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Management of End Stage Liver Disease

Dr Peter Lewindon

Paediatric Gastroenterologist / Hepatologist Lady Cilento Children’s Hospital and QLTS, Brisbane

George Abbott Paediatric Symposium

Christchurch August 2015

Congratulations NZ and Christchurch’s favourite son

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FISPGHAN Survey 2008 Paediatric Liver Transplant - Indication Frequency Diagnosis Frequency Mean Range

(% of all transplants)

Biliary Atresia 49.1 % 36.3 % - 67 % Fulminant liver failure 14.3 % 2.7 % - 32 % Autoimmune hepatitis/PSC 7.8 % 1% - 13 % Other cholestatic diseases 7.6 % 2 % - 13 % Other metabolic disorders 7.1 % 2 % - 11.3 % Cirrhosis of previous Graft 6.1 % 1 % - 10 % α - 1 antitrypsin deficiency 3.3 % 0 % - 7 % Tumours (hepatoblastoma) 2.5 % 0 % - 5 % Cystic fibrosis 2.1 %

Internationally - Cholestatic disorders responsible 60-70% LTs Sokal, JPGN 2008

ESLD -Definition Critical and Irreversible impairment function/architecture Liver function “Filters” Intestinal / Splanchnic blood Bile excretion Synthesis of essential proteins Growth, hemostasis, albumin, carrier proteins Glycemic control Immune Function Blood supply (Portal Hypertension)

PELD Score 0.436 x Age (1 y) - 0.687 Loge Albumin + 0.48 Loge Bilirubin

+ 1.857 Loge INR Ratio + 0.667 Growth Failure

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Microscope – Blood filtered / bile made

When the liver gets damaged

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Persistent Inflammation - 2-10 yrs Progressive scarring - Cirrhosis

- Liver Fails

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What does Liver Do ? – Blood supply

Understanding Essential Liver Function

75% liver blood supply from Portal Vein

PV constituted by SMV/SV (includes IMV)

Whatever comes from the GUT goes through to Liver

Liver Function linked to GIT / Immune function

Nutrition, Growth & management bacterial translocation 20% of Cardiac Output via Hepatic Artery

So what ? PHT – blood bypasses liver - collaterals / shunts Hepatocyte survival = Hepatic artery perfusion Sepsis/bleed = reduced diastolic flow = ischeamia

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Liver Function - “Filters” Blood from GIT Impaired as porto-systemic “shunt” increases

1. Removes splanchnic vasodilators Dilatation systemic capacitance vessels Hyperdynamic circulation (!REE α pulse) Hepato-renal, Hepato-pulmonary, encephalopathy

2.  Removes / Monitors bacteria / LPS /Allergens Failure to manage bacterial translocation, SBP, HRS, HPS, HE

3.  Products bacterial fermentation (SBBO, colon) Hyperammonia

4.  Nutrition CHO / Glucose, Protein, triglycerides

5.  Drugs, Systemic Hormones, Miscellaneous Drug pharmacokinetics, Gynaecomastia

Liver Functions - Reticuloendothelial

Surveys antigens Removes bacteria

translocated from bowel into portal blood stream

Important role in tolerance to food antigens

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Liver Functions - Synthesis Essential Proteins

Anti-coagulant factors-Protein C, S, AT-111 = Thrombosis

Coagulation Factors (V, VII,) Fibrinogen = Bleeding

Albumin = reduced GFR, increased ecw, ascites IGF-1 / GH responsive growth factors (growth failure) Carrier proteins (Transferrin / Retinol Binding Protein)

“Glucose” From Stored Glycogen / Gluconeogenesis

Responsible 70% circulating BSL within hours of meal Fasting - catabolism / loss LBM / hypoglycemia

ESLD and abnormal INR “auto-anticogulated” ?

INR / Prothrombin Time measure of (reduced) coagulation in patients with normal liver function on Warfarin measure reduced liver synthetic function (factors II, V, VII, X and fibrinogen) in advanced liver disease

CONFUSION ? In ESLD - INR NOT measure coagulation / hemostasis

“rebalanced / fragile hemostasis” “serious thrombosis > serious bleeding”

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Liver Functions – Exocrine Gland (Bile) Bile Acids essential for micelles / lipase function

Reduced LCFA absorption – Steatorrhoea, Calorie Loss, EFA deficiency (phospho-lipid membrane integrity, skin, gut)

Near total failure absorb FSVs - FSV Deficiency Bile salt synthesis/transporter defects = FSV deficiency > liver dysfunction

Reflux BAs into circulation- Dermal deposit, “intense” Pruritus Failure of Cholesterol excretion – xanthomas

Bicarbonate / Gastric pH buffering Bile acid emulsification / lipase failure

Secretory IgA / Luminal immune surveillance Increased SBBOG (30-60%) - diarrhoea, malabs, dist’n

Case Study - EHBA.

9 month old male from St Elsewhere Kasai at 60 days, Established Cirrhosis Despite iv Prednisolone 4mg/kg / e.o.d.

incomplete clearance of Jaundice Bilirubin 3/12 post Kasai 50mmol/l (> 30 poor prog) Presents for OLT listing.

Miserable Jaundiced Malnourished Weight 6kg Abdominal distension - HSM, ascites

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Nutrition

•  Why is it important? •  Why has malnutrition occurred •  What are you going to address it?

Actuarial Survival vs weight for ht Z-score

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Nutrition in Paediatric ESLD

Reasons for Malnutrition / Poor Growth 1. Anorexia Pruritus and disturbed sleep

Inflammatory cytokines IL-6 (background sepsis) Portal gastroenteropathy / slowed motility Fat malabsorption slows motility SBBOG -Bloating/enteropathy/malabs Ascites

Reasons for Malnutrition 2. Increased Energy Expenditure

PHT increases REE to 120 - 130% Despite reduced LBM (Greer et al)

Infections (Cholangitis, SBP, septicemia, SBBOG) Systemic bile acids stimulate TGR-5 –cAMP-D 2

signalling pathway in skeletal muscle muscle G protein-coupled receptor New obesity strategy

3. Steatorrhoea - Failure of Bile Salt release esp EFAs 4. Reduced tolerance of fasting - earlier catabolism

within 8 hours in Adults with ESLD, less in children 5. Growth Hormone Resistance

Inability to synthesis IGF-1, II and IGF-BP Inability to synthesise LBM despite adequate intake

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Treatment of Malnutrition

Anorexia Increased Energy Expenditure Steatorrhoea Treat tendency to Catabolism Growth Hormone Resistance

Treatment of Malnutrition Anorexia

Pruritus – skin measures (avoid heat, moisturise, nails) rifampicin, ondansetron, naltrexone cholestyramine, Colesevalam, Biliary Drain NGT Motility Agents? (Propranolol?) Albumin to reduce ascites / ecw ? Treat infections – Prophylaxis?

Increased Energy Expenditure Treat infections Increase calorie intake Propranolol?

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Treatment of Malnutrition

Treat Steatorrhoea MCT predominant formula TPGS (Vit E, facilitates/chaperones other FSVs) Intravenous Lipids Parenteral Vit K, A, E, D

Treat tendency to Catabolism / prevent fasting

Continuous NG Feeds, especially overnight Treat GH resistance

BCAA enriched formula (Leucine, isoleucine, valine) Directly stimulate LBM synthesis bypassing GH / IGF - 1

hepatic and muscle protein

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Next – GI Bleeding

Steve, Now 15 months of Age Profuse Meleana for past few hours Hb 60 (was 105 last clinic) WCC 4.0 Platelets 51 INR pending (1.8) Pulse 140, poorly perfused

What is the Risk What to do immediately What to do Long Term

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Risks Immediate/ Long Term Immediate

Shock Hepatic Failure (Ischemia, poor diastolic flow) Hepatic Encephalopathy from luminal metabolism

Long Term

50% children with Kasai surviving without transplant have had significant GI Bleed by 5 years Survival after first bleed 50% at 5 year (cf Adult survival at 5 years of 17%)

ESLD

Immediate Treatment GI Bleed?

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ESLD - Immediate Treatment GI Bleed

Resuscitate IV Access, Saline bolus 10-20mls/kg FBC, X-match, Coags ELFTs, Ammonia, Blood cultures Transfuse Blood (15mls/kg) FFP ? / Cryoprecipitate (extra fibrinogen / vWF) Platelets ? Esp is <50 Recombinant Factor VIIa? And?

Immediate Resuscitation IV PPI – Upper GI Bleed, Platelet dysfunction

IV Antibiotic – Sepsis precipitates variceal bleeding

(Burroughs, Lancet 1999) Bacterial infection in up to 65% bleeders Bacterial infection independent predictor of rebleeding SBP common before bleed Antibiotics reduce blood transfusion and rebleeding Improve Survival (immed/LT) by up to 10% IV Octreotide – (3-5mcg/kg/min) – inactive within hours Reduces ‘meal-driven” splanchnic blood flow (Cochrane review, no firm evidence of benefit)

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What next?

“Intestinal Decontamination” Colonic Flora generate Ammonia etc “Clear” with neomycin ? “Suppress” with Lactulose ?

Lactulose - SCFAs – acidic stool- inhibition colonic flora Give 2-6 hourly to provide 4-6 sloppy stools/day

Endoscopy?

Site of Bleeding Gastric erosions Duodenal erosions Oesophageal Varices Portoenterostomy “stomal” varices Gastric Varices Other (capsule endoscopy)

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Oesophageal Varices Should we treat and how ? If Bleeding – EVL “Banding” (If >7kg)

necrosis/perforation? Sclerotherapy (Harder) less effective, strictures

If not?? Yes, if “cherry red” / telangiectasia

Will get worse in ESLD - Waiting List?

And After – Prophylaxis ?

Beta Blockers - Beta 2-splanchnic vasoconstriction Primary - Elective Endoscopy and no bleed Secondary – Post portal hypertension related bleed In Adults, data clearly FOR Propranol in Both 1o and 2o

In Children – No good data

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ESLD-Summary

Many Issues not covered Focussed on Underlying Issues

Nutrition Bleeding Infection

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Timeline of impact of Baveno meetings on variceal bleeding related mortality

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And After – Prophylaxis ?

FOR Propranolol

Anecdotal experience - well tolerated - effective reducing

portal gastropathy / severity of varices Scientific evidence multiple benefits including:

reduced bacterial translocation improved intestinal motility Reduced REE

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Against Propranol?

Infants and small children need tachycardia response to shock to maintain organ perfusion.

Do we need 25% drop in pulse to be effective?

10-20% cannot tolerate Nightmares Dizziness

Not tolerated ? = ACE Inhibitors/Statins – No data

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Hepatic encephalopathy

The biliary HC03 umberella

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Alcohol and Balance

Answers or waiting for Inspiration ?

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Some of you haven’t answered have you?

Has everyone had a go at answering?

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Now time for some fun with our sponsors

Looking for Insight into ESLD?