Chronic intestinal failure and short bowel syndrome in Crohn’s disease

Table 1 Pathophysiological classification of intestinal failure (adapted from Pironi et al[2], 2015)

Type	Primary cause	Underlying disease
Short bowel type	Quantitative/qualitative loss of resorptive surface	Post-operative, in patients with mesenteric infarction, Crohn’s disease, radiation enteritis, familial polyposis, abdominal traumata, necrotizing enterocolitis1, bariatric obesity surgery (biliopancreatic diversion with or without duodenal switch), gastroileal anastomosis, extensive tumor resection.
		Congenital, in patients with gastroschisis1, intestinal atresia1, intestinal malformation, omphalocele
Fistula type	Bypass of resorptive surface due to jejunocolic fistula	Inflammatory bowel disease (Crohn’s disease2, diverticulitis, radiation enteritis)
		Post-operative3 in patients with neoplasia (colorectal carcinoma, ovarian carcinoma, Crohn’s disease)
		Iatrogenic (post-op, percutaneous drainage)
		Traumata
		Foreign bodies
Dysmotility type	Restricted (insufficient) nutrition intake due to postprandial exacerbation of symptoms, to the point of non-mechanic ileus in severe cases	Ogilvie syndrome (acute non-mechanic obstruction of the colon)
		Chronic intestinal pseudo-obstruction: Primary/idiopathic (neuropathic/myopathic); Secondary (collagenous vascular disease, e.g., PSS, LE, Ehlers-Danlos syndrome; neurological disorders such as Morbus Parkinson, intestinal hypoganglionosis; endocrinopathies)
Obstruction type	Reduced nutrition intake; Increased secretion of liquid and electrolytes in obstructive segments of the intestine; Loss of liquids and nutrients due to recurrent vomiting and/or "overflow sensors"	"Frozen abdomen" in patients with peritoneal carcinomatosis, extensive intestinal adhesion, recurrent peritonitis.
		Neoplastic stenoses and/or strictures
		Incarceration/strangulation of the intestine (hernia)
		Volvulus
Mucosa type	Extensive loss or damage of mucosa results in insufficient resorption of nutrients and pronounced enteral loss	Microvillus inclusion disease1
		Tufting enteropathy (intestinal epithelial dysplasia)
		Tricho-hepato-enteric syndrome
		Autoimmune enteropathy
		Intestinal lymphangiectasia
		Protein-losing enteropathy (Morbus Waldman)
		Radiation enteritis
		Chemotherapy-induced/associated enteritis

¹Causes 70% of pediatric cases[4].

²75%-85% of enterocutaneous fistulae (EF).

³15%-25% of EF[3].

LE: Lupus erythematosus; PSS: Progressive systemic sclerosis.

Table 2 Recommended laboratory monitoring for patients receiving parenteral nutrition (adapted from Lappas et al[29], 2018)

Parameter	Frequency
	Initiation of therapy (acute care)	Long-term therapy
Capillary glucose	Every 6 h until advanced to goal and as needed to maintain 140-180 mg/dL	Not routine, as needed basis to coordinate with PN infusion cycle
Basic metabolic panel Phosphorus, magnesium	Daily, until advanced to goal and stable; then 1-2 times/wk	Weekly, then decrease frequency as stable
CBC (with differential)	Baseline; then 1-2 times/wk	Monthly, then decrease frequency as stable
Liver function: ALT, AST, ALP, total bilirubin	Baseline; then weekly	Monthly, then decrease frequency as stable
Serum triglycerides	Baseline if at risk; then as needed	Not routine, as needed
Iron studies, 25-OH vitamin D	Not routine (see Table 4)	Baseline, then every 3-6 mo
Zinc, copper, selenium, manganese	Not routine (see Table 4)	Baseline, then every 6 mo

25-OH vitamin D: 25-hydroxyvitamin D; ALP: Alkaline phosphatase; ALT: Alanine transaminase; AST: Aspartate transaminase; CBC: Complete blood count; PN Parenteral nutrition.

Table 3 Nutrition therapy (macronutrients) according to presence or absence of colon (modified from Pironi et al[46], 2016)

Nutrient	Colon present (partial/complete)	Colon removed or disabled
Carbo-hydrates	Slow increase of the proportion of complex carbohydrates up to approx. 40%-50% of total calorie intake, no low molecular weight sugars	Slowly increase the proportion of complex carbohydrates up to approx. 40%-50% of total calorie intake, no low molecular weight sugars, modified FODMAP diet
Protein	Up to 20%-30% of total energy intake	Protein: up to 20%-30% of total energy intake
Fat	Up to 20%-30% of total energy intake	Fat: up to 40% of total energy intake
	Ensure adequate essential fatty acids (high EFA content)	Ensure adequate essential fatty acids (high EFA content)
	Consider MCTs	Limit MCTs
Fiber	Dietary fiber supplements: up to 5-10 g/d	Dietary fiber supplements: up to 5-10 g/d
Oxalate	Diet low in oxalic acid and fats; Replacement of up to 50%-75% of dietary fat with MCTs	No restriction of oxalic acid necessary
Fluids	Even if liquids are well tolerated, iso- and hypotonic drinks are preferable	Oral rehydration solutions frequently required
Lactose	Low lactose diet (10-12 g)	Unrestricted lactose intake

EFA: Essential fatty acids; FODMAP: Fermentable oligo-, di-, monosaccharides and polyols diet; MCT: Medium-chain triglyceride.

Table 4 Symptoms, prophylactic supplementation, and therapy of frequent (critical) nutrient deficiencies in chronic intestinal failure

Nutrient	Symptoms of deficiency	Normal values (blood/serum)	Additional lab tests	Prophylaxis	Therapy in case of deficiency
Calcium	Neuromuscular hyperarousal, cardiovascular symptoms, osteopathy	2.1-2.7 mmol/L	↑Alkaline phosphatase; ↑intact PTH; ↓Bone mineral density	Calcium citrate, oral 1200–2000 mg/d	Bisphosphonate if T-Score < 2.5
Magnesium	Neuromuscular hyperarousal, osteopathy (PTH effect ↓)	0.75-1.15 mmol/L	↓Magnesium in urine	Magnesium citrate, oral 300 mg/d	10 – 15 mmol magnesium, e.g., in 1000 mL NaCl 0.9 %
Vitamin A	Night blindness, wound healing disorders	1.05-2.80 µmol/L	↓Plasma retinol; ↓Retinol binding protein	10000-50000 U/d, if liver function normal	No corneal changes: 10000–25000 IU/d oral for 1–2 wk; Corneal changes: 50000–100000 IU i.m. followed by 50000 IU/d i.m. for 2 wk
Vitamin D	Osteopathy, wound healing disorders, immune system disorders	< 20 µg/L: deficiency; 20-30 g/L: insufficiency; > 30 µg/L: sufficient supplies	↑Alkaline phosphatase; ↑intact PTH; ↓Bone mineral density	Oral vitamin D (400–800 U/d) [ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3)] or 100000 U/3–6 mo orally	50000–150000 IU oral 3-5 times a week; If required: calcitriol [1,25(OH)2D] oral
Vitamin K	Hemorrhagic diathesis	INR < 1.2	PIVKA	10 mg/wk	N/A
Vitamin B1	Polyneuritis (“dry form“), edema, tachycardia, Cardiac insufficiency (“wet form“); Wernicke encephalopathy, ataxia (“central form“)	10.64 µg/L	↓Thiamine pyrophosphate; ↓Erythrocyte transketolase activity	If vomiting, aggressive oral thiamine supplementation with 100 mg/d for 7–14 d	Treatment of Wernicke Encephalopathy: 500 mg i.v. 3 ×/d for 2-3 d; ≥ 250 mg/d i.v. for 5 d; 30 mg oral 2 ×/d
Vitamin B12	Megaloblastic anemia, glossitis, skin and mucous membrane pallor, paresthesia, polyneuropathy, funicular myelosis	156-675 pmol/L	↓Holo-TC; ↓MMA; ↑Homocysteine	Oral: 1000 μg/wk or 250–350 μg/d, i.m./s.c.: 1000 μg/mo or 3000 μg every 6 mo	1000 or 2000 μg/d oral or 1000 μg/wk i.m.
Zinc	Wound healing disorders, hair loss, taste disturbances, predisposition to infection	11-23 mol/L	↓Zinc in urine	In presence of fistula, diarrhea or stomata: 12 mg; Otherwise: 3-4 mg	30-45 mg (as zinc histidine), 220-440 mg (as zinc sulphate). For each 8–15 mg of elementary zinc, 1 mg copper should be substituted
Iron	Anemia, hair loss, cognitive disorders, predisposition to infection	CRP < 5 µg/L: > 30 µg/L; CRP ≥ 5 µg/L: ≥ 100 g/L	↓Transferrin saturation; ↑Soluble transferrin receptor; ↑Zinc protoporphyrin	Oral max: 100–150 mg iron	Parenteral, depending on iron status: Aim: normalization of Hb plus transferrin saturation 35%-50% (calculated according to Ganzoni)
Copper	Neutropenia, iron deficiency anemia, central venous development disorders	11-22 µmol/L	↓Copper/zinc superoxide dismutase	Copper gluconate, oxide or sulphate equivalent to 2 mg elementary copper; 1 mg copper for each 8-15 mg zinc	Copper sulphate equivalent to 2.4 mg elementary copper in 100 ml 0.9% NaCl i.v. administered one hour/d for 5 d. Subsequently, oral substitution as required

CRP: C-reactive protein; Holo-TC: Holo-transcobalamin; INR: International normalized ratio; MMA: Methylmalonic acid; PTH: Parathyroid hormone.

Table 5 Symptomatic treatment options in short bowel syndrome

Symptom	Drug/therapy	Dose (per day)
Gastral hypersecretion	Proton pump inhibitors	20-40 mg i.v. (p.o.)
	Clonidine	2 × 75-150 µg s.c./p.o.
	Octreotide (sandostatin)1	3-4 × 50-100 µg s.c.
Hypermotility	Loperamide	4-6 mg p.o. (max daily dose 16 mg)
	Diphenoxylate	4 × 2.5-7.5 mg (max daily dose 20-25 mg)
	Codeine	30 mg p.o.
	Opium tincture	4 × 0.3-1 mL (10-60 mg) p.o.
Secretory diarrhea	Octreotide (sandostatin)1	2-3 × 50-100 µg s.c.
	Budesonide (e.g., entocort)	3 × 3 mg p.o.
	Clonidine	2 × 75-150 µg s.c.
Fat malabsorption	Pancrelipase (e.g., Creon)	40000 IU with main meals (15000 IU with snacks)
Lactose malabsorption	Lactase formulations (L-products)	Depending on severity
Reduced fluid resorption	Locust/carob bean gum flour added to drinks (yoghurt)	Approx. ½-1 tablespoon per glass/pot
	Kaopectate (kaolin/pectin)	4 × 1 tablespoon

¹Not in the adaptive phase.

Table 6 Major complications of short bowel syndrome: risk factors, prevention and treatment (adapted from Pironi et al[46], 2016)

	Risk factors	Prevention and/or treatment
Bacterial overgrowth/ miscolonization	Ileocecal valve resection; Reduced intestinal motility (Ogilvie syndrome; chronic intestinal pseudo-obstruction)	Metronidazole (500 mg, 2 times per day), vancomycin (125 mg, 4 times per day), neomycin (500 mg, 3 times per day), clindamycin (300 mg, 3 times per day) tetracycline (500 mg, 3 times per day), rifaximin (550 mg, 2 times per day)
Renal failure	Dehydration; CRBSI; Nephrocalcinosis; Kidney stones	Optimize fluid and sodium balance; Optimize CVC care; Prevent urinary calcium oxalate formation
Calcium oxalate, kidney stones	SBS with colon in continuity and fat malabsorption (enteric hyperoxaluria); Pyridoxine or thiamine deficiency; Excess of ascorbic acid; Dehydration; Low urinary citrate; Low urinary magnesium	Reduce or avoid excess lipid in the diet; Reduce food with high oxalate content; Oral calcium at mealtime (1 g); Oral cholestyramine; Optimize fluid balance; Optimize acid-base balance; Optimize magnesium status; Limit ascorbic acid supplementation
BAMS
—Compensated	Extent of resection < 100 cm; Fecal bile acid excretion increased; Adequate hepatic compensation of bile acid loss; ≥ reduction of bile acid pool; no or minimal steatorrhea	Colestyramine/Colesevelam
—Decompensated	Extent of resection > 100 cm, fecal bile acid excretion increased; Inadequate hepatic compensation of bile acid loss; ≥ reduction of bile acid pool ≥ steatorrhea	Fat-modified/-reduced diet; Cholylsarcosine/ox gall1
Gallstones	Prolonged oral fasting; Interrupted bile acid entero-hepatic circulation; Prolonged treatment with anticholinergic and narcotic drugs	Limit periods of oral fasting; Limit narcotic or anticholinergic treatment; Use oral and/or enteral feeding as much as possible
IFALD-cholestasis	SBS with < 50 cm of residual small bowel; SBS without colon; CRBSI episodes; Chronic intraabdominal inflammation and/or small bowel bacterial overgrowth; Interrupted enterohepatic circulation of bile acid; Oral fasting; PN-overfeeding; i.v. soya-based lipid emulsion ≥ 1 g/kg/d	Avoid oral fasting; Optimize CVC care; Treat intraabdominal inflammation foci; Rehabilitative surgical procedures; Optimize i.v. feeding; i.v. soya-based lipid emulsion < 1 g/kg/d and/or i.v. fish oil lipid emulsion
D-lactic acid acidosis	SBS with a colon in continuity; Carbohydrate and soluble fiber-based diet; Ingestion of rapidly fermentable simple sugars; Feeding D-lactate containing food; High blood and urinary oxalate; Thiamine deficiency; Antibiotic and/or probiotic courses; Dehydration; Decreased renal function; Decreased liver function	Low carbohydrate and simple sugar diet; Antibiotics active against D-lactate-producing bacteria orally, such as metronidazole (500 mg, 2 times per day), vancomycin (125 mg, 4 times per day), neomycin (500 mg, 3 times per day), clindamycin (300 mg, 3 times per day), tetracycline (500 mg, 3 times per day), rifaximin (550 mg, 2 times a day); Thiamine supplementation; Reduction of oxalate absorption; Optimize fluid balance

¹If colon has been removed or disabled. BAMS: Bile acid malabsorption syndrome; CRBSI: Catheter-related bloodstream infection; CVC: Central venous catheter; i.v.: Intravenous; PN: Parenteral nutrition; PPI: Proton pump inhibitor; PTH: Parathyroid hormone; SBS: Short bowel syndrome.

Table 7 Pathophysiological characteristics of short bowel syndrome with and without colon in continuity (adapted from Pironi et al[46], 2016)

Characteristic	End-jejunostomy	Jejunocolic or jejunoileal anastomosis
Structural and functional adaptation, to increase nutrient absorption	No evidence thereof at any time after surgery	Possible up to 2 yr after surgery
Gastric hypersecretion (up to 6 mo after resection)	Present	Present
Gastric emptying and small bowel transit	Accelerated gastric emptying for liquids	Slowed
	Accelerated small bowel transit
GI hormone secretion (PYY, GLP-1, GLP-2)	Decreased/absent	Increased
Energy absorption from microbiota SCFA, production in the colon	Absent	Increased up to 1000 kcal (4.2 MJ) per day
Water and sodium absorption in the remnant small bowel	Possible “net secretion” when jejunum length < 100 cm (more fluid and sodium lost than ingested)	Colon adaptation can increase the absorption of water up to 6 liters and sodium up to 800 mmol per day
Vitamin B12 and bile salt absorption	Absent	Partially conserved or absent
Magnesium absorption	Decreased	Decreased
Remnant small bowel cut-off length for HPN weaning	> 115 cm	Jejunocolic anastomosis > 60 cm
		Jejunoileal anastomosis with ICV and entire colon
		> 35 cm

GI: Gastrointestinal; GLP: Glucagon-like peptide; HPN: Home parenteral nutrition; IVC: Ileocecal valve; PYY: Peptide tyrosine-tyrosine; SCFA: Short chain fatty acid.

Table 8 Intestinal failure-associated liver disease risk factors in adult patients with home-based parenteral nutrition (adapted from Van Gossum et al[157], 2019)

PN-related	Patient-related
Energy overfeeding	Lack of oral feeding
Glucose overload > 7 mg/kg/min	Short bowel syndrome (small bowel remnant < 50 cm)
Lipid emulsion overload	Inflammation/infection
Soya-based lipid emulsion > 1 g/kg/d	Sepsis (e.g., central venous catheter related)
Continuous infusion (24/24 h)	Small intestinal bacterial overgrowth
Contaminants (phytosterols)	Gut inflammation
Antioxidant deficiency	Viral infection (e.g., hepatitis B, C)
Nutrient deficiency (choline, carnitine, methionine, taurine, essential fatty acid deficiency, etc.)	Autoimmune
	Hepatotoxic medications

PN: Parenteral nutrition.