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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

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Fatty liver disease

Fatty Liver Disease

Jamie Blazek, MPH, APRN, FNP-C

Liver Transplant Department

Ochsner Health Systems

New Orleans, La


  • Identify risk factors for fatty liver disease

  • Order appropriate screening tests

  • Diagnose and treat

    fatty liver disease

  • Initiate appropriate referrals


  • 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


  • NASH: Non-Alcoholic Steatohepatitis

    steatosis with inflammation,

    hepatocyte injury

    with or without fibrosis

    *Sanyal, et al Hepatology 2011


  • 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

Natural History of FLDfatty liver steatohepatitis steatohepatitis + fibrosis steatohepatitis + cirrhosiscryptogenic cirrhosis

Mortality risk cirrhotics with nafld vs hepatitis c
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


Rapid weight loss

Starvation/refeeding syndrome

Reye’s syndrome

Auto-immune disease



Overgrowth of bacteria in small intestines


Acute fatty liver of pregnancy

HELLP syndrome

Hispanic ethnicity


NAFLD: risk factors

Risk factors established association
Risk factors: Established association

  • Obesity

  • Type 2 DM: insulin resistance (IR)

  • Dyslipidemia

  • Metabolic syndrome (MS)

Risk factors emerging association
Risk factors: Emerging association

  • Polycystic ovary syndrome

  • Hypothyroidism

  • Obstructive sleep apnea

  • Hypopituitarism

  • Hypogonadism

  • Pancreatic-duodenal resection

Risk factor medications
Risk factor: Medications

  • Amiodarone

  • Methotrexate

  • Tamoxifen

  • Corticosteroids

  • Diltiazem

  • Valproic acid

  • Highly active antiretroviral therapy

Risk factor bacteria overgrowth
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
Screening ConsiderationsAASLD 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
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




NAFLD fibrosis score





Platelet count

Nafld fibrosis score1
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
Algorithm for evaluating NAFLD**taken from AGA position paper 2002

Accidental discovery Screen those with risk factors


Symptomatic liver disease

elevated normal

r/o other causes of liver disease


ongoing alcohol

yes no

Abstain Imaging study

Echogenic US or fat on CT

May need biopsy

Liver biopsy aasld rec s
Liver biopsyAASLD 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


  • 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
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

Lifestyle Interventions

Management medications

Insulin sensitizing agents
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 alAliment Pharm Ther 2004

      *Nair, et alAliment Pharm Ther 2004

      **Ratziu, et alGastroenterology 2008

      ***Sanyal, et alNE 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
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
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
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
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
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
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


  • 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
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
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
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
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

Ms immunosuppression
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 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 transplant1
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 transplant2
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
Metabolic Syndrome in Kidney Transplant: Blood Pressure

Choice of antihypertensive post KTx: Cochrane Group Review


blood-pressure-medication-for-kidney- transplant-recipients

Metabolic syndrome in kidney transplant hyperlipdemia
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
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
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 transplant1
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 transplant2
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 transplant3
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
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

Impact of fld on donors
Impact of FLD on Donors

Deaths due to CVA and CVD result in atherosclerotic


  • Poorer quality organs

  • Fewer organs

    • Discarded livers with>30% steatosis

Nash and hepatocellular carcinoma
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
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

Hispanic ethnicity



Schwimmer, et al. Pediatrics 2006

Schwimmer, et al. Hepatology 2005

Schwimmer, et al. Gastroenterology 2009

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

Pediatric issues1
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: screening

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

Pediatric issues treatment1
Pediatric Issues: treatment improves ALT and steatosis by ultrasound*

  • 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 treatment2
Pediatric Issues: treatment improves ALT and steatosis by ultrasound*

  • 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
AASLD Pediatric Recommendations improves ALT and steatosis by ultrasound*

  • 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.