consecutive withEDs (81% of the sample had AN). The authors dem-onstrated that pooled esophageal and GI symptomssignificantly decreased at 6 months’ follow-up andthat GI symptoms significantly correlated withhypochondriasis, a finding which has been demon-strated in non-ED patients with functional GI disor-ders.171 The authors did not offer any indication asto what percentage, if any of patients underwentclinical testing to investigate the GI symptoms.Boyd et al. studied FGID symptoms in 108 consecu-tive ED patients at admission and 12 month followup172. They noted 97% prevalence of at least oneFGID at admission and that 77% continued withsymptoms at 1-year follow-up. Few FGIDsdecreased over time and significant patient varia-tion was noted in the disappearance, persistence,and appearance of individual FGIDs and FGIDregional categories. Of note, 34% of patients metcriteria for at least one new FGID regional categoryat follow-up. There was no relationship betweenchanges in BMI, symptoms such as self-inducedvomiting, or laxative use, or co morbid mental

health diagnoses. They concluded that FGID symp-toms are prevalent in patients for prolonged peri-ods, and that there were no relationships betweenFGIDs and weight or ED behaviors.

Discussion

Many patients with AN struggle with various diges-tive symptoms, which is important given the criticalrole of feeding and requirement for weight gain intreatment. As patients with AN generally requirehigh caloric feeds for extended periods; it is impor-tant that clinicians understand the medical compli-cations that patients may experience as aconsequence of weight loss and of the refeeding pro-cess. While case reports have demonstrated objec-tive evidence of dysfunction affecting every elementof the GI system and at all points on the treatmentspectrum, many patients report GI related symp-toms and distress despite the absence of measure-able medical pathology. It is important to investigatemedical symptoms that persist or fail to remit withweight restoration. As demonstrated in this review,the possibility of underlying, possibly comorbid,medical illness must at times be considered.

This review raises several other issues. First, thissystematic review is limited by the likelihood thatdespite the comprehensiveness of the focusedsearch supplemented by reference list review theremay be some reports and studies that were not cap-tured. Studies published in languages for whichtranslation was unavailable were excluded. Further-more 27 identified articles could not be located.

Combined with the small sample size and themerging in some studies of different AN subtypes(AN-R, AN-B/P), the bias inherent to case control,case series, and case report designs, caution mustbe exercised in drawing strong conclusions.

The majority of articles that were retrieved werecase reports or case series (74%) with few con-trolled experimental studies identified. Of the pro-spective studies that were completed, the majorityinvestigated issues related to gastric motility, gas-tric emptying and intestinal transit.

It should be noted that only one controlled studywas identified that medically investigated esopha-geal related complaints.39 In this single study,Benini and colleagues showed that despite the factthat esophageal symptoms were frequent andsevere in patients with AN, they could not beexplained by manometric abnormalities.

Findings from esophageal, gastric, and intestinaltransit studies suggest that the majority of patients

NORRIS ET AL.


with AN experience delays in gastric emptying andintestinal transit. Results however were not alwaysconsistent, and delays in gastric emptying did notuniformly relate to subjective feelings of hungerand satiety. Based upon the results in Robinson’sstudy, the authors concluded that AN patients over-estimate gastric contents in an analogous way tothe overestimation of body image.42

Although pro-kinetic medications were shown toimprove gastric emptying, studies have also clearlydemonstrated that weight rehabilitation and refeed-ing alone have demonstrated normalization of gas-tric emptying in a majority of patients. This isrelevant when considering the utility of targetedpharmacological treatment. Pro-kinetics were theonly class of medications investigated in any trial,and medications such as cisapride and domperidonehave documented cardiac side effects that synergisti-cally with severe malnutrition may endanger the EDpatient through prolongation of the QTc.154 Becauseof such risks cisparide can no longer be prescribedin Canada or the United States and health advisorieshave been issued by Health Canada regarding dom-peridone.154,173 Prescribers must balance the needfor medication for symptoms such as bloating, full-ness and satiety with a careful risk-benefit analysis.Depending on case specifics, confirmation and dem-onstration of gastroparesis by nucleur gastric empty-ing scan may be considered prior to theadministration of a pro-kinetic agent.

Evidence of liver complication and dysfunctionwas largely limited to case reports and descriptivecase series. Despite these limitations, studies sug-gest that increased liver transaminases in low weightpatients with AN is common and not provokedexclusively by rapid refeeding95,108 While mostpatients with AN and elevated transaminasesrecover with appropriate nutrition and supportivetherapy alone, it is important that severely malnour-ished patients be monitored carefully to ensureearly identification and effective management, withthe appropriate level of medical support, for meta-bolic abnormalities that evolve negatively. Refeedingsyndrome (RFS), (which was recognized in at leastone of the three cases of noted liver-related mortal-ity) can result in mortality if not anticipated, recog-nized early and managed carefully.

Although limited in sample size and number,intestinal transit studies demonstrate that the major-ity of low weight patients that underwent testingshowed evidence of slowed CTT, which would pre-dispose to constipation. Of note, all patients studiedcomplained of severe constipation but not allpatients had prolonged CTT, even at low BMIs, again

suggesting the discrepancy between subjective feel-ings of fullness, bloating, and constipation andobjective findings. Evidence suggests that CTTs nor-malize within weeks of starting targeted nutritionaltreatment programs. No reports or studies werefound that looked at the potentially controversialrole of prescribed laxatives in patients with AN,despite its potential to alleviate constipation notedin most patients during the early refeeding phase.

Outside of the evidence presented above, almostall remaining case reports and case series were lim-ited to individual descriptions of GI related findingsand complications. Indeed, complications, such asgastric dilatation and perforation, pancreatitis,superior mesenteric artery syndrome and rectalprolapse have been noted by multiple authors.Each of these respective complications occurs gen-erally as a result of severe malnutrition (a propor-tion of which can be a complication of RFS) andED-related symptoms (such as self-induced vomit-ing). Given the nature of reporting, it is difficult toestablish incidence rates for any of these complica-tions. Larger databases with common measurablevariables could however shed better light into theprevalence of some more commonly reported com-plications (gastric dilatation for example).

In conclusion, there is an intricate interplaybetween organic pathology, subjective symptoma-tology and cognitive resistance to eating, andweight gain associated with AN—an illness whereinthe integrity of the GI tract is compromised by mal-nutrition and any effort to reverse this malnutritionis opposed by ED cognitions. The greater the degreeof malnutrition, the more intense the cognitions.This poses a complex challenge to the providerwhose job it becomes to discern between thosecomplications that have been referred to as func-tional and those that may be life-threatening.Adequately powered prospective research is lackingthat might help with this task. A thorough under-standing of the pathophysiology of the various mor-bidities, careful consideration of the manydimensions of GI symptomatology in AN, a solidunderstanding of refeeding syndrome and judicioususe of investigation and medication is essential tooptimizing outcome.

Appendix

Search Strategies

Medline

1. exp Gastrointestinal diseases2. Anorexia nervosa3. 1 and 2.



Embase

1. Anorexia nervosa2. exp *Digestive system disease3. 1 and 2

The authors would like to acknowledge the assistance

of Mrs. Patricia Graziano for her help in article retrieval.

MN is the guarantor and led the development of the pro-

tocol. MN, MH, LI, AR and SF executed the review of pro-

posed studies, and drafted the manuscript. MN, MH, LI,

AR and MS helped develop the selection criteria, the risk

of bias assessment strategy and data extraction criteria.

MS developed the search strategy. All authors read, pro-

vided feedback, and approved the final manuscript.

There are no disclosures.

Earn CE Credit for this article! Visit http://www.ce-

credit.com for additional information. There may be a

delay in the posting of the article, so continue to check

back and look for the section on Eating Disorders. Addi-

tional http://www.aedweb.org/ information about the

program is available at www.aedweb.org

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