Alison B. Jazwinski, MD, MHS

Management of Complications of NASH: When to Biopsy? How to Treat? Alison Jazwinski, Jazwinski MD, MD MHS Assistant Professor University of Pittsburgh Medical Center

Clinical Case • 31 yo female referred for evaluation of elevated liver enzymes x 1year. 1year • PMH: mild hyperlipidemia, BMI 28.2 • Alcohol use described to be approximately 2 drinks per month. No viral hepatitis risk factors, autoimmune disease. • Family history of diabetes, hypertension. Also notes that her father had elevated liver enzymes

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Alison B. Jazwinski, MD, MHS

Clinical Case • ALT 346, AST 157, Alk Phos 115, Tbili 0.5 • Viral hepatitis, autoimmune, and genetic serologic markers are negative • RUQ US reveals hepatomegaly with fatty infiltration Would you do a liver biopsy?

Clinical Case • Liver biopsy: – Severe macrovesicular steatosis involving >75% of hepatocytes – NAFLD activity score 7 of 8 – Fibrosis 2 of 4 How would you manage this patient?

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Alison B. Jazwinski, MD, MHS

Overview • Background – Diagnosis and definitions – Natural history

• Who to biopsy? – Indications for biopsy – Noninvasive markers

• How to treat – Lifestyle modification – Pharmacologic agents – Bariatric Surgery

Diagnosis of NAFLD 1. Evidence of hepatic steatosis (imaging/histology) 2. No significant alcohol consumption 3. No competing etiologies for steatosis 4. No co-existing causes for chronic liver disease Chalasani N, et al. Hepatology. 2012: 2005

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Alison B. Jazwinski, MD, MHS

NAFLD and Alcohol Consumption >21 drinks d k per weekk in men and d >14 drinks d k per week in women is a reasonable definition for significant alcohol consumption when evaluating patients with suspected NAFLD

Chalasani N, et al. Hepatology. 2012: 2005

Other conditions associated with steatosis GENETIC -Abetalipoproteinemia -Weber-Christian disease -Galactosemia NUTRITIONAL/INTESTINAL -Type 1 glycogen -Surgical: J-I bypass, B-P diversion storage disease -TPN -Wilson’s disease DRUGS/TOXINS -Rapid weight loss -Tyrosinemia -Amiodarone -Severe protein calorie -Systemic carnitine -Methotrexate malnutrition deficiency -Jejunal j diverticulosis with -Tamoxifen/synthetic estrogens -Glucocorticoids Gl i id bacterial overgrowth -Nucleoside analogs -Calcium channel blockers

Chalasani N, et al. Hepatology. 2012: 2005

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Alison B. Jazwinski, MD, MHS

Definitions NAFLD: Encompasses the entire spectrum of fatty liver disease in individuals without significant alcohol consumption

Chalasani N, et al. Hepatology. 2012: 2005

Definitions NAFL: Presence of hepatic steatosis with no evidence of hepatocellular injury

Chalasani N, et al. Hepatology. 2012: 2005 Brunt E. Clinical Liver Disease 2012:107

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Alison B. Jazwinski, MD, MHS

Definitions NASH: Presence of hepatic steatosis and inflammation with hepatocyte p y injury j y (ballooning) with or without fibrosis

Chalasani N, et al. Hepatology. 2012: 2005 Brunt E. Clinical Liver Disease 2012:107

Definitions • NASH cirrhosis: present of cirrhosis with current or previous histologic evidence of steatosis or steatohepatitis • Cryptogenic cirrhosis: presence of cirrhosis with no obvious etiology. Patients with cryptogenic t i cirrhosis i h i are heavily h il enriched i h d with metabolic risk factors such as obesity and metabolic syndrome Chalasani N, et al. Hepatology. 2012: 2005

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Alison B. Jazwinski, MD, MHS

Natural History • Patient with NAFLD have increased overall mortality compared to the general population • The most common cause of death in patients with NAFL and NASH is cardiovascular disease • Patients with NASH (but not NAFL) have an increased liver-related mortality rate Chalasani N, et al. Hepatology. 2012: 2005

What is the role of liver biopsy? 1. Differentiate NAFL from NASH 2. Stage disease 3. Rule out concurrent liver diseases (particularly iron overload and autoimmune)

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Alison B. Jazwinski, MD, MHS

Noninvasive markers of fibrosis Test name/Study Markers (mild vs severe fibrosis)

AUROC Training

AUROC Validation

ELF

Hyaluronic acic, TIMP1, P3NP

NR

0.9

Modified ELF

ELF + BMI, albumin, platelet count, albumin, AST/ALT ratio

NR

0.98

NAFLD fibrosis score

Age, BMI, hyperglycemia, platelet count, albumin, AST/ALT ratio

0.77-0.93

NR

Fibrometer

Glucose, AST, age, weight, ferritin, ALT, platelet count

0.929

0.888

Fibro test

Α2-macroglobulin, haptoglobin, apolipoprotein l A1, GGT, tbili, b l ALT

0.932

0.81

BARD

BMI, AST/ALT ratio, DM

0.81

0.78

BAAT

BMT, ALT, TG

0.84

NR

FIB-4

Age, AST, ALT, platelet count

0.802

0.86

APRI

AST/platelet x 100

0.86

NR

Adapted from Noureddin and Loomba. Clinical Liver Disease 2012:104

Elevated ALT/AST and steatosis on imaging

No

Co-existing liver disease, possible alternative dx

Diabetes or metabolic syndrome Yes

No

Biopsy Yes

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Yes

Work-up for alternative dx, biopsy if needed

AST>ALT OR Low serum albumin OR Low platelet count

No

Age >65 OR Family history of diabetes OR Family history of cirrhosis

Biopsy

Adapted from Noureddin and Loomba. Clinical Liver Disease 2012:104

Algorithm for Liver biopsy

Yes

No

Consider Biopsy

Re-assess q6mo

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Alison B. Jazwinski, MD, MHS

Management of NASH • Lifestyle interventions – Weight loss • 3-5% of body weight improves steatosis • 10% of body weight improves inflammatory activity

– Exercise 2-3 sessions per week for 30-60 minutes improves NAFLD even in absence of weight loss Chalasani N, et al. Hepatology. 2012: 2005

Pharmacologic Agents

Ineffective Treatments: Potential Treatments: Metformin

Statins

Ursodiol

Pentoxifylline

Orlistat

Obeticholic Acid

Treatments for Specific groups (guideline based): Pioglitazone Vitamin E

Probiotics

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Alison B. Jazwinski, MD, MHS

Pioglitazone Cons: -No improvement p in fibrosis -Concerns regarding risk of cardiovascular disease, congestive heart failure, bladder cancer and bone loss -Weight gain

Pros: -Improvement Improvement in steatosis and inflammation

“Pioglitazone can be used to treat steatohepatitis in patients with biopsy proven-NASH. However it should be noted that the majority of the patients that participated in clinical trials were nondiabetic and that long term safety and efficacy of pioglitazone in patients with NASH is not established.” (Strength – 1, Evidence – B) Chalasani N, et al. Hepatology. 2012: 2005

Vitamin E Pros: -Decrease in aminotransferases -Improvement in steatosis, inflammation, ballooning

Cons: -No effect on fibrosis -Concerns about i increased d allll cause mortality and prostate cancer in men

“Vitamin E administered at daily dose of 800 IU/day improves liver histology in non-diabetic adults with biopsy-proven NASH and therefore it should be considered first line pharmacotherapy for this patient population. (Strength – 1, Quality – B). “Until further data supporting its effectiveness become available, vitamin E is not recommended to treat NASH in diabetic patients, NAFLD without liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis.” (Strength – 1, Quality – B) Chalasani N, et al. Hepatology. 2012: 2005

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Alison B. Jazwinski, MD, MHS

Bariatric Surgery

Lap Band

Roux-en-Y

Whattacheril and Chalasani. Clinical Liver Disease 2012:118

Gastric sleeve

Bariatric Surgery • Most studies show significant improvement in steatosis and inflammation • May lead to increased fibrosis • Not well studied in patients with cirrhosis • Too early to recommend primarily for NASH but may have benefit Whattacheril and Chalasani. Clinical Liver Disease 2012:118

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Alison B. Jazwinski, MD, MHS

Hyperferritinemia

Pancreatic steatosis

Hypothyroidism

Vitamin D deficiency

Polycystic Ovary Syndrome

NAFLD

Hyperuricemia

Coronary Artery Disease

Colonic Adenomas

Diabetes Obstructive Sleep Apnea

Hypertension

Established and emerging associated diseases

Clinical Case Discussion • Recommended – Weight loss of 10-15 lbs (starting weight 165lbs) – Regular exercise 2-3x per week for 30-60 minutes – Probiotics – Vitamin E 800IU daily

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Alison B. Jazwinski, MD, MHS

Take Home Points • NAFL is considered relatively benign, while NASH is a progressive disease • Biopsy should be performed in patients at high risk of having advanced disease – Patients with metabolic syndrome and elevated liver enzymes

• Treatments are still limited for NASH – Vitamin E for patients without diabetes – Pioglitazone? – Lifestyle modification

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