Recurrence and Nutrition in IBD

From New Advances in Inflammatory Bowel Disease, presented by Scripps Conference Services and CME

Educational Objectives

The goal of this program is to improve the medical, surgical, and nutritional management of inflammatory bowel dis­ease (IBD). After hearing and assimilating this program, the clinician will be better able to:

1.   Review the indications for surgery in Crohn’s disease (CD).

2.   Discuss the factors associated with increased risk for recurrence of CD after surgery.

3.   Describe the symptoms and management of vitamin D deficiency and metabolic bone disease in IBD.

4.   Recognize and treat vitamin B₁₂ deficiency in IBD.

5.   Describe the signs and symptoms of zinc deficiency in IBD.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Rubin has received grant support and has been a consultant for Procter & Gamble and Prometheus Laboratories, and has been a consultant for Abbott Immunology, Centocor, Salix Pharmaceuticals, Shire Pharmaceuticals, and UCB. Dr. Heller and the planning committee reported nothing to disclose. In his lecture, Dr. Rubin presents information related to the off-label or in­vestigational use of a therapy, product, or device.

Acknowledgements

Drs. Rubin and Heller were recorded at New Advances in Inflammatory Bowel Disease, held September 12-13, 2009, in San Diego, CA, and sponsored by Scripps. The Audio-Digest Foundation thanks the speakers and Scripps for their cooperation in the production of this program.

Preventing Postop Recurrence of Crohn’s Disease

David T. Rubin, MD, Associate Professor of Medicine, Co-Director, Inflammatory Bowel Disease Center, and Program Di­rector, Fellowship in Gastroenterology, Hepatology, and Nutrition, University of Chicago Medical Center, Chicago, IL

Challenges in management of Crohn’s disease (CD): physicians not aggressive enough in identifying recurrence and developing treatment strategies that change natural history of disease; surgery  —  still required and most effec­tive therapy; too often used as last resort; should embrace as effective treatment option early; immunosuppressive therapy may cause perioperative complications; mechanism of particular therapy may be ineffective for stage of disease (possible reason for “failure of therapy”); depending on reason for failure, previously “failed therapy” may be retried after surgery; timing extremely important; do not wait for recurrence of symptoms after surgery (too long)

Indications for surgery: failure of medical therapy due to steroid dependence or steroid-related complications; re­current obstruction resistant to medical treatment; fistula or abscess; hemorrhage; growth retardation (children); perforation; cancer

Diagnosis: previously, relied on small bowel x-rays; presently, computed tomographic (CT) enterography utilized more; magnetic resonance (MR) enterography able to distinguish active inflammation from fibrosis

Probability of surgery in CD: study data show cumulative incidence of surgery increases over time, depending on how long CD present; likelihood of needing surgery based on location (most common in ileocolonic region), then small intestine, colon, and anorectal region

Recurrence after surgery: factors associated with increased risk for recurrence  —  smoking; penetrating disease; small bowel disease; ileocolonic disease; perianal fistulas (worst quality of life); duration of disease (before sur­gery); age at diagnosis and first surgery

Complications: surgery; recurrent surgery; hospitalization; exposure to steroids; disability; unemployment; avoid by changing natural history of disease; the earlier treatment provided, the more likely natural history of disease changed; after ileocecectomy perfect time to change natural history

Current theory of pathogenesis of recurrent inflammatory bowel disease (IBD): involves environmental factors and bacteria; role of bacteria in postoperative recurrence in CD  —unknown whether specific bacteria involved or bacteria in general; possibilities include stasis and exposure to bacteria along mucosal lining; byproducts of bacte­ria drive inflammatory response and dysregulation; indirect evidence suggests diversion leads to remission; recur­rence after end ileostomy and proctocolectomy for CD — 1) recurrent CD develops in end ileostomy due to stomal complications (eg, peristomal hernia); 2) as patient gains weight, tension placed on stoma, stretching bowel, and leading to more stasis of fecal stream against mucosa; 3) patient had small bowel CD not fully appreciated before need for other surgery; role of bacteria — indirect evidence suggests antibiotics delay recurrence of CD in many patients; some evidence that probiotics play role; highest number of bacteria in colon; proximal small intestine al­most sterile; CD most likely to be expressed in terminal ileum

Postoperative prophylaxis with metronidazole: associated with prevention of CD in ileocecectomy patients; prob­lem dropout rate due to intolerable side effects of metronidazole; metronidazole given for only 3 mo after ileo­cecectomy; after 1 yr, still better than placebo for preventing or delaying recurrence; after 2 or 3 yr, no long-term benefit seen; postoperative ornidazole prophylaxis  —  derivative of metronidazole; given twice daily for 1 yr; shown to prevent recurrence; when stopped, likelihood of recurrence after 2 or 3 yr no different from placebo

Probiotics: Lactobacillus rhamnosus GG as single therapy no better clinically than placebo for postoperative recur­rence of CD; not known whether probiotics, combination of probiotics, or additive therapy with probiotics benefi­cial in preventing recurrence

Does immunosuppressive therapy change course of CD? French study  —  unable to conclude that azathioprine and 6-mercaptopurine (6-MP) do not change course of CD; meta-analysis  —  found thiopurines more effective than con­trols (placebo, mesalamine, or antibiotics) for prevention of severe endoscopic relapse at 1 yr, but not for very se­vere endoscopic recurrence; also more effective than controls for prevention of clinical relapse at 1 yr and 2 yr, with number needed to treat (NNT) of 13 and 8, respectively; Belgian study  —  started patients at high risk for recurrence on metronidazole for 3 mo upon discharge from hospital, as bridge to azathioprine therapy; at month 12, 3 mo of metronidazole followed by azathioprine found more beneficial than placebo when looking at hard end point (ie, no lesions); determining whether complete mucosal response achieved problematic; study by Regueiro  —found inflix­imab superior to placebo for endoscopic recurrence after ileocecectomy; should embrace approach of identifying which patients require infliximab after surgery; recurrence at 2 yr seen in patients who elected to stop after 1 yr of infliximab; adverse events no different for infliximab and placebo at 1 yr; high rates of remission seen in early CD when treated with adalimumab

Postsurgical considerations: discuss postoperative plans with patient before surgery; warn of possibility of postop­erative non-IBD diarrhea; perform imaging of bowel 3 to 6 mo after surgery to aid in decisions about treatment; new lesions visualized endoscopically within weeks after resection; should attempt to prevent first surgery, not sec­ond surgery; serologic and genetic markers important to determine patients at high risk for recurrence

Nutritional Issues in IBD

Arthur D. Heller, MD, Clinical Assistant Professor of Medicine, Weill Cornell Medical College, New York, NY

Case: woman, 70 yr of age, referred for recurrent dehydration, episodic fainting associated with sweats, and in­creased ostomy output; no palpitations, chest discomfort, dyspnea, or neurologic symptoms

Medical and surgical history: Crohn’s ileocolitis; ileostomy in 1984; multiple bowel obstructions and resections; surgeries for rectovaginal fistula; ileocolectomy for dysplasia; steroid use for >20 yr; multiple internal hernias treated with surgery without resection; cholecystectomy; breast cancer treated with lumpectomy, radiation ther­apy (RT), and tamoxifen; uterine cancer treated with surgery and RT to pelvis; osteoporosis in hips, with previ­ous low-velocity fracture of wrist; medications  —  anastrazole; alendronate; calcium carbonate (CaCO₃); vitamin D 800 U/day; folic acid; magnesium sulfate (MgSO₄) 2 mL intramuscularly (IM) weekly; family history of pso­riasis; by history, height 5 ft 2.5 in with usual weight of 140 lb; paresthesias; no diet restrictions, other than eating small meals; 3 cans of soda daily

Physical examination (PE): height measured at 5 ft; tongue well papillated (rules out vitamin B and iron deficien­cies); otherwise normal

Laboratory tests: azotemia, mostly prerenal; albumin, Ca, and Mg normal; alkaline phosphatase elevated; g-gluta­myl transpeptidase (GGTP) normal (indicates elevated alkaline phosphatase due to bone and in this patient indic­ative of vitamin D deficiency with or without true osteomalacia); normocytic normochromic slightly decreased hemoglobin (Hb); ferritin normal; methylmalonic acid (MMA) and homocysteine elevated (indicative of vitamin B₁₂ deficiency); 25-hydroxyvitamin D (25-OHD) level (best screening test for determining vitamin D status) in­sufficient and borderline deficient; 1,25-OHD level low; creatinine 2.3 mg/dL; secondary hyperparathyroidism; IgA levels normal; dual energy x-ray absorptiometry (DEXA) revealed T score 2.9 standard deviations below mean for spine (moderate to severe osteoporosis) and T score for hip -2.6

Urinary N-telopeptide (UNTx): marker of osteoclast activity and product of bone breakdown; normal, but in this patient, normal value indicates excessive bone breakdown; ideal UNTX for case patient »20 nmol/mmol; can check UNTx 3 mo after starting treatment (1.5-2 yr before changes seen in DEXA scan); bone density and risk for fractures not improved in osteoporosis until vitamin D deficiency treated

Treatment: oral rehydration solution 1 to 2L daily; ostomy output monitored; vitamin B₁₂ 1000 µg/wk for 8 wk, then 1000 µg/mo; vitamin D₂ 50,000 IU 3 times/wk for 8 wk, then 800 IU daily after checking 25-OHD; MgSO₄ and CaCO₃ discontinued (CaCO₃ increases risk for kidney stones; more Ca absorbed if given in low doses more fre­quently); follow-up laboratory tests  —  1,25-OHD normalized; 25-OHD increased to >35 ng/mL; MMA normal­ized; homocysteine nearly normal (vitamin B₁₂ deficiency treated); 24-hr urine for creatinine clearance and stone profile found markedly decreased citrate and elevated uric acid; started on potassium citrate supplementation to prevent development of kidney stones

Discussion: patients with IBD at increased risk for metabolic bone disease; patients with CD at greater risk than pa­tients with ulcerative colitis (UC); 2003 American College of Gastroenterology (ACG) position paper notes that screening for and treatment of metabolic bone disease in IBD patients responsibility of gastroenterologist; risk factors  —  ileal disease or resection; history of steroid use, renal stones, previous fracture, amenorrhea from any cause, tobacco use, thyroid disease or excessive thyroid supplementation, and parathyroid disease; family history of osteoporosis; low body weight (weight <120 lb increases risk for osteoporosis); duration of disease; poor nutri­tional support; symptoms include height loss, arthralgias and myalgias (seen with vitamin D deficiency)

Case: man, 71 yr of age, presents with 32-lb weight loss over 1.5 yr, anorexia and sitophobia; diarrhea but no arthral­gias, dermatologic, or ophthalmic symptoms, or steatorrhea; frequent prolonged upper respiratory infections that required prolonged steroid use

History: Crohn’s jejunoileitis; small bowel resection of »1 ft and multiple small bowel obstructions; osteopenia and osteoporosis; hypogonadism; asthma and chronic obstructive pulmonary disease (COPD) treated with predni­sone; secondary hyperparathyroidism; benign prostatic hyperplasia; hypertension; agranulocytosis due to ibupro­fen; 1 episode of transient global amnesia

Medications: quinapril; mesalamine; metronidazole; calcitriol (1,25-OHD), CaCO₃; montelukast; alendronate; tes­tosterone; baby aspirin; height diminished by 2 in; no libido; nocturia leading to daytime somnolence; thin; in no acute distress; reported height 5 ft 7 in (actual 5 ft 5.75 in); weight 137 lb; tongue well papillated; anicteric; unre­markable skin; kyphotic, with S₄ gallop; lungs clear; abdomen scarred, with diastasis recti; heme-negative stool; smooth but enlarged prostate; testicular atrophy; decreased hair distal to midcalf with decreased pulses (indicat­ing atherosclerosis); normal neurologic examination

Laboratory tests: normocytic normochromic anemia; low iron and total iron binding capacity but normal ferritin; elevated MMA and homocysteine; low total albumin and prealbumin levels; serum half-life of albumin 18 to 21 days (3-4 days for prealbumin; better marker for acute changes in nutritional status and rehabilitation); markedly low vitamin D; markedly elevated parathyroid hormone (PTH) indicative of secondary hyperparathyroidism due to prolonged vitamin D deficiency, despite ingestion of calcitriol; vitamins A and E normal; zinc (Zn) normal; carnitine deficiency common in chronic renal insufficiency, chronically starved patients, or those with chronic weight loss; small bowel follow-through markedly abnormal, with skip lesions, possibly fistula, and 4 to 5 ft of relatively uninvolved midjejunum; computed tomography (CT) revealed edema with inflammatory wall thicken­ing in one-half of remaining bowel; mucosal effacement with strictures seen

Treatment: methotrexate (MTX); Saccharomyces boulardii (probiotic) added and improved symptoms of diarrhea, gas, and bloating; started on low-dose cholestyramine; fluticasone and salmeterol inhaler; oral steroids discontin­ued; L-carnitine and vitamin D₂ 50,000 U 5 times weekly; alendronate continued; monthly vitamin B₁₂ injections

Discussion: patients with CD or ileal disease at increased risk for vitamin B₁₂ deficiency; symptoms nonspecific and may not include anemia or macrocytosis; bone marrow showed adequate iron, but patient subsequently developed iron deficiency and given iron infusions; folic acid masks anemia and macrocytosis from vitamin B₁₂ deficiency, but does not affect neuropsychologic symptoms (eg, depression, memory loss, dementia, hearing loss, apathy); clues on PE include loss of vibration sense and position sense; testing should include vitamin B₁₂, MMA, and ho­mocysteine levels; folic acid, vitamin B₁₂, vitamin B₆, and betaine deficiency increase homocysteine levels; only vi­tamin B₁₂ deficiency elevates both MMA and homocysteine levels

Case: man, 24 yr of age, with CD for 3 yr involving distal 20 cm of ileum and entire colon and rectum; referred due to failure to respond to prednisone and 6-MP; 6 to 8 nonbloody diarrheal stools daily, up to 1L/day

Physical examination: height 6 ft; weight 130 lb (body mass index [BMI] 17.6); febrile, tachycardic, and tachy­pneic; generalized wasting; thinning hair pluckable; scaling eruption at corners of lips, eyes, ears, and nose; skin pale, dry, and flaky, with pale conjunctiva; abdomen soft but tender, with fistula in right lower quadrant; 2+ pitting edema and sacral edema; generalized weakness and hyperreflexia; Zn deficiency  —indicated by scaly rash in acral area; sometimes seen in groin and commonly seen in exposed areas; microcytic anemia seen, with increased plate­lets; low complete blood count; prealbumin and albumin levels low; aspartate aminotransferase slightly elevated; alkaline phosphatase  —low; Zn-dependent enzyme; bound to albumin in blood; »15 mg of Zn lost per liter of diar­rheal stool; patient dehydrated, with low Mg level; copper (Cu) level obtained (anemia possibly due to iron or Cu deficiency and ingestion of 6-MP); selenium (Se) level obtained (deficiency described in severe IBD and may cause heart failure and edema); colon diffusely involved, with strictures; distal 20 cm of ileum with mucosal effacement and narrowing of distal 10 cm (no dilatation)

Nutritional assessment: severe mixed marasmus (combined protein-calorie malnutrition) and kwashiorkor-like (pro­tein depletion); low alkaline phosphatase indicates Zn deficiency; patient likely vitamin D-deficient

Treatment: intravenous adrenocorticotropic hormone, antibiotics, lower dose of 6-MP, sulfasalazine, and rehydra­tion; initial nutritional therapy included enteral predigested formula and total parental nutrition (TPN); fistula closed initially; nutritional status improved

Suggested Reading

Alvarez-Lobos M et al: Crohn's disease patients carrying Nod2/CARD15 gene variants have an increased and early need for first surgery due to stricturing disease and higher rate of surgical recurrence. Ann Surg 242:693, 2005; Bourreille A et al: Wireless capsule endoscopy versus ileocolonoscopy for the diagnosis of postoperative recurrence of Crohn's disease: a pro­spective study. Gut 55:978, 2006; Cabré E et al: Nutritional and metabolic issues in inflammatory bowel disease. Curr Opin Clin Nutr Metab Care 6:569, 2003; D'Haens GR et al: Therapy of metronidazole with azathioprine to prevent postoperative recurrence of Crohn's disease: a controlled randomized trial. Gastroenterology 35:1123, 2008; Frei P et al: Analysis of risk factors for low bone mineral density in inflammatory bowel disease. Digestion 73:40, 2006; Hanauer SB et al: Postoperative maintenance of Crohn's disease remission with 6-mercaptopurine, mesalamine, or placebo: a 2-year trial. Gastroenterology 127:723, 2004; Hartman C et al: Nutritional status and nutritional therapy in inflammatory bowel diseases. World J Gastroen­terol 15:2570, 2009; Marteau P et al: Ineffectiveness of Lactobacillus johnsonii LA1 for prophylaxis of postoperative recur­rence in Crohn's disease: a randomised, double blind, placebo controlled GETAID trial. Gut 55:842, 2006; Peyrin-Biroulet L et al: Vascular and cellular stress in inflammatory bowel disease: revisiting the role of homocysteine. Am J Gastroenterol 102:1108, 2007; Regueiro M et al: Infliximab prevents Crohn's disease recurrence after ileal resection. Gastroenterology 136:441, 2009; Rutgeerts P et al: Ornidazole for prophylaxis of postoperative Crohn's disease recurrence: a randomized, dou­ble-blind, placebo-controlled trial. Gastroenterology 128:856, 2005; Wagnon JH et al: Survey of gastroenterologists' aware­ness and implementation of AGA guidelines on osteoporosis in inflammatory bowel disease patients: are the guidelines being used and what are the barriers to their use? Inflamm Bowel Dis 15:1082, 2009.