Liver Diseases of Primary Care Practice Ray Chung, M.D.

Director of Hepatology Vice Chief, GI Division

Kevin and Polly Maroni Research Scholar Massachusetts General Hospital

Gilead Research Grant Abbvie Pharmaceuticals Research Grant Merck Research Grant BMS Research Grant Roche Research Grant Boehringer Ingelheim Research Grant

Disclosures

Liver disease an important cause of mortality

Overview

• Viral hepatitis • Nonalcoholic fatty liver disease (NAFLD) • Other liver diseases

Source of virus

feces blood/ blood-derived

body fluids

blood/ blood-derived

body fluids

blood/ blood-derived

body fluids

feces

Route of transmission

fecal-oral percutaneous permucosal

percutaneous permucosal

percutaneous permucosal

fecal-oral

Chronic infection

no yes yes yes yes, in I/C

Prevention pre/post- exposure

immunization

pre/post- exposure

immunization

blood donor screening;

risk behavior modification

pre/post- exposure

immunization; risk behavior modification

ensure safe drinking

water; immunization

Viral Hepatitis - Overview Type of Hepatitis

A B C D E

Hepatitis B Virus

• Small partially double-stranded DNA virus

• Prototype of the hepadnavirus family

• 4 major gene products

Precore mutant

CCC DNA

HBV mRNA

ER

Golgi

HBsAg

HBeAg “Dane Particle”

* Includes sexual contact with acute cases, carriers, and multiple partners. Source: CDC Sentinel Counties Study of Viral Hepatitis

Heterosexual* (41%)

MSM (9%)

Household Contact (2%) Health Care Employment (1%)

Other (1%) Unknown (31%)

Injecting Drug Use

(15%)

Risk Factors for Acute Hepatitis B United States, 1992-1993

Symptoms

HBeAg anti-HBe

Total anti-HBc

IgM anti-HBc anti-HBs HBsAg

0 4 8 12 16 20 24 28 32 36 52 100

Acute HBV Infection with Recovery Typical Serologic Course

Weeks after Exposure

Titer

Symptoms

HBeAg anti-HBe

Total anti-HBc

IgM anti-HBc anti-HBs HBsAg

0 4 8 12 16 20 24 28 32 36 52 100

Acute HBV Infection with Recovery Typical Serologic Course

Weeks after Exposure

Titer

IgM anti-HBc

Total anti-HBc

HBsAg

Acute (6 months)

HBeAg

Chronic (Years)

anti-HBe

0 4 8 12 16 20 24 28 32 36 52 Years

Progression to Chronic HBV Infection Typical Serologic Course

Weeks after Exposure

Titer

Symptomatic Infection

Chronic Infection

Age at Infection

Chr

onic

Infe

ctio

n (%

)

Sym

ptom

atic

Infe

ctio

n (%

)

Birth 1-6 months 7-12 months 1-4 years Older Children and Adults

0

20

40

60

80

100 100

80

60

40

20

0

Outcome of HBV Infection is Dependent on Age at Infection

Natural History of Chronic HBV Infection

Adapted from Feitelson, Lab Invest, 1994.

Acute Infection

Chronic Carrier

Resolution

30-50 Years

Chronic Hepatitis

Stabilization

Progression (Replicators)

Cirrhosis

Compensated Cirrhosis

Liver Cancer Death

Decompensated Cirrhosis (Death)

Normal Elevated Elevated Normal Normal Elevated ALT

- or low +

>2,000 IU/mL

>20,000 IU/mL - - +

HBV DNA (PCR)

- - - - - + IgM anti-HBc

+ + + - + + anti-HBc

+ + - - +/- - anti-HBe

- - + - - + HBeAg

- - - + + - Anti-HBs

+ + + - - + HBsAg

Inactive Carrier

Chronic* eAg(-)

(replicative)

Chronic* eAg(+)

(replicative) Vaccinated

Past Exposures (Immunity)

Acute Hepatitis B

Test

Interpretation of HBV Diagnostic Tests

*indicated for antiviral therapy

HBV DNA level predicts clinical outcome

Iloeje U, Gastro 2006;130:678-86.

Approved agents for chronic HBV • Interferon-alfa-2b • Lamivudine • Adefovir • Entecavir • Tenofovir / tenofovir alafenamide • Telbivudine • PEG-interferon-alfa-2a Other approved agents with anti-HBV activity • Emtricitabine

Lok AS, et al. Hepatology. 2007;45:507-539. Marcellin P et al NEJM 2008.

*By PCR based assay (LLD ~ 50 IU/mL).

67

25

Pat

ient

s W

ith U

ndet

ecta

ble

H

BV

DN

A (%

)

0-16

Not head-to-head trials

76

Virologic Response in HBeAg+ Patients (Undetectable HBV DNA at Wk 48-52)

100

80

60

40

20

0 ETV TDF Peg-

IFN PLB

HBsAg loss During Therapy HBeAg positive CHB at 1 Year

Chang et al New Engl J Med 2006;354:1001; Lai et al New Engl J Med 2007;357:2576; Heathcote Hepatology 2007;46:LB6; Lau New Engl J Med 2005;352:2682;

Chart1

No Rx

ETV

TDF

Peg IFN

Column3

Percent HBsAg Loss

1.8

2

3.2

3

Sheet1

Column3Column2Column1

No Rx1.82.42

ETV24.42

TDF3.21.83

Peg IFN32.85

To update the chart, enter data into this table. The data is automatically saved in the chart.

Rates of Genotypic Resistance FDA approved nucs

24

4 0 0 0

38

22

3 0 0

49

111

71

18

1

65

29

10

1020304050607080

Lamivudine Telbivudine Adefovir Tenofovir Entecavir

Year 1 Year 2 Year 3 Year 4 Year 5

Perc

ent

0%

10%

20%

30%

40%

50%

Any Endpoint CTP increase HCC

% w

ith S

tudy

End

poin

t

Placebo (n = 215) Lamivudine (n = 436)

9%

18%

8% 3%

Antiviral therapy prevents clinical outcomes in cirrhotic HBV

≥2 point CTP elevation, HCC, SBP, renal insufficiency, bleeding varices

Study terminated early after 72 endpoints

Median time to event 32 months

Liaw Y-F et al. N Engl J Med 2004; 351:1521

P=0.001

P=0.023

4% 7% P=0.047

HCC screening for HBV Who? • HBsAg carriers: Asian men >40, women >50 • HBV cirrhosis • All HBsAg+ over 40yo with HBV DNA >2000 IU/mL • 1st generation Africans >20yo • Family History of HCC How? • Semiannual US +/- AFP

HBV immunization • Confers protective immunity • Universally offered at birth • HBV vaccines – 3 doses over 6M

– Engerix – Recombivax – Twinrix (with HAV)

• Heplisav-B approved 2018 – Adjuvanted with TLR9 agonist – 2 dose schedule (0, 4 weeks) – Higher protection in those with DM, CKD

HBV Reactivation with I/S, Chemo: Suggested approach

Test Significance Action HBsAg HBV infection Prophylaxis indicated (ETV, TDF) Anti-HBs alone Immunity to HBV None Anti-HBc ± anti-HBs

Exposure to HBV **low risk for standard chemotherapy, monitor If rituximab and/or combined

regimens for hematological malignancies or BMT or cirrhotic, prophylaxis indicated

**If observation is chosen, monitor liver tests, HBsAg and HBV DNA q1-3 months

HBV Management: Summary • HBsAg identifies chronically infected persons • Screen patients from endemic areas, MSMs, pregnant women,

HD, pts undergoing Rx with chemotherapy, steroids rituximab, biologics

• HBV DNA levels have prognostic value • Treat replicative, active HBV (eAg+ or eAg-)

– Entecavir, Tenofovir 1st line monotherapy agents • Must be monitored! • Vaccine preventable • Screen for HCC • We need curative strategies directed against other viral lifecycle

steps

C p7 NS2 NS3 NS4B NS5B NS4A E1 E2 Core Envelope Glycoproteins Protease Serine Helicase Protease

Serine Protease Cofactor

RNA-dependent RNA polymerase

NS3-4A protease inhibitors

NS5B polymerase inhibitors

nucleoside inhibitors

non-nucleoside inhibitors

NS5A

Hepatitis C Virus Polyprotein

McGovern B, Abu Dayyeh B, and Chung RT. Hepatology. 2008; 48:1700-12

Needed for Replication Assembly

NS5A

inhibitors

HCV life cycle

Moradpour, Nat Rev Microbiol 2007;5:453

HCV Genotypes and Subtypes

1

6 3

4

5

2

Simmonds P, Journal of Hepatology, 1999

Americas + Western Europe Developed countries

South Africa

Middle East North Africa

Asia IDU

U.S. 1 75% (45%SVR) 2,3 25% (80%SVR)

Sources of Infection for Persons With Acute Hepatitis C in 6 Months Prior to Illness

Onset, 1994-2006

Sexual 20%

Occupational 3%

None reported 8%

Injecting drug use 65%

Household 1%

Williams IT, et al. Arch Intern Med. 2011;171:242-248

CDC data. Armstrong GL et al. Ann Intern Med 2006;144:705-14 Denniston MM et al, Ann Intern Med 2014; 160:293-300

In general, the HCV cohort has aged…

NHANES 2003-10: 2.7M chronically infected

…but there has been a youthful spike

Onofrey et al. MMWR May 6, 2011 / 60(17);537-541

Serologic Pattern of Acute HCV Infection with Progression to Chronic Infection

Normal

HCV RNA

Symptoms +/-

1 2 3 4 5 6 1 2 3 4 0 Months Years

Tite

r

Time after Exposure

ALT

anti-HCV

Adapted from MMWR 1998; 47(No. RR19)

Natural History of HCV Infection Exposure

(Acute phase)

Resolved Chronic

Cirrhosis Stable or variably progressive

Slowly Progressive

HCC Transplant

Death

20%

20% 80%

25%

80%

75%

EtOH HIV

25 yrs 20 yrs

Histologic Progression of HCV

Normal Mild Chronic Hepatitis (F1)

Moderate Chronic Hepatitis (F3) Cirrhosis (F4)

New Tools: Liver Stiffness by Transient Elastography

Ultrasound-based technique Determines liver “stiffness” Correlates well with fibrosis No ceiling, ie, increases with worsening cirrhosis → predicts complications (eg, varices) Simple to use – minimal training

Liver Stiffness by Transient Elastography (Fibroscan)

Vergera. CID. 2007.

Very good for minimal fibrosis (F0-2) vs cirrhosis (F4)

2.0

1.8

1.6

1.4

1.2

1.0

0.8

0.6

0.4

100

63

40

25

16

10

6.3

4.0

2.5

P < 0.001 Lo

garit

hm o

f Tra

nsie

nt E

last

omet

ry

Mea

sure

men

t (lo

g kP

a)

Tran

sien

t Ela

stom

etry

Mea

sure

men

t (kP

a)

0 1 2 3 4

n = 15 n = 49 n = 26 n = 14 n = 65

Fibrosis Stage

Good news: SVR Reduces All-Cause and Liver-Related Mortality 530 pts with F4-6, IFN-based Rx, median

F/U 8.4Y

van der Meer A, JAMA, 2013

C p7 NS2 NS3 NS4B NS5B NS4A E1 E2 Core Envelope Glycoproteins Protease Serine Helicase Protease

Serine Protease Cofactor

RNA-dependent RNA polymerase

NS3-4A protease inhibitors

NS5B polymerase inhibitors

nucleoside inhibitors

non-nucleoside inhibitors

NS5A

Targets for Direct Acting Antivirals (DAA)

McGovern B, Abu Dayyeh B, and Chung RT. Hepatology. 2008; 48:1700-12

Needed for Replication Assembly

NS5A

inhibitors

ION-1: Sofosbuvir + Ledipasvir (NS5A Inhibitor) Genotype 1: Treatment Naïve, n=865

Cirrhosis in 16% n=468

12 weeks 24 weeks

SVR12 (%)

209/214 211/217 212/217 215/217

99 97

Afdhal N et al, N Engl J Med 2014;370:1889

98 99

Chart1

SOF/LDV

SOF/LDV+RBV

SOF/LDV

SOF/LDV+RBV

Series 1

99

97

98

99

Sheet1

Series 1Series 2Series 3

SOF/LDV992.42

SOF/LDV+RBV974.42

SOF/LDV981.83

SOF/LDV+RBV992.85

To resize chart data range, drag lower right corner of range.

A Pangenotypic regimen: SOF + Velpatasvir (NS5A) x 12 wks

Feld J et al, NEJM 2015;373:2599

*pangenotypic, high-potency

Glecaprevir (PI*) + Pibrentasvir (NS5A*) in Rx-Naïve Pts with GT3: Noncirrhotic (8 wks) and Cirrhotic (12 wks)

Muir AJ, et al (“SURVEYOR-II”). J Hepatol 2016;64(Suppl 2):S186. EASL 2016 Abstract PS098.

% w

ith S

VR12

Noncirrhotic 8 wks

28/28

Kwo P, et al (“SURVEYOR-II, part 2”). J Hepatol 2016;64(Suppl 2):S208. EASL 2016 Abstract LB01.

Cirrhotic 12 wks

24/24

Chart1

1

Series 1

Sheet1

Series 1

100%

Chart1

1

Series 1

Sheet1

Series 1

100%

www.hcvguidelines.org

You can’t treat them if you can’t find them!

• CDC recommendations (1998) — Ever injected illegal drugs — Received clotting factors made before

1987 — Received blood/organs before

July 1992 — Ever on chronic hemodialysis — Evidence of liver disease (elevated ALT) — Infants born to HCV infected mothers — HIV infection

MMWR 1998;47 (No. RR-19)

• CDC recommendations (1998) — Ever injected illegal drugs — Received clotting factors made before

1987 — Received blood/organs before

July 1992 — Ever on chronic hemodialysis — Evidence of liver disease (elevated ALT) — Infants born to HCV infected mothers — HIV infection

• CDC (2012) –Born between 1945-64 (80% of adults with

HCV) –Single time screening –Expected to identify up to 1M new cases of

prevalent HCV

Ly et al, Ann Intern Med 2012

You can’t treat them if you can’t find them!

HCC screening for HCV Who? Patients with F3-4 disease

– Continue screening after cure of HCV

How? Semiannual US +/- AFP

HCV: Summary Minimally symptomatic acute infection but high chronicity HCV RNA distinguishes chronic from cleared infection All HCV RNA+ should be treated All oral, tolerable, high efficacy regimens (>95% cure) now

available for all genotypes High cure rates now possible in historically difficult populations

(cirrhotics, decompensated, post-LT, HIV) Not yet vaccine preventable Screen all born between 1945-65 and those with RFs Can be noninvasively staged (serum tests, elastography) Advanced fibrosis (F3-4) should be screened for HCC with

semiannual US +/- AFP – HCC screening should be continued even after HCV cure

Steatosis Steatohepatitis

Cirrhosis

Nonalcoholic Fatty liver Disease

Demographics of NAFLD Most common chronic liver disease in US 3rd most common indication for liver transplant

– Projected to be the most common in 10 years

Affects up to 30% of adults NASH

– 3% of adults

– 15-20% of obese adults

– 25-70% of those undergoing bariatric surgery

• Recent evidence in NASH underscores prognostic significance of fibrosis but not other histologic features

Progression of NAFLD

10-30%

Modified from Schuppan et al. JGH 2013

Risk factors: Established association

Obesity Type 2 DM: insulin resistance (IR) Dyslipidemia Metabolic syndrome (MS)

Risk factors: Emerging associations

Polycystic ovary syndrome Hypothyroidism Obstructive sleep apnea Hypopituitarism Hypogonadism

Medications that can produce fatty liver

Amiodarone Methotrexate Tamoxifen Corticosteroids Diltiazem Valproic acid Highly active antiretroviral therapy (PIs)

Screening Recommendations AASLD Guidelines

Who? – abnormal LFTs – existing risk factors

Imaging – Ultrasound – CT – MRI

Staging – NAFLD fibrosis score – Fibroscan (CAP) – MR elastography

NAFLD fibrosis score

http://nafldscore.com

Age

BMI

Hyperglycemia

Platelet count

Albumin

AST

ALT

< -1.455: absence of significant fibrosis (F0-F2) ≤ -1.455 to ≤ 0.675: indeterminate > 0.675: presence of significant fibrosis (F3-F4)

Liver biopsy

Should be prompted by abnormal findings on noninvasive markers

Presence of metabolic syndrome, T2DM, BMI>35 or persistently elevated biochemistries may benefit from liver biopsy

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

Lifestyle Interventions Weight loss by lower caloric intake and increased

physical exercise – 10% weight loss 30% improvement in steatosis and

improvements in necrosis and inflammation, not fibrosis

Alcohol consumption – heavy intake should be avoided – light intake (

AASLD recommendations for treatment

Pioglitazone 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 established (issue: wt gain)

Vitamin E 800 IU/day improves liver histology in NASH pts

– Not recommended in those with other chronic liver diseases, diabetics, NASH cirrhosis, NAFLD without biopsy

– Slight increased RR for prostate CA, hemorrhagic CVA

Ongoing trials

– Many compounds, including obeticholic acid (FXR agonist), cenicriviroc (CCR2/5 antagonist), elafibrinor (PPARα/δ agonist)

NAFLD: Summary Remarkably common condition

Subset will produce progressive liver disease

Challenge remains to identify at-risk population

Screen for NAFLD in high risk pts, those with abnormal LFTs

Low threshold for liver biopsy to identify those with fibrosis

Management: lifestyle changes difficult, other therapies less than optimal

Reciprocal risk for CVD

Ongoing trials

HCC screen: F2-4, diabetes

Other Liver Diseases for the PCP Alcoholic liver disease

– Abnormal LFTs (AST > ALT), steatosis on routine US, hepatomegaly – Steatosis alcoholic hepatitis cirrhosis

Hemochromatosis – Most common Mendelian monogenic disorder – Associated with diabetes, hyperpigmentation, arthropathy, cardiomyopathy – Check Fe/TIBC/ferritin – TS >45%, ferritin > 300 should prompt HFE testing, referral for evaluation

(liver biopsy) – Phlebotomy can prevent end organ complications

Other liver diseases Primary biliary cholangitis (PBC)

– Autoimmune destruction of small intrahepatic bile ducts – Isolated abnormal alkaline phosphatase in a middle aged woman – AMA+ in 95% of patients – Can be treated with ursodiol

Primary sclerosing cholangitis (PSC) – Autoimmune destruction of larger intrahepatic and/or extrahepatic BD – Predominantly AP elevations in younger men – Associated with UC/Crohn’s in 70% of cases – Dx: MRCP/ERCP

Other liver diseases Autoimmune hepatitis

– Abnormal LFTs in a woman – Predominantly hepatocellular in nature, can be rapidly progressive – Exquisitely responsive to steroids +/- azathioprine – +ANA, ASMA, elevated IgG

Wilson’s disease – Rare AR disorder of excessive copper accumulation – Abnormal LFTs in a young person, low ceruloplasmin – Can be accompanied by hemolytic anemia, neuropsych Sx

Alpha-1-antitrypsin deficiency – Rare disorder producing progressive liver and/or lung disease – Low A1AT levels, abnormal A1AT phenotype

Other liver diseases Drug induced liver injury

– Always take a comprehensive medication, herbal, complementary, recreational drug history

– Hepatocellular (acetaminophen) – Cholestatic (many classes, including antibiotics, hormones,

psychotropics) – Autoimmune (minocycline, nitrofurantoin) – Trial of withdrawal warranted

Summary Key Points: Liver disease is a major cause of morbidity and mortality in the

population

There are major developments in the management of liver disease that make diagnosis of these conditions essential

Next Best Steps: GI/Hepatology consultation should be considered when chronic

liver disease is uncovered

Liver Diseases of Primary Care PracticeSlide Number 2Slide Number 3Overview Slide Number 6Slide Number 7Slide Number 8Slide Number 9Slide Number 10Slide Number 11Slide Number 12Natural History of Chronic HBV InfectionInterpretation of HBV Diagnostic TestsHBV DNA level predicts clinical outcomeApproved agents for chronic HBVVirologic Response in HBeAg+ Patients (Undetectable HBV DNA at Wk 48-52)HBsAg loss During Therapy HBeAg positive CHB at 1 YearRates of Genotypic Resistance�FDA approved nucsAntiviral therapy prevents clinical outcomes in cirrhotic HBVHCC screening for HBVHBV immunizationHBV Reactivation with I/S, Chemo: Suggested approachHBV Management: SummarySlide Number 25HCV life cycleHCV Genotypes and SubtypesSources of Infection for Persons With Acute Hepatitis C in 6 Months Prior to Illness Onset, 1994-2006Slide Number 29…but there has been a youthful spikeSerologic Pattern of Acute HCV Infection with Progression to Chronic InfectionNatural History of HCV InfectionHistologic Progression of HCVNew Tools:�Liver Stiffness by Transient Elastography �Liver Stiffness by Transient Elastography (Fibroscan) Good news: SVR Reduces All-Cause and Liver-Related Mortality�530 pts with F4-6, IFN-based Rx, median F/U 8.4Y Slide Number 37ION-1: Sofosbuvir + Ledipasvir (NS5A Inhibitor)�Genotype 1: Treatment Naïve, n=865�Cirrhosis in 16%�n=468Slide Number 39Glecaprevir (PI*) + Pibrentasvir (NS5A*) in Rx-Naïve Pts with GT3:�Noncirrhotic (8 wks) and Cirrhotic (12 wks)www.hcvguidelines.orgYou can’t treat them if you can’t find them!Slide Number 43HCC screening for HCVHCV: SummarySlide Number 46Demographics of NAFLDProgression of NAFLDRisk factors: Established associationRisk factors: Emerging associationsMedications that can produce fatty liverScreening Recommendations�AASLD GuidelinesNAFLD fibrosis scoreLiver biopsy�Lifestyle InterventionsAASLD recommendations for treatmentNAFLD: SummaryOther Liver Diseases for the PCPOther liver diseasesOther liver diseasesOther liver diseasesSummary