Mata Kuliah Pakar

2. SPECTRUM AND MANAGEMENT OF

CHRONIC LIVER DISEASE
(CLD)
HSAR LELOSUTAN
SUBDIVISION OF GASTROENTEROLOGY-HEPATOLOGY
DEPARTMENT OF INTERNAL MEDICINE
CENTRAL ARMY HOSPITAL (RSPAD) GATOT SOEBROTO - JAKARTA

08/30/15

Diagram of Chronic Liver Diseases (CLD) :

08/30/15

SPECTRUM OF CLD IN RSPAD GATOT SOEBROTO JAKARTA

INTO JANUARY 1 DECEMBER 31, 2005.

NO SPECTRUM
1.

a.
b.
c.

2.

8
102
18

VISIT
(R=3012)
17
196
72

EXPLANATION
AST/ALT was NL
AST/ALT was increased
AST/ALT, g-GT, ALP were
increased, Dislipidemia

Liver cirrhosis
a.
b.
c.

3.

Chronic in
active hepatitis
Chronic active
hepatitis
Steato-hepatitis

PATIENT
(n=409)

Compensated LC
Decompensated
LC
Hepatoma

Deaths

SUMBER
08/30/15

82

816

110
63

1290
621

26

---

Childs-Pugh Score A
CPS B or C
AFP was inreased

ESHF

: Medical Record RSPAD GS, Pav. Kartika, Pav Darmawan. 2005.

08/30/15

ANATOMI SISTIM DIGESTIVUS (The alimentary tract.)

Parotid gland

Salivary glands

08/30/15

Berat hati
:
1,2 1,5 kg
SIRRHOSIS
HEPATIS
Faal hati
:
metabolisma, RES,
sintesis, sistim koagulasi,
detoksifikasi,
regulasi endokrin.

08/30/15

DEFINISI :
Hepatitis = keradangan hati

PENYEBAB :
1. Infeksi :
parasit (malaria, amoeba),
bakteri (tbc, banal), jamur,
viral (hepatitis A, B, C, D, E, F,
TT, CMV, EBV)
2. Kerusakan hati :
alkohol, obat-obat (asetaminofen,
metildopa, INH, fenitoin, valproat, CPZ, amiodaron, TMP-SMZ,
eritromisin), bahan beracun
3. Autoimun
4. Fibrosis kistik
5. Penyakit Wilson
:
deposit Cu berlebihan dalam hati
6. Sindroma Reye
7. Sindroma Budd-Chiari
08/30/15

Viral Hepatitis
Type of Hepatitis
A

Feces

Blood/
body fluids

Blood/
body fluids

Blood/
body fluids

Feces

Route of
Fecal-oral Childbirth
transmission
, needles,
sex,
transfusio
n

Needles,
transfusio
n,
sex,
childbirth

Source of
virus

Chronic
infection

No

Prevention Vaccine,
immune
globulin

Yes

Yes

Needles, sex, Fecal-oral

transfusion
(requires HBV
co-infection)
Yes

No

Vaccine,
Blood donor HBV vaccine Ensure safe
immune
screening,
drinking
globulin,risk management,
water
education

08/30/15
CDC fact sheets, available at www.cdc.gov

PATOGENESIS
HEPATITIS VIRAL
Hepatocyte
regeneration

Uninfected
hepatocyte
s
Infection

Immune
respons
e

HBV or HCV
-infected
hepatocytes
Inflammation
and cell death

Re-infection

HBV or HCV
production

Alcohol,
co-infection
etc.

Averett DR and Mason WS.

Viral Hep. Rev. 1995; 1:12942

Clinical hepatitis
08/30/15

PATOGENESIS
HEPATITIS VIRAL KRONIK
Viral replication
Tissue
damage
Immune
response
Host and
environmental
factors

Evidence of disease

Scarring
Cirrhosis

Transplant
or
Death

(e.g. alcohol, coHCC

Adapted frominfection)
Dr Z Goodman, Armed Forces Institute of Pathology, Washington, DC
08/30/15

10

Chronic
severe hepatitis
08/30/15

11

Adalah :
Proses pengerasan parenkhim hati akibat nekro-inflamasi yang
berlarut-larut/kronik
Cirrhotic = pengerasan, batu

PARENKHIM
HATI

CIRRHOSIS HEPATIS
inflamasi

BERBAGAI
PENYEBAB
08/30/15

nekrotik

fibrotik

HEPATOMA
12

Patologi Anatomi :

Etiologi :

Drug Induced
Hepatitis

Nodul-nodul

Viral Hepatitis

Fatty Liver/
Steato Hepatitis

08/30/15

<-----------------------------------------------------------kronik<-----------akut
6 bulan 13

Definisi SH
Istilah kirrhos
Laennec tahun 1826
Kuning / ketengguli tenggulian
WHO :
proses difus yang dikarakteristik oleh
adanya fibrosis dan perubahan struktur
normal hepar mjd struktur nodul abnormal
tanpa adanya organisasi lobular

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14

Indonesia :
Pria > wanita 2 4,5 : 1
>> usia dekade ke-5
AS :
Angka kematian 26.000 35.000 /tahun
Penyebab kematian no.9
08/30/15

15

Patogenesis SH
Hepar Injury

Etiologi

08/30/15

Nekrosis
Hepato
seluler

Patofisiologi

Jaringan
Kolagen /
fibrotik

Nodul
nodul

Sirosis

Patologi Anatomi

16

 Klasifikasi Klinis (Patofisiologi)

Klasifikasi Morfologi (Patologi Anatomi)
Klasifikasi Penyebab (Etiologi)

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17

Klasifikasi Etiologi
Penyebab tersering :
- hepatitis C (26 %)
- alcoholic liver disease (21%)
- hepatitis C dengan alcoholic liver disease (15%)
- kriptogenik (18%)
- hepatitis B yang koinsiden dgn hepatitis D (15%)
- penyebab tidak diketahui (5%)

08/30/15

18

KLASIFIKASI KLINIS
Berdasarkan : CHILDs-PUGH Score

SIROSIS HATI LATEN/TERKOMPENSASI (CPS A)

SIROSIS HATI DEKOMPENSATA
(CPS B or C)

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19

Klasifikasi CHILDs-PUGH
SKOR

Albumin (g/dL)

> 3.5

2.8 - 3.5

< 2.8

Ascites

None

Mild

Marked

Bilirubin (umol/dL)

< 3.4

3.4 5.0

> 5.0

Ensefalopati

None

Mild

Marked

PT (s prolonged)

<4

46

>6

Nilai SKOR
Childs A
Childs B
Childs C
08/30/15

:
:
:
:

Jika jumlah angka

<7
79
>9
the poorest prognostic group,
is less than 12 months
20

Hayes, et al. Churchills Pocketbook of Medicine, 3rd Edition. China, 2002.

PATOFISIOLOGI :
Sitokin & Hepatic Growth Factors
Hepar sitokin pro inflamasi :
- IL 1
- IL 6
- IFN
Hepatic Growth Factors HGF
EGF
TGF
TGF -
08/30/15

- TNF -

21

Klasifikasi Morfologi
I . Sirosis Mikronodular
Ditemukan pada :
- hemokromatosis
- sirosis hati akibat alkohol
- nutritional cirrhosis
- obstruksi bilier
- obstruksi aliran vena hepatik
- jejunoileal bypass
- indian chillhood cirrhosis
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22

Sirosis Mikronodular

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23

II. Sirosis Makronodular

Ditemukan pada :
- hepatitis C kronis
- hepatitis B kronis
- defisiensi alpha 1 anti tripsin
- sirosis bilier primer
III. Sirosis Campuran

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24

Sirosis Makronodular

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25

Fibrogenesis

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26

Pola Histologis Fibrosis

Fibrosis Portal
Fibrosis Periportal
Fibrosis Periseluler
Fibrosis Perivenular
Fibrosis Septal
Fibrosis Bentuk Lain

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27

Fibrosis Periduktal

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28

Fibrosis Periportal

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29

Fibrosis Periseluler

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30

Fibrosis Perivenular

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31

Fibrosis Septal

08/30/15

32

Liver
cirrhosis
08/30/15

33

KOMPLIKASI SIROSIS HATI

HIPERTENSI PORTAL :
- Varises Esofagus (VE),
- Pecahnya VE (HEMETEMESIS MELENA)
- Asites : SBP
HEPATOMA
ENSEFALOPATI HEPATIKUM
GAGAL HATI TAHAP AKHIR (ESHF):
- Sindroma Hepatorenal
- Sindroma Hepatopulmoner
- Koma Hepatikum
08/30/15

34

08/30/15

35

Epidemiologi :
Kanker hati banyak didapatkan di daerah
Timur Jauh dan Afrika.
Penyebab utama : infeksi Hepatitis B dan
C
Di Indonesia sering disertai oleh Sirosis
Hati

08/30/15

36

Hepatocellular carcinoma
08/30/15size)
(large

37

Hepatocellular
08/30/15
carcinoma(small
size)

38

08/30/15

39

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40

08/30/15

41

ENSEFALOPATI
HEPATIKUM
08/30/15

42

When the Liver

fails, the Brain
fails
R Butterworth
2000

08/30/15

43

Ammonia makes the

Brain Swell!!!
Brain
N <0.1
LF

08/30/15
Jalan et al. Int J Biochem Mol Biol 2003, Jalan Gut 2000.

mM

0.5-5 mM

44

The pathogenesis

Ammonia
False neurotransmitter
Endogenous toxin: Mercatan
GABA
Benzodiazepam
Zn. Mg

08/30/15

45

Ammonia in Liver Failure patients

BRAIN
LIVER
Urea

Glutamine

MUSCLE

GUT

NH3

KIDNEY

CIRRHOSIS
Shawcross
08/30/15 and Jalan, Lancet 2005

46

Clinical Signs of Hepatic Encephalopathy

Mental status disorder

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47

Clinical Signs of Hepatic Encephalopathy

Flapping tremor

08/30/15

48

08/30/15

49

08/30/15

50

08/30/15

51

08/30/15

52

Encephalohepatic stage

Minimal
Grade 1
Grade 2
Grade 3
Grade 4

08/30/15

: confused
: drowsy
: Stuporous
: Coma

53

Spectrum of hepatic encephalopathy

Coma
Manifest
HE
Minimal HE

Precipitated (85-90%)
Bleeding
Dehydration
Sepsis

Spontaneous (10-15%)

40-70% cirrhotics

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54

Manifest HE
Definition - not precise, no good tests
(psychometric test, number connection
test)
Impact on the patient - minimal, if any
quality of life
ability to work
prognosis

08/30/15

55

08/30/15

56

PENATALAKSANAAN.
Diagnostik :
Klinis, Laboratorium dan Biopsi Hati.
Terapeutik :
Pencegahan.
Pengobatan / medikamentosa.
Edukasi :

08/30/15

57

KLINIS
LABORATORIUM
BIOPSI HATI

08/30/15

58

Prevalence of HBV and Incidence of

Hepatocellular Carcinoma (HCC)

World prevalence of HBV carriers

Annual incidence of primary HCC

HBsAg carriersprevalence

Cases/100,000 population

<2%
27%
>8%
Poorly documented

13
310
10150
Poorly documented

08/30/15

WHO 59
1999

Faktor risiko dan Gejala

08/30/15

60

FAKTOR RISIKO HEPATITIS

VIRAL KRONIK
1.
2.
3.
4.
5.
6.
7.
8.

IDU (pemakai obat suntik), Tatoo

Overdosis asetaminofen, alkohol atau obat lain
Kebiasaan seksual risiko tinggi / freesex
Terkontaminasi : family, travel, eating, living
Resipien : - transfusi darah sblm th. 1990,
- transplantasi organ
AIDS
Bayi dengan ibu pengidap Hepatitis B atau C
Pekerja Kesehatan, Dentists and Dental Hygienists

08/30/15

61

Perjalanan Klinis HEPATITIS :

Penyakit Hepatitis akut kronik FAILURE
Komplikasi kegagalan hati :
Sirosis hati :
hipertensi portal varises esofagus :
pecah
HEMATEMESIS MELENA
hipoalbuminemia
asites : SBP
Hepatoma : HCC (diffuse parenchymal)
Lobulated hepatoma
Ensefalopati hepatikum
Sindroma hepatorenal

08/30/15

62

Diagnotic of Hepatitis B
Viral markers
HBV-DNA, HBsAg, HBeAg, Anti-HBs,
Anti-HBe and Anti-HBc.
Other markers
ALT (SGPT), Liver histology.
Clinical examination, Ultrasound.

08/30/15

63

Importance of Serum Markers

08/30/15

64

Diagnostic of Hepatitis C
HCV antibody tests
enzyme immunoassays (EIA)
recombinant immunoblot (RIBA)

HCV-RNA tests
Qualitative: AMPLICOR HCV Test [50 IU/mL]
Quantitative: AMPLICOR MONITOR Test [600
IU/mL]

08/30/15

65

Utility of HCV Diagnostic Tests

Method

Screen

ALT/AST

Enzyme
immunoassay (EIA)

Supplemental assay
(RIBA*)

HCV RNA qualitative

assay

Confirmation

Length
of Therapy

Predicting
Sustained
Response

HCV RNA quantitative

assay
HCV genotype

Assessing
Response
to Therapy

*No longer widely used.

08/30/15

66
NIDDK. Chronic hepatitis C: current disease management.

GEJALA DAN TANDA SH

GEJALA :

Cepat lelah, mengantuk siang hari,

tidak bisa tidur malam hari.
Ngomong ngaco.

TANDA-TANDA :
Badan kurus, perut membuncit (ascites),
muntah darah (hematemesis), tremor,
berak darah warna hitam/coklat
marun (melena), kesadaran berkabut
(encefalopati)
LABORATORIUM :
Hiperglobulinemia (rasio Alb/Glob terbalik)
Trombositopenia
08/30/15

67

 Sirosis hepatis selalu diawali dengan proses nekrosis hepato

seluler. Pembentukan jaringan parut / fibrosis merupakan dampak
dari peningkatan pembentukan serta penurunan degradasi matriks
ekstra seluler. Yang kemudian diikuti oleh kematian sel sel hati
sehingga memicu pembentukan nodul nodul abnormal.
Fibrosis merupakan marker penting dari distribusi perlukaan hati
yang luas , dan berdasarkan gambaran gambaran ini , beberapa
pola histologis dapat dibedakan. Dalam beberapa kasus , penentuan
pola histologis ini dapat sangat membantu dalam melakukan
diagnosa , mempersempit diagnosa banding , memperkirakan
kemungkinan etiologi serta mempertimbangkan prognosis.

08/30/15

68

Gejala dan Tanda HEPATOMA:

Bervariasi
Berlangsung perlahan-lahan
ikterus
Nyeri epigastrium
Rasa tidak enak pada perut kanan atas
BB menurun
Asites hemorrhagik

08/30/15

69

Diagnosis HEPATOMA:

Laboratorium : AFP (alfa feto protein)

USG Abdomen
CT-scan
Angiografi
Biopsi hati

08/30/15

70

Assess severity of
fibrosis and
necroinflammation1,2

Confirm clinical
diagnosis

Role of Liver
Biopsy
Evaluate possible
concomitant disease
processes (eg,
alcoholic liver disease,
NASH)1,2

08/30/15

Assess
therapeutic
intervention1

1. NIH Consensus Statement Online. Management of hepatitis C.

2. British Liver Trust Information Service. A guide to liver function71
tests.

Minimal HE and fitness to drive

Schomerus et al. Dig Dis Sci 1981;26:622

60-85% of cirrhotic patients are unfit to drive

Watanabe et al. Metab Brain Res 1995; 10:239

31-44% of cirrhotic patients are unfit to drive

Srivistava et al. J Hepatol 1994; 21:1039

No deficits in real driving

Wein et al. Neurol Rehabil 2001, 7:242-262

Driving deficits in SHE

08/30/15

Risk alertness ?
Epidemiological studies required
Behaviour in risky traffick situations

72

HE and fitness to drive

Preliminary results with
SHE patients:
reduced reaction time
Problems with track-keeping
correlation to HE severity
and age

Test ?
08/30/15

73

NUMBER CONNECTION TEST

08/30/15

74

Diagnosis of
of hepatic
hepatic encephalopathy
encephalopathy
Diagnosis
Manifest HE:

Subclinical HE:

Clinical picture

Gold-standard:
Computerpsychometry

West Haven Criteria

Subjective
classification
Imaging: for
No diagnostic value
HE grade I-II
Laboratory test:
No diagnostic value

08/30/15

Paper-Pencil-Tests:

Routine:
low sensitivity
Paper-Pencil-Tests
and specifity
Training effects
Age dependence
75

KRITERIA PENILAIAN WEST HAVEN

UNTUK UJI MENGHUBUNGKAN ANGKA
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4

15 - 30 sec.
31 - 50 sec.
51 - 80 sec.
81 - 120 sec.
> 120 (unable to do test)

L-ornithin-L-aspartate in the Therapy of Hepatic Encephalopathy, Merz Pharma

Frankfurt, Germany, 1995:9-Tab.4)
08/30/15
76

Flimmerfrequenz Analyzer
- Hepatonorm Analyzer-

08/30/15

77

Cause of Encephalohepathic

Liver cirrhosis
Acute Hepatitis
Hepatitis Chronic
Fatty Liver
NASH

08/30/15

78

PENCEGAHAN
MEDIKAMENTOSA
MINIMAL INTERVENSI

08/30/15

79

Terapi Pencegahan :
Menjaga dan meningkatkan Daya Tahan
Tubuh.
Menghindari :
- pemakaian jarum suntik berulangulang.
- seks bebas
- transfusi darah sembarangan
Memelihara higiene-sanitasi.
Imunisasi / Vaksinasi (untuk HBV).
08/30/15

80

Terapi Medikamentosa :
Uninfected
Hepatocyte
hepatocyte
regeneration
s
with Hepatoprotektor/stimulator
Infection

CAM

HBV or HCV
production
Immune
respons
e

Stimulate immune
response with IFN-

HBV or HCV
-infected
hepatocytes
Inflammation
and cell death

Averett DR and Mason WS. Viral Hep.

Clinical
Rev. 1995; 1:12942
08/30/15

Block HBV or HCV

production and/or reinfection
with antiviral,
Therapy N.A

hepatitis

Alcohol,
co-infection
etc.

Lysis of infected
hepatocytes and
regulation
of viral replication
Anti Encephalopathic

81

Pilihan Obat :
INTERFERON

ANTIVIRAL
NUKLEOSIDA
ANALOGUE

IMMUNE SUPPORT

HEPATOPROTEKTOR
:
ANTI ENSEFALOPATIK :
08/30/15

IFN Standar
Peg-IFN
Ribavirin
Lamivudine
Adevofir dipivoxil
Glicirrhizine, SST (TJ-9),
Thymosin
PPC 95,
LOLA
82

Treatment of hepatic
encephalopathy

TREATMENTS BASED UPON THE AMMONIA HYPOTHESIS

Reduction in ammoniagenic substrates
- Enemas
- Dietary protein reduction
Inhibition of intestinal ammonia production and absorption
- Oral antibiotics
- Lactulose and lactitol
- Modification of colonic flora
TREATMENTS BASED UPON THE FALSE
NEUROTRANSMITTER HYPOTHESIS
BCAA infusions
Oral BCAA supplements
TREATMENTS BASED UPON THE GABA HYPOTHESIS
MISCELLANEOUS TREATMENTS
Zinc
Melatonin

08/30/15

83

Stepwise approach to treatment of

hepatic encephalopathy in cirrhotics
Initial treatment:
correct precipitating factors
iv.fluids, REDUCED NH3 serum
restricted protein, neomycin
lactulose oral

+
Lactulose oral
BCAA oral

continue intensive care

parenteral nutrition
iv. Antibiotics,
BCAA infusion

+
Flumazenil
(antidotum CSE)

Protein intolerance < 50 g

Suplementation BCAA
08/30/15

Lactulose oral, TJ-9

84

No Drug for Hepatic

Encephalopathy? There is
..

Lactulose
Neomycin
BCAA

08/30/15

85

TERAPI ENSEFALOPATI HEPATIK

(Porto-Systemic Encephalopathy as a Complication of Liver Cirrhosis,

1. LOLA,vs.
Retriction protein-intake
Dr. Falk Pharma GmbH, Germany, 1995)
08/30/15

2. Anti-biotics

86

 If drug treatment is needed only treatments

with proven efficacy should be used:
flumazenil (only in case of BZD-induced HE)
lactulose enemas (in pts. with GI hemorrhage or
constipation)

ornithine-aspartate iv.
(hymerammonemia)
BCAA (longterm therapy in severe protein
intolerance)

08/30/15

87

INTERVENSION OPTIONS :
MINIMAL INTERVENSION :
1. PHLEBOTOMY
2. TACE
LIVER TRANSPLANTATION

08/30/15

88

Kapan dinyatakan sembuh dari

serangan infeksi Hepatitis

Serangan akut

Kondisi kronis

HBV

HCV

HBV

HCV

:
:
:

HBV

Fatty liver
Steato-hepatitis

Keadaan sembuh

HCV
:
Steat-hep:

08/30/15

HBsAg (+),
IgM anti HBc (+).
sulit diidentifikasi.
Anti HBc total (HBc + Hbe) neg(-)
HBsAg (+)
HBeAg (+) replikasi aktif
Anti HCV (+).
Dislipidemia, USG hati : FL (+)
Fatty liver, g-GT me , ALP me
HBsAg (-),
Anti HBs / Anti Hbe (+)/(+), HBV DNA (-)
Anti HCV (-), HCV RNA (-)
Lipid profil DBN, g-GT dan ALP DBN

89

08/30/15

90

Quran Ch 94 Ver.7-8
ALAM NASYRAH

Selesai satu urusan, kerjakanlah urusan lain

Dan hanya kepada Tuhanmulah

Hendaknya kamu berharap.

08/30/15

91