Fatty Liver Disease I Gede PalgunadiFK UNRAM/RSUP NTB

ObjectivesIdentify risk factors for fatty liver disease

Order appropriate screening tests

Diagnose and treat fatty liver disease

Initiate appropriate referrals

TerminologyALD: Alcoholic Liver Disease Significant alcohol consumption* > 21 drinks/week for males > 14 drinks/weeks for femalesNAFLD: Non-Alcoholic Fatty Liver Disease steatosis without hepatocyte injuryNASH: Non-Alcoholic Steatohepatitis steatosis with inflammation, hepatocyte injury with or without fibrosis*Sanyal, et al Hepatology 2011

Fatty liver Normal liver

StatisticsAlcoholic liver disease15 million people abuse/overuse ETOH in USA90% of those will develop fatty liversModerate use with another risk factorNon-alcoholic liver diseaseMost common chronic liver disease in USA4th most common reason for liver transplantProjected to be the most common in 10-20yrsUp to 20-40% adults6 million children

By 2020

Natural History of FLD

fatty liver

steatohepatitis

steatohepatitis + fibrosis steatohepatitis + cirrhosis

cryptogenic cirrhosis

Mortality risk: Cirrhotics with NAFLD vs hepatitis CSanyal,et al Hepatology 2006: NAFLD had lower rate of mortality Yatsuji, et al Gastroenterology and Hepatology 2009: No differenceBoth showed pts with NAFLD at lower risk for HCC than Hepatitis C pts.

NAFLD: risk factorsMiddle ageFemale genderOver-weight or obeseViral hepatitis Iron overloadMedicationsRapid weight lossStarvation/refeeding syndromeReyes syndrome

Auto-immune diseaseMalnutritionAbetalipoproteinemiaOvergrowth of bacteria in small intestinesTPN Acute fatty liver of pregnancyHELLP syndromeHispanic ethnicityHereditary

Risk factors: Established associationObesityType 2 DM: insulin resistance (IR)DyslipidemiaMetabolic syndrome (MS)

Risk factors: Emerging associationPolycystic ovary syndromeHypothyroidismObstructive sleep apneaHypopituitarismHypogonadismPancreatic-duodenal resection

Risk factor: MedicationsAmiodaroneMethotrexateTamoxifenCorticosteroidsDiltiazemValproic acidHighly active antiretroviral therapy

Risk factor: Bacteria overgrowth

Grieco, et al. Hepatology 200935 pts with NAFLD bx confirmed27 pts with celiac disease24 healthy individualsThose with FLD had increased intestinal permeability and increased small bowel bacterial overgrowthCompare, et al Nutrition Metabolism & Cardiovascular Disease Feb 2012Liver is 1st line of defense against gut-derived antigensLevels of bacterial lipopolysaccharide (component of GN bacteria) are increased in the circulation in several types of chronic liver diseaseCan modulation of gut microbia represent a new way to treat/prevent NAFLD????

Screening ConsiderationsAASLD recsLiver biochemistries can be normalUltrasounds are expensiveGeneral 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 indicatedIncidental finding on imaging for some other reasonAbnormal liver enzymesSymptoms of liver diseaseRule out other causes: alcohol, medications, hepatitis, etc.

NAFLD fibrosis scorehttp://nafldscore.comAgeBMIHyperglycemiaPlatelet count

AlbuminASTALT

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 biopsyAASLD recsIncidental finding on imagery with normal enzymes: no biopsy indicated, monitor.Presence of metabolic syndrome and persistently elevated biochemistries may benefit from liver biopsyPatients with biopsy proven NASH cirrhosis should be screened routinely for esophageal varices and HCC

AssessmentSymptomsMalaise, fatigue, RUQ discomfortSnores, disturbed sleep, wakes up tiredChronic pain disorders, achy musclesPhysical examAbdominal obesity Enlarged liverRUQ tenderness on palpationLabs Consistent with metabolic syndromeElevated bilirubin, AST, ALT, AP, GGT

Management: Lifestyle Interventions

Lifestyle InterventionsWeight 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 fibrosis3-5% weight loss improves steatosis but more is needed to improve inflammationAlcohol consumption: heavy intake should be avoidedlight intake (

ManagementMedications

Insulin sensitizing agentsMetformin * reduction in IR and enzymes, no improvement in histologyThiazolidinedionesRosiglitazone**: improved enzymes and steatosis, but not inflammationPioglitazone:***+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 StudyPioglitazone , Vitamin E, placebo96 weeksAdults with NASHwithout DM, cirrhosis, Hep C, heart failurelimited alcohol intake over previous 5 years Randomized trialPio group: 80Vit E group: 84Placebo: 83 Sanyal et al, New England J of Medicine 2010

Primary outcome Vitamin E vs placebo43% improvement vs 19%: significant (Steatosis, lobular inflammation, hepatocellular ballooning and fibrosis) Pio vs placebo34% improvement vs 19%: not significant

Sanyal et al, New England J of Medicine 2010

Secondary outcomeVitamin E vs placeboAlso reduction in SGOT/SGPT

Pio vs placeboReduction in SGOT/SGPTReduction in steatosis, lobular inflammationImprovement in IRIncrease in weight that did not resolve after discontinuance of Pio

Sanyal et al, New EngJ of Med 2010

PIVEN ConclusionsVitamin 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 establishedVitamin E 800 IU/day improves liver histology in NASH ptsNot 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 concernsMeta-analysis* including 136,000 participants found taking Vitamin E supplements > 400 IU/day had a higher risk of all cause mortalityVitamin 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 NASHUrsodeoxycholic acid*no histologic benefitOmega-3 fatty acids**Effective in treating hypertriglyceridemia in pts with NAFLDEvidence for treatment of NASH inconclusive to dateLarge 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 NASHStratify risks and treat accordinglySeveral 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 NASHAthyros et al Lancet 2010

AASLD Recommendation on StatinsGiven 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 surgeryNo RCTsCochrane review 2010: lack of RCTs prevents definitive assessment of risks/benefitsProspective study*381 adults with severe obesity, fibrosis score

AASLD Recommendation on Bariatric SurgeryPremature to consider foregut surgery as an option to specifically treat NASHForegut surgery is not contra-indicated in otherwise eligible pts with NASH or NAFLD WITHOUT cirrhosisFor those with cirrhosis: type, safety and efficacy of foregut surgery is not established

Transplant Considerations

MS & Immunosuppression Steroids BP induce IRlipid metabolism weight gain gluconeogenesis peripheral glucose utilizationCNIs : pancreatic beta cell toxicityNephrotoxicityTAC - glucose intolerance and de novo DMCSA - HTN and hyperlipdemiamTOR inhibitors hyperlipidemia

Metabolic Syndrome in Kidney Transplant*Metabolic syndrome (MS) may play a role in allograft loss and poor functionPathophysiology of MS is altered by immunosuppression

* Hricik, Clin J of ASN 2011

Metabolic Syndrome in Kidney TransplantPrevalence 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 TransplantMS lowered creatinine clearance by 5mL/min after 7 yearsSystolic 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/CD003598/ blood-pressure-medication-for-kidney- transplant-recipients

Metabolic Syndrome in Kidney Transplant: HyperlipdemiaALERT 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 obesityTAC based regimenDMHyperglycemiaHTNETOH as primary cause for transplantPre-transplant allograft biopsy showing steatosis*Dumortier, et al Am J of Gastro March 2010

MS Post Liver Transplant44-58% of pts > 6months post OLTBMI increase of 10% increases risk of post OLT NAFLDAssociated with increased cardiovascular and cerebrovascular eventsCVD causes 19-42% non-liver related deaths Diabetes, HTN, IR add 2-fold increased mortality risk Watt & Charlton J Hepatology 2010

MS Post Liver TransplantObesityBetween 1990 and 2002 the % of obese OLT recipients increased from 15% to 25% and average increase of 1kg/year*Orlistat (tetrahydrolipstatin)** Limited efficacyMay interfere with drug absorptionPost 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 OLT5 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 freeHigh cholesterol: Statins:pravastatin most studied; does not require P450 enzyme systemWith other statins: reduction in TAC/CsA dose???Mediterranean dietHigh Triglycerides: fish oilsFenofibric acids derivatives: reduction in TAC/CsA dose???ezetimide

* Watt & Charlton J Hepatology 2010

MS and Heart Transplant*48% of heart transplant recipientsLong term survival better without MS

Differences observed in MS groupMedian age olderPre-tx creatinine higherPre-tx HTN higherBMI higherDyslipidemia higher rate

No difference MS vs nonMSGenderUnderlying etiologySmokingDM history pre-txImmunosuppression

*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 vesselsPoorer quality organsFewer organsDiscarded livers with>30% steatosis

Special Considerations

NASH and Hepatocellular CarcinomaRetrospective study* 6,508 pts with NAFLD by USF/up 5.6 yearsPrimary end point: onset of HCC16 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 & PregnancyPresents at 35-36 weeksMitochondrial dysfunction preventing oxidation of FFA which accumulate in liverPresents with malaise, N/V in 3rd trimester, RUQ pain, UGI bleed, ARF, FHF, confusion, HTN, jaundice, hypoglycemiaMortality: maternal 12.5-18%, infant 7-66%Postpartum: may resolve or proceed to needing a transplant

Pediatric IssuesNAFLD reported as early as 2 y/oNASH-related cirrhosis as early as 8 y/oIndependent predictors of FLD in adolescenceObesityOlder ageMale genderDyslipidemia

Hispanic ethnicityHTNIRSchwimmer, et al. Pediatrics 2006Schwimmer, et al. Hepatology 2005Schwimmer, et al. Gastroenterology 2009

Pediatric IssuesChildren very young or not overweight who have NAFLD should be worked up for other causes of liver diseaseAlcoholInborn errors of metabolismStorage disordersWilsons diseaseAuto-immune hepatitisCystic fibrosisViral hepatitis

Pediatric Issues: screeningExpert 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: treatmentProspective: Intensive lifestyle behavior modification improves ALT and steatosis by ultrasound*>20% body weight reduction94% were able to lose weight by calorie reduction and exercise

* Nobili, et al. Hepatology 2006

Pediatric Issues: treatmentRCT: Antioxidant therapy* GroupsLifestyle modification aloneLifestyle modification with Vitamin E (600IU/d) and Vitamin C (500mg/d)Both groups improved ALT, steatosis, inflammation, ballooning equallyConcluded: no advantage to adding Vitamins E & C to lifestyle modifications

* Nobili, et al. Hepatology 2008

Pediatric Issues: treatmentTONIC study* vitamin E (800IU/d) or metformin (500mg BID) vs placebo8 to 17 y/os with NAFLDPrimary outcome: sustained reduction of ALT not achieved in either groupStatistically significant improvement in resolution of NASH in Vitamin E group over placeboMetformin offered no benefit over placebo

*Lavine, et al JAMA 2011

AASLD Pediatric RecommendationsIntensive lifestyle behavior modification, including dietitian consultation, is first line treatmentMetformin 500mg BID offers no benefitVitamin E 800 IU/d offers histological benefit but confirmatory studies are needed before it can be recommended in clinical use.

*Liver is divided histologically into lobules. The center of the lobule is the central vein. At the periphery of the lobule are portal triads. Functionally, the liver can be divided into three zones, based upon oxygen supply. Zone 1 encircles the portal tracts where the oxygenated blood from hepatic arteries enters. Zone 3 is located around central veins, where oxygenation is poor. Zone 2 is located in between. *Dallas heart study: 31% by MRIIn a study of 400 middle aged individuals: 46% by US, 12.2% by biopsySeverely obese who were undergoing bariatric surgery: 90% with 5% already had cirrhosis.In diabetics: studies range 69%-87%Pts with dyslipidemia: 50%

*There are reports of this event particularly in the setting of rapid weight loss following bariatric surgery most frequently after jejunoileal bypass and only rarely after proximal gastric bypass or vertical banded gastplasty. About 20% of patients with NASH develop increasing fibrosis and develop eventually cirrhosis. Following cirrhosis the hepatic steatosis and the other features of NASH may disappear leading to the presentation of cryptogenic cirrhosis. (7-14% of all patients referred for liver transplantation have cryptogenic cirrhosis)Once cirrhosis develops 4% annual rate of decompensation is noted.Since most of the studies are cross sectional natural history of NAFL is not well described. It is debated that whether steatosis progresses to steatohepatitis . There are reports of this event particularly in the setting of rapid weight loss following bariatric surgery most frequently after jejunoileal bypass and only rarely after proximal gastric bypass or vertical banded gastroplasty. NASH + CIRRHOSIS = HIGHER RISK OF HCC10 year survival rate of 81.5% for pts with NAFLD with advanced fibrosis and cirrhosis similar to pts with hepatitis C cirrhosis.

*Males:31%, females 16%Hispanics: high incidenceNon-hispanic blacks: lower incidenceAmerican indian and alaskan-natives lower 0.6-2.2%Abetalipoproteinemia: unable to properly absorb dietary fats in the intestinesRefeeding syndrome: Gaudinani et al. Current Nutrition & Food Science 2009HELLP: hemolysis elevated liver enzymes and low platelets*Weight loss 1-2 pounds per week*Rosiaglitazone: avandia USA restriction due to MIPioglitazone: actos: risk of CHF*Cardiovascular outcomes study* *European- Canadian multi-center trial *Pre-Tx BMI difficult to assess due to ascites*Burkholderia cepacia GNR in cystics