jazwinski - nash acg june 2014 - american college of...

Alison B. Jazwinski, MD, MHS

Management of Complications of NASH:

When to Biopsy? How to Treat?

Alison Jazwinski MD MHSAlison Jazwinski, MD, MHSAssistant Professor

University of Pittsburgh Medical Center

Clinical Case

• 31 yo female referred for evaluation of elevated liver enzymes x 1yearelevated liver enzymes x 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

ACG Eastern Regional Postgraduate Course - Washington, DC Copyright 2014 American College of Gastroenterology

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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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Overview• Background

– Diagnosis and definitions– Natural historyNatural 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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NAFLD and Alcohol Consumption

d k k d d k>21 drinks per week in men and >14 drinks per week in women is a reasonable definition for

significant alcohol consumption when evaluating patients with suspected NAFLD


GENETIC-Abetalipoproteinemia

Other conditions associated with steatosis

-Weber-Christian disease-Galactosemia

-Type 1 glycogen storage disease

-Wilson’s disease-Tyrosinemia

-Systemic carnitinedeficiency

NUTRITIONAL/INTESTINAL-Surgical: J-I bypass, B-P diversion

-TPN-Rapid weight loss

-Severe protein calorie malnutrition

-Jejunal diverticulosis with

DRUGS/TOXINS-Amiodarone

-Methotrexate-Tamoxifen/synthetic estrogens

Gl i idjbacterial overgrowth -Glucocorticoids

-Nucleoside analogs-Calcium channel blockers



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DefinitionsNAFLD: Encompasses the entire spectrum of

fatty liver disease in individuals without significant alcohol consumption


DefinitionsNAFL: Presence of hepatic steatosis with no

evidence of hepatocellular injuryevidence of hepatocellular injury

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


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DefinitionsNASH: Presence of hepatic steatosis and

inflammation with hepatocyte injury p y j y(ballooning) with or without fibrosis

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

Definitions

• NASH cirrhosis: present of cirrhosis with current or previous histologic evidence ofcurrent or previous histologic evidence of steatosis or steatohepatitis

• Cryptogenic cirrhosis: presence of cirrhosis with no obvious etiology. Patients with

t i i h i h il i h dcryptogenic cirrhosis are heavily enriched with metabolic risk factors such as obesity and metabolic syndrome



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Natural History

• Patient with NAFLD have increased overall mortality compared to the general populationmortality 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


What is the role of liver biopsy?

1. Differentiate NAFL from NASH1. Differentiate NAFL from NASH

2. Stage disease

3. Rule out concurrent liver diseases (particularly iron overload and autoimmune)


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

Markers AUROCTraining

AUROCValidation

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,l b l

0.932 0.81apolipoprotein A1, GGT, tbili, ALT

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

Elevated ALT/AST and steatosis on imaging

Co-existing liver disease, possible

alternative dxYesNo

Algorithm for Liver biopsy

Work-up for alternative dx, biopsy

if needed

Diabetes or metabolic syndrome

BiopsyAST>ALT OR

Low serum albumin ORLow platelet count

No

No

Yes

Yes

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

BiopsyAge >65 OR

Family history of diabetes OR Family history of cirrhosis

ConsiderBiopsy

Re-assess q6mo

NoYes


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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


Pharmacologic Agents

Ineffective Treatments:

Metformin

Ursodiol

Potential Treatments:

Statins

Pentoxifylline

Treatments for Specific groups

(guideline based):

Pioglitazone

Orlistat Obeticholic Acid

Probiotics

Vitamin E


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Pioglitazone

Pros:Improvement in

Cons:-No improvement in fibrosis

“Pioglitazone can be used to treat steatohepatitis in patients with

-Improvement in steatosis and inflammation

p-Concerns regarding risk of

cardiovascular disease, congestive heart failure, bladder cancer and

bone loss-Weight gain

“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 non-diabetic and that long term safety and efficacy of pioglitazone in

patients with NASH is not established.” (Strength – 1, Evidence – B)


Vitamin EPros:

-Decrease in aminotransferases

Cons:-No effect on fibrosis

-Concerns about i d ll

“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

-Improvement in steatosis, inflammation, ballooning

increased all cause mortality and prostate

cancer in men

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)



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Bariatric Surgery

Lap Band

Roux-en-Y

Gastric sleeveWhattacheril and Chalasani. Clinical Liver Disease 2012:118

Bariatric Surgery

• Most studies show significant improvement in steatosis and inflammationsteatosis 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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Vitamin D deficiency

Hyper-ferritinemia

Pancreatic steatosis

Polycystic

Hypo-thyroidism

NAFLD

Colonic Adenomas

Coronary Artery

Disease

Hyper-uricemia

deficiencyOvary

Syndrome

AdenomasDiabetes

HypertensionObstructive

Sleep Apnea

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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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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jazwinski - nash acg june 2014 - american college of...

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