Neeral L. Shah, M.D., F.A.C.P

Assistant Professor of Medicine

Division of Gastroenterology and Hepatology

Transplant Clinic Director

GI Clinical Pearls

Clinical Pearls

■ Upper GI DiseasesPPI Therapy

■ Lower GI DiseasesColon - C. diff

■ HepatologyAmmonia LevelsPain Management

Case #1 – Acid Reflux

■ 56M resolved acid reflux and heart disease■ PMHx – CAD with stent on Clopidogrel■ Presents to clinic for recommendations■ Currently on PPI therapy■ What would you advise?A. Stop PPI immediately – reflux has resolved

B. Stop PPI & Use H2 blockers PRN for one week

C. Taper off PPI – take every other day PRN

D. Stop PPI due to interaction with Clopidogrel

PPI: Mechanism of Action

■ PPI are activated in the acidic compartments of parietal cells

■ THUS, they only inhibit actively secreting proton pumps

■ IRREVERSIBLY block the proton pump until new molecules synthesized (24-48 hours)

Proton Pump Functioning

1. Del Valle J, et al. Acid peptic disorders. In: Yamada et al, eds. Textbook of Gastroenterology.4th ed. Philadelphia, Pa: Lippincott Williams and Wilkins; 2003:1321-1376.

Unstimulated proton pumpsActive proton pumps

Unstimulated proton pumpsin cytoplasmic tubules

1. Blair JA, et al. J Clin Invest. 1987;79:582-587.2. Sachs G. Pharmacotherapy. 1997;17:22-37.

Gastrin

H2

ACh

H2 = Histamine

ACh = Acetylcholine

Proton pumps become activated in response to food1

Inactive Parietal Cell

After activation, the parietal cell undergoes a series of changes,allowing proton pumps to reach the surface of the parietal cell1

Active Parietal Cell

Only active proton pumps can secrete acid1However, not all pumps become activated1,2

ATPase

ATPase

H+

H+

H+

H+

K+

K+

K+

K+

Proton Pump Inhibitors

Acid is required to convert a PPI into its active form1

1. Del Valle J, et al. Acid peptic disorders. In: Yamada et al, eds. Textbook of Gastroenterology.4th ed. Philadelphia, Pa: Lippincott Williams and Wilkins; 2003:1321-1376.

PPIs only bind to active proton pumps1

Unstimulated proton pumps remain

PPI

PPI PPI

PPI

H+

H+

Optimal Timing of PPI Dose

■ Ensures that maximum plasma concentration of PPI coincides with the activation of proton pumps

Results of a recent survey:

More than one-third of all primary care physicians fail to educate patients

properly on the timing of PPI dosing

Chey Am J Gastroenterol 2005;100:1237.

DOSING: ADMINISTER PPI:

QD 30 minutes before breakfast

BID 30 minutes before breakfast & evening meal

Overuse of PPI

1. Heidelbaugh et al. Am J Gastro 2006; 101: 2200-22052. Glew et al. J Am Med Dir Assoc 2007; 9:280-2813. Choudhry et al. QJM 2008; 101:445-448.4. Bajaj et al. Am J Gastro, 2009; 104: 1130-1134.

■ Retrospective, chart review of non-ICU admits1

■ 22% received stress ulcer prophylaxis■ 54% of those were discharged home on it

■ Retrospective chart review of nursing home admits2

■ 50% did NOT have an appropriate diagnosis for PPI

■ Retrospective chart review of C.diff positive patients3

■ 63% of did NOT have valid indication for PPI

■ Retrospective chart review of cirrhotics + SBP4

■ 47% did NOT have valid reason for PPI

Stopping a PPI: Rebound Acid

■ High Gastrin Levels■ Rebound Acid■ Step down therapy?■ Warn patients of

symptoms

■ Advise PRN H2 blocker therapy

Reimer et al. Gastro 2009; 137: 80-87Niklasson et al. Am J Gastro 2010; 105: 1531-1537.

PPI interaction with Clopidogrel

1. Khalique et al. Cardiology in Review 2009; 17: 198-200 2. Gilard, et al. J Am Coll Cardiol 2008; 51: 256–2603. Sibbing et al. Thromb Haemost 2009; 101: 714-7194. O’Donaghue et al. Lancet 2009; 374:989-997

■ Clopidogrel is a prodrug that is converted to an active metabolite which irreversibly binds to the platelet P2Y12 receptor, blocking activation and aggregation

■ Active metabolite formed via cytochrome P450 system

■ Certain PPIs inhibit the cytochrome P450 2C19 pathway and may interfere with conversion of clopidogrel to the active form2-4

■ Newer studies question this finding?

■ Pantoprazole studied and no increased risk

Case #2 – Chronic Diarrhea – C. Diff

■ 72F with recurrent chronic diarrhea after hospitalization - diagnosed with C. diff

■ Placed on Metronidazole then oral Vancomycin■ 10-15 bowel movements per day after

completing therapy

A.Repeat Metronidazole course

B.Prolonged course of oral Vancomycin

C.Consider Fecal Transplant

D.Add probiotics to oral Vancomycin

Clostridium Difficile Increasing Rates

NAP1 Virulent Strain of C. Diff

Pepin, J, Mortality attributable to nosocomial Clostridium difficile-associated disease during an epidemic caused by a hypervirulent strain in Quebec. CMAJ 2005; 173: 1–6.

■ Hypervirulent strain:■NAP1/BI/027

■First report in N. America 2002: 30 Quebec hospitals

■30 day mortality of 23% compared to matched controls (Pepin)

■Universally resistant to fluoroquinolones (selective advantage) (Gould. Bench to bedside review, Critical Care 2009)

■ Number of discharges diagnosed with C diff. doubled from 2001 – 2005

■ Length of stay in association with C diff. is 3x average & mortality 4.5x average

Fecal Transplant for C. Diff

UVA Medical Center FMT Program

• Call 434-924-2959• Currently evaluating and treating limited

numbers of patients for FMT• FMT via colonoscopy• Rule out predisposing conditions• Full scale program begins 9/1/2013

Case #3 – Appropriate Diet?

■ 45F with HCV cirrhosis with asterixis■ Admitted to the hospital for fever work up■ History of severe encephalopathy and SBP■ What diet is appropriate for this admission?

A. Low fat dietB. Low sodium dietC. Low protein dietD. Low taste diet

Nutritional Management

Merli & Riggio, Metabolic Brain Disease, Dec 2008.

Nutritional Management

■ Cirrhosis depletes body mass – catabolic state■ Liver unable to derive glucose■ Decreased ability for gluconeogenesis■ Glucose thus derived from muscle and adipose

catabolism■ Increases protein requirements

Ammonia Level in PSE

■ Nicolao et al., 2003■17 patients followed with PSE resolved■Ammonia levels did NOT decrease■Some levels increased with PSE resolution

■ Conclusion■Ammonia levels of limited use for diagnosis

or clinical management

Nicolao et al., Journal of Hepatology, 2003, 38, 441-446.

Ammonia Level in PSE

■ Kundra et al., 2005■Evaluated 20 patients with CLD■Stage II mean ammonia level - 72.3■Stage III mean ammonia level - 58.7■Stage IV mean ammonia level - 42.0

Kundra et al.,Clinical Biochemistry, 2005, 38, 696-699.

Ammonia Level - Utility?

■ No utility in diagnosis of PSE

■ Ammonia levels may give provider false security or worry

■ Assess asterixis, objective functioning

■ “Only confusion an ammonia level measures is the confusion of the provider ordering the test.”

Case #4 – Groin Pain

■ 56M significant alcohol use – cirrhosis■ 3rd and 4th degree burns in groin and scrotum■ Burning off frayed edges of jean shorts “jhorts”■ Admitted for 3-4 days at time of consult■ Pain medications for dressing changes?

A. AcetaminophenB. IbuprofenC. MorphineD. Tramadol

Pain Medication in Cirrhosis

■ Issues with clearance■ Altered metabolism■ 3 modes of metabolism, often hindered:

■ P450 Pathway■ Conjugation■ Biliary Excretion

■ Tylenol - up to 2g per day?

NSAIDs in Cirrhosis

■ NSAIDs heavily protein bound

■ Elevated levels in cirrhosis

■ Renal Impairment - decreased perfusion

■ Increased bleeding risk with thrombocytopenia

Opioids in Cirrhosis

Chandock, Watt, Mayo Clinic Proceedings, 2010, 85(5), 451-8.

Preferred Opioids in Cirrhosis?

■ Tramadol■ Works on peripheral pain■ Low affinity for opiod receptors■ Less sedation effect■ Lower potential for tolerance

■ Fentanyl IV or Hydromorphone PO■ Least affected by renal function■ Order in lower doses and longer intervals

Pain Medication Algorithm

Chandock, Watt, Mayo Clinic Proceedings, 2010, 85(5), 451-8.

Start with Acetaminophen

Try Tramadol

Use opiates for intractable pain

Clinical Pearls

■ Proton Pump Inhibitors■ Dose 30 min before meals■ Stopping therapy may cause rebound symptoms

■ Refractory C. Diff■ Consider Fecal Transplant

Clinical Pearls

■ Hepatic Encephalopathy■ Ammonia level of limited use■ Low protein diets can harm patient

■ Pain Medication■ Attempt Tylenol in limited doses■ Next would attempt Tramadol■ Consider Fentanyl or Hydromorphone in lower

doses, less frequency

Thank you for your attention