Fatty Liver DiseaseFatty Liver DiseaseJamie Blazek, MPH, APRN, FNP-CJamie Blazek, MPH, APRN, FNP-C

Liver Transplant DepartmentLiver Transplant DepartmentOchsner Health SystemsOchsner Health Systems

New Orleans, LaNew Orleans, La

DisclosuresDisclosures NoneNone

ObjectivesObjectives Identify risk factors for Identify risk factors for

fatty liver diseasefatty liver disease

Order appropriate Order appropriate screening testsscreening tests

Diagnose and treat Diagnose and treat fatty liver diseasefatty liver disease

Initiate appropriate Initiate appropriate referralsreferrals

TerminologyTerminology ALDALD: : Alcoholic Liver DiseaseAlcoholic Liver Disease

Significant alcohol consumption* Significant alcohol consumption* > 21 drinks/week for males> 21 drinks/week for males > 14 drinks/weeks for females> 14 drinks/weeks for females

NAFLDNAFLD: : Non-Alcoholic Fatty Liver DiseaseNon-Alcoholic Fatty Liver Disease steatosis without hepatocytesteatosis without hepatocyte injuryinjury NASHNASH:: Non-Alcoholic SteatohepatitisNon-Alcoholic Steatohepatitis steatosis with inflammation, steatosis with inflammation, hepatocyte injury hepatocyte injury with or without fibrosiswith or without fibrosis*Sanyal, et al *Sanyal, et al HepatologyHepatology 2011 2011

Fatty liver Normal Fatty liver Normal liverliver

StatisticsStatistics Alcoholic liver diseaseAlcoholic liver disease

– 15 million people abuse/overuse ETOH in 15 million people abuse/overuse ETOH in USAUSA

– 90% of those will develop fatty livers90% of those will develop fatty livers– Moderate use with another risk factorModerate use with another risk factor

Non-alcoholic liver diseaseNon-alcoholic liver disease– Most common chronic liver disease in USAMost common chronic liver disease in USA– 44thth most common reason for liver transplant most common reason for liver transplant

Projected to be the most common in 10-20yrsProjected to be the most common in 10-20yrs

– Up to 20-40% adultsUp to 20-40% adults– 6 million children6 million children

By 2020By 2020

Natural History of FLDNatural History of FLD

fatty liver fatty liver

steatohepatitis steatohepatitis

steatohepatitis + fibrosis steatohepatitis + fibrosis

steatohepatitis + cirrhosis steatohepatitis + cirrhosis

cryptogenic cirrhosiscryptogenic cirrhosis

Mortality risk: Mortality risk: Cirrhotics with NAFLD vs hepatitis Cirrhotics with NAFLD vs hepatitis

CC

Sanyal,et al Sanyal,et al Hepatology Hepatology 2006: 2006: – NAFLD had lower rate of mortality NAFLD had lower rate of mortality

Yatsuji, et al Yatsuji, et al Gastroenterology and Gastroenterology and HepatologyHepatology 2009: 2009: – No differenceNo difference

Both showed pts with NAFLD at lower Both showed pts with NAFLD at lower risk for HCC than Hepatitis C pts.risk for HCC than Hepatitis C pts.

NAFLD: risk factorsNAFLD: risk factors

Middle ageMiddle age Female genderFemale gender Over-weight or obeseOver-weight or obese Viral hepatitis Viral hepatitis Iron overloadIron overload MedicationsMedications Rapid weight lossRapid weight loss Starvation/refeeding Starvation/refeeding

syndromesyndrome Reye’s syndromeReye’s syndrome

Auto-immune diseaseAuto-immune disease MalnutritionMalnutrition AbetalipoproteinemiaAbetalipoproteinemia Overgrowth of bacteria in Overgrowth of bacteria in

small intestinessmall intestines TPN TPN Acute fatty liver of Acute fatty liver of

pregnancypregnancy HELLP syndromeHELLP syndrome Hispanic ethnicityHispanic ethnicity HereditaryHereditary

Risk factors: Established Risk factors: Established associationassociation

ObesityObesity Type 2 DM: insulin resistance (IR)Type 2 DM: insulin resistance (IR) DyslipidemiaDyslipidemia Metabolic syndrome (MS)Metabolic syndrome (MS)

Risk factors: Emerging Risk factors: Emerging associationassociation

Polycystic ovary syndromePolycystic ovary syndrome HypothyroidismHypothyroidism Obstructive sleep apneaObstructive sleep apnea HypopituitarismHypopituitarism HypogonadismHypogonadism Pancreatic-duodenal resectionPancreatic-duodenal resection

Risk factor: MedicationsRisk factor: Medications

AmiodaroneAmiodarone MethotrexateMethotrexate TamoxifenTamoxifen CorticosteroidsCorticosteroids DiltiazemDiltiazem Valproic acidValproic acid Highly active antiretroviral therapyHighly active antiretroviral therapy

Risk factor: Bacteria Risk factor: Bacteria overgrowthovergrowth

Grieco, Grieco, et al. Hepatologyet al. Hepatology 2009 2009– 35 pts with NAFLD bx confirmed35 pts with NAFLD bx confirmed– 27 pts with celiac disease27 pts with celiac disease– 24 healthy individuals24 healthy individuals– Those with FLD had increased intestinal permeability and Those with FLD had increased intestinal permeability and

increased small bowel bacterial overgrowthincreased small bowel bacterial overgrowth Compare, Compare, et al Nutrition Metabolism & et al Nutrition Metabolism &

Cardiovascular DiseaseCardiovascular Disease Feb 2012 Feb 2012– Liver is 1Liver is 1stst line of defense against gut-derived antigens line of defense against gut-derived antigens– Levels of bacterial lipopolysaccharide (component of GN Levels of bacterial lipopolysaccharide (component of GN

bacteria) are increased in the circulation in several types bacteria) are increased in the circulation in several types of chronic liver diseaseof chronic liver disease

– Can modulation of gut microbia represent a new way to Can modulation of gut microbia represent a new way to treat/prevent NAFLD????treat/prevent NAFLD????

Screening ConsiderationsScreening ConsiderationsAASLD rec’sAASLD rec’s

Liver biochemistries can be normalLiver biochemistries can be normal Ultrasounds are expensiveUltrasounds are expensive General population screening not General population screening not

recommended recommended Undergoing surgical procedure?Undergoing surgical procedure? Planned pregnancy with obese mother?Planned pregnancy with obese mother? Systematic screening of family Systematic screening of family

members: not recommended at this members: not recommended at this timetime

Further work-up indicatedFurther work-up indicated

Incidental finding on imaging for Incidental finding on imaging for some other reasonsome other reason

Abnormal liver enzymesAbnormal liver enzymes Symptoms of liver diseaseSymptoms of liver disease Rule out other causes: alcohol, Rule out other causes: alcohol,

medications, hepatitis, etc.medications, hepatitis, etc.

NAFLD fibrosis scoreNAFLD fibrosis score

http://nafldscore.comhttp://nafldscore.com

AgeAge

BMIBMI

HyperglycemiaHyperglycemia

Platelet countPlatelet count

AlbuminAlbumin

ASTAST

ALTALT

NAFLD fibrosis scoreNAFLD fibrosis score

< -1.455: predictor of < -1.455: predictor of absenceabsence of of significant fibrosis (F0-F2 fibrosis)significant fibrosis (F0-F2 fibrosis)

≤ ≤ -1.455 to ≤ 0.675: indeterminate -1.455 to ≤ 0.675: indeterminate scorescore

> 0.675: predictor of > 0.675: predictor of presencepresence of of significant fibrosis (F3-F4 fibrosis) significant fibrosis (F3-F4 fibrosis)

Algorithm for evaluating Algorithm for evaluating NAFLD*NAFLD*

*taken from AGA position paper 2002 *taken from AGA position paper 2002 Accidental discovery Accidental discovery Screen those with risk factors Screen those with risk factors

AST or ASTAST or AST

Symptomatic liver diseaseSymptomatic liver disease

elevated normalelevated normal

r/o other causes of liver disease r/o other causes of liver disease

monitormonitor

ongoing alcoholongoing alcohol

yes no yes no

Abstain Imaging studyAbstain Imaging study

Echogenic US or fat on CTEchogenic US or fat on CT

May need biopsyMay need biopsy

Liver biopsyLiver biopsyAASLD rec’sAASLD rec’s

Incidental finding on imagery with Incidental finding on imagery with normal enzymes: no biopsy indicated, normal enzymes: no biopsy indicated, monitor.monitor.

Presence of metabolic syndrome and Presence of metabolic syndrome and persistently elevated biochemistries persistently elevated biochemistries may benefit from liver biopsymay benefit from liver biopsy

Patients with biopsy proven NASH Patients with biopsy proven NASH cirrhosis should be screened routinely cirrhosis should be screened routinely for esophageal varices and HCCfor esophageal varices and HCC

AssessmentAssessment SymptomsSymptoms

– Malaise, fatigue, RUQ discomfortMalaise, fatigue, RUQ discomfort– Snores, disturbed sleep, wakes up tiredSnores, disturbed sleep, wakes up tired– Chronic pain disorders, achy musclesChronic pain disorders, achy muscles

Physical examPhysical exam– Abdominal obesity Abdominal obesity – Enlarged liverEnlarged liver– RUQ tenderness on palpationRUQ tenderness on palpation

Labs Labs – Consistent with metabolic syndromeConsistent with metabolic syndrome– Elevated bilirubin, AST, ALT, AP, GGTElevated bilirubin, AST, ALT, AP, GGT

Management: Management: Lifestyle InterventionsLifestyle Interventions

Lifestyle InterventionsLifestyle InterventionsWeight lossWeight loss by lower caloric intake and by lower caloric intake and

increased physical exercise * led to increased physical exercise * led to improvement in biopsy.improvement in biopsy.

9.3% weight loss: improvement in 9.3% weight loss: improvement in steatosis, steatosis, necrosis, and inflammation; not necrosis, and inflammation; not fibrosisfibrosis

3-5% weight loss improves steatosis but 3-5% weight loss improves steatosis but more is needed to improve inflammationmore is needed to improve inflammation

Alcohol consumption: Alcohol consumption: – heavy intake should be avoidedheavy intake should be avoided– light intake (<1/day) may have benefits**, may not***light intake (<1/day) may have benefits**, may not*** * Promrat, * Promrat, et al. Hepatologyet al. Hepatology 2010 2010

** Dunn, ** Dunn, et al. Hepatology 2008et al. Hepatology 2008** Gunji. et al. Am J Gastro 2009** Gunji. et al. Am J Gastro 2009** Moriya, et al. Alim Pharm Ther 2011** Moriya, et al. Alim Pharm Ther 2011***Ruhl , et al. Clin Gastro Hepatol ***Ruhl , et al. Clin Gastro Hepatol

20052005

ManagementManagementMedicationsMedications

Insulin sensitizing agentsInsulin sensitizing agents

Metformin Metformin ** – reduction in IR and enzymes, reduction in IR and enzymes, – no improvement in histologyno improvement in histology

ThiazolidinedionesThiazolidinediones– Rosiglitazone**: improved enzymes and Rosiglitazone**: improved enzymes and

steatosis, but not inflammationsteatosis, but not inflammation– Pioglitazone:***+weight gain, but improvement Pioglitazone:***+weight gain, but improvement

in hepatocellular injuryin hepatocellular injury **Uygun, Uygun, et alet al Aliment Pharm TherAliment Pharm Ther

20042004 *Nair, *Nair, et alet al Aliment Pharm TherAliment Pharm Ther 2004 2004 **Ratziu, **Ratziu, et alet al Gastroenterology Gastroenterology 20082008 ***Sanyal, ***Sanyal, et alet al NE J MedNE J Med 2010 2010

PIVENS StudyPIVENS Study

Pioglitazone Pioglitazone ,, Vitamin E, placebo Vitamin E, placebo 96 weeks96 weeks Adults Adults

– with NASHwith NASH– withoutwithout DM, cirrhosis, Hep C, heart failure DM, cirrhosis, Hep C, heart failure– limited alcohol intake over previous 5 years limited alcohol intake over previous 5 years

Randomized trialRandomized trial– Pio group: 80Pio group: 80– Vit E group: 84Vit E group: 84– Placebo: 83Placebo: 83 Sanyal Sanyal et al,et al, New England J of MedicineNew England J of Medicine

20102010

Primary outcomePrimary outcome

Vitamin E Vitamin E vsvs placeboplacebo

43% improvement 43% improvement vs 19%: significantvs 19%: significant

(Steatosis, lobular (Steatosis, lobular inflammation, inflammation, hepatocellular hepatocellular ballooning and ballooning and fibrosis)fibrosis)

Pio Pio vsvs placebo placebo

34% improvement vs 34% improvement vs 19%: not significant19%: not significant

Sanyal Sanyal et al,et al, New England J of MedicineNew England J of Medicine 20102010

Secondary outcomeSecondary outcome

Vitamin E Vitamin E vsvs placeboplacebo– Also reduction in Also reduction in

SGOT/SGPTSGOT/SGPT

Pio Pio vsvs placebo placebo– Reduction in Reduction in

SGOT/SGPTSGOT/SGPT– Reduction in steatosis, Reduction in steatosis,

lobular inflammationlobular inflammation– Improvement in IRImprovement in IR– Increase in weight Increase in weight

that did not resolve that did not resolve after discontinuance after discontinuance of Pioof Pio

Sanyal Sanyal et al,et al, New EngJ of Med New EngJ of Med 20102010

PIVEN ConclusionsPIVEN Conclusions

Vitamin E was superior to placebo in Vitamin E was superior to placebo in adults with NASH and without DM adults with NASH and without DM

Pioglitazone may have a role in Pioglitazone may have a role in treating patients with biopsy-proven treating patients with biopsy-proven NASH, however long term safety and NASH, however long term safety and efficacy has not been establishedefficacy has not been established

Sanyal Sanyal et al,et al, New EnglJ of MedNew EnglJ of Med 2010 2010

AASLD recommendations:AASLD recommendations:

Pio can be used to treat certain Pio can be used to treat certain patients with biopsy-proven NASH who patients with biopsy-proven NASH who do not have DM but long term safety do not have DM but long term safety and efficacy has not been establishedand efficacy has not been established

Vitamin E 800 IU/day improves liver Vitamin E 800 IU/day improves liver histology in NASH ptshistology in NASH pts– Not recommendedNot recommended to treat NASH in those to treat NASH in those

with other chronic liver diseases, with other chronic liver diseases, diabetics, those with NASH cirrhosis or diabetics, those with NASH cirrhosis or cryptogenic cirrhosis, NAFLD without cryptogenic cirrhosis, NAFLD without biopsy biopsy

Vitamin E: other concernsVitamin E: other concerns

Meta-analysis* including 136,000 Meta-analysis* including 136,000 participants found taking Vitamin E participants found taking Vitamin E supplements > 400 IU/day had a supplements > 400 IU/day had a higher risk of all cause mortalityhigher risk of all cause mortality

Vitamin E** > 400 IU/day increases Vitamin E** > 400 IU/day increases risk of prostate cancer in relatively risk of prostate cancer in relatively healthy menhealthy men

*Miller *Miller et al et al Annals of Internal MedicineAnnals of Internal Medicine

20052005

** Klein, et al, ** Klein, et al, JAMA JAMA 20112011

Other meds for NASHOther meds for NASH

Ursodeoxycholic acid*Ursodeoxycholic acid*– no histologic benefitno histologic benefit

Omega-3 fatty acids**Omega-3 fatty acids**– Effective in treating hypertriglyceridemia Effective in treating hypertriglyceridemia

in pts with NAFLDin pts with NAFLD– Evidence for treatment of NASH Evidence for treatment of NASH

inconclusive to dateinconclusive to date– Large multi-center trial on-going nowLarge multi-center trial on-going now

*Lindor, et al. Hepatology 2004*Lindor, et al. Hepatology 2004

**Capanni, et al. Alimen Pharm Ther **Capanni, et al. Alimen Pharm Ther 20062006

StatinsStatins

CVD common cause of death for CVD common cause of death for NAFLD and NASHNAFLD and NASH

Stratify risks and treat accordinglyStratify risks and treat accordingly Several studies show NAFLD and Several studies show NAFLD and

NASH pts are not at increased risk of NASH pts are not at increased risk of liver injury over general population*liver injury over general population*

No RCTs with histological end points No RCTs with histological end points using statins to treat NASHusing statins to treat NASH

*Chalasani, *Chalasani, et al. Am J Gastroet al. Am J Gastro 2012 2012

GREACE study*GREACE study*

Concluded statins significantly Concluded statins significantly improve liver biochemistries and improve liver biochemistries and CV outcomes in pts with elevated CV outcomes in pts with elevated enzymes likely due to NASHenzymes likely due to NASH

Athyros Athyros et al Lancetet al Lancet 2010 2010

AASLD Recommendation on AASLD Recommendation on StatinsStatins

““Given lack of evidence that patients Given lack of evidence that patients with NAFLD and NASH are at with NAFLD and NASH are at increased risk for serious drug-increased risk for serious drug-induced liver injury from statins, they induced liver injury from statins, they can be used to treat can be used to treat dyslipidemiadyslipidemia in in patients with NAFLD and NASH.”patients with NAFLD and NASH.”

Bariatric surgeryBariatric surgery No RCTsNo RCTs Cochrane review 2010: lack of RCTs Cochrane review 2010: lack of RCTs

prevents definitive assessment of prevents definitive assessment of risks/benefitsrisks/benefits

Prospective study*Prospective study*– 381 adults with severe obesity, fibrosis score<3381 adults with severe obesity, fibrosis score<3– Clinical, metabolic, liver biopsy comparisons at 1 Clinical, metabolic, liver biopsy comparisons at 1

year and 5 yearsyear and 5 years– Significant improvement in steatosis, ballooning, Significant improvement in steatosis, ballooning,

resolution of probable/definite NASH at 1 and 5 resolution of probable/definite NASH at 1 and 5 yearsyears

– Small but significant increase of fibrosis score at Small but significant increase of fibrosis score at 5 years (96% had improvement)5 years (96% had improvement)

*Mathurin *Mathurin et al Gastroenterologyet al Gastroenterology 2009 2009

AASLD Recommendation on AASLD Recommendation on Bariatric SurgeryBariatric Surgery

Premature to consider foregut surgery Premature to consider foregut surgery as an option to specifically treat NASHas an option to specifically treat NASH

Foregut surgery is not contra-indicated Foregut surgery is not contra-indicated in otherwise eligible pts with NASH or in otherwise eligible pts with NASH or NAFLD WITHOUT cirrhosisNAFLD WITHOUT cirrhosis

For those with cirrhosis: type, safety For those with cirrhosis: type, safety and efficacy of foregut surgery is not and efficacy of foregut surgery is not establishedestablished

Transplant ConsiderationsTransplant Considerations

MS & Immunosuppression MS & Immunosuppression

SteroidsSteroids– BP induce IRBP induce IR– lipid metabolism weight gainlipid metabolism weight gain– gluconeogenesis peripheral glucose gluconeogenesis peripheral glucose

utilizationutilization CNIs : CNIs : pancreatic beta cell toxicitypancreatic beta cell toxicity

– NephrotoxicityNephrotoxicity– TAC - glucose intolerance and de novo DMTAC - glucose intolerance and de novo DM– CSA - HTN and hyperlipdemiaCSA - HTN and hyperlipdemia

mTOR inhibitors mTOR inhibitors – hyperlipidemiahyperlipidemia

Metabolic Syndrome Metabolic Syndrome in Kidney Transplant* in Kidney Transplant*

Metabolic syndrome (MS) may play a Metabolic syndrome (MS) may play a role in allograft loss and poor role in allograft loss and poor functionfunction

Pathophysiology of MS is altered by Pathophysiology of MS is altered by immunosuppressionimmunosuppression

* Hricik, * Hricik, Clin J of ASNClin J of ASN 2011 2011

Metabolic Syndrome Metabolic Syndrome in Kidney Transplant in Kidney Transplant

Prevalence of MS post KTx Prevalence of MS post KTx – 22.6% at 1 year*22.6% at 1 year*– 37.7% at 18 months*37.7% at 18 months*– 63% at a median of 6 years**63% at a median of 6 years**

* Porrini * Porrini et al, Amer J of Kid Dis 2006et al, Amer J of Kid Dis 2006

** de Vries et al, ** de Vries et al, Amer J of TransAmer J of Trans 2004 2004

Metabolic Syndrome Metabolic Syndrome in Kidney Transplant in Kidney Transplant

MS lowered creatinine clearance by MS lowered creatinine clearance by 5mL/min after 7 years5mL/min after 7 years

Systolic BPSystolic BP and and hypertriglyceridemiahypertriglyceridemia had most negative impacthad most negative impact

*de Vries et al, *de Vries et al, Amer J of TransAmer J of Trans 2004 2004

Metabolic Syndrome Metabolic Syndrome in Kidney Transplant: Blood in Kidney Transplant: Blood

PressurePressure

Choice of antihypertensive post KTx: Choice of antihypertensive post KTx: Cochrane Group ReviewCochrane Group Review

http://summaries.cochrane.org/CD00359http://summaries.cochrane.org/CD003598/8/

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

Metabolic Syndrome Metabolic Syndrome in Kidney Transplant: in Kidney Transplant:

HyperlipdemiaHyperlipdemia ALERT trial*ALERT trial*

– Randomized, double blind, placebo control Randomized, double blind, placebo control (N=1100)(N=1100)

– Fluvastatin was superior to placebo in significantly Fluvastatin was superior to placebo in significantly lowering total and LDL cholesterol in renal lowering total and LDL cholesterol in renal transplant pts and in lowering rates of cardiac transplant pts and in lowering rates of cardiac death and MI death and MI

Hypertriglyceridemia: anecdotal use of Hypertriglyceridemia: anecdotal use of fenofibric acid, fish oils, ezetimibe fenofibric acid, fish oils, ezetimibe

*Fellstrom *Fellstrom et al Kid Internatet al Kid Internat 2004 2004

Risk factors for Risk factors for NASH after liver transplant*NASH after liver transplant*

Post transplant obesityPost transplant obesity TAC based regimenTAC based regimen DMDM HyperglycemiaHyperglycemia HTNHTN ETOH as primary cause for transplantETOH as primary cause for transplant Pre-transplant allograft biopsy Pre-transplant allograft biopsy

showing steatosisshowing steatosis*Dumortier, *Dumortier, et al Am J of Gastroet al Am J of Gastro March 2010 March 2010

MS Post Liver TransplantMS Post Liver Transplant

44-58% of pts > 6months post OLT44-58% of pts > 6months post OLT BMI increase of 10% increases risk of post BMI increase of 10% increases risk of post

OLT NAFLDOLT NAFLD Associated with increased cardiovascular Associated with increased cardiovascular

and cerebrovascular eventsand cerebrovascular events CVD causes 19-42% non-liver related deaths CVD causes 19-42% non-liver related deaths Diabetes, HTN, IR add 2-fold increased Diabetes, HTN, IR add 2-fold increased

mortality risk mortality risk Watt & Charlton Watt & Charlton J HepatologyJ Hepatology 2010 2010

MS Post Liver TransplantMS Post Liver Transplant

ObesityObesity– Between 1990 and 2002 the % of obese OLT recipients Between 1990 and 2002 the % of obese OLT recipients

increased from 15% to 25% and average increase of increased from 15% to 25% and average increase of 1kg/year*1kg/year*

– Orlistat (tetrahydrolipstatin)** Limited efficacyOrlistat (tetrahydrolipstatin)** Limited efficacy May interfere with drug absorptionMay interfere with drug absorption

– Post transplant bariatric surgery: few reported cases***Post transplant bariatric surgery: few reported cases*** May interfere with drug absorptionMay interfere with drug absorption

* Everhart * Everhart et al, Liver Transplet al, Liver Transpl Surg 1998 Surg 1998

* Richards * Richards et al, Transpl Intet al, Transpl Int 2005 2005

** Cassiman ** Cassiman et al, Transpl Intet al, Transpl Int 2006 2006

***Takata ***Takata et al, Surg Obes Relat Diset al, Surg Obes Relat Dis 2008 2008

*** Butte *** Butte et al, Obes Surget al, Obes Surg 2007 2007

*** Campsen *** Campsen et al, Obes Surget al, Obes Surg 2008 2008

MS Post Liver Transplant*MS Post Liver Transplant*

Diabetes post OLTDiabetes post OLT– 5 year occurrence of advanced fibrosis is 5 year occurrence of advanced fibrosis is

increased in patients treated for DM increased in patients treated for DM (49%) when compared to those with (49%) when compared to those with normal insulin sensitivity (20%)normal insulin sensitivity (20%)

– Treatment goals same as general Treatment goals same as general populationpopulation

** Watt & Charlton Watt & Charlton J HepatologyJ Hepatology 2010 2010

MS Post Liver Transplant*MS Post Liver Transplant*

Dyslipidemia post OLT: Dyslipidemia post OLT: 45-69% 45-69% – Changing immunosuppression: CsA to TAC, Rapa to TAC, Changing immunosuppression: CsA to TAC, Rapa to TAC,

steroid freesteroid free– High cholesterol: Statins:High cholesterol: Statins:

pravastatin most studied; does not require P450 enzyme systempravastatin most studied; does not require P450 enzyme system With other statins: reduction in TAC/CsA dose???With other statins: reduction in TAC/CsA dose??? Mediterranean dietMediterranean diet

– High Triglycerides: High Triglycerides: fish oilsfish oils Fenofibric acids derivatives: reduction in TAC/CsA dose???Fenofibric acids derivatives: reduction in TAC/CsA dose??? ezetimideezetimide

** Watt & Charlton Watt & Charlton J HepatologyJ Hepatology 2010 2010

MS and Heart Transplant*MS and Heart Transplant*

48% of heart transplant recipients48% of heart transplant recipientsLong term survival better without MSLong term survival better without MS

Differences observed Differences observed in MS groupin MS group– Median age olderMedian age older– Pre-tx creatinine higherPre-tx creatinine higher– Pre-tx HTN higherPre-tx HTN higher– BMI higherBMI higher– Dyslipidemia higher Dyslipidemia higher

raterate

No difference MS vs No difference MS vs nonMSnonMS– GenderGender– Underlying etiologyUnderlying etiology– SmokingSmoking– DM history pre-txDM history pre-tx– ImmunosuppressionImmunosuppression

*Sanchez-Lazaro et al Transplantation Proc *Sanchez-Lazaro et al Transplantation Proc 20112011

MS and Lung TransplantMS and Lung Transplant

Impact of FLD on DonorsImpact of FLD on Donors

Deaths due to Deaths due to CVA and CVD CVA and CVD result in result in atherosclerotic atherosclerotic

vesselsvessels– Poorer quality Poorer quality

organsorgans– Fewer organsFewer organs

Discarded livers Discarded livers with>30% with>30% steatosissteatosis

Special ConsiderationsSpecial Considerations

NASH and Hepatocellular NASH and Hepatocellular CarcinomaCarcinoma

Retrospective study* 6,508 pts with NAFLD Retrospective study* 6,508 pts with NAFLD by USby US

F/up 5.6 yearsF/up 5.6 years Primary end point: onset of HCCPrimary end point: onset of HCC 16 new cases of HCC (0.25%)16 new cases of HCC (0.25%) Cumulative rates of NAFLD-related HCC:Cumulative rates of NAFLD-related HCC:

– 0.02% at year 4 0.02% at year 4 – 0.19% at year 80.19% at year 8

– 0.51% at year 120.51% at year 12

**Kawamura Kawamura et al, Am J Gastroenterologyet al, Am J Gastroenterology 20112011

Acute Fatty Liver & Acute Fatty Liver & PregnancyPregnancy

Presents at 35-36 weeksPresents at 35-36 weeks Mitochondrial dysfunction preventing Mitochondrial dysfunction preventing

oxidation of FFA which accumulate in liveroxidation of FFA which accumulate in liver Presents with malaise, N/V in 3Presents with malaise, N/V in 3rdrd

trimester, RUQ pain, UGI bleed, ARF, FHF, trimester, RUQ pain, UGI bleed, ARF, FHF, confusion, HTN, jaundice, hypoglycemiaconfusion, HTN, jaundice, hypoglycemia

Mortality: maternal 12.5-18%, infant 7-Mortality: maternal 12.5-18%, infant 7-66%66%

Postpartum: may resolve or proceed to Postpartum: may resolve or proceed to needing a transplantneeding a transplant

Pediatric IssuesPediatric Issues

NAFLD reported as early as 2 y/oNAFLD reported as early as 2 y/o NASH-related cirrhosis as early as 8 y/oNASH-related cirrhosis as early as 8 y/o Independent predictors of FLD in Independent predictors of FLD in

adolescenceadolescence ObesityObesity Older ageOlder age Male genderMale gender DyslipidemiaDyslipidemia

Hispanic ethnicityHispanic ethnicity HTNHTN IRIR

Schwimmer, Schwimmer, et al. Pediatricset al. Pediatrics 2006 2006Schwimmer, Schwimmer, et al. Hepatology 2005et al. Hepatology 2005Schwimmer, Schwimmer, et al. Gastroenterology 2009et al. Gastroenterology 2009

Pediatric IssuesPediatric Issues

Children very young or not overweight Children very young or not overweight who have NAFLD should be worked up who have NAFLD should be worked up for other causes of liver diseasefor other causes of liver disease– AlcoholAlcohol– Inborn errors of metabolismInborn errors of metabolism– Storage disordersStorage disorders– Wilson’s diseaseWilson’s disease– Auto-immune hepatitisAuto-immune hepatitis– Cystic fibrosisCystic fibrosis– Viral hepatitisViral hepatitis

Pediatric Issues: screeningPediatric Issues: screening

Expert panel recommendations: Expert panel recommendations: Biannual AST/ALT starting at age 10 Biannual AST/ALT starting at age 10 in obese children and those whose in obese children and those whose BMI >85% percentile with other risk BMI >85% percentile with other risk factors*factors*

AASLD has no recommendationsAASLD has no recommendations

* Barlow * Barlow et al. Pediatricset al. Pediatrics 2007 2007

Pediatric Issues: treatmentPediatric Issues: treatment

Prospective: Intensive lifestyle behavior Prospective: Intensive lifestyle behavior modification improves ALT and steatosis by modification improves ALT and steatosis by ultrasound*ultrasound*– >20% body weight reduction>20% body weight reduction– 94% were able to lose weight by calorie 94% were able to lose weight by calorie

reduction and exercisereduction and exercise

* Nobili, * Nobili, et al. Hepatologyet al. Hepatology 2006 2006

Pediatric Issues: treatmentPediatric Issues: treatment

RCT: Antioxidant therapy* RCT: Antioxidant therapy* – GroupsGroups

Lifestyle modification aloneLifestyle modification alone Lifestyle modification with Vitamin E (600IU/d) and Lifestyle modification with Vitamin E (600IU/d) and

Vitamin C (500mg/d)Vitamin C (500mg/d)

– Both groups improved ALT, steatosis, Both groups improved ALT, steatosis, inflammation, ballooning equallyinflammation, ballooning equally

– Concluded: no advantage to adding Vitamins E Concluded: no advantage to adding Vitamins E & C to lifestyle modifications& C to lifestyle modifications

* Nobili, * Nobili, et al. Hepatologyet al. Hepatology 2008 2008

Pediatric Issues: treatmentPediatric Issues: treatment

TONIC study* vitamin E (800IU/d) or TONIC study* vitamin E (800IU/d) or metformin (500mg BID) vs placebometformin (500mg BID) vs placebo

8 to 17 y/o’s with NAFLD8 to 17 y/o’s with NAFLD Primary outcome: sustained reduction of ALT Primary outcome: sustained reduction of ALT

not achieved in either groupnot achieved in either group Statistically significant improvement in Statistically significant improvement in

resolution of NASH in Vitamin E group over resolution of NASH in Vitamin E group over placeboplacebo

Metformin offered no benefit over placeboMetformin offered no benefit over placebo

*Lavine, *Lavine, et al JAMAet al JAMA 2011 2011

AASLD Pediatric AASLD Pediatric RecommendationsRecommendations

Intensive lifestyle behavior Intensive lifestyle behavior modification, including dietitian modification, including dietitian consultation, is first line treatmentconsultation, is first line treatment

Metformin 500mg BID offers no Metformin 500mg BID offers no benefitbenefit

Vitamin E 800 IU/d offers histological Vitamin E 800 IU/d offers histological benefit but confirmatory studies are benefit but confirmatory studies are needed before it can be needed before it can be recommended in clinical use.recommended in clinical use.