online evaluation · 2016) • new acute hcv infection in 2016 – reported cases (n=2967) –...

Online Evaluation

To get your online CME Certificate,

please use the following URL to complete

the evaluation form:

https://chronicliverdisease.org/SHM19-EVAL

2

This program is supported

by educational grants from

Mallinckrodt Pharmaceuticals

and Salix Pharmaceuticals

Disclosures

All faculty and staff involved in the planning or presentation of continuing

education activities provided by Rehoboth McKinley Christian Health Care

Services are required to disclose to the audience any real or apparent commercial

financial affiliations related to the content of the presentation or enduring material.

Full disclosure of all commercial relationships must be made in writing to the

audience prior to the activity. The following disclosures were made:

Planning Committee Member

Lisa D. Pedicone, PhD – No Relevant Relationships

Faculty

All faculty disclosures can be found in your meeting guide.

5

Welcome and Introduction

Robert Brown, Jr., MD, MPH

Pre-Test Questions

Breaking News in Chronic Liver Disease

Kimberly Brown, MD, FAST,

FAASLD, AGAF

Acute Hepatitis C on the Rise

CDC (2013-2016): Estimated HCV Prevalence Among Adults in the United States

• HCV antibody positive (including past

and current infection)

– Number: 4.1 million (95% CI 3.4-4.9)

– Prevalence: 1.7% (95% CI 1.4-2.0)

• HCV RNA positive

(including current infection)

– Number: 2.4 million (95% CI 2.0-2.8)

– Prevalence: 1.0% (95% CI 0.8-1.1) 0

1

2

3

4

5

Nu

mb

er

(in

mil

lio

ns)

73%

3.5

Number (in millions) With HCV Infection

NHANES NHANES adjusted

HCV Ab Positive

HCV RNA Positive

HCV Ab Positive

HCV RNA Positive

2003-2010 2013-2016

2.7

57%

2.4

2.1

Estimated adult US population in 12/2016: 245 million.

Datasets analyzed: National Health and Nutrition Examination Survey (noninstitutionalized civilian population).

Combination of literature reviews and population size estimation approaches (incarcerated people, unsheltered homeless people, active-duty

military personnel, and nursing home residents).

Hofmeister MG, et al. Hepatology. 2018;Nov 6. [Epub ahead of print]. 10

Changing Trends in Acute HCV in the US (2001-2016)

• New acute HCV infection in 2016

– Reported cases (n=2967)

– Estimated (n=41,200, adjusted for under-

ascertainment and under-reporting)

• 3.5-fold increase in new cases since 2010

– Reflects new infections associated with

rising rates of injection-drug use

• Most newly acquired acute HCV infections

occurred among young, white, PWIDs,

who live in non-urban areas (i.e.,

Appalachian, Midwestern, and New

England states)

Acute HCV Rate in US 2001-2016

CDC. Surveillance for viral hepatitis - United States, 2016. https://www.cdc.gov/hepatitis/statistics/2016surveillance/index.htm 11

0

0.5

1

1.5

2

2.5

3

2001 2004 2007 2010 2013 2016

Rate

(p

er

100,0

00 p

op

ula

tio

n)

Year

0-19 yrs

20-29 yrs

30-39 yrs

40-49 yrs

50-59 yrs

> 60 yrs

Populations at Risk

1960s Up to 300,000 cases

of acute HCV per year; risk of

exposure via blood

transfusion up to 33%

30-70% prevalence

Baby Boomers (born 1945-1965) People Who Inject

Drugs (PWID)

1992 Widespread

introduction

of HCV antibody

testing

1970s Volunteer donor system

reduces risk of exposure

via blood transfusion

1989 HCV

discovered

Alter HJ. Nat Med. 2000;6:1082-1086. 12

CDC report identified >220

counties vulnerable to outbreaks of

HIV and HCV among people who

inject drugs

Risk Factors – Unemployment rates

– Overdose deaths

– Prescription opioid sales

Counties Vulnerable to Outbreaks of HIV and Hepatitis C

Geographic Areas Most at Risk for HCV

Van Handel MM. J Acquir Immune Defic Syndr. 2016;73:323. 13

WHO Goal:

Global Elimination of Viral Hepatitis

Global Health Sector Strategy:

Eliminate Viral Hepatitis as a Major Public Health Threat by 2030

30%

Reduction

90%

Reduction

NEW INFECTIONS

DEATHSHEPATITIS B + C HEPATITIS B + C

2015 2020 2025 2030 2015 2020 2025 2030

10 million

9 million

8 million

7 million

6 million

5 million

4 million

3 million

2 million

1 million

0 million

10%

Reduction 65%

Reduction

2 million

1,8 million

1,6 million

1,4 million

1,2 million

1 million

0,8 million

0,6 million

0,4 million

0,2 million

0 million

Reduction in new infections by 90% Reduction in deaths by 65%

Programmatic Targets

90% of people

infected are

diagnosed

80% of people

diagnosed are

treated

90% coverage of BD

and B3 doses

(PAHO: 95%)

100% of blood

products are safe

90% of injections in

health facilities

are safe

Impact Targets

15

HCV No Longer a Disease Limited to Baby Boomers H

CV

Cases (

nu

mb

er)

2005

0

50

100

150

200

250

300

350

400Male

Female

20 30 0 10 60 70 40 50 80 90

Age (years)

2012

0

50

100

150

200Male

Female

20 30 0 10 60 70 40 50 80 90

Age (years)

2015

0

50

100

150

200Male

Female

20 30 0 10 60 70 40 50 80 90

Age (years)

Data for New York State (excluding NYC).

https://www.health.ny.gov/statistics/diseases/communicable/index.htm. 16

https://www.health.ny.gov/statistics/diseases/communicable/index.htm

Effectiveness of HCV Screening in the US (2010-2016)

• In the US, to meet the 2030 diagnosis

targets, this means diagnosing at least

– 110,000 cases/year until 2020

– 89,000 cases/year between 2020-2024

– >70,000 cases/year between 2025-

2030

• At the current screening rate, 92% of

US states are not on target to meet

WHO screening goals of HCV

elimination by 2030

Timeline to Achieve WHO Screening Target for HCV Elimination

Reach WHO Target by: 2030 2040 2050 Beyond 2050

Claims data for HCV Ab screening from a single large commercial payer (CPT and ICD-9 codes):

Screened (n=1,056,583); not screened (n=1,243,581).

Factors that increased the odds of getting screened: female gender, Medicare, presence of comorbidities.

Mehta D, et al. J Hepatol. 2018;68(suppl S1):S177. Abstract THU-113. 17

Negative

Positive

Test for

Quantitative HCV RNA

Refer to specialist for Disease

Staging and Management Plan

Positive

Negative Retest in

6 months

STOP

Genotyping testing

also recommended

Screening Test for Anti-HCV

HCV Screening Is Straightforward: Algorithm for Screening/Diagnosis

Modified from http://www.cdc.gov/hepatitis/HCV/PDFs/hcv_flow.pdf.

Ghany MG, et al. Hepatology. 2011;54(4):1433-1444. 18

HCV Continuum of Care Among PWIDs: Philadelphia Department of Health

• Random sample of newly reported

HCV antibody positive persons

(n=29,820; 2013-2017)

– Interviewed and disclosed being a

PWID (n=2390)

• Measurable gaps exist in the HCV

continuum of care for PWIDs,

especially those ≤35 years of age

– Among those HCV RNA positive

• Only 29% and 10% of PWIDs >35

and ≤35 years of age, respectively,

were treated

• Need for enhanced navigation

to services

0

20

40

60

80

100

Pati

en

ts (

%)

81% 85%

90%

75%

HCV Continuum of Care Among

HCV Ab-Positive PWIDs

Years of age

>35 (n=1151)

≤35 (n=1239)

Ever Tests for HCV RNA

HCV RNA Positive

Initiated HCV Care

Treated

66%

25%

41%

8%

Addish E, et al. Hepatology. 2018;68:929A-930A. Abstract 1632. 19

Important New Treatment for

Primary Biliary Cholangitis

PBC is characterized by destruction of the interlobular and septal bile ducts

that may lead to cirrhosis

Immune

response

Bile duct

damage

Environment

Genetics

Primary Biliary Cholangitis (PBC) Is a Chronic, Progressive Autoimmune Disease

• Factors possibly associated with onset

and perpetuation of bile-duct injury in PBC

Poupon R. J Hepatol. 2010;52(5):745-758; Selmi C, et al. Lancet. 2011;377(9777):1600-1609;

Carey EJ, et al. Lancet. 2015;386(10003):1565-1575. 21

Farnesoid X Receptor Signaling

Bile Acids

(Primary ligands

for FXR)

↓ Bile Acid

Synthesis

and

Uptake

↑ Gene

Expression (BSEP, MDR3, MRP

2/3/4, OST α/β)

↓ Gene

Expression (CYP7A1, NTCP,

OATP)

FXR

(Hepatocytes, biliary

epithelium, small

bowel enterocytes,

renal tubular cells,

adrenal cells,

adipocytes, beta

cells)

Binding

Direct

Effects

Indirect

Effects

↑ Bile Acid

Efflux

Abbreviations: BSEP, bile salt export pump; FXR, farnesoid X receptor; MRP 2/3/4, multidrug resistant protein 2/3/4;

NTCP, sodium/taurocholate cotransporting polypeptide; OATP, organic anion transporting polypeptide; OST α/β, organic soluble transporter α/β.

Neuschwander-Tetri BA. Curr Gastroenterol Rep. 2012;14:55-62. 22

Obeticholic Acid (OCA): Approved FXR Agonist for PBC

• PBC: OCA is associated with statistically significant, clinically

meaningful improvements

– Biochemical criteria correlated with clinical benefit (alkaline

phosphatase and bilirubin)

– Markers of inflammation (C-reactive protein) and apoptosis (CK18)

• Nonalcoholic steatohepatitis (NASH): Phase 3 topline results

released February 19th

– OCA showed statistically significant improvement in liver fibrosis without

worsening of NASH at 18 months

– Very active research area; however, OCA is expected to be the first FDA

approved drug for NASH 23

New Treatments Allow for Improved

Procedure Safety in Patients with Cirrhosis

Relative Bleeding Risk Associated with Common Medical

Procedures Performed in Patients with Chronic Liver Disease

• Thoracentesis

• Paracentesis

• Endoscopy

• Upper GI endoscopy

– ± biopsy

– ± variceal banding ±

sclerotherapy

• Colonoscopy ± polypectomy

biopsy

Low

• Liver biopsy

• Bronchoscopy ± biopsy

• Ethanol ablation

• Chemoembolization for HCC

Medium

• Biliary interventions

• Dental procedures

• Transjugular intrahepatic

portosystemic shunt

• Laparoscopic interventions

• Nephrostomy tube placement

• Radiofrequency ablation

• Renal biopsy

• Vascular catheterization

High

Terrault N, et al. Hepatology. 2017;66(suppl S1):124A-125A. Abstract 217. 25

Current Landscape in Patients with Thrombocytopenia and CLD

• Patients require 1-3 procedures annually

• Different procedures are associated with different risks of bleeding

– Procedures are required to clinically manage patients with CLD

– Thrombocytopenia can lead to serious uncontrolled bleeding in these

patients negatively impacting clinical care

• Prolonged hospitalizations

• Serious complications

• Poor clinical outcomes

Szczepiorkowski ZM and Dunbar NM. Hematology Am Soc Hematol Educ Program. 2013;2013:638-44;

Lin Y and Foltz LM. BCMJ. 2005;47(5):245-248. 26

Guideline Recommendations for Appropriate Platelet Levels Based on Procedure

Guideline Year Transfusion Recommendations and Cited Evidence

American Association of

Study of Liver Diseases (AASLD)

2009

• Platelet transfusion should be considered when levels are

less than 50-60x109/L (this applies whether one is attempting

liver biopsy transcutaneously or transvenously)

American Society of

Gastrointestinal

Endoscopy

(ASGE)

[Gastroenterologist]

2012 • Platelet threshold 20x109/L for diagnostic endoscopy;

50x109/L if biopsies performed

Rockey et al. Hepatology. 2009;49(3):1017-1044; Ben-Menachem et al. Gastrointest Endosc. 2012. 27

Guideline Recommendations

Guideline Year Transfusion Recommendations and Cited Evidence Grade/Level of Evidence

American Association of

Blood Bankers (AABB)

United States

[Transfusion

Medicine/Blood Bankers]

2015

• Prophylactic platelet transfusion for elective diagnostic lumbar puncture

with PC<50x109 cells/L

• Prophylactic platelet transfusion for major elective nonneuraxial surgery

with PC<50x109 cells/L

• Weak recommendation;

very-low-quality evidence

American Society of

Hematology

[Hematologist/

Transfusion Medicine]

2013 • Patients who are bleeding or have scheduled an invasive procedure within

the next 4 hours can be transfused for platelet count <50,000/mL7

• Not graded, but based on

1991 cancer publication

American Society of

Clinical Oncology

[Oncologists/Hem/Oncs]

2001

• Platelet count of 40,000/μL to 50,000/μL is sufficient to perform major

invasive procedures with safety, in the absence of associated coagulation

abnormalities

• Not provided

Kaufman et al. Ann Intern Med. 2015;162(3):205-13;

Szczepiorkowski ZM and Dunbar NM. Hematology Am Soc Hematol Educ Program. 2013;638-644; Weiss et al. Chest. 1993;104:1025-1028. 28

Treatment Options for Severe Thrombocytopenia in Chronic Liver Disease

• Standard

– Platelet transfusions

– Splenic artery embolization

– Splenectomy

– Transjugular intrahepatic portosystemic shunts

• Thrombopoietin Receptor Agonists

– FDA-approved in 2018: avatrombopag and lusutrombopag

– Oral medications 29

22.9%

65.6%

38.2%

88.1%

0%

20%

40%

60%

80%

100%

p<0.0001

p<0.0001

Avatrombopag P

ati

en

ts (

%)

No platelet transfusion

Or rescue therapy

4.2%

68.9%

20.6%

88.1%

0%

20%

40%

60%

80%

100%

p<0.0001 p<0.0001

Platelet count >50K

Day of procedure

30

Lusutrombopag

29

64.8

0

10

20

30

40

50

60

70

No platelet transfusions or rescue therapy (%)

Placebo Lusu

p<0.0001

13

64.8

0

10

20

30

40

50

60

70

Platelet > 50K and increased > 20K (%)

Placebo Lusu

p<0.0001

31

Patients

%

Key Points

• New HCV infections in people who inject illicit drugs is rising

especially in young adults

• If we are to eliminate HCV here in the US, it requires improved

testing and linkage to care

• Obeticholic acid currently available for PBC but may also be used

for NASH in near future

• Thrombopoietin receptor agonists are a new class for

thrombocytopenia in cirrhotic patients allowing for improved safety in

patients undergoing procedures

32

Diagnosing and Managing

Cirrhosis and Complications

Steven Flamm, MD, FAASLD, FACG

Cirrhosis Is the Final Pathway for Most Chronic Liver Diseases

Hepatocellular carcinoma

Liver transplantation

Decompensation/

liver failure

Accumulation of collagen

deposition= fibrosis → cirrhosis

Histology image obtained from http://en.wikipedia.org/wiki/Cirrhosis. Accessed March 26, 2018.

Ge PS, Runyon BA. N Engl J Med. 2016;375:767-777. 34

http://en.wikipedia.org/wiki/Cirrhosis. Accessed January 2014

Compensated Cirrhosis May Be Difficult to Recognize

• Most patients remain asymptomatic until decompensation occurs

• Clues may be overlooked

– Thrombocytopenia

– Muscle wasting

– AST>ALT without alcohol consumption

– Liver enzymes are frequently normal

• Etiology may be remoted or subtle

– Prior alcohol use

– Uncontrolled diabetes mellitus and obesity

Tsochatzis EA et al. Lancet. 2014;383:1749-1761; Heidelbaugh JJ, Bruderly M. Am Fam Phys. 2006;74:756-762. 35

Thrombocytopenia in Cirrhosis

• Be suspicious when platelet count

<100,000 x 109/L

• Decreased hepatic production of

thrombopoietin is a critical factor

in the development of

thrombocytopenia in cirrhosis

• Prevalence and severity of

thrombocytopenia correlate with

and parallel the severity of

underlying liver disease,

particularly, the extent of fibrosis

Decreased c-mpl binding

Megakaryocytes

Splenic Sequestration

Reduced Platelet Production

Thrombocytopenia

Increased Thrombopoietin

Binding and Internalization

Cirrhosis

Decreased Thrombopoietin

Levels

Varghese LN, et al. Front Endocrinol. 2017;8:59; Peck-Radosavljevic M. Liver Int. 2016;37:778-793; Mitchell O, et al. Hepat Med. 2016;8:39-50. 36

Survival Is Significantly Longer in Compensated Cirrhosis Compared with Decompensated Cirrhosis

Compensated cirrhosis

n=806

Decompensated cirrhosis

n=843months

A

1.00

0.75

0.50

0.25

0.00

0 12 24 36 48 60 72 84 96 108 120

Pts at risk

806843

600288

450133

33555

27526

24813

B

Survival According to Decompensation At Diagnosis

>12 year

median survival in patients with

compensated cirrhosis

D’Amico G et al. J Hepatol. 2006;44:217-231. 37

Points

1 2 3

Encephalopathy None Precipitant Recurrent

Ascites None Controlled Refractory

PT (sec prolonged)

or INR

<4

<1.7

4-6

1.7-2.3

>6

>2.3

Bilirubin <2 2-3 >3

Albumin >3.5 3.0-3.5 <3.0

Child-Pugh Score: A Prognostic Score in Cirrhosis

Child A: 5-6 pts

Compensated

Child B: 7-9 pts

Start transplant evaluation

Child C: 10-15 pts

38

Classification of Cirrhosis Severity Model for End Stage Liver Disease Score

• Calculated from 3 variables:

– International normalized ratio (INR; calculated from prothrombin time)

– Bilirubin

– Serum creatinine

• The MELD score equation:

– [9.57 x log creatinine mg/dL + 3.78 x log bilirubin mg/dL + 11.20 x log

INR + 6.43 (constant for liver disease etiology)]

• Eliminates subjectivity of encephalopathy and ascites evaluation

used in Child Pugh Score

Murray KF, Carithers RL. Hepatology. 2005;41:1-26; Wiesner R et al. Gastroenterology. 2003;124:91-96. 39

3 Month Mortality Risk Based on MELD Score

2.9 7.7

23.5

60

81

0

10

20

30

40

50

60

70

80

90

<9 10 to 19 20 to 29 30 to 39 >40

% M

ort

ality

n=124 n=1800 n=1038 n=295 N=126

MELD Score Murray KF, Carithers RL. Hepatology. 2005;41:1-26; Wiesner R et al. Gastroenterology. 2003;124:91-96. 40

Liver insufficiency

Variceal hemorrhage

Ascites Hydrothorax

Encephalopathy

Portal hypertension Spontaneous bacterial

peritonitis

Hepatorenal syndrome

“Coagulopathy”

Jaundice

Hypoalbuminemia

Portopulmonary hypertension

Hepatopulmonary syndrome

Complications of Cirrhosis: Decompensated Cirrhosis

Cirrhosis

30-40% of cirrhotic patients

Amodio P et al. J Hepatol. 2001;35:37-45 41

Varices

Esophageal Varices

Small

Large

43

Management of Acute Hemorrhage

• Patients with suspected acute variceal hemorrhage require intensive-care unit setting

for resuscitation and management

• Acute GI hemorrhage requires:

– Intravascular volume support

– Blood transfusions

– Maintaining hemoglobin of ~7 g/dL

• Institute short-term (7-day) antibiotic prophylaxis

– Ceftriaxone 1 gm/d is preferred

• Initiate therapy with octreotide (or its analogs) (2-5 days)

• Perform EGD within 12 hours; treat with endoscopic band ligation

• Rescue therapy: Emergent TIPS, balloon tamponade, esophageal stent placement

Garcia-Tsao et al. Hepatol. 2017. 44

Bacterial Infection and Variceal Bleeding

• Increased risk of bacterial infection

– SBP or bacteremia without obvious source

• Develops in 20% of patients within 48 hours and 35-66% within 2 weeks

• More common in hospitalized patients with variceal bleeding than

other complications

• Compared to patients without infection presence of infection is

associated with

– Failure to control bleeding (65% vs 15%)

– Early rebleeding

– Mortality (40% vs 3%)

Vivas et al. Dig Dis Sci. 2001. 45

Antibiotic Prophylaxis During/After Acute Variceal Bleeding

• Prophylatic ofloxacin vs antibiotics

only at diagnosis of infection

• infections (2/59 vs 16/61)

• Less rebleeding within 7 days

• blood transfusions for rebleeding

• IV ceftriaxone for a maximum

of 7 days is recommended

in management of acute

variceal hemorrhage Patients at risk

Prophylactic: 59 48 42 38 17 8 2

On demand: 51 36 34 30 19 9 2 P

rob

ab

ilit

y

Follow-up (Months)

0.0

1 2 3 12 18

1.0

0.8

0.6

0.4

0.2

0 24 30

On-demand antibiotics (n=61)

Polyphylatic antibiotics (n=59)

Hepatology. 2004;39:746; AASLD Practice Guidelines 2017. 46

Renal Dysfunction

Prevention of Acute Renal Injury in Cirrhotics

• Avoid aminoglycoside antibiotic

– 10-fold increase renal toxicity

• Avoid NSAIDs

• Avoid I.V. contrast if possible or hydrate and use NAC

• Frequent monitoring of renal function in cirrhotic patient

with ascites is essential

• Patient instruction on use of diuretics, lactulose,

antibiotics, NSAID

• Early transfer of patients 48

Hepatorenal Syndrome


• Functional renal failure without histological

renal lesions

• Intense renal vasoconstriction

• Decreased renal perfusion and GFR associated

with activation of renin-angiotensin system,

ADH, SNS to maintain arterial pressure

50

Hepatorenal Syndrome: Diagnostic Criteria

• Cirrhosis with ascites

• Serum creatinine >1.5 mg/dL

• No improvement of serum creatinine ( to a level of 1.5 mg/dL after at

least 2 days with diuretic withdrawal and volume expansion with albumin;

the recommended dose of albumin is 1 g/kg of body weight per day up to a

maximum of 100 g/day

• Absence of shock

• No current or recent treatment with nephrotoxic drugs

• Absence of parenchymal kidney disease as indicated by proteinuria >500

mg/day, microhematuria (>50 red blood cells per high power field), and/or

abnormal renal ultrasonography

Arroyo V et al. Semin Liver Dis. 2008;28:81-95. 51

HRS: 2 Types

• Type 1 – rapidly progressive, oliguria, very low urine Na,

hyponatremia, precipitating event (SBP or other bacterial

infection, surgery, GI bleed)

– See death within 2-3 weeks

– Dialysis is unhelpful unless transplantation planned

• Type 2 – moderate renal insufficiency (Cr 1.5-2.5

mg/dL), steady for months, can degenerate into Type 1

with precipitant

52

Hepatic Encephalopathy (HE)

HE Symptoms Can Be Subtle Should Be Considered in Any Patient with Cirrhosis

Minimal I II III IV

Overt HE

Affects 30-45%

No observable

symptoms. Only

detectable using

psychometric

testing

1. Euphoria or anxiety

2. Trivial lack of awareness

3. Shortened attention span

4. Impairment of ability to add or subtract

1. Lethargy or apathy

2. Disorientation with respect to time

3. Obvious personality change

4. Inappropriate behavior

1. Somnolence or semi-stupor

2. Confusion

3. Responsiveness to stimuli

4. Gross disorientation

5. Bizarre behavior

1. Coma

Covert HE

Affects 20-60%

HE = hepatic encephalopathy

Vilstrup, H et al. Hepatic encephalopathy in chronic liver disease. 2014; Practice Guideline by the American Association for the Study Of

Liver Diseases and the European Association for the Study of the Liver. Hepatology. 60: 715–735. 54

No Role for Ammonia Testing in HE

• “Increased blood ammonia alone does

not add any diagnostic, staging, or

prognostic value for HE in patients with

CLD. A normal value calls for diagnostic

reevaluation (GRADE II-3, A, 1)”1

• Except in acute liver failure, ammonia

level>200 µmol/L is predictive of

poor outcome2

• HE is a clinical diagnosis

1. Vilstrup H et al. Hepatology. 2014;60(2):714-735; 2. Bernal W et al. Hepatology. 2007;46(6):1844-1852. 55

Treatment Goals for OHE

• Provision for supportive care

• Identification and removal of precipitating factors

– Infection, GI bleed, dehydration

• Reduction of nitrogenous load from the gut

• Correct electrolyte abnormalities

• Assessment of the need for long-term therapy

– Control of potential precipitating factors

– Higher likelihood of recurrent encephalopathy

– Assessment of the need for liver transplantation

Blei AT et al. Am J Gastroenterol. 2001;96(7):1968-1976. 56

Precipitating Factors for HE

UGI hemorrhage

Excessive dietary protein

Blood transfusion

Dehydration/electrolyte imbalance

Constipation

Increased ammonia production

Spontaneous

Iatrogenic (eg, TIPS)

Portosystemic shunts

Drugs (eg, opioids, benzodiazepines)

Infections (eg, SBP)

Malignancy (eg, hepatoma)

Other

Vilstrup H et al. Hepatology. 2014;60(2):714-735. 57

AASLD Recommends 4-Pronged Approach to Treating OHE*

Initiate care for

patients with

altered

consciousness

Seek and treat

alternate causes

of altered

mental status

Identify

and correct

precipitating

factors

Begin

empirical

HE treatment

1 2 3 4

*Grade II-2, A, 1 recommendation.

Vilstrup H et al. Hepatology. 2014;60(2):714-735. 58

Treatment Options for OHE

• Reduction in the nitrogenous load arising from the gut

– Bowel cleansing

– Non-absorbable disaccharides (lactulose)

– Antibiotics (rifaximin, metronidazole)*

– Agents that bind NH3 in the gut and increase activity of the urea cycle

• Na benzoate

• Na phenylacetate

• Na hydroxybutyrate

• Drugs that affect neurotransmission (flumazenil, bromocriptine)

• Manipulation of the splanchnic circulation (occlusion of portal-systemic collaterals)

– Occlude TIPS shunt if present

*Neomycin (historical interest)

Adapted from Blei AT et al. Am J Gastroenterol. 2001;96(7):1968-1976. 59

HCC Screening: Patients with Cirrhosis

Major Guidelines Recognize the Importance of Routine Surveillance in High-Risk Populations

Society/Institution Guidelines

AASLD1 American Association for the Study of Liver Diseases

US +/- every 6 months

EASL2 European Association for the Study of the Liver

US every 6 months

APASL3 Asian-Pacific Association for the Study of the Liver

AFP + US every 6 months

NCCN4 National Comprehensive Cancer Network

AFP + US every 6-12 months

JSH-HCC6 Japan Society of Hepatology

High-risk: US every 6 months + AFP/DCP/AFP-L3 every 6 months

Very High-risk: US every 6 months + AFP/DCP/AFP-L3 every 6 months

+ CT/MRI (optional) every 6-12 months

AFP=alpha-fetoprotein; AFP-L3=Lens culinaris agglutinin-reactive fraction of AFP; CT=computerized tomography; DCP=des-γ-carboxyprothrombin;

MRI=magnetic resonance imaging; US=ultrasound.

1.Marrero JA et al., Hepatology, 2018; 68(2): 723-750; 2. EASL, EORTC. J Hepatol. 2012;56(4):908-943; 3. Omata M et al. Hepatol Int. 2010;4(2):439-474;

4. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Hepatobiliary Cancers v1.2016. © National Comprehensive Cancer Network, Inc. 2016.

All rights reserved. Accessed February 10, 2016; 5. Kokudo N et al. Hepatol Res. 2015;45. 61

Outcomes Are Improved Among Patients Who Undergo Routine HCC Surveillance

Su

rviv

al,

%

Symptoms

Surveillance

P < .001

Months Follow up

0 12 24 36 48 60 72 84 96

0

20

40

60

80

100

Tong MJ et al. J Clin Gastroenterol. 2010;44:e63-70. 62

Take Home Points

• Further work up for advanced liver disease if platelets

<100,000 x 109/L

• Don’t rule out advanced liver disease if LFTs WNL

• Order INR in all patients with jaundice

• Order upper endoscopy if upper GI bleed

• Blood ammonia levels not important if HE is suspected

• Order abdominal US if no evidence of one within the

past 6 months in all patients with advanced liver disease

63

Clinical Case Forum I:

Current and Emerging Management

Approaches for the Patient with HRS

Kimberly Brown, MD, FAST,

FAASLD, AGAF

Acute Impairment of Kidney Function in Cirrhosis

• Traditional criteria (IAC criteria)1

– 50% increase in SCr over

baseline

– Cut-off value of SCr: 1.5 mg/dL

• New definition of AKI2

– in SCr ≥0.3 mg/dL within 48

hours or % SCr ≥50% from

baseline that is known or

presumed to have occurred within

the prior 7 days

1. Angeli P, et al. J Hepatol. 2015;62:968-974; 2. J Hepatol. 2018;69:406-460.

Stage AKI1 Criteria

Stage 1 Increase in SCr ≥0.3 mg/dL or an increase

in SCr ≥1.5-fold to 2-fold from baseline

Stage 2 Increase in SCr >2- to 3-fold from baseline

Stage 3

Increase of SCr >3-fold from baseline or

SCr ≥4.0 mg/dL with an acute increase ≥0.3

mg/dL or initiation of renal replacement

therapy

65

Main Types of AKI in Cirrhosis: Differential Diagnosis

• Hypovolemia: diuretics, GI bleeding, diarrhea

• Hepatorenal syndrome

• Acute tubular necrosis: shock, nephrotoxic drugs, other

• Nephrotoxicity: NSAIDs

• Intrinsic renal disease

• Miscellaneous, unknown

66 Graupera I, et al. Clin Liver Dis. 2013;2:128-131.

AKI in Patients with Cirrhosis: IAC Definitions

European Association for the Study of the Liver. J Hepatol. 2018;69:406-460.

Criteria Definition

Baseline SCr

SCr obtained within 3 months prior to admission

If >1 value within the previous 3 months, the value closest to the admission

If no previous SCr, the SCr on admission should be used

Progression of AKI Progression of AKI to a higher stage

and/or need for RRT Regression of AKI to a lower stage

Response to treatment No response

No regression of AKI

Partial response

Regression of AKI stage

with a decrease in SCr to

≥0.3 mg/dL above baseline

Full response

Return of SCr to a value

within 0.3 mg/dL of

baseline

67

AKI and Cirrhosis

• AKI diagnosed with AKIN criteria has been shown

to be associated with increased mortality in patients

with cirrhosis1

• Progression through stages strongly correlates with

increased mortality in these patients2

• However, cutoff of 1.5 mg/dL is still accurate3

– Identifies patients at risk

1. Piano S, et al. Hepatology. 2013;57:753-762; 2. Belcher JM, et al. Hepatology. 2013;57:753-762;

3. Fagundes C, et al. J Hepatol. 2013;59:474-481. 68

Prospective Studies in Nonselected Hospitalized Patients

Fagundes C et al. J Hepatol. 59(3), 474-481; Piano S et al. J Hepatol. 59(3), 482-489.

Pro

ba

bil

ty o

f s

urv

iva

l (%

)

100

75

50

25

00 30 60 90

p <0.0001

88% No-AKI

84% AKI-1#

68% AKI-1*

42% AKI-2

31% AKI-3

Days

No AKIN Stage 1 Stage 2 Stage 3

AKIN

Mo

rta

lity

(%

)

100

80

60

40

20

0

p <0.0001

p <0.0001

n.s.n.s.

p <0.001p <0.01

sCR <1.5 mg/dlsCR ≥1.5 mg/dl

No AKI (n = 198 191 182 172

AKI-1 (n = 44) 41 39 37

AKI-1 (n = 66) 57 48 40

AKI-2 (n = 30) 18 11 11

AKI-3 (n = 37) 18 12 10

69

HISTORY

& PE

Patient Case

MEDICATIONS LABS PROGRESS

NOTES

60-Year Old Woman

with End-Stage

Liver Disease

• Alcoholic liver disease

• Listed for orthotopic liver transplant

• History of ascites, HE, esophageal varices with

prior bleeding

• Admitted to the hospital with worsening HE

• Labs 12 weeks ago in clinic show: Na 136, Cr 1.1, bilirubin

1.8, INR 1.3, MELD 13

70


NOTES HISTORY

& PE

Patient Case (cont.)

• Over the past 3 months she has developed

worsening ascites

• Diuretics were adjusted to Lasix 40 mg daily,

spironolactone 150 mg daily

• She was now requiring large volume

paracentesis every 2 weeks

• Last paracentesis was 5 days ago at an

outside hospital

71

60-Year Old Woman

with End-Stage

Liver Disease


NOTES HISTORY

& PE


• On admission she is confused

• BP is 102/54, HR 78

• PE shows moderately distended abdomen with

erythema and induration at the previous

paracentesis site

• Labs now show Cr 1.7, INR 2.0, Bili 4.5, Na 131

• Urinary output is 10 cc/hour

• Urinary analysis shows a Na <10, no protein or RBC

72

60-Year Old Woman

with End-Stage

Liver Disease


NOTES HISTORY

& PE


• ConMeds: Lasix 40 mg daily, aldactone 150 mg daily, lactulose 30 cc

bid, rifaximin 550 mg bid, propranolol 20 mg tid

• Lasix and spironolactone are discontinued

• Propranol is discontinued

• Pan cultures are done

• Lactulose and rifaximin continued

• Doppler US shows moderate ascites, no hydronephrosis and patent

portal vein

• Started on IV antibiotics with vancomycin and amp/sulbactam and

albumin 100 g IV given with 75 cc NS per hour

73

60-Year Old Woman

with End-Stage

Liver Disease

Case 1 (cont.): Renal Function

74

0

0.5

1

1.5

2

2.5

3

1 2 3 4 5

Octreotide/Midodrine S

eru

m C

reati

nin

e m

g/d

l

Time, Days

Case 1 (cont.): Urine Output

75

-2000

-1500

-1000

-500

0

500

1000

1500

2000

Volume Intake/Output

output intake

1 2 3 4 5

Vo

lum

e m

L

Time, Days

Hydration 75 cc/hr

Common Precipitating Factors of AKI

Nephro-

toxic

drugs

Surgical

jaundice

Over-

diuresis

GI blood

loss

Alcoholic

hepatitis

Bacterial

infection

AKI

76

Differential Diagnosis of AKI in Cirrhosis

• Hepatorenal syndrome

– Associated with bacterial infections

– Not associated with bacterial infections

• Hypovolemia: diuretics,

GI bleeding, diarrhea

• Acute tubular necrosis: shock,

nephrotoxic drugs, other

• Nephrotoxicity: NSAIDs

• Intrinsic renal disease

• Miscellaneous, unknown

• Medical history

– Physical examination

– Blood tests

– Urine tests

– Abdominal ultrasound

Graupera I, et al. Clin Liver Dis. 2013;2:128-131. 77

Hepatorenal Syndrome International Ascites Club – Diagnostic Criteria

• Diagnosis of cirrhosis and ascites

• Meet AKI criteria

• No response after 2 days with withdrawal of diuretics and volume

expansion with albumin (1 g/kg/day with max of 100 g/day)

• Absence of shock and recent use of nephrotoxic drugs

• No parenchymal kidney disease

– Proteinuria > 500 mg/day, no microhematuria (> 50 RBC) and/or

abnormal renal ultrasound

EASL website. Hepatorenal Syndrome. 78

Initial Management

• Early identification

• Assess and treat bacterial infection

– Blood, urine, ascitic fluid culture

• Avoid large-volume paracentesis

• Stop β-blockers

• Stop nephrotoxic medications: NSAIDs, diuretics

• Volume expansion Tapper EB, et al. Am J Med. 2016;129:461-467. 79

Case 1 (cont.)

Octreotide SC plus midodrine plus IV albumin administered

• UO increased to 500 mL/day

• SCr = 2.7

• MELD = 31

80

Case 1 (cont.): Renal Function

81

0

0.5

1

1.5

2

2.5

3

1 2 3 4 5 6 7 8 9

Octreotide/Midodrine S

eru

m C

reati

nin

e m

g/d

l

Time, Days

Pharmacological Therapy for HRS

IV Albumin

• 20 to 40 g/day

Plus

Vasoconstrictors

• Midodrine + octreotide

• Noradrenaline

Nature Reviews Disease Primers. Ginès P, et al. Nat Rev Dis Primers. 2018;4:23;

Rheumatoid arthritis. Ginès P, et al. Nat Rev Dis Primers. 2018;4:23. 82

Midodrine Plus Octreotide: Dosing

Midodrine: initially 7.5 mg oral 3 times daily

• Titrate to maximum of 12.5 mg 3 times daily

Octreotide: 100 µg SC 3 times daily

• Target dose 200 µg SC 3 times daily

• Titrate to achieve increase of MAP by 15 mmHg

Runyon BA. Hepatology. 2013;57:1651-1653. 83

Noradrenaline

Catecholamine with α-adrenergic activity

• Administered as a continuous IV infusion at 0.5 to 3 mg/hour via central

venous access, usually requires ICU-level care1

• Limited data

– Systematic review: HRS reversal, mortality rates, and recurrence rates similar

when comparing norepinephrine and terlipressin2

– 12 patients showed 83% reversal of HRS with improvements in urine output,

sodium excretion, serum sodium concentration, CrCL, MAP3

– 22/30 patients achieved SCr < 1.5 mg/dL; at baseline, responders and

nonresponders differed only regarding initial bilirubin levels and INR values4

1. EASL website. Hepatorenal Syndrome; 2. Nassar Junior AP, et al. PLOS One. 2014;9:e107466;

3. Davenport A, et al. Nephrol Dial Transplant. 2012;27:34-41; 4. Gupta K, et al. Clin Exper Gastroenterol. 2018;11:317-324. 84

Comparative Efficacy of Midodrine and Adrenaline: Systematic Review and Network Meta-Analysis

Facciorusso A, et al. Lancet Gastroenterol Hepatol. 2017;2:94-102.

Short-Term Mortality Reversal of HRS

OR (95% CI) Quality of Evidence OR (95% CI) Quality of Evidence

Efficacy vs Placebo

Midodrine + octreotide 0.61 (0.19, 1.93) Low (network) 0.44 (0.06, 3.23) Low (network)

Noradrenaline 0.75 (0.32, 1.76) Low (network) 4.17 (1.37, 12.50) Low (network)

Efficacy vs Midodrine + Octreotide

Noradrenaline 1.50 (0.60, 3.78) Low (network) 10.00 (1.49, 50.00) Low (network)

85

Treatment with Terlipressin and Albumin

Solà E, et al. Curr Opin Organ Transplant. 2013;18:265-270.

Diagnosis of HRS

Terlipressin bolus IV 1 mg/4 to 6 hours or continuous IV infusion (2 to 12 mg/day)

0 3 6 9 12 15 Days

Albumin IV

1 g/kg

Albumin 20 to 40 g/day

Increase terlipressin dose if creatinine

does not decrease by 25% on day 3

86

Improvement in Renal Function: TERLI vs MID/OCT

Cavallin M, et al. Hepatology. 2015;62:567-574.

70.4

28.6

55.6

4.8

0

10

20

30

40

50

60

70

80

90

100

Terlipressin Midodrine + Octreotide

Resp

on

se t

o T

reatm

en

t, %

Complete/partial response Complete response

87

P=0.01

P <0.001

Su

rviv

al

Time (days)

P< 0.0011,0

0,8

0,6

0,4

0,2

0,0

0 30 60 90

Group TERLI

Su

rviv

al

Time (days)

P = N.S.1,0

0,8

0,6

0,4

0,2

0,0

0 30 60 90

Group MID/OCT

TERLI vs MID/OCT: Cumulative 3-month Survival

Fig. 4. Cumulative 3-month survival in patients who were randomized to terlipressin plus albumin (TERLI group) or to midodrine and

octreotide plus albumin (MID/OCT group) according to the response: solid line represents responders; dotted line represents nonresponders.

Abbreviation: N.S., nonsignificant.

Cavallin M, et al. Hepatology. 2015;62:567-574.

Probability of 90-Day, Transplant-Free Survival

According to Response to Treatment

88

Systematic Review with Meta-Analysis: Vasoactive Drugs for the Treatment of HRS Type 1

Gifford FJ, et al. Aliment Pharmaceutical Ther. 2017;45:593-603. 89

Safety: Terlipressin and Albumin

Adverse Cardiovascular Effects n (%)

Arrhythmias 2 (9)

Circulatory overload 7 (3)

Suspected intestinal ischemia 3 (13)

Arterial hypertension 1 (4)

Myocardial infarction 1 (4)

Martin-Liahi, et al. Gastroenterology. 2008;134:1352-1359.

EASL website. Hepatorenal Syndrome. 90

Efficacy: Terlipressin and Albumin

• Cumulative incidence of mortality

at 90-day according to ACLF

grade in responders and

nonresponders to treatment with

terlipressin and albumin

– Baseline SCr and ACLF grade

independently associated

with response

– Patient age, WCC, ACLF grade,

and no response to treatment

associated with mortality

Piano S, et al. Clin Gastroenterol Hepatol. 16(11), 1792-1800.

A

Cu

mu

lati

ve i

ncid

en

ce o

f d

ea

th

Days

0 30 60 90

1.0

0.8

0.6

0.4

0.2

0.0

P = .001

Responders

ACLF III

ACLF II

ACLF I

B

Cu

mu

lati

ve i

ncid

en

ce o

f d

ea

th

Days

0 30 60 90

1.0

0.8

0.6

0.4

0.2

0.0

P < .001

Nonresponders

ACLF III

ACLF II

ACLF I

Patients at risk

ACLF I

ACLF II

ACLF III

106

43

7

90

36

5

81

27

3

70

21

2

68

47

20

44

24

4

33

19

3

18

14

3

91

Response Rates: Terlipressin vs Noradrenaline in Patients with ACLF and HRS-AKI

Continuous IV infusion of terlipressin (2 to 12 mg/day) vs noradrenaline (0.5 to 3 mg/hour)

Arora V, et al. Hepatology. 2019; 0:1-11.

Response Rate, n/N (%)

Noradrenaline Terlipressin P Value

Day 4 7/60 (11.7%) 16/60 (26.7%) 0.03

Day 7 12/60 (20%) 25/60 (41.7%) 0.01

Reversal of HRS-

AKI (Day 14) 10/60 (16.7%) 24/60 (40%) 0.004

92


• Devastating complication of decompensated cirrhosis.

• Early recognition essential to improve outcomes; new diagnostic

tools offer promise.

• Currently available treatment in the United States has limited efficacy.

• Terlipressin is superior to other vasoconstrictors in reversing HRS.

• In suitable patients, liver transplantation is the best treatment option.

• Improving renal function reduces short-term mortality and need for RRT and

improves post-liver transplant outcomes.

93

Clinical Case Forum II:

Inpatient Care and Transition of Care

Strategies for the HE Patient

Robert Brown, Jr., MD, MPH


NOTES

OTHER

Patient Case

HISTORY

& PE

67-yr-old man

admitted for OHE for

the first time

HPI

• History of NASH and noted

cirrhosis based on abdominal US

about 3 years ago

• Noted melena for 3 days

• His spouse noted that he has

become confused in the last few

days and became unresponsive

on the day of admission

Social History

• Used to drink heavily as an

auto plant worker when he

was young

• Quit drinking and smoking for

the last 12 years

• Lives with wife in an apartment

• Wife has chronic medical issues

95


NOTES

OTHER


HISTORY

& PE

67-yr-old man


the first time

PE

• Confused, disoriented

• Anemic, but not icteric

• Positive flapping, tremor

• No ascites, not tender

• Trace edema

• Stool tarry and hemoccult (+)

BP 110/60 mm Hg

PR 110/min

RR 20/min

BMI 35 kg/m2

96

HISTORY

& PE LABS PROGRESS

NOTES

OTHER


67-yr-old man


the first time

Lisinopril

Metformin

Simvastatin

Baby aspirin

MEDICATIONS

97

MEDICATIONS HISTORY


LABS PROGRESS

NOTES

OTHER

H/H 9.8/31

Platelets 95,000

INR 1.6

Ammonia

level

120

BUN 30

Creatinine 1.5

Na 133

K 3.2

Albumin 3.1

AST/ALT 52/30

Bilirubin 1.1

Alk phos 122

98

67-yr-old man


the first time

Patient Case

How do you classify this

patient’s HE?

What is the role of

ammonia testing?

99

Normal “Covert” HE I II III IV

“Overt” HE Stages

Categorization is often arbitrary and

varies between raters

Clinical

Diagnosis

Worsening cognitive dysfunction

coma

Characterization of HE Stages

Bajaj JS et al. Hepatology. 2009;50:2014-2021. 100

Role of Ammonia Testing in HE

• “Increased blood ammonia alone does not add any

diagnostic, staging, or prognostic value for HE in patients

with CLD. A normal value calls for diagnostic

reevaluation (GRADE II-3, A, 1)”

Vilstrup H, et al. Hepatology. 2014;60:715-35. 101

Patient Case

How do you manage

this patient?

102

US Hospital Discharges Due to Cirrhosis Are Increasing

403,665 411,029 436,901 444,883 459,496 498,181

526,096 576,573

0

100000

200000

300000

400000

500000

600000

700000

2004 2005 2006 2007 2008 2009 2010 2011

10% increase

*ICD-9-CM diagnosis codes 571.2. 571.5, 571.6; all listed diagnoses.

HCUPnet, Healthcare Cost and Utilization Project. Agency for Healthcare Research and Quality, Rockville, MD.

http://hcupnet.ahrq.gov. Accessed January 2014. 103

Resource Utilization for Patients Hospitalized with Hepatic Encephalopathy, 2005-2009

0

10000

20000

30000

40000

50000

60000

70000

2005 2006 2007 2008 2009

Health Care Resource Utilization in Patients Discharged

with HE Diagnosis

Avera

ge c

harg

e,

2009 U

SD

P<0.001

0

0.4

0.8

1.2

1.6

2

2.4

2005 2006 2007 2008 2009

Number of procedures

P<0.001

Average hospitalization charges

Nu

mb

er

of

pro

ced

ure

s

Stepanova M et al. Clin Gastroenterol Hepatol. 2012;10(9):1034-1041. 104

Specific Approach to Overt HE Treatment

• Four-pronged approach to management of HE

(GRADE II-2, A, 1):

– Initiation of care for patients with altered consciousness

– Alternative causes of AMS should be sought and treated

• e.g. diabetic ketoacidosis, drugs (benzodiazepines, neuroleptics,

opioids), neuroinfections, electrolyte disorders, intracranial bleeding

and stroke1

– Identification of precipitating factors and their correction

– Commencement of empirical HE treatment

Vilstrup H, et al. Hepatology. 2014;60:715-35. 105

Current Therapy Options for HE

Agent Drug Class Indication

Lactulose1 Poorly absorbed disaccharide

• Decrease blood ammonia concentration

• Prevention and treatment of

portal-systemic encephalopathy

Rifaximin2 Non-aminoglycoside semi-

synthetic, nonsystemic antibiotic

Reduction in risk of OHE recurrence in

patients ≥18 years of age

Neomycin3 Aminoglycoside antibiotic Not to be used, renal and ototoxic risk

Metronidazole1 Synthetic antiprotozoal and

antibacterial agent Not approved for HE

Vancomycin1 Aminoglycoside antibiotic Not approved for HE

1. USNLM. DailyMed. Available at https://dailymed.nlm.nih.gov/dailymed. Accessed March 22, 2018; 2. Xifaxan (rifaximin) [prescribing information].

Valeant Pharmaceuticals North America LLC; Bridgewater, NJ; 2018; 3. Mullen KD et al. Semin Liver Dis. 2007;27(Suppl 2):32-47. 106

https://dailymed.nlm.nih.gov/dailymed

Rifaximin Randomized, Controlled Trial:

Time to First Breakthrough HE Episode Primary Endpoint

0

100

80

60

40

20

028 56 84 112 140 168

Pro

po

rtio

n o

f P

ati

en

ts W

ith

ou

t

Bre

akth

rou

gh

HE

(%

) Rifaximin*

(77.9%)

Placebo*

(54.1%) Hazard ratio with rifaximin, 0.42 (95% Cl, 0.28–0.64)

P<0.001

Days Since Randomization

*Rifaximin 550 mg or placebo twice daily. 91% of patients in both arms received concomitant lactulose.

Bass NM et al. N Engl J Med. 2010;362:1071-1081. 107

Rifaximin Randomized, Controlled Trial:

Time to First HE-Related Hospitalization (Secondary End Point)

108

LABS MEDICATIONS HISTORY


OTHER PROGRESS

NOTES

Hospital Course

• He has EGD with variceal banding and bleeding stopped

• Mental status improved with lactulose but dosage has to be

reduced due to significant diarrhea and rifaximin was added

3 days before discharge

– His wife was instructed to follow up in one week after discharge

109

67-yr-old man


the first time

Prevention of Overt HE (OHE)

• Lactulose is recommended for prevention of recurrent episodes of HE after

the initial episode (GRADE II-1, A, 1)

• Rifaximin as an add-on to lactulose is recommended for prevention of

recurrent episodes of HE after the second episode (GRADE I, A, 1)

• Routine prophylactic therapy (lactulose or rifaximin) is not recommended for

the prevention of post-TIPS HE (GRADE III, B, 1)

• Under circumstances where the precipitating factors have been well

controlled (i.e., infections and VB) or liver function or nutritional status

improved, prophylactic therapy may be discontinued (GRADE III, C, 2)

AASLD Practice Guideline, 2014. 110


What is the social burden

of HE?

111

56 46

16 15 11 10 7 5

0

20

40

60

80

100

Stoppedsaving

In debt Noeducation

Late on bills No food Moved out Bankrupt Evicted

HE Impacts Family Daily Functioning

Impact of Cirrhosis-Related Expenses on Daily Activities

of Affected Families Within Past 3 Years

Pati

en

ts r

esp

on

din

g y

es,

%

Bajaj JS et al. Am J Gastroenterol. 2011;106(9):1646-1653. 112

Caregiver Burden Increases with HE Severity

Mean (±SE) Caregiver Scores in the Objective Burden

Domain of the Caregiver Burden Inventory

10

8

6

4

2

0

-2

-4Unimpaired (n=7) Minimal HE (n=6) Overt HE (n=18)

CB

I O

bje

cti

ve

Bu

rde

n

*

1.8(1.3)

Montagnese S et al. Metab Brain Dis. 2012;27(4):567-572. 113

LABS MEDICATIONS HISTORY


OTHER PROGRESS

NOTES

Hospital Course

• He was re-admitted 9 days later due to recurrent grade III

encephalopathy without melena

• He is taking lactulose only since unable to obtain rifaximin after

discharge due to high co-pay

– He has not seen his PCP yet

114

67-yr-old man


the first time

Hospital Readmissions Among Patients with Decompensated Cirrhosis Are Common

• Retrospective study of 402 patients from an

academic transplant center

– Follow-up time censored at death, elective

admissions such as transplant or post-

procedure observation, or the date of last clinic

note; median follow-up was 203 days

– Included cirrhotic patients hospitalized for

ascites, SBP, renal failure, hepatic

encephalopathy, or variceal hemorrhage

• Median time to readmission was 67 days

• Median number of readmissions was

2 (range 0-40); overall rate was 3

hospitalizations/person-year

14%

37%

69%

0

10

20

30

40

50

60

70

80

Within 1 wk Within 1 mo Overall

Pati

en

ts,

%

Hospital Readmissions

Volk ML et al. Am J Gastroenterol. 2012;107(2):247-252. 115

All-Cause and HE-Related Re-Hospitalization for Patients with Hepatic Encephalopathy

N=8,125 alive

at discharge

27.4

49.7

56.4

17.6

33.7 39.5

0

10

20

30

40

50

60

30 days 180 days 1 year

Pati

en

ts (

%)

All-cause HE-related

Neff GW et al. Poster presented at AASLD Annual Liver Meeting 2013. November 2, 2013. Abstract No. 374. 116

Unadjusted and Adjusted Odds Ratios for 30-Day Readmissions

by Condition for Complications of Liver Disease

Unadjusted OR

(95% Cl)

Model 1 OR

(95% Cl)

Model 2 OR

(95% Cl)

Ascites 1.28 (1.20-1.37) 1.47 (1.37-1.58) 1.78 (1.66-1.90)

Variceal hemorrhage 1.85 (1.71-2.00) 1.69 (1.56-1.83) 1.55 (1.43-1.69)

Hepatic

encephalopathy 2.62 (2.41-2.83) 2.67 (2.46-2.89) 3.23 (2.97-3.52)

Hepatorenal syndrome 2.33 (1.90-2.85) 2.46 (2.00-3.02) 1.41 (1.13-1.77)

Hepatocellular

carcinoma 1.79 (1.61-2.00) 1.64 (1.45-1.84) 1.70 (1.51-1.91)

30-Day Hepatology Readmission

Tapper EB et al. Clin Gastro Hepatol. 2016;14:1181-1188. 117

Unadjusted and Adjusted Odds Ratios for 90-Day Readmissions

by Condition for Complications of Liver Disease

118

Unadjusted OR

(95% Cl)

Model 1 OR (95%

Cl)

Model 2 OR (95%

Cl)

Ascites 1.11 (1.05-1.18) 1.31 (1.23-1.39) 1.60 (1.52-1.69)

Variceal hemorrhage 2.03 (1.90-2.16) 1.83 (1.71-1.95) 1.70 (1.60-1.82)

Hepatic

encephalopathy 2.44 (2.28-2.60) 2.53 (2.37-2.70) 3.07 (2.86-3.30)

Hepatorenal syndrome 2.06 (1.75-2.43) 2.31 (1.96-2.73) 1.43 (1.20-1.71)

Hepatocellular

carcinoma 1.98 (1.82-2.15) 1.79 (1.63-1.96) 1.83 (1.67-2.01)

Tapper EB et al. Clin Gastro Hepatol. 2016;14:1181-1188.

90-Day Hepatology Readmission

Frequency and Duration of Hospitalization Associated with Lactulose and Rifaximin in HE

1.6

0.5

0

0.5

1

1.5

2

Mea

n n

um

ber

of

ho

sp

italizati

on

s

Lactulose n=145

Rifaximin n=141

Mean Number of Hospitalizations Mean Days per Hospitalization

7.3

2.5

0

2

4

6

8

Lactulose n=141

Rifaximin n=138

Mea

n d

ays p

er

ho

sp

italizati

on

P<0.001 P<0.001

*P <0.001 rifaximin period versus lactulose period, paired t-test

Leevy CB, Phillips JA. Dig Dis Sci. 2007;52:737-741. 119

Hospitalization Duration and Charges Associated with Lactulose and Rifaximin in HE

1.8

0.4

0

0.5

1

1.5

2

Mea

n t

ota

l w

eek

s

of

ho

sp

italizati

on

Lactulose n=145

Rifaximin n=141

Total Time Hospitalized Hospitalization Charges

56,635

14,222

0

10,000

20,000

30,000

40,000

50,000

60,000

Lactulose n=141

Rifaximin n=138

Mea

n d

ays p

er

ho

sp

italizati

on

P<0.001 P<0.001

*Charges were calculated in 2005 dollars based on average cost per hospital day as determined by the 2003 Healthcare Cost Utilization Project for

ICD-9-CM principal diagnosis code 572.2. A healthcare cost index was used to predict2004 and 2005 costs.

Leevy CB, Phillips JA. Dig Dis Sci. 2007;52:737-741. 120

Impact of Rifaximin Treatment on Hospital Resource Utilization

0

0.1

0.2

0.3

0.4

-12 to -6 -6 to -3 -3 to 0 0 to +3 +3 to +6 +6 to +12Ho

sp

ital

Len

gth

of

Sta

y

(Days p

er

Mo

nth

)

Months Relative to Rifaximin Commencement

Mean Number of Admissions Prior to Rifaximin Initiation

(N=326)

Data from a retrospective study of 326 patients from 7 UK liver treatment centers.

Orr JG et al. Liver Int. 2016;36(9):1295-1303. 121

Impact of Rifaximin Treatment on Hospital Resource Utilization

0

1

2

3

4

5

-12 to -6 -6 to -3 -3 to 0 0 to +3 +3 to +6 +6 to +12

Ho

sp

ital

Len

gth

of

Sta

y

(Days p

er

Mo

nth

)

Months Relative to Rifaximin Commencement

Mean Length of Emergency Hospital Admissions

(N=326)

Data from a retrospective study of 326 patients from 7 UK liver treatment centers.

Orr JG et al. Liver Int. 2016;36(9):1295-1303. 122

Impact of Affordable Care Act on Patients with HE

• Under the ACA, CMS assigns penalties

to hospitals for underperformance in

certain conditions

• CMS has selected certain core conditions to

measure and evaluate

• Measures

– 30-day readmission rates

– Average length of stay

– Mortality

• While the ACA does not currently include

regulations for HE, in a retrospective review

of 21 million inpatient admissions in 2014,

42% of patients admitted with HE presented

with a core measure comorbidity

Care Measure

Conditions Hospital-Acquired Conditions

Acute myocardial

infarction (AMI)

• Central-line associated blood

stream infection (CLA-BSI)

• Methicillin-resistant

staphylococcus aureus

(MRSA)

Heart failure (HF)

• Catheter-associated urinary

tract infection (CA-UAT)

• Clostridium difficile

Chronic obstructive

pulmonary disorder

(COPD)

• Sepsis

• Falls

Pneumonia • Pressure ulcers ACA, Affordable Care Act; CMS, Centers for Medicare & Medicaid Services.

Data on File, Salix Pharmaceuticals, 2014. 123

Reasons for Readmission

Polypharmacy

Psychological

Comorbidities

Frailty

Malnutrition

Home situation

Communication issues

Transplant candidacy

Inpatient care

Goals of care

Discharge instructions

Outpatient care

Multidisciplinary management

Patient Factors

System Factors

Medical Factors

Tapper EB et al. Clin Gastroenterol Hepatol. 2016;14:1181-1188. 124

The Majority of Overt HE Patients Do Not Receive Proper Management Therapy After Discharge

• Analysis of medical and

hospital claims

– Outpatients who had ≥1 OHE

episodes from 2009 to 2011

during a 3-year period

• >60% of patients did not

receive ongoing prophylactic

therapy to reduce risk of HE

recurrence after discharge

Neff GW, Frederick RT. Hepatology. 2012;56(suppl 1):945A. 125

Reducing 30 Day Readmission by Intervention Phase

• Electronic phase

– Checklist items incorporated

into electronic provider

order system

• Check list phase

– QI checklist prompted

medication review and dosing

Reasons for 30-day Readmission

By Intervention Phase

Electronic n=146

Checklist n=139

Control n=194

Percentage

Study phase

0 100

HE

Infection

GI bleeding

Symptomatic

ascites

Other

Tapper EB, et al. Clin Gastro Hepatol. 2016;14:753-759. 126

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