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From short gut to
Dr Jonathan Hind
Consultant Paediatric Hepatology, Intestinal Rehabilitation and
Transplantation
King’s College Hospital
Johannesburg
November 2017
enteral autonomy
Case
Baby boy
• 26+5 weeks 780g
• Built up to full feeds and at day 25 started a milk-thickener for reflux concerns
• 1 day later deteriorated and ?perforation
• At 1 month age – NEC - transferred to surgical centre
• “Clip and drop” – small bowel length 34cm
• Further resection next day with loss of ICV
• Feeds built up but high stoma
• Unwell neonate
• Recurrent episodes of sepsis
• At 3 months closure of stoma
• Developed further gram negative sepsis
• Stricture
H
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3 0 0
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5 0 0
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7 0 0
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J u l2 0 1 2
O c t J a n 2 0 1 3 A p r J u l
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um
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B i l i r u b i n ( C o n j u g a t e d ) ( u m o l / L )
• Liver disease at this time with maximum
conjugated bilirubin of 754
• Further surgery at 6 months with resection of stricture and ileocolonic anastomosis
• 2 weeks later further resection and ileostomy and mucous fistula
• Further episode of severe cholestasis
• Period of wound breakdown
• Realistic expectations? – Premature
– Long-term PN
– Recurrent sepsis
– Ultra-short gut
– Liver disease
Topics
• INTESTINAL FAILURE – Definition and aetiology – Problems
• INTESTINAL REHABILITATION – Management of intestinal failure
• Parenteral Nutrition – Problems
• Surgical options • Outcomes
• INTESTINAL TRANSPLANTATION
• Development and outcomes
• ENTERAL AUTONOMY?
Intestinal Failure
• Critical reduction of functional gut mass below the minimum required for adequate digestion and absorption to satisfy body fluid, nutrient and electrolyte requirements
• Total, partial, temporary, permanent • Limited options • Parenteral Nutrition is mainstay of therapy
• Prevalence 5-6/million population
Causes of Intestinal Failure in children
• Congenital or acquired disorders of GIT
1. Anatomical reduction of gut length (SBS)
2. Neuromuscular disease of GIT e.g. long segment Hirschsprung
3. Congenital disease of GI epithelium e.g. MVA
NEC 27%
Volvulus 24%
Atresia 23%
Gastroschisis 14%
Problems of IF • Growth failure • High bowel fluid losses and malabsorption • Dehydration • Electrolyte deficiencies • Nutrient deficiencies • Bowel dilatation • Dysmotility • Complications of IF treatments
– Prior to 1970, prognosis dismal – In recent years, much improved
Intestinal Adaptation
• Progressive recovery from IF secondary to SBS – allowing adequate GI function within weeks to months to over 1 year
• Most babies do adapt (eg prem)
• Chance of adaptation depends on – Remaining bowel length
– Type of remaining bowel
– Function of remaining bowel
– Presence of IC valve
Duodenum - Iron
Jejunum - Carbohydrates,
proteins, fat, vitamins (better
absorption/less adaptation)
Ileum - Bile acids, vitamin B-
12 (less specialised
absorption/better adaptation)
1. Provide the nutrition necessary to maintain health and promote growth
2. Reduce the severity of intestinal failure
3. Promote adaptation of remaining bowel
4. Prevent complications of IF
5. Treat complications of IF
6. Promote good quality of life for the family
• Medium term - life at home
• long-term - independence from PN
Intestinal Rehabilitation
Team approach
• MDM assessment of IF
• Gastroenterologist, Surgeon, Radiologist, Specialist Nurse, Dietitian – Cause of IF
– Remaining anatomy • Surgical review, GI series ?surgical option
– CVC number, site and septic episodes • Doppler US of access sites
– Liver disease, ?portal H/T ?biopsy
– Nutritional assessment
Enteral feeding
• Tube feeding (NG/NJ, Gastrostomy/GJ, Colonic etc)
• Continuous feeding vs bolus
• Oral aversion (SALT)
– Non-nutritive sucking
– Sham feeding
– Oral feeds as well as tube
– Introduction of solids (often well-tolerated)
Refeeding
• Losses from proximal stoma refed into distal mucous fistula
• Use every centimetre of gut available
• Absorptive capacity
• Stimulate enterocytes for growth and adaptation
• Healthy bowel for future reconnection
• Avoid complications such as diversion colitis
• By definition, enteral feeding is not sufficient
• Parenteral Nutrition is therefore the mainstay of treatment and if long-term, then Home PN should be the aim
– Better QoL
– Less complications
Historical perspective
• Attempts of intravenous infusions, including wine and ale into dogs leading to intoxication
• Successful treatment of cholera patients with infusions of electrolytes and milk
• 1800s Administration of fat subcut
• Late 1800s iv glucose and amino acid solutions
• 1924 continuous glucose infusion
Development of parenteral nutrition
• Early 20th century complex operations and outcomes associated with nutritional state
• 1937 Amigen – iv amino acid infusion
– Large volumes for adequate calories
• Alcohol tried for more calories but SE’s!
– Thrombophlebitis with high glucose
• CVC not yet developed
– EFA deficiency
Development of fat emulsion
• 1920s Attempts but no emulsifying agent
• 1950s Cotton Seed – but SEs
• 1961 – Sweden - Arvid Wretlind developed a relatively non-toxic formulation of soy bean oil emulsified by egg yolk phospholipids in glycerol - Intralipid
Development of parenteral nutrition
• Protein solution and fat emulsion but still high volume due to necessity of low glucose concentration in peripheral veins
• In the 1960s CVC use was tried successfully
• In 1967 at the University of Pennsylvania a child with intestinal atresia dying of starvation weighed only 2kg and was given TPN. She survived for 22 months, developed normally and gained weight to 8.3kg
Parenteral Nutrition
• Effective and safe therapy – Intrusive
– Expensive
– Significant morbidity
• Complications 1. Catheter-related
2. Metabolic
3. Bone disease
4. Organ dysfunction (liver, kidney)
UK Paediatric Type III IF point prevalence, 1993, 2010, 2012 complete ascertainment 32 nutrition centres
1993 2010 20120.0
2.5
5.0
7.5
10.0
12.5
15.0
17.5
p=0.03
4.4
13.9
Year of Study
Poi
nt p
reva
lenc
e ra
te
per
mill
ion
child
ren
<16y
rs o
f ag
e
16.4
0
50
100
150
200
250
300
350
1
1993
2010
2012
2015
UK Paediatric Type III IF point prevalence,
1993, 2010, 2012, 2015* from 32 nutrition centres
* Extrapolated from 63% ascertainment of centres
0
50
100
150
200
250
300
350
UK Paediatric Type III IF point prevalence, 1993, 2010,
2012, 2015* from 32 nutrition centres
* Extrapolated from 63% ascertainment of centres
CVC complications • Common • Sepsis (and subsequent increase in IFALD) • Occlusion • Thrombosis
– Dedicated team – Line Hygiene – Recognition and prompt treatment of infection
(Local services and parental education)
– Home PN
Intestinal Failure Associated Liver Disease
• IFALD or PNALD? – Aetiology complex
• PN factors
• Patient factors
• Definition – LFTs >1.5x normal >2 weeks – no other cause
Incidence – Acute PN
– Early reports with lipid-free PN and high glucose content showed abnormal AST in 68% and abnormal bilirubin in 21% of patients after only 2 weeks
• Lindor KD, Fleming CR, Abrams A, et al. Liver function values in adults receiving total parenteral nutrition. JAMA 1979;241:2398–400
– More recently, with better PN, this is lower but still common, with abnormal AST in 27% and abnormal bilirubin in 31% after 4 weeks
• Clarke PJ, Ball MJ, Kettlewell MG. Liver function tests in patients receiving parenteral nutrition. JPEN J Parenter Enteral Nutr 1991;15:54–9
– Most of these abnormalities are minor and will resolve as PN decreases and enteral feeding commences
Steatosis • Hepatic accumulation of lipid or glycogen
– Excess calories • Zaman N, Tam YK, Jewell LD, Coutts RT. Effects of intravenous
lipid as a source of energy in parenteral nutrition associated hepatic dysfunction and lidocaine elimination: a study using isolated rat liver perfusion. Biopharm Drug Dispos 1997;18(9):803–19
– Excess lipid infusion • Soy-bean based lipid infusions • Goulet O, Joly F, Corriol O, Colomb-Jung V. Some new insights in
intestinal failureassociated liver disease. Curr Opin Organ Transplant 2009 Jun;14(3):256–61.
– EFA deficiencies – AA deficiencies
• Buchman AL. The addition of choline to parenteral nutrition. Gastroenterology 2009 Nov;137(5 Suppl):S119–28.
Histology shows fatty
infiltration of the liver
Incidence – long-term PN. Infants
– In neonates especially, IFALD is common, and closely related to degree of prematurity, birth weight, duration of PN, and sepsis
• Beale EF, Nelson RM, Bucciarelli RL, et al. Intrahepatic cholestasis associated with parenteral nutrition in premature infants. Pediatrics 1979;64:342–7.
• Beath SV, Davies P, Papadopoulou A, et al. Parenteral nutrition related cholestasis in postsurgical neonates: multivariate analysis of risk factors. J Pediatr Surg 1996;31:604–6
– Cholestasis is more common than steatosis, and present in as many as 90% of neonates who receive PN for >3months (Beale)
– Overall, the incidence is around 40-60% • Buchman A. Total parenteral nutrition-associated liver disease. J Parenteral Enteral Nutr 2002;26(5):S43–8
– It can be rapidly progressive to hepatic failure. Up to 17% of neonates with infection and intestinal resection
• Sondheimer JM, Asturias E, Cadnapaphornchai M. Infection and cholestasis in neonates with intestinal resection and long-term parenteral nutrition. J Pediatr Gastroenterol Nutr 1998;27:131–7
Risk factors for IFALD
Age Prematurity
Co-morbidity Loss of mucosal
integrity
SBS <25cm, no ICV
CVC infection >3
Lipid >3.5g/kg/day
Lack of MDT Increase CVC sepsis
Lack of enteral
feeding
Biliary sludge
-Beath SV, Davies P,
Papadopoulou A, et al. Parenteral
nutrition related cholestasis in
postsurgical neonates: multivariate
analysis of risk factors. J Pediatr
Surg 1996;31:604–6
-Christensen RD, Henry E,
Wiedmeier SE, Burnett J, Lambert
DK. Identifying patients, on the
first day of life, at high-risk of
developing parenteral nutrition
associated liver disease. Perinatol
2007 May;27(5):284–90
No single risk factor
Age and septic
episodes have a big
impact
Features of IFALD
Early Established Late
Clinical Hepatomegaly Jaundice
Splenomegaly
Deep jaundice
GI bleed
Biochem ALP and GGT 1.5x Bili 50-100, LFT rise,
plt fall
Bil>200 plt<100
hypoglycaemia
Imaging Echo-bright US Splenomegaly biliary
sludge
Cirrhotic liver, varices
Histology Fatty change Mild fibrosis Cirrhosis, bile plugs
Prognosis 70-90% 5yr survival Die within 1yr if no
treatment
Die within 2 months
Willis TC, JPEN 2010;34:32-27
Aetiology
Multifactorial aetiology
Fasting Sepsis
Lipid
peroxidation
Cholestasis Liver injury
Entero-hepatic
circulation TLR4 Endotoxin,
TNF
Free
radicals
AA
deficiency
Activated
macrophages Toxic
components
Prematurity
Immature
liver
Phytosterols
Microbiota
Fasting
• Reduced GI hormones (gastrin, motilin, pancreatic polypeptide, insulinotropic polypeptide and glucagon) – Biliary stasis
• Biliary sludge, Gallstones
• Changes in intestinal microbiome (Shigella, citrobacter,
anaerobes) • Bacterial overgrowth • Translocation, Sepsis
• Impaired bile acid recirculation – (may be compounded in short gut patients by loss of terminal ileum or
proximal stoma)
Lambert JR, Thomas SM. JPEN 1985;9;501-3
Greenberg GR, Wolman SL, Christofides ND, et al. Effect of total
parenteral nutrition on gut hormone release in humans.
Gastroenterology 1981;80:988–93
Brown MR, Thunberg BJ, Golub L, Maniscalo WM, Cox C, Shapiro DL. Decreased cholestasis with enteral instead of intravenous protein in the very low-birth weight infant. J Pediatr Gastroenterol Nutr 1989;9:21–7
Mouse model Epithelial and whole-bowel changes with TPN. Unfed bowel demonstrates decreased epithelial cell proliferation (green = PCNA, proliferating cells; red=DAPI, all nucleated cells) compared to fed intestine (A). Representative images of harvested mouse intestine demonstrate decreased length with TPN-dependence (B).
Intestinal epithelial cell apoptosis and loss of barrier function in the setting of altered microbiota with enteral nutrient deprivation Farokh R. Demehri , Meredith Barrett , Matthew W. Ralls , Eiichi A. Miyasaka , Yongjia Feng and Daniel H. Teitelbaum Frontiers in cellular and infection microbiology. 2013
Bile acids in the liver • Cholestasis leads to
increased bile acids
• Resultant bile acid toxicity thought to activate hepatic phagocytes
• Phagocytes release cytokines which lead to hepatocyte damage
Bile acids in the Gut
• Nuclear receptor Farnesoid X Receptor is abundant in liver and gut
• Chenodeoxycholic acid is a potent FXR agonist
• In normal enterohepatic circulation, bile acid absorption in the ileum is associated with activation of FXR in the epithelium
– Upregulates the growth factor FGF19 in the gut (mucosal integrity)
– Regulatory effects on CHO and lipid metabolism in the liver
– Suppresses CYP7A1 (bile acid synthesis)
• Animal model shows FGF19 is higher in enteral fed compared to TPN infused animals
A. K. Jain, B. Stoll, D. G. Burrin, J. J. Holst, and D. D. Moore, “Enteral bile acid treatment improves parenteral nutrition related liver disease and intestinal mucosal atrophy in neonatal pigs,” The American Journal of Physiology: Gastrointestinal and Liver Physiology, vol. 302, no. 2, pp. G218–G224, 2012
A. K. Jain, J. H. Teckman, “Newly identified mechanisms of total parenteral nutrition related liver injury” Advances in Hepatology, vol. 214, Article ID 621380
Sepsis
• Strongly correlated with the development of IFALD – Catheter-related blood stream infections
– Bacterial translocation from mucosal atrophy and bacterial overgrowth
• Systemic inflammatory response known to be associated with liver disease
• Preventable with good line care!
Moss R, Semin Pediatr Surg 1999;8:140-7
Hermans D, Talbotec C, Lacaille F, Goulet O, Ricour C, Colomb V. Early central catheter infections may contribute to hepatic fibrosis in children receiving longterm parenteral nutrition. J Pediatr Gastroenterol Nutr 2007 Apr;44(4):459–63
Beath SV, Booth IW, Murphy MS. Nutritional care in candidates for small bowel transplantation. Arch Dis Child 1995;73:348–50
Le HD, Fallon EM, de Meijer VE, Malkan AD, Puder M, Gura KM. Innovative parenteral and enteral nutrition therapy for intestinal failure. Semin Pediatr Surg 2010 Feb;19(1):27
Endotoxin
• Intestinal hypomotility promotes bacterial overgrowth
• Atrophic gut may promote permeability to bacteria
• Thus endotoxin is increased in the portal bloodstream
• Endotoxin
– Affects levels of BSEP
– Inhibits transcription of bile acid transporters on canalicular membrane
• Cholestasis is exacerbated
Kumpf VJ, Nutr Clin Pract 2006;21:279-9
Trauner M, J Clin Invest 1998;1-1:2092-2100
Endotoxin
Paik YH; Hepatology 2003;37:1043-55
• Inflammation mediated by activated hepatic macrophages and bacterial
toxins via TLR4 perpetuates hepatocyte injury and promotes fibrosis
• Endotoxin (lipopolysaccharide (LPS)) is a component of the cell wall of
gram negative bacteria. Released when the cell wall breaks down and
a major trigger in the pathogenesis of sepsis
Altered microbiome
Phylum-level changes in intestinal microbiota with TPN. Enteric bacteria from TPN-dependent mice (A) demonstrate a relative increase in Proteobacteria and Bacteroidetes vs.fed mice (B), where Firmicutes dominates.
Miyasaka,E.A.,Feng,Y.,Poroyko,V.,Falkowski,N.R.,Erb-Downward,J.,Gillilland, M.G. 3rd., et al. (2013). Total parenteral nutrition-associated lamina Propria inflammation in mice is mediated by a MyD88-dependent mechanism. J. Immunol. 190, 6607–6615.
Intestinal microbiome and IFALD
• Infants with NEC independent of bowel resection have a higher incidence of IFALD
• ?absorption of cell wall components of microbiota activates TLR signalling in Kupffer cells in the liver, leading to high IL6 and TNFa
• Mouse model showed mice with inflamed gut + PN developed liver disease with high IL6 and TNFa
• Mice with inflamed gut/no PN or inflamed gut/no PN/bowel decontamination did not develop as much liver disease
• Shigella and Citrobacter spp were uniquely present in the inflamed gut + PN mice
Hepatology. 2012 May;55(5):1518-28. doi: 10.1002/hep.25500. Epub 2012 Mar 18. Toll-like receptor 4-dependent Kupffer cell activation and liver injury in a novel mouse model of parenteral nutrition and intestinal injury. El Kasmi KC1, Anderson AL, Devereaux MW, Fillon SA, Harris JK, Lovell MA, Finegold MJ, Sokol RJ
Summary of TPN-induced epithelial signalling changes
Lack of enteral nutrition leads to a change in luminal microbiota where Gram-negative Proteobacteria dominate. Lipopolysaccharide(LPS) derived from these bacteria signal lamina propria(LP) cells via Toll-like receptors (TLR), leading to increased NF-κB transcription. This creates a pro-inflammatory state with increased TNF-α and IFN-γ, loss of Treg cells, and decreased intraepithelial lymphocyte(IEL)-derived IL-10 and EGF. These changes lead to breakdown of tight junctions, loss of epithelial barrier function, bacterial translocation, and sepsis
Prematurity
• IFALD higher incidence in prems and in prems <1000g – Many studies have shown this
• Immaturity of the neonatal liver – Reduced bile acid pool and circulation – Underdeveloped capacity for transulfuration – Low activity of other enzyme systems
• Poor bilirubin conjugation and sulphation • More toxic bile salts
• Increased speed of progression of liver disease in infants
Watkins JB, Szczepanik P, Gould JB, Lester R. Bile salt metabolism in the human premature infant. Gastroenterology 975;69:706–13
Watkins JB. Placental transport bile acid conjugation and sulphation in the fetus.J Pediatr Gastroenterol Nutr 1983;2:365–73
Transulfuration pathway
Cysteine is then oxidised and decarboxylated
in the pancreas ultimately forming taurine
Zlotkin SH, Anderton GH. The development of cystothianase activity during the first
year of life. Pediatr Res1982;16:65–8.
Taurine
• From Taurus (bull/ox) as first isolated from ox bile
• Major constituent of bile acids and enhances surfactant properties of bile in the gut
• Shown to increase bile flow
• Antioxidant
• Thought to aid recovery from shock and prevent negative effects of endotoxin
Supplementation? Cooke RJ, Whitington PF, Kelts D. Effect of taurine supplementation on hepatic function during short-term parenteral nutrition in the premature infant. J Pediatr Gastroenterol Nutr 1984;3:234–8
PN factors
• Amino acids implicated – Relative lack of taurine, carnitine and glutamine
– Methionine • Transulfurated ultimately aiding production of choline, cysteine, serine and
taurine
• Bypassed if given iv
• Choline deficiency leads to hepatic steatosis
• Manganese excess
• Glucose excess, insulin/glucagon imbalance
– Lipogenesis and steatosis
Buchman Al, JPEN 2001;25:260-268
Chawla RK, Am J Clin Nutr 1985;42:577-84
Phytosterols
• Sterols are important in cell membranes and are precursors for bile acids and steroids
• Phytosterols are found in soybean based lipids • Accumulate in long-term PN • Associated with IFALD
– Normally only 5% of ingested phytosterols are absorbed from the GI tract, most
sterols are cholesterol – Soybean lipid emulsion phytosterol level exceeds the ability to excrete the
phytosterols in bile, they accumulate and the phytosterol/cholesterol ratio is reversed – Implicated in disrupted bile synthesis and flow
• Mouse model of PN and intestinal injury • Mediated via suppression of cannalicular bile transporter expression • Disrupt hepatocyte nuclear Farnesoid X receptor (FXR) which usually helps maintain safe intrahepatic bile
acid levels, therefore hepatocytes are exposed to bile acid toxicity
El Kasmi KC et al, Sci Transl Med 5; 206: ra137
Essential fatty acids
Fatty acids
• Produce pro-inflammatory eicosanoids
• Compete with w3 FAs for enzymic transformation
• Amount of pro-inflammatory eicosanoids therefore depends on the ratio of w6:w3 FAs given
• High w6:w3 ratio in the western diet is thought to be behind the rise in inflammatory disorders such as atherosclerosis and implicated in IFALD
• Alpha linoleic acid (ALA), converted to eicosa pentaenoic acid (EPA) and docosa hexaenoic acid (DHA) but process slow and metabolically costly, and competitively inhibited by w6
• Plant w3 are only ALA
• Fish oils are a source of EPA and DHA
• EPA and DHA produce anti-inflammatory eicosanoids
• Thought to be protective for IFALD
Omega 6 Omega 3
Omega 3 fatty acids
• Mouse model of IFALD has shown that mice with inflamed bowel given w6 FAs developed IFALD
• Those with inflamed bowel given w3 FAs did not develop IFALD
• Thought to attenuate TLR signalling in Kuppfer cells of liver, leading to reduced production of IL6 and TNFa
FISH-OIL BASED INTRAVENOUS LIPID EMULSION AS A RESCUE IN SEPTIC INFANTS WITH INTESTINAL FAILURE AND WITH OR AT RISK OF DEVELOPING LIVER DISEASE
Huey Miin Lee, Ann Hickey, Helen Callaby, Marie O'Meara, Lucy Thompson, Jonathan Hind
Hepatic Fibrosis Persists and Progresses Despite Biochemical Improvement in Children Treated With Intravenous Fish
Oil Emulsion
• Examined sequential biopsy data in 6 children treated with fish-oil based lipid
• Hyperbilirubinaemia reversed
• Synthetic liver function preserved
David F. Mercer, Brandy D. Hobson, Ryan T. Fischer, Geoffrey A. Talmon, Deborah A. Perry, Brandi K. Gerhardt, Wendy J. Grant, Jean F. Botha, Alan N. Langnas, and Ruben E. Quiros-Tejeira
JPGN Volume 56, Number 4, April 2013
Hepatic Fibrosis Persists and Progresses Despite Biochemical Improvement in Children Treated With Intravenous Fish Oil Emulsion
Representative histology of subject 3. Images A to D show Masson stain of liver biopsies from subject 3 at (A) 7 weeks, (B) 34 weeks, (C) 40 weeks, (D) 67 weeks of age (extent of fibrosis indicated in blue) Increasing enteral feed Improving biochemistry
Hepatic Fibrosis Persists and Progresses Despite Biochemical Improvement in Children Treated With Intravenous Fish Oil
Emulsion
• Fibrosis
– Regressed in only 1
– Persisted in 2
– Progressed in 3
• Remained severe (ISHAK 2) in 5 of 6
• Cholestasis improved in all
• Inflammation improved in 5 of 6
• Mixed results for steatosis
Children with IFALD should have active ongoing treatment and be considered for early referral to an Intestinal Failure Program even with a normalized bilirubin
Non-transplant short-gut surgery
• Bianchi procedure / LILT
Non-transplant short-gut surgery
• STEP
Baby boy
• 26+5 weeks 780g
• Built up to full feeds and at day 25 started a milk-thickener for reflux concerns
• 1 day later deteriorated and ?perforation
• At 1 month age – NEC - transferred to surgical centre
Current
• At home
• Feed Nutrini overnight 12 hours plus solids
• Full enteral Nutrition
• Stoma reconnected summer 2014
Current
• Normal liver function tests
• Good growth, weight and height 91st centile
• Normal development
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B i l i r u b i n ( C o n j u g a t e d ) ( u m o l / L )
Case 2
• Mother – primary ovarian failure
• Baby antenatal mid-gut volvulus
• Surgery day 1 of life
– 16cm small bowel surviving, 1cm distal ileum
– Extra-hepatic biliary atresia, splenic malformation noted
– Prognosis grim
• At KCH – liver management and intestinal rehabilitation – Surgery 11/7 – Modified Kasai
(duodenoportoenterostomy), jejunostomy, colonic mucous fistula.
– Maintained on PN (and HPN) – Surgery 8/12 – STEP, reconnection – Surgery 9/12 – Anastomotic imbrication and distal
access point for refeeding – Parenteral nutrition management and HPN – Enteral feeding
• Course
– Complicated by fistulating bowel, poor GI motility and intra-abdominal sepsis
– Home on 16 hours per day PN, plus tube EN, plus dressings etc
– Eventually deterioration of liver function
– Assessed early for liver/bowel transplantation
• Outcome
– Combined liver/bowel transplant at 17/12 age
– PICU 6 days
– Inpatient 30 days
– Full EN
• Current – age 5.7yrs
– At home
– Normal diet, no nutritional support, normal growth
– Normal developmental progress, at school
– Father back at work full time
– 4 medications
– Stoma reconnected
Intestinal transplantation
The development of intestinal transplantation
Alexis Carrel
Medical student in Lyon who
developed the idea and
technique of blood vessel
anastomosis around 1900
In the Rockefeller Institute,
developed the idea further
and developed organ
preservation – Nobel Prize
in 1912
Attempted organ
transplants in dogs –
including intestinal
transplant
World War II Alexis Carrel took a controversial role in
the Vichy government after the German
invasion of France Many British pilots were
being severely burned
Skin grafting was
technically possible but
donor grafts would not
survive long-term
Peter Medawar
• Brazilian born British zoologist
• Commissioned by British Government
• Developed rabbit model of skin grafting
• Suggested that the
immune system was
responsible for the
destruction of the graft
• Nobel prize 1960
Joseph Murray et al.
• Understanding of surgical and biological basis of transplantation
• First successful kidney
transplant 1954
• Harvard
• Identical twins
Lillehei and Starzl • Minnesota – Lillehei performed autotransplants
and homotransplants in dogs
•Showed the intestine
withstood preservation and
functioned after implantation
– 1959
•Pittsburgh – Thomas Starzl
reported multivisceral
transplantation in dogs -
1960
Poor outcomes
• For 25 years there were no survivors of intestinal transplantation
• However, long-term parenteral nutrition was not available until the mid 1970s
• Other organs such as liver and kidney were having successes
• Therefore the impetus to succeed was still present
Later success • 1987 – ciclosporin
• Pittsburgh - multivisceral transplant into a 3yr old girl
• Survival 6 months
• 1989 – Tacrolimus
• All transplantation
results improved
• Bowel transplant
became feasible
• 1990 – first report of long-term survival with enteral
autonomy by David Grant
• Improving results ever since
Types of Intestinal Transplant
• Improvement in outcomes in ITx last two decades
• Standardisation of surgical techniques
– Isolated small bowel, Liver and small bowel, Multivisceral
Isolated small bowel transplant
Liver/small bowel (en-bloc)
Multivisceral transplant
Including the colon and ICV
• Improved outcome in terms of frequency of stools
• Initial reports risk morbidity and mortality – Todo S, Reyes J, Furukawa H et al. Outcome analysis of 71 clinical intestinal transplantations. Ann Surg 1995: 222: 270
• Later reports no outcome difference – Goulet O, Auber F, Fourcade L et al. Intestinal transplantation including the colon in children. Transplant Proc 2002: 34: 1885.
– Lacaille F, Vass N, Sauvat F et al. Long-term outcome, growth and digestive function in children 2 to 18 years after intestinal transplantation. Gut 2008: 57: 455
• Recently more favourable in multivisceral – Kato T, Selvaggi G, Gaynor JJ et al. Inclusion of donor colon and ileocecal valve in intestinal transplantation. Transplantation
2008: 86: 293.
• Unpublished registry data – Survival advantage
Retransplantation
• Higher morbidity, graft loss and mortality, but – Mazariegos GV, Soltys K, Bond G et al. Pediatric intestinal retransplantation: techniques,
management, and outcomes. Transplantation 2008: 86: 1777.
• 47 patients reptransplanted (10% of total)
• Indication usually rejection
• High early problems but 5 year survival similar to primary allograft
• Retransplant including liver better survival than liver-free
• Desensitisation of recipients
• Enterectomy and period off immunosuppression and on PN
The right patient
Indications 1. Irreversible intestinal failure
a) Life-threatening complications of PN
b) Very poor quality of life thought to be correctable by transplantation
2. Extensive surgery requiring evisceration
3. Transplantation of other organs where excluding the intestine would adversely affect survival
Complications of PN
• Progressive liver disease despite remedial action
– Objective
– Judged on biochemistry and biopsy
• Consider combined liver and bowel transplant rather than isolated small bowel
– Liver/bowel candidates have higher priority than bowel alone
on the UK waiting list
Complications of PN • Severe sepsis
– More than one life-threatening episode of catheter-related sepsis
– Endocarditis or other metastatic infection
• Limited central venous access • 3 major ⃰ venous access sites in adults (above and below the
diaphragm)
• 2 major ⃰ venous access sites in children (above the diaphragm)
– ⃰ Internal jugular, subclavian, femoral
Contraindications • Absolute
– Metastatic malignant disease
– Systemic disease with a poor prognosis
– (<50% expected survival at 3 years)
– Severe progressive neurological disease
• Relative
– Acute generalised sepsis
– Requirement for ventilator support
– Neurological disease (permanent)
– Insufficient venous access
– Systemic disease (life expectancy <5yrs)
– Neoplastic disease with uncertain prognosis
The right time • High mortality on waiting list
– Fryer J et al. Liver Transpl 2003;9:748-53
– In 2015, this depends on the indication
• Pre-transplant morbidity affects post-transplant survival
– Middleton SJ et al. Transpl proc 2010;42:19-21
• Patients should be discussed on a case by case basis with an intestinal transplant centre BEFORE life-threatening complications develop
– Fecteau A et al. J Pediatr Surg 2001:36:681-84
Outcome of SBTx assessments 1992-2008 – Birmingham UK
75 for intestinal transplant
25 for liver Tx only
• 45 received intestinal transplants
• 21 liver transplant only
• 26 died before organs offered
100 registered
Survival of children with bilirubin > 350
micromol/L at the time of intestinal Tx
0.00 2.00 4.00 6.00 8.00
Survival post transplant (years)
0.0
0.2
0.4
0.6
0.8
1.0
Cu
mu
lati
ve s
urv
ival
Bilirubin <350 at transplant n =10
Bilirubin >350 at time of transplant n=28
Overview
Overview
Experience and outcomes in King’s,
UK, and worldwide
ITR and recent published reviews • Actuarial graft survival 71% 1y 60% 5yr
• Conditional graft survival 76% 5 year
• Paediatric outcome continues to improve • Paediatric conditional 5yr survival 80%
• Short term survival now excellent (up to 95% 1 yr in experienced
centres) • Hospital stay decreasing to 40 days
• 5 yr patient survival improving (up to 75% - higher in children) • Still problems of long-term graft survival, particularly isolated SBT
(60% 5 year) • Main cause of death remains sepsis (50%)
Intestine Transplantation
20 years of registry data in the
United Kingdom
Transplant activity
Paediatric transplants
Paediatric transplant survival – 90 days
King’s outcomes 2009-17
• Transplanted 23 intestinal grafts, 20 patients – Isolated small bowel 10 – Liver/small bowel 5 (one living-related) – Multivisceral 6
– Isolated liver 2 (IFALD, on PN)
• On list 4 – Liver/small bowel 1 (Chronic rejection - redo) – Multivisceral 2 (Dysmotility / acute rejection) – Isolated small bowel 1 (chronic rejection – Oxford - redo)
• Current assessment 3 – Short gut liver disease, microvillous inclusion disease, loss of venous access
King’s outcomes 2009-17
• Diagnoses
– Short gut liver disease 8 • NEC, Gastroschisis, Ischaemia, Hirschsprung’s, Volvulus/biliary atresia
– Dysmotility 5 – Autonomic dysfunction, dysmotility 2 – Intestinal lymphangiectasia 1 – MVID 1 – PFIC 1 1 – Vascular thrombosis 1 – TTC7A (SCID, MIA) 1 – Rejection (retransplant) 3
• Indications
– Liver disease 12 – Line access 5 – Fluid shifts/sepsis 3 – Acute rejection 3
Major Complications • PTLD 5
– 3 responded to rituximab – 2 chemotherapy – 1 bowel loss (retransplanted)
• Severe acute rejection 3
– 1 died, sepsis and multi-organ failure – 1 PTLD and lost graft – 1 retransplanted x2 (relisted)
• Severe late acute rejection 2
– 30 months post, and 4.5 years post transplant – 1 responded to ATG, 1 graft enterectomy (retransplanted)
• GvHD 2
– 1 steroid responsive – 1 steroid refractory – ECP, MSC - died
• Chronic rejection 2
– 1 Graft enterectomy (Adult, Oxford, relisted) – 1 Relisted
King’s outcomes 2009-17
• Overall survival – Patient 1 year survival 94% – Patient 5 year survival 77% – Graft survival (overall) 78%
• Follow up – median 63 months [range 5-109]
King’s outcomes 2009-17
• Nutrition – 12 fully weaned from PN – 2 on partial PN
• chronic rejection, living-related, short gut
– 2 full PN • post enterectomy
• Social
– 1 transitioned to adult services – chronic rejection –
enterectomy – 8 school full time – 4 registered for school/nursery – 3 post transplant
Bowel transplant
• Small bowel transplantation offers the hope of survival and excellent quality of life
• Remains indicated only for irreversible IF with complications
Short gut to enteral autonomy
9TH INTERNATIONAL PEDIATRIC INTESTINAL FAILURE AND REHABILITATION SYMPOSIUM
FRIDAY OCTOBER 28, 2016
OUTCOMES OF EXTREMELY PREMATURE
CHILDREN WITH SHORT BOWEL SYNDROME IN AN INTESTINAL FAILURE PROGRAM
David Mercer MD PhD1, Brandi Gerhardt BScN1, Brandy Hobson
RD2, Samantha List RD2, Angela Iverson RD2, Sara Iwansky
BScN1, Ann Anderson-Berry MD, PhD3, Ruben Quiros-Tejeira
MD4
1 Department of Surgery, Division of Transplantation, University of Nebraska Medical Center; 2 Nutrition Services,
Nebraska Medicine; 3 Department of Pediatrics, Division of Neonatology; 4 Department of Pediatrics, Division of
Gastroenterology
Methods
IRB approved retrospective chart review
Cohort: children born at 29 weeks or earlier and evaluated by UNMC intestinal failure program between 2001-15
Data expressed as median [IQR] using Mann-Whitney U test to compare groups (p<0.05 sig)
Category Count/Median IQR
Sex (M:F) 58:40
Gestational age (weeks) 27 25-28
Birth weight (g) 8301 652-1031
ROP grade2 0
1
2
3
present but NOS
22 (33%)
10 (15%)
8 (12%)
17 (25%)
10 (15%)
IVH grade2 0
1
2
3
4
41 (61%)
7 (10%)
11 (16%)
5 (8%)
3 (5%)
Etiology
NEC 84
Gastroschisis 1
Atresia 3
Volvulus 3
Aganglionosis 1
Ischemic/post-surgical 1
Meconium ileus 2
Pseudoobstruction 3
Category Median/count IQR
Height Z score -2.03 -3.66 to -0.80
Weight Z score -1.51 -2.62 to -0.02
Total bilirubin (mg/dL) 7.7 0.6 to 12.2
Direct bilirubin (mg/dL) 4.8 1.3 to 8.1
Albumin (g/dL) 3.2 2.7 to 3.7
PT INR 1.2 1.1 to 1.3
Platelets (x103/L) 168 98 to 259
Spleen (%ile) 79 38 to 96
Fibrosis on liver biopsy
Not done 48
None 1
Grade 1 4
Grade 2 11
Grade 3 22
Grade 4 12
Moderately growth impaired
Jaundiced
Reasonably well preserved hepatic function
Histologically advanced liver disease
v
Recommend Tx had: higher INR (1.3 vs 1.1) higher Tbili (11.1 vs 7.4) lower platelets (84 vs 178)
(p<0.05, Mann-Whitney U)
Ever Tx (red) had: shorter bowel length [30cm (range 3-60cm) vs 45cm (range 0-250cm)]
(p<0.05, Mann-Whitney U)
Mortality rates for Tx vs Non-Tx are not significantly different
(p<0.05, Mann-Whitney U)
For Non-Tx kids: enterally independent have more bowel (56.5cm vs 26.5cm) and longer time in program (68m vs 20m)
(p<0.05, Mann-Whitney U)
Median follow-up overall 48 months (range 1-187)
