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Fatty Liver Disease

I Gede Palgunadi
FK UNRAM/RSUP NTB

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
liver

Normal

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
Reyes 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 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


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 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

Physical exam

Malaise, fatigue, RUQ discomfort


Snores, disturbed sleep, wakes up tired
Chronic pain disorders, achy muscles
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
2004

*Uygun, et al Aliment Pharm Ther

*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
2006

*Lindor, et al. Hepatology 2004


**Capanni, et al. Alimen Pharm Ther

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 druginduced 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
utilization

CNIs : pancreatic beta cell toxicity

induce IR
weight gain
peripheral glucose

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-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 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
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
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.