Understanding NAFLD/NASH and the Nutritional Implications

Amanda Wieland, MD March 14, 2018

Learning Objectives:

• Understanding NAFLD/NASH definitions, disease mechanisms, and natural history

• Focus on weight loss as primary treatment

• Case studies of liver disease with NAFLD/NASH

DefinitionNon-alcoholic Fatty Liver Disease

(NAFLD)

Non-alcoholic Fatty Liver(NAFL)

Non-alcoholic Steatohepatitis(NASH)

1. The presence of fat in the liver either on imaging or histology

2. The exclusion of secondary causes

Histology

Hepatic Steatosis with no evidence of hepatocellular injury (hepatocyte

ballooning)

Hepatic Steatosis and inflammation with hepatocyte injury (ballooning) with or

without fibrosis

“Bland Steatosis” or “Simple Steatosis”

NAFLD Spectrum

Rinella ME. JAMA, 2015.

NAFLD Spectrum

Rinella ME. JAMA, 2015.

Normal Liver

NAFLD Spectrum

Rinella ME. JAMA, 2015.

NAFLD Spectrum

Rinella ME. JAMA, 2015.

Secondary Causes of Fatty Liver

Angulo, Review in NEJM, 2002

Alcoholic Liver DiseaseSignificant EtOH intake?

Men: > 21 drinks per weekWomen: >14 drinks per week

(although no consensus)

Epidemiology NAFLD• Most common cause of abnormal liver tests in the United

States

• True prevalence is unknown → estimated about 20-30% of the general population

323 million US population = 97 million NAFLD

• Strong association with Metabolic Syndrome and Insulin Resistance– High risk groups such as obese and diabetics up to 70% prevalence

Clark, et al, 2003

Disease Mechanisms

Machado, Gastro, June 2016

First Hit -> SteatosisWestern Diet + GeneticsInsulin resistanceIncreased FFA

Second Hit -> InflammationLeads to progressive

damage and fibrosis

Pathogenesis of inflammation NASH is complex…

Torres DM, Clin Gastro Hepatol 2012;32:30-38.

Research into the pathophysiology of NASH is dynamic

Younossi Z, et al. Nat Rev Gastroenterol Hepatol. Sep 2017.

Natural History

Bland Fatty Liver

NASH

70%

Stable or Regression of

Fibrosis

Cirrhosis

20-30%Liver Failure

HCC

Transplant or Death

40-60% over 5-7 years

10% over 7 years

Ong et al, Clin Liver Dis, 2007

NASH Cirrhosis as Indication for Transplant

Charlton, Liver Transplant, 2011

NASH as indication has been increasing

1.2% in 20019.7% in 2009

Currently, 3rd most common indication for transplant

Risk Factors for NASH (Advanced Fibrosis)

Angulo, Review in NEJM, 2002

General Health Implications:• The most common cause of death in patients with NAFLD is

cardiovascular disease

• Important to treat underlying metabolic derangements:– Obesity – Hyperlipidemia – Statins are okay– Insulin resistance/T2DM

Therapeutics Specific for Liver:

• Lifestyle intervention: our focus today– Diet and Exercise Counseling

• Pharmacologic: No FDA approved therapies

• Surgical: Briefly touch on bariatric surgery

• Future directions….– Ongoing Clinical Trials

Weight Loss in the Treatment of NAFLD/NASH

• Weight loss is the primary and most effective treatment to date in reversing the disease – It works!

• Improvements in steatosis, ballooning, inflammation and fibrosis correlate with percent weight loss (Vilar-Gomez, et al., 2015):

Romero-Gomez M, et al., 2017

Not easy to lose weight…

What diet is best?

• There is no one specific diet

• Hypocaloric diet to achieve a 5-10% weight reduction

• Caveat that severe calorie restriction can lead to increased energy efficiency, thwarting effort to lose weight– Energy efficiency is different between different individuals

Chalasani et al, AASLD Guidelines, 2012, Zelber-Sagi et al, WJG, 2011Dulloo, AG, Curr Obes Rep, 2017

Mediterranean Diet?• Mediterranean diet: – High in mono-unsaturated fatty acids (MUFA)– Enriched in olive oil, nuts, fruit, legumes, vegetables, fish– Low intake of red meat, processed meat, sweets

• Pilot study: 12 pts with biopsy proven NAFLD• 6 week diet, crossover design• Compared Mediterranean Diet to Low fat high carb diet• Significant reduction in hepatic steatosis measured by MR and also

insulin sensitivity• No difference in weight reduction

Ryan et al, J of Hep, 2013

Promote Good Healthy Choices

• Counseling on what can’t have possibly makes want more – try to given healthy alternatives– Focus on healthy options and healthy portion size

• Try to take focus away on short term “diet” and more on change in long term behavior to healthy eating

• Specific recs:– Reduce saturated/trans fat – Minimize added sugars (especially fructose)– Minimize excess carbohydrates

Harvard Healthy Eating Platehttps://www.hsph.harvard.edu/nutritionsource/healthy-eating-plate/

Good resource for patients

Overall, well rounded diet

Emphasize, not dieting but instead change in overall food choices

Fructose

• Process of conversion of carbohydrate into fat = De novo lipogenesis

• Glucose feeds into de novo lipogensis and in tightly regulated fashion

• Fructose is not regulated in its entry into lipogenesis– Soda turns directly into fat into the liver– Of note, sucrose (table sugar) is half fructose

Coffee• Emerging epidemiological data that might be beneficial in liver

disease• In patients with NAFLD, coffee consumption is an independent

protective factor for fibrosis (1)• Mouse models of NAFLD have shown beneficial effects of coffee

administration (2,3)– working to elucidate the mechanism– Possible improvement in mitochondrial function

• Data support the consumption of coffee as a component for a healthy diet in patients with NAFLD

1. Molloy et al, Hepatology 2012; 2. Oyzrzun et al, AASLD 2012 Abstract ID 165; 3. Salomone, et al, Translational Research, 2013, in press. 4. Romero-Gomez M, et al., 2017

Alcohol?

• Epidemiological data suggests moderate alcohol (< 1 drink per day women, <2 drinks per day men) does not promote NASH progression, and may be associated with decreased fibrosis

• If there is a history of alcohol abuse = no alcohol best

• If there is advanced fibrosis/cirrhosis = no alcohol

• Alcohol = empty calories

McHenry, Clinical Liver Disease, Feb 2018Dunn W, et al, J Hepatology, 2012

Summary of Nutrition Intervention

Romero-Gomez M, Journal of Hepatology, 2017

Reversing NAFLD with Exercise

• Exercise itself can have benefits in reduction of liver fat, though less than with weight loss through diet (20-30% vs 80% relative reduction)

• Those with greater cardiorespiratory fitness though have better response to dietary interventions

Romero-Gomez M, Journal of Hepatology, 2017

Paredes, Clinical Liver Disease, August 2012

Bariatric Surgery• General Recommendations:– Patients with BMI of >/= 40– Patients with BMI of >/= 35 and features of metabolic syndrome

• But should it be done for primary indication of NAFLD/NASH?

Bariatric Surgery in NASH

• Pros:– 18 showed improved

steatosis– 11 showed improved

inflammation

• Cons:– 4 showed some worsening

of fibrosis

• Cochrane Review in 2010 reviewed 21 prospective and retrospective cohort studies

• Bottom Line: No unbiased conclusion could be made on the benefit or harm of bariatric surgery in NAFLD based on lack of randomized controlled data

Chavez-Tapia et al, The Cochrane Collaboration, 2010

Bariatric Surgery Outcomes

Bariatric Surgery in Cirrhosis

• Contraindicated in Decompensated Cirrhosis

• Compensated Cirrhosis – Contraindicated in most centers– Can consider in very selective centers with experience– No evidence of portal HTN (no varices, normal sized spleen, etc)

Decompensated NASH Cirrhosis

• Decompensated cirrhosis often associated with malnutrition/sarcopenia– Sarcopenic obesity, severe muscle depletion in the setting of obesity, is reported

in 30% to 42% of obese patients with cirrhosis

• Focus on improvements in nutrition and muscle mass, rather than weight loss.

• Low calorie = risk to worsen sarcopenia, frailty, and malnutrition. – starvation state that can increase catabolism, muscle breakdown, and fatty acid

oxidation.

• Request high-protein, high-nutrient meals with a nighttime snack may be more beneficial than traditional dieting

Spengler, et al Transplantation 2017

Gastric Sleeve at Time of Transplant – Mayo Protocol

• Protocol for Candidate for Liver transplant with BMI > goal 35• 1200-1400 kCal for women and 1400-1600 kCal for men• Daily food record and review at visits with dietician + weight weekly• Encouraged increase activity as able – target of 30 minutes daily• Follow up ideally every 3 months to review weight loss goals

• 37 patients met the weight loss goal with protocol -> went to transplant

• 7 did not reach goal and underwent gastric sleeve at time of transplant

Gastric Sleeve

Wattacheril, Clinical Liver Disease, 2012

Restrictive Bariatric surgery – Reduction in stomach size by ~80%

No malabsorption component – concern for malabsorption of meds with post-transplant

Outcomes after Gastric Sleeve at Time of LTx

Key Points

• NAFLD is extremely common - ~30% population

• The concerning subtype of NASH with fibrosis has potential to progress to advanced liver disease, cirrhosis, and HCC

• Primary treatment of weight loss is able to reverse NASH and fibrosis– Dietary counseling is critical – Focus on healthy choices that can be sustained

Key Points

• Further research and follow up needed to guide bariatric surgery as treatment for NASH

• Decompensated cirrhosis is particularly challenging with sarcopenic obesity being common

• Obesity incidence in transplant candidates is increasing, and so is the indication of NASH. There is a need for new strategies to attain weight loss goals both before and after liver transplant

Time for some cases…