Program Disclosure

• This activity has been planned and implemented in accordance with

the Essential Areas and Policies of the Accreditation Council for

Continuing Medical Education (ACCME) through the joint

providership of Purdue University College of Pharmacy and the

Chronic Liver Disease Foundation. Purdue University School of

Pharmacy is accredited by the ACCME to provide continuing

medical education for physicians.

• This program is supported by an educational grant from Salix

Pharmaceuticals.

Program Disclosure (cont.)

• Credit Designation –Purdue University College of Pharmacy designates this live activity

for a maximum of .5 AMA PRA Category 1 Credit(s) ™. Physicians should claim only the

credit commensurate with the extent of their participation in the activity.

• Faculty Disclosure Statement- All faculty and staff involved in the planning or

presentation of continuing education activities sponsored/provided by Purdue University

College of Pharmacy 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.

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accredited as a provider of continuing nursing education by the American Nurses

Credentialing Center's Commission on Accreditation. This program has been approved for

.5 contact hours.

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accredited by the Accreditation Council for Pharmacy Education as a provider of

continuing pharmacy education. This is knowledge based, continuing education activity of

Purdue University, an equal access/equal opportunity institution. Universal Activity Number

(UAN): 0018-9999-15-007-L01-P, .5 contact hours (.5 CEU).

Faculty, Staff and Reviewer Disclosure

Statement

• Medical Writer: Lisa Pedicone, PhD- No Relevant Relationships

• All faculty, staff and reviewers involved in the planning, review or presentation of

continuing education activities sponsored/provided by Purdue University College of

Pharmacy are required to disclose to the audience any relevant 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.

“All additional planning committee members, Chronic Liver Disease Foundation

and Purdue University College of Pharmacy staff have no relationships to disclose.”

Educational Objectives

• Discuss the natural history and complications of cirrhosis

including management options

• Review data on the screening, diagnosis

and management of chronic liver disease

• Describe the importance of linking patients with chronic

liver disease into specialty care

Case 1

• Paul is a 62 year old black man who presents to the ER

with severe abdominal pain.

• PMHx: “liver problem” years ago when drinking

– Developed ascites but resolved with abstinence

• Exam: Diffusely tender abdomen with some guarding

• Labs:

– CBC: WBC 7.2, Hb 10.1, Plts 71

– CMP: Alb 3.4, TB 1.2, AST 32, ALT 25, AP 251, Cr 1.2

– Viral hepatitis screen: negative

• CT with large heterogeneous mass

Discussion

1. Does Paul have cirrhosis?

– What do you suspect is the reason for his pain?

2. How do you diagnose cirrhosis?

– Biopsy

– Imaging

– Non-invasive markers? And for which etiologies?

– Transient elastography?

3. What would you do next?

Compensated Cirrhosis May Be

Difficult to Recognize

• Asymptomatic (compensated)

– Subtle clues may be overlooked • Thrombocytopenia

• Muscle wasting

• AST>ALT without alcohol consumption

• Liver enzymes may not be abnormal

– Etiology may be remote • Prior alcohol use

• Uncontrolled DM and obesity

• Decompensated (Symptomatic)

– Portal hypertension: ascites, OHE, variceal bleeding – Hepatic failure: Jaundice, Coagulopathy

From http://digestive.niddk.nih.gov/ddiseases/pubs/cirrhosis/. Accessed January 2014.

Trichrome stain micrograph from http://en.wikipedia.org/wiki/Cirrhosis. Accessed January 2014.

History --or

Physical --or

Examination

Laboratory or

Studies

Radiographic

Studies

Physical examination

findings consistent with

liver disease or high

suspicion for chronic liver

disease

Confirm history via signs

and symptoms of chronic

liver disease and positive

risk factors

Confirm history via signs and

symptoms of chronic liver disease

and positive risk factors and

screen for hallmark physical

examination findings

Diagnosis of Cirrhosis and

Chronic Liver Failure

Obtain liver panel*, CBC with platelets, PT/INR, and targeted serologic studies to determine etiology

Obtain abdominal imaging for confirmation of cirrhosis and HCC screening

Refer for possible liver biopsy if diagnosis of cirrhosis is uncertain, as well as possible determination of etiology via

histology if not readily determinable through serologic testing and if potential benefit outweighs risk of procedure

*Tests typically include ALT, AST, alkaline phosphatase, and -glutamyltransferase, total, direct and indirect serum bilirubin, and serum albumin.

Adapted from Heidelbaugh JJ, Bruderly M. Am Fam Physician 2006;74:756-762.

Non-Invasive Markers

• Indirect biomarkers

– APRI, FIB4 etc

• Direct biomarkers

– Fibrotest, Fibrosure, etc

• Transient Elastography

• Clinically obvious cirrhosis does not require confirmation

Prevalence of Cirrhosis

1. Schuppan D, Afdhal NH. Lancet 2008;371(9615):838-851.

2. Available at http://pubs.niaaa.nih.gov/publications/surveillance83/Cirr05.htm; Accessed February 2015.

3. Khungar V, Poordad F. Clin Liver Dis 2012;16:73-89.

• The prevalence of cirrhosis, both worldwide and in

the US, is unknown1

– Cirrhosis is an outcome of a variety of causes; underlying

cause is commonly used for surveillance purposes2

– Compensated cirrhosis often goes undetected for

prolonged periods of time1

• Experts estimate that 5.5 million people in the

United States have cirrhosis3

Annual Prevalence Rates Between 1996 and 2006 Among HCV-Infected Veterans

Progressive Increase in Incidence of

HCV-Related Cirrhosis and HCC in US

El-Serag HB. Gastroenterology 2012;142:1264–1273.

He

pa

toc

ellu

lar C

an

ce

r (HC

C)

Cirrhosis

Decompensated

Cirrhosis

HCC

1996

20%

18%

16%

14%

12%

10%

8%

6%

4%

5%

4%

3%

2%

1%

0%1997 1998 1999 2000 2001 2002 2003 2004 2005 2006

Cir

rho

sis

an

d

De

co

mp

en

sa

ted

Cir

rho

sis

Liver Cancer Projected to Be the 3rd Leading

Cause of Cancer-Related Death by 2030

“Projecting Cancer Incidence and Deaths to 2030: The

Unexpected Burden of Thyroid, Liver and Pancreas

Cancers in the United States.”

• Cancer incidence/deaths projected for 2020 and 2030

• Breast, prostate, and lung cancers remain top cancer

diagnoses

• Lung cancer is projected to remain top cancer killer

– Pancreas and liver cancers projected to surpass breast, prostate, and

colorectal cancers to become the 2nd and 3rd leading causes of cancer-

related death

Cancer Res. 1–9. 2014 AACR

Early Recognition Allows

Preventative Measures

• HCC screening

• Screening for varices

• Recognition of encephalopathy

• Recognition of ascites

• Life style and nutrition counseling

• Early intervention when decompensation first recognized

HCC Screening

• HCC detected after the onset of symptoms has a

very poor prognosis

– With 0-10% survival at 5 years

• Early recognition can improve outcomes

– Resection or liver transplantation

– 5-year disease-free survival of greater than 50%

• Screening with Ultrasound recommended at 6 month

intervals in all individuals with cirrhosis

• MUST RECOGNIZE CIRRHOSIS

HCC Diagnostic Algorithm

"Bruix J and M Sherman, Hepatology, Vol 53, No. 3, 2011.”

Arterial hypervascularity

AND venous or delayed

phase washout

Liver nodule

Repeat US at 3 months

Growing/changing

character

Investigate

according

to size

Other contrast

Enhanced study (CT or MRI)

< 1 cm > 1 cm

4-phase MDCT/ dynamic

contrast enhanced MRI

Arterial hypervascularity

AND venous or delayed

phase washout Stable

Yes No

No

Biopsy

Yes

HCC

Case 2

• Tim is a 56 year old white man with HCV cirrhosis complicated by

ascites and non-bleeding varices. He is listed for transplantation

with a MELD of 17.

• His wife calls his coordinator because Tim has been sleeping all day.

• The coordinator advises her to take Tim to the nearest ER.

• Primary complications of cirrhosis include:

– Ascites

– Jaundice

– Variceal hemorrhage

– Hepatic encephalopathy

• Other complications that can occur include:

– Hepatocellular carcinoma

– Spontaneous bacterial peritonitis

– Hepatic hydrothorax

– Hepatorenal syndrome

– Portopulmonary hypertension

– Portal vein thrombosis

– Hepatopulmonary syndrome

How would you explain Tim’s symptoms?

Lefton HB et al. Med Clin N Am 2009;93:787-799.

Overt Hepatic Encephalopthy (OHE)

• Overt hepatic encephalopathy (OHE) occurs in:

‒ 30% to 45% of cirrhotic patients

‒ 10% to 50% of patients with TIPS

• Covert hepatic encephalopathy (CHE) affects

approximately 20% to 60% of patients with liver disease

– Has been called subclinical encephalopathy or minimal

encephalopathy (MHE) in the past

TIPS = transjugular intrahepatic portosystemic shunt.

Mullen KD, et al. Semin Liver Dis. 2007;27(Suppl 2):32-47.

Mullen KD, Prakash RK. Clin Liver Dis 2012;16:91-93,

Poordad FF. Aliment Pharmacol Ther. 2006;25(Suppl 1):3-9.

Diagnosis of OHE

• Clinical recognition of the distinctive neurologic features of HE

• Knowledge that underlying cirrhosis is present

• Exclusion of other etiologies of neurologic and/or metabolic

abnormalities

• Identification of precipitating factors

• Grading the severity

Adapted from:

Mullen KD. Semin Liver Dis. 2007;27(suppl 2):3-9.

Lawrence KR, Klee JA. Pharmacotherapy. 2008;28(8):1019-1032.

Common Less Common

• Confusion or coma

• Asterixis

• Loss of fine motor skills

• Hyper-reflexia

• Cognitive deficits detected by

special testing

• Babinski sign

• Slow, monotonous speech

• Extrapyramidal-type movement

disorders

• Clonus

• Decerebrate posturing

• Decorticate posturing

• Hyperventilation

• Seizures*

Neurologic Manifestations of OHE

*Seizures seen primarily in type A HE.

Mullen KD. Semin Liver Dis. 2007;27(suppl 2):3-9.

Other Causes of Altered Mental Status*

• Intracranial hematomas

• Thyroid dysfunction

• Hypoglycemia

• Hypoxia

• Hypercapnia

• Drug intoxication

*Most entities can be diagnosed by brain imaging or laboratory tests. Severe sepsis can cause encephalopathy or precipitate HE.

Mullen KD. Semin Liver Dis. 2007;27(suppl 2):3-9.

• Hypoglycemia

• Hyperglycemia

• Acidosis

• Encephalitis

• Severe sepsis

• Uremia

Characterization of HE Stages

Normal Covert HE I II III IV

Overt HE Stages

Categorization is often arbitrary and

varies between raters

Simple Clinical

Diagnosis

Worsening cognitive dysfunction

coma

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

Grade Features

0 No abnormalities detected

I Trivial lack of awareness; Euphoria or anxiety; short attention span; Impairment of addition

or subtraction

II Lethargy or apathy, Disorientation for time, Obvious personality change, Inappropriate

behavior

III Somnolence to semi-stupor, Responsive to stimuli, Confused, Gross disorientation, Bizarre

behavior

IV Coma, unable to test mental state

West Haven Criteria

Measuring Serum Ammonia Level in

Patients with Altered Mental Status

Elgouhari HM, O’Shea R. Cleve Clin J Med 2009;76:252-254.

• One’s clinical impression is the main guide to diagnosing

hepatic encephalopathy (HE)

• A normal or modestly elevated blood ammonia level does not

rule out a diagnosis of HE

• Blood ammonia testing may be helpful if there is no clear

evidence of underlying chronic liver disease

– An increased blood ammonia level may have prognostic value

(e.g., acute liver failure) or may be the basis for further

evaluation for uncommon metabolic disorders (e.g., urea cycle

disorders)

How would you manage Tim?

Patient with possible OHE

Confirm that it is HE: Yes

No HE: Other causes of

altered mental status

Initiate empiric treatment for HE;

Search for precipitating factor

Precipitating factors

found

Precipitating factors

not found

Treatment directed to

the precipitating factor

Evaluate for liver transplant

Proposed Algorithm for

Inpatient OHE Management

Adapted from Bajaj JS. Aliment Pharmacol Ther 2010;31:537-547 and Prakash R, Mullen KD. Nat Rev Gastroenterol

Hepatol 2010;7:515-525

• Admit to ICU for grade 3 HE

• Continue HE therapy with lactulose

and rifaximin

Treatment Approach for Acute

Overt Hepatic Encephalopathy

• Precipitating factors:

– GI bleeding

– Infection

– Sedating medications

– Electrolyte abnormalities

– Constipation

– Renal Failure

76%

24%

44% 49%

0

10

20

30

40

50

60

70

80

Reversal of HE Death

% o

f P

ati

en

ts

Lactulose + Rifaximin

Lactulose + Placebo

48/63 25/57 15/63 28/57

P=0.004

P=<0.05 • Treatment was given

through nasogastric

tube and continued until

recovery of HE or a

maximum of 10 days

• Hospital stay was

shorter with lactulose +

rifaximin than with

lactulose + placebo

(5.8±3.4 vs. 8.2±4.6

days, P=0.001)

Treatment Approach for Acute Overt Hepatic

Encephalopathy: Lactulose + Rifaximin vs. Lactulose

Sharma BC et al. Am J Gastroenterol 2013;108:1458-1463.

General supportive and nutritional interventions

General supportive care • Fall precautions in disoriented patients

• Prevention of infections--changing IV lines, prevent

aspiration pneumonia, isolation

Nutritional support • Regular protein diets are recommended

• Consider addition of branched-chain amino acids

(valine, leucine, and isoleucine) and zinc; consider

eliminating wheat and milk proteins

Khungar V, Poordad F. Clin Liver Dis 2012;16:73-89.

Treatment Approach for Acute

Overt Hepatic Encephalopathy

• Treatment goals

– Prevention of recurrent episodes of HE

– Improvement of daily functioning

– Evaluation for liver transplant

Outpatient Management after

an Episode of OHE

Bajaj JS. Aliment Pharmacol Ther. 2010;31:537-547.

Sharma BC et al. Gastroenterology. 2009;137:885-891.

Prophylactic Treatment of HE

• Treating patients with covert HE to prevent

development of a first episode is referred to as

primary prophylaxis of HE

• Preventing recurrence of HE in patients who had a

previous episode of HE is referred to as

secondary prophylaxis of HE

182,843 196,521 215,767

239,425

323,564 345,887

419,389 454,441

0

50000

100000

150000

200000

250000

300000

350000

400000

450000

500000

2004 2005 2006 2007 2008 2009 2010 2011

To

tal N

um

be

r o

f D

isch

arg

es

†

8% growth

Year

US Hospital Discharges Associated with

Hepatic Encephalopathy* Are Increasing

HE = hepatic encephalopathy; ICD = International Classification of Diseases.

*Data calculated using ICD-9-CM codes 291.2 (alcoholic dementia, not elsewhere classified), 348.30 (encephalopathy,

not otherwise specified), and 572.2 (hepatic coma). †Includes all listed discharge diagnoses.

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

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

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

• Population included cirrhotic patients

hospitalized for ascites, spontaneous

bacterial peritonitis, renal failure,

hepatic encephalopathy, or variceal

hemorrhage

• Median time to first readmission was

67 days

• Median number of readmissions was

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

hospitalizations/person-years

14%

37%

69%

0

10

20

30

40

50

60

70

80

Within1 wk

Within1 mo

Overall

Hospital Readmissions

Volk ML et al. Am J Gastroenterol 2012;107:247-252.

% o

f P

atients

100

80

60

40

20

0

Su

rviv

al, %

0 12 24 36 48

Months

42% survival at

1 year 23% survival at

3 years

Overt HE Is Associated with a

Poor Prognosis

• <50% survival at 1 year after diagnosis of HE;

<25% survival at 3 years

Bustamante et al. J Hepatol. 1999;30:890-895.

Other Management Concerns

• Tim’s OHE is well controlled on medical therapy.

He returns after his hospitalization for follow-up to

pre-transplant clinic.

• On review on his medication list his MD sees that

he is on a beta-blocker as primary prophylaxis.

• Would you continue this medication?

Background

• Non-selective beta-blockers (NSBBs) prevent

portal hypertensive bleeding in patients with

cirrhosis.

• But studies suggest NSBB use is associated

with decreased survival in patients with

refractory ascites.

– NSBBs may reduce perfusion of vital organs

NSBBs Increase AKI

• Nested case-control of liver transplant waitlist

registrants at Mayo clinic

– Cases developed AKI (2-3 fold increase in serum Cr)

– Matched by MELD-Na score, age at registration, baseline

creatinine, and follow-up duration

• Impact of NSBB on AKI incidence was different

according to the presence of ascites:

– NSBB use with ascites was associated with development of AKI

(hazard ratio [HR], 2.79; 95% confidence interval [CI], 1.40-5.54),

– Without ascites, NSBB was protected (HR, 0.19; 95% CI, 0.06-0.60)

Conclusions

• Cirrhosis can be asymptomatic

• Screening and surveillance of life threatening

complications can allow early recognition and

preventative strategies

• Individuals with symptomatic cirrhosis and

liver cancer should be considered for liver

transplantation

– Linkage to experienced providers is instrumental