9/27/2011 Disclosures 2011 NASPGHAN Meeting CF Liver Disease: • I receive research funding from Roche and Schering From Elevated Liver Enzymes to • These studies are unreldlated to Cystic Fibros is Portal Hypertensive Bleeding Jean Pappas Molleston, MD Professor of Clinical Pediatrics Indiana University School of Medicine Learning Objectives General Epidemiology of CFLD • Describe presentations of CF liver disease • Outline management of CFLD including role of • CF affects 1 in 2500 newborns liver transplantation • Liver disease is the third most common cause of • Evaluate impact of CFLD on nutriiition and dhdeath in CF pulmonary status • Liver disease accounts for 2% of mortality in CF CFLD Presents in Youth Physiology of CF Liver Disease Age of Liver Disease Diagnosis in CFLD Subjects Genetic Modifiers Study Update 2007 From: Hepatology –A Textbook of Liver Disease, 5th Edition, 2006. 1 9/27/2011 Environmental Factors that Could Risk Factors for CFLD Contribute to CFLD • Nutrition: Essential fatty acids, carnitine, • Pancreatic insufficiency: Essentially all CFLD choline, trace metals • Alpha‐1‐antitrypsin Z allele as genetic modifier: • Hormones Odds ratio for CFLD 5 • Antioxidants • Male sex • Medications • ? Meconium ileus • Viral Hepatitis • Abdominal surgery • TPN Bartlett: JAMA 2005. Presentations of Liver Disease in CF Hepatomegaly: Prevalence of PE Findings • Hepatomegaly • Elevated liver enzymes • Ling: Arch Dis Child 1999. 124 children with CF • Abnormal radiographic studies – 6% with hepatomegaly or splenomegaly • Gallstones • Scott‐Jupp: Arch Dis Child 1991. 1100 CF patients • NAFLD (non‐alcoholic fatty liver disease) – 4.2% with hepatomegaly or hepatosplenomegaly • Neonatal cholestasis • Other biliary diseases: Primary sclerosing cholangitis, hepatocellular carcinoma, etc • Non‐cirrhotic portal hypertension • Cirrhosis/portal hypertension CFLD: Biochemical Abnormalities Variable Patterns of Liver Enzyme • Ling: Arch Dis Child 1999 Elevation in Study Patients with CF – 126 children, 4 years – 42% with AST/ALT >ULN at start, 80% at follow‐up • Lamireu: J Hepatol 2004 – 241 patients, 8 years – 27% with AST/ALT >ULN • Colombo: Hepatology 2002 – 177 CF patients in screening program – 50% with 2 of 3 enzymes >ULN at least once • Woodruff: JPGN 2007 – 383 patients identified at newborn screening – 50% ALT > 1.5 x ULN; 25% GGT > 1.5 x ULN Goss CH: J Cyst Fibros 2007. 2 9/27/2011 LFTs: xNL CFLD: Radiographic Abnormalities Correlation • of Liver Ling et al: 124 children with CF – 35% ultrasound abnormality (size, texture, scalloping or Enzymes flows) with – 67% at 4 year follow‐up Fibrosis • Colombo: 189 patients with CF – 51% with heterogeneous liver – 11% cirrhosis • Lenaerts: 106 children with CF U/S followed 10 years – 15% became heterogeneous, 5% nodular or CFLD Lindblad: Hepatology 1999. – 2/3 of heterogeneous progressed Fibrosis Lenaerts: J Pediatr 2003. CFLD Histology: Biopsy, Not Clinical Parameters, Focal Biliary Cirrhosis Predicts Development of Portal HTN • Maurage: JPGN 1989: Autopsies evaluated in 38 of 73 deaths – 5 normal, 9 steatosis, 8 hypoxia – 16 (42%) biliary cirrhosis (6 multilobular) • Oppenheimer: Perspect Pediatr Pathol 1975 – Focal biliary cirrhosis on autopsy: Infants <3 months 10%, children >1 year 27% • Vawter: Pathol Ann 1979: – Prevalence in adult autopsy studies up to 72% Clinical Parameters Biopsy Lewindon: Hepatology 2011. Biliary Problems • Gallstones: 15% of patients with CF • Microgallbladder: 30% of patients with CF • Sclerosing cholangitis: Uncommon Debray: J Cystic Fibrosis 2011. 3 9/27/2011 Hepatic Steatosis Fatty Liver in a Cystic Fibrosis Patient • Hepatic steatosis occurs in 23‐67% of patients with CF (30% moderate to severe in one series) • NAFLD can occur in the context of malnutrition, nutrient dfiideficienc ies, and iliinsulin resistance • Relationship of NASH to CF cirrhosis unclear Kelly: Diseases of the Liver and Biliary System in Children 2008. Lindblad: Hepatology 1999. Fibrosis on Liver Biopsy Predicts Portal Neonatal Cholestasis Hypertension… but not Always • Cholestasis can be seen in 5% of infants with CF • In the young infant, the differential diagnosis Survival without includes biliary atresia, alpha‐1‐antitrypsin Portal HTN deficiency, viral infection • Cystic fibrosis can mimic biliary obstruction; care must be taken to properly diagnose/avoid unnecessary surgery Lewindon: Magoffin: Pediatric Pulmonol 2002. Hepatology 2011. Follow‐Up Time (years post liver biopsy) Non‐Cirrhotic Portal Hypertension (NCPH) in Cystic Fibrosis • 12 biopsies from children with CF and portal HTN examined • No cihirrhos is in 7: 4 hdhad F3 fibros is, 3 hdhad F 0‐2 • Normal HVPG in 2 patients • Portal venopathy on biopsy in those with NCPH Witters: Hepatology 2011. 4 9/27/2011 CF‐Related Cirrhosis CFLD: Clinical Liver Disease (cont) • Lindblad: 124 patients – Clinical cirrhosis 4% • Lamireau: J Hepatol 2004: 241 kids – Cirrhosis 7.8%; average age onset 10 years • Colombo: 177 children with CF – Cirrhosis in 3% at enrollment, 10% by year 5 – Incidence rate cirrhosis = 4.5 cases/100 LD patients/year • Feigelson: Arch Dis Child 1993: 450 patients (38 years) – Cirrhosis in 7%; average age at onset liver disease 7 years Cirrhosis/Portal Hypertension • Advanced CFLD can lead to cirrhosis • Portal hypertension is the most prominent feature of CFLD: • Varices in as many as 90% • Bleeding in as many as 50% • Portal hypertension can lead to complications such as ascites, hypersplenism, encephalopathy • Liver synthetic failure is a late complication of CFLD Colombo: Hepatology 2002. Management of CF Liver Disease URSO for Treatment of CFLD • Consider other causes of liver disease • Some small studies have demonstrated: • Optimize protein/calorie nutrition – Improved biochemistries (RCT) • Monitor and supplement fat‐soluble vitamins – Improved liver histology (limited data) • Ascertain that patient is appropriately immunized • UkUnknown effec t on liver tlt/iltransplant/survival for hepatitis A and B • Cochrane review, updated in 2010: • Caution against the use of NSAIDS (ibuprofen) “insufficient evidence to justify routine use” • Caution against alcohol use • Large studies needed • ?? URSO 5 9/27/2011 Management of CFLD (cont) • Monitor for complications of end‐stage liver disease: – Ascites: May need diuretics, may affect lungs – Spontaneous bacterial peritonitis: Antibiotics – Encephalopathy: May need lactulose, antibiotic – Hepatopulmonary syndrome: Bubble echo can show evidence of AV shunting in lung – Variceal bleeding (most characteristic of CF cirrhosis) AGA Slide set Outcome of CFLD Lung Function in CFLD CFLD Participant Outcome Number % Status • Dead/transplant Liver failure/transplant 4 11 Case control study of 60 children with CFLD Pulmonary failure 3 8 followed for 7 years: Alive at 7 year Severe liver disease – baseline and – FEV1 65% CFLD, 73% controls, p = 0.1 925 follow‐up follow‐up – Annual decline 22%2.2% CFLD, 15%1.5% controls, p = 020.2 Progression of liver disease since 11 30 baseline* • Case‐control study of CFF Registry patients 3 years No evidence of liver disease at 822 before liver transplant: follow‐up – FEV1 71% CFLD, 75% controls, p = 0.012 Not classifiable 1 3 Total 36 100 – Decline ‐0.05% CFLD, ‐1.35% controls, p = 0.01 * No evidence of varices radiologically or on endoscopy at baseline Rowland: Am J Gastroenterol 2011. Table taken from Rowland: Am J Gastroenterol 2011. Miller: Pediatr Pulmonol 2010. Liver Transplantation in CFLD: Nutritional Status in CFLD 203 Patients in UNOS Database • Potential nutritional issues in CFLD: • Indications: Liver synthetic failure – Increased fat malabsorption due to cholestasis • Other issues: (Appeals for PELD points in 11%) – Increased risk of fat‐soluble vitamin malabsorption – Malnutrition – Poor appetite due to ascites, splenomegaly, etc – Intractable variceal bleeding – Increased energy expenditure – Refractory ascites • 70 patients case‐controlled study at 7 years: – Incapacitating hepatic encephalopathy –BMI: CFLD 20 Control 21 p = 0.28 – –Mid‐upper arm circ: CFLD 24 Control 25 p = 0.33 Hepatocellular carcinoma –Sum skinfolds: CFLD 32 Control 42 p = 0.01 • 5 year survival: 86% children, 73% adults Mendizabal: Liver Transpl 2011. Rowland: Am J Gastroenterol 2011. 6 9/27/2011 Post‐Liver Transplant Issues in CF Combined Liver/Pancreas Transplant in CF is Possible, with Excellent Outcomes (no enzymes, no insulin) • Nutrition and BMI improve after transplant • Diabetes may develop (20‐75%) • Pulmonary function: 193 patients in CFF Registry between 1989 & 2007: PFT’s 3 yrs pre‐ and post‐ in liver transplant cases and matched controls ‐FEV1↓ pre‐tx: CFLD 71%, contr 75% p=0.012 ‐FEV1↓ pre‐tx: CFLD 0.05%, contr 1.35% p=0.001 ‐FEV1↓ post‐tx: CFLD 1.53%, contr 2.2% p=0.125 Colombo: Transpl Int 2005. Mekeel: Liver Transpl 2007. Miller: Pediatr Pulmonol 2010. CFLD Research Network: Does Hetero‐ What is the Future for CFLD? geneous Liver on Ultrasound Predict CFLD? • Evaluate approaches to early diagnosis • Drug trials: – CFTR‐directed drugs – Bile‐flow directed drugs – Fibrosis‐directed drugs • Evaluate management strategies for portal HTN due to CFLD • Study selection, timing, outcomes of organ transplantation for CFLD (including related organs) Acknowledgements • Thanks to the organizers for asking me to speak • Thanks to the CFLD Research Network, an amazing group of investigators to work with and learn from • Thanks to Vicki Haviland‐Wilhite for expert secretarial support 7.