Trapianto di intestino e insufficienza intestinale cronica benigna: un update

Loris Pironi

Centro Insufficienza Intestinale Cronica Benigna “M. Miglioli”

Dipartimento Malattie Digestive

Policlinico S. Orsola – Università di Bologna

PROFESSORE ASSOCIATO, SSD MED/09, presso il Dipartimento di Scienze Mediche e Chirurgiche dell'Universitа di Bologna,

&

RESPONSABILE DEL“CENTRO REGIONALE DI RIFERIMENTO PER INSUFFICIENZA INTESTINALE CRONICA BENIGNA”

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Attività scientifica

INSUFFICIENZA INTESTINALE NUTRIZIONE CLINICA IN AMBITO OSPEDALIERO E DOMICILIARE TRAPIANTO INTESTINALE

Home Artificial Nutrition & Chronic Intestinal Failure Special Interest Group

1992, membro fondatore

2006 ad oggi, coordinatore

The CIF pathway

1st definition of IF, Fleming 1981

ESPEN HPN Guidelines, 2009

ESPEN definition and classification of IF, 2015

ESPEN CIF Guidelines, 2016

ESPEN AIF Pos P, 2016

IF inclusion in ICD-11, 2018

1st ITx, 1964

1st HPN, 1969

Tacrolimus for ITx, 1989

All-in-One PN bag, 1972

Portable HPN, ’90s

PACIFHAN (Int. Pts. All., 2015)

ESPEN indications for ITx, 2012

Medicare indications for ITx, 2001

Fish oil lipid E., 2000

CVC taurolidine lock, 2003

GLP-2, intestinal growth factor EMA, 2012

Specific QoL tool, 2010

Intestinal lengthening procedures Bianchi (1981), STEPS (2003), ...

The reduction of gut function below the minimum necessary for the absorption of macronutrients and/or water and electrolytes, such that intravenous supplementation (IVS) is required to maintain health and/or growth.

Warning: PN and IF are not synonymous

Definition

• Type III – chronic condition, in metabolically stable patients, requiring IV supplementation over months or years

Functional classification

• Type I – acute, short-term and usually self limiting condition, requiring IV supplementation for a few days (PO or ICU setting)

• Type II – prolonged acute condition, often in metabolically unstable patients, requiring complex multi-disciplinary care and IV supplementation for weeks or months (abdominal catastrophe)

(Based on onset, metabolic and expected outcome criteria)

Pironi L, BMC Nutrition 2017

12 casi/106 abitanti (adulti 9.5 – pediatrici 2.5)

Indagine SINPE

•Regioni: 18 (90%) • ASLs: 95 (65%) • Abitanti (Mln): 44 (73%)

• Territorio (Km2): 204 (68%)

Prevalenza della IICB in Italia nel 2012

Pironi L, Am J Gastroenterol 2006

Cross-sectional investigation on HPN for benign CIF in Europe

Pathophysiological Classification

Pironi L, Clin Nutr 2012

Narrative Review - Sept 2011

Survival on HPN for benign CIF in adults

Causes of death on HPN for benign CIF in adults

IFALD, intestinal failure associated liver disease CVC, central venous catheter

Narrative Review - Sept 2011

Pironi L, Clin Nutr 2012

Mechanisms • Broad antimicrobial activity • Non toxic – rapidly metabolised • Reacts irreversibly with cell wall • Prevents bacterial adhesion bio-

surface • No resistance reported • Proved efficacy in hemodialysis

Number of CVC-infection free days

Taurolidine

Heparin

Bisseling TM, Clin Nutr 2010

Taurolidine Lock for the prevention of CVC-infection

Guidelines for CIF We suggest, for prevention of CVC-related infections: • ……… • CVC-locking with taurolidine may be used • ………

Proposed mechanisms

•Improved bile flow •Immunomodulatory (↓ inflamm.) •Decreased steatosis •↑ content of α-tochopherol •Replacement of soybean oil LE

Studies with liver histology in adults

Pironi L, eSPEN 2010; Jurewitsch B, JPEN 2011;Xu Z, Clin Nutr 2012

Fish oil lipid emulsion for IFALD prevention and treatment

Guidelines for CIF We suggest for treatment of intestinal failure-associated liver disease: • ……… • to revise the lipid component of the PN admixture, in order to decrease the

total amount and/or to decrease the ω6/ω3 PUFA ratio • ………

Joly F, Clin Nutr Suppl 2010; Pironi L, Clin Nutr 2012

Intestinal rehabilitation - weaning off HPN in benign CIF in adults

472 adults

Jeppesen PB, GUT 1999; Martin GR, World J Gastroenterol 2006; Wallis K, Curr Opin Clin Nutr Metab Care 2009

Glucagon-Like Peptide-2 analogue (teduglutide, FDA and EMA approved)

↑ mucosal growth in small and large bowel (↑ crypt cell proliferation + ↓ villous cell apoptosis)

↑ absorptive capacity

↑ mesenteric blood flow

↓ gastric emptying and acid secretion

↓ intestinal permeability

• anti-inflammatory action

Intestinal growth factors Intestinal rehabilitation in SBS

• Patients 88 (time from surgery: > 1 yr)

• Dosage 0.05 mg/Kg/day

• Treatment duration 24-36 (months)

• Discontinuation 23 (26%) Acute Events 16 Pt. decision 4 Investig. decision 2 Death 1 (CVC-sepsis)

Schwartz L, Clin Transl Gastroenterol. 2016

• Treatment Emergent AEs 85 (95%) Abdominal pain 34% CVC-sepsis 28% Decreased weight 25% Others 17%

• Possible long-term risk: GI cancer • Colonoscopy (50 pts) Polyps 9 (adenoma 5; hyperplastic 1, inflammatory 1, unclassified 2

• ITT clinical response (≥ 20% reduction of PN): 57 (65%)

Schwartz L, Clin Transl Gastroenterol. 2016

HPN weaned off

Guidelines for CIF We recommend …….. to objectively evaluate and balance the benefit and clinical meaningfulness of the interventions versus the inconveniences, adverse effects, potential risks, and cost-effectiveness.

Data from January 1985 to February 2013

Grant D. et al, AJT 2014

Contributing centers 82

Transplant activity • North America • Europe • Asia+Australia+South America

76% ~ 20% ~ 4%

Total transplants • Children (< 18 yr) • Adults

2887 (2699 pts) 1611 (55.8%) 1276 (44.2%)

Type of transplant • SBT • Liver-SB • MVT+Modified MVT

582 (36.2%) 734 (45.5%) 257+38 (18.3%)

Conditional 5-yr actuarial graft survival (defined as graft survival after 1-year)

Actuarial Graft Survival Over Time (All Recipients)

Grant D. et al, AJT 2014

Intestinal Transplants Performed Grant D. et al, AJT 2014

Possible causes of the decline of ITx rate

• Improved ability to prevent or resolve IFALD

• Improved medical therapy and non-transplant surgical rehabilitative procedures

• Narrow risk–benefit ratio for ITx, in an era of improving outcomes with long-term HPN

Grant D. et al, AJT 2014

Disease-related risk of death • Invasive intra-abdominal desmoids • Congenital mucosal diseases • Ultra short bowel

High morbidity IF / HPN refusal • Frequent hospitalization, poor pain

control, … • Pt. unwillingness to continue HPN

HPN-Failure

• Liver failure: impending or overt

• CVC-Thrombosis: occluding ≥ 2 central veins

• CVC-Sepsis: severe and ≥ 2 /yr

• Dehydration: frequent and severe

Indications for ITx – 2001 devised by U.S.A. Medicare-Medicaid & Am Soc of Transplantation

AGA,Gastroenterology 2003; Kaufman SS,Pediatr Transplant 2001

We recommend assessment for candidacy for intestinal transplantation, when one of the following indications exists:

Survival rate and Relative risk of death on HPN according to the indications for ITx

High morbidity 100%

Pironi L et al, ESPEN-HAN & CIF WG, Am J Gastroenterol, 2006 , Gastroenterology, 2008, GUT, 2011

Listing for intestinal transplantation

Recommend listing for a life-saving ITx

Recommend listing for a life-saving ITx on a “case-by-case basis”

•Do not recommend listing for a life-saving ITx •Suggest that patients with high morbidity or low acceptance of HPN might be listed for a “rehabilitative ITx” on a “careful case-by-case basis”

Referral for potential “rehabilitative ITx” in case-by-case carefully selected and appropriately informed patients with irreversible intestinal failure

The clinical dilemma

F , 42 year old Married 2 daughters (14 and 2 yr old) Employed Sept 2012, surgery for benign mesenteric tumor, complicated by post-operative intestinal ischemia:

• total enterectomy • remnant duodenum closed • PEG for gastric empting • sigma colon and rectum in situ

Good clinical condition No solid organ complications On HPN and liquid diet

Rehabilitative ITx a clinical dilemma

• Factors determining the choice •Survival •Safety •Efficacy •Timing for ITx

HPN or ITx a clinical dilemma

HPN or ITx Survival

ITx registry

ITx Pittsburgh

HPN unselected

HPN selected (no contraindications to ITx)

Pironi L, Clin Nutr 2012

HPN (A)

ITx (A+C)

Osteoporosis 41% 42%

Acute rejection 40%

De-novo cancer Rare 17%

Diabetes Rare 17%

Renal dialysis or Tx Rare 9%

PTLD 4%

↑ LFT/Liver disease 15-85% Rare

CVC-sepsis (per CVC-yr) 0.14-0.48

CVC-thrombosis (CVC-yr) 0.02-0.09

HPN (A)

ITx (A+C)

Total Liver failure CVC-sepsis CVC-thrombosis

14% (4) (8) (2)

Total Graft failure Complications of therapy

85% (37) (48)

HPN or ITx Safety

Treatment related death (% of total death)

Late morbidities (% of patients)

A, adults C, children

Abu-Elmagd K. Ann Surg 2012; Pironi L et al Clin Nutr 2012

HPN or ITx Efficacy – Quality of Life

PN dependency after ITx: ~ 25% of recipients

Pironi L, Am J Transpl 2012; Grant D. et al, Am J Transpl 2014

Risk factors for death or graft failure Timing for ITx

2008 OPTN/SRTR Annual Report; Grant D. ITA Registry Report 2011at http://www.tts.org

0

10

20

30

40

50

60

Unadjusted 5-year survival of ITx recipients for patient age

HPN or ITx a clinical dilemma

Information to the patient Survival Probably longer on HPN

Safety Better on HPN

Efficacy QoL probably better after successful ITx Risk of PN dependency after ITx ~ 25%

Timing for ITx Optimal timing for a successful ITx due to both patient clinical status and age (42 yr)

Patient ‘s decision: listed for ITx

but …4.5 years later • General well being on HPN • Working part time • Good family and social life

• Mild increase of LFT, normal bilirubin • One episode of CVC-infection • 100% survival on HPN

Patient’s decision: stay on HPN

HPN or ITx a clinical dilemma