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Danielle Brandman, MD, MASProgram director, Transplant hepatology fellowship

Director, UCSF Fatty Liver ClinicAssociate Professor of Clinical MedicineUniversity of California San Francisco

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¡ Research/clinical trials: Gilead, Allergan

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Drugs and Toxins– Alcohol– Corticosteroids– Tamoxifen– Amiodarone– Industrial solvents

Inherited Metabolic Diseases– Lipodystrophy– Abetalipoprotinemia– Wilson Disease

Metabolic Syndrome– Abdominal Obesity– IGT/Diabetes– Dyslipidemia– Hypertension

Nutritional Syndromes– JI Bypass– TPN– Rapid weight loss

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Drugs and Toxins– Alcohol– Corticosteroids– Tamoxifen– Amiodarone– Industrial solvents

Inherited Metabolic Diseases– Lipodystrophy– Abetalipoprotinemia– Wilson Disease

Metabolic Syndrome– Abdominal Obesity– IGT/Diabetes– Dyslipidemia– Hypertension

Nutritional Syndromes– JI Bypass– TPN– Rapid weight loss

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¡ Prevalence of NAFLD: ___ US population

¡ Prevalence of NASH: ___% population

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¡ Prevalence of NAFLD: 16-29% US population

¡ Prevalence of NASH: 2-7% population

Farrell, Hepatology, 2006.

Younoussi, Hepatology, 2015.

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¡ Prevalence of NAFLD: 16-29% US population§ 2/3 of obese adults§ 84-96% bariatric surgery population§ Up to 76% of diabetics

¡ Prevalence of NASH: 2-7% population§ 10-30% of NAFLD§ 20% of obese adults

Farrell, Hepatology, 2006.

Younoussi, Hepatology, 2015.

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Study (year) CountryNumber of

subjectsSteatosis assessment Prevalence of NAFLD

Hadigan, C (2007) USA 33 MR spectroscopy 42%

Moreno-Torres, A (2007) Spain 29 MR spectroscopy 58%

Mohammed, SS (2007) Canada 26 Liver biopsy 45%

Guaraldi, G (2008) Italy 225 CT 37%

Crum-Cianflone, P (2009) USA 216 Ultrasound 31%

Ingiliz, P (2009) France 30 Liver biopsy 60%

Nishijima, T (2014) Japan 435 Ultrasound 31%

Price, JC (2014) USA 465* CT 13%

Macias, J (2014) Spain 505* CAP** 40%

Lui, G (2016) Japan 80 MR spectroscopy 29%

Lombardi, R (2016) Greece 125 Ultrasound 55%

Vuille-Lessard, E (2016) Canada 300 CAP 48%

Price, JC (2017) USA 122 MR spectroscopy 28%

*Includes HIV + HCV or HBV; **CAP= controlled attenuation parameter, obtained with FibroscanSlide courtesy of Dr. Jennifer Price

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▪ NAFLD prevelance: 13% HIV+ vs 19% HIV-, p=0.02▪ HIV aOR 0.44, p=0.002

HIV-monoinfected and uninfected women (n=87)

and men (n=141)

▪HIV+ women 36% less fat (vs HIV-), p=0.02▪HIV+ men 5.3% less fat (vs HIV-), p=0.66

Courtesy of Dr. Jennifer Price, adapted

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Variable Mean Difference (MD) or Odds Ratio (OR) P-valueBMI MD 2.9 (2.4 to 3.7) p<0.001Waist circumference MD 8.0 (5.5 to 10.6) p<0.001Type 2 diabetes OR 1.6 (1.1 to 2.4) p=0.02Hypertension OR 1.8 (1.3 to 2.4) p=0.001Triglycerides MD 62 (24 to 99) p=0.001HDL MD -4.2 (-6.8 to -1.6) p=0.002Duration of HAART

Cumulative ddi exposureMD -15 (-33 to 3.5)OR 1.4 (1.1 to 2.0)

p=0.11P=0.02

CD4 count MD 55 (12 to 98) p=0.01Courtesy of Dr. Jennifer Price, adapted

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¡ 54yo woman was found to have fatty liver on ultrasound done for abdominal pain

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¡ 54yo woman was found to have fatty liver on ultrasound done for abdominal pain

¡ The pain has since resolved, but she wonders how worried she should be about fatty liver

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¡ Her weight has fluctuated within the past few years, during which time her BMI has ranged from 30-33

¡ PMH: HIV, prediabetes (HbA1c 5.9), dyslipidemia (HDL 36, TGs 180), HTN

¡ Meds: DRV/c/TAF/FTC atorvastatin, lisinopril

¡ Family history: Parents with diabetes14

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¡ Labs: AST 38, ALT 71, albumin 4.1, INR 1.0, platelets 200

¡ Upon review of prior lab results, she has largely had AST 20s-40s and ALT 40s-80s since 2015

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A. Liver biopsyB. Counsel her on lifestyle modification to

try to lose weight and repeat liver tests again in 6 months

C. Evaluate for other causes of chronic liver disease

D. Transient elastography (Fibroscan)16

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A. Liver biopsyB. Counsel her on lifestyle modification to

try to lose weight and repeat liver tests again in 6 months

C. Evaluate for other causes of chronic liver disease

D. Transient elastography (Fibroscan)17

§ Symptoms:– None: 20 - 77%– Right upper quadrant pain: 25 - 48%– Fatigue: 50 - 75% (Obstructive sleep apnea in 40%)

§ Signs:– Overweight/Obese: 85 - 95%– Acanthosis nigricans: 10 -15%– Hepatomegaly: 25 - 50%

§ Laboratory:– ALT, AST - modest elevation– “Normal enzymes”

– Normal ALT <19-25 for women, <30-35 for men18

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¡ Diagnostic criteria§ Hepatic steatosis on imaging or liver biopsy§ No “significant” alcohol intake§ Absence of other causes of liver disease§ No medications known to cause hepatic steatosis

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¡ Diagnostic criteria§ Hepatic steatosis on imaging or liver biopsy§ No “significant” alcohol intake§ Absence of other causes of liver disease§ No medications known to cause hepatic steatosis

NAFLD is a diagnosis of exclusion

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¡ Liver tests¡ Abdominal ultrasound¡ Other serologic evaluation:

§ HBsAg, sAb, cAb§ HCV Ab§ [AMA, IgM (for PBC)]§ ASMA, ANA, IgG§ A1AT phenotype§ Iron, Tsat, ferritin§ Ceruloplasmin age < 45 § HAV Ab (for vaccination status)

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NAFLD

NAFLSteatosiswithout

inflammation

NASHSteatosis +

inflammation

NASH +

fibrosis

Cirrhosis

HCC

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A. FibroscanB. MR elastographyC. Liver biopsy

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A. FibroscanB. MR elastographyC. Liver biopsy

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¡ Liver biopsy is the only method to reliably distinguish between NAFL and NASH

¡ Noninvasive assessment of fibrosis§ Fibroscan§ Clinical prediction rules (e.g., FIB-4, NAFLD

fibrosis score)

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NAFLD fibrosis score= -1.675 + 0.037*age + 0.094*BMI +

1.13*IFG/DM + 0.99*AST:ALT –0.13*platelets – 0.66*albumin

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¡ Suspicious for NASH§ Significant liver enzyme elevation§ Diabetes

¡ Suspicious for advanced fibrosis or cirrhosis - Thrombocytopenia- Imaging (e.g., splenomegaly)- Noninvasive assessment: FIB-4, Fibroscan- Diabetes- Older age

§ Unable to rule out other diseases Chalassani, Hepatology 2017.Chalassani, Hepatology 2012.

NASH

Advanced fibrosis

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NASH 7 years per 1 stage~28 years 0à cirrhosis

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NASH 7 years per 1 stage~28 years 0à cirrhosis

NAFL 14 years per 1 stage~56 years 0à cirrhosis

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AUROCAny fibrosis ≥F2 F3-4 Cirrhosis

Transient elastography

0.74-0.78 0.79-0.84 0.83-0.88 0.86-0.93

MR elastography

0.83 0.91 0.89 0.97

NAFLD fibrosis score

0.82 0.72-0.82 0.73-0.86 0.77-0.92

FIB-4 0.8 0.72-0.83 0.78-0.86 0.78-0.88

Siddiqui, . . .Brandman et al. Clin Gastro Hep, 2018. Boursier, J Hepatol 2016.Imajo, Gastroenterology 2016. Hsu, Clin Gastro Hep, 2018.

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Hagstrom, J Hep, 2017.

Overall mortality Liver-related event

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¡ The patient was reluctant to undergo liver biopsy and opted instead for Fibroscan

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¡ The patient was reluctant to undergo liver biopsy and opted instead for Fibroscan§ Liver stiffness measurement: 13kPa (IQR 0.9)§ CAP score: 330 (IQR 13)

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¡ The patient was reluctant to undergo liver biopsy and opted instead for Fibroscan§ Liver stiffness measurement: 13kPa (IQR 0.9)§ CAP score: 330 (IQR 13)§ Interpretation: Cirrhosis (F4), though LSM could be

overestimated due to the presence of severe steatosis(CAP>300)

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¡ The patient was reluctant to undergo liver biopsy and opted instead for Fibroscan§ Liver stiffness measurement: 13kPa (IQR 0.9)§ CAP score: 330 (IQR 13)§ Interpretation: Cirrhosis (F4), though LSM could be

overestimated due to the presence of severe steatosis(CAP>300)

§ NFS -0.4 (indeterminate), FIB-4 1.24 (90% NPV for advanced fibrosis)

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¡ Because of the concern for cirrhosis, you again recommend liver biopsy for more definitive diagnosis and staging

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¡ Because of the concern for cirrhosis, you again recommend liver biopsy for more definitive diagnosis and staging

¡ The patient is now amenable to liver biopsy

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¡ Impression: steatohepatitis§ >20 portal tracts present, no fragmentation§ Severe steatosis (>66%)§ Ballooned hepatocytes§ Moderate lobular inflammation§ Fibrosis: stage 3, withbridging fibrosis and areas ofcentrizonal fibrosis

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A. Cardiovascular diseaseB. MalignancyC. Liver diseaseD. Kidney disease

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A. Cardiovascular diseaseB. MalignancyC. Liver diseaseD. Kidney disease

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Hagstrom, J Hep, 2018.43

SteatosisNASH ±F1-F2fibrosis

HCC

Death/LTx Cirrhosis

AdvancedF3fibrosis

12-40%

5-10%

0-50%

8%

13%

25-50%

14%

25%7%

Day, J Hep, 2008.44

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Wong, Gastroenterology, 2015.45

¡ This 54F with HIV, metabolic syndrome (BMI 33, pre-DM, HTN, HL), and biopsy-proven NASH with advanced fibrosis is interested to know what can be done to treat disease and prevent or reverse fibrosis

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A. Bariatric surgeryB. Vitamin EC. UrsodiolD. Lifestyle modifcation for weight lossE. B & D

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A. Bariatric surgeryB. Vitamin EC. UrsodiolD. Lifestyle modifcation for weight lossE. B & D

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• Diet & Exercise¡ Combination is best¡ Avoid fructose-sweetened beverages, added sugars¡ Loss of >7 - 10% weight to improve NASH+fibrosis¡ Exercise alone reduces liver fat

o Aerobic >150-250 minutes per weeko Resistance training 45 minutes/day x 3 days/week

Harrison. Hepatology, 2009.Promrat, Hepatology , 2010 Vilar-Gomez, Gastro, 2015Chalasani , Hepatology 2012 .

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¡ Currently available§ Vitamin E, pioglitazone (PIVENS trial; NEJM 2011)

¡ Potentially available in the future§ Obeticholic acid§ Elafibranor§ Cenicriviroc§ Many others in phase 2 trials

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¡ Tesamorelin▪ Synthetic growth hormone-releasing hormone, targets visceral fat▪ 60 HIV+ patients randomized to tesamorelin 2 mg or placebo SC daily x

6 months, followed by all receiving tesamorelin 2mg▪ Modest but significant reduction in liver fat in tesamorelin group vs

placebo¡ Aramchol

▪ Fatty acid-bile acid conjugate▪ Reduction in liver fat in phase 2 trial in primary NAFLD▪ 50 HIV+ patients with lipodystrophy and NAFLD ▪ Failed to meet primary endpoint of improvement in liver fat at 12 weeks

Stanley TL, JAMA, 2014. Stanley TL, Lancet HIV, 2019. Safadi R, Clin Gastroenterol Hepatol, 2014.

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Rotman, Gut, 2017.53

¡ Statins§ Safe for use in NAFLD§ Potential benefits of NAFLD/liver enzyme improvement and

reduced risk of liver death or HCC▪ Not proven in randomized controlled trials

¡ Metformin§ Safe for use in NAFLD§ Some studies show improvement in liver biopsy and liver

enzymes▪ Not proven in randomized controlled trials

§ Possible anti-neoplastic effects

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¡ NAFLD is common, and most patients with metabolic syndrome comorbidities will have NAFLD, with ~16 million in the US having NASH

¡ NAFLD is an umbrella term that includes NAFL and NASH§ NASH>>>NAFL has risk of progression to cirrhosis§ Biopsy is needed to characterize NAFLD

¡ Management hinges on weight loss, exercise, avoiding added carbohydrates, metabolic syndrome control§ Vitamin E only for biopsy-proven NASH§ Many drugs in the pipeline for NASH and fibrosis

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