Whipple’s disease Ana Mae H. Quintal Medical Resident

1. Whipple’s diseaseAna Mae H. QuintalMedical Resident

2. General Objectives • To present and discuss a case of a 33/F who presented with chronic diarrhea • To discuss the diagnostic approach to chronic diarrhea; • To discuss Whipple’s disease: • Epidemiology • Pathogenesis • Clinical manifestations • Diagnostic methods • Treatment • Prevention and control

3. General Data • 33 year old • Female • Filipino • Single • Manila resident

4. Chief Complaint diarrhea

5. History of Present Illness • 2006 May Consulted with a gastroenterologist due to diarrhea, abdominal pain, and weight loss, treated as a case of TB ilietis with Econokit (HRZE) until Aug 2007 (15 months). • Weight gain noted on the first 3 months, • however started to lose weight again • after the succeeding months

6. 18 mos PTA Referred to an ID specialist due to recurrent diarrhea despite more than 1 year of anti- koch’s medication. Managed as a case of Tropical sprue; started on folic acid, cyanocobalamin, vitamin C and ferrous sulfate.

7. 18 mos PTA Outpatient work-ups: • Stool for TB culture and Sputum AFB • smears were negative • Thyroid function Tests—normal

8. 3 weeks PTA Presented with soft, non-bloody, non- mucoid, loose stools, ~3 episodes per day, accompanied by bouts of abdominal pain and flatulence. • No fever or no vomiting; still noted to have anorexia and progressive weight loss

9. 2 weeks PTA Diarrhea increased in severity to >10 episodes per day. • Day of admission Persistence of diarrhea with generalized body weakness

10. Review of Systems SKIN No easy bruisability, sores, rashes, pruritus, or hyperpigmentation HEENT No headaches, dizziness or vertigo. Does not wear corrective glasses. No history of eye pain, blurring of vision, excessive tearing, diplopia; gross hearing is intact. No ear pain, discharge or infection. No post- nasal drip or sinus pain. No history of frequent sore throats PULMO No cough, hemoptysis, or dyspnea CVS No history of orthopnea, PND, palpitations, chest pain, or bipedal edema.

11. Review of systems URINARY No history of UTIs, intermittency, decreased caliber of urine flow, or incontinence. RHEUMA Back pain. Generalized myalgia. No joint pains. NEURO Memory lapses No history of syncope, seizures or tremors. No numbness or loss of sensation. HEMA No history of prolonged bleeding. ENDOCRINE No history of polyuria, polyphagia, polydipsia. No excessive sweating.

12. Past Medical History • 1999- abdominal pain (Status post EGD: • pseudodiverticulum) • 1999- PTB (treated with anti-Koch’s medication for 6 months then was lost to follow- up) • 2001- diffuse non- toxic goiter (no meds taken; last thyroid test 2004- normal)

13. Personal/Social and Family History • Non- alcoholic beverage drinker; non- smoker • Denies illicit drug use • Family history of DM type 2; no other herido-familial diseases

14. Physical Exam VITAL SIGNS BP 80/ 50mm Hg, CR 121bpm, RR 22 cpm T 36.8C JVP 4 cm H2O GENERAL Cachectic, conscious, coherent, oriented to person, place, and time Weight 23 kg, Height 1.57 m, BMI 9.3 kg/m2 SKIN All extremities were warm to touch. No discolorations, bruises or rashes. No hyperpigmentation HEENT Normocephalic; anicteric sclerae, pale conjunctivae; no naso-aural discharge; dry oral mucosa; no tonsillopharyngeal congestion; no neck mass; no cervicolymphadenopathy.

15. Physical exam CHEST/LUNGS Equal chest expansion, no retractions, clear breath sounds, equal tactile and vocal fremitus CVS Adynamic precordium, tachycardic, regular rhythm, distinct S1/S2, no S3 or S4, no murmurs/gallops, PMI and apex beat at the 5th intercostal space left midclavicular line; full and equal pulses bilaterally. ABDOMEN flat, normoactive bowel sounds, soft; no guarding, direct tenderness, or rebound tenderness; no splenomegaly EXTREMITIES no cyanosis, edema or deformities; no limitation of motion; pale nail beds RECTAL good sphincteric tone, no fissures, no masses, stool on examining finger

16. Salient Features • 33/ F • Previously treated with anti- Koch’s • Previously treated as a case of Tropical sprue • Chronic diarrhea • Weight loss

17. Chronic Diarrhea • To Flow Through

18. Diarrhea AGA definition: • Decrease in fecal consistency lasting for >4 weeks • Stool >= 200grams/day, or • >3 loose or watery stools/day, or • Increased water content of stool • Impaired water absorption, • Active water secretion

25. Lab work- ups • CBC, electrolytes, total protein, albumin, thyroid function tests, radiologic work- ups, endoscopy • Stool analysis- stool osmolality, ph, occult blood, fecal leukocytes, stool fat (quantitative, sudan III) • Fecalysis, stool culture, C. difficile toxin • Selective testing for plasma peptides • Laxative screen

26. Classification of Diarrhea • By time course ( acute vs chronic ) • Site ( large vs small ) • Pathophysiology ( secretory vs osmotic ) • Epidemiology ( epidemic vs travel- related vs immunosuppression- related ) • Stool characteristics ( watery vs fatty vs inflammatory)

27. Time course • Acute: < 2 weeks in duration • Persistent: > 14 days • Chronic: >4 weeks • Severe: >4 fluid stools/day for > 3 days

28. Small vs. Large Bowel Diarrhea Small bowel: secretory & nutrient absorbing functions • Watery, large volume diarrhea • Bloating, gas, cramping, profound weight loss, electrolyte disturbances, malabsorption (D-xylose, B12) Large bowel: storage organ, addtitional absorption of water • Frequent, small volume, painful stools • Bloody, mucoid

34. Infectious • Parasites: Giardialamblia, Entamoebahistolytica, Cyclospora • AIDS-related: • Viral: Cytomegalovirus, HIV infection (?) • Bacterial: Clostridium difficile, Mycobacterium avium complex • Protozoal: Microsporida, Cryptosporidium, Isospora belli Non- infectious • Primary GI diseases – IBS, IBD, malabsorption,celiac, etc. • Non-GI disease states – hyperthyroid, carcinoid, etc. • Drugs (laxatives) • Carbohydrate (Lactose) intolerance

35. Principal causes of diarrhea depend upon the socioeconomic status of the population. In developing countries, • chronic infections, • although functional disorders, malabsorption, and inflammatory bowel disease are also common. In developed countries, • irritable bowel syndrome (IBS), • inflammatory bowel disease, • malabsorption syndromes (as lactose intolerance and celiac disease), and • chronic infections (particularly in the immunocompromised).

36. Secretory vs. Osmotic • Secretory • Volumes > 1L/day • Occurs day and night • Continues despite fasting • Osmotic gap < 50 • Osmotic • Due to an unabsorbable solute • High osmotic pressure -> increased water output • Stops with fasting • Osmotic gap > 125 Osmotic gap = 290 – 2x [(stool Na + stool K)]

37. Osmotic diarrhea CLUES: Stool volume decreases with fasting; increased stool osmotic gap 1. Medications: antacids, lactulose, sorbitol 2. Disaccharidase deficiency: lactose intolerance 3. Factitious diarrhea: magnesium (antacids, laxatives) Secretory Diarrhea CLUES: volume ( >1 L/d); little change with fasting; normal stool osmotic gap 1. Hormonally mediated: VIPoma, carcinoid, medullary carcinoma of thyroid (calcitonin), Zollinger-Ellison syndrome (gastrin) 2. Factitious diarrhea (laxative abuse): phenolphthalein, cascara, senna 3. Villous adenoma 4. Bile salt malabsorption (ileal resection; Crohn's ileitis; postcholecystectomy) 5. Medications

38. Inflammatory • Fever, hematochezia, abdominal pain 1. Ulcerative colitis 2. Crohn's disease 3. Microscopic colitis 4. Malignancy: lymphoma, adenocarcinoma (with obstruction and pseudodiarrhea) 5. Radiation enteritis

39. Malabsorption:weight loss, abnormal laboratory values, fecal fat > 7- 10 g/ day Causes: • Intraluminal maldigestion • Pancreatic insufficiency • Bacterial overgrowth • Defective bile secretion • Mucosal – malabsorption • Celiac disease • Tropical sprue • Infection – bacteria, parasites • Whipple’s disease • Intestinal resection –short gut • Abetalipoproteinemia • Crohn’s disease

40. Motility disorders • Systemic disease or prior abdominal surgery 1. Postsurgical: vagotomy, partial gastrectomy, blind loop with bacterial overgrowth 2. Systemic disorders: scleroderma, diabetes mellitus, hyperthyroidism 3. Irritable bowel syndrome

41. Case • History • Gradual onset • Intermittent, watery, non- bloody diarrhea • Weight loss • More than 4 wks duration • Non- diabetic • No history of travel • Non- promiscuous • No family history of malabsorption (celiac disease) • Physical exam • Cachexia • Signs of anemia • No mouth ulcers, skin rash, anal fissures/ fistula, no blood on EF on rectal • No exolphthalmos, no thyroid enlargement • Good sphincteric tone • No glossitis, protruberant abdomen, pedal edema

42. Admitting Impression • Chronic diarrhea probably secondary to GITB (TB Ileitis) vs Inflammatory Bowel Disease vs Tropical Sprue • Hypovolemic Shock sec to GI Loss

43. Course in the Wards

44. Problem#1: HYPOVOLEMIC SHOCK sec to GI Loss • Upon admission, BP 85- 90/ 70- 75, HR 121, cvp 4- 6; • Impression : • Hypotension secondary to hypovolemia sec to GI Loss; • TB Ileitis vs Inflammatory Bowel disease vs Tropical sprue. • ER: Fast dripped a total of 900 cc PNSS. IVF rate increased

45. Patient was referred to Nephrology service for fluid and electrolyte management. • On 1st HD, CVP was noted to be at 10- 12, BP 90- 110/ 60- 80, HR 120s, afebrile, I and O=3625 vs 1180. • On the 3rd HD, BP stabilized at 90- 100/ 60- 70, HR 90- 100. • However, later on the 3rd HD, CVP was noted to be elevated at 15- 16 cm H2O, RR 24, with neck vein distention. Clear breath sounds by auscultation. • Chest XRAY : pulmonary congestion. • Lasix 20 mg/SIVP was given ; Aldactone 50 mg/tab together with Lasix

46. Problem #2: ELECTROLYTE IMBALANCE and Hypoalbuminemia • Upon admission, HYPOKALEMIA was noted. • K= 2 – 2.6 – 3 – 4 • Central line insertion was done. • KCL drip started: 40 meq KCl in 100 cc PNSS to run for 8 hours and Kalium durule 1 tab TID

47. On 1st HD, HYPOALBUMINEMIA • Alb= 0.6 – 1.6 • Albumin 25% infusion. • On 3rd HD, HYPOCALCEMIA and HYPOMAGNESEMIA • Calcium gluconate 4 amps + 5 grams MgSO4 in 2500 cc D5W at 10 cc/ hr. Despite resolution of diarrhea, hypokalemia was still noted; subsequent potassium correction was done.

48. Problem #3: DIARRHEA And Seizure • Impression on admission was TB Ileitis vs Inflammatory Bowel disease vs Tropical sprue. • Ciprofloxacin 500 mg/ tab BID, and Isoniazid + Rifampicin +Pyrazinamide+ Etambutol (Myrin P Forte) 3 tabs once daily were started upon admission.

49. On 1st HD, 4 episodes of generalized tonic- clonic seizures of both upper and lower extremities, lasting for 5 secs each, associated with upward rolling of eyeballs; PE: motor 2/5 in the Right UE/LE. • Referred to Neurology service. • Impression: Hypokalemic Periodic Paralysis; Seizure, etiology to be determined. • O2 at 2LPM PRN • Diazepam 5 mg IV PRN and started on Epival 250 BID.

50. On 2nd HD, still with seizure episode ~6x. • complained of difficulty moving head to the right, nape pain, numbness of Left LE. On PE: left- sided hemiplegia, flaccidity, hyperactive DTR, L. • Impression: Todd’s paralysis. • EEG was abnormal due to excess theta waves.