PEMICU 02

HEPATO
Joshua Kurniawan
405170101
Learning Issues
1. MM Embriologi Hati, Duktus Biliaris, Kantung Empedu
2. MM Metabolisme Bilirubin
3. MM Definisi dan Etiologi Ikterus
4. MM Klasifikasi Ikterus
5. MM Patofisiologi Ikterus
6. MM Faktor Resiko Ikterus
7. MM DD Ikterus Berdasarkan Usia
8. MM Pendekatan Diagnosis Ikterus
9. MM Tatalakasana Ikterus
Harrison’s Internal Medicine Ed 20 th
Robbins and Cotran Pathologic Basis of Disease
Embriologi Hati, Duktus
Biliaris, Kantung Empedu
Hati
• Primordium hati muncul di pertengahan minggu ke-3  penonjolan epitel
endodermis di ujung distal usus depan  Divertikulum hati  menembus
septum transversum
• Sel hati terus berkembang  hubungan antara divertikulum hati dan usus depan
(duodenum) menyempit  Duktus biliaris
• Duktus biliaris  kantung empedu dan duktus sistikus
• Epitel korda hati + v. vitelina dan v. umbilikalis  sinusoid hati
• Korda hati berdiferensiasi menjadi parenkim (sel hati) dan membentuk lapisan
ductus biliaris
• Sel hematopoietik, sel Kupffer, sel jaringan ikat berasal dari mesoderm septum
transversum
Embriologi Kedokteran Langman Ed 12
Embriologi Kedokteran Langman Ed 12
Hati
• Sel hati menginvasi seluruh septum transversum  organ menonjol di
kaudal ke dalam rongga abdomen
• Mesoderm septum transversum antara [hati-usus depan] dan [hati-
dinding abdomen ventral]  omentum minus dan ligamentum falciforme
• Omentum minus + Ligamentum falciforme  Mesenterium ventral /
Mesogastrium ventral
• Ligamentum falciforme mengandung vena umbilikalis  obliterasi
sesudah lahir  ligamentum teres hepatis (lig. rotundum hati)
• Tepi bebas omentum minus  lig. hepatoduodenale dan trias porta, juga
membentuk atap foramen epiploikum Winslow

Embriologi Kedokteran Langman Ed 12

Embriologi Kedokteran Langman Ed 12
Embriologi Kedokteran Langman Ed 12
Hati
• Mesoderm di permukaan hati
berdiferensiasi  peritoneum
viserale (KEC. di permukaan
kranial  area nuda)
• Area nuda tetap berkontak
dengan sisa septum
transversum yang asli
(mesoderm), membentuk
tendon sentral diafragma

Embriologi Kedokteran Langman Ed 12

Hati
• Minggu ke-10  berat hati ±10% BB total, akibat sinusoid dan fx
hematopoietik
• Fx hematopoietic mereda 2 bulan terakhir kehamilan
• Berat hati saat lahir ±5% BB total

Embriologi Kedokteran Langman Ed 12

Kandung Empedu dan Duktus
Biliaris
• Minggu ke-12  kandung empedu dan duktus biliaris berkembang
dan duktus sistikus telah bergabung dengan duktus hepatikus
membentuk duktus biliaris
• Perubahan posisi duodenum  muara duktus biliaris bergeser
bertahap dari anterior ke posterior  duktus biliaris berjalan di
belakang duodenum

Embriologi Kedokteran Langman Ed 12

Embriologi Kedokteran Langman Ed 12
Embriologi Kedokteran Langman Ed 12
Regulasi Molekular Pembentukan
Hati
• Endoderm usus depan mengekspresikan gen spesifik hati
• Dihambat oleh faktor yang diproduksi oleh jaringan sekitarnya termasuk
ectoderm, mesoderm non-jantung dan terutama notokorda
• Kerja inhibitor ini dihambat region bakal hati oleh fibroblast growth factor
(FGF2) yang disekresikan mesoderm jantung dan oleh sel endotel pembentuk-
pembuluh darah yang berdekatan dengan tabung usus di tempat tonjolan
tunas hati
• Faktor lainnya yang berperan  bone morphogenetic protein (BMP) oleh
septum transversum
• Sel hati berdiferensiasi (hepatosit & turunan sel empedu) sebagian diatur
oleh hepatocyte nuclear transcription factor 3 dan 4 (HNF3 dan 4)
Embriologi Kedokteran Langman Ed 12
Embriologi Kedokteran Langman Ed 12
Metabolisme Bilirubin
Porfirin - bilirubin
Porfirin adalah senyawa siklik yang dibentuk oleh ikatan 4 cincin pirol melalui jebatan metin (=HC- )
sifat khasnya adalah oembentukkan kompleks dengan ion logam yang berikatan pada atom nitrogen cincin pirol.

porfirin + besi = heme

porfirin + mg = klorofil

di alam hanya dapat ditemukan 2 jenis porfirin, yaitu porfirin tipe I ( simetris ) dan porfirin tipe III ( asimetris ). namun
diantara keduanya porfirin III yang lebih sering dijumpai, bahkan Heme menggunakan perkusor protoporfirin IX yang
berasal dari porfirin tipe III
Biokimia Harper Ed.29
sintesis Heme ditunjukkan dalam
beberapa gambar berikut

Keterangan :
• piridoksal phosphate berguna untuk
mengaktifkan glisin
• ALA sintase merupakan katalis
sekaligus enzim penentu kecepatan
biosintesis ( sintesis ALA terjadi di
mitokondria )
• di sitosol 2 molekul ALA dikondensasi
oleh ALA dehydratase membentuk
profobilinogen

Biokimia Harper Ed.29

lanjutan pembentukan heme

keterangan :
• uroporfirinogen I sintase dissebut juga PBG deaminase atau
HMB sintase
• pada kondisi normal hampir seluruh yang terbentuk
merupaka isomer tipe III
• A = asetat, P = propionat
• setelah terbentuk uroprofirinogen, akan terjadi dekarboksilasi
semua gugus asetat menjadi metil shg menjadi coproporfirin.
rx ini dikatalis oleh uroporfirinogen dekarboksilase

Biokimia Harper Ed.29

koporfirinogen III akan masuk ke mitokondria untuk diubah menjadi protoporfirinogen III ( dikatalisis oleh
koproporfirinogen oksidase ) dan kemudian menjadi protoporfirin III ( dikatalis oleh protoporfirinogen
oksidase )

protoporfirin III akan berikatan dengan fe dengan bantuan ferokelatase

ringkasan di slide berikutnya

Biokimia Harper Ed.29

Biokimia Harper Ed.29
Hubungan ALA sintase ,Heme dan
Sitokrom P450
• sintesis heme terjadi di sel prekursor ertiroid di sumsum tulang ( 85% ) dan
sebagian besar sisanya di hepatosit dan heme adalah regulator negatif
terhadap pembentukkan ala sintase melalui suatu molekul aporeceptor
• banyak obat yang menyebabkan peningkatan ALAS-1 secara bermakna,
dikarenakan metabolisme obat ini akan menggunakan suatu hemoprotein
spesifik yaitu sitokromP450. pemakaian heme oleh sitokrom akan
meningkat,shg akan meningkatkan ALAS 1 secara bersamaan
• pemberian glukosa dan hematin ( heme yang teroksidasi ) dapat membantu
mencegah depresi ALAS 1 ( hepatik )
• ALAS II ( eritroid ) tidak terpengaruh obat dan tidak mengalami umpan balik
negatif dari heme
Biokimia Harper Ed.29
Porfiria
• adalah sekelompok penyakit yang diitas jalur biosintesis heme,
bersifat genetik atau juga bs didapat
• fotosensitivitas dan bentuk tubuh yang aneh juga diidap sebagian
penderita
• koproporfirin dan uroporfirin berguna untuk mendeteksi karena
umumnya pada penyakit ini, 2 senyawa tersebut dieksresikan dalam
jumlah besar

Biokimia Harper Ed.29

Katabolisme heme menghasilkan
bilirubin

Biokimia Harper Ed.29

Metabolisme bilirubin
• dalam 100 ml plasma, sekitar 25 mg bilirubin dapat berikatan erat dengan
albumin, bila berlebih maka akan terlepas dan mudah terdifusi ke dalam
jaringan ( karena bilirubin larut lemak )
• bilirubin juga bersaing dengan bbrp obat dan antibiotik untuk berikatan
dengan abumin
• di hati bilitubin dikelluarkan dari albumin dan diserap pada permukaan
sinusoid hepatosit oleh suatu sistem yang diperantarai oleh karier perantara
yang dapat jenuh. sistem transpor terfasilitasi itu memiliki kapasitas yang
besar bahkan dalam keadaan patologis sekalipun
• di dalam sel hati, bilirubin akan berikatan dengan suatu protein tertentu
( ligandin dan portein Y )
Biokimia Harper Ed.29
Metabolisme bilirubin
• selanjutnya bilirubin akan mengalami
konjugasi ( ex : dengan glukoronat
atau lainnta seperti sulfat )
• hasil akhirnya yaitu bilirubin
diglukuronida akan disekresi ke dalam
epeduu melalui suatu mekanisme
transpor aktif dengan bantuan protein
MRP-2 ( multidrug resistance like
protein 2 ) atau disebut juga MOAT -
multispesific organic anion transporter
• protein itu terletak pada membran
kanalikulus empedu
Biokimia Harper Ed.29
Bilirubin
• Bilirubin diproduksi di sistem retikuloendotelial sebagai hasil akhir
dari katabolisme heme melalui reaksi oksidasi-reduksi
• Bilirubin indirek/unconjugated
• Larut dalam lemak
• Bilirubin direk/conjugated
• Larut dalam air
Fase metabolisme bilirubin:
- Fase pembentukan bilirubin
- Fase transport plasma
- Fase liver take up
- Fase konjugasi
- Fase ekskresi bilier
(Jika terjadi gangguan pada salah satu dari 5 fase
metabolisme bilirubin  ikterus)

Dapat juga dibagi menjadi 3 fase:

• Prahepatik  hemolisis, pemecahan heme
• Intrahepatik  liver take up, konjugasi
• Pascahepatik  ekskresi bilirubin
 Hemoglobin

Heme Globin
Terikat dengan albumin
Heme oksigenase menuju plasma
Biliverdin reduktase

Biliverdin Bilirubin Dalam hepatosit

indirek bilirubin berikatan
dengan ligandin
Masuk ke hati
Besi CO
Bilirubin + asam glukorinik
dikatalisasi oleh uridine
diphosphoglucuronyltransfer
ase (UDPGT)
Pool besi Paru-paru
Urobilin
Bilirubin direk larut air
Sterkobilin (90%)  masuk ke aliran cairan
Siklus enterohepatik empedu
• Sebagian cairan empedu
yang mengandung bilirubin
mengalami dekonjugasi
melalui proses hidrolisis
dengan B-glucuronidase
 peningkatan kadar
bilirubin plasma total

• Sirkulasi enterohepatik
lebih ekstensif pada
neonatus karena asupan
yang terbatas
 perpanjangan waktu
transit usus
Biokimia Harper Ed.29
1. Normal bilirubin production from heme (0.2–0.3
gm/day) is derived primarily from the
breakdown of senescent circulating erythrocytes
2. Extrahepatic bilirubin is bound to serum albumin
and delivered to the liver
3. Hepatocellular uptake and
4. Glucuronidation in the endoplasmic reticulum
generate bilirubin monoglucuronides and
diglucuronides, which are water soluble and
readily excreted into bile
5. Gut bacteria deconjugate the bilirubin and
degrade it to colorless urobilinogens. The
urobilinogens and the residue of intact pigments
are excreted in the feces, with some
reabsorption and excretion into urine.
Robbins and Cotran Pathologic Basis of Disease
Definisi dan Etiologi
Ikterus
Jaundice
• Jaundice is a yellowish discoloration of body tissues resulting from the
deposition of bilirubin.
• The common causes of jaundice are bilirubin overproduction,
hepatitis, and obstruction of the flow of bile
• Alterations of bile formation become clinically evident as yellow
discoloration of the skin and sclera (jaundice and icterus, respectively)
due to retention of bilirubin, and as cholestasis, characterized by
systemic retention of not only bilirubin but also other solutes
eliminated in bile.

Harrison’s Internal Medicine Ed 20 th , Robbins and Cotran

Pathologic Basis of Disease
Jaundice
• Serum bilirubin levels in the normal adult vary between 0.3 and 1.2
mg/dL
• Rate of systemic bilirubin production is equal to the rates of hepatic
uptake, conjugation, and biliary excretion.
• Jaundice becomes evident when the serum bilirubin levels rise
above 2.0 to 2.5 mg/dL; levels as high as 30 to 40 mg/dL can occur
with severe disease

Robbins and Cotran Pathologic Basis of Disease

Jaundice
• Jaundice occurs when the equilibrium between bilirubin production and
clearance is disturbed by one or more of the following mechanisms:
1. Excessive extrahepatic production of bilirubin;
2. Reduced hepatocyte uptake;
3. Impaired conjugation;
4. Decreased hepatocellular excretion;
5. Impaired bile flow.
• The first three mechanisms produce unconjugated hyperbilirubinemia,
and the latter two produce predominantly conjugated
hyperbilirubinemia.

Robbins and Cotran Pathologic Basis of Disease

Harrison’s Internal Medicine Ed 20 th , Robbins and Cotran
Pathologic Basis of Disease
Cholestasis
• Cholestasis denotes a pathologic condition of impaired bile formation
and bile flow, leading to accumulation of bile pigment in the hepatic
parenchyma
• It can be caused by extrahepatic or intrahepatic obstruction of bile
channels, or by defects in hepatocyte bile secretion
• Patients may have jaundice, pruritus, skin xanthomas (focal
accumulation of cholesterol), or symptoms related to intestinal
malabsorption, including nutritional defi ciencies of the fat-soluble
vitamins A, D, or K

Robbins and Cotran Pathologic Basis of Disease

Cholestasis
• Common to both obstructive and non-
obstructive cholestasis is the accumulation
of bile pigment within the hepatic
parenchyma (Figs. 18–6 and 18–7)
• Elongated green-brown plugs of bile are
visible in dilated bile canaliculi (Fig. 18–7B)

Robbins and Cotran Pathologic Basis of Disease

 Obstruction of the biliary
Biliary Cirrhosis
tree

Cholestas
is
Distention of upstream bile
Portal tract fibrosis
ducts and ductules by bile

Feathery change of
hepatocytes, focal
Bile stasis and ↑ back- dissolution of hepatocytes
pressure by detergents, ( bile lakes
Robbins and Cotran Pathologic Basis of Disease
filled with cellular debris
and pigment)
Jaundice
Two conditions result from specific defects in hepatocellular bilirubin
metabolism:
• Neonatal Jaundice
• Hereditary Hyperbilirubinemias

Robbins and Cotran Pathologic Basis of Disease

Neonatal Jaundice
• Because the hepatic machinery for conjugating and excreting
bilirubin does not fully mature until about 2 weeks of age, almost
every newborn develops transient and mild unconjugated
hyperbilirubinemia, termed neonatal jaundice or physiologic
jaundice of the newborn
• This may be exacerbated by breastfeeding, as a result of the presence
of bilirubin-deconjugating enzymes in breast milk. Nevertheless,
sustained jaundice in the newborn is abnormal, discussed later under
neonatal hepatitis.

Robbins and Cotran Pathologic Basis of Disease

Hereditary Hyperbilirubinemias

Robbins and Cotran Pathologic Basis of Disease

Harrison’s Internal Medicine Ed 20 th
Harrison’s Internal Medicine Ed 20 th
Jaundice and Carotenemia
• Jaundice must be distinguished from yellow or green skin color resulting from
carotenemia or quinacrine ingestion.
• Eating large quantities of green and yellow vegetables, tomatoes, or yellow corn may
result in excess carotene intake
• The resultan yellow skin color is differentiated from jaundice by the absence of
yellow color in mucous membranes and sclerae, the normal urine color, and the
accentuation of yellow-brown carotenoid pigment in the palms, soles, and nasolabial
folds.
• Quainacrine, commonly used for treatment in giardiasis, may produce a yellow skin
color, but the urine remains normal.
• Serum bilirubin levels are normal in patients with yellow skin caused by carotenemia
or quinacrine.
https://www.ncbi.nlm.nih.gov/books/NBK413/
Klasifikasi Ikterus
??????????????
Patofisiologi Ikterus
Bilirubin
• Both unconjugated bilirubin and conjugated bilirubin (bilirubin
glucuronides) may accumulate systemically
• 2 important pathophysiologic differences between the two forms of
bilirubin
• Unconjugated bilirubin is virtually insoluble in water at physiologic pH and
exists in tight complexes with serum albumin. This form cannot be excreted
in the urine even when blood levels are high
• Conjugated bilirubin is water-soluble, nontoxic, and only loosely bound to
albumin. Because of its solubility and weak association with albumin, excess
conjugated bilirubin in plasma can be excreted in urine

Robbins and Cotran Pathologic Basis of Disease

Pathophysiology
• Jaundice is a yellowish discoloration of body tissues resulting from the
deposition of bilirubin. Tissue deposition of bilirubin occurs only in
the presence of serum hyperbilirubinemia and is a sign of either liver
disease or, less often, a hemolytic disorder or disorder of bilirubin
metabolism.
• As serum bilirubin levels rise, the skin will eventually become yellow
in light-skinned patients and even green if the process is long-
standing; the green color is produced by oxidation of bilirubin to
biliverdin.

Harrison’s Internal Medicine Ed 20 th

Neonatal Jaundice
• In newborn infants, bilirubin is mostly produced from the breakdown
of red blood cells
• Most newborn infants develop jaundice in the first week of life
• In term infants, the serum bilirubin level reaches a clinically
detectable level by day 3 or 4
• This gradually falls over the next few days before reaching the normal
childhood serum bilirubin level by the end of the second week of life
• This is generally referred to as physiological jaundice

Mitra, S., & Rennie, J. (2017). Neonatal jaundice: aetiology,

diagnosis and treatment. British Journal of Hospital Medicine,
78(12), 699–704. doi:10.12968/hmed.2017.78.12.699
Neonatal Jaundice
• Although prolonged unconjugated jaundice was previously attributed mainly
to ‘breast milk jaundice’, it is becoming clear that many of these cases have
an underlying genetic explanation (Bhutani, 2012)
• A confident diagnosis of breast milk jaundice can only be made after
exclusion of other possible causes and parents need an explanation of the
nature of the problem
• Beta-glucuronidase is present in breast milk and can cause increased levels
of unconjugated bilirubin that enters the enterohepatic circulation from the
gut
• Altered gut flora in breast-fed infants has also been implicated in the
reduction of the conversion of bilirubin glucuronides to urobilinoids
Mitra, S., & Rennie, J. (2017). Neonatal jaundice: aetiology,
diagnosis and treatment. British Journal of Hospital Medicine,
78(12), 699–704. doi:10.12968/hmed.2017.78.12.699
Neonatal Jaundice
• Jaundice in preterm infants is characterized by a higher peak in serum
bilirubin levels along with a longer duration of hyperbilirubinaemia
compared to term infants
• Infants with bruising related to birth trauma, scalp haematoma (e.g.
cephalhaematoma) and born after delayed cord clamping need to be
carefully monitored early on as they have an increased risk of
developing jaundice
• Glucose-6-phosphatase deficiency (G6PD) is an important underlying
cause of kernicterus

Mitra, S., & Rennie, J. (2017). Neonatal jaundice: aetiology,

diagnosis and treatment. British Journal of Hospital Medicine,
78(12), 699–704. doi:10.12968/hmed.2017.78.12.699
Neonatal Jaundice - Aetiology
Early Jaundice (within 24hrs of life)
• is likely to be pathological and commonly a result of isoimmunisation
(most commonly ABO or rhesus incompatibility) or other causes of
significant haemolysis

Mitra, S., & Rennie, J. (2017). Neonatal jaundice: aetiology,

diagnosis and treatment. British Journal of Hospital Medicine,
78(12), 699–704. doi:10.12968/hmed.2017.78.12.699
Neonatal Jaundice - Aetiology
Prolonged Jaundice
• Persistent clinical jaundice in term infants at 2weeks and in preterm
infants at 3weeks of age
• Feeding history, colour of stool and urine and clinical examination can
mostly rule out pathological causes

Mitra, S., & Rennie, J. (2017). Neonatal jaundice: aetiology,

diagnosis and treatment. British Journal of Hospital Medicine,
78(12), 699–704. doi:10.12968/hmed.2017.78.12.699
Neonatal Jaundice - Aetiology
Prolonged Jaundice
• Initial investigations for infants
with prolonged jaundice:
• Check the colour of stool (whether • Urine culture and sensitivity
yellow or pale chalky stool) • Ensure Guthrie card sent for
• Check the urine (whether it is dark routine metabolic screening
and stains the nappy easily) • Thyroid function test
• Measure total and split bilirubin • G6PD level.
• Full blood count, blood group and
DAT
• Liver function test

Mitra, S., & Rennie, J. (2017). Neonatal jaundice: aetiology,

diagnosis and treatment. British Journal of Hospital Medicine,
78(12), 699–704. doi:10.12968/hmed.2017.78.12.699
Neonatal Jaundice - Aetiology
Conjugated Jaundice
• Serum conjugated bilirubin level of >25 mmol/litre
• Although in clinical practice a 10% cut-off value for total serum
bilirubin level is sometimes used, this can give false reassurance in the
case of high total bilirubin level

Mitra, S., & Rennie, J. (2017). Neonatal jaundice: aetiology,

diagnosis and treatment. British Journal of Hospital Medicine,
78(12), 699–704. doi:10.12968/hmed.2017.78.12.699
Faktor
Resiko
Ikterus
Neonatoru
m

Mitra, S., & Rennie, J. (2017). Neonatal jaundice: aetiology,

diagnosis and treatment. British Journal of Hospital Medicine,
78(12), 699–704. doi:10.12968/hmed.2017.78.12.699
Bilirubin Encephalopathy
• The deposition of bilirubin in the brain, noted during autopsy of
infants who had died as a result of acute bilirubin toxicity, was
described as ‘kernicterus’
• Hypoxia, acidosis, hypercarbia, sepsis, seizures and disturbances to
the blood–brain barrier are co-existing risk factors for acute bilirubin
toxicity (Wennberg et al, 2006)
• Medications that interfere with bilirubin albumin binding or inhibit p-
glycoprotein are implicated in increasing the risk of acute bilirubin
encephalopathy (Watchko et al, 2002).

Mitra, S., & Rennie, J. (2017). Neonatal jaundice: aetiology,

diagnosis and treatment. British Journal of Hospital Medicine,
78(12), 699–704. doi:10.12968/hmed.2017.78.12.699
Bilirubin Encephalopathy
• It is difficult to correlate a specific serum bilirubin level to the onset of
bilirubin neurotoxicity. The report from the Pilot USA Kernicterus
Registry suggested that a bilirubin level >598mmol/litre can have a
profoundly deleterious effect (Bhutani and Johnson, 2009)
• Analysis of the NHS Resolution data regarding settled kernicterus
claims in England also found that term babies had bilirubin levels
above 600mmol/litre at presentation (J Rennie et al on behalf of the
NHS Improvement Patient Safety Programme, 2017, unpublished
data).

Mitra, S., & Rennie, J. (2017). Neonatal jaundice: aetiology,

diagnosis and treatment. British Journal of Hospital Medicine,
78(12), 699–704. doi:10.12968/hmed.2017.78.12.699
Faktor Resiko Kernikterus

Mitra, S., & Rennie, J. (2017). Neonatal jaundice: aetiology,

diagnosis and treatment. British Journal of Hospital Medicine,
78(12), 699–704. doi:10.12968/hmed.2017.78.12.699
Faktor Resiko Ikterus
Faktor
Resiko
Ikterus
Neonatoru
m

Mitra, S., & Rennie, J. (2017). Neonatal jaundice: aetiology,

diagnosis and treatment. British Journal of Hospital Medicine,
78(12), 699–704. doi:10.12968/hmed.2017.78.12.699
Dewasa???
DD Ikterus Berdasarkan
Usia
Harrison’s Internal Medicine Ed 20 th
Harrison’s Internal Medicine Ed 20 th
Pendekatan Diagnosis
Ikterus
Assessment of Neonatal Jaundice
• Examination of the newborn for visual assessment of clinical jaundice
should be performed in a well-lit room
• For any infant with clinical jaundice, the serum bilirubin level must be
measured to allow planning of management
• Transcutaneous bilirubinometer  measurements from these instruments
correlate well with serum bilirubin level and can avoid unnecessary blood tests
and/or referral to hospital
• But, the average difference between these measurements was
12.7±32.9mmol/litre (Campbell et al, 2011), and this discrepancy increases
further above levels of 250mmol/litre. NICE guidance recommends checking a
serum sample when transcutaneous bilirubinometer records indicates a bilirubin
level higher than 250mmol/litre
Mitra, S., & Rennie, J. (2017). Neonatal jaundice: aetiology,
diagnosis and treatment. British Journal of Hospital Medicine,
78(12), 699–704. doi:10.12968/hmed.2017.78.12.699
Assessment of Neonatal Jaundice
• Examination of the newborn for visual assessment of clinical jaundice
should be performed in a well-lit room
• For any infant with clinical jaundice, the serum bilirubin level must be
measured to allow planning of management
• Transcutaneous bilirubinometer  measurements from these instruments
correlate well with serum bilirubin level and can avoid unnecessary blood tests
and/or referral to hospital
• But, the average difference between these measurements was
12.7±32.9mmol/litre (Campbell et al, 2011), and this discrepancy increases
further above levels of 250mmol/litre. NICE guidance recommends checking a
serum sample when transcutaneous bilirubinometer records indicates a bilirubin
level higher than 250mmol/litre
Mitra, S., & Rennie, J. (2017). Neonatal jaundice: aetiology,
diagnosis and treatment. British Journal of Hospital Medicine,
78(12), 699–704. doi:10.12968/hmed.2017.78.12.699
 Mitra, S., & Rennie, J. (2017). Neonatal jaundice: aetiology,
diagnosis and treatment. British Journal of Hospital Medicine,
78(12), 699–704. doi:10.12968/hmed.2017.78.12.699
 Assessment for
Jaundice (Adults)
Evaluation of the patient with jaundice.
ALT, alanine aminotransferase; AMA,
antimitochondrial antibody; ANA, antinuclear
antibody; AST, aspartate aminotransferase;
CMV, cytomegalovirus; EBV, Epstein-Barr
virus; LKM, liver-kidney microsomal antibody;
MRCP, magnetic resonance
cholangiopancreatography; SMA, smooth-
muscle antibody; SPEP, serum protein
electrophoresis

Harrison’s Internal Medicine Ed 20 th

History
• The use of or exposure to any chemical or medication, whether physician-
prescribed, overthe-counter, complementary, or alternative medicines (e.g.,
herbal and vitamin preparations) or other drugs such as anabolic steroids
• Carefully ask about possible parenteral exposures, including transfusions,
intravenous and intranasal drug use, tattooing, and sexual activity
• Recent travel history; exposure to people with jaundice; exposure to
possibly contaminated foods; occupational exposure to hepatotoxins;
alcohol consumption; the duration of jaundice; and the presence of any
accompanying signs and symptoms, such as arthralgias, myalgias, rash,
anorexia, weight loss, abdominal pain, fever, pruritus, and changes in the
urine and stool
Harrison’s Internal Medicine Ed 20 th
Physical Examination
• Patient’s nutritional status
• Temporal and proximal muscle wasting suggests long-standing
disease such as pancreatic cancer or cirrhosis
• Stigmata of chronic liver disease, including spider nevi, palmar
erythema, gynecomastia, caput medusae, Dupuytren’s contractures,
parotid gland enlargement, and testicular atrophy, are commonly
seen in advanced alcoholic (Laennec’s) cirrhosis and occasionally in
other types of cirrhosis
• Ascites in the presence of jaundice suggests either cirrhosis or
malignancy with peritoneal spread
Harrison’s Internal Medicine Ed 20 th
Physical Examination
• An enlarged left supraclavicular node (Virchow’s node) or a periumbilical nodule (Sister Mary
Joseph’s nodule) suggests an abdominal malignancy. Jugular venous distention, a sign of right-
sided heart failure, suggests hepatic congestion
• Right pleural effusion even in the absence of clinically apparent ascites may be seen in
advanced cirrhosis
• The abdominal examination should focus on the size and consistency of the liver, on whether
the spleen is palpable and hence enlarged, and on whether ascites is present
• A grossly enlarged nodular liver or an obvious abdominal mass suggests malignancy
• An enlarged tender liver could signify viral or alcoholic hepatitis; an infiltrative process such
as amyloidosis; or, less often, an acutely congested liver secondary to right-sided heart failure
• Severe right-upper-quadrant tenderness with respiratory arrest on inspiration (Murphy’s sign)
suggests cholecystitis

Harrison’s Internal Medicine Ed 20 th

Lab Tests
• Total and direct serum bilirubin measurement with fractionation;
• Determination of serum aminotransferase, alkaline phosphatase, and albumin
concentrations; and prothrombin time tests
• Enzyme tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and
alkaline phosphatase [ALP]) are helpful in differentiating between a hepatocellular
process and a cholestatic process
• All jaundiced patients should have additional blood tests—specifically, an albumin level
and a prothrombin time—to assess liver function
• An elevated prothrombin time indicates either vitamin K deficiency due to prolonged
jaundice and malabsorption of vitamin K or significant hepatocellular dysfunction
• The failure of the prothrombin time to correct with parenteral administration of vitamin
K indicates severe hepatocellular injury.

Harrison’s Internal Medicine Ed 20 th

Lab Tests
• Total and direct serum bilirubin measurement with fractionation;
• Determination of serum aminotransferase, alkaline phosphatase, and albumin
concentrations; and prothrombin time tests
• Enzyme tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and
alkaline phosphatase [ALP]) are helpful in differentiating between a hepatocellular
process and a cholestatic process
• All jaundiced patients should have additional blood tests—specifically, an albumin level
and a prothrombin time—to assess liver function
• An elevated prothrombin time indicates either vitamin K deficiency due to prolonged
jaundice and malabsorption of vitamin K or significant hepatocellular dysfunction
• The failure of the prothrombin time to correct with parenteral administration of vitamin
K indicates severe hepatocellular injury.

Harrison’s Internal Medicine Ed 20 th

Tatalakasana Ikterus Anak
Management of Neonatal Jaundice
• Identifying the rare baby who has a rapidly rising bilirubin level
• Target neonates which is at risk of kernicterus from the majority of
term babies whose jaundice will remain harmless
• Adequate early support (both pre-discharge and in the community)
for mothers and infants for establishment of breast feeding reduces
the risk of developing raised serum bilirubin level and can avoid the
need for hospital readmission

Mitra, S., & Rennie, J. (2017). Neonatal jaundice: aetiology,

diagnosis and treatment. British Journal of Hospital Medicine,
78(12), 699–704. doi:10.12968/hmed.2017.78.12.699
Management of Neonatal Jaundice
Unconjugated Jaundice – Phototherapy
• Phototherapy is the first step in the management of raised
unconjugated jaundice in newborn infants.
• Safe and convenient method of lowering serum bilirubin levels and
reduces the need for more invasive treatment, exchange transfusion
• Phototherapy is effective only after bilirubin enters the skin at
serum bilirubin level >80mmol/ litre (Tan, 1982).

Mitra, S., & Rennie, J. (2017). Neonatal jaundice: aetiology,

diagnosis and treatment. British Journal of Hospital Medicine,
78(12), 699–704. doi:10.12968/hmed.2017.78.12.699
Management of Neonatal Jaundice
Unconjugated Jaundice – Phototherapy
• The efficacy of phototherapy depends on the dose and wavelength of
light used as well as the surface area of the infant’s body exposed to it
• Increasing the dose can be achieved by placing phototherapy units at
the minimum safe distance from the infant and increasing the number
of units used

Mitra, S., & Rennie, J. (2017). Neonatal jaundice: aetiology,

diagnosis and treatment. British Journal of Hospital Medicine,
78(12), 699–704. doi:10.12968/hmed.2017.78.12.699
Management of Neonatal Jaundice
Unconjugated Jaundice – Phototherapy
• Fibreoptic biliblankets  help to continue phototherapy during
cuddles with parents and can be an effective way to give ‘double’
phototherapy when used together with an overhead unit
• They can be placed in direct contact with the infant as they emit an
insignificant degree of heat

Mitra, S., & Rennie, J. (2017). Neonatal jaundice: aetiology,

diagnosis and treatment. British Journal of Hospital Medicine,
78(12), 699–704. doi:10.12968/hmed.2017.78.12.699
Phototherapy
The predominant method of bilirubin elimination is the irreversible
photoalteration of bilirubin to a structural isomer called lumirubin,
which is a water-soluble compound and is excreted with bile and urine.
Two other important pathways of bilirubin photoalteration are
photooxidation of bilirubin to colourless polar molecules that are
excreted in the urine and configurational isomerization of bilirubin
isomer to more water-soluble and less toxic isomers (Vreman et al,
2004).

Mitra, S., & Rennie, J. (2017). Neonatal jaundice: aetiology,

diagnosis and treatment. British Journal of Hospital Medicine,
78(12), 699–704. doi:10.12968/hmed.2017.78.12.699
 Mitra, S., & Rennie, J. (2017). Neonatal jaundice: aetiology,
diagnosis and treatment. British Journal of Hospital Medicine,
78(12), 699–704. doi:10.12968/hmed.2017.78.12.699
Pharmacological Agents
• High dose intravenous immunoglobulin is the only pharmacological
treatment used in clinical practice for infants presenting with high
jaundice levels secondary to rhesus or ABO isoimmunisation
• Although it reduces the need for exchange transfusion, the duration
of phototherapy and the length of hospital stay (Gottstein and Cooke,
2003), it is mostly used to buy time before starting exchange
transfusion in severe cases of unconjugated jaundice.

Mitra, S., & Rennie, J. (2017). Neonatal jaundice: aetiology,

diagnosis and treatment. British Journal of Hospital Medicine,
78(12), 699–704. doi:10.12968/hmed.2017.78.12.699
Exchange Transfusion
• Important intervention for infants who do not respond well to multiple
phototherapy and appropriate hydration
• Also indicated in infants born with significant anaemia as a result of in utero
haemolysis
• In addition to the small risk of blood-borne infection, exchange transfusion
carries a risk of morbidity and mortality from vascular injuries,
cardiovascular complications, biochemical and haematological disturbance
(Keenan et al, 1985)
• It is vital to monitor the infant closely throughout the procedure and check
the haematological and biochemical parameters before, during and after
exchange transfusion.
Mitra, S., & Rennie, J. (2017). Neonatal jaundice: aetiology,
diagnosis and treatment. British Journal of Hospital Medicine,
78(12), 699–704. doi:10.12968/hmed.2017.78.12.699
Conjugated Jaundice
• Identification of the aetiology is key for the management of an infant with
conjugated jaundice
• If a congenital obstruction is suspected, the infant needs to be reviewed
in a surgical centre for further investigations and management (Biliary
atresia is the most common surgically correctable liver condition in this
age group)
• Prolonged use of parenteral nutrition causes cholestasis and
hepatocellular damage in early infancy and the incidence increases with
the degree of prematurity. Treatment focuses on increasing the bile flow
with either ursodeoxycholic acid or phenobarbital and early introduction
of enteral feeding.
Mitra, S., & Rennie, J. (2017). Neonatal jaundice: aetiology,
diagnosis and treatment. British Journal of Hospital Medicine,
78(12), 699–704. doi:10.12968/hmed.2017.78.12.699
Biliary Atresia
• In one third of infants with biliary atresia stools are pigmented initially as
the intra- and extrahepatic bile ducts may remain patent in the first few
weeks of life
• As they become atretic, the flow of bile stops and the colour of the stool
changes to a white, chalky appearance
• Success of surgery is highest in earlier infancy, as with time, the intrahepatic
biliary ducts obliterate and the chance of success of portoenterostomy
drops significantly.
• Ursodeoxycholic acid (Willot et al, 2008) and phenobarbital (Davenport et al,
1997) are used to improve the bile flow, and supplementation of fat-soluble
vitamins is also required.
Mitra, S., & Rennie, J. (2017). Neonatal jaundice: aetiology,
diagnosis and treatment. British Journal of Hospital Medicine,
78(12), 699–704. doi:10.12968/hmed.2017.78.12.699
Tatalakasana Ikterus
Dewasa
• Treat the cause 

Harrison’s Internal Medicine Ed 20 th