Fatty liver disease
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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


Disclosures

Disclosures

None


Objectives

Objectives

  • Identify risk factors for fatty liver disease

  • Order appropriate screening tests

  • Diagnose and treat

    fatty liver disease

  • Initiate appropriate referrals


Terminology

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

Fatty liver Normal liver


Statistics

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

By 2020


Fatty liver disease

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

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

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

Albumin

AST

ALT

NAFLD fibrosis score

http://nafldscore.com

Age

BMI

Hyperglycemia

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

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 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


Assessment

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

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

ManagementMedications


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

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


Statins

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

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


Transplant considerations

Transplant Considerations


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

http://summaries.cochrane.org/CD003598/

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


Ms and lung transplant

MS and Lung Transplant


Impact of fld on donors

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

Special Considerations


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

HTN

IR

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

  • 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

  • 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

  • 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.


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