Short bowel syndrome and nutritional consequences Alastair Forbes University College London

Intestinal failure Inadequate functional intestine to allow health to be maintained by ordinary food and drink

Intestinal failure Critical reduction of functional gut mass below the minimum amount necessary for adequate digestion and absorption to satisfy body nutrient and fluid requirements Jan DM, in Intestinal failure, Ed: Langnas et al

Acute intestinal failure Usually follows major resection May be exacerbated by coexistent intestinal dysfunction because of severe inflammation or disorders of motility (Post-operative ileus) Type 2 intestinal failure

Intestinal failure rare: prevalence 1-2 per 100,000 incidence 1-5 per 1,000,000 Crohn's, ischaemia, and surgical mishap account for most benign long-term cases more common if cancer cases included

Intestinal failure: adaptation Mostly in first 6 months Hyperplasia and hypertrophy Ileum better at this than jejunum Possibly responsive to trophic factors

Intestinal failure: adaptation Mostly in first 6 months Hyperplasia and hypertrophy Ileum better at this than jejunum Possibly Responsive to trophic factors

Intestinal failure Ileostomy and <200cm small bowel <150cm with colon Stoma or fistula output >1.5L/day

Intestinal losses Output proportional to jejunal length Positive fluid balance requires ~1m Concept of net absorber/net secretor If high/normal secretion and poor absorption, output may be dramatic

Net absorber/net secretor ? Normal person is net absorber Drink more  absorb more

Net absorber/net secretor ? Normal person is net absorber Dehydration  Thirst  Drinking  Increased fluid retention  Resolution

Normal physiology Osmosis and sodium gradients Proximal intestinal response is secretory Threshold about 100mmol/L

Net absorber/net secretor ? If <1.5m small intestine Normal proximal secretion is not compensated by distal absorption

Net absorber/net secretor ? Drink more  absorb LESS

Net absorber/net secretor ? Dehydration  Thirst  Drinking  Increased fluid loss  Deterioration

Net secretor and fluid restriction Fluid restriction is central challenge Thirst requires LESS drinking severe - iv saline moderate - oral rehydration solutions mild - limit (sodium-free) fluids

The colon in short bowel Retained colon (>half) equivalent to ~50cm small intestine Value mainly in fluid balance Some nutritional gain from fermentation

Assessment Observations Serum electrolytes Plasma osmolarity Serum urea nitrogen/creatinine Complete blood picture Serum magnesium

Urine sodium Marked sodium retention in dehydration Very early feature Simple untimed sample sufficient <20 mmol/L almost diagnostic Unreliable if renal failure or diuretics

Short bowel syndrome management S can for sepsis S kin care N utritional care A ssessment P lan for future surgery

Short bowel syndrome management S can for sepsis S kin care N utritional care SSNAP A ssessment P lan for future surgery

Short bowel syndrome management Resuscitate if necessary with iv saline Reduce oral intake of low sodium fluid Increase sodium intake Don’t render nil per os / nil by mouth

Food selection Regular food Encourage high energy density Separate food from liquid Avoid fluids (as low Na + ) Little and often

Enteral fat intake If no colon useful : energy dense If retained colon may give steatorrhoea fat less utilized than carbohydrate less (beneficial) fermentation

Formula feeds in SBS NOT elemental - because high osmolality low energy density high volume poor palatability

Polymeric not inferior to semi-digested No advantage to modified/supplemented feeds Regular (1kcal/ml) or high energy (1.5kcal/ml) determined by needs and tolerance of osmolality Formula feeds in SBS

Simple electrolyte mix 20g glucose 3.5g NaCl 2.5g NaHCO 3 (or citrate) Na + = 90mmol/L

glucose salt bicarbonate or citrate

SBS: enteral therapy Limit “free” fluid intake to 500ml/day Oral rehydration solution (>60mmol/l) ad libitum Antisecretory regime Encourage oral feeding ± formula feed ± tube feed

Intestinal failure: pharmacological therapy Proton pump inhibitors reduce gastric secretion Loperamide reduces speed of transit

Intestinal failure: pharmacological therapy Proton pump inhibitors reduce gastric secretion Loperamide reduces speed of transit Codeine less favored – sedative Anticholinergics less favored – dry mouth Somatostatin and derivatives disappointing Teduglutide (GLP-2) great promise Citrulline - interesting

Intestinal failure parenteral nutrition Continue all components of enterally based regime (but less rigidly) Always aim for maximal possible enterally Usually give more nutrition than estimated or measured because of malabsorption

Intestinal failure: parenteral nutrition Usually give more nutrition than predicted Example: patient needs 2000 kcal/day But has SBS and absorption of 50% Eats 2000kcal - absorbs 1000kcal Needs 1000kcal parenterally Total 3000kcal administered Correct 2000kcal received

Intestinal failure: parenteral nutrition Usually give more nutrition than predicted Example: patient needs 2000 kcal/day But has SBS and absorption of 50% Eats 2000kcal - absorbs 1000kcal Needs 1000kcal parenterally Total 3000kcal administered Correct 2000kcal received Same applies to other nutrients

Intestinal failure research New forms of assessment Modified parenteral feeds Drugs and trophic factors Surgical options The artificial intestine?

Growth hormone Uniquely approved by the FDA for use in SBS Mediates its trophic effects through IGF-1 Increases serum IGF-1 and IGF-1 in intestine Increases crypt cell proliferation inhibits apoptosis in intestine Enhances intestinal absorption of nutrients Best in combination with a optimal SBS care

Glucagon-like peptide 2 Intestinal trophic activities recognized 1996 From intestinal L cells exposed to luminal nutrients Degraded by DPP IV, t ½ 7 min Increases crypt cell proliferation Inhibits villous apoptosis Enhanced digestive and absorptive function Reduces gastric secretion and slows emptying Increases intestinal blood flow Rapidly reversible changes

Teduglutide Longer acting analogue of GLP-2 –1 amino acid alteration –enzyme resistant More effective than native ? –growth of juvenile primate small bowel Particular benefit for fluid balance Mean of 800mL/d reduction in Phase II Jeppesen Gut 2005

Teduglutide Phase 3 study – 24 week evaluation n=83 End-point = 20% reduction in PN Placebo, 0.05/kg, 0.1/kg 15/16; 27/35 & 29/32 completed AEs few - 1, 5 and 2 drop-outs Jeppesen 2009

Teduglutide Weight change Placebo: 61.5  61.6 Low dose:57.2  59.7 High dose:59.5  61.4

Teduglutide Weight change Placebo: 61.5  61.6 Low dose:57.2  59.7 High dose:59.5  61.4 Response Placebo: 1/16 6% Low dose:16/3546% p=0.005 High dose: 8/3225% Combined:24/6736% p=0.077

Citrulline in intestinal failure Produced by intestine (only) Degraded/excreted by kidneys Excellent marker of intestinal integrity Paris group

Citrulline in intestinal failure Produced by intestine (only) Degraded/excreted by kidneys Excellent marker of intestinal integrity In various conditions and independent of inflammation Clinically predictive Paris group London/Parma/Zambia group

Therapeutic citrulline in intestinal failure ? A “safer” arginine donor Preserves nitrogen balance in resected rats (Gut 2004) Reduces splanchnic sequestration of amino acids Treatment for sarcopenia in rats (AJPEM 2006) Prevents TPN muscle atrophy (Clin Sci 2008) Paris/Warsaw group Osowska et al

The Bianchi Operation From Thomson 2004

STEP - serial transverse enteroplasty procedure From Thomson 2004

years10 Transplantation or HPN HPN vs “best” Tp 2007

Mange Takk