Sombat Treeprasertsuk, MD., Ph.D.

Chulalongkorn University

Mar 23, 2013-13.20-13.40

Common consultation in

Metabolic Liver Diseases

Metabolic disorders presenting with organomegaly.

Isolated hepatomegaly

Glycogen storage disease types 1, 3, 4, 6 and 9

Cholesterol ester storage disease

Fat oxidation defects

Hereditary fructose intolerance

Mucopolysaccharidosis

Isolated splenomegaly

Niemann-Pick disease type C

Gaucher disease type 1

Hepatosplenomegaly

Lysosomal storage disease

Metabolic Liver Diseases

Pat Mckiernan. Clin Res in Hepatolo and Gastroenterol 2012; 36: 287-290.

Fatty liver ตบคงไขมน

๖ ส.ค. ๒๕๔๔

http://rirs3.royin.go.th/coinages/webcoinage.php

Alcohol = แอลกอฮอล

cirrhosis = ๑. โรคตบแขง ๒. ภาวะเปนพงผด Fibrosis = ภาวะเกดพงผด Prognosis ๑. การพยากรณโรค / ค าพยากรณโรค Morbidity ๑. พยาธภาวะ [มความหมายเหมอนกบ pathosis]

๒. อตราการเกดโรค [มความหมายเหมอนกบ rate, morbidity; rate, sickness]

Normal liver by US/CT

Hamer OW, et al. Radiographics 2006 Nov-Dec;26(6):1637-53

Fatty liver by US/CT

Hamer OW, et al. Radiographics 2006 Nov-Dec;26(6):1637-53

MetS and NAFLD

Nseir W, et al. World J Gastroenterol. 2010 Jun 7;16(21):2579-88

71% had NAFLD

Mets

1/ 3 had MetS

NAFLD

What are the linkages between Diabetes and NAFLD ?

ผปวยหญงไทยค อาย 55 ป ภมล าเนา จงหวด สมทรปราการ

CC: ผลเลอดการท างานของตบผดปกต 1 ป

PI: 1 ปกอนมาโรงพยาบาล ตรวจสขภาพมผลเลอดการท างานของตบ

ผดปกต US- showed fatty liver

- 3 เดอนกอนไปตรวจเลอดซ ายงมผลเลอดผดปกต

PH: -DM type 2, HT, dyslipidemia Current medication: Metformin 2g/d, Simvastatin

10 mg/d, Enaril 5 mg/d, Glipizide 5 mg/d, HCTZ 25mg/d, ไมมประวตกนเหลา

PE: Weight 73 kg, Height 155 cm, BMI 30 kg/m2

No chronic liver stigmata

Case 1

26/6/55 31/7/55 23/8/55

TB 0.37 - 0.4

DB 0.18 - 0.2

AST 47 55 70

ALT 78 76 97

ALP 87 - 107

Alb 4.6 - 4.4

Glo

b

3.4 - -

INR 0.9 - 0.8

23/8/55

Hct 40.1%

WBC 9,210

%Neu 73%

Plt 272,000

Cr 0.73 mg/dl

HbA1C 7.3%

BARD SCORE = DM+ Obesity = 2

HBsAg: negative Anti-HCV: negative Ultrasound upper abdomen: fatty liver, no evidence of cirrhosis

ANA 1/80, Homogeneous type

Do we need to do liver biopsy? What additional tests are needed to do?

false positive?

Number (%)

Positive auto-antibodies 51 (22.7%)

ANA 46 (20%)

SMA 6 (3%)

ANA and SMA 1 (0.4%)

AMA 0

Adam LA, et al, Am J Gastroenterol. 2004 Jul;99(7):1316-20.

Prevalence of auto-antibodies in NAFLD patients

BARD : Simple NAFLD score

• B-AR-D score: Independent indicator of

advanced liver fibrosis

• Variables Score

AST/ALT ratio (> 0.8) 2

Diabetes mellitus 1

BMI (> 28 kg/m2) 1

A score of 2-4 points assoc. with advanced fibrosis

(OR = 17;

95% CI 9-32)

Harrison SA, et al. GUT 2008;57: 1441-7.

Validation of 4 noninvasive scoring systems to identify

patients with advanced fibrosis in the Thai NAFLD population

N= 115 liver biopsy proven NAFLD patients

Mean age of 50.5 12.4 years and 49.6% = male

70% impaired fasting glucose or diabetes

Prevalence of advanced liver fibrosis = 13%

BARD score >2 is the best tool with highest

sensitivity to screen patients with advanced fibrosis, followed by NFS with cut-off >-1.455

Piyachaturawat P, Treeprasertsuk S, et al. Digestive Disease Week 2013; Abstract # 1597417, 20/5/2013

Validation of 4 noninvasive scoring systems to identify

patients with advanced fibrosis in the Thai NAFLD population

Test Cut-off Sensitivity (%)

Specificity (%)

PPV (%)

NPV (%)

Patients avoiding

liver biopsy

False negative result

BARD score 2 80% 68% 27.3% 95.8% 71(62%) 3(2.6%)

NAFLD fibrosis score

-1.455

0.676

60%

13.3%

63%

98%

19.6%

50%

91.3%

88.3%

69(60%) 6(5.2%)

FIB-4 score 1.45

3.25

40%

13.3%

76%

100%

20%

100%

89.4%

88.5%

85(74%) 6(5.2%)

AST/ALT ratio 0.8 33.3% 86% 26.3% 89.6% 96(84%) 10(8.7%)

BARD<2 or NFS <-1.5 = “low probability of advanced liver fibrosis”

Piyachaturawat P, Treeprasertsuk S, et al. Digestive Disease Week 2013; Abstract # 1597417, 20/5/2013

Transient elastography 10 valid results

NAME; BIRTH DATE

• Results are expressed in kiloPascals (kPa) • Median of 10 validated measurements. • Liver stiffness values range from 2.5 to 75 kPa. • Reults are immediately available, Operator-independent

Diagnostic performance of transient elastography for the detection of fibrosis NAFLD

Study Patients Fibrosis stage Cut-offs (kPa) AUROC Se (%) Sp (%)

Yoneda et al.61 97 NAFLD F > 2

F > 3 F4

6.6

9.8 17.5

0.86

0.90 0.99

88

85 100

74

81 97

Nobili et al.62 52 NASH F > 2

F > 3

7.4 10.2

0.99 1

100 100

92 100

Wong et al.63 246 NAFLD F > 2

F > 3 F4

7.0

8.7

10.3

0.84

0.93 0.95

79

84 92

76

83 88

Lupsor et al.64 72 NASH F > 2

F > 3

6.8 10.4

0.78 0.98

67 100

84 97

Petta et al.46 169 NAFLD F > 2

F > 3

7.25 8.75

0.79 0.87

69 76

70 78

AUROC, area under ROC curve; Se, sensitivity; Sp, specificity; PPV, positive predictive value; NPV,

negative predictive value; NAFLD, non-alcoholic fatty liver disease; NASH, non- alcoholic steatohepatitis.

D. festi, et al. Aliment Pharmacol Ther 2013; 37: 392-400.

CAP and NAFLD

Controlled Attenuation Parameter : CAP is very efficient to detect even low grade steatosis.

Measures the ultrasound attenuation at the centre

frequency of the FibroScan; use M probe (3.5 MHz).

de Le´dinghen V, et al. Liver Inter 2012; 911-8.

• Cut-off CAP:

S0: steatosis <10%: >S1: >11% to 33%: >215 dB/m), >S2: >34% to 66%: >252 dB/m > S3: > 67% to 100% : >296 dB/m

CAP and NAFLD

• Cut-off CAP: S0: steatosis <10%: >S1: >11% to 33%: >215 dB/m), >S2: >34% to 66%: >252 dB/m > S3: > 67% to 100% : >296 dB/m

S3: > 67% to 100% F1 fibrosis

NASH Clinical Research Network system for scoring activity

Kleiner DE et al. Hepatology 2005; 41: 1313-1321

NASH Clinical Research Network system for scoring Fibrosis

Stage 0: None Stage 1: Perisinusoidal or periportal •1A: mild, zone3, perisinusoidal •1B: Moderate, zone3, perisinusoidal •1C: portal/periportal

Stage 2: Perisinusoidal and portal/periportal Stage 3: Bridging fibrosis Stage 4: Cirrhosis

? unknown

17.3%

32.9%

27.2%

22.7%

<5%5%-33%>33%-66%>66%

A7.0%

0.2%

16.3%

12.1%

64.2%

01234

C

Fibrosis stageSteatosis grade

Francque SM, et al. CGH 2012; 10: 1162-68

Noninvasive FibroScan assessment of NAFLD in

Obese or overweight patients

s0

s1

s2

s3

F0 F1

F3

F2

F4

Lobular inflammation

Case 1-Pathological findings

Gross examination

The specimen consists of a piece of pale brown

needle cored tissue, measuring 1.8 cm in length

Diagnosis

Steatohepatitis, NASH is likely

Fatty change = grade III (70%)

Inflammation = grade II

Cellular swelling = grade I

Case 1 ; NAS = 6

NAS : Liver biopsy - gold standard for diagnosis

and assess severity: Grading of NASH

For NAFLD Activity Score (NAS=0-8), combined these

criteria:

- Grading of steatosis (0-3)

- Lobular inflammation (0-3)

- Ballooning (0-2)

A score of >5 correlated with a diagnosis of NASH and

scores of <3 correlated with ‘not NASH’.

Kleiner DE, et al. Hepatology 2005; 41:1313-21.

Fibrosis was not included in NAS, as it is less reversible and

thought of as a result of disease activity

Management of NAFLD. Practice guideline by AASLD/ACG/AGA 2012

Recommendations 10. As the metabolic syndrome predicts the presence of steatohepatitis in patients with NAFLD, its presence can be used to target patients for a liver biopsy.(Strength 1 Evidence - B) 11. NAFLD Fibrosis Score is a clinically useful tool for identifying NAFLD patients with higher likelihood of having bridging fibrosis and/or cirrhosis. (Strength 1, Evidence - B) 12. Serum/plasma CK18 is a promising biomarker for identifying steatohepatitis, it is premature to recommend in routine clinical practice.(Strength 1, Evidence - B)

Chalasani N, et al. Hepatology 2012 Jun;55(6):2005-23

Markers of hepatic inflammation

Caspase-Generated CK-18 Fragments

Apoptotic process: activate the effector caspases (mainly

caspase-3), Cleave a number of different substrates inside cell

including CK-18

CK-18 : major intermediate filament protein in liver

The most potential biomarker for distinguish NASH vs.

simple steatosis*

A cutoff value of 300 microgm/L: PPV 81%, NPV 85%

Increased plasma CK-18 fragment correlated with having liver

fibrosis

Feldstein AE, et al. Hepatology 2009; 50:1072-8 Yilmaz Y, et al. World J Gastroenterol. 2009;15:4387-91. Cheung O, Sanyal AJ. Curr Opin Gastroenterol 2010;26:202-8

Accuracy of biomarkers Biomarker AUROC Cut-off Sensitivity

(%) Specificity (%)

PPV (%)

NPV (%)

LR+ LR-

NAFLDa CK-18 (U/L)

0.91 (0.87-0.95)

110 94.6 56.8 81.2 84 2.2 0.10

180 84.2 91.9 95.4 74.7 10.4 0.17

310 56.8 94.6 95.4 52.6 10.5 0.46

NASHb CK-18 (U/L)

0.70 (0.61-0.78)

203 90.0 34.4 63.7 73.3 1.4 0.29

338 66.2 65.6 71.1 60.2 1.9 0.52

670 24.4 90.6 76.9 48.3 2.6 0.83

aRepresent the performance for discriminating NAFLD from control cases. bRepresent the performance for discriminating NASH from non-NASH.

Cut-offs with sensitivity >90%, highest overall accuracy and specificity >90% are presented.

Jiayun Shen, et al. HEPATOLOGY 2012; 56: 1363-1370.

discriminating NASH from non-NASH

CASE 2

61-yr old man cryptogenic cirrhosis CPT-C

with previous history of diabetes and

obesity for 20 years

Cirrhosis was diagnosed 7 years ago by ultrasound and abnormal LFT.

- Present with jaundice, recurrent EV

bleeding and drowsiness

- Consult for liver transplantation

23/3/55 8/55 11/55 1/56 2/56

INR 1.6 1.8 1.6 1.9 1.6

Alb/Glb 2.8 2.4/3.1 2.7/4.0 2.6/3.7

TB 3.2 6 4 7 8

DB 2 4.5 3.2 5 7

SGOT 61 80 55 250 110

SGPT 54 60 50 211 89

ALP 123 152 130 155 170

BUN/Cr. 35/1.3 - - - 40/1.5

Clinical S/S EV bleeding

SBP Herbal med.

EVB

drowsiness

MELD Score = 23

Isolated fatty liver

NAFLD

NASH

NASH Cirrhosis

HCC

Decompensation

1. None to very minimal progression to cirrhosis

2. No increased risk of death

compared with the general population

~11% over 15 years,

but sig. variability

~7% over 6.5 years

~31% over 8 years

1. Increased risk of death compared

with general population. Causes of death, in order:

a. Cardiovascular, b. Malignancy, c. Liver-related

2. NASH with fibrosis portends worse prognosis

a. Fibrosis progression associated

with DM, severe IR, BMI, weight gain >5 kg, rising ALT,

AST, cigarette smoking

* >80%

Torres DM, et al. CGH 2012; 10: 837-58

ROBERT D. MAIR, et al. CLlN GASTROENTEROL HEPATO 2012; 10: 1412-1417.

Kaplan-Meier plot of cumulative HCC incidence in US patients with viral and nonviral cirrhosis (log-rank, p = .04).

HCC incidence

Frequency and Outcomes of Liver Transplantation for NASH in the United States.

Fre

qu

en

cy a

s I

nd

icati

on

(%)

CHARLTON MR, et al. GASTROENTEROL 2011; 141: 1249-1253.

5-7%

Frequency and Outcomes of Liver Transplantation for NASH in the United States.

Charlton MR, et al. GASTROENTEROL 2011; 141: 1249-1253. Watt KD, Charlton MR, et al. J Hepatol 2010 ;53(1):199-206.

Peri-operative issues for Liver transplant (LT) candidates

Martinez-Palli G, Cárdenas A. Ann Hepatol 2011 Oct-Dec;10(4):421-33.

CV Events in Patients Transplanted for NASH Versus ETOH Cirrhosis

•Follow up av. 12 months after liver transplantation (LT). •Those with HCC or coexisting liver diseases were exclude.

VanWagner LB, et al. Hepatology 2012; 56: 1741-1750.

CV Events in Patients Transplanted for NASH Versus ETOH Cirrhosis

Characteristic NASH (N=115)

ETOH (N=127

)

NASH Versus ETOH, OR* (95% CI)

P Value†

Any CV even within 1 year of Tx, no. (%) 30 (26) 10 (8) 4.12 (1.91-8.90) <0.001

Acute pulmonary edema 21 (18) 30 (16) 0.73 (0.39-1.37) 0.33

New-onset atrial fibrillation 11 (10) 10 (8) 1.26 (0.52-3.09) 0.61

Cardiac arrest 9 (8) 2 (1) 5.37 (1.13-25.39) <0.05

Acute heart failure 3 (3) 10 (8) 0.31 (0.08-1.16) 0.07

Stroke 6 (5) 7 (6) 0.95 (0.31-2.90) 0.92

Stable ventricular tachycardia 2 (2) 0 (0) 1.02 (0.99-1.04) 0.14

Supraventricular tachycardia 2 (2) 1 (1) 2.23 (0.20-24.98) 0.92

Non-ST elevation myocardial infarction 2 (2) 3 (2) 0.73 (0.12-4.47) 0.74

ST elevation myocardial infarction 1 (1) 2 (1) 0.73 (0.12-4.47) 0.74

*Adjusted for recipient age, sex, smoking status, pre-transplant diabetes, CV disease, and presence of metabolic syndrome.

VanWagner LB, et al. Hepatology 2012; 56: 1741-1750.

N=30 NASH subjects who had at least 1 cardiovascular event within the first year of LT

70% of the events occurred in the immediate periop. period

37% of these patients did not achieve maximal heart rate

40% patients with a CV event had an invasive coronary angiography performed, and 58% of those patients had no or minimal CAD.

77% of NASH patients who had a cardiac event were noted to have had a prolonged QT interval on preop-ECG

VanWagner LB, et al. Hepatology 2012; 56: 1741-1750.

ผปวยหญงไทยค อาย 58 ป ภมล าเนา กทม.

CC: เหลองมากมา 7 วน

PI: 6 เดอนกอนตรวจเลอดพบผลเลอดการท างานของตบผดปกต

แพทยใหลดน าหนก บอกวาเปนไขมนตบ

-3 เดอนกอน ไปตรวจเลอดซ า น าหนกเทาเดมแตยงมตบอกเสบมาก

ขน แพทยใหหยดยาลดไขมน Simvastatin 10 mg/day และปรบยา

เปน fenofibrtae 160 mg/day

-เหลองมากมา 7 วน

PH: -HT/DM type 2 - 10 ป, dyslipidemia 2 ป

Current medication: Metformin 2g/d, Enaril 5 mg/d, Glipizide

5 mg/d, ไมมประวตกนเหลา ยาอนๆหรอสมนไพร

PE: Weight 70 kg, Height 150 cm, BMI 31 kg/m2

No chronic liver stigmata

Case 3

26/8/55 30/11/55 22/2/56

TB 0.4 - 4

DB 0.2 - 3.2

AST 47 75 290

ALT 65 120 255

ALP 87 - 185

Alb 4.6 - 4.0

Glob 3.4 - 3.5

INR 0.9 - 0.95

30/11/55

Hct 40%

WBC 9,500

%Neu 70%

Plt 262,000

Cr. 1.1 mg/dl

Chol 270 mg/dl

Trig 248 mg/dl

HbA1C 7.0%

BARD SCORE = DM+ Obesity = 2

1st abn LFT Off simvas jaundice

Off simvas

- HBsAg: negative - Anti-HCV: negative - Ultrasound upper abdomen: increased liver echogenicity, a normal gallbladder, non-dilated intra- and extrahepatic bile ducts Imp: fatty liver

ANA : 1/1280, Homogeneous type SMA: negative ?false positive?

- Does abn. LFT associated with NAFLD? - Do we need to do Any tests/ liver biopsy?

Fenofibrate-induced severe liver injury is rare. Autoimmune mechanisms were suspected

Abn. LFT correlated with BMI, high serum levels of triglycerides, and ALP before therapy

Glucocorticoid treatment would improve LFT injury by moderating immune mechanisms.

Hajdu D, et al. J Clin Pharm Ther 2009;34(5):599-602.

Fibrate-induced chronic hepatitis

Fenofibrate withdrawal and ursodeoxycholic acid (750 mg/daily) administration was rapidly followed by favorable outcome (case report)

AST, ALT normalized within 6 weeks either spontaneously (n = 3) or under immunosuppressive treatment (n = 2)

Immunosuppression was withdrawn in 2 patients (<18 months) without relapse.

Ganne-Carrié N, et al.Gastroenterol Clin Biol 1998 May;22(5):525-9. Hajdu D, et al. J Clin Pharm Ther 2009;34(5):599-602.

Comparison of clinical S/S-LFT at presentation in patients with AIH and DIAIH

AIH Patients

(n = 237)

DIAIH

(n = 24)

P value

ANA positive (%) 70% 83% ns

SMA positive (%) 45% 50% ns

Steroids alone 14% 43% 0.0024

Trial of discontinuation successful

35% 100% <0.0001

AST <48 U/L 392 (154-1031 679 (291-956) ns

ALT<55 U/L 480 (185-1141) 728 (255-1141) ns

ALP <115U/L 241 (138-350) 376 (229-514) 0.0166

TB 2.0 (1.0-8.0) 4.0 (1.0-12.0) ns

Bjornsson E, et al. HEPATOLOGY 2010;51:2040-48

Comparison Between DILI/AIH and AIH Alone

Bjornsson E, et al. HEPATOLOGY 2010;51:2040-48

Modality Effect Comments

Pharmacotherapy

Vitamin E 800-1000 IU daily Improves NASH when used for 2 years. No fibrosis benefit.

Validation studies in diabetics and

various ethnic groups needed to

confirm benefit. May increase risk of prostate cancer.

Pioglitazone 30-45 mg daily Improves NASH when used for

6 months to 2 years. May have

a fibrosis benefit based on recent meta-analysis.

Expect a 4 kg weight gain, possible

increased risk for CHF and

osteoporosis. Not FDA approved for

NASH treatment. Limit use to those

with stage 2 fibrosis or greater who

failed an adequate challenge with diet and exercise.

Pentoxifylline Improves NASH and fibrosis. Small pilot trial data. Need

confirmation in large, multi-centered trial.

Statins Limited data on histopathology Safe in NAFLD patients. Reduces risk of cardiovascular disease.

Bariatric surgery

RYGB, LAGB, sleeve gastrectomy

Improves or resolves NASH in

60-80% of cases. Likely fibrosis benefit as well

Lack of randomized, controlled trials.

Caution in cirrhotic patients. Lifestyle modification attempted first.

Torres DM, et al. CGH 2012; 10: 837-58

Strength or resistance training

http://health.usnews.com/health-news/diet-fitness/articles/2009/04/10/10

Summary : NASH

Exclude treatable causes esp. AIH, DILI.

Control co-morbidities: DM, Dyslipidemia, HT

DM- High risk group- Aggressive anti-diabetic treatment

Resume statin if indicated for lipid lowering

Focus on identify NASH patients with Advanced Fibrosis

(F3–F4)

Lifestyle changes for everyone:

- healthy diet + exercise regularly+ resistance training

Prevent CAD and liver complications

E-mail: battan5410@gmail.com

Tel : 02-2564265

Thank you and Questions