UPPER AND LOWER GI REVIEW

Michael Saunders, MDClinical Professor of Medicine

Director, Digestive Disease CenterDivision of Gastroenterology

University of Washington Medical Center

Case 1 36yo male with chronic

dysphagia and multiple food impactions (earliest at age 6)

Ongoing dysphagia Constant, primarily solids has to drink water with

bread to get it to go down Last food impaction 3

months ago No heartburn PmHx includes asthma

and ectopic dermatitis

Endoscopy

Correct statements regarding this condition include which of the following?

a) Typically affects white, middle-aged men

b) High prevalence of co-existing allergic disorders (allergic rhinitis and asthma)

c) Characterized by eosinophilic infiltration of the mucosa (>15-20 eosinophils/hpf)

d) Corticosteroid therapy produces symptomatic, endoscopic and histologic improvement in the majority of patients

e) All of the above

Approach to dysphagia

Eosinophilic esophagitis (EoE):

Chronic inflammatory disorder of the esophagus characterized by eosinophilic infiltration of the mucosa >15-20 eosinophils/hpf

Presenting symptoms: dysphagia (>90%) food impaction (62%) heartburn (25%) children: vomiting, regurgitation, abd pain

In adults, typically presents in white, middle-aged men (average age 38)

High prevalence of allergies (allergic rhinitis and asthma) in both pediatric and adult EoE pts

Suggests food allergies may play a role in pathogenesis

EoE: Treatment Systemic or topical corticosteroids

produces symptomatic, endoscopic and histologic improvement/resolution in the majority of pts

sxs and eos return w/in 3–6mo after d/c endoscopic dilation Allergy testing dietary therapy

Elimination diet leads to symptom and histologic improvement

Most common identified food triggers: ○ milk, wheat, soy, egg

J Clin Gastroenterol. 2010 ;44(1):22-7; Gastroenterol 2012; 142:1451

A 53 year old female with chronic GERD presents toestablish care. Her symptoms are completely resolved onPPI therapy. You recommend continued therapy with aPPI. The patient inquires about long-term efficacy andsafety of PPIs. Which of the following statements is correct?

a) Co-administration with clopidrogel should be avoided due to increased risk of cardiovascular outcomes

b) Therapy should be limited to 6 months as there is gastric atrophy with an risk of adenocarcinoma in long-term users

c) PPI therapy may be associated with an increased risk of infections in hospitalized patients

d) Long term therapy should be avoided due to the increased risk of hip fracture with long term use

Safety of PPI’sConcern Reality

Gastric cancer No atrophic gastritis, metaplasia or dysplasia

Infections Slight risk of dysentery during foreign travel­ risk of C. diff↑ infections in cirrhotic patients

B12 malabsorption No cases of Pernicious anemia

Osteoporois No bone density changes or calcium malabsorption evident in prospective trials

Hypomagnesemia Rare, clinical significance uncertain

Reduced effectiveness of clopidrogel

Conflicting dataNo association with adverse events in prospective studies

Fioca et al. Aliment Pharm Ther 2012;36:959; Brunner et al. Aliment Pharm Ther 2012; 36:372007; 5:1418; Bajaj et al. Aliment Pharmacol Ther 2012; 36:866

Calcium and acid secretion Acid facilitates the release of ionized calcium from

insoluble calcium salts gastrectomy and pernicious anemia are linked to

increased risk of osteopenia and fracture Calcium carbonate absorption decreases at higher pH

People with achlorhydria have decreased absorption of calcium carbonate on an empty stomach

Absorption is normal when calcium carbonate is ingested with a meal

Therapy with a full dose of omeprazole did not reduce the absorption of calcium contained in milk and cheese in normal controls

In vitro osteoclast activity impaired by PPIsYang and Metz. GASTROENTEROLOGY 2010;139:1115–1127

Is acid reducing therapy associated with risk of hip fracture?

Data is confusing at best likely due to confounding variables

No convincing data available that PPI’s decrease calcium absorption or bone density

Premature to avoid prescribing acid-reducing agents to those who have a clear indication

Weigh risk of fracture to benefit of acid suppression

Yang and Metz. GASTRO 2010;139:1115–1127

11/17/09 Press Release

“Until further information is available FDA recommends the following:Healthcare providers should re-evaluate the

need for starting or continuing treatment with a PPI, including Prilosec OTC, in patients taking clopidogrel. 

Patients taking clopidogrel should consult with their healthcare provider if they are currently taking or considering taking a PPI, including Prilosec OTC. “

Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT)

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

Probability of Remaining Free of Primary Cardiovascular events

Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT)

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

Probability of Remaining Free of Primary Gastrointestinal Events

The potential of PPIs to attenuate the efficacy of clopidogrel could be minimized by the use of dexlansoprazole or lansoprazole

Frelinger et al. J Am Coll Cardiol 2012;59:1304–11

Which of the following statements pertaining to esophageal cancer and GERD are correct?

a) The incidence of esophageal cancer is rising, surpassing that of colon cancer.

b) Approximately 10% of patients with chronic GERD develop esophageal cancer

c) Acid suppression and antireflux surgery do not eliminate BE or its cancer risk

d) Most patients with Barrett’s esophagus will present with chronic GERD symptoms and be detected at upper endoscopy

Incidence of Esophageal Adenocarcinoma

In 2009, ~16,400 new cases of esophageal cancer60% adeno-

carcinomas5-year survival

rate, 15 to 20%

Sharma. N Engl J Med 2009;361:2548-56

Barrett’s esophagus

premalignant lesion detected in the majority of patients with esophageal adenocarcinoma

Occurs in ~10% of patients having endoscopies for chronic GERD

The reported incidence of Barrett’s esophagus is rising

Risk factors include advanced age, male sex, white race, symptoms of reflux, and obesity

30 fold risk of esophageal cancer Acid suppression/antireflux surgery do not

eliminate BE or its cancer risk

Sharma. N Engl J Med 2009;361:2548-56

What is the best estimate of annual risk fordeveloping adenocarcinoma with Barrett’sesophagus?

a) 100%b) 50%c) 25%d) 5%e) 0.5%

How often does non-dysplastic Barrett’s (NDBE) progress to cancer?

the annual incidence of EAC would need to be >1.9% per year for surveillance of NDBE at 5-year intervals to be cost-effective2

low rate of progression to cancer reinforces the current expert consensus that routine endoscopic ablation of NDBE is not justified

1-Wani et al. Clin Gastroenterol Hepatol 2011 Mar; 9:220; 2 – Inadomi et al. Ann Intern Med 2003; 138:176

Diagnosis No. of cases Incidence rate Mean time to development

LGD 217 3.6% 4.59y

HGD 32 0.48% 5.6y

EAC 18 0.27% 5.297

HGD/EAC 42 0.63% 5.41y

Incidence of Dysplasia and EAC in 1204 patients with NDBE1

Incidence of Cancer in Barrett’s dysplasia

Paulson, Reid. Cancer Cell. 2004 Jul;6(1):11-6.

Mean annual incidence <0.5%

Management of Barrett’s esophagus

Sharma. N Engl J Med 2009;361:2548-56

Management of Barrett’s dysplasia

Sharma. N Engl J Med 2009;361:2548-56; Spechler et al. Gastroenterol 2011

*HGD should be treated

Endoscopic mucosal resection (ER)* Radiofrequency ablation (RFA)* Photodynamic therapy (PDT)* Cryotherapy Other (argon plasma coagulation, multipolar

electrocautery, laser)

Endoscopic treatments for Barrett’s esophagus

* Prospective data available

EMR in early esophageal cancer

Radiofrequency ablation (RFA)

Multi-modality therapy for early Barrett’s neoplasia: endoscopic resection followed

by radiofrequency energy ablation.

Multi-modality therapy for early Barrett’s neoplasia: endoscopic resection followed

by radiofrequency energy ablation.

Case Presentation

An 52-year-old woman with sudden onset of epigastric/RUQ pain

PE: temp 37.0 C; HR 90, BP 110/70 mm Hg; no scleral icterus; Abdominal exam reveals mild RUQ tenderness without guarding or rebound

Labs:WBC 12,000; aminotransferases:   AST 935   ALT 1346; alk phos 98 , amylase 143, bilirubin (total) 1.8

abd u/s reveals a CBD 9 mm; No gallstones peri-cholecystic fluid are noted

What is the most likely diagnosis?

1. Acute viral hepatitis

2. Ischemic hepatitis

3. Acute common bile duct obstruction

4. Acute pancreatitis

5. Acute cholecystitis

Differential diagnosis of acute transaminase elevation > 1000

Viral hepatitis Toxin/drug Ischemia Acute CBD obstruction (stone)

Biliary tract stone disease

•Cholelithiasis :• symptomatic cholelithiasis• acute cholecystitis

•Choledocholithiasis• symptomatic CBD stone• cholangitis• pancreatitis

An 82-year-old woman presents with sudden onset of right upper quadrant abdominal pain, fever, and shaking chills.

PE: temperature is 39.0 C (102.2 F). Pulse rate is 110 per minute, and blood pressure is 90/70 mm Hg. Slight jaundice is noted. Heart and lungs are normal. Abdominal examination reveals mild right upper quadrant tenderness without guarding or rebound. Mental status is normal.

Leukocyte count 12,000 ;  AST 235   ALT 343, alkaline phosphatase 298 , amylase 78, bilirubin (total) 4.5Abd u/s : common bile duct measuring 15 mm in diameter; distended gallbladder with sludge, no peri-cholecystic fluid or stones are noted.

The most likely diagnosis is?

1 2 3 4

25% 25%25%25%1. Acute cholangitis

2. Acute cholecystitis

3. Perforated peptic ulcer disease

4. Acute mesenteric ischemia

Cholangitis - infection in biliary tree Cholangitis requires:

• Bacteria (Bile is normally sterile)Source of bacteria in bile:

• intestinal translocation and portal bacteremia• reflux from duodenum• gallbladder/stones

• Obstruction of biliary tract Death may result within hours of presentation Associated with significant morbidity/mortality Early recognition and treatment are essential Urgent biliary decompression

Acute cholangitis:Clinical Presentation and diagnosis

Charcot’s Triad (~70%):• Abdominal pain• Fever• Jaundice

Labs: Leukocytosis Abnormal LFT’s

Blood cultures

Imaging: Ultrasound/CT scan

- choledocholithiasis (<50%)

- biliary dilation (~75%)

Case (continued)

Broad spectrum ABx are begun, but the patient develops rigors after receiving the initial dose. Temperature is now 39.6 C (103.3 F). Pulse rate is 120 per minute, and blood pressure is 82/60 mm Hg. She appears slightly confused.

Which of the following is most appropriate now? 1. Continuation of antibiotic

regimen with the addition of imipenem

2. Immediate ERCP with biliary drainage

3. Immediate percutaneous transhepatic cholangiography and external biliary drainage

4. Immediate surgery

Management of Cholangitis

• Volume resuscitation

• Antibiotics (Pip/Tazo, Amp/Sul, Ticar/Clav, 3o Ceph, Imipenem, Levofloxacin, Cipro)

• Biliary decompressionTimingRoute (ERCP > PTC > Surgery)

Case Presentation 45 yo man developed acute onset of epigastric

pain requiring transport via ambulance to the ER PMHX: unremarkable. No chronic meds. No EtOH. Exam: T 38.0, BP 150/100, HR 110

Moderate distress, in obvious discomfortmod-severe tenderness with guarding, distention,

hypoactive BS, no peritoneal signs LABS:

WBC 20,000, Hct 50, BUN 60, Cr 2.2, AST 350, ALT 460, Total Bilirubin 5.0, Alk phos 270, Amylase 1200

The most likely diagnosis is?1. Acute mesenteric

ischemia

2. Acute cholecysitis

3. Acute pancreatitis

4. Small bowel obstruction

5. Rupture abdominal aortic aneurysm

Diagnosis of acute pancreatitis Clinical (requires 2 of the following):

Characteristic epigastric painElevated pancreatic enzyme levels (>3x upper

limits of normal)Abnormal imaging (inflammatory changes in

pancreas)

Evaluation of acute pancreatitis

Edematous/Interstitial (IP) vs. Necrotizing (NP)

Organ failure in 15% compared with 80%

The most likely cause of the pancreatitis is?

a) Alcohol abuse

b) Gallstones

c) Hypertriglyceridemia

d) Trauma

e) idiopathic

Etiology of acute pancreatitis

Obstructive

Toxins/drugs

Metabolic

Infection

Vascular

Trauma

Idiopathic

ALT 3x normal has a 95% PPV for biliary pancreatitis

Am J Gastro 1994; 89:1863

The most appropriate management of the patient includes?

1 2 3 4 5

20% 20% 20%20%20%1. Admission to the ICU

2. Aggressive volume resuscitation

3. Empiric broad spectrum antibiotics

4. Urgent ERCP for biliary decompression

5. All of the above

Principles of treatment of acute pancreatitis

• Intravascular volume

• Analgesia

• Put pancreas to "rest"

• Treat complications–pulmonary, shock, renal, metabolic

• ERCP for biliary obstruction/cholangitis

• Antibiotics for severe disease

• Percutaneous aspiration of pancreas to document infection in patient who fails to respond

• Drainage/debridement for infected necrosis

Step up approach for necrotizing pancreatitis

Major complications/death

17 (40%)

17 (40%)

N Engl J Med. 2010;362(16):1491

31 (69%)

Open necrosectomy

Minimally invasive step-up approach

Management of Severe Acute Pancreatitis

Clinical Assessment of severity

Contrast-enhancedCT scan

Supportive therapy

Antibiotics (imipenem)

Continue ABX for 7-14 days

CT guided aspiration

Percutaneous, endoscopic and/or surgical debridement

Continued supportive therapy

Yes

No

Severe Mild

Infected

< 30% necrosis> 30% necrosis

ImprovementYes

No

True statements regarding celiac disease include all of the following except?

1 2 3 4 5

20% 20% 20%20%20%

1. The prevalence in the U.S. is 1:300

2. Diagnosis requires a compatible small bowel biopsy with clinical response to gluten withdrawal

3. Tissue transglutaminase IgA is the most sensitive serologic test

4. Is strongly associated with HLA DQ locus

5. Serologic tests are not affected by dietary gluten restriction

Answer 5 Pearls:

20% of patients > 60 years at diagnosisHLA-DQ2 and/or DQ8 > 95%*IgA tissue transglutaminase and endomysial

antibodies have sensitivities and specificities > 95%

Anti-gliadin non specific (PPV ~30%)Levels fall with adherence to gluten-free diet

*Kaukinen et al. Am J Gastroenterol 2002

Case presentation

67 yo male w/ 2-3 days of increasing abdominal pain, distention, fever, and non-bloody diarrhea

Admitted to ICU 2 weeks earlier for urgent cardiac bypass

Course complicated by bacterial pneumonia with respiratory failure

Temp 38.5, WBC 16,000

The most appropriate management includes?

1 2 3 4 5

20% 20% 20%20%20%

1. Neostigmine IV

2. Surgical resection

3. Colonoscopy

4. Empiric antibiotics with oral vancomycin and IV metronidazole

5. Fecal transplantation

Pseudomembranous colitis

Differential diagnosis of nosicominal diarrhea

Medications (antibiotics!) Infectious (C. diff) Dietary (tube feedings) Ischemic colitis

Clostridium difficile infection Rate of hospital acquired C. diff is ~3% Incidence of refractory cases and

multiple relapses is rising Probiotics prevent CDAD Fecal transplantation:

associated with 94% cure ratesafe and effective treatment for refractory C.

difficile infection

Johnson et al. Ann Intern Med 2012; 13. Mattila et al. Gastroenterol 2012; 142:490

67 year old male from a NH with prior CVA and COPD is admitted for treatment of pneumonia with antibiotics. He has been receiving tube feedings via a PEG placed 3 months ago. After 5 days of IV abx he develops watery, non-bloody diarrhea, low grade fever, and elevated WBC count (32 K). Stool is positive for fecal leukocytes. C difficile toxin A is negative, but antigen is positive. What is the most likely explanation for his clinical findings?

a) He is a carrier for C difficile

b) He has uncomplicated antibiotic-associated diarrhea

c) He has toxin A (-), B (+) C difficile

d) His diarrhea is due to hyperosmolar tube feeds

Answer C Pearls:

Many commericial EIA tests will test for toxin A and antigen

3-4% of C difficile strains produce toxin B onlyElevated WBC, fecal leukocytes, and fever suggest

C difficile infectionRisk factors for infection include older age, use of

antibiotics, PPI’s, and virulent NAPI strain

Johnson et al. J Clin Microbiol 2003; 41:1543-1547Loo et al. N Engl J Med 2011; 365:1693

57 year old male with long-standing diabetes mellitus type 1 presents with over 5 years of daily diarrhea and weight loss (35 lbs). His course has been complicated by poor glucose control and peripheral neuropathy. A quantative stool collection yielded a fecal fat output of 24g/24h.

Possible causes for this picture include all of the following except:

a) Diabetic enteropathy

b) Excessive sorbitol ingestion

c) Small bowel bacterial overgrowth

d) Celiac disease

e) Pancreatic exocrine insufficiency

Answer B

Diarrhea is a frequent complication of long standing IDDM, occurring in ~ 20%

Bacterial overgrowth, celiac disease, and exocrine pancreatic insufficiency occur with a greater frequency in diabetics than in the general population

Sorbitol produces an osmotic diarrhea without steatorrhea

24 year old female with a new diagnosis of Crohn’s disease after presenting with chronic abdominal pain, diarrhea and weight loss of 2 years duration

Colonoscopy revealed moderate-severe terminal ileal and right colon disease

True statements regarding management of her disease include which of the following?a) Therapy should be initiated with 5-ASA agents because of the favorable side

effect profileb) Steroids are the treatment of choice for maintenance of remission in Crohn’s

diseasec) Therapy should be initiated with anti-TNF therapy as this has the greatest

likelihood of achieving and maintaining remissiond) No therapy for Crohn’s disease has been shown to improve long term outcomes

and reduce need for surgery

Goals of Therapy Have Expanded Induce and maintain

gastrointestinal healing(Mucosal Healing)

Prevent strictures and penetrating complications

Prevent extra-intestinal complications

Avoid/reduce corticosteroid use

Decrease hospitalization

Decrease surgery

Decrease long-term cost

Dis

eas

e

Co

mp

lic

atio

ns

Years

Natural Course

TREAT

Odds Ratio 95% CI P-Value

Current use of infliximab 1.015 0.531-1.942 P=0.96

Current use of 6MP/AZA/MTX 0.731 0.398-1.340 P=0.31

Current use of corticosteroids 2.096 1.147-3.832 P=0.016

Current use of narcotic analgesics 1.787

0.946-3.379P=0.74

Mortality in Crohn’s disease Logistic Regression Data (Multivariate)

Lichtenstein G et al. Clin Gastroenterol Hepatol. 2006;4:621-630.

Top-Down vs. Step-Up Endoscopic Results

30

73

0

20

40

60

80

100

Step-up Top-down

Complete endoscopic healing at 2 years

P=0.0028

D’Haens et al. Lancet. 2008;371:660-667.

% o

f p

atie

nts

Key Messages: Early Intervention with Biologic Therapy

Early intervention with immunotherapies improves likelihood of response/remission.

Steroid sparing strategies early in the disease course are associated with mucosal healing

Biologics are current best therapy for Crohn’s Disease

Intervention with anti-TNF therapy improves outcomes in Crohn’s disease

Which of the following are correct statements regarding the safety of medical therapy for Crohn’s disease?

a) Long term therapy with anti-TNF should be avoid due to the risk of serious infections

b) Long term therapy with anti-TNF should be avoided due to the risk of lymphoma

c) Anti-TNF therapy is contraindicated in pregnancy

d) Steroid use is the most important risk factor for serious infections in Crohn’s disease

Risk of Serious Infections in Crohn’s Disease: Meta-Analysis of All Controlled Trials

Anti-TNF Control 95% CI

Serious Infections 70 (2.09%) 43 (2.13%) 0.45-0.65

Peyrin-Biroulet et al CGH 2008;6:664.

TREAT

Odds Ratio 95% CI P-Value

Current use of infliximab 0.991 0.641- 1.535 P=0.97

Current use of 6MP/AZA/MTX 0.782 0.519- 1.179 P=0.24

Current use of corticosteroids 2.212 1.464-3.342 P<0.001

Current use of narcotic analgesics 2.380 1.560-3.631 P<0.001

Serious Infections Logistic Regression Data (Multivariate)

Lichtenstein G et al. Clin Gastroenterol Hepatol. 2006;4:621-630.

Key Messages: Risk/Benefit of Therapy in IBD

Risks of therapy must be considered in the context of the risk of untreated disease and progression of disease.

Steroids remain the most dangerous medical therapy for IBD.

Lymphoma risk in IBD is associated with thiopurine therapy and concomitant therapy with biologics and thiopurines.

Disease control at conception improves pregnancy outcomes

anti-TNF therapies are safe during pregnancy

A 35-year-old man asks your advice about screening for colon cancer. His father had colon cancer at age 61. An older brother had asymptomatic adenomatous polyps found on a screening colonoscopy at age 50. No other family members have had colon polyps or cancer. The patient has no gastrointestinal symptoms. Physical examination is normal.

Which of the following should you recommend? (A) Screening for an average-risk individual beginning at

age 50(B) Fecal occult blood testing annually beginning at age 40;

screening colonoscopy beginning at age 50 and every ten years thereafter

(C) Screening colonoscopy beginning at age 40 and every five years thereafter

(D) Screening colonoscopy beginning at age 40 and every ten years thereafter

American College of Physicians (ACP) guidance statement for colorectal cancer (CRC) Average-risk individuals should begin screening at age 50 High-risk adults should begin at age 40 or 10 years younger than

the age at which their youngest affected relative received a diagnosis of CRC.

The screening for average risk: annual stool-based test, flexible sigmoidoscopy every 5 years or optical colonoscopy every 10 years

Optical colonoscopy every 5 years in high-risk patients. Clinicians should select the test based on the benefits and harms of

the screening test, availability of the test, and patient preferences. Clinicians should stop screening for CRC in adults >75 or with a life

expectancy of <10 years. Screening in blacks is appropriate beginning at age 40

Ann Intern Med 2012 Mar 6; 156:378

Screening for Persons with Familial Risk

Familial risk category Recommendation*

Second or third degree relatives with colorectal cancer

Same as average risk

First-degree relative with colon cancer or polyps diagnosed at age 60 yr

Same as average risk but begin at age 40 yr

Two or more first degree relatives with colon cancer, or first degree relative with colon cancer or polyps diagnosed at age < 60 yr

Colonoscopy q 5 yr, begin at age 40 yr or 10 yr younger than earliest diagnosis in family

* Synthesis of guidelines from Multidisciplinary expert panel and ACS

When should you recommend that the next surveillance

colonoscopy be performed?

a) In 6 months

b) In 1 year

c) In 3 years

d) In 5 years

e) In 10 years

A 55-year-old man has a history of a 0.5-cm pedunculated tubular adenoma removed a screening colonoscopy 5 years previously. A follow up colono-scopy is normal with no polyps evident.

Recommendation for Surveillance Colonoscopy in Patients with Neoplasia

Most serious baseline exam findings

Recommended surveillance interval

1-2 small adenomas (<10 mm)

5 years or more

3 or more small tubular adenomas

3 years

Advanced adenoma 3 years

Cancer, post-resection 1 year, then every 3-5 years

Lieberman. Gastroenterol 2004; 126:1167

New guidelines for postpolypectomy surveillance after colonoscopy Intervals are now based on results not

only from most recent exam but also from baseline exam that identified neoplasia

Patients with low risk findings at baseline, and no subsequent adenomas on surveillance should be returned to average risk with next surveillance at 10 years

Lieberman et al. Gastroenterol 2012; 143:844

Common mistakes made in colon cancer screening/surveillance

Restarting annual FOBT after normal screening colonoscopy

What constitutes a worrisome family hx Under utilization of surveillance in high risk

subjects~50-60% of patients with advanced baseline findings had

f/u exam at 5 years Over utilization of surveillance in low risk subjects

~25% with no polyps had f/u exams within 5 yearsInappropriate f/u for non neoplastic (hyperplastic)

lesions

Schoen et al. Gastroenterol 2010; 138:73