HEPATOBILIARY SYSTEM BLOCK

CASE 1

Ronald Chrisbianto Gani 405090223 Faculty of Medicine 2009 Tarumanagara University

LEARNING OBJECTIVES
Anatomy of Liver and Gallbladder Histology of Liver and Gallbladder Physiology of Liver and Gallbladder Embriology of Liver and Gallbladder Metabolism of Porphyrins and Bilirubin Hyperbilirubinemia and Jaundice in Newborn Kernicterus / Bilirubin Encephalopathy

ANATOMY OF LIVER AND GALLBLADER

BED OF LIVER

Grays Anatomy 40th ed

LIVER

Netter Atlas of Human Anatomy

LIVER SURFACES

Grays Anatomy 40th ed

LIVER ANATOMICAL RELATION

Grays Anatomy 40th ed

Netter Atlas of Human Anatomy

Moore, Keith L. - Clinically Oriented Anatomy

Moore, Keith L. - Clinically Oriented Anatomy

LIVER VASCULAR SUPPLY

Perdarahan liver 30% dari arteri hepatica propria (dari aorta) 70% dari vena porta hepatis (dari sal pencernaan)
Grays Anatomy 40th ed

LYMPHATIC NODES

Moore, Keith L. - Clinically Oriented Anatomy

LIVER INNERVATION

Moore, Keith L. - Clinically Oriented Anatomy

VAS

Netter Atlas of Human Anatomy

GALLBLADDER VASCULAR SUPPLY

Grays Anatomy 40th ed

GALLBLADDER INNERVATION

Moore, Keith L. - Clinically Oriented Anatomy

HISTOLOGY OF LIVER AND GALLBLADDER

LIVER

Junqueira's Basic Histology, Twelfth Edition

HEPATIC LOBULE

Junqueira's Basic Histology, Twelfth Edition

HEPATIC LOBULE
Hepatic Lobule of mammals Hepatic Lobule of Human

A : ARTERIOLE, C : CENTRAL VENULE, D: SMALL BILE DUCT BRANCH, V: VENULE

Junqueira's Basic Histology, Twelfth Edition

HEPATIC LOBULE MICROVASCULATURE

The hepatic lobules central vein (CV) is actually a venule consisting of little more than an endothelial tube with smaller sinusoids (S) coming in from all directions. X200. H&E.

Junqueira's Basic Histology, Twelfth Edition

HEPATIC LOBULE MICROVASCULATURE

PV : Portal Venule A : Arteriole D : Bile duct S : Sinusoid Arrow : Blood Flow

Junqueira's Basic Histology, Twelfth Edition

HEPATIC LOBULE MICROVASCULATURE

Reticulin (collagen type III) fibers running along the plates of hepatocytes are the major support for the sinusoids and central venules. Most connective tissue in the liver is found in the septa and portal tracts. X400. Silver.
Junqueira's Basic Histology, Twelfth Edition

HEPATIC SINUSOID
Stellate macrophages are seen as black cells in a liver lobule from a rat injected with particulate India ink. X200. H&E.

Junqueira's Basic Histology, Twelfth Edition

HEPATIC SINUSOID
H : Hepatocytes M : Stellate Macrophages S: Sinusoid PS : Perisinusoidal Space F : fibroblastic fatstoring cells (ito cell)

Junqueira's Basic Histology, Twelfth Edition

SINUSOID WALL
H : Hepatocytes E : Endothelial Cell PS : Perisinusoid Space

Junqueira's Basic Histology, Twelfth Edition

HEPATOCYTES & BILE CANALICULI

BC : Bile Canaliculi M : Mitochondria G : Golgi Complexes PS : Perisinusoid Space E : Endothelial Cell S : Sinusoid

Junqueira's Basic Histology, Twelfth Edition

HEPATOCYTE & BILE CANALICULI

BC : Bile Canaliculi H : Hepatocyte

Junqueira's Basic Histology, Twelfth Edition

BILE DUCTULES

Junqueira's Basic Histology, Twelfth Edition

BILE SECRETION
90% bile acid recirculated 10% synthesized producing glycocholic and taurocholic acids

Junqueira's Basic Histology, Twelfth Edition

GALLBLADDER

LP : Lamina Propria, M : Muscularis A: Adventitia

G: Secretory Granule, MV : Microvili

Junqueira's Basic Histology, Twelfth Edition

PHYSIOLOGY OF LIVER AND GALLBLADDER

 Fungsi Hati

HATI

Sekresi garam empedu Pengolahan metabolik kategori nutrien utama Detoksifikasi atau degradasi zat sisa Sintesis protein plasma Penyimpanan glikogen, lemak, besi, tembaga, Vit2 Pengaktifan vit D Pengeluaran bakteri dan SDM yg usang Ekskresi kolestrol dan bilirubin

Semua fungsi tsb dikerjakan oleh hepatosit Aktifitas fagositik dikerjakan oleh sel Kupffer Hati mendapat darah dari 2 sumber
Vena dari saluran pencernaan miskin oksigen Arteri dari aorta kaya oksigen
Human Physiology: From Cells to Systems by Lauralee Sherwood 7th ed

LIVER BLOOD FLOW

Human Physiology: From Cells to Systems by Lauralee Sherwood 7th ed

 Unit fungsional hati : Lobulus Tiap potongan tepi luar lobulus trdapat 3pembuluh : cab a.hepatica, cab v.porta, duktus biliaris Ruang kapiler yg melebar di pinggir lobulus tmpat darah mengalir : sinusoid Sel kupffer melapisis bagian dalam sinusoid Vena sentral di lobulus menyatu : v. Hepatica Saluran tipis penyalur empedu : kanalikulus biliaris duktus biliaris komunis Pengeluaran empedu diatur oleh Sfingter oddi, jika tertutup, empedu masuk ke kantung empedu dipekatkan Sekresi empedu 250ml 1L / hari Garam empedu dikeluarkan ke duodenum direabsorbsi di ileum terminal masuk ke hati, didaur ulang (SIRKULASI ENTERO HEPATIK) Total garam empedu 3-4g, hanya 5% masuk ke tinja
Human Physiology: From Cells to Systems by Lauralee Sherwood 7th ed

LOBULUS HATI

Human Physiology: From Cells to Systems by Lauralee Sherwood 7th ed

Color Atlas of Physiology 5th ed

EMULSIFIKASI LEMAK O/ EMPEDU

Garam empedu mengubah globulus lemak besar menjadi emulsi lemak yang lebih kecil Dengan tujuan meningkatkan luas permukaan tempat lipase pankreas bekerja Lalu garam empedu membentuk lapisan bermuatan negatif di luar setiap butir lemak Fungsi selaput adalah u/ mencegah butiran2 kecil menyatu kembali
Human Physiology: From Cells to Systems by Lauralee Sherwood 7th ed

EMULSIFIKASI LEMAK O/ EMPEDU

Human Physiology: From Cells to Systems by Lauralee Sherwood 7th ed

PEMBENTUKAN MISEL
Berguna u/ mengangkut bahan tidak larut air, mis : monogliserida, FFA, vitamin larut lemak Menjaga homeostasis kolestrol Kelebihan kolestrol batu empedu

Human Physiology: From Cells to Systems by Lauralee Sherwood 7th ed

 Bilirubin sama sekali tidak berperan pd pencernaan Bilirubin merupakan produk sisa pemecahan SDM yg sudah usang yg disekresikan ke empedu dan merupakan pigmen utama empedu Pigmen kuning di pencernaan modifikasi warna coklat khas pd tinja Peningkatkan sekresi empedu dipengaruhi o/
Kimiawi : garam empedu yg direabsorbsi dari ileum dan dibawa ke hati merangsang hepatosit mengeluarkan empedu Hormonal : sekretin Saraf : Saraf Vagus (sedikit)
Human Physiology: From Cells to Systems by Lauralee Sherwood 7th ed

BILIRUBIN METABOLISM & EXCRETION

Color Atlas of Physiology 5th ed

KANTUNG EMPEDU
Kantung empedu menyimpan dan memekatkan empedu di antara waktu makan dan mengeluarkannya saat makan Pengeluaran dirangsang oleh CCK (respon thd lemak) relaksasi sfingter oddi dan kontraksi kantung empedu Jika kantung empedu diangkat / dibuang, empedu akan disimpan di duktus biliaris yang mengalami dilatasi
Human Physiology: From Cells to Systems by Lauralee Sherwood 7th ed

EMBRIOLOGY OF LIVER AND GALLBLADDER

EMBRIO 36 HARI

Langmans Medical Embriology 11th ed

HATI DAN KANTUNG EMPEDU

Liver primordium muncul pd pertengahan minggu ke 3 pada epitel di ujung distal foregut (hepatic diverticulum / Liver Bud) Terdiri atas sel hati yang akan berproliferasi menembus septum transversum Saluran antara liver bud dan foregut menyempit membentuk duktus biliaris Pertumbuhan ke ventral dari duktus biliaris akan membentuk duktus sistikus dan kantung empedu Epitel korda hati, melilit dengan vena umbilikus dan vena vittelinus akan membentuk sinusoid hati Setelah sel hati menginvasi seluruh septum transversum, liver-foregut lesser omentum, liver ventral abdominal wall lig. Falciforme. Lesser omentum + lig. Falciforme ventral mesogastrium
Langmans Medical Embriology 11th ed

HATI DAN KANTUNG EMPEDU

Mesoderm di permukaan liver visceral peritoneum Bagian kranial yg tidak ditutupi nuda area Minggu ke-10, liver = 10% BB, karena bnayak sinusoid dan fungsi hematopoietic, pd 2 bulan terakhir, hematopoiesis berkurang. Lahir, liver =5% BB Minggu ke-12, duktus sistikus dan duktus hepatikus sudah terbentuk duktus koledokus, empedu masuk ke sal. Cerna menyebabkan warna hijau tua Pertumbuhan duodenum lebih lanjut menyebabkan perubahan lokasi duktus koledokus, dari anterior ke posterior.
Langmans Medical Embriology 11th ed

METABOLISM OF PORPHYRINS AND BILIRUBIN

Marks Basic Medical Biochemistry - A Clinical Approach

PORPHYRIA

Harper's Illustrated Biochemistry 28Ed

BILIRUBIN METABOLISM

Marks Basic Medical Biochemistry - A Clinical Approach

CONDITIONS WHICH CAUSES ELEVATED BILIRUBIN

UNCONJUGATED BILIRUBIN Hemolytic Anemia Neonatal Physiologic Jaundice Crigler-Najjar Syndrome type I and II Gilbert Syndrome Toxic Hyperbilirubinemia CONJUGATED BILIRUBIN Obstruction of Biliary Tree Dubin-Johnson Syndrome Rotor Syndrome

Harper's Illustrated Biochemistry 28Ed

CAUSES OF JAUNDICE

Harper's Illustrated Biochemistry 28Ed

LAB RESULT IN JAUNDICE

Harper's Illustrated Biochemistry 28Ed

JAUNDICE AND HYPERBILIRUBINEMIA IN THE NEWBORN

HYPERBILIRUBINEMIA
Hyperbilirubinemia:
Unconjugated : neurotoxic Conjugated : not neurotoxic

Uncojugated hyperbilirubinemia caused by

Increases of bilirubin to be metabolized by liver reduces the activity of the transferase enzymes Compete for or blocks transferase enzymes Decreases amount of enzyme or reduction of bilirubin uptake

Breast-feeding increase serum level of bilirubin The neonatal production rate of bilirubin is 6-8 mg/kg/24 hr
Nelson Textbook of Pediatrics 18th ed

HYPERBILIRUBINEMIA

Nelson Textbook of Pediatrics 18th ed

FAKTOR RESIKO HIPERBILIRUBINEMIA BERAT PD BAYI KEHAMILAN >35MGG

Major Minor
Sebelum pulang, kadar bilirubin Sebelum pulang, kadar bilirubin serum atau bilirubin transkutaneus atau bilirubin transkutaneus resiko tinggi sedang Ikterus pd 24jam pertama Umur kehamilan 37-38mgg kehidupan Sebelum plg, bayi kuning Inkompatibilitas gol darah dg tes Riwayat ank sebelumnya antiglobulin direk + atau peny Bayi makrosomia dr ibu DM hemolitic lain (G6PD def, ETCO ++) Umur ibu >=25th Umur kehamilan 35-36mgg Laki2 Riwayat fototerapi pd anak Kurang sebelumnya Sefalhematom yg bermakna Kadar bilirubin normal ASI eksklusif dg perawatan tdk baik, Umur kehamilan >=41 mgg weight loss Minum susu formula penuh Ras asia timur Kulit hitam Dipulangkan dari RS >72jam
Buku Ajar Neonatologi IDAI edisi I

JAUNDICE
Jaundice begin in face (5mg/dL) to abdomen (15mg/dL) and feet (20mg/dL) Revealed by dermal pressure
Indirect : bright yellow / orange Direct : greenish / muddy yellow

Differential Diagnosis
1st day of life : erythroblastosis fetalis, concealed hemorrhage, sepsis, or intrauterine infections 2nd -3rd day : Maybe physiologic 3rd day 1week : bacteria sepsis, urinary tract infection
Nelson Textbook of Pediatrics 18th ed

JAUNDICE
Persistent during 1mo of life: inspissated bile syndrome hyperalimentation-associated cholestasis, hepatitis, cytomegalic inclusion disease, syphilis, toxoplasmosis, familial nonhemolytic icterus, congenital atresia of the bile ducts, or galactosemia Prolonged : hypertiroidism, pyloric stenosis

Physiologic Jaundice usually arise in 2nd -3rd day, peak disappear in 6th or 7th day
Nelson Textbook of Pediatrics 18th ed

IKTERUS FISIOLOGIS
Faktor2 yang berhubungan dg ikterus fisiologis
Dasar Penyebab Peningkatan SDM Penurunan umur SDM Peningkatan early Bilirubin Peningkatan aktv B-glukoronidase Late meconium

Peningkatan Bilirubin
Peningkatan produksi

Peningkatan resirkulasi

Penurunan Bilirubin Clereance Penurunan Clereance plasma Penurunan metabolik hepatik

Defisiensi protein karier

Penurunan aktivitas UDPGT

Buku Ajar Neonatologi IDAI edisi I

FAKTOR ETIOLOGI YG MUNGKIN PD BAYI YANG MENDAPAT ASI

Asupan cairan
Kelaparan Frekuensi Menyusui Weight Loss/ dehidrasi

Intestinal reabsorbtion of bilirubin

Pasase meconium terlambat Pembentukan urobilinoid bakteri Beta-glukoronidase Hidrolisis alkaline Asam ampedu

Hambatan eksresi bilirubin

Pregnandiol Lipase-FFA Unidentified inhibitor

Buku Ajar Neonatologi IDAI edisi I

DIAGNOSIS
Search to determine causes if
Appear in 1st day of life Bilirubin serum rising at rate > 5mg/dL/24hr Serum bilirubin >14mg/dL (full term) or 12mg/dL (pre-term) Persist after 10-14 days of life Direct-reacting bilirubin >2mg/dL at any time

Suggest non physiologic if : family history of hemolytic disease, pallor, hepatomegaly, splenomegaly, failure of phototherapy to lower bilirubin, vomiting, lethargy, poor feeding, excessive weight loss, apnea, bradycardia, abnormal vital signs, light-colored stools, dark urine positive for bilirubin, and signs of kernicterus
Nelson Textbook of Pediatrics 18th ed

Nelson Textbook of Pediatrics 18th ed

RISK FACTOR

Nelson Textbook of Pediatrics 18th ed

Nelson Textbook of Pediatrics 18th ed

TATA LAKSANA FARMAKOTERAPI

Imunoglobulin IV : pd bayi Rh dan inkompatibilitas ABO Fenobarbital : merangsang aktivitas enzime, kontroversial u/ dipakai pd hari ke 1 Metalloprotoporphyrin : analog heme. Mencegah katabolisme heme Tin-protoporphyrin dan tin-mesoporphyrin (masih diteliti), + phototerapy = toksik Inhibitor Beta glukoronidase : meningkatkan eksresi bilirubin feses, ikterus berkurang
Buku Ajar Neonatologi IDAI edisi I

FOTOTERAPI DAN TRANSFUSI TUKAR

KADAR BILIRUBIN TOTAL SERUM (mg/dL [mmol/L]) USIA (JAM) Pertimbangkan Fototerapi >= 12 (170) >= 15 (260) >= 17 (290) Fototerapi Transfusi Tukar Transfusi Tukar jika Fototerapi dan Fototerapi Gagal Intensif >= 20 (340) >= 25 (430) >= 25 (430) >= 25 (430) >= 30 (510) >= 30 (510)

25 -48 49 - 72 72

>= 15 (260) >= 18 (310) >= 20 (340)

Bayi cukup bulan dg BBL >2500 g, fototerapi diindikasikan pd kadar bilirubin total serum 15-18 mg/dL, kecuali keadaan sakit 12-15 mg/dL Pada bayi kurang bulan, batas kadar bilirubin total untuk dilakukan fototerapi lebih rendah
Buku Ajar Neonatologi IDAI edisi I

PENCEGAHAN
Primer
Ibu menyusui bayi 8-12x/hri pd bbrp hari pertama Tidak ada cairan tambahan kec dehidrasi

Sekunder
Pemeriksaan gol darah ABO dan rh Rutin memonitor bayi u/ ikterus dan vital sign per 8-12jam. Ikterus ukur bilirubin total, transkutaneus
Bayi Keluar RS <24 jam Harus dilihat pd umur 72 jam

24 jam 47,9 jam 48 jam 72 jam

96 jam 120 jam

Buku Ajar Neonatologi IDAI edisi I

KERNICTERUS / BILIRUBIN ENCEPHALOPATHY

KERNICTERUS
Neurologic syndrome resulting from the deposition of unconjugated bilirubin in the basal ganglia and brainstem nuclei Range of bilirubin serum : 21-50 mg/dL Rarely happened in healthy infant without hemolysis with bilirubin serum level under 25mg/dL The onset is usually first 3 week of life, mostly 1st week, day 2-5, lately day 7 Occur in 1/3 infant with untreated hemolytic disease. Premature infants = 2-16% risk Prognosis : >75% die, 80% survivors have bilateral choreoathetosis with involuntary muscle spasms. Mental retardation, deafness, and spastic quadriplegia are common
Nelson Textbook of Pediatrics 18th ed

KERNICTERUS
Potentially preventable causes
Early discharge with no follow up (<48hrs) Failure to check the bilirubin level in an infant noted to be jaundiced in the 1st 24 hr Failure to recognize the presence of risk factors for hyperbilirubinemia underestimating the severity of jaundice lack of concern regarding the presence of jaundice delay in measuring the serum bilirubin level or initiating phototherapy failure to respond to parental concern

Nelson Textbook of Pediatrics 18th ed

CLINICAL FEATURE

Nelson Textbook of Pediatrics 18th ed

MANAGEMENT
Phototherapy
Bilirubin in skin absorbs light energy, maximum in blue range (420-470nm) or blue-green (430-490) Change the bilirubin
4Z,15Z 4Z,15E (reversible) secreted in bile Bilirubin lumirubin (irreversible) secreted via kidney

Phototherapy indication
Presence of pathologic hyperbilirubinemia Reduce the incidence of exchange transfusion Prophylactic phototherapy in VLBW infants

Complication
loose stools, Erythematous macular rash, purpuric rash associated with transient porphyrinemia, Overheating, Dehydration, bronze baby syndrome

Contraindication : porphyria
Nelson Textbook of Pediatrics 18th ed

MANAGEMENT
Exchange transfusion
Indicated if phototherapy failed Complication : acidosis, electrolyte abnormalities, hypoglycemia, thrombocytopenia, volume overload, arrhythmias, NEC, infection, graft vs host disease, and death

Other therapy
Tin (Sn)-protoporphyrin : used when jaundice is anticipated (G6PD deficiency, Jehovahs witness) Intravenous immunoglobulin : used for Coombs + in hemolytic anemia
Nelson Textbook of Pediatrics 18th ed

REFERENCES
Grays Anatomy 40th ed Keith L Moore Clinically Oriented Anatomy 2nd ed Netter Atlas of Human Anatomy Marks Basic Medical Biochemistry Harper's Illustrated Biochemistry 28Ed Human Physiology - From Cells to Systems 7ed Nelson Textbook of Pediatrics 19th ed Buku ajar Neonatologi IDAI 1st ed Junqueira's Basic Histology 12th ed Langmans Medical Embriology 11th ed Despopoulos Color Atlas of Physiology 5th ed