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Emerging Challenges in Primary Care: 2016

Non-Alcoholic SteatoHepatitis (NASH): Identification &

Evolving Treatment Strategies

Faculty§  Kalyan R. Bhamidimarri, MD, MPH

Assistant Professor/ Transplant HepatologyUniversity of Miami/ Miami Transplant Institute Miami, FL

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Disclosures§  Kalyan R. Bhamidimarri, MD, MPH has no relevant relationships to disclose.

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Learning Objectives After participating in the proposed educational activities, clinicians should be better able to:

1. Identify patients at high risk for nonalcoholic fatty liver disease (NAFLD) 

2. Distinguish non-alcoholic fatty liver (NAFL) from nonalcoholic steatohepatitis (NASH) and understand how to stage the disease

3. Implement ongoing evidence based general management of patients with NASH

4. Describe the available and emerging treatment options for patients with NASH 4

PRE-TEST QUESTIONS

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Pre-test ARS Question 1On a scale of 1 to 5, please rate how confident you would be treating a patient with non-alcoholic steatohepatitis:

1.  Not at all confident 2.  Slightly confident 3.  Moderately confident 4.  Pretty much confident 5.  Very confident

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Pre-test ARS Question 2Which of the following patients are not at high risk for the development of NAFLD:

1.  Patient with Rheumatoid arthritis taking methotrexate for > 10 years

2.  Obese woman who lost 100lbs after jejuno-ileal bypass (bariatric surgery)

3.  Man with BMI 35 who has DM2 and OSA

4.  Young boy with Crohn’s s/p multiple intestinal resections on TPN

5.  Middle aged woman with colon cancer in cecum s/p hemicolectomy 7

Pre-test ARS Question 3

62 year old Caucasian man with Obesity (BMI 45), DM2, Hypertension, Hyperlipidemia, Obstructive Sleep Apnea, and Osteoarthritis of the knees has mildly elevated LFT’s in the past which were attributed to him being on statins. Despite all efforts to lose weight, the patient was able to lose only 2% of his weight due to his limited exercise capacity. Ultrasound demonstrates increased echogenicity of the liver suggestive of fatty liver.

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CASE

Pre-test ARS Question 3What is the current gold standard to distinguish NAFLD from NASH:

1.  Liver biopsy

2.  LFT’s

3.  Ultrasound

4.  MR Spectroscopy

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Pre-test ARS Question 4

68 year old Hispanic woman with Metabolic syndrome has new onset ascites and was hospitalized recently for fluid overload. Blood tests show serum albumin of 2.4, platelets of 98k and upper endoscopy which showed grade 2 varices. She underwent a transjugular liver biopsy which shows stage 4 fibrosis.

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CASE

Pre-test ARS Question 4Given the clinical picture which is consistent with decompensated cirrhosis, how would you screen the patient for hepatocellular carcinoma?

1.  MRI abdomen every 2 years

2.  CT scan abdomen & pelvis every 2 years

3.  Ultrasound abdomen every 6 months

4.  Fibroscan every year

5.  All the above

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Pre-test ARS Question 5

55 year old non-diabetic woman is recently diagnosed with NASH and advanced fibrosis (stage 3) on liver biopsy. You recommend aggressive life-style modifications but the patient was unable to lose > 1% of her body weight over a period of 1 year.

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CASE

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Pre-test ARS Question 5Given the presence of advanced fibrosis in the setting of NASH, which of the following additionally would you recommend in her management that would improve her liver histology?

1.  Metformin

2.  Orlistat

3.  Cholecystectomy

4.  Vitamin E

5.  Ursodiol

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Edward, A 55-year-old obese male BMI 35 kg/m2 with borderline diabetes went to his PMD. Upon his suggestion, he started a crash diet and “ORANGE CRUSH” exercise program. HE lost 60lbs in 6months. Denies drinking.

His mother died of end-stage liver disease of uncertain etiology.

His laboratory tests revealed the following: AST 106, ALT 118, with normal bilirubin, alkaline phosphatase and prothrombin time.

A liver ultrasound showed diffusely echogenic liver.

What do you suspect:

1. Surreptious drinking

2. NAFLD

3. DILI

4. Viral Hepatitis

ARS Question

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NAFLD: Etiology Spectrum

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§  Metabolic Syndrome

§  Starvation/ PEM

§  TPN

§  Drugs: Amiodarone, Diltiazem, ChemoRx, Tamoxifen, Methotrexate, HIV –PI

§  Lipodystrophy: Congenital or Acquired

§  Celiac disease

§  Short Bowel Syndrome: Jejuno-ileal bypass

§  Genetic disorders

§  Abetalipoproteinemia, LAL deficiency, Weber-Christian Syndrome

§  Chronic Inflammation: RA, SLE

§  Terminology: Non-diagnostic

§  Anything that is not related alcohol

NAFLD Phenotype Spectrum

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NAFLD Host Spectrum

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NAFLD Pathologic Spectrum§  NAFL (nonalcoholic fatty liver)

§  Excess fat accumulation (steatosis)

§  NASH (nonalcoholic steatohepatitis)§  Defines a subgroup within NAFL§  Steatosis co-exists with liver cell injury and inflammation

§  Cirrhosis/ ESLD§  Liver decompensation§  Portal HTN

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Fat + inflammation

NASH: Histologic Spectrum

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Microvesicular Macrovesicular

Mixed Steatosis

Steatosis, Lobular Inflammation, Hepatocyte Ballooning, Mallory-Denk Bodies, Pericellular fibrosis

Do you think obesity/ NAFLD is: 1. Endemic2. Epidemic3. Pandemic 4. Hereditary

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ARS Question

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True Incidence & Prevalence of NAFLD: Unknown

§  Heterogeneous data: population, race, alcohol inclusion

§  Inconsistent§  Clinical definitions§  Competing etiologies§  Diagnostic techniques§  Histologic parameters

§  Under-diagnosis

§  Under-appreciation

§  Unawareness

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Worldwide Obese: 400M

NAFLD: 75% (300M)

NASH: 20%

(80M) Cirrhosis (5-10y):

33% (26M)

Caldwell et al; Dig Dis 2010

Torres DM, Clin Gastro Hepatol 2012;32:30-38.

NAFLD Prevalence

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NASH Prevalence: Ethnicity

24Pan JJ et al; WJG 2015

AA: Risk factors for fatty liver present but no steatosis (? Protective factors)

NHW: Non-Hispanic Whites NHB: Non-Hispanic Blacks

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NAFLD Risk Factors for Progression

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Risk Factors for NAFLDNon-Modifiable

§  Age: Older§  Gender: Men, Post

menopausal women (esp Caucasian)

§  Race: Higher in Hispanics/ Native Indian

§  Genetic: PNPLA3 mutation§  Baseline Histology

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Modifiable§  Obesity§  Insulin Resistance§  DM2§  Dyslipidemia§  Lifestyle:

§  Diet§  Sedentary§  Alcohol§  Smoking

Metabolic Syndrome: NAFLD/ NASH is the hepatic manifestation

27Lazo Sem Liv Dis 2008

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Obesity Prevalence: US Adults

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1998

2008

1990

No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

Diabetes not only increases risk of NASH but also of HCC

29El-Serag et al; Gastro 2004

NASH: Genetics§  2 Candidate genes identified by Genome Wide

Association Studies (GWAS)§  TM6SF2: lipid transporter gene§  PNPLA3/ Adiponutrin: Stronger genetic determinant (p < 10-9)

§  Patients with PNPLA3 mutation (SNP): High rates of§  Steatosis§  Inflammation§  Fibrosis

30PNPLA3: Patatin like phospholipase SNP: Single nucleotide polymorphism

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PNPLA3: Racial Differences

31Palmer et al; Hepatology 2013

NASH: Gut Microbiome

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Diet Alcohol Medications Bacterial overgrowth

NAFLD Pathophysiology

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Torres DM, Clin Gastro Hepatol 2012

***

NAFLD: Prognosis

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NAFLD: Clinical Presentation

Asymptomatic

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Symptomatic

Abnormal LFT’s Fatty liver on imaging

Liver Related - Decompensated cirrhosis - Hepatocellular carcinoma Extrahepatic: - CVS risks - Malignancy (GI, Renal, Breast) - Chronic Kidney Disease

Non-Specific Symptoms Hepatomegaly Fatigue

Are there any blood tests to assess NAFLD/ NASH?1. Yes2. No 3. Don’t Know

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ARS Question

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Non-Invasive TestsFibrosis

§  Fibrometer

§  NAFLD fibrosis score

§  Fib-4

§  APRI

§  BARD

§  AST/ALT ratio

§  Fibrotest (Markers of ECM)

§  ELF - European liver fibrosis (Markers of extracellular matrix)

§  Fibroscan

§  ARFI (acoustic radiation force impulse): US based technique

§  MR Elastography 37

Steatosis/ Steatohepatitis

§  Caspase cleaved CK-18

§  Soluble Fas

§  M65 (Caspase cleaved and uncleaved proteins)

§  ALT

§  HOMA score

Steatosis§  US§  CT§  MRI (all degrees of NAS)

Mod – severe NAS

Steatosis: Ultrasound

Normal Liver:

Echogenecity similar to R-Kidney cortex

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Fatty Liver:

Liver more echogenic than R-Kidney cortex

Loss of portal vessel outlines

Schwenzer et al; J Hepatol 2009

Normal LiverNon-contrast: hyperdense > vessels

C +/-: Liver hyperdense > Spleen

NAFLD/ NASHLiver density < Spleen/ Vessels

Steatosis: CT Scan

39Schwenzer et al; J Hepatol 2009

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Steatosis: MRI Techniques§  MRS: Spectroscopy (best)

§  Fat Quant signal

§  Accurate/ Reproducible

Limitations:

§  Small 2d Voxel

§  Need number of corrections

§  Not widely available

§  Expensive

40Hussain et al; Radiology 2005

Serum markers of NASH§  NASH è inflmm è Apoptosis

§  Apoptosis markers: correlate inflammation

§  Apoptosis mediated by caspase-3 cleaves CK 18

§  CK-18 abundant in hepatocytes

§  Others: M30, M65, M65ED

41Wieckowska et al; Hepatology 2006 Musso et al; Ann Med 2011

Only + in NASH but not in NAFLD

Non-invasive markers of NASH/ Inflammation will avoid need for liver biopsies: Extensive Research ongoing

Fibrosis: Serum Tests

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McPherson et al; Gut 2010

distinguishing between simple steatosis from NASH, but thetest is far from perfect as indicated by the lower 95% CI in the0.60 range for sensitivity and specificity.

Other biomarkers or predictive models combining clini-cal and laboratory parameters have been proposed to makethe diagnosis of NASH. One is the NashTest (Biopredictive,Paris, France), a proprietary formula that includes 12variables and has an AUROC of 0.79.50 In a recent meta-analysis from the developer, in 494 obese patients with aprevalence of NASH of 17.2%, the weighted AUROC of theNashTest was 0.84.6Other predictive models include scorescombining other parameters with CK-18 such as the theNASH diagnostics (CK18, adiponectin, and resistin),46,51

and the Nice model (ALT, CK-18, and the presence ofmetabolic syndrome),52 or without CK-18 such as theHAIR (hypertension, increased ALT, and IR),53 the oxNASH(13-hydroxyl-octadecadienoic acid/linoleic acid ratio, age,BMI, and AST),54 the NASH score (PNPLA3 genotype, AST,and fasting insulin)55 and the Palekar’ score.56 However,most of these scores rely on small and highly selectedpopulations (morbidly obese patients) and have not beenexternally validated.57

Imaging TechniquesAlthough there are numerous experimental studies that haveexplored different imaging modalities to differentiate simplesteatosis fromNASH (diffusion-weightedmagnetic resonanceimaging [MRI], MR elastography, TE, computed tomography[CT] perfusion), there are too few studies in humans to drawany conclusions.58

Diagnosis and Staging of Hepatic Fibrosis

Serum BiomarkersAmong the available serum biomarkers, some are specificsuch as the BARD score and the NAFLD fibrosis score (NFS),whereas others are not specific and mostly come from thehepatitis C virus (HCV) field such as AST/ALTratio, APRI, FIB-4,FibroTest, Fibrometer NAFLD, Hepacore, and enhanced liverfibrosis panel (ELF) score.

As shown in ►Table 2, the NFS was created using sixvariables that were significantly associated in multivariateanalysis with severe fibrosis-cirrhosis in an internationalmulticenter study including 733 patients (estimation group480; validation group 253) with liver-biopsy confirmed

Table 2 Performance of serum biomarkers of fibrosis for severe fibrosis-cirrhosis

Predictive score Patients (n) Variables/formula Cutoff AUC Se(%)

Sp(%)

Specific for NAFLDNAFLD fibrosis score59

733 !1.675 þ 0.037 # age [y] þ 0.094# BMI [kg/m2] þ 1.13 # IFG/diabetes [yes ¼ 1, no ¼ 0] þ 0.99# AST/ALT ratio ! 0.013 # plateletcount [#109/L] ! 0.66 # albumin[g/dL]

% !1.455& 0.676

0.88 8251

7798

BARD score62 827 BMI & 28 ¼ 1AST/ALT ratio & 0.8 ¼ 2Diabetes ¼ 1Score & 2, odds ratio for adv.fibrosis ¼ 17

< 2 points ! 62 66

Not specificFIB-4 score66

541 Age [y] # AST [U/L] / platelet[#109/L] # ALT [U/L]

% 1.30& 2.67

0.80 7433

7198

FibroMeter NAFLD69 235 Patented formula using0.4184 glucose (mmol/L) þ 0.0701AST (IU/L) þ 0.0008 ferritin (μg/L)!0.0102 platelet (G/L) ! 0.0260 ALT(IU/L) þ 0.0459 body weight (kg)þ 0.0842 age (y) þ 11.6226

0.94 ! !

Hepascore71 242 Exp[!4.185818 – (0.0249 age)þ (0.7464 sex) þ (1.0039 α2-mac-roglobulin) þ (0.0302 hyaluronicacid) þ (0.069 bilirubin) – (0.0012GGT)

0.37 0.81 75 84

FibroTest68 267 Patented formula 0.30.7

0.88 9225

7197

ELF74 192 ¼ !7.412 þ (ln(HA) ' 0.681) þ(ln(P3NP) ' 0.775) þ (ln(TIMP1) '

0.494)

!0.10680.3576

0.93 9080

7590

Abbreviations: ALT, alanine transaminase; AST, aspartate aminotransferase; AUC, area under the curve; BMI, body mass index; ELF, enhanced liverfibrosis panel; GGT, gamma-glutamyl transpeptidase; IFG, impaired fasting glucose; NAFLD, nonalcoholic fatty liver disease; Se, sensitivity; Sp,specificity.

Seminars in Liver Disease Vol. 35 No. 3/2015

Noninvasive Evaluation of Nonalcoholic Fatty Liver Disease Castera294

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Fibrosis: Serum Tests§  Well studied

§  Available on internet

§  < -1.455: No fibrosis

§  >0.676: significant fibrosis

§  Limitations: §  Intermediate range§  Inaccurate§  Validation needed

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http://nafldscore.com/

Fibrosis: Fibroscan§  Transient Elastography

§  Studied since 2003

§  Measures liver stiffness by wave velocity

§  Values range: 2.5 – 75 kPa

§  Easy/ Portable (<5min)

§  Available > 70 countries

44FDA approved on April 15, 2013 All that’s stiff is not FIBROSIS !!

Limiting Factors: BMI/ Fat/ Ascites: interefere with resultsWaist circumference ***Inflammation/ Congestion/ Cholestasis(falsely high scores)Operator experience

MR Elastography§  Reliable

§  Higher success rates

§  Higher Sn/ Sp: 86%/ 85%

§  Identifies Fat & Fibrosis

BUT

§  Expensive

§  Not readily available

45Chen et al; Radiology 2011

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Steatosis/ Fibrosis: Radiology

46

Liver Steatosis

MRI-Spect TE-CAP

Objective & Quantitative

Yes Yes

Failure < 0.5% 8-35%

Accuracy Whole range

Only in high fat range

Longitudinal Monitoring

Whole range

-

Probe independent

Yes M probe only

Cost $$$$ $$

Liver Fibrosis

TE US-ARFI MRE

Yes Yes Yes

< 50% M < 35% XL 13% S

< 21% 2%

Cirrhosis Y/N Cirrhosis Y/N

Cirrhosis Y/N

Feasible - -

No No Yes

$$ $$ $$$$

Invasive Tests: Liver Biopsy§  Gold/ Clinical

Standard

§  To confirm diagnosis

§  To prognosticate:§  Is there

inflammation/ NASH?

§  How much fibrosis?

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Disadvantages:§  Invasive§  Risks:

§  Bleeding§  Injury to adjacent

structures§  Death (0.2%)

§  Sampling errors: Patchy distribution

§  Expensive

Liver Biopsy

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with the management of MetS (such as endocrinologists,cardiologists, and hepatologists) is needed, while the priori-tization of funding for wider availability of key supportiveservices (namely dieticians, exercise physiologists, and psy-chologists) is also crucial. Additionally, the extension of well-organized primary care services and community programswill be critical for earlier disease detection, triage, education,and preliminary management (see ►Fig. 1).

It is evident thatWestern societies are becomingmore andmore “obesogenic,” and it is exactly these environmentalconstructs that can negate individual and general progress,and also promote the reversion of maladaptive behaviors. InAustralia, for example, Astell-Burt and colleagues have shownthat disadvantaged socioeconomic areas often have the high-est concentration of fast-food outlets, coupled with limitedaccess to fresh-food grocers and “green-space” for exer-cise.219–221 Awareness and education on the associated mor-bidity and adverse consequences of obesity and sedentarylifestyles also tends to be limited in such areas.222,223

Thus, global improvements will ultimately require public-level change, for no one physician, nor individual institutions,can be expected to achieve any real progress alone. Suchchanges should involve all levels of government, includingfederal policy makers and local governing communities,working to improve mass education, and promote healthierbehaviors through improved townplanning and better access,especially in areas of need. Other examples of measures thathave been proposed by the UK Academy of Medical RoyalColleges in their report on the obesity crisis224,225 includehigher tariffs on sugary drinks, more cohesive labeling on

food and beverages, improved nutritional standards providedin schools, banning televised advertisements of unhealthyfoods before 9 pm, and the promotion of physical activities(such as through greater walking and safer cycling routes).Mexico has also pioneered the introduction of an 8% tax onfoods with an energy content of more than 275 kcal/100 g,225

as well as government initiatives that aim to support low-income and extremely poor families with nutritional educa-tion, in addition to food supplies. This would enable moreempowered, and healthier choices to be made within indi-vidual financial circumstances. All of these measures are onlysome of the small, but vital future investments that must becollectively undertaken if any turnaround of this nonsustain-able problem, with its multitude of enduring medical, psy-chosocial, and economic consequences, is to be realisticallyachieved.

Abbreviations

1,25(OH)2D 1,25-dihydroxyvitamin DADA American Diabetes AssociationALA alpha-linoleic acidALT alanine aminotransferaseAMP adenosine monophosphateAMPK adenosine monophosphate-activated protein

kinaseAT aerobic trainingATP adenosine triphosphateBCAA branched-chain amino acidsBGL blood glucose level

Referral sources: primary care physicians, diabetes clinics, obesity clinics, etc..

NAFLD diagnosis confirmed and staged (noninvasive score, transient elastography, biopsy)

F0 F1F0-F1 F2/F3 Cirrhosis

Con!nue specialist follow-up depending on disease severity/progressionReturn to primary care

Normal weight:- Screen for CVS risk factors (diabetes

Normal weight:- Screen for CVS risk factors (diabetes

- Screen for CVS risk factors (diabetes, hypertension dyslipidemia) and- Screen for CVS risk factors (diabetes,

hypertension, dyslipidemia) and manage accordingly.

- Referral for individualized dietary and exercise advice.

- Screen for CVS risk factors (diabetes, hypertension, dyslipidemia) and manage accordingly.

- Referral for intensive, individualizedlifestyle interven!on.

hypertension, manage accordingly.

- Individualized nutri!on and dietary assessment, and individualizedphysical ac!vity advice – liaise withexercise advice.

- Ongoing maintenance program and psychological support to assist with long-term change.

- 1-2 yearly follow-up.

lifestyle interven!on.- Ongoing maintenance program and

psychological support to assist with long-term change.

- Yearly follow-up.

physical ac!vity advice liaise with liver transplant unit as appropriate.

- Psychological support.- Minimum 6-monthly follow-up.- HCC surveillance.y y p

Overweight:- As above, but:- Referral for more intensive,

individualized lifestyle interven!on

y pOverweight:- As above, but:- Referral for intensive, individualized

lifestyle interven!on program with

- Screening and management of complica!ons of portal hypertension.

- Referral for liver transplanta!on as indicated.

program. specific weight loss goals.

Fig. 1 Suggested algorithm for lifestyle interventions in the management of nonalcoholic fatty liver disease (NAFLD). CVS, cardiovascular system;HCC, hepatocellular cancer.

Seminars in Liver Disease Vol. 35 No. 3/2015

NAFLD: Dietary and Lifestyle Modifications Nguyen, George330

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Surveillance in Cirrhosis§  Esophageal Varices:

§  50% of Cirrhotics§  85% in Child’s C§  20% Mortality w/ bleed§  EGD: Standard of Care

§  Hepatocellular Carcinoma§  IMAGING: Every 6 months§  US or CT or MRI §  AFP: normal in 40% of HCC

§  AFP alone: Not recommended

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HCC

Which of the following have a beneficial role in managing your NASH patient?1. Switch PUFA to SFA in diet2. Sweetened ice tea 3. Coffee 4. Statins

51PUFA: Polyunsaturated fatty acids SFA: Saturated fatty acids

ARS Question

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Weight loss: Diet, Exercise, Orlistat, Bariatric Surgery TZD, Omega 3FA, UFA, Metformin, Incretins

Insulin Resistance

Oxidative Stress

Inflammation

Fibrosis

Vitamin E, Statins, Pentoxifylline, Bile acids, Probiotics

Statins, A-glycosidase inhibitors (Acarbose), Pentoxifylline, Bile acids, Probiotics, KD-025, Vitamin D, Betaine

Angiotensin Receptor Blockers, Coffee, Lysyl Oxidase Like 2 inhbitor (LOXL2)

NAFLD Treatment Targets

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Life-Style ModificationsModality Effect Comments

Diet

Weight Loss: -  7-10% -  Calorie restriction by

500-750kcal/ day

Improves histopathology of NASH

- Clinical Trials: Only 40% able to achieve the goal - Real life: ~10%

Eliminate or reduce SFA & High Fructose

Fructose better substrate for NAFL è lipogenesis

Known risk for NAFLD

Omega-3 Fatty Acids -  Improves TG -  May reduce NAFL

Lower CVS risk: 1gm/d x 1y

Coffee: 2-3 Cups/ day Decreased fibrosis Regular caffeinated coffee

Exercise

Moderate Exercise: Treadmill/ Elleptical/ Pool: 4-5 per week, 3-45min Resistance Training: 3 times/ week, total 45min

-  Improves insulin resistance

-  Improves LFT’s, Steatosis

Rigorous results when combined with diet

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Torres DM et al; Clin Gastro Hepatol 2012

Coffee: Brewing Evidence for Hepatoprotection

54Klatsky et al; AJE 1992 Molloy et al; Hepatology 2012

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NAFLD: Bariatric Surgery

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Antioxidants§  Oxidative stress is "second hit" in pathogenesis of

NAFLD.

§  Vitamin E à inhibits TGF β1 è Anti-inflm è Anti-fibrotic§  Pediatric NAFLD: Not superior§  Adults: Dose > 400 IU is associated with increased mortality

§  Other Anti-oxidants in studies: §  N-acetyl-cysteine§  Betaine§  S-Adenosyl methionine

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Pioglitazone and Vitamin EPIVENS Trial

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Sanyal AJ et al; NEJM 2010

LI- lobular inflammation HB- hepatocyte ballooning * Statistically significant

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Pioglitazone and Vitamin EPIVENS Trial

Vitamin E Pioglitazone

Superior histologic improvement Placebo Pioglitazone (non-DM, non-Cirrhotics)

Placebo (Lasting effects only on Rx)

Weight Gain No Yes (remains even after drug stopped)

Insulin sensitivity No Yes

CHF risk No Yes

Fracture risk No Yes (similar to all TZD’s)

All cause mortality Mild increase ? No data

58Sanyal AJ et al; NEJM 2010

Insulin Sensitizers§  Metformin:

§  ↓ Hepatic gluconeogenesis§  ↓ Intestinal glucose

absorption §  ↓ Serum lipid levels and

hepatic FA oxidation

§  Promotes weight loss

§  Human data: no improvement in histology

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§  TZD’s: §  Pioglitazone, Rosiglitazone§  Several studies (Only 3 RCTs)§  Small samples (10-70 patients)§  Improved ALT & Histology§  Irreversible weight gain§  Long term use: risk of CHF,

fractures, Bladder Cancer ?

§  Other Insulin Sensitizers:§  Exenatide, Liraglutide§  Induces weight loss§  ↓ hepatic steatosis§  Ongoing research

NASH: Statins§  No additional

hepato-toxicity

§  LFT’s although initially elevated will normalize after few months

§  Significantly lower CVS risks: 10% vs 30% (P < 0.0001)

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Obeticholic Acid

§  OCA: Semi-synthetic bile acid

§  FXR agonist

§  Insulin sensitizer

§  Weight loss

§  Filed for FDA approval

61Adorini L, Drug Dis Today 2012;17:988-997

Obeticholic Acid

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LI- lobular inflammation HB- hepatocyte ballooning * Statistically significant

Brent et al; NASH CRN; Lancet 2015

Novel TherapeuticsDrug Mechanism Human Trials Outcomes improved

Incretin Mimetics (Exenatide, Liraglutide)

GLP1 R agonist Insulin sensitizer

Yes ALT NAS Fibroblast GF 21

Bile Acids: Obeticholic A FXR agonist Insulin sensitizer

Yes (phase II, 2013)

ALT, biomarkers Insulin resistance Wt. loss trend

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Lysyl Oxidase Like2-inh (LXL2-i)

Anti-fibrotic, inhibits collagen crosslinking

Ongoing phase II (NASH: S3-4)

Fibrosis

Angiotensin RB (ARB) Telmisartan

Anti-fibrotic, remodelling

Yes Not significant

Pentoxifylline TNF-inhibitor Anti-inflmm/ fibrotic

Yes NAS Fibrosis trend

Probiotics (VSL3, Lactobacillus)

Anti-inflmm Yes (4 studies) ALT, NAS, Biomarkers (USA- ?results)

Exendin 4 (Byetta), Carbamazepine, PUFA

Anti-inflmm, Autophagy + Yes (few) Mice

NAS, Insulin R, Fibrosis

KD-025 Anti-inflmm, ROCK2 inhibitor

No NAS, hepatic lipids

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NAFLD: Transplant §  Current: 9-10% of all LT

§  Increasing x last decade

§  NASH + HCC: on the rise

§  LT evaluation: Thorough§  CVD risks (12-15% peri-

LT)§  Risk of other cancers§  BMI > 40 (poor

outcomes)

64O’Leary et al; Gastro 2008

Post LT: Recurrent NASH (~60%) De novo NASH (~15%) NASH Cirrhosis (rare) Tailor immunosuppression Control Metabolic Syndrome

Summary§  Epidemiology:

§  Increasing in prevalence/ indication for LT

§  Diagnosis: §  Several non-invasive methods being tested: NASH/ Fibrosis§  Liver Biopsy: Still the “gold standard”

§  Treatment:§  Life-style modifications ***§  Target agents against specific pathway are cautiously tested

§  Transplant related:§  Thorough evaluation necessary§  Recurrent/ de novo NAFLD common§  Graft loss rare but significant morbidity from metabolic syndrome

65Current Gaps: Several which need to be addressed soon

Post-Test Questions

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Post-test ARS Question 1Which of the following patients are not at high risk for the development of NAFLD:

1.  Patient with Rheumatoid arthritis taking methotrexate for > 10 years

2.  Obese woman who lost 100lbs after jejuno-ileal bypass (bariatric surgery)

3.  Man with BMI 35 who has DM2 and OSA

4.  Young boy with Crohn’s s/p multiple intestinal resections on TPN

5.  Middle aged woman with colon cancer in cecum s/p hemicolectomy

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Post-test ARS Question 2

62 year old Caucasian man with Obesity (BMI 45), DM2, Hypertension, Hyperlipidemia, Obstructive Sleep Apnea, and Osteoarthritis of the knees has mildly elevated LFT’s in the past which were attributed to him being on statins. Despite all efforts to lose weight, the patient was able to lose only 2% of his weight due to his limited exercise capacity. Ultrasound demonstrates increased echogenicity of the liver suggestive of fatty liver.

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CASE

Post-test ARS Question 2What is the current gold standard to distinguish NAFLD from NASH:

1.  Liver biopsy

2.  LFT’s

3.  Ultrasound

4.  MR Spectroscopy

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Post-test ARS Question 3

68 year old Hispanic woman with Metabolic syndrome has new onset ascites and was hospitalized recently for fluid overload. Blood tests show serum albumin of 2.4, platelets of 98k and upper endoscopy which showed grade 2 varices. She underwent a transjugular liver biopsy which shows stage 4 fibrosis.

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CASE

Post-test ARS Question 3Given the clinical picture which is consistent with decompensated cirrhosis, how would you screen the patient for hepatocellular carcinoma?

1.  MRI abdomen every 2 years

2.  CT scan abdomen & pelvis every 2 years

3.  Ultrasound abdomen every 6 months

4.  Fibroscan every year

5.  All the above

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Post-test ARS Question 4

55 year old non-diabetic woman is recently diagnosed with NASH and advanced fibrosis (stage 3) on liver biopsy. You recommend aggressive life-style modifications but the patient was unable to lose > 1% of her body weight over a period of 1 year.

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CASE

4/26/16  

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Post-test ARS Question 4Given the presence of advanced fibrosis in the setting of NASH, which of the following additionally would you recommend in her management that would improve her liver histology?

1.  Metformin

2.  Orlistat

3.  Cholecystectomy

4.  Vitamin E

5.  Ursodiol

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Post-test ARS Question 5On a scale of 1 to 5, please rate how confident you would be treating a patient with non-alcoholic steatohepatitis:

1.  Not at all confident 2.  Slightly confident 3.  Moderately confident 4.  Pretty much confident 5.  Very confident

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Post-test ARS Question 6Which of the statements below describes your approach to the evaluation and management of Non-Alcoholic Fatty Liver Disease and Non-Alchoholic Steatohepatitis?

1. I do not evaluate patients at risk for NAFLD/NASH or manage this condition, nor do I plan to this year.

2. I did not evaluate patients at risk for NAFLD/NASH or manage this condition, but as a result of attending this course I’m thinking of screening for it and managing patients now.

3. I do evaluate patients at risk for NAFLD/NASH and manage this condition, and this course helped me change my treatment methods.

4. I do evaluate patients at risk for NAFLD/NASH and manage this condition. This course confirmed that I don’t need to change my treatment methods.

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