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: Non-Alcoholic Fatty Liver Disease
steatosis without hepatocyte
injury
NASH: 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 Auto-immune disease
Female gender Malnutrition
Over-weight or obese Abetalipoproteinemia
Viral hepatitis Overgrowth of bacteria in
small intestines
Iron overload
TPN
Medications Acute fatty liver of
Rapid weight loss pregnancy
Starvation/refeeding HELLP syndrome
syndrome Hispanic ethnicity
Reyes syndrome Hereditary
 Risk factors: Established
association

Obesity
Type 2 DM: insulin resistance (IR)
Dyslipidemia
Metabolic syndrome (MS)
 Risk factors: Emerging
association
Polycysticovary syndrome
Hypothyroidism
Obstructive sleep apnea
Hypopituitarism
Hypogonadism
Pancreatic-duodenal resection
 Risk factor: Medications
Amiodarone
Methotrexate
Tamoxifen
Corticosteroids
Diltiazem
Valproicacid
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 recs

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

Incidentalfinding 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 Albumin
BMI AST
Hyperglycemia ALT
Platelet count

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 AST
Symptomatic liver disease
elevated normal

r/o other causes of liver disease

monitor
ongoing alcohol

yes no

Abstain Imaging study

Echogenic US or fat on CT
May need biopsy
 Liver biopsy
AASLD recs

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
* Promrat, et al. Hepatology 2010
light intake (<1/day) may have benefits**, may not***
** 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 Pio vs placebo

placebo 34% improvement vs
43% improvement 19%: not significant
vs 19%: significant
(Steatosis, lobular
inflammation,
hepatocellular
ballooning and
fibrosis)
Sanyal et al, New England J of Medicine
2010
 Secondary outcome
Vitamin E vs Pio vs placebo
placebo Reduction in
Also reduction in SGOT/SGPT
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 induce IR
lipid metabolism weight gain
gluconeogenesis 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/CD00359
8/
blood-pressure-medication-for-kidney-
transplant-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 No difference MS vs

in MS group nonMS
Median age older Gender
Pre-tx creatinine higher Underlying etiology
Pre-tx HTN higher Smoking
BMI higher DM history pre-tx
Dyslipidemia higher Immunosuppression
rate

*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 3 rd 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 Hispanic ethnicity
Older age
Male gender
HTN
Dyslipidemia 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
Wilsons 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/os 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.