Lecture slide of Pathology of Liver and Biliary Tract

1. Liver and Biliary Tract
Fadel Muhammad Garishah
School of Medicine, Diponegoro University
50 Years Anniversary

2. Macrostructure of Liver
The liver is the largest visceral
organ in the body and is primarily
in the right hypochondrium and
epigastric region, extending into the
left hypochondrium
The right lobe of liver is the
largest lobe, whereas the left lobe
of liver is smaller.
The porta hepatis serves as the
point of entry into the liver for the
hepatic arteries and the portal vein,
and the exit point for the hepatic
ducts
• Vascularization from the Hepatic Artery
• Venous drainages come into Liver from Portal Hepatic Vein, receiving drainage from
intestines (Mesenteric Veins, and Splenic Vein)
• From Liver, the sinusoids united into Hepatic Vein, that drainages into Inferior Cava
Vein

3. Microstructure of Liver
The Lobule Model: hexagonal lobules
oriented around the terminal tributaries of
the hepatic vein (terminal hepatic veins), with
portal tracts at the periphery of the lobule.
The hepatocytes in the vicinity of the terminal
hepatic vein are called “centrilobular”; those
near the portal tract are “periportal”
• The acinar model: the hepatocytes near the terminal hepatic veins are the distal
apices of roughly triangular acini, whose bases are formed by the penetrating septal
venules from the portal vein extending out from the portal tracts. In the acinus the
parenchyma is divided into three zones, zone 1 being closest to the vascular supply,
zone 3 abutting the terminal hepatic venule and most remote from the afferent
blood supply, and zone 2 being intermediate. http://www.niaaa.nih.gov

5. Which one is the
central vein? Which
one is the triad
portal?

6. Microstructure of Liver
Between the plates of hepatocytes are vascular sinusoids. The sinusoids are lined
by fenestrated and discontinuous endothelial cells. Deep to the endothelial cells
lies the space of Disse, into which protrude abundant microvilli of hepatocytes.
Scattered Kupffer cells of the mononuclear phagocyte system are attached to the
luminal face of endothelial cells, and fat-containing hepatic stellate cells (HSCs) are
found in the space of Disse. Between abutting hepatocytes are bile canaliculi, these
channels drain into the canals of Hering, ductular structures that connect the bile
canaliculi to bile ductules in the periportal region.

7. • Zonation of the parenchyma is an important concept
because of the gradient of activity displayed by many
hepatic enzymes, and the zonal distribution of
certain types of hepatic injury.
• While the acinar model best describes the
physiologic relationships between hepatocytes and
their vascular supply, the histopathology of the liver
is usually discussed on the basis of a lobular
architecture.

8. Metabolism of Bilirubin
• Classic Theory
Hb---(release Globin)---Hematin---
(release Fe)---Protoporphyrin---
(Oxidized)---Biliverdin--(Reduction)-
-- Bilirubin
• Lamberg Theory
Hb---(Oxidized)---Choleglobin---
(release Fe and Protein)---
Biliverdin---(reduction)---Bilirubin

9. Bilirubin(s)
Unconjugated (indirect): Erythrocytes (red blood cells)
generated in the bone marrow are disposed of in the spleen
when they get old or damaged. This releases hemoglobin, which
is broken down to heme as the globin parts are turned into
amino acids. The heme is then turned into unconjugated
bilirubin, not soluble in water, bound to albumin and sent to the
liver.
Conjugated (direct): In the liver it is conjugated with glucuronic
acid by the enzyme glucuronyltransferase, making it soluble in
water. (bilirubin covalently bound to albumin, which appears in
serum when hepatic excretion of conjugated bilirubin is
impaired in patients with hepatobiliary disease).

10. Perbedaan Antara Bilirubin Indirek/Direk
Bilirubin Indirek/Unconjugated bilirubin Bilirubin Direk/Conjugated Bilirubin
• Afinitas otak, toksik • Tidak memiliki afinitas dengan SSP,
• Tidak mewarnai jaringan kurang toksik dibanding Indirek
• Tidak larut dalam air • Mewarnai jaringan lain
• Hijman/Bergh positif dengan alkohol • Larut air
• Hijman/Bergh positif tanpa alkohol

11. Jaundice
1. Prehepatik/Hemolitik
2. Hepatik/Parenkim
3. Posthepatik/Obstruktif

12. 1. Ikterus Akibat Kenaikan Produksi Bilirubin
a. Ikterus hemolitik: peningkatan hemolisis
eritrosit, akut/kronik. Hemolytic Anemia, Sickle Cell
Anemia, Malaria, Thalassemia, Keracunan dan
Hipersplenisme.
a. Pada bayi yang baru lahir, destruksi eritrosit tinggi, tapi enzim
Glukoronil transferase masih rendah.
b. Defisiensi GT menyebabkan bilirubin indirek meninggi, terikat
albumin, larut lemak, toksisitas SSP, menyebabkan kernikterus
(ikterus dan kejang).
b. Diseritropoietik (shunt) hiperbilirubinemia: maturasi
abnormal eritrosit, destruksi prematur pada sumsum
tulang. Tapi di perifer tetap normal.

13. 2. Ikterus Akibat Gangguan Uptake Bilirubin Hepatosit
Penyakit Gilbert: Familial inherited, Autosomal Dominan,
Gangguan Uptake Bilirubin, menyebabkan nonfamilial
hemolitik acholuric.
3. Ikterus Akibat Gangguan Konjugasi Bilirubin Hepatosit
a. Fisiologik pada neonatus, membaik 2-3 minggu setelah
kelahiran
b. Sindroma Crigler Najj

14. Diagnostic Of Liver
Laboratory Assessment
– Biochemistry
– Immunology/Serologic
Histopathologic Biopsy
Radiologic diagnostic

15. Biochemistry
Bilirubin unconjugated and conjugated
Hepatic enzymes: ALT, AST and γ-GT
Albumin: a low serum albumin concentration is an
important manifestation of liver failure, which results in
peripheral oedema and contributes to the presence of
ascites, due to a reduction in plasma oncotic pressure.
Blood clotting factors: the risk of unexpected haemorrhage

16. Laboratory Assessment

17. Laboratory Assesment

18. Histopatologic Biopsy

19. Acute Liver Injury

20. Hepatitis

21. Immunopathogenesis
HAV menunjukkan
injury yang direct pada
hepatosit
HBV menunjukkan
immune mediated
hepatosit injury
HCV juga menggunakan
mediasi sistem immune
dalam prosesnya

22. Hepatitis A Virus (HAV) - infectious hepatitis
Characteristics:
– 'faecal-oral' spread
– relatively short incubation period
– sporadic or epidemic
– directly cytopathic virus
– no carrier state
– mild illness, full recovery usual.
Young people, often mild, jaundice rarely appear, virus excreted
before the jaundice (isolation of patient absence)
Specific diagnosis is made by seeking an IgM-class antibody to
HAV in the patient's serum; this indicates recent infection. A
carrier state does not exist.

23. Hepatitis B Virus (HBV) – serum hepatitis
Characteristics:
– spread by blood, blood-contaminated instruments, blood products and
venereally, narcotics needle, tattoo needle, transmitted between
homosexual males via anal sexual acts
– relatively long incubation period
– liver damage by antiviral immune reaction
– carrier state exists
– relatively serious infection.
high incidence of the carrier state in underdeveloped countries
and the virus can be transmitted vertically from mother to child-
in utero, during delivery or through intimate post-natal contact.
Specific diagnosis is made by seeking the hepatitis B surface
antigen (HBsAg, formerly known as 'Australia antigen' because it
was first detected in the serum of an Australian aborigine).

24. Hepatitis C Virus (HCV) – serum hepatitis
Characteristics:
– spread by blood, blood-contaminated instruments, blood products and possibly
venereally
– relatively short incubation period
– often asymptomatic
– fluctuating liver biochemistry
– tendency to chronicity.
In many countries, transmission of HCV by blood transfusion and blood
product administration is much less common now that donors are
screened for HCV.
The initial illness is often asymptomatic and the abnormalities of liver
biochemistry (e.g. raised serum transaminases) are usually fluctuant.
However, despite these misleadingly benign signals, the infection is
prone to chronicity and cirrhosis is a frequent consequence eventually.
Specified diagnosis via PCR will be recognized the serotype of virus.

25. Hepatitis E virus and other non-A, non-B viruses
There are other authentic hepatitis viruses. The best
characterised is a water-borne agent, distinct from HAV,
that has been responsible for outbreaks of hepatitis in
India; it has been designated hepatitis E virus (HEV).
Fortunately, the disease rarely progresses to chronicity
and, as with HAV, full recovery is usual except in pregnancy,
when it is associated with a high mortality rate.
Other non-A, non-B viruses associated with blood
transfusions and blood products include hepatitis G virus
and the TT virus. Their role in liver disease appears to be
relatively minor.

26. Delta agent and other nonhepatitis viruses
Delta agent is a defective RNA virus that requires the
presence of HBV, which supplies the outer layers of the
viral coat, for its replication and assumed role as a
pathogen. Its main effect is to aggravate the consequences
of HBV infection.

27. Alcoholic Hepatitis
Cellular energy is diverted from essential metabolic pathways, such as fat
metabolism, to the metabolism of alcohol so fat accumulates in the liver
cells.
Acetaldehyde, the main product of alcohol metabolism, binds to liver cell
proteins, resulting in injured hepatocytes and an inflammatory reaction.
Alcohol stimulates collagen synthesis in the liver, leading to fibrosis and
eventually cirrhosis.

28. Drug-induced Hepatic Injury
Approximately 10% of all adverse reactions to drugs involve the
liver.
This is not surprising in view of the central role played by the
liver in metabolism and in the conjugation and elimination of
toxic substances from the body.
Through injury to the liver cells (hepatocellular), which is
pathologically indistinguishable from viral hepatitis, or to bile
production or excretion (cholestatic).
Predictable reactions will occur in any individual if a sufficient
dose is administered; examples include coagulative
centrilobular necrosis due to paracetamol overdose and
cholestatic jaundice due to methyl testosterone

29. Acute Biliary Obstruction
Acute obstruction of the main bile ducts is most commonly
due to gallstones. Clinically, it usually results in colicky pain
and jaundice. If there is superimposed infection of the
biliary tract, the ducts become inflamed (cholangitis) and
the patient develops a fever. Cholangitis can lead to the
formation of liver abscesses.

30. Chronic Hepatic Injury

31. Chronic Hepatic Injury
Chronic Hepatitis Injury: HBV, HCV, Alcoholic Hepatis,
Drugs induced, Autoimmune
Iron overload in Liver:
– Haemosiderosis is the name given to the mere presence of excess
iron, in the form of haemosiderin, in the liver. The liver architecture
is usually normal.
– Haemochromatosis is a more serious disorder in which the
presence of excess iron, as haemosiderin, is associated with a risk
of progression to cirrhosis.
Wilson's disease (hepatolenticular degeneration)
α1-Antitrypsin deficiency

32. Autoimmune Liver Disease
Sclerosing cholangitis: a chronic inflammatory process
affecting intrahepatic, and sometimes extrahepatic, bile
ducts. Initially, the ducts are surrounded by a mantle of
chronic inflammatory cells, but this is eventually replaced
by fibrosis and obliteration of the ducts.
Steatohepatitis is used for liver biopsies in which the only
abnormalities are steatosis (fat vacuoles in hepatocytes)
and inflammation. Fatty liver (e.g. diabetes mellitus,
obesity, hyperlipidaemia).

33. Cirrhosis Hepatis
Aetiology:
– viral hepatitis (HBV and HCV)
– alcohol
– haemochromatosis
– autoimmune liver disease (autoimmune hepatitis and primary
biliary cirrhosis)
– recurrent biliary obstruction (e.g. gallstones)
– Wilson's disease.
micronodular-nodules up to 3 mm diameter
macronodular-nodules greater than 3 mm diameter.

34. The major complications of cirrhosis are:
– liver failure
– portal hypertension
– liver cell carcinoma.
Liver Failure
– inadequate synthesis of albumin, clotting factors, etc.
– failure to eliminate endogenous products such as bilirubin,
hormones, nitrogenous waste, etc.

35. Pathophysiological basis of clinical features of
chronic liver disease
Oedema Reduced albumin synthesis resulting in
hypoalbuminaemia
Ascites Hypoalbuminaemia, secondary
hyperaldosteronism, portal hypertension
Haematemesis Ruptured oesophageal varices due to portal
hypertension
Spider naevi Gynaecomastia Hyperoestrogenism
Purpura and bleeding Reduced clotting factor synthesis
Coma Failure to eliminate toxic gut bacterial
metabolites ('false neurotransmitters')
Infection Reduced Kupffer cell number and function

36. Hepatic Failure
Liver Failure
Ascites
Portal Tension
Splenomegaly
Caput Medusae
Varices Oesophageii
Renal Failure
Cirrhosis Hepatis

37. Tumors of the Liver
Benign tumours of the liver include: liver cell adenoma,
angioma, bile duct hamartoma , focal nodular hyperplasia.
Malignant
– Primary malignant tumours of the liver include:
• liver cell carcinoma (hepatocellular carcinoma)
• cholangiocarcinoma (adenocarcinoma of bile ducts)
• angiosarcoma (malignant neoplasm of vascular endothelium)
• hepatoblastoma (primary liver tumour in childhood).
– Secondary metastases include the entire gastrointestinal tract
including pancreas and bowel, the lung and the breast.

38. Cysts of Liver
simple cysts
hydatid cysts: due to the parasite Echinococcus granulosus
choledochal cysts

39. Gall Bladder Pathology
Fadel Muhammad Garishah
School of Medicine, Diponegoro University

40. Topography of Gallbladder

41. Hepatobilier ductal system

42. Congenital Gall Bladder Pathology
biliary atresia, in which there is failure of the biliary tree to
develop and normally anastomose with intrahepatic
structures
choledochal cysts (see above), sometimes associated with
congenital hepatic fibrosis.

43. Diseases of Gall bladder
Cholelithiasis
Cholesterosis
Cholecystitis
Mucocele
Carcinoma of the gallbladder
Carcinoma of the bile duct
Biliary obstruction

44. Cholelithiasis
Cholesterol stones may form if
there is an imbalance between
the ratio of cholesterol and bile
salts; normally, the latter form
micelles which have a
hydrophilic exterior enclosing
the hydrophobic cholesterol.
Thus, gallstones can result from:
an excess of cholesterol or a
deficit of bile salts.
Bile pigment, Cholesterol, or
mixture of cholesterol and bile
pigment

45. Cholesterosis
Cholesterosis is the name given to the clinically
unimportant occurrence of cholesterol-laden macrophages
in the lamina propria of the gallbladder mucosa. This
occurrence gives the mucosa a yellow-speckled appearance
known as 'strawberry gallbladder'.

46. Cholecystitis
Cholecystitis is an inflammatory condition of the
gallbladder.
Acute:
– Usually associated with gallstones
– Initially sterile, then infected
– Complications include empyema and/or rupture
Chronic:
– Invariably associated with gallstones
– Fibrosis and Aschoff-Rokitansky sinuses

47. Mucocele
A mucocele of the gallbladder is the result of sterile
obstruction of the neck by a gallstone. The lack of
inflammation permits the gallbladder to distend with
mucus without rupturing.
Carcinoma of Gallbladder
Usually an adenocarcinoma
Invariably associated with gallstones
Carcinoma of Bile Ducts/Cholangiocarcinoma
Adenocarcinoma
Increased incidence in ulcerative colitis
Presents with jaundice

48. Biliary obstruction
Bile duct obstruction is a fairly common event and may be due to:
– gallstones
– carcinoma of the common bile duct
– carcinoma of the head of the pancreas
– inflammatory stricture of the common bile duct
– accidental surgical ligation of the common bile duct.
The patient becomes jaundiced, deeply so if the obstruction is not relieved,
with a raised conjugated serum bilirubin, pale stools and dark urine. A
raised serum alkaline phosphatase with only modest elevation of
transaminases is usual.
If the biliary obstruction persists, there is a risk that the static bile
becomes infected, causing cholangitis and liver abscesses. Lack of bile in
the small intestine interferes with the absorption of fat and fat-soluble
substances (e.g. some vitamins).
Diseases of intrahepatic bile ducts : A clinical picture similar to that of
biliary obstruction can result from diseases of intrahepatic bile ducts such
as:
– biliary atresia
– primary biliary cirrhosis
– sclerosing cholangitis.