ULKUS PEPTIKUM

Siti Nurdjanah
Subbagian Gastroenterologi-Hepatologi
Bagian Ilmu Penyakit Dalam FK UGM/RS Dr. Sardjito
Yogyakarta

Dibacakan di Pelatihan Lanjut Farmasi Klinik UGM, 18 Januari 2007

 Ulkus peptikum mempengaruhi
kualitas hidup
Minimal 4 faktor lingkungan :
Faktor Etiologik
NSAID
Rokok
Stress lingkungan
Kebiasaan diit
Helicobacter pylori
Faktor Genetika
Golongan darah O + non sekretor
Kembar identik
HLA B5
 Patogenesis ulkus peptikum

Asam + Pepsin = mukus + sel-sel

INFLAMASI + Faktor-faktor lokal = ULKUS

 Patogenesis Ulkus Peptikum
1. Hipersekresi asam, gastrin dan pepsin
2. Resistensi mukosa
3. Bikarbonat endogen sebagai barier mukosa
4. Mukus sebegai pelindung mukosa
5. Integritas mukosa
6. Aliran darah mukosa
7. Faktor pertumbuhan (growth factors)
8. Mediator radang platelet-activating factor dan
leukotrien
9. Faktor virulensi H.pylori
Hipersekresi asam, gastrin & pepsin

Penderita ulkus duodeni:

produksi asam:
Basal
Maksimal (pembebanan histamin/pentagastrien)
Rangsang cephalic (shaw feeding/hipoglikemia
insulin)
Meningkat >< kontrol.
Sebaliknya ulkus gaster: N /
 Ulkus duodeni & gastric gastrin post
prandial.
Perokok produksi asam maksimal
Infeksi H.pylori gastrin
Pepsinogen I (PG I) dihasilkan chief cells
mukosa fundus lambung)
Ulkus duodeni PG I
Ulkus gastrik PG
H.pylori PG I
Perokok PG I
 Resistensi Mukosa

Pada penderita ulkus produksi asam N

mungkin ada penurunan resistensi mukosa
 Bikarbonat endogen sebagai barier mukosa

Bikarbonat dihasilkan epitel permukaan lambung

& duodenum meningkat ~ sekresi asam

Stimulasi vagal
Prostaglandin seri E
Opioid endogen
Poli peptida intestinal vasoaktif

H.pylori
NSAID menghambat bikarbonat
Rokok
 Mukus protektif mukosa
Mukus melindungi difusi balik asam &
pepsin
Prostaglandin mempercepat sintesis &
sekresi mukus
NSAID & rokok menghambat
prostaglandin
H. Pylori hidrofobitas mukus menurun
difusi balik asam & pepsin mukosa
rusak
 Integritas mukosa

Berperanan penting pertahanan ulserasi

Tergantung :
Lap. Lipoprotein
Integritas jaringan padat
Sekresi mukus
Restitusi normal sel-sel epitel permukaan
 Aliran darah mukosa

Vaskularisasi mukosa mengirim

oksigenasi & nutrien epitel permukaan
Ion-ion bikarbonat dibawa oleh arterial
mukosa epitel permukaan.
Ulkus gastrik & duodeni aliran darah
menurun.
 Faktor pertumbuhan

Epidermal growth factors:

Sitoproteksi gastrik ditemukan di :
kelenjar liur, kelenjar bruner, kelenjar
pankreas.
Ulkus peptikum rendah
 Mediator radang
Platelet-activating factor & leukotrien.
Lipid-lipid endogen terlibat dalam
proses peradangan sifat lipid
ulserogenik. disentesis mukosa
gastroduodenalis. Akibat rangsang stres &
iritan lokal.
 Faktor-faktor H.pylori
H.pylori pada lambung gastritis neutrofilik
akut lokal gastritis kronik aktif.
H.pylori menghasilkan :
Enzim proteasa, katalasa, lipasa, fosfolipasa Az,
sitotoksin (faktor virulensi).
Melepas faktor kemotaktik :
Leukotrien
Platelet aggregating factor.

mukosa radang rentan asam / peptik

 GASTROPATI AKIBAT
OBAT ANTI INFLAMASI
NON STEROID

Siti Nurdjanah
 Kasus
Seorang wanita 65 tahun penderita
osteoarthritis mendapatkan terapi dari
dokter keluarga berupa OAINs. Mula-mula
bisa mentolerir obat tersebut. Namun 3
bulan kemudian mengeluh ulu hati pedih
dan berak berwarna hitam. Masalahnya
penderita ini masih memerlukan OAINs.
Cause of Formation
- +
Of Digestive Ulcer
(Balance Theory) Gastric acid
Pepsin
Drugs (such as NSAID)
Mucous membrane barrier
Stress
Mucus
Alcohol
Bicarbonate ion
H.pylori
Blood current the mucous
membrane Free radical
Proliferating factoers Offensive Factors
AG in the mucous membrane

Defensive factors

Internal secretion system

Central nerves system

Constitution
Heredity
Environment

Other Factors
 Defensive Mechanism for Gastric Mucous Membrane and Each
Factors Affect the Mechanism

Offensive Factors
Acid, Pepsin Free radical
NSAIDs
Alcohol
Bilious acid

Defensive Factors
pH2
Mucus, alkali
pH7
Phosphoric lipid
PG
Cell
membrane
(Cell proliferating
factors
Cell migration )

Small circulation
Contents of AGML by Each Kind of Drug

Oral Others
hypoglycemi 9%
c agents
7%
Anti-
malignant
tumor drug
9%
NSAIDs
46%
Antibiotics
14%

Corticosteroi
ds
15%
 NSAID
Induced Gastrointestinal Toxicity:
Dyspepsia
Nausea and Vomiting
Esophagitis
Peptic Ulcers
GE-hemorrhage
GE-Perforation
 NSAID

NSAID - related Gastrointestinal injury

includes a combination of sub epithelial :
- Hemorhages
- Erosions
- Ulceration

Figure 1. Schematic diagram of gastroduodenal injury caused by nonsteroidal

antiinflammatory drugs. Mucosal hemorrhage is limited to the mucosa (M),
while erosions and ulcers extend to the submucosa (SM) and muscularis
externa (ME), respectively.
 Acute NSAID effect superficial injury
100% subject lesion after 650 - 1,300 mg
dose of aspirin
Long-term NSAID effect Gastroduodenal
ulceration
Hemorrhage
Perforation
Death
50 - 75% of arthritis patients mucosal
damage
10 - 20% gastric and duodenal ulcers
A value 5 - 15 fold greater than in an-matched
healthy population.
Table 2. Risk factors for nonsteroidal antiinflammatory
drug (NSAID) ulcer complications.

Definite
Age > 60
Prior ulcer disease or complication
High-dose, multiple NSAIDS
Concomitant corticosteroid therapy
Duration of therapy (<3 months)
Possible
Condition necessitating NSAID treatment
(e.g., rheumatoid arthritis)
Female sex
Smoking
Alcohol
Helicobacter pylori
 NSAID

TOPICAL INJURY SYSTEMIC INJURY

1. Tissue prostaglandins
2. Platelet acetylation
DIRECT EFFECT INDIRECT EFFECT
1. Ion trapping Reflux of bile containing
2. H+ back diffusion active metabolites
DECREASES
- Epithelial mucus
- Secretion of bicar-
bonate
- Mucosal blood flow
- Epithelial proliferation
- Mucosal resistance
to injury

Figure 3. Mechanisms by which nonsteroidal antiinflammatory drugs (NSAIDS)

induce gastroduodenal mucosal injury. (Adapted from the dual injury
hypothesis of Schoen and Vender [10].
 Role of PG

Cytoprotection

Restraining Expending Action

Action for Acid For Mucous
Secretion Secretion

Expending
Action for Alkaline Increasing Action
Secretion For Blood Current
 Subtypes of PG synthetase (COX) and Roles in the
Gastric Mucous Membrane

COX-1 COX-2
Contructive Inductive

Location Gastric Mucous Membrane Monocyte/Macrophage/

Vascular endithelium Fibroblast

NSAIDs

Protection of Gastric
Action Inflamation
Mucous Membrane

The Significance of PG to the Damage of Gastric Mucous Membrane by NSAIDs.

Testsuo et al., 1996. Digestive Ulcer-Basis and Clinic 15:43-49.
 Phospholipids
Phospholipase A2

Arachidonic Acid
Cyclooxygenase Lipoxygenase
(PGHS-1 and -2)

Cyclic Endoneroxide 5-HPETE

Prostacyclin Thromboxane A2 Leukotrienes

Prostaglandins

Figure 2. Pathways depicting the synthesis of prostaglandins and leukotrienes,

derived from membrane phospholipids. PGHS-1 and 2 = prostaglandin H
synthase-1 and -2.
 Obat-obat Pengendali Keasaman Lambung

Antasida
(murah, compilance rendah, tak efektif untuk ulkus
gaster, tidak konsisten mempertahankan pH
Intragastrik, interaksi dengan obat-obat lain, masih
bermanfaat pada refluks esofagitis ringan/sedang)
Antagonis reseptor-H2
(Cimetidine, ranitidine, famotidine)
(konsisten mempertahankan pH Intragastrik 4-8 jam,
kurang efektif pada meal stimulated maupun day time
acid secretion, cepat takhifilaksis, tidak efektif
mencegah ulkus gaster pada pemakai OAINS, masih
bermanfaat pada refluks esofagitis ringan/sedang)
 Penghambat Pompa Proton (omeprazole,
lanzoprazole, pantopazole, rabeprazole)
(long acting, efektif pada tindakan kuratif &
preventif ulkus duodenum dan ulkus gaster pemakai
OAINS dan kekambuhan refluks esofagitis, tidak
takhifilaksis, komponen penting tx. Eradikasi H.pylori)
Obat Sitoprotektif (sucralfat, teprenone)
(memelihara faktor-faktor pertahanan mukosa)
 Parietal cell

H+ Cl-
Cl-
Proton pump H+K+ATPase
Inhibitor
(-)
K+
Antagonis H2

(-)
Gastrin Acetylcholine Histamine

Sel parietal dan pompa proton (H+, K+-ATPase)

(Robinson, 1999)
 Tabel 8. Kemungkinan efek samping yang bisa timbul pada
pemakaian obat-obat pengendali keasaman lambung

Obat-obat pengontrol
Efek samping yang bisa timbul
asam lambung
Antagonis reseptor Sakit kepala, dizziness, nausea, mialgia, skin
histamin2H : rash, dan gatal-gatal

Penghambat pompa Nausea, diare, mungkin juga kolik abdominal.

proton : Keluhan sakit kepala, dizziness, dan somnolen
jarang dijumpai peningkatan ringan serum
transaminase

Obat-obat sitoprotektif : Sukralfat jarang menimbulkan efek samping,

bila ada konstipasi atau mulut kering, kadang-
kadang abdominal discomfort. Tidak ada efek
sampng serius dari teprenone kecuali hanya
peningkatan ringan serum aminotransferase.

(Shirakabe, 1995; Brunton, 1996)

 Kekuatan supresi asam lambung Lansoprazole
dibandingkan PPI lain yang pernah diteliti
Referensi Obat & Dosis Lama Efikasi keseluruhan
N (mg/hari)
Lansoprazole vs Omeprazole (hari) (bermakna)
Timmer et al L30 9 L60 > O 40
L30 b.d.
20 L45 b.d. 7 O 40 > L30
L60 b.d
O20 b.d.
Verdu et al. (hp+ve) L30 7 L 30 = O 20
18
O20 7
Tolman et al. L15 5 L30>L15,O20
17 L30
O20
Briley Des Varannes et al L30 7 L30 > O20
12
O20
Blum et al L15 5 L30 > L15, O20
29 L30
O20
Sensalu et al L15 5 O20 = L15, L30
L30 O 40 = L 60
16 L60
O20
O40
 Referensi N Obat & Dosis Lama Efikasi keseluruhan
(mg/hari) (hari) (bermakna)

L15 L30 > O20

Dammann et L30 L30 = O40
10
al O20
O40
Lansoprazole vs pantoprazole
L30 1 L30 >P40
7
Florent et al 12
P40 1
7
Lansoprazole vs pantopralozo/omeprazole
P40 L>O
Scholtz et al 18 L30 5 L=P
O20

(Stedman & Barclay, 2000)

 Lansoprazole mempunyai efek supresi asam lebih
kuat dibanding omeprazole pada dosis standar
(Howden, 1997)

Lansoprazole (30 mg) memberikan perbaikan

gejala lebih awal dan lebih baik dibanding Proton
pump inhibitor yang lain
(Steidman & Barclay, 2000)
 Rekomendasi untuk terapi OAINS Evidence Level

1. Penderita yang membutuhkan terapi OAINs pertamakali harus diberi

resep Ibuprofen dengan dosis rendah yang efektif. 2A

2. Penderita dengan riskiko tinggi komplikasi yang diinduksi OAINs harus

dipertimbangkan diberi profilaksi . 2B

3. Profilaksi ulkus pertama kali digunakan misoprostol, tetapi harus

diberitahukan efek samping GI. Bila obat ini tidak bisa ditoleransi harus
1A
diberikan PPI. Infeksi Hpylori harus dieradikasi pada awal pemberian
AOINs bila mungkin.
4. Ulkus peptikum yang diinduksi OAINs disembuhkan dengan PPI.
Misoprostal seefektif tapi kurang baik toleransinya. Diperkirakan sembuh
1A
dengan PPI, tak ada keuntungan dari eradikasi H pylori.

5. Semua penderita dengan ulkus peptik sebelumnya, ada risiko untuk

kambuh. Bila OAINs diteruskan, harus diberikan bersamaan PPI.
Misoprostol dan ranitidine kurang efektif daripada PPI. Eradikasi H 1A
pylori untuk pencegahan kekambuhan ulkus tidak berperanan.
 Kesimpulan
Ibuprofen OAINs terapi awal.
Penghambat pompa proton
pencegahan & terapi komplikasi
penggunaan OAINs.
Mesoprostol identik PPP kurang ditolerir
penderita
GASTROEOPHAGEAL
REFLUX DISEASE

Siti Nurdjanah
 The atypical presentation of
GERD
Heartburn &
Regurgitation
Dysphagia
Odynophagia

Associated with pulmonary symptoms and diseases

(Table I)
 Table 1. Extraesophageal symptoms and signs associated with
gastroesophageal reflux disease

Ear, Nose, and Throat

Hoarness
Globus
Pharingitis
Otitis
Laringitis
Vocal cord granuloma
Subglottic stenosis
Laryngeal cancer

Pulmonary
Asthma
Bronchitis
Bronchestasis
Aspiration pneumonia
Idiopathic Pulmonary fibrosis
Other
Noncardiac chest pain
Dental erosion
Sleep Apnea
 Pathophisiology of Reflux
esophagitis
Normal : integrity of esophageal mucosa :
Balance
Aggressive forces Defensive forces

Acid reflux Esophageal acid clearance

Potency of refluxate Mucosal resistance

ESOPHAGITIS
 Mechanisms of Reflux
Primary event : movement of gastric juice
from the stomach into the esophagus
The antireflux barrier at gastroesophageal
junction anatomically & physiologically
complex and vulnerable to several
potential mechanisms of reflux.
 Pathophysiologic mechanisms of
gastroesophageal junction incompetence :
3 Dominant

Transient lower esophageal sphincter

relaxations (TLERS)
A hypotensive lower esophageal sphincter
(LES)
Anatomic disruption of the
gastroesophageal junction hiatal hernia
 Transient lower esophageal sphincter
relaxations response to gastric
distension of food orgas
tLERs : integrated motor responses
LES relaxation
Crural diaphragmatic inhibition
Contraction of costal diaphragmatic
 Hypotensive lower esophageal
sphincter

- < 10 mmHg
Causes :
Gastric distension
Cholecystokinin
Various food (fat, chocolate, coffeine,
alcohol), smoking, many drugs.
 Hiatal hernia and the diaphragmatic
sphincter
Hiatus hernia reduced threshold for
eliciting tLESRs in renpose to gastric
distention
Malfunction of the gastroesophageal barier
Esophagogastric junction
compliance

Impotant in regulating :
Volume and content of reflux
 Esophageal acid clearance

Following
reflux period of
esophageal pH < 4 : acid clearance
time
 Esophageal emptying :

Peristaltic dysfunction failed on

hypotensive peristaltic contructions
Hiatal hernias impair esophageal
emptying
 Salivary function in GERD:
Reduced salivation or diminished salivary
neutralizing capacity prolongs acid
clearance.
Examples :
During sleep
Immediately prior to going to sleep
Cigarette smokers
 Ent manifestations of GERD
laryngeal disorders
Table : Laringeal conditions associated with GERD
Reflux laryngitis
Subglotic stenosis
Ca larynx
Contact ulcer and granulomas
Endotracheal intubation injury
Paroxysmal laryngospasm
Arytenoid pharingeus
Vocal nodules
Laryngomalacia
Pachyderma laryngis
Recurrent leukoplakia
Wong RKH, et al. 2000
 Pathophysiology
I. Direct : acid peptic injury to larynx
& surrounding tissues via EPR
II. Acid in the distal esophagus
stimulates vagally mediated reflexes
chronic throat clearing & coughing
laryngeal lesion & symptoms
III. I & II
 EPR + other risk factor
laringeal injury
Voice overuse
Chronic throat clearing behavior
Severe coughing
vomiting
 The other investigations : esophageal
dysmotility reflux laryngitis

Diagnosis reflux laryngitis

Symptoms :
Hourseness
Globus sensation
Frequent throat clearing
Halitosis
Frequent sorethroats
Chronic cough

Indirect mirror laryngoscope

Flexible fibreoptic laryngoscopes
 ASMA and GER
Asthma is on inflammatory disease with
multiple triggers
GER trigger asthma (Prev. 34
89%)
Patogenesis GER asthma

Asthma symptoms with

Esophageal Acid
 Vagally mediated esophageal bronchial
reflex

Stimulasi reseptor esophagus

refleks vagal asthma

Heightened bronchial reactivity respon

bronchomotor
Mikroaspirasi
Mikroaspirasi asam lambung PEF
 Airway inflamation
Esophageal acidity aktivasi refleks aksonal
lokal ( aktivasi) saraf sensorik) pelepasan
takikinin inflamasi neurogenik.
Konstriksi otot polos
Sekresi bronchial
Permeabilitas vaskular
Ekstra vasasi
Edema saluran nafas
resistensi pulmonar
 Asthma GER
Mechanism
Flattening diaphragma tonus LES
kontraktilitas
Tekanan intrathorakal
asthma attacs intrathoracal pressure
Pemakaian bronkodilator memperburuk
LES
 Asthma Symptoms with
Esophageal Acid

Esophageal Acid-induced
Bronchocontriction : Increase in minute ventilation
Vagally mediated esophageal bronchial reflex and respiratory rate
Heightened bronchial reactivity
Microaspiration

Evidence of Airway Inflammation :

Substance P and tachykinin release

Figure : Mechanisms of asthma symptoms with esophageal acid.

Acute Viral Hepatitis

Oleh :
Siti Nurdjanah
 Acute Viral Hepatitis
Hepatitis Virus Infections : The most
common cause of liver disease
Many Hepatitis episodes :aninteric,
inapparent, or subclinical
Glorally, viral hepatitis is the major cause
of persistent viremia
 The agents of viral hepatitis :
classified into two groups
Blood Borne Agents
Enterically transmitted
Hepatitis B Virus (HBV)
Hepatitis A Virus (HAV)
Hepatitis D Virus (HDV)
Hepatitis E Virus(HEV)
Hepatitis C Virus (HCV)
Possibly third agent (?HFV)
Hepatitis G Virus (HGV)
 HAV, HEV, and etc are non enveloped
viruses

Survive intact when exposed to bile

Shed in feces
Not linked to chronic liver disease
Dont result in a viremic or intestinal carrier
state
 HBV, HCV, HDV and HGV are :

Enveloped viruses
Disrupted by exposure to bile / detergents
Not sheld in feces
Linked to chronic liver diseases
Associated with persistent viremia
Model of the Hepatitis B Virus
Model of the Hepatitis C Virus
 Virus Hepatitis A, B, C, D, E, G
Hepatitis A B C D E G
Family Picornavirus Hepadnavirus flavivirus Viroid Calicivirus Flavivirus ?
27-32 nm 42 nm ? 36 nm 27-32 nm ?
Nucleic acid RNA single DNA double RNA single strand, RNA single strand, RNA single strand, RNA single strand,
strand, linear strand, circular circular circular linear linear
Incubation period 14-45 d (30d) 30-180 d(70 d) 14-180 d (50 d) - - -1 14-60 d (40 d) ?
(mean)
Transmission Yes No No No yes No
- fecal-oral route
-Blood No Yes yes yes No
-Vertically No Yes yes yes No ?
-Sexually No Yes yes yes No ?
Antigens HAAg HBsAg, HBeAg --- HDAg HEAg ---
Antibodies Anti-HAV Anti-HBs Anti-HCV Anti-HDV
Anti-HAV, IgM Anti-HBe Anti-HCV, Anti-HDV, Anti-HEV ---
Anti-HBc IgM IgM
Fulminant hepatitis 0,001-0,5% 0,5-1,0% 0,5 1,0% 1-3-25% 2% (25%-?) ?

Healing acute Hepatitis >99% >90% 10-40% 50-80% >95% ?

Chronic active 0% <10% (0,5%) 30-90% (<10) 20-50% ? (<5%) Yes (? %)
Hepatitis
Liver cirrhosis <0,1% 1% 5-30%? 10% ? ? Yes (? %)
Active immun Yes Yes No No No No
Passive immun yes yes No No No ? No
 Epidemiology and risk factors HAV
Incubation period : 15-50 days
Worldwide distribution : highly endemic in developing
countries
HAV is excreted in the stools
Viremia is short lived
Prolonged fecal excretion
Enteric
Other risk factors include exposure
No evidence for maternal-neonatal transmission
Prevalence correlates with sanitary standards & large
houseshold size
Percutaneous transmission rare
 Epidemiology and risk factors HEV

Incubation period : 40 days

Widely distributed : epidemic and endemic forms
HEV RNA in serum and stool during acute phase
The most common form of sporadic hepatitis
A largely waterborne epidemic disease
Intrafamilial, secondary cases are uncommon
Maternal-neonatal transmission has been
documented
Prolonged viremia or fecal shedding unusual
 Epidemiology and risk factors HBV

Incubation period: 15 to 180 days (average 60-90 days)

HBV viremia lasts for weeks to months after acute infection
1-5% of adults, 90% of infected neonates, and 50% of infants
develop chronic infection and persistent viremia.
Persistent infection linked with chronic hepatitis, cirrhosis,
hepatocellular carcinoma
Worldwide distribution : HBV carrier prevalence >15% in Asia.
HBV present in blood, semen, cervicovaginal secretions, saliva,
other body fluids.
 Modes of transmission
Bloodborne
Recipients of multiple blood
products
Injecting drug user
Hemodialysis patients
Health care and other workers
exposed to blood
Sexual transmission
Tissue penetrations
(percutaneous) or permucosal
transfer
Needlestick accidents
Shared razoblades
Tattoo
Acupuncture
Shared toothbrushes
Maternal-neonatal, maternal-
infant transmission
No evidence for fecal-oral spread
 Epidemiology and risk factors HDV

Incubation period : 4-7 weeks

Endemic in Mediterranean basin, European parts of
former Soviet Union, parts of Africa, Middle East, and
Amazon basin.
Viremia short lived (acute infection) or prolonged
(chronic infection).
HDV infections occur solely in individuals at risk for
HBV infection (coinfections or superinfections)
Modes of transmission
 Epidemiology and risk factors HCV

Incubation period :15 to 160 days (major peak

at about 50 days)
Prolonged viremia and persistent infection
common : wide geographic distribution
Persistent infection linked with chronic hepatitis,
cirrhosis, hepatocellular carcinoma
Modes of transmission
 Epidemiology and risk factors HGV

Incubation period uncertain

Prolonged viremia and persistent infection
common
HGV RNA in 10 20% of patients with
Chronic hepatitis
Chronic hepatitis B
Chronic hepatitis C
Cryptogenic cirrhosis
Modes of transmission
 Pathophysiology
Cell-mediated immune mechanisms of
hepatocyte injury in HAV and HBV,
uncertain for HCV.
Membrane attack complex of complement
fulminant and acute hepatitis
Activation of the complement terminal pathway,
leading to deposition of the membrane attack
complex on hepatocytes necrosis.
Direct viral cytopathic effect HCV and HDV
(no direct evidence)
Limited information : HEV, HGV
 Clinical Features
A. Self-limited diseases
Clinically a symtomatic in apparent
infection fulminant, fatal disease
Clinical syndromes: non specific prodromal
Malaise, anorexia, nausea and vomiting
Flu-like symptoms of pharyngitis, cough, coryza,
photophobic, headache, and myalgias.
Onset of symptoms tends to about for
HAV & HEV, the other : insidious.
 Fever uncommon except HAV infection
Serum sickness syndrome < 10% of
HBV infection
Prodromal symptom disappear onset
jaundice, dark urine, pruritus (mild,
transient).
Hepatomegaly
Splenomegaly
 B. Fulminant disease
Changes in mental status (encephalopaty)
Lethargy, drowsiness, coma
Reversal of sleep patterns
Personality changes
Cerebral edema
Coagulopathy
Multiple organ failure
Development of ascites, anasarca
Case fatality rate : 60%
Serial physical examinations : shrinking liver
Extraordinarily high rates, approaching 10-
20%, in pregnant women with hepatitis E,
particularly during the third trimester.
 C. Cholestatic hepatitis

Jaundice may be striking and persist for several

months prior to complete resolution
Pruritus may be prominent
Persistent anorexia and diarrhea in a few patients
Excellent prognosis for complete resolution
Most commonly seen in HAV infection
 D. Relapsing Hepatitis

Symptoms and liver test abnormalities recur weeks

to months after improvement or apparent recovery
Most commontly seen in HAV infection IgM anti-
HAV may remain positive, and HAV may once again
be shed in stool.
Arthritis, vasculitis, and cryoglobulinemia may be
seen.
Prognosis is excellent for complete recovery even
after multiple relapses (particularly common in
children)
 Laboratory Features

Self-limited disease
Serum aminotransferasa (AST & ALT) :
Serum bilirubin
Alkaline phosphatase N/middly elevated
Peripheral blood counts : N/mild leukopenia
 Fulminant disease
Striking coagulopathy
Leukocytosis, hyponatremia, and hypokalemia
coomon
Hypoglycemia
Bil, AST & ALT the latter
Cholestatic disease
Bil
AST & ALT N
Alakali phosphatase
Relapsing hepatitis
Bil, AST and ALT N during convalescence
 Diagnosis
A. Differential diagnosis
Drug and toxin induced liver disease
Ischemic hepatitis
Autoimmune hepatitis
Alcoholic hepatitis
Acute biliary trac obstruction
 Serologic Diagnosis
Agent Acute phase convalescence
HAV Total anti HAV (+) Development of IgG anti-HAV
IgM anti HAV (+) Desappearance of IgM anti-HAV
HEV IgM anti HEV (+) and.or HEV RNA Loss of HEV RNA : development of IgG
(in stool) anti-HEV
IgG anti HEV may be present Loss of IgM anti-HEV
HBV HBsAg (+) and IgM anti-HBc (+) Loss of HBsAg: later loss of IgM anti-HBc;
development of IgG anti-HBc; late
development of anti-HBs
HDV HDV RNA (+) or HDV antigen (+) Loss of HDV RNA or antigen: development
or IgM anti HDV (+) in HBsAg (+) of IgG anti-HDV or loss of anti HDV
patient
HDV/HBV Coinfection : IgM anti HBc (+) Above plus usual loss of HBsAg
HDV/HBV Superinfection : IgG anti HBc (+) Above usually without loss of HBsAg
HCV Early presence of HCV RNA : Loss of HCV RNA (in a minor proportion of
presence of or development of patients): anti-HCV persistent
anti-HCV
HGV HGV RNA (+) ?
 Treatment
A. Self-limited infection
Outpatient care unless persistent vomiting or
severe anorexia leads to dehydration
Maintenance of adequate caloric and fluid intake
No specific dietary recommendations
A large breakfast may be best-tolerated meal
Prohibitation of alcohol during acute phase
Vigorous or prolonged physical activity should be
avoided
Limitation of daily activities and rest periods
determined by the severity of fatigue and malaise
No specific drug treatment; cortcosteroids of no
value
All nonessential drugs discontinued.
B. Fulminant hepatitis
Hospitalization required
As soon as diagnosis made
Management best undertaken in a center with a liver
transplantation program
No specific therapy available
Goals
Continous monitoring and supportive measures while
awaiting spontaneous resolution of infection and
restoration of hepatic function
Early recognition and treatment of life-threatening
complications
Maintenance of vital functions
Preparation for liver transplantation if recovery appears
unlikely
Survival rates of about 65% or greater achieved
by early referral for liver transplantation
C. Cholestatic hepatitis
Course may be shortened by short-term
treatment with prednisone or
ursodeoxycholic acid, but no clinical trials
available
Pruritus may be controlled with
cholestyramine
D. Relapsing hepatitis
Management identical to that of self-
limited infection
 Prevention of transmitted
infections
HAV : immunoprophylaxis is the cornerstone of
preventive efforts
Pre-exposure immunoprophylaxis : inactivated HAV
vaccine dose and schedule :
Adults : 2 dose regimen (1440 Elisa units), second dose at 6-12
months after first.
Children > 2 years : 3 dose regimen (360 elisa Units) 0,1 and 6-
12 months or 2-dose regimen (720 elisa units), 0 and 6-12
months.
Post-exposure immunoprophylaxis : immune globulin :
0,02 ml/kg body weight, deltoid injection, as early as
possible after exposure.
 HBV : the cornerstone of immunoprophylaxis is
the pre-exposure administration of HBV vaccine

Pre-exposure immunoprophylaxis,
Adults : 10 or 20 ug of HBsAg protein i.m. injection (in
deltoid)
Infants : 2.5, 5, or 10 ug doses initial injection, repeated 1
and 6 months later.
Post-exposure
0,04 0,07 ml/kg HBG as soon as possible after
exposure vaccine doses given 1 & 6 months later.
A dose of 0.5 ml of HBIG given within 12 hours of birth into
the anterolateral muscle of the thigh. HBV vaccine, in doses
of 5-10 ug given within 12 hours of birth (at another site in
the anterolateral muscle) repeated at 1 and 6 months.
Chronic Viral
Hepatitis

By
Siti Nurdjanah
 Chronic Viral Hepatitis
Def. Persistent inflammation of the liver >
6 month after initial exposure and /or
initial detection of liver disease.
Etiology : HBV, HCV and HDV
Complication :
Cirrhosis Portal hypertension
hepatic failure
HCC (Hepatocellular Carcinoma)
Gambar 4 : Mekanisme replikasi HVB dan tempat kerja dari terapi yang berbeda
Malik A & Lee W, Ann Int of Med 132(9)2000
 Hepatitis B
Clinical manifestation/natural history acute
illness mild. The risk of chronicity depend on :

Age at acquisition Risk of HBV chronicity

Immunocompetent adult <5%

Immunocompromised adult >50%
Early childhood 50%
Newborn 90%
Immunocompromised :
Reduced ability to recognize and/or clear viral infections
 Symptoms of Chronic hepatitis :
asymptomatic

Nonspecific Advanced disease

complaints Variceal bleeding
Fatique Encephalopathy
Right upper quadrant Ascites
pain Infection
Arthralgias (spontaneous
bacteriil peritonitis)
Hepatocellular Ca
 Symptoms extrahepatic
manifestations
Arthralgis (common)
Glomerulonephritis (rare)
Polyarteritis nodusa (rare)
Vasculitis (rare)
Pericarditis (rare)
Pancreatitis (rare)
 Serological and virological tests
HBV serological & virologic markers Stage of disease/interpretation

HBsAg Ongoing in infection

IgM anti-HBc Recent infection or reactivation of chronic
infection
IgG anti-HBc with anti-HBs Prior infection
IgG anti-HBc alone Prior infection, low-level infection or false-
positive test
Anti-HBs alone Vaccine-induced immunity
HBeAg Active viral replication
Anti-HBe Low replication and infectivity
HBV DNA (varous methods of detection) Active disease with active viral replication;
when present in inactive disease, sensitive
molecular methods neededs for detection.
HBV DNA in the absence of HBe-Ag Mutations in the precore gene results in failure
of HBeAg production; associated with
fulminant acute infection and aggressive
chronic disease
 TERAPI
Goals of therapy include :
Prevention of long term complications
Reduction in morbidity and mortality
Symptomatic improvement
Loss of HBV DNA
Seroconversion : HBeAg pos anti HBe pos.
ALT : N
Hepatic inflamation reduced (PA)
Prevention of secondary spread of infection
 Specific Drugs
A. Interferon : 5 MU three times/week : 16
weeks
B. Lamivudine : 100 mg/day 1 year
C. Famciclovir
Liver transplantation : endstage chronic
liver disease
 HEPATITIS C
Natural history
Infection >80% persist
Progression of disease silent identifed :
On routine biochemical screening
During the course of blood donation
15% LC HCC
20-30 years of infection develop
clinically significant disease.
 Risk factors for
Proportion in the USA
acquisition
Percutaneous
Transfusion associated <5%
Injection drug use 40%
Needlestick exposure 1%

Non percutanous
Sexual contact Unknown (probably low)
Perinatal exposure Unknown (probably low)
sporadic 40%
 Clinical finding
Fatigue most frequent
Depression
Nausea
Anorexia
Abdominal discomfort
Difficulty with concentration
Advanced :
Ascites
Encephalopaty portal hypertension
GE bleeding
Hepatic decompensation jaundice
 Pathogenesis of HCV liver injury

Direct cytopathic damage

Immun directed hepatocyte inflamation
and distruction
Viral induced autoimmunity
 Therapy : I drugs
Interferon -2b 3 mU 3x weekly/6 months
initial response rate : 40-50% sustained
biochemical response rate : 25%.
Combination INF + Ribavirin improving
sustained response rate
Response therapy :
ALT : N
HCV-RNA neg.
II Liver transplantation
 CIRRHOSIS
Definition : a diffuse process characterized
by fibrosis and the conversition of normal
liver architecture into structurally
abnormal nodules which lack normal
lobular organization (WHO)
 Failure function of hepatic cells &
interference blood flow in the liver
Jaundice
Portal hypertension & varices
Ascites
Hepatic encephalopathy
Ultimately hepatic failure
 Classification
Morphologic less useful considerable
overlap
Micronodular C uniform nodules < 3 mm in
diameter
Macronodular C nodular variation > 3 mm
Mixed C

Etiologic
Most usefull clinically
Excessive alcohol use & viral hepatitis
 Clinical features
General features Renal
Gastrointestinal Endocrine
Hematologic Neurologic
Pulmonary Musculoskeletal
Cardiac : hyperdinamic Dermatologic
circulation
 General features
Fatigue
Anorexia
Malaise
Weight loss
Muscle wasting
fever
 Gastrointestinal
Parotid enlargement
Diarrhea
Cholelithiasis
Gastrointestinal bleeding
Esophageal/gastric/duodenal/rectal varices
Portal hypertensive gastropathy/colopathy
Peptic ulcer disease
gastritis
 Hematologic
Anemia
Folate deficiency
Spur cell anemia
Splenomegally with resultant pancytopenia
Thrombocytopenia
Leukopenia
Impaired coagulation
Disseminated intravascular coagulation
Hemosiderosis
 Pulmonary
Decreased oxygen saturation
Altered ventilation-perfusion relationships
Primary pulmonary hypertension
Hyperventilation
Reduced pulmonary diffusion capacity
Hepatic hydrothorax
Hepatopulmonary syndrome
 Renal
Secondary hyperaldosteronism-leads to
sodium and water retention
Hepatic glomerulosclerosis
Renal tubular acidosis (more frequent in
alcoholic cirrhosis, Wilsons disease, and
primary biliary cirrhosis)
Hepatorenal syndrome
 Endocrine
Hypogonadism
Males; loss of libido, testicular atrophy, impotence, decreased
amounts of testosterone
Females : infertility, dysmenorrhea, loss of secondary sexual
characteristics
Feminization=acquisition of estrogen-induced
characteristics :
Spider telangiectases
Palmar erythema
Gynecomastia
Changes in body hair patterns
Diabetes
Elevated parathyroid hormone levels-may be due to
hypovitaminosis D and secondary hyperparathyroidism
 Neurologic
Hepatic encephalopathy
Peripheral neuropathy
 Musculoskeletal
Reduction in lean muscle mass
Hypertrophic osteoarthropathy: synovitis,
clubbing, and periostitis
Hepatic osteodystrophy
Muscle cramps
Umbilical herniation
 Dermatologic
Spider telangiectasis
Palmar erythema
Nail changes : clubbing, white nails, azure
lunules
Dupuytrens contractures
Jaundice
 Potential complications of cirrhosis

Ascites
Spontaneous bacterial peritonitis
Variceal hemorrhage
Hepatic encephalopathy
Hepatocellular carcinoma
Hepatorenal syndrome
 Diagnosis of cirrhosis
Physical examination
Laboratory evaluation
Imaging modalities
 Management
Spicific treatment
Phlebotomy for hemochromatosis
Alcohol ovoidance for alcohol induced cirrhosis
Antiviral drug
Most cases focuses on treatment of
complication
Screening for HCC
Serial USG (every 6 months)
Serum alpha feto protein
Liver transpantation
 Prognosis
Depend on the development of cirrhosis
related complication
Proposed to access survival childs
classification
TERIMAKASIH