END STAGE LIVER DISEASE

IN

PRIMARY CARE SETTING

Thwin Maung Aye

National University Hospital

18th October 2014

ROLE OF FAMILY PHYSICIAN

Understanding natural history of cirrhosis and

shared care with the institution

Prevention of liver cirrhosis

Understanding tumor (HCC) biology and surveillance

Understanding role of liver transplant and timely referral

OBJECTIVES OF THE TALK

To acknowledge the common scenarios, outline

management plan and appreciate role of primary

physician

To update new DAA for hepatitis C

To understand the rationale and indication of

transplantation for appropriate referral

COMMON SCENARIOS?

1. Known fatty liver, regular follow up with LFT and

USG which was reported as nodular surface

2. First time diagnosis of HBsAg+ve in view of

abnomal LFT. USG reported as nodular surface

3. Patient present with leg swelling. Blood tests

showed abnormal LFT and nodular liver surface

COMMON SCENARIOS?

4. Patient known cirrhotic but defaulted follow up and

came to see you with bleeding PR

5. Known cirrhotic patient, on diuretics, lactulose and

propranolol and come to see with confusion and

worsening of ascites before hospital appointment

6. Patient came for weight loss, jaundice and palpable

mass in RHC

CASE SCENARIO FOR ESLD

50 years old man, Mr Ng, came to see you as a routine

follow up for her hypertension, diabetes and

hyperlipidaemia. He has been taking amlodipine, glipizide

and simvastatin. He had no compliant. His BP was 140/90

mmHg and BMI was 30. Other clinical examination were

unremarkable. USG done was reported as early cirrhosis

and mild splenomegaly. His blood tests were as followed.

Hb 12, TWC 5.2, Platelet 120

Na 135, K 3.5, Urea 7, creatinine 98,

AST 80, ALT 68, Albumin 32, Bilirubin 8, AFP 5, INR 1.2

HBA1c 7.8, LDL 3.2, cholesterol 5.8, Tg 1.2

WHAT ARE YOU GOING TO DO NEXT?

A)

Review

his.

..

B) R

efer t

o ho...

C) R

efer t

o ho...

D) A

+B

E) A

+C

0% 0% 0%0%0%

A) Review history & investigations

and optimize the control his

metabolic syndrome and review

in 3-6 months

B) Refer to hospital in view of USG

finding

C) Refer to hospital in view of

transaminitis

D) A+B

E) A+C

Countdown

15

IF YOU PLAN TO REFER, WHAT WILL YOU DO

BEFORE REFERRAL?

A) F

urther r

eleva

nt hist

...

B) H

epatitis

mark

er

C) D

ietic

ian re

view

D) C

omplia

nce to

medic.

..

E) A

ll of a

bove

0% 0% 0%0%0%

A) Further relevant history

including social history

B) Hepatitis marker

C) Dietician review

D) Compliance to medication

E) All of above

Countdown

15

IF HBSAG+VE, WHAT IS POSSIBLE DIAGNOSIS?

A) N

ASH

B) H

epB liver .

..

C) C

rypto

genic...

D) A

lcoholic

c...

D) A

+B

0% 0% 0%0%0%

A) NASH

B) HepB liver cirrhosis

C) Cryptogenic cirrhosis

D) Alcoholic cirrhosis

D) A+B

Countdown

15

WHAT IS/ARE YOUR PLAN(S) OF MANAGEMENT?

A) L

ife st

yle ..

.

B) O

ptimiza

tio...

C) F

urther e

va...

D) R

eferra

l to...

E) A

ll of a

bov...

0% 0% 0%0%0%

A) Life style modification (dietician

review , exercises)

B) Optimization of his metabolic

syndrome control

C) Further evaluation of hepatitis B

/ other aetiologies

D) Referral to hospital for

evaluation of possible cirrhosis

E) All of above

Countdown

15

MR NG WAS REFERRED TO NUH DC

Here are the tests / evaluation done in NUH

Confirmed Child A cirrhosis after the followings.

Hepatitis B viral load: 6 log, HBeAg-ve, HBeAb+ve

Hepatitis C (-)ve, HIV (-)ve, Autoimmune screening (-)ve

Fibroscan: 19.8 kpa

Liver biopsy: NI 4/16, Fibrosis 5/6

Tenofovir was started

OGD: Small 2 column of varices, for surveillance

Advice on low salt diet

Advice for regular 6 monthly follow up in NUH

MR NG HAS REGULAR FOLLOW UP WITH YOU

FOR HIS METABOLIC SYNDROME. WHAT IS

YOUR CONCERN REGARDING HIS CIRRHOSIS?

A) N

o conce

rn ..

.

B) A

dequate co

...

C) m

ake su

re h

...

D) A

ll ab

ove

E) A

ll above e

...

0% 0% 0%0%0%

A) No concern as he has

appointment with NUH

B) Adequate control of his

metabolic syndrome

C) make sure he has regular

follow up for varices and HCC

D) All above

E) All above except A

Countdown

15

BEFORE HIS NUH APPOINTMENT , YOU SAW HIM

FOR HIS REGULAR CLINIC. MR NG SAID HE NOTICED

ABDOMINAL DISTENSION WITHIN 1-2 WEEKS. WHAT

IS YOUR IMPRESSION?

A) a

scite

s fro

m ci

rrhosis

...

B) P

ortal

vein th

rom

bosis..

C) P

oor com

pliance

to d

i..

D) T

o rule

out C

ardia

c / ..

.

E) A

ll of a

bove

0% 0% 0%0%0%

A) ascites from cirrhosis

progression

B) Portal vein thrombosis

/ HCC

C) Poor compliance to diet

particularly salt

intake

D) To rule out Cardiac /

Renal failure

E) All of above

Countdown

15

WHAT WILL YOU DO NEXT?

A) S

tart

diu

r...

B)

Furth

er ev...

C)

Bring fo

rw...

D) A

ll ab

ove

E) A

ll above e

...

0% 0% 0%0%0%

A) Start diuretics

straightaway and

review again

B) Further evaluation

including blood tests

and USG

C) Bring forward his

appointment with

NUH

D) All above

E) All above except A

Countdown

15

MR NG HAS USG AND BLOOD TESTS DONE BY

YOU. THE RESULTS WERE AS FOLLOWED.

USG: moderate ascites, no focal lesion in the liver

was reported

Albumin 28

INR 1.5

Creatinine 98, Na 130

Bilirubin 10, ALP 150

AFP 7.5,

Hb 10.5, TWC 3.8, Platelet 110

Child B

WHAT IS YOUR NEXT PLAN OF MANAGEMENT?

A)

Start

Diuretic

s and re

...

B) T

o monito

r his

weigh...

C) Dieta

ry advic

e toge

th..

D) S

end to N

UH for f

ur...

E) A

ll above exce

pt D

0% 0% 0%0%0%

A) Start Diuretics and

review in 1-2 weeks

B) To monitor his weight

and renal function

C) Dietary advice

together with salt

restriction

D) Send to NUH for

further management

rather than bringing

forward

E) All above except D

Countdown

15

MR NG WAS SEEN BY NUH AS APPOINTMENT

WAS BROUGHT FORWARD

NUH made minor adjustment of diuretics for ascites

Dignostic paracentesis showed neutrophil count of > 250

and ciprofloxacin was started

Repeat OGD: Moderate varices 2 columns and beta

propranolol was started

Appointment was given in 3 months to review (with scan

and blood tests)

WHAT IS YOUR CONCERN NOW?

A) C

irrhosis

care

must

b...

B) J

oint c

are w

ith you is

s...

0%0%

A) Cirrhosis care must be

under NUH

B) Joint care with you is

still possible titrating

diuretics, monitoring

compliant of meds and

diet and follow up

Countdown

15

JUST BEFORE APPOINTMENT WITH NUH , HIS SON

CALLED YOU TO TELL YOU THAT MR NG IS

CONFUSED AND VERY SLEEPY. WHAT DO THINK

THE POSSIBLE CAUSE(S)?

A) H

epatic encephalopath

y

B) S

troke

C) Sepsis

D) D

ehydratio

n and ure...

E) Possib

le all above

0% 0% 0%0%0%

A) Hepatic encephalopathy

B) Stroke

C) Sepsis

D) Dehydration and

ureamic

encephalopathy

E) Possible all above

Countdown

15

WHAT WILL YOU DO NEXT?

A) R

eview

the ..

.

B) A

dvice to

s...

0%0%

A) Review the

patient to find

out precipitating

causes

B) Advice to send to

NUH

straightaway

Countdown

15

THE FOLLOWINGS ARE FINDINGS WHEN YOU

REVIEW.

GCS 15/15, drowsy but orientated to time, place , person

BP 100/70mmHg, HR 90/min, afebrile, HC 7, neurology: NAD,

PR: stale maleana

Bloods: Na 130, Urea 18, Creatinine 180, CRP 15, INR 1.5, Hb

10.2, platelet 120

No new drugs were taken lately

WHAT IS YOUR IMPRESSION?

A) E

lectrolyte

imbala

nce

B) G

rade I e

ncephalo

pathy

C) Varic

eal Bleedin

g

D) S

epsis

E) P

ossible all o

f above

0% 0% 0%0%0%

A) Electrolyte imbalance

B) Grade I encephalopathy

C) Variceal Bleeding

D) Sepsis

E) Possible all of above

Countdown

15

WHAT IS YOUR NEXT ACTION?

A) G

ive st

at dose

of b

ro..

B) S

top d

iure

tics

C) 2

larg

e bore

IV p

lug an...

D) A

dvice to

go to E

D, ...

E) A

ll of a

bove

0% 0% 0%0%0%

A) Give stat dose of broad

spectrum antibiotics

B) Stop diuretics

C) 2 large bore IV plug and IV

drip

D) Advice to go to ED, NUH

ASAP

E) All of above

Countdown

15

MR NG WAS ADMITTED TO NUH. HE WAS TREATED FOR

VARICEAL BLEEDING BY EVL, ANTIBIOTICS, PPI.

ELECTROLYTE WAS CORRECTED. HE HAD REPEAT USG

SCAN DURING ADMISSION.

USG showed suspicious lesion in segment 6 about 1.2 cm and

confirmed HCC with CT after his AKI settled

Further blood tests: Bill 34, INR 1.8, Creatinine 132, Albumin

27, Moderate ascites, Ecolic in blood

Multidisciplinary team discussion on risk of treatment of HCC

in view of his Child C status vs liver transplant option as of

MELD 20 (MELD 20-29: mortality 76% 3 months) once

infection is under control

LEARNING POINTS

Natural history of cirrhosis

stable but can be suddenly deteriorating

Joint care will optimize patient’s condition

Adjusting threshold of both sides for optimizing care

Recognition of primary care involvement in cirrhosis

Antiviral reduced risk of HCC not prevent HCC

ROLE OF FAMILY PHYSICIAN

Shared care of patients with institution Ascites, hepatic encephalopathy, GI bleeding

HCC surveillance / understanding of tumor biology 6-12 monthly scan and LFT, AFP

Timely referral to liver transplant centre Clinical indications (CP score, bleeding, ascites, HE, HCC)

MELD ≥15

Prevention of cirrhosis Alcohol abuse, screening for viral hep, control risk factors for NAFLD

Vaccination programme

NATURAL HISTORY OF END STAGE LIVER DISEASE

Fattovich et al. Hepatology 1995; Liaw et al. Liver 1989; Ikeda et al. J Hepatol 1998.

Cirrhosis 18-20%

HCC 6-15% Decompensation 20-30%

Death

DIAGNOSIS OF CIRRHOSIS

Modality Ultrasound CT MRI

Sensitivity 65-95% 65-84% 68-87%

Specificity 38-93% 68-80% 70-92%

Accuracy 64-88% 67-72% 68-70%

Kudo M et al. Intervirology 2008; 51: Suppl 1,

Ito K et al. Radiology 1999; 211(3): 723-36.

Kristin N et al. Scan J Gastroenterol 2005;40:76-82.

TRANSIENT ELASTOGRAPHY

Shaheen, Am j Gastro 2007, Castera J Hepatol 2008

Metavir score All HBV NAFLD/NASH PSC/PBC HCV

% >F2 fibrosis 50-82% 58% 49-50.4% 60% 2.5-65%

Cutoff level 4-7.9 7 6.6-8.7 7.3 4.5-8.7

AUROC 0.74-0.86 0.81 0.86-0.87 0.920 0.72-0.83

PORTAL HYPERTENSION & CONSEQUENCES

Ascites and its consequences Ascites responsive to diuretics

Recurrent ascites (intolerance, poor compliance, resistant)

SBP

Hepatic encephalopathy Precipitating causes (infection, electrolyte, GI bleeding, stroke,

constipation, poor compliance, neuro meds)

GI bleeding Variceal bleeding (oesophageal / gastric)

ASCITES

Treatment of underlying cause

Salt (/fluid) restriction(2g/day ie 88mmol/day) when?

Diuretics (Spironolactone / +/- frusemide) Stop beta blocker, ACEI and ARB

Weight monitoring (weight loss ≤ 0.5kg)

Spontaneous bacterial peritonitis

Primary prophlaxis (ascite fluid albumin <1.0g/dL, bil>2.5) Secondary prophylaxis

Response assessment Responsive, intolerant, compliance, resistant

ROLE OF MIDODRINE FOR ASCITES

Hepato-renal syndrome

hypotension, post ascites drainage

Diuretics resistant recurrent ascites

Oral formula 7.5-12.5 mg TDS

Improve clinical outcome and survival

Comparison of midodrine and albumin in the prevention of paracentesis-induced circulatory

dysfunction in cirrhotic patients: a randomized pilot study J Hepatol 2012;56:348-354

VAPTANS FOR ASCITES

Vasopressin receptor antagonists

For euvolaemic and hypervolaemic hyponatraemia

(tolvaptan1)

For ascites rather then HypoNa (Satavaptan2)

Side effects, doubtful survival benefit and cost

effectiveness

1. Cardenas A, Gines P, Marotta P, Czerwiec F, Oyuang J, Guevara M, Afdhal NH. Tolvaptan, an oral

vasopressin antagonist, in the treat- ment of hyponatremia in cirrhosis. J Hepatol 2012;56:571-578

2. Wong F, Watson H, Gerbes A, Vilstrup H, Badalamenti S, Bernardi M, Gines P, et al. Satavaptan for the

management of ascites in cirrho- sis: efficacy and safety across the spectrum of ascites severity. Gut

2012;61:108-116

HEPATIC ENCEPHALOPATHY

• Lactulose (reduced absorption of ammonia)

• Rifaximine

• BO at least 2-3 /day

• Precipitating factors • Infection

• Electrolyte

• Compliance

• GI bleeding

• CVA

• Constipation

• Drugs (neuro suppressant)

RIFAXIMIN IN HEPATIC ENCEPHALOPATHY

Prevention of recurrent HE

Minimal, Overt or prevention of recurrent HE

The Effects of Rifaximin in Hepatic Encephalopathy.

Aliment Pharmacol Ther. 2014;40(2):123-132

VARICEAL BLEEDING

• Baseline severity of cirrhosis (Child-Pugh)

• Rate of progression of cirrhosis

• ± Medication and Compliance (Propranolol/Carveidolol)

• Last scope and findings (site of varices) & treatment

• Splanchnic vasoconstrictors and antibiotics

Carveidolol Vs Propranolol ?

Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to

propranolol.Gut.2013 Nov;62(11):1634-41. doi: 10.1136/gutjnl-2012-304038. Epub 2012 Dec 18

HEPATOCELLULAR CARCINOMA (HCC)

• Tumor biology • High risk nature of tumor • Size and number of tumor • Level of AFP

• Treatment history • Last surveillance duration • Previous treatment and modality • Resection • TACE • RFA

STEREOTACTIC BODY RADIATION THERAPY

(SBRT)

Precisely deliver external radiation therapy to tumor

Few side effects

Requires high degree of precision

Un-resectable tumor, not suitable for convetional RT

RISK FOR HCC & LIVER-RELATED DEATH

IN HEPB IMMUNE CONTROL CARRIER

1932 inactive carriers in REVEAL-HBV

Seronegative for HBeAg

Serum HBV DNA <10,000 copies (<2000 IU)/mL

No cirrhosis, HCC, nor elevated ALT

Annual incidence

rates

Inactive

carriers

Controls

(sAg-ve)

Adjusted

hazard

ratio

95% CI

HCC 0.06% 0.02% 4.6 2.5-8.3

Liver-related

deaths

0.04% 0.02% 2.1 1.1-4.1

Older age and alcohol drinking habits were independent predictors of risk for

carriers of inactive HBV to develop HCC

Chen JD et al. Gastroenterology 2010;138:1747-54.

GOALS OF TREATMENT

APASL guidelines 2008

To permanently suppress HBV replication.

The ultimate long-term goal is to achieve “durable response” to prevent hepatic decompensation, reduce or prevent progression to cirrhosis and/or HCC, and prolong survival

AASLD guidelines 2012

To achieve sustained suppression of HBV replication and remission of liver disease.

The ultimate goal is to prevent cirrhosis, hepatic failure and HCC.

EASL guidelines 2009 To improve quality of life and survival by preventing progression of

the disease to cirrhosis, decompensated cirrhosis, end-stage liver disease, HCC and death.

This goal can be achieved if HBV replication can be suppressed in a sustained manner.

Liaw YF et al. Hepatol Int 2008; 2: 263–83; Lok AS et al. Hepatol 2009; AASLD Practice Guidelines; EASL, J Hepatol 2012; Vol.57 167-185.

SELECTION OF TREATMENT FOR CHB

Oral nucleosides

One tab/d

Very few side effects

Can be used for the whole

spectrum of CHB cases

Suppresses virus but does

not eradicate

HBeAg seroconversion 20-

25%

Long term therapy is the

norm

Moderate cost

Immunomodulators

Once weekly injections

Many side effects but usually

tolerable

Cannot be used for advanced

liver disease

Can clear virus in small % of

patients

HBeAg seroconversion >30%

Treatment course is 48 wks

Expensive

INTERNATIONAL GUIDELINES ON RECOMMENDATIONS

AASLD Chronic Hepatitis B: Update 2009. Hepatology 2009;50:1-36 EASL Clinical Practice Guidelines: Management of chronic hepatitis B. J Hepatol. 2012; Vol.57 167-185

Liaw, Hpeatol Int (in press) 20112

2012

EASL

• Drugs with high potency and low resistance rate , eg. ETV, TDF

2009

AASLD

• Drugs with high potency and high genetic barrier, eg. ETV, TDF

• LAM, ADV and LdT are not preferred for for naïve patients

2012

APASL

• ETV or TDF is the preferred Nuc

IMPROVEMENT IN FIBROSIS (ENTECAVIR)

IMPROVEMENT IN FIBROSIS (TENOFOVIR)

REDUCE HCC OCCURENCE

HCC INCIDENCE IN ENTECAVIR TREATMENT

HCC INCIDENCE IN NON-CIRRHOTICS

Hepatitis C structure target for new Direct Antiviral Agent

Combination therapy

Future speculation

New drugs on the horizon

Predictors of response

Combination therapy

concept

Timeline?

Now or wait ?

WHY PATIENT NEEDS TRANSPLANT AND WHEN?

Patient’s ESLD survival

Life expectancy and OLT survival (1 yr 80-90%)

Organ availability and waiting time

Blood group

Child score / MELD

Quality of life from the disease

Summary flowchart for cirrhosis and complication

PREVENTIVE AND COMMUNITY ASPECT

Ensure adequate nutrition (including calorie & protein

intake) and supplement (eg. Zinc)

Alcohol cessation, community programme

Prophylactic antibiotics for SBP (for bleeding)

Osteoporosis risk assessment and primary prevention

Life style modification for NAFLD/NASH

Vaccination for hepatitis A, B, pneumonia, influenza

Compliance to treatment and follow up

Thank you for your attention