Fatty Liver Disease
Jamie Blazek, MPH, APRN, FNP-C
Liver Transplant Department
Ochsner Health Systems
New Orleans, La
Disclosures
None
Objectives

Identify risk factors for
fatty liver disease

Order appropriate
screening tests

Diagnose and treat
fatty liver disease

Initiate appropriate
referrals
Terminology

ALD:
Alcoholic Liver Disease
Significant alcohol consumption*
> 21 drinks/week for males
> 14 drinks/weeks for females

NAFLD:

NASH:
Non-Alcoholic Fatty Liver Disease
steatosis without hepatocyte
injury
Non-Alcoholic Steatohepatitis
steatosis with inflammation,
hepatocyte injury
with or without fibrosis
*Sanyal, et al Hepatology 2011
Fatty liver
Normal liver
Statistics

Alcoholic liver disease
– 15 million people abuse/overuse ETOH in USA
– 90% of those will develop fatty livers
– Moderate use with another risk factor

Non-alcoholic liver disease
– Most common chronic liver disease in USA
– 4th most common reason for liver transplant
 Projected to be the most common in 10-20yrs
– Up to 20-40% adults
– 6 million children
By 2020
Natural History of FLD
fatty liver
steatohepatitis
steatohepatitis + fibrosis
steatohepatitis + cirrhosis
cryptogenic cirrhosis
Mortality risk:
Cirrhotics with NAFLD vs hepatitis C

Sanyal,et al Hepatology 2006:
– NAFLD had lower rate of mortality

Yatsuji, et al Gastroenterology and
Hepatology 2009:
– No difference

Both showed pts with NAFLD at lower risk
for HCC than Hepatitis C pts.
NAFLD: risk factors
Middle age
 Female gender
 Over-weight or obese
 Viral hepatitis
 Iron overload
 Medications
 Rapid weight loss
 Starvation/refeeding
syndrome
 Reye’s syndrome

Auto-immune disease
 Malnutrition
 Abetalipoproteinemia
 Overgrowth of bacteria in
small intestines
 TPN
 Acute fatty liver of pregnancy
 HELLP syndrome
 Hispanic ethnicity
 Hereditary

Risk factors: Established association
Obesity
 Type 2 DM: insulin resistance (IR)
 Dyslipidemia
 Metabolic syndrome (MS)

Risk factors: Emerging association
Polycystic ovary syndrome
 Hypothyroidism
 Obstructive sleep apnea
 Hypopituitarism
 Hypogonadism
 Pancreatic-duodenal resection

Risk factor: Medications
Amiodarone
 Methotrexate
 Tamoxifen
 Corticosteroids
 Diltiazem
 Valproic acid
 Highly active antiretroviral therapy

Risk factor: Bacteria overgrowth

Grieco, et al. Hepatology 2009
–
–
–
–

35 pts with NAFLD bx confirmed
27 pts with celiac disease
24 healthy individuals
Those with FLD had increased intestinal permeability and
increased small bowel bacterial overgrowth
Compare, et al Nutrition Metabolism & Cardiovascular
Disease Feb 2012
– Liver is 1st line of defense against gut-derived antigens
– Levels of bacterial lipopolysaccharide (component of GN bacteria)
are increased in the circulation in several types of chronic liver
disease
– Can modulation of gut microbia represent a new way to
treat/prevent NAFLD????
Screening Considerations
AASLD rec’s
Liver biochemistries can be normal
 Ultrasounds are expensive
 General population screening not
recommended
 Undergoing surgical procedure?
 Planned pregnancy with obese mother?
 Systematic screening of family members:
not recommended at this time

Further work-up indicated
Incidental finding on imaging for some
other reason
 Abnormal liver enzymes
 Symptoms of liver disease
 Rule out other causes: alcohol,
medications, hepatitis, etc.

NAFLD fibrosis score
Age
BMI
Hyperglycemia
Platelet count
Albumin
AST
ALT
http://nafldscore.com
NAFLD fibrosis score

< -1.455: predictor of absence of
significant fibrosis (F0-F2 fibrosis)

≤ -1.455 to ≤ 0.675: indeterminate score

> 0.675: predictor of presence of
significant fibrosis (F3-F4 fibrosis)
Algorithm for evaluating NAFLD*
*taken from AGA position paper 2002
Accidental discovery
Screen those with risk factors
AST or
Symptomatic liver disease
AST
elevated
normal
r/o other causes of liver disease
monitor
ongoing alcohol
yes
Abstain
no
Imaging study
Echogenic US or fat on CT
May need biopsy
Liver biopsy
AASLD rec’s
Incidental finding on imagery with normal
enzymes: no biopsy indicated, monitor.
 Presence of metabolic syndrome and
persistently elevated biochemistries may
benefit from liver biopsy
 Patients with biopsy proven NASH cirrhosis
should be screened routinely for
esophageal varices and HCC

Assessment

Symptoms
– Malaise, fatigue, RUQ discomfort
– Snores, disturbed sleep, wakes up tired
– Chronic pain disorders, achy muscles

Physical exam
– Abdominal obesity
– Enlarged liver
– RUQ tenderness on palpation

Labs
– Consistent with metabolic syndrome
– Elevated bilirubin, AST, ALT, AP, GGT
Management:
Lifestyle Interventions
Lifestyle Interventions
Weight loss by lower caloric intake and increased
physical exercise * led to improvement in biopsy.
9.3% weight loss: improvement in steatosis,
necrosis, and inflammation; not fibrosis
 3-5% weight loss improves steatosis but more is
needed to improve inflammation
 Alcohol consumption:
– heavy intake should be avoided
– light intake (<1/day) may have benefits**, may not***
* Promrat, et al. Hepatology 2010
** Dunn, et al. Hepatology 2008
** Gunji. et al. Am J Gastro 2009
** Moriya, et al. Alim Pharm Ther 2011
***Ruhl , et al. Clin Gastro Hepatol 2005
Management
Medications
Insulin sensitizing agents

Metformin *
– reduction in IR and enzymes,
– no improvement in histology

Thiazolidinediones
– Rosiglitazone**: improved enzymes and steatosis, but
not inflammation
– Pioglitazone:***+weight gain, but improvement in
hepatocellular injury
*Uygun, et al Aliment Pharm Ther 2004
*Nair, et al Aliment Pharm Ther 2004
**Ratziu, et al Gastroenterology 2008
***Sanyal, et al NE J Med 2010
PIVENS Study
Pioglitazone , Vitamin E, placebo
 96 weeks
 Adults

– with NASH
– without DM, cirrhosis, Hep C, heart failure
– limited alcohol intake over previous 5 years

Randomized trial
– Pio group: 80
– Vit E group: 84
– Placebo: 83
Sanyal et al, New England J of Medicine 2010
Primary outcome
Vitamin E vs placebo
43% improvement vs
19%: significant
(Steatosis, lobular
inflammation,
hepatocellular
ballooning and
fibrosis)
Pio vs placebo
34% improvement vs
19%: not significant
Sanyal et al, New England J of Medicine 2010
Secondary outcome

Vitamin E vs placebo
– Also reduction in
SGOT/SGPT

Pio vs placebo
– Reduction in
SGOT/SGPT
– Reduction in steatosis,
lobular inflammation
– Improvement in IR
– Increase in weight that
did not resolve after
discontinuance of Pio
Sanyal et al, New EngJ of Med 2010
PIVEN Conclusions
Vitamin E was superior to placebo in
adults with NASH and without DM
 Pioglitazone may have a role in treating
patients with biopsy-proven NASH,
however long term safety and efficacy has
not been established

Sanyal et al, New EnglJ of Med 2010
AASLD recommendations:
Pio can be used to treat certain patients
with biopsy-proven NASH who do not
have DM but long term safety and efficacy
has not been established
 Vitamin E 800 IU/day improves liver
histology in NASH pts

– Not recommended to treat NASH in those
with other chronic liver diseases, diabetics,
those with NASH cirrhosis or cryptogenic
cirrhosis, NAFLD without biopsy
Vitamin E: other concerns
Meta-analysis* including 136,000
participants found taking Vitamin E
supplements > 400 IU/day had a higher
risk of all cause mortality
 Vitamin E** > 400 IU/day increases risk
of prostate cancer in relatively healthy
men

*Miller et al Annals of Internal Medicine 2005
** Klein, et al, JAMA 2011
Other meds for NASH

Ursodeoxycholic acid*
– no histologic benefit

Omega-3 fatty acids**
– Effective in treating hypertriglyceridemia in pts
with NAFLD
– Evidence for treatment of NASH inconclusive to
date
– Large multi-center trial on-going now
*Lindor, et al. Hepatology 2004
**Capanni, et al. Alimen Pharm Ther 2006
Statins
CVD common cause of death for NAFLD
and NASH
 Stratify risks and treat accordingly
 Several studies show NAFLD and NASH pts
are not at increased risk of liver injury
over general population*
 No RCTs with histological end points using
statins to treat NASH

*Chalasani, et al. Am J Gastro 2012
GREACE study*
Concluded statins significantly improve
liver biochemistries and CV outcomes
in pts with elevated enzymes likely
due to NASH

Athyros et al Lancet 2010
AASLD Recommendation on Statins
“Given lack of evidence that patients with
NAFLD and NASH are at increased risk for
serious drug-induced liver injury from
statins, they can be used to treat
dyslipidemia in patients with NAFLD and
NASH.”
Bariatric surgery
No RCTs
 Cochrane review 2010: lack of RCTs prevents
definitive assessment of risks/benefits
 Prospective study*

– 381 adults with severe obesity, fibrosis score<3
– Clinical, metabolic, liver biopsy comparisons at 1 year
and 5 years
– Significant improvement in steatosis, ballooning,
resolution of probable/definite NASH at 1 and 5 years
– Small but significant increase of fibrosis score at 5
years (96% had improvement)
*Mathurin et al Gastroenterology 2009
AASLD Recommendation on
Bariatric Surgery
Premature to consider foregut surgery as
an option to specifically treat NASH
 Foregut surgery is not contra-indicated in
otherwise eligible pts with NASH or NAFLD
WITHOUT cirrhosis
 For those with cirrhosis: type, safety and
efficacy of foregut surgery is not
established

Transplant Considerations
MS & Immunosuppression

Steroids
– BP
– lipid metabolism
– gluconeogenesis

induce IR
weight gain
peripheral glucose utilization
CNIs : pancreatic beta cell toxicity
– Nephrotoxicity
– TAC - glucose intolerance and de novo DM
– CSA - HTN and hyperlipdemia

mTOR inhibitors
– hyperlipidemia
Metabolic Syndrome
in Kidney Transplant*
Metabolic syndrome (MS) may play a role
in allograft loss and poor function
 Pathophysiology of MS is altered by
immunosuppression

*
Hricik, Clin J of ASN 2011
Metabolic Syndrome
in Kidney Transplant

Prevalence of MS post KTx
– 22.6% at 1 year*
– 37.7% at 18 months*
– 63% at a median of 6 years**
* Porrini et al, Amer J of Kid Dis 2006
** de Vries et al, Amer J of Trans 2004
Metabolic Syndrome
in Kidney Transplant
MS lowered creatinine clearance by
5mL/min after 7 years
 Systolic BP and hypertriglyceridemia had
most negative impact

*de Vries et al, Amer J of Trans 2004
Metabolic Syndrome
in Kidney Transplant: Blood Pressure
Choice of antihypertensive post KTx:
Cochrane Group Review
http://summaries.cochrane.org/CD003598/
blood-pressure-medication-for-kidneytransplant-recipients
Metabolic Syndrome
in Kidney Transplant: Hyperlipdemia

ALERT trial*
– Randomized, double blind, placebo control (N=1100)
– Fluvastatin was superior to placebo in significantly
lowering total and LDL cholesterol in renal transplant
pts and in lowering rates of cardiac death and MI

Hypertriglyceridemia: anecdotal use of fenofibric
acid, fish oils, ezetimibe
*Fellstrom et al Kid Internat 2004
Risk factors for
NASH after liver transplant*
Post transplant obesity
 TAC based regimen
 DM
 Hyperglycemia
 HTN
 ETOH as primary cause for transplant
 Pre-transplant allograft biopsy showing
steatosis

*Dumortier, et al Am J of Gastro March 2010
MS Post Liver Transplant





44-58% of pts > 6months post OLT
BMI increase of 10% increases risk of post OLT
NAFLD
Associated with increased cardiovascular and
cerebrovascular events
CVD causes 19-42% non-liver related deaths
Diabetes, HTN, IR add 2-fold increased mortality
risk
Watt & Charlton J Hepatology 2010
MS Post Liver Transplant

Obesity
– Between 1990 and 2002 the % of obese OLT recipients
increased from 15% to 25% and average increase of
1kg/year*
– Orlistat (tetrahydrolipstatin)** Limited efficacy
 May interfere with drug absorption
– Post transplant bariatric surgery: few reported cases***
 May interfere with drug absorption
* Everhart et al, Liver Transpl Surg 1998
* Richards et al, Transpl Int 2005
** Cassiman et al, Transpl Int 2006
***Takata et al, Surg Obes Relat Dis 2008
*** Butte et al, Obes Surg 2007
*** Campsen et al, Obes Surg 2008
MS Post Liver Transplant*

Diabetes post OLT
– 5 year occurrence of advanced fibrosis is
increased in patients treated for DM (49%)
when compared to those with normal insulin
sensitivity (20%)
– Treatment goals same as general population
* Watt & Charlton J Hepatology 2010
MS Post Liver Transplant*

Dyslipidemia post OLT:
45-69%
– Changing immunosuppression: CsA to TAC, Rapa to TAC, steroid free
– High cholesterol: Statins:
 pravastatin most studied; does not require P450 enzyme system
 With other statins: reduction in TAC/CsA dose???
 Mediterranean diet
– High Triglycerides:
 fish oils
 Fenofibric acids derivatives: reduction in TAC/CsA dose???
 ezetimide
* Watt & Charlton J Hepatology 2010
MS and Heart Transplant*
48% of heart transplant recipients
Long term survival better without MS

Differences observed in
MS group
–
–
–
–
–
Median age older
Pre-tx creatinine higher
Pre-tx HTN higher
BMI higher
Dyslipidemia higher rate

No difference MS vs nonMS
–
–
–
–
–
Gender
Underlying etiology
Smoking
DM history pre-tx
Immunosuppression
*Sanchez-Lazaro et al Transplantation Proc 2011
MS and Lung Transplant
Impact of FLD on Donors
Deaths due to CVA
and CVD result in
atherosclerotic
vessels
– Poorer quality
organs
– Fewer organs
 Discarded livers
with>30%
steatosis
Special Considerations
NASH and Hepatocellular Carcinoma





Retrospective study* 6,508 pts with NAFLD by US
F/up 5.6 years
Primary end point: onset of HCC
16 new cases of HCC (0.25%)
Cumulative rates of NAFLD-related HCC:
– 0.02% at year 4
– 0.19% at year 8
– 0.51% at year 12
*Kawamura et al, Am J Gastroenterology 2011
Acute Fatty Liver & Pregnancy
Presents at 35-36 weeks
 Mitochondrial dysfunction preventing
oxidation of FFA which accumulate in liver
 Presents with malaise, N/V in 3rd trimester,
RUQ pain, UGI bleed, ARF, FHF, confusion,
HTN, jaundice, hypoglycemia
 Mortality: maternal 12.5-18%, infant 7-66%
 Postpartum: may resolve or proceed to
needing a transplant

Pediatric Issues
NAFLD reported as early as 2 y/o
 NASH-related cirrhosis as early as 8 y/o
 Independent predictors of FLD in
adolescence

Obesity
 Older age
 Male gender
 Dyslipidemia




Hispanic ethnicity
HTN
IR
Schwimmer, et al. Pediatrics 2006
Schwimmer, et al. Hepatology 2005
Schwimmer, et al. Gastroenterology 2009
Pediatric Issues

Children very young or not overweight
who have NAFLD should be worked up for
other causes of liver disease
– Alcohol
– Inborn errors of metabolism
– Storage disorders
– Wilson’s disease
– Auto-immune hepatitis
– Cystic fibrosis
– Viral hepatitis
Pediatric Issues: screening
Expert panel recommendations: Biannual
AST/ALT starting at age 10 in obese
children and those whose BMI >85%
percentile with other risk factors*
 AASLD has no recommendations

* Barlow et al. Pediatrics 2007
Pediatric Issues: treatment

Prospective: Intensive lifestyle behavior
modification improves ALT and steatosis by
ultrasound*
– >20% body weight reduction
– 94% were able to lose weight by calorie reduction and
exercise
* Nobili, et al. Hepatology 2006
Pediatric Issues: treatment

RCT: Antioxidant therapy*
– Groups
 Lifestyle modification alone
 Lifestyle modification with Vitamin E (600IU/d) and Vitamin C
(500mg/d)
– Both groups improved ALT, steatosis, inflammation,
ballooning equally
– Concluded: no advantage to adding Vitamins E & C to
lifestyle modifications
* Nobili, et al. Hepatology 2008
Pediatric Issues: treatment





TONIC study* vitamin E (800IU/d) or metformin
(500mg BID) vs placebo
8 to 17 y/o’s with NAFLD
Primary outcome: sustained reduction of ALT
not achieved in either group
Statistically significant improvement in resolution
of NASH in Vitamin E group over placebo
Metformin offered no benefit over placebo
*Lavine, et al JAMA 2011
AASLD Pediatric Recommendations
Intensive lifestyle behavior modification,
including dietitian consultation, is first line
treatment
 Metformin 500mg BID offers no benefit
 Vitamin E 800 IU/d offers histological
benefit but confirmatory studies are
needed before it can be recommended in
clinical use.
