Nonalcoholic Steatohepatitis Eric Tibesar MD Ann Scheimann MD

Non-alcoholic Steatohepatitis Eric Tibesar, MD Ann Scheimann, MD, MBA Johns Hopkins Children’s Center 2013 Resident Education Series Reviewed by John Stutts, MD of the Professional Education Committee

Case Presentation • 12 year old male presents to your pediatric GI clinic with complaints of abdominal pain • Pain has been persistent for the last 6 months, mainly epigastric without radiation • He denies nausea, vomiting, and his stools have been irregular but soft without diarrhea • Diet consists of high carb, high fat and low protein meals with multiple snacks daily

Case Presentation • Growth measurements – Height 160 cm (91 st percentile for age) – Weight 95 kg (>99 th percentile for age) – BMI 37. 1 (>99 th percentile for age, z score +2. 6) • Physical exam – Marked abdominal obesity with striae, acanthosis nigricans noted on back of neck, liver palpated 3 cm below costal margin, otherwise normal exam

Case Presentation • Screening laboratory markers – Negative celiac and thyroid studies – Electrolytes and CBC normal – INR 1. 1, AST 52 IU/L, ALT 62 IU/L, T. bili 1. 1 mg/d. L, fasting glucose 135 mg/d. L, serum insulin 32 μU/m. L (normal 2. 6 -24. 4 μU/m. L) • Imaging – Abdominal ultrasound read: • Hepatomegaly with increased echogenicity, normal gallbladder and spleen

Case Presentation • Liver biopsy – Macrovesicular steatosis, diffuse inflammation, ballooning hepatocytes with Mallory-Denk/hyaline bodies

Definition “Lipid deposition in hepatocytes in individuals who drink little or no alcohol” Hepatic Steatosis-fatty liver, fat accumulation in >5% hepatocytes ↓ Nonalcoholic steatohepatitis (NASH) – fatty changes with inflammation and hepatocellular injury or fibrosis ↓ advanced fibrosis and cirrhosis

Epidemiology • One of the leading indications for liver transplantation in adults in the United states • Adults: – NAFLD 20 -30% population in Western countries – NASH: 3% adults and 20% obese people • Children: – NAFLD: 3 -10% in Western countries – Obese children: 23 -77%

Epidemiology • Boys 40% > Girls • Ages 2 -17 years (avg 12 years) • Autopsy data: – Fatty liver in 9. 6% of 742 pediatric autopsies – Fatty liver: Hispanic 12%, Asian 10. 2%, White 8. 6%, African-American 1. 5% – Fatty liver in 38% of obese children – NASH in 3% (23% of the subjects with fatty liver) Patton et al, JPGN 2006; 43: 413 Schwimmer et al, Pediatrics 2006; 118(4): 1388

Pathophysiology • ‘Two hit’ hypothesis – First hit: Hepatic steatosis is caused by insulin resistance: • Leptin may stimulate inflammation, fat storage • Adiponectin is anti-inflammatory, anti-steatotic – Levels of free fatty acid uptake and synthesis, with subsequent esterification to triglycerides (termed ‘input’), is greater than the levels of FFA oxidation and secretion (termed ‘output’)

Pathophysiology Alisi et al, Nat. Rev. Gastroenterol. Hepatol. 9, 152 -161 (2012)

Pathophysiology • Second hit: – Several factors promote oxidative stress (along side FFA and insulin resistance) • Proinflammatory cytokines • Mitochondrial dysfunction • Adiponectin (produced by a adipocytes) – Lipotoxicity: Direct toxicity to hepatocytes (lipid peroxidation) • Bacterial endotoxins • Stellate cell activation/mediators of fibrosis

Presentation • Signs and symptoms – Most often asymptomatic, discovered incidentally with elevation of liver enzymes – Common symptoms: • Malaise • Fatigue • RUQ/diffuse abdominal pain

Presentation • Hepatomegaly (33 -55%) • Acanthosis nigricans (30%) - more common in children than adults • Usually obese • Have associated features of metabolic syndrome – Insulin resistance in most patients – Impaired glucose tolerance (10%) – Type 2 diabetes (2%) – Variable incidence of hyperlipidemia and hypertension • Cirrhosis – stigmata of chronic liver disease

Diagnosis • Diagnosis of exclusion • Rule out other causes of transaminase elevation and fatty liver • Careful history and physical examination – Ask about alcohol consumption – Enquire about other causes of liver disease • Drugs (illicit or prescribed), viral hepatitis, family history of liver disease, nutrition

Differential diagnosis Wyllie et al, (2006) Pediatric Gastrointestinal and Liver Disease 3 rd Ed. Philidelphia, PA; Elsevier

Diagnostic work-up • Other diseases to screen for: – Hepatitis B, C – Autoimmune hepatitis (some children with NAFLD have positive antibodies) – Wilson’s disease – A 1 AT deficiency – +/- screening inborn errors metabolism • Baseline laboratory evaluations: – Transaminases • 4 -6 x upper limit of normal but variable • AST: ALT <1, ratio increased as fibrosis advances • Normal levels do not exclude presence of fibrosis/cirrhosis – Total and direct bilirubin – GGT – Fasting serum glucose, insulin and lipid panel

Be careful of lab values • Regional laboratories use local population for norms – do not exclude overweight/obese or other causes of liver disease – Median ULN at children’s hospitals 53 U/L (range 30‐ 90) – Too high to detect chronic liver disease (sensitivity 32‐ 42%) • 95 th percentile for ALT in healthy weight, metabolically normal, liver disease free, NHANES adolescent group (12‐ 17 yrs) • Persistently 2 x ULN (45‐ 50 U/L) may be threshold for more screening Schwimmer JB. Gastroenterology 2010; 138: 1357

Diagnostic work-up • Imaging – Ultrasound • Most commonly used • Diffuse increase in echogenicity and vascular blurring • Cannot rule out steatohepatitis/fibrosis • Sensitivity drops when degree of steatosis <30% • Lower sensitivity in morbidly obese patients – CT and MRI more sensitive for quantification of steatosis • Poor sensitivity and specificity for staging of disease

Alisi et al, Nat. Rev. Gastroenterol. Hepatol. 9, 152 -161 (2012)

Liver biopsy findings • Steatosis – >5% hepatocytes – mainly macrovesicular • Inflammation – Inflammatory infiltrate including lymphocytes, histiocytes and Kupffer cells • Ballooning Hepatocytes – Cytoplasm can contain Mallory-Denk/hyaline bodies • Fibrosis Weingarten, et al OBES SURG (2011) 21: 1714– 1720

NAFLD ACTIVITY SCORE (NAS) • Range 0 -8 • Individual scores for: – Steatosis (0 -3) – Lobular inflammation (0 -3) – Ballooning (0 -2) • NAS: – <3 – not NASH – >5 Definite NASH • Does not take into account portal injury in pediatric patients and often underestimates scores

Liver biopsy findings • Two subtypes described in biopsy specimens: – Type 1 NASH: steatosis with ballooning degeneration of hepatocytes and perisinusoidal fibrosis – Type 2 NASH: steatosis with portal inflammation and/or portal fibrosis without evidence of ballooning degeneration

Treatment • No one medicine proven to be effective • Treat associated risk factors – obesity, OSA, type 2 diabetes • Lifestyle changes are most effective – Diet and Exercise – Weight reduction shown to improve biochemical parameters and liver histology • Avoid rapid weight loss as may accelerate inflammation – Avoid alcohol

Treatment • Pharmacologic Therapy – Insulin sensitizers (metformin) • No more effective than lifestyle changes for biochemical and liver histology parameter – Antioxidants (Vitamin E +/- Vitamin C) • Not superior to placebo • Vitamin E was shown to reduce ballooning of hepatocytes – Docosahexaenoic acid • Promising preliminary results • No current pediatric recommendations

Treatment • Surgical: – Bariatric surgery • Adult studies show improvement in histology but no analogous pediatric studies – Liver transplantation • Indicated in patients with decompensated cirrhosis • NAFLD can recur in allograft, and progress to steatohepatitis