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Gastroenterology for the Primary Care Physician Walter J. Coyle, MD

Update in GI: WhatUpdate in GI: What’’s s New and UsefulNew and Useful

Walter J. Coyle, MD, FACP,FACGWalter J. Coyle, MD, FACP,FACG

Scripps Primary Care 2011Scripps Primary Care 2011

Movement of the TalkMovement of the Talk

Eosinophilic esophagitis: What is it and how do Eosinophilic esophagitis: What is it and how do I treat it?I treat it?

GERD: WhatGERD: What’’s New?s New?

Celiac Sprue: The epidemicCeliac Sprue: The epidemic

Hepatitis B and C: Newer RxHepatitis B and C: Newer Rx

Inflammatory Bowel Disease: Newer RxInflammatory Bowel Disease: Newer Rx

CRC screening: Follow the guidelinesCRC screening: Follow the guidelines


Movement of the Talk Part IIMovement of the Talk Part II

Stool Transplants: The New RageStool Transplants: The New Rage

Rosacea and SIBO: New evidenceRosacea and SIBO: New evidence

Chronic nausea: a new linkChronic nausea: a new link

The Human Microbiome: Hot topicThe Human Microbiome: Hot topic Pro and Pre biotics: a rational approachPro and Pre biotics: a rational approach

C. difficileC. difficile: It will not go away!: It will not go away!

ConclusionsConclusions

Question Number 1Question Number 1

27 year old male 27 year old male presents with presents with intermittent solid food intermittent solid food dysphagia for years. He dysphagia for years. He has had 2 food has had 2 food impactions. He had impactions. He had childhood asthma. childhood asthma. The most likely The most likely diagnosis is?diagnosis is?

A.A. Peptic stricturePeptic stricture

B.B. SchatzkiSchatzki’’s rings ring

C.C. Eosinophilic esophagitisEosinophilic esophagitis

D.D. Adenocarcinoma of the Adenocarcinoma of the distal esophagusdistal esophagus

E.E. AchalasiaAchalasia


Eosinophilic EsophagitisEosinophilic Esophagitis

Common, may be increasingCommon, may be increasing

Higher in males, younger pts with h/o atopyHigher in males, younger pts with h/o atopy

Strong association with food and aeroallergensStrong association with food and aeroallergens THE ALLERGIC ESOPHAGUSTHE ALLERGIC ESOPHAGUS

Adults: present with dysphagia, atypical GERD Adults: present with dysphagia, atypical GERD symptoms: Usually have years of symptomssymptoms: Usually have years of symptoms

Children: Failure to thrive, nausea or vomiting.Children: Failure to thrive, nausea or vomiting.


Linear FurrowsLinear Furrows

RingsRings

Diagnosis: Biopsy Diagnosis: Biopsy at endoscopyat endoscopy



Eos. AbscessesEos. Abscesses

Long, often Long, often complex stricturescomplex strictures

Careful dilationCareful dilation


Mucosal tear after Mucosal tear after scope passagescope passage

Try medical Try medical treatment firsttreatment first


Eosinophilic Esophagitis:Eosinophilic Esophagitis:TreatmentTreatment

PPIs have shown efficacy in up to 50% of ptsPPIs have shown efficacy in up to 50% of pts

Topical steroids useful but recent PC/Rand Topical steroids useful but recent PC/Rand studies have shown less efficacy then open label studies have shown less efficacy then open label studiesstudies Fluticosone or budesonide: Swallowed (not inhaled)Fluticosone or budesonide: Swallowed (not inhaled)

Allergy consultation: May be helpful in finding Allergy consultation: May be helpful in finding food or aeroallergen that is main culpritfood or aeroallergen that is main culprit

Am J Gastroenterol 2010; 105:747–756

GERD: WhatGERD: What’’s Hots Hot


Nighttime GERD and SleepNighttime GERD and Sleep

National GERD survey:National GERD survey: GERD pts reported lower quality of life (QOL) than GERD pts reported lower quality of life (QOL) than

unaffected subjectsunaffected subjects11

Nocturnal GERD pts symptoms had lower physical and Nocturnal GERD pts symptoms had lower physical and mental QOL scores than other GERD subjects and controlsmental QOL scores than other GERD subjects and controls

Another national survey :Another national survey : 78% GERD pts have nighttime symptoms78% GERD pts have nighttime symptoms

75% noted that nighttime heartburn affected their sleep75% noted that nighttime heartburn affected their sleep

63% of those with nighttime heartburn believed it negatively 63% of those with nighttime heartburn believed it negatively influenced their ability to sleep wellinfluenced their ability to sleep well

Arch Intern Med 2009;161:45-52 Am J Gastroenterol 2003;98:1487-1493

GERD and BMI: WomenGERD and BMI: Women

N Engl J Med 2006;354:2340-2348.

An increase in BMI of 3.5 was associated with increased risk of frequent GERD symptoms, even in women with normal baseline weight

P<0.001 Multivariate odds in women with at least weekly GERD symptoms (n=2306) or no symptoms (n=3904)0

0.51

1.52

2.53

3.54

Od

ds

Rat

io

<20 20 22 25 27 30 ≥35


GERDGERD

PPIs are no longer viewed as innocuous medsPPIs are no longer viewed as innocuous meds Malabsorption of nutrientsMalabsorption of nutrients

Iron, calcium, Vitamin B12Iron, calcium, Vitamin B12

Increase risk for fracturesIncrease risk for fractures

Increase risk for infections including Increase risk for infections including Clostridium Clostridium difficiledifficile

Interaction with clopidogrelInteraction with clopidogrel

PPI use and Hip fracturePPI use and Hip fracture

CaseCase--control study of patients older than 50 control study of patients older than 50 years in a large UK databaseyears in a large UK database PPI users had a 4 /1000 risk for hip fx vs 1.8 /1000 in nonPPI users had a 4 /1000 risk for hip fx vs 1.8 /1000 in non--

users of acid related medsusers of acid related meds

Absolute risk still lowAbsolute risk still low

Seven case control or cohort trials have shown Seven case control or cohort trials have shown a small absolute increased risk of fracturesa small absolute increased risk of fractures

Recent metaRecent meta--analysis (DDW abs only) showed a analysis (DDW abs only) showed a slight increase in hip fx with PPI therapyslight increase in hip fx with PPI therapy

JAMA 2006;296:2947-29Calcif Tissue Int. 2008;83:251-259


Long term PPI useLong term PPI use

AGA now recommends Calcium / Vit D in long AGA now recommends Calcium / Vit D in long term usersterm users

No guidelines for monitoring B12 or ironNo guidelines for monitoring B12 or iron Be aware, check when clinically indicatedBe aware, check when clinically indicated

Be aware of meds that absorb better with acidBe aware of meds that absorb better with acid Digoxin, amoxicillin, ketoconazole, iron, calciumDigoxin, amoxicillin, ketoconazole, iron, calcium

Organic (heme derived) iron now availableOrganic (heme derived) iron now available

PPIs and InfectionsPPIs and Infections

Studies have linked acid suppresion meds Studies have linked acid suppresion meds including PPIs with including PPIs with C. difficile C. difficile infectioninfection Higher recurrence of C diff if on PPI at time of RxHigher recurrence of C diff if on PPI at time of Rx

May increase risk for hospital acquired May increase risk for hospital acquired pneumoniapneumonia

Am J Gastro 2007;102:2047-56 CMAJ 2004;171:33-38JAMA. 2004;292:1955-60 Ann Intern Med. 2008;149:391-98Arch Intern Med 2010;170:772-8


Arch Intern Med. 2010;170(9):772-778

42% more likely to recur if on PPIs

PPIs and clopidogrelPPIs and clopidogrel

US Food and Drug Administration: Drug Safety Information Nov 2009


N Engl J Med 2010;363:1909-17.

PPIs: WaltPPIs: Walt’’s Recss Recs

Right drug, right disease, right patientRight drug, right disease, right patient If your patient needs the PPI for PUD, GI bleeding, If your patient needs the PPI for PUD, GI bleeding,

BarrettBarrett’’s esophagus, then use the PPIs esophagus, then use the PPI Lowest dose that worksLowest dose that works

Use Calcium and Vit D in long term usersUse Calcium and Vit D in long term users

If it is symptomatic GERD only, other optionsIf it is symptomatic GERD only, other options Lifestyle changes, H2 blockers, antacidsLifestyle changes, H2 blockers, antacids

Informed consent to patient until final dataInformed consent to patient until final data

NB. More GI bleeding in Cogent study in nonNB. More GI bleeding in Cogent study in non--PPI PPI usersusers


Celiac Sprue: WhatCeliac Sprue: What’’s New!s New!

Common gene: DQ2 and DQ8: Up to 25%Common gene: DQ2 and DQ8: Up to 25% Predisposes you only to CeliacPredisposes you only to Celiac

Actual disease in 1% in US: Iceberg analogyActual disease in 1% in US: Iceberg analogy

Gluten enteropathy VS Gluten intoleranceGluten enteropathy VS Gluten intolerance Gluten avoidance is in vogue!!!Gluten avoidance is in vogue!!!

Diagnosis: Gold standard remains SB biopsyDiagnosis: Gold standard remains SB biopsy

Serology: Tissue Transglutaminase and Serology: Tissue Transglutaminase and Endomysial antibody excellent sens/specificityEndomysial antibody excellent sens/specificity ALWAYS check serum IgA (IgA deficiency)ALWAYS check serum IgA (IgA deficiency)

Celiac BurdenCeliac Burden


Celiac Issues and DilemmaCeliac Issues and Dilemma

Pt presents for Celiac testing on gluten free dietPt presents for Celiac testing on gluten free diet

Pt has negative serology (maybe even normal SB Pt has negative serology (maybe even normal SB biopsy) and insists they have celiacbiopsy) and insists they have celiac Role for genetic testingRole for genetic testing

Gluten intolerance vs Gluten enteropathyGluten intolerance vs Gluten enteropathy

Health Maintenance:Health Maintenance: Bone healthBone health

Liver diseaseLiver disease

Vitamin and mineral deficienciesVitamin and mineral deficienciesAm J Gastroenterol advance online pub, 1 March 2011

Gluten Causes Gastrointestinal Symptoms in Subjects Without Celiac Disease: A Double-Blind

Randomized Placebo-Controlled Trial

Jessica R. Biesiekierski , B Appl Sci 1 , Evan D. Newnham , MD, FRACP 1 , Peter M. Irving , MD, MRCP 1 , Jacqueline S. Barrett ,PhD, BSc, MND 1 , Melissa Haines , MD 1 , James D. Doecke , BSc, PhD 2 , Susan J. Shepherd , B Appl Sci, PhD 1 , Jane G. Muir ,PhD, PGrad Dip(Dietetics) 1 and Peter R. Gibson , MD, FRACP 1

Am J Gastroenterol advance online publication, 11 January 2011; doi: 10.1038/ajg.2010.487


Results

Am J Gastroenterol advance online publication, 11 January 2011; doi: 10.1038/ajg.2010.487

Results


Discussion

No prior randomized controlled trials demonstrating that the entity of “gluten intolerance” does actually exist

This study supports the existence of non-celiac gluten sensitivity based on the following symptoms: Bloating

Dissatisfaction with stool consistency

Abdominal pain

Tiredness

Future studies

Gluten may have the following deleterious effects in non-celiac patients: Increase fermentation, and thus, distension

Increase cholinergic activation, and thus, increased smooth muscle contractility

Increase enteric NS stimulation by gluten digestion creating neurally active peptides

Symptoms may not be related to gliadin proteins of gluten Carbohydrates – fructans (in wheat)


Novak Djokavic claims his energy improved on gluten-free diet and coincided with his winning streak

“A gluten-free diet can have implications far beyond the physical, especially in tennis, which taxes the mind like few other sports.”

Hepatitis B Virus (HBV)

Image at left (10229): Courtesy of Centers for Disease Control and Prevention Public Health Image Library at: http://phil.cdc.gov/phil/home.aspImage at right adapted from Block TM, et al. Clin Liver Dis. 2007;11:685-706.

Transmission electron micrograph of HBV from blood of patient with

hepatitis B

Hepatitis B Virus

HBVDNA

pol

(–)(+)

Lipid Bilayer Envelope

CapsidCapsid

Lipid bilayer envelope


Question Number 2

Most deaths from chronic hepatitis B are due to???

A. Portal hypertension

B. Glomerulonephritis

C. Spontaneous bacterial peritonitis

D. GI hemorrhage

E. Hepatocellular Ca

Complications of CHB

w Fibrosis• Consequence of ongoing liver

injury and repair1

w Cirrhosis• Risk of progression to cirrhosis of

untreated CHB is 2-6% per year2

w End-stage Liver Disease• Typically presents 3-5 years after

a diagnosis of CHB with cirrhosis2

w Hepatocellular Carcinoma• 70% of deaths in patients with

CHB are due to HCC, with or without cirrhosis3

1. Lim YS and Kim WR. Clin Liver Dis. 2008;12:733-746.2. Weisberg IS, et al. Clin Liver Dis. 2007;11:893-916. 3. Asian Liver Center. 2007 Physician’s Guide to Hepatitis B.

http://liver.stanford.edu/Media/publications/Handbook/2007Handbook.pdf. Accessed January 9, 2009.


Treatment Guidelines:Recommendations for Patients With Cirrhosis

Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.

Compensated Cirrhosis

Note: therapies are approved for monotherapy only. *Early cirrhosis only.†Contraindicated.

Preferred PotentialNot

Preferred

Tenofovir DF Peg-IFN alfa-2a*

Lamivudine

Entecavir Adefovir Telbivudine

Decompensated Cirrhosis

PreferredNot

Preferred

Tenofovir DF plus lamivudine

Peg-IFN alfa-2aand alfa-2b†

Tenofovir DF

Entecavir

Treatment Guidelines: Recommendations for First-Line Therapy in Patients Without Cirrhosis

HBeAg Positive or Negative Chronic HBV

*HBV DNA must be undetectable at 24 weeks to continue (Keeffe). AASLD guidelines: lamivudine and telbivudine not preferred due to relatively high rate of resistance. Adefovir not preferred due to weak antiviral activity and relatively high rate of resistance in HBeAg-negative studies.

Preferred Alternative Not Preferred

Tenofovir DF Adefovir Lamivudine

Entecavir Telbivudine*

Peg-IFN alfa-2a

Lok AS, et al. Hepatology. 2009;50:661-662. Available at: http://www.aasld.org.Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341.


Duration of Treatment for Chronic HBV

HBeAg(+)• 6 to 12 months after HBsAg seroconversion to reduce relapse rate

HBeAg(-)• Relapse common after cessation of therapy; long-term treatment

currently recommended

Cirrhosis• Long-term therapy required

• Combination therapy commonly used

Keeffe EB. Clin Gastroenterol Hepatol. 2006;4:936-962.

Paul Pockros: The Last Great Hope


Question Number 3

Hepatitis C is found in what percentage of US citizens???

A. 1%

B. 2%

C. 3%

D. 4%

E. 5%

Predictions for 2010-2019

• 193,000 HCV deaths– 720,700 million years of advanced liver disease– 1.83 million years of life lost

• $11 billion in direct medical care costs

• $21.3 and $54 billion societal costs from premature disability and mortality

Wong Am J Pub Health 2000


Screening for HCV

2010 IOM Recommendation

-All patients born 1945-1964!

Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C Released: January 11, 2010 .


Targets of New Hepatitis C Antiviralscapsid

NS3 Protease domain

NS5B RNA-dependentRNA polymerase

C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B

NS3 Helicase domain

NS3 Bifunctionalprotease / helicase

© 2002 JG McHutchison, DUMC

envelope protease/helicase polymerase

p7

ProteasesDrug Company Phase

Telaprevir Vertex III

Boceprevir Merck III

TMC 435 Tibotec, Medivir IIb

BI 1335 Boehringer Ingelheim IIb

Vaniprevir (MK 7009) Merck II

Narleprevir Merck IIa (discontinued)

Danoprevir Roche/Genentech II

BMS-850032 BMS I

ACH 1625 Achillion Ib

GS 9256 Gilead Ib

ABT 450 Abbott/Enanta I

IDX 320 Idenix I (FDA hold)

GS 9451 Gilead I

ACH 2684 Achillion I

MK 6172 M k I


Emerging HCV Treatment Paradigm

• 2011: Peg-IFN + RBV + protease inhibitor

↓• 2014: Protease + polymerase +/or

other agents (+/or Peg-IFN +/or RBV)

Inflammatory Bowel DiseaseInflammatory Bowel Disease

Newer ConceptsNewer Concepts

TreatmentTreatment

Top down VS Step upTop down VS Step up


IMMUNE RESPONSE

GENETICSUSCEPTIBILITY

ENVIRONMENTALTRIGGERS & MODIFIERS

Current Model:Current Model:Pathogenesis of CrohnPathogenesis of Crohn’’s s

Disease and UCDisease and UC

Bickston SJ, et al. Curr Gastroenterol Rep. 2003;5:518.Bickston SJ, et al. Curr Gastroenterol Rep. 2003;5:518.

Environment and IBDEnvironment and IBD

Geographic distributionGeographic distribution Increase incidence in emigrants to NorthIncrease incidence in emigrants to North

SmokingSmoking

Germ free animals do not get IBDGerm free animals do not get IBD Influence of the microbiomeInfluence of the microbiome

? Infectious (? Infectious (M. paratuberculosis, E.coliM. paratuberculosis, E.coli, , Measles) Measles) –– Antibody testing Antibody testing

Diet and Diversion of fecal streamDiet and Diversion of fecal stream


Environmental TriggersEnvironmental TriggersInflammatoryBowel Disease

Infections

NSAIDsNSAIDs

StressStressSmokingSmoking

DietDiet

AntibioticsAntibiotics

IBDIBD

Normal Intestine vs. Normal Intestine vs. Intestine With IBDIntestine With IBD

Normal bowel: controlled inflammationNormal bowel: controlled inflammation

Normally: inflammationIs down-regulatedNormally: inflammationIs down-regulated

IBD: failure todown-regulate inflammation

IBD: failure todown-regulate inflammation

Chronic uncontrolledinflammation = IBDChronic uncontrolledinflammation = IBD

Environmentaltriggers (medicationsinfections, diet?)

Environmentaltriggers (medicationsinfections, diet?)

Inflamed bowelInflamed bowel

Normal bowel:controlled inflammation

Normal bowel:controlled inflammation


Management Goals in IBDManagement Goals in IBD

Define disease extent and severity and type Evaluate for extra-intestinal disease and

complications Induction of clinical remission

– Short term side effects balanced vs. disease severity

Maintenance of remission– Medical vs. Surgical– STEROID SPARING************************

Education and improvement of quality of life “Step up” vs “Top down therapy”

Therapeutic Options in IBDTherapeutic Options in IBD

Crohn’s Disease– 5-Aminosalicylates– Antibiotics– Corticosteroids– 6-MP/AZA– Methotrexate– Biologics (TNFs)– Tacrolimus– Probiotics?– Surgery

Ulcerative Colitis– 5-Aminosalicylates

– Corticosteroids

– 6-MP/AZA

– Cyclosporine

– Biologics (only infliximab to date)

– Probiotics?

– Surgery


Top down vs Step up RxTop down vs Step up Rx

Should we use TNFs earlierShould we use TNFs earlier


Summary for IBDSummary for IBD

Pathogenesis remains obscure stillPathogenesis remains obscure still Role of Microbiome keyRole of Microbiome key

Serology has limited role in diagnosisSerology has limited role in diagnosis Helpful in borderline casesHelpful in borderline cases

Treatment options have increasedTreatment options have increased Individualized therapy bestIndividualized therapy best

Top down appropriate for some patientsTop down appropriate for some patients


Which of the following Which of the following extraextra--intestinal intestinal manifestations of IBD manifestations of IBD does not respond to does not respond to treatment of the IBD???treatment of the IBD???

A.A. Primary sclerosing Primary sclerosing cholangitischolangitis

B.B. Erythema nodosumErythema nodosum

C.C. SacroileitisSacroileitis

D.D. Acute arthritisAcute arthritis

E.E. A and CA and C

F.F. B and DB and D


Colon Cancer ScreeningColon Cancer Screening

Review of the GuidelinesReview of the Guidelines


What is the lifetime What is the lifetime risk for colon risk for colon cancer in the cancer in the United States?United States?

A.A. 2%2%

B.B. 4%4%

C.C. 6%6%

D.D. 8%8%

E.E. 10%10%


Colon CancerColon Cancer

Second most common cause of cancer deathSecond most common cause of cancer death

Prototypical disease for screeningPrototypical disease for screening Intermediate probability of diseaseIntermediate probability of disease

Significant impact on public healthSignificant impact on public health

Well defined, modifiable disease progressionWell defined, modifiable disease progression

USPSTFUSPSTF ACS ACRACS ACR

USMSTFCCUSMSTFCC

ACGACG

AgeAge 5050--7575 5050 50/45 AfAm50/45 AfAm

ColonoscopyColonoscopy 10 yrs10 yrs 10 yrs10 yrs 10yrs10yrs

Flex SigFlex Sig 5 yrs5 yrs 55--10 yrs10 yrs

FS/FOBTFS/FOBT 5 yrs/ 3 yrs5 yrs/ 3 yrs

DCBEDCBE 5 yrs5 yrs

CT CT ColonographyColonography

Insuff EvidInsuff Evid 5 yrs5 yrs 5 yrs5 yrs

FOBTFOBT YearlyYearly YearlyYearly YearlyYearly

FITFIT YearlyYearly YearlyYearly Pt refusesPt refuses

Stool DNAStool DNA ??

Current Guidelines


Average Risk Screening: Average Risk Screening: RecommendationsRecommendations

Stool cards(yearly); FIT??

Flexiblesigmoidoscopy(every 3–5 years)

Colonoscopy(every 10 years)

Barium enema(every 5 years)

OR

OR

AND

FUTURE?Stool DNACT colonographyCapsule Colonoscopy

≥50 years old

Preferred: ACG and MSGITFPreferred: ACG and MSGITF

Option: USPSTF, ACS, AGAOption: USPSTF, ACS, AGA

New Recommendations for New Recommendations for AfricanAfrican--AmericansAmericans

Younger mean age at diagnosis (60Younger mean age at diagnosis (60––66 years)66 years)

Higher incidence ratesHigher incidence rates

Higher mortality ratesHigher mortality rates

More proximal distribution of cancers and adenomasMore proximal distribution of cancers and adenomas

Recent American College of Gastroenterology Recent American College of Gastroenterology recommendations to beginrecommendations to begin averageaverage--risk screening at risk screening at age 45age 45

http://seer.cancer.gov/csr/1975http://seer.cancer.gov/csr/1975--2000. Access February 23, 2006. Agrawal S, et al. 2000. Access February 23, 2006. Agrawal S, et al. Am J Gastroenterol.Am J Gastroenterol. 2005;100:5152005;100:515––523. Ghafoor A, et al. 523. Ghafoor A, et al. CA Cancer J Clin.CA Cancer J Clin.2002;52:3262002;52:326––341.341.


Screening Compliance is LowScreening Compliance is Low

Cancer Prevention and Early Detection, Fact s and Figures 2008

Stool Transplants:Stool Transplants:Everyone is doing it!Everyone is doing it!


Stool Transplants: How ToStool Transplants: How To

Stool transplants: Stool transplants: ““preparedprepared”” feces by feces by NGT or enema or colonoscopyNGT or enema or colonoscopy

Usually family member; 30Usually family member; 30--50 g fresh 50 g fresh stoolstool

Stool homogenized for deliveryStool homogenized for delivery

No infectious complications to dateNo infectious complications to date

Screen for Hepatitis, HIV, etcScreen for Hepatitis, HIV, etc……

7373--100% response reported in C Diff100% response reported in C Diff

Gastro 2006;130 Clin Infect Dis 2003;36

Stool Transplant: EvidenceStool Transplant: Evidence

2003 case series of refractory 2003 case series of refractory C diffC diff patients patients Stool via NG from healthy family memberStool via NG from healthy family member

15 of 18 became recurrence15 of 18 became recurrence--freefree

2009 case series of refractory 2009 case series of refractory C diff C diff patientspatients 11 of 15 became recurrence11 of 15 became recurrence--freefree

2010 case series of refractory C diff patients2010 case series of refractory C diff patientsStool via colonoscopyStool via colonoscopy

12 of 12 with immediate and sustained response12 of 12 with immediate and sustained response

Clin Infect Dis 2003;36: 540-544 QJM 2009;102:781-784 Yoon, J of Clin Gastro 2010, 44:562-66


Colonoscopy Stool TransplantsColonoscopy Stool Transplants

Coming to your neighborhood soonComing to your neighborhood soon……..

Stool transplants done here.

Donations accepted.


CoyleCoyle’’s Corollarys Corollary

It is better to be a stool donor

than a recipient.

Stool donor cards will be made available after this

lecture.


Stool Donor Card

Share your stool; stop C diff

Clinical Gastro Hep 2008; 759-764


MethodsMethods

Prosp. study; 113 pts with rosacea 60 controlsProsp. study; 113 pts with rosacea 60 controls

Derm Assessment by two docsDerm Assessment by two docs 7 point scale7 point scale

All subjects completed global scoreAll subjects completed global score

Baseline labs, Urease BT, H2 Breath testsBaseline labs, Urease BT, H2 Breath tests Lactulose BT: 1Lactulose BT: 1stst, + test if double peak seen, + test if double peak seen

Glucose BT: 2Glucose BT: 2ndnd (1 wk later), + test single peak(1 wk later), + test single peak

Hp + pts, treated then reHp + pts, treated then re--tested by H2 BTtested by H2 BT

If both Hp + and SIBO+: rx SIBO 1stIf both Hp + and SIBO+: rx SIBO 1st

Results: SIBO pos and neg ptsResults: SIBO pos and neg pts

Clinical Gastro Hep 2008; 759-764


Rosacea and the MicrobiomeRosacea and the Microbiome

DiscussionDiscussion

SIBO common in Rosacea ptsSIBO common in Rosacea pts

Esp those with papulopustulesEsp those with papulopustules

Rx of SIBO results in dramatic improvement of rashRx of SIBO results in dramatic improvement of rash

78% resolved/17% improved (95% total)78% resolved/17% improved (95% total)

Affect is sustained (9 months); relapse can be reAffect is sustained (9 months); relapse can be re--treatedtreated

Hypothesis: SIBO increases intest absorption of Hypothesis: SIBO increases intest absorption of bacterial products, esp endotoxin, proinflam cytokinesbacterial products, esp endotoxin, proinflam cytokines

SIBO more important then colonic bacteria (SIBO SIBO more important then colonic bacteria (SIBO neg rosacea pts did not respond as well)neg rosacea pts did not respond as well)


Question number 4.Question number 4.What is the cause of discoloration?What is the cause of discoloration?

A.A. Strep toxic shock Strep toxic shock syndromesyndrome

B.B. Gray Turner sign from Gray Turner sign from pancreatitispancreatitis

C.C. Cannabinoid Cannabinoid hyperemesis syndromehyperemesis syndrome

D.D. HeparinHeparin--induced induced cutaneous hemorrhagecutaneous hemorrhage

Cannabinoid Hyperemesis Cannabinoid Hyperemesis SyndromeSyndrome

First reported in AustraliaFirst reported in Australia

Chronic, heavy marijuana useChronic, heavy marijuana use More common in malesMore common in males

Recurrent episodes of abdominal pain and Recurrent episodes of abdominal pain and vomitingvomiting

Compulsive hot bathing and showers for relief Compulsive hot bathing and showers for relief of symptomsof symptoms

Rx: Rx: Quit the Weed!Quit the Weed!

Singh E, Coyle W. Am J Gastro 2008;103:1048-49


The Microbiome and The Microbiome and ProbioticsProbiotics

The Human MicrobiomeThe Human Microbiome

Definitions: Definitions: Microbiome: Aggregate of all gut speciesMicrobiome: Aggregate of all gut species Microbiota: Individual bacterial species in the biomeMicrobiota: Individual bacterial species in the biome

Over 100 trillion organisms (10Over 100 trillion organisms (101414)) Passengers in the mobile colonic petri dishPassengers in the mobile colonic petri dish Over 500 species identified so far (70 divisions)Over 500 species identified so far (70 divisions) 90% of the cells in our body our microbial!90% of the cells in our body our microbial!

100 fold more genes in our gut then in us100 fold more genes in our gut then in us Our flora are an integral part of our genetic Our flora are an integral part of our genetic

landscape and evolutionlandscape and evolution


The Human Gut Flora

DiBiase, et al. Mayo Clin Proc 2008;83:460-469

Microbes and Humans

Dethlefsen Nature 2007; 449:812-818


Gut Flora and MetabolismGut Flora and Metabolism

Microbial genomes enhance our metabolic activityMicrobial genomes enhance our metabolic activity May indirectly or directly effect our metabolismMay indirectly or directly effect our metabolism

The colon is very active metabolicallyThe colon is very active metabolically 2020--70 gms of carbos and 570 gms of carbos and 5--20 gms of protein/day20 gms of protein/day

Over 100 kcal per day!Over 100 kcal per day!

Mass of colonic microbiome = single kidneyMass of colonic microbiome = single kidney Metabolically as active as the liverMetabolically as active as the liver

Hooper, et al. Annu Rev Nutr, 2002

ProbioticsProbiotics

Definition: Live microorganisms which when Definition: Live microorganisms which when ingested in adequate amounts confer a health ingested in adequate amounts confer a health benefit on the host. benefit on the host.

Majority of probiotics are Gram +, lactic acid Majority of probiotics are Gram +, lactic acid producers (ie. Firmacutes)producers (ie. Firmacutes) Bifidobacterial species and Bifidobacterial species and LactobacillusLactobacillus speciesspecies Survive transit through stomach and duodenumSurvive transit through stomach and duodenum

Others include: nonOthers include: non--pathogenic streptococci, pathogenic streptococci, enterococci, enterococci, E coliE coli Nissle 1917, Nissle 1917, Saccharomyces Saccharomyces boulardiiboulardii (yeast)(yeast)

Fooks, et al. Int Dairy J, 1999 Sheil, et al. In Gastrointestinal Microbiology, 2006



Which probiotic Which probiotic has been shown to has been shown to decrease mucosal decrease mucosal ILIL--6 levels?6 levels?

A.A. Lactobacillis acidopholusLactobacillis acidopholus

B.B. Bifidobacter infantisBifidobacter infantis

C.C. Saccharomyces boulardiiSaccharomyces boulardii

D.D. Lactobacillus rhamnosus Lactobacillus rhamnosus GGGG


VSL #3VSL #3

4 lactobacilli4 lactobacilli L. plantarum, casei, L. plantarum, casei,

acidopholus, delbrueckii acidopholus, delbrueckii sppspp

3 bidifobacteria3 bidifobacteria B. infantis, breve, longumB. infantis, breve, longum

1 streptococcus1 streptococcus Streptococcus salivarius ssp. Streptococcus salivarius ssp.

thermophilusthermophilusRand, PC studies have shown efficacy in pouchitis and IBSSome efficacy in mild/mod UC in new study



Digestive AdvantageDigestive Advantage Ganeden BCGaneden BC3030

Bacillus coagulansBacillus coagulans

ErythritolErythritol

CelluloseCellulose

Other minor ingredients Other minor ingredients

Some data for IBSSome data for IBS Mostly bloatingMostly bloating

Postgrad Med, Vol. 121, Issue 2, March 2009


Bifidobacterium infantisBifidobacterium infantis35624 aka Bifantis 35624 aka Bifantis

““PatentedPatented”” strain of strain of probiotic in Alignprobiotic in Align

Decreased symptoms in Decreased symptoms in two large trials in two large trials in subjects with IBS*subjects with IBS*

*Whorwell P, et al. Am J Gastro 2006; 101O’Mahoney L, et al. Gastro 2005;128



Saccharomyces Saccharomyces boulardiiboulardii

Other minor ingredientsOther minor ingredients

Shown in Rand / PC Shown in Rand / PC trials to help prevent trials to help prevent recurrent recurrent C. difficileC. difficileinfectioninfection

Decreases antibiotic Decreases antibiotic associated diarrheaassociated diarrhea

Am J Gastroenterol. 2006 Apr;101(4):812-22McFarland, et al. JAMA 1994;271:1913-8

Probiotics in Food (Actimel)Probiotics in Food (Actimel)

L. caseiL. casei ImmunitasImmunitas™™

Claim it is scientifically Claim it is scientifically proven to be effectiveproven to be effective

““Each bottle contains Each bottle contains 10 billion live10 billion live”” bacteria bacteria ““that survive and that survive and remain active in theremain active in the

digestive tract.digestive tract.””


Probiotics in Food (Activia)Probiotics in Food (Activia)

Contains Contains Bifidus regularisBifidus regularis

Bifidobacterium animusBifidobacterium animus

Scientific trials show Scientific trials show increased transit time in increased transit time in adults and womenadults and women

““Helps with slow transit in Helps with slow transit in women and the elderlywomen and the elderly””

Bioscience and Microflora, 2001;20:43-48,Aliment Pharn Ther 2002;16:587-93

Probiotics for Immune SystemProbiotics for Immune System

Lactobacillus rhamnosusLactobacillus rhamnosus GG (ATCC GG (ATCC 53103)53103)

Patented by Gorbach and GoldinPatented by Gorbach and Goldin

Various studies have shown it to Various studies have shown it to be better than placebo for diarrheal be better than placebo for diarrheal illnessesillnesses

Proven to survive the stomach, Proven to survive the stomach, produces lactic acid and binds to produces lactic acid and binds to human colonocyteshuman colonocytes

BMJ 2007; 335 : 340-345


Probiotics and prebiotics in maintenance of Probiotics and prebiotics in maintenance of remission in Crohnremission in Crohn’’s diseases disease

Study Groups Relapse Rate (%)

n Intervention Comparator Dur Intervention Comparator p

Guslandi (2000)

32 S. Bouliardii +

Mesalamine

Mesalamine 6 6 38 0.04

Campieri (2000)

40 VSL #3 Mesalamine 12 20 40 NR

Prantera (2002)

45 LGG Placebo 12 17 11 0.3

Schultz (2004)

11 LGG Placebo 6 60 67 NS

Bousvaros (2005)

75 LGG Placebo 24 31 17 0.18

Marleau (2006)

98 L. johnsonii Placebo 6 49 64 0.15

Van Gossum (2007)

70 L. johnsonii Placebo 3 15 14 0.91

Chermesh (2007)

30 Synbiotic 2000

Placebo 24 25 20 NS

Clostridium difficileClostridium difficile


Clostridium difficile Clostridium difficile and altered and altered microbiotamicrobiota

Confirmed BI NAP1 strainConfirmed BI NAP1 strain

Gerding, et al. GASTRO 2009;136:1913–1924


Metronidazole failuresMetronidazole failures

Leffler and Lamont in GASTRO 2009;136:1899–1912

New New C Difficile C Difficile Rx GuidelinesRx Guidelines

Infect Control Hosp Epidemiol 2010; 31(5):431-455


Burden Of CDI in USBurden Of CDI in US

Gerding, et al. GASTRO 2009; 136:1913–1924

TreatmentTreatment

DC offending antibiotic (s) if possibleDC offending antibiotic (s) if possible

Avoid antiperistaltic agents (incl narcs)Avoid antiperistaltic agents (incl narcs)

Supportive care (hydrate, electrolytes)Supportive care (hydrate, electrolytes)

Antimicrobial therapy:Antimicrobial therapy: Oral metronidazole: 250 mg qid or 500 mg TID Oral metronidazole: 250 mg qid or 500 mg TID

for 10 days; low cost, effectivefor 10 days; low cost, effective

Oral Vancomycin: 125Oral Vancomycin: 125--250 mg QID for 10 days250 mg QID for 10 days High costHigh cost

Ann Intern Med 2006;145

Gastro 2009; 136:1913–1924


Recurrence: Probiotic Treatment Recurrence: Probiotic Treatment of of C difficileC difficile


Saccharomyces boulardii: 500 mg bid for 4Saccharomyces boulardii: 500 mg bid for 4--6 wks6 wks

Best evidence of all probioticsBest evidence of all probiotics

Several DB / PC trials show good efficacySeveral DB / PC trials show good efficacy

Lactobacilli: 1 g qid for 4Lactobacilli: 1 g qid for 4--6 weeks6 weeks

Evidence not as convincingEvidence not as convincing

PO nontoxicogenic C Diff: experimentalPO nontoxicogenic C Diff: experimental

Effective but only case reports to dateEffective but only case reports to date

Gastro 2006;130 Ann Intern Med 2006; 145 Am J Gastroenterol 2006; 101:812–822.

FidaxomicinFidaxomicin

Macrocyclic antibioticMacrocyclic antibiotic

Cure: 88.2% vs 85.8% vancomycinCure: 88.2% vs 85.8% vancomycin

Recurrence Rate: 15.4 % vs 25.3 % Recurrence Rate: 15.4 % vs 25.3 %

FDA approved.FDA approved.



NEJM 2011;364:422-431


FDA approved May 2011FDA approved May 2011

Macrolide Ab: Aka Macrolide Ab: Aka DificidDificid

Dose: 200 mg BID for 10 daysDose: 200 mg BID for 10 days

Estimated cost: $2800 for full courseEstimated cost: $2800 for full course

WaltWalt’’s Recs Rec: : Not first line, too expensiveNot first line, too expensive Save for recurrent Save for recurrent C. difficileC. difficile infectionsinfections


Probiotics and DiarrheaProbiotics and Diarrhea

135 hospitalized pts given antibiotics135 hospitalized pts given antibiotics

DB, PC, Rand trialDB, PC, Rand trial

Probiotic Yogurt (Actimel) or PC BIDProbiotic Yogurt (Actimel) or PC BID

Diarrhea: 34% PC vs 12% active (NNT:5)Diarrhea: 34% PC vs 12% active (NNT:5)

C DiffC Diff: Less often in Rx arm (NNT: 6): Less often in Rx arm (NNT: 6)

First rand trial to show prevention of First rand trial to show prevention of C diff C diff with with probioticsprobiotics

Hickson M, et al. BMJ, 2007:335-80

Probiotics and PancreatitisProbiotics and PancreatitisNot all good news!Not all good news!

296 hospitalized pts with acute pancreatitis given 296 hospitalized pts with acute pancreatitis given probioticsprobiotics

DB, PC, Rand trial; Given in tube feedingsDB, PC, Rand trial; Given in tube feedings

Probiotic : Ecologic 642 (Probiotic : Ecologic 642 (L. acidophilus, casei, L. acidophilus, casei, salivarius, lactis and B. bifidum, lactissalivarius, lactis and B. bifidum, lactis.).)

Morbidity: No difference in infectionsMorbidity: No difference in infections

Mortality: 24 (16%) vs 9 (6%) in PCMortality: 24 (16%) vs 9 (6%) in PC 9 pts in Rx arm developed ischemic bowel9 pts in Rx arm developed ischemic bowel

Besselink M, Gooszen H, et al Lancet 2008:371:651-659


PrebioticsPrebiotics


Ingested substances that selectively stimulate the Ingested substances that selectively stimulate the proliferation and/or activity of desirable proliferation and/or activity of desirable bacterial populations present in the host bacterial populations present in the host intestinal tract.intestinal tract.

Usually target bifidobacteria and lactobacilliUsually target bifidobacteria and lactobacilli Bifidogenic or bifidus factors explored in the 50sBifidogenic or bifidus factors explored in the 50s

Usually are nonUsually are non--digestible oligosaccharides digestible oligosaccharides (NDOs)(NDOs) Lactulose, galactoLactulose, galacto--oligosaccharides, lactosucroseoligosaccharides, lactosucrose……

Crittenden and Playne. In Gastrointestinal Microbiology, 2006, pg 285-314.



Inulin: plant polymers Inulin: plant polymers mainly comprising mainly comprising fructose units, use have a fructose units, use have a terminal glucoseterminal glucose

Indigestable fiberIndigestable fiber

Gut flora produce H2, Gut flora produce H2, CO2, methane gas from CO2, methane gas from inulininulin


Inulin: plant polymers mainly Inulin: plant polymers mainly comprising fructose units, comprising fructose units, use have a terminal glucoseuse have a terminal glucose

Indigestable fiberIndigestable fiber

Gut flora produce H2, CO2, Gut flora produce H2, CO2, methane gas from inulinmethane gas from inulin

““Breakfast of FlatulanceBreakfast of Flatulance””



Feed your flora!!!


Is is possible to design a food, sugar, protein, or Is is possible to design a food, sugar, protein, or fat that would alter your gut flora to promote fat that would alter your gut flora to promote weight loss?weight loss?

More likely possibility is to give a prebiotic that More likely possibility is to give a prebiotic that decreases your decreases your ““Energy HarvestEnergy Harvest”” of colonic of colonic bacteriabacteria ie. lose weight by making your gut flora less efficient ie. lose weight by making your gut flora less efficient

at digesting your left over food at digesting your left over food


Designing Probiotics: The Future?Designing Probiotics: The Future?

GASTROENTEROLOGY 2009;136:2015–2031

ConclusionsConclusions

Future studies must focus on the mechanisms of Future studies must focus on the mechanisms of influence of our gut flora.influence of our gut flora.

Studies must be placebo controlled and high Studies must be placebo controlled and high quality.quality.

Truly need translational science to work at the Truly need translational science to work at the levels of the petri dish, genomics, and clinical levels of the petri dish, genomics, and clinical outcomes.outcomes.

Much more to come!Much more to come!


GI Update: SummaryGI Update: Summary

Longstanding dysphagia: Think EoELongstanding dysphagia: Think EoE

PPIs: Use them thoughtfullyPPIs: Use them thoughtfully

Be smart about Celiac disease: Know the testsBe smart about Celiac disease: Know the tests

Many new options for Hepatitis B and CMany new options for Hepatitis B and C

TNFs will be used more often for IBDTNFs will be used more often for IBD

Colon cancer screening: DO IT!Colon cancer screening: DO IT!

GI Update: SummaryGI Update: Summary

Stool transplants: Not ready for prime timeStool transplants: Not ready for prime time

Think SIBO with RosaceaThink SIBO with Rosacea

Pot and vomiting: Ask about hot bathsPot and vomiting: Ask about hot baths

Microbiome: research will explodeMicrobiome: research will explode

C. difficileC. difficile: the pest is here to stay: the pest is here to stay


QuestionsQuestions

Break TimeBreak Time

THE CALLTHE CALL


First Rule: Never go to “check” a puppy out

The Visit

Review of Bloodline


Rule two: Never believe that parents have anything to do with the pup

Rule Three: Never bring the puppy home


The InfectionThe Infection


The DecisionThe Decision


Probiotics and Probiotics and C. DifficileC. Difficile

124 Adults with 124 Adults with C difficile C difficile (Rand, PC)(Rand, PC) 64 164 1stst episode, 60 recurrent CDADepisode, 60 recurrent CDAD

Standard Ab with Standard Ab with S. boulardii S. boulardii or PBO or PBO

Outcome: Recurrence of CDADOutcome: Recurrence of CDAD 11stst Episode: 19.3% vs 24.2% (P=.86)Episode: 19.3% vs 24.2% (P=.86)

Rec CDAD: 34.6% vs 64.7% (P=.04)Rec CDAD: 34.6% vs 64.7% (P=.04)

S. boulardii S. boulardii reduces risk for recurrence in subjects reduces risk for recurrence in subjects with recurrent with recurrent C difficileC difficile

McFarland, et al. JAMA 1994;271:1913-8


PPIs and ClopidogrelPPIs and Clopidogrel

Most PPIs are metabolized partly via CYP 2C19Most PPIs are metabolized partly via CYP 2C19

CYP 2C19 critical for activation of clopidogrelCYP 2C19 critical for activation of clopidogrel

Very mixed data whether PPIs decrease efficacy Very mixed data whether PPIs decrease efficacy of clopidogrel: ie. of clopidogrel: ie. Concern is stent patencyConcern is stent patency

Prompted FDA warningPrompted FDA warning

The only Rand/PC controlled studyThe only Rand/PC controlled study Showed no effect from PPIs on stent occlusionShowed no effect from PPIs on stent occlusion

Study stopped due to funding shortageStudy stopped due to funding shortage

COGENT TRIALCOGENT TRIAL

N Engl J Med 2010;363:1909-17

-3761 subjects-CV Event Rate:

4.9% vs 5.7%


COGENT TRIALCOGENT TRIAL

N Engl J Med 2010;363:1909-17

-3761 subjects-GI event rate:1.1% vs 2.9%

COGENT TrialCOGENT Trial

End point Placebo, n PPI, n p

All CV events 67 69 NS

MI 37 36 NS

Revascularization 67 69 NS

GI events 67 38 0.007

COGENT event ratesCOGENT event rates

Bhatt D. TCT 2009; Sept 24, 2009; San Francisco, CA.

update in gi: what’s new and useful - scripps.org for the primary care physician walter j. coyle,...

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