Dr Dinah Parums. Principal Pathologist. Liver and Biliary Tract Pathology. Teaching Handout.

1. The Liver and the
Biliary Tract
Dr Dinah Parums
Principal Histopathologist
July 2007

2. Normal Liver




QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.

A ver ag e liver weig h t is 1 ,4 0 0
to 1 ,8 0 0 g m s
L ower b or d er can b e felt
u n d er th e r ig h t cost al m ar g in
on d eep in sp ir ation
T h e r ig h t lob e is six tim es th e
size of t h e left
D u al b lood su p p ly - 4 0 %
h ep atic ar t er y - th e r est b y
th e h ep atic p or tal vein
B ile d r ain s in t o th e r ig h t an d
left h ep atic d u ct s, in to th e
com m on h ep atic d u ct wh ich
join s with th e cyst ic d u ct fr om
th e g allb lad d er , t o for m th e
com m on b ile d u ct d r ain in g in
to t h e d u od en u m via th e
A m p u lla of V ater

3. Normal Liver

P

HV
QuickTime™ and a
TIFF (Uncompressed) decompressor
are needed to see this picture.


H ist olog y of t h e liver sh ows a
solid m ass of p ar en ch ym a
co m p osed of h ep at ocyt es an d
cells lin in g t h e sin u soid s p ier ced
b y p or t al t r act s an d t r ib u t ar ies of
t h e h ep at ic vein s
T h e liver lob u le h as an
ar ch it ect u r e d efin ed b y t h e liver
vascu lat u r e
H V - t h e h ep at ic vein is at t h e
cen t r e of t h e liver lo b u le
( som et im es called t h e C en t r al
V ein )
P - t h e p or t al t r act - con t ain s t h e
p or t al t r iad






h epat ic ar ter iole,
bile d u ct an d
por t al vein
B lood flow is fr om P t o H V
B ile flow is fr om H V t o P
T h e d ist an ce b et ween t h e H V an d
t h e P is 0.5 m m

4. Normal Liver
The Kupffer Cell and Sinusoids

One type of cell lining the hepatic sinusoids, the Kupffer cell, is phagocytic and is a
component of the mononuclear phagocyte system.

The Kupffer cell helps clear the blood of foreign substances and old erythrocytes.

The other major type of lining cell is a special endothelial cell containing numerous
pores permitting free passage of plasma macromolecules between hepatocytes and
blood. It is not phagocytic.

Finally, there are scattered lipocytes that store vitamin A and also are responsible for
collagen synthesis in liver fibrosis.

5. Normal Liver
Bile
Bile, the exocrine product of the hepatocytes, is initially secreted into intercellular bile
canaliculi and then passes into branches of the bile (hepatic) duct.
The bile canaliculi are tiny passageways between adjacent hepatocytes.
They are difficult to visualize with the light microscope unless they are selectively
stained.
Apart from the connective tissue of the portal triads, the structural framework of
hepatic lobules consists of reticular fibers which are arranged in small bundles
located in the space between the endothelial cells lining the sinusoids and the
hepatocytes. This space is called the space of Disse.
The space of Disse is too narrow to be seen with the light microscope

6. Hepatic Injury

Inflammation = hepatitis


Portal tracts, lobules
Degeneration
Damage from toxic or immunologic insult
 Accumulation of substances, e.g., steatosis


Cell death


Fibrosis


Centrilobular, submassive, massive necrosis
Usually irreversible
Cirrhosis

7. Bile

Two major functions
Elimination of bilirubin, excess cholesterol, and
xenobiotics that are insufficiently water soluble to be
excreted in urine
 Emulsification of dietary fat in the gut by bile acids
(cholic acid, chenodeoxycholic acid)



Unconjugated → Conjugated
Reabsorbed in terminal ileum (enterohepatic
circulation)

8. Jaundice

Excessive production of bilirubin



Hemolytic anemias, ineffective erythropoiesis
Reduced hepatic uptake
Impaired conjugation
Physiologic jaundice of the newborn
 Crigler-Najjar syndromes types I and II
 Gilbert syndrome
 Viral or drug-induced hepatitis, cirrhosis


Decreased hepatocellular excretion


Dubin-Johnson syndrome, Rotor syndrome
Impaired bile flow

9. Cholestasis






Systemic retention of not only bilirubin but also
other solutes eliminated in bile, particularly bile
salts and cholesterol
Due to hepatocellular dysfunction or biliary
obstruction
Accumulation of bile pigment within the hepatic
parenchyma – Kupffer cells
Bile ductular proliferation
Bile lakes
Portal tract fibrosis

10. Hepatic Failure


80% to 90% of hepatic functional capacity must
to destroyed
Massive hepatic necrosis
Fulminant viral hepatitis
 Drugs and chemicals, e.g., acetaminophen, carbon
tetrachloride, mushroom poisoning



Chronic liver disease
Hepatic dysfunction without overt necrosis
Acute fatty liver of pregnancy
 Tetracycline toxicity
 Reye syndrome


11. Clinical Features








Jaundice
Hypoalbuminaemia
Hyperammonaemia
Fetor hepaticus
Palmar erythaema
Spider angiomas
Hypogonadism
Gynaecomastia

12. Complications



Multiple organ failure
Coagulopathy
Hepatic encephalopathy
Metabolic disorder of the CNS and NMS
 Elevated blood ammonia level and deranged
neurotransmission
 Rigidity, hyperreflexia, seizures
 Asterixis


Hepatorenal syndrome

Idiopathic renal failure

13. Cirrhosis




Bridging fibrous septa
Parenchymal nodules
Disruption of the architecture of the entire liver
Aetiologies
Alcoholic liver disease 60% to 70%
 Viral hepatitis 10%
 Biliary diseases 5% to 10%
 Hereditary hemochromatosis 5%
 Wilson disease rare
 Cryptogenic cirrhosis 10% to 15%


14. Portal Hypertension

Prehepatic


Occlusive thrombosis, narrowing of the portal vein
Intrahepatic
Cirrhosis
 Schistosomiasis, massive fatty change, diffuse
granulomatous diseases (sarcoidosis, miliary TB)


Posthepatic

Right-sided heart failure, constrictive pericarditis,
hepatic vein outflow obstruction

15. Clinical Sequelae


Ascites
Portosystemic venous shunts
Oesophageal varices 65% of cases
 Hemorrhoids
 Caput medusae



Splenomegaly
Hepatic encephalopathy

16. Drug Induced Liver Disease




Liver is the major drug metabolizing and
detoxifying organ in the body
Direct toxicity
Hepatic conversion of a xenobiotic to an active
toxin
Immune mechanisms

17. Alcoholic Liver Disease

Hepatic steatosis



Alcoholic hepatitis





Micro and macrovesicular
Initially centrilobular
Hepatocyte swelling and
necrosis
Mallory bodies
Neutrophilic reaction
Fibrosis
Alcoholic cirrhosis


Micronodular
Irreversible

18. Pathogenesis







Shunting of normal substrates away from
catabolism toward lipid biosynthesis
Induction of cytochrome P-450
Free radicals generated by microsomal ethanol
oxidizing system
Alcohol directly affects microtubular and
mitochondrial function
Acetaldehyde induces lipid peroxidation
Neutrophil infiltration
Immunologic attack of hepatocytes

19. Causes of Death





Hepatic failure
Massive GI hemorrhage
Infection
Hepatorenal syndrome
Hepatocellular carcinoma

20. Nonalcoholic Fatty Liver




Elevated serum aminotransferase levels
Low risk for development of hepatic fibrosis or
cirrhosis
Associated with obesity, type 2 DM,
hyperlipidemia
Need to exclude other causes

21. Hemochromatosis

Primary or hereditary


HLA-linked autosomal recessive disease
Secondary
Transfusion dependent
 Chronic liver disease


22. Pathogenesis



Total body iron pool 2 to 6 gm
Primary defect in regulation of intestinal
absorption of dietary iron, leading to a net iron
accumulation of 0.5 to 1.0 g/yr
HFE gene on 6p




Interacts with transferrin receptor of intestinal
enterocyte and modulates interaction with
transferrin-iron complexes
C282Y – disulfide bridge disrupted
H63D
Lipid peroxidation, collagen formation, DNA
interactions

23. Morphology



Deposition of hemosiderin in the liver, pancreas,
myocardium, pituitary, adrenal, thyroid and parathyroid
glands, joints, and skin
Cirrhosis, micronodular
Pancreatic interstitial fibrosis and parenchymal atrophy
→ DM

24. Clinical Features







M:F = 5-7:1
Symptoms usually appear in the fifth to sixth
decades of life.
Classic triad: cirrhosis with hepatomegaly, skin
pigmentation, DM (late in course)
Cardiac dysfunction, e.g., arrhythmias,
cardiomyopathy
Atypical arthritis
Hypogonadism
Tx: phlebotomy, iron chelators

25. Wilson Disease






Autosomal recessive disorder of copper
metabolism
ATP7B on chr 13 ATP-dependent metal ion
transporter on the Golgi of hepatocytes
Failure to excrete copper into bile
Copper causes progressive liver injury
Affects brain, cornea, kidneys, bones, joints, and
parathyroid glands
Dx: ↓ serum caeruloplasmin, ↑ hepatic copper
content, ↑ urinary copper

26. Morphology

Liver – fatty change, acute
hepatitis, chronic hepatitis,
cirrhosis





Rhodanine stain for copper
Orcein stain for copperassociated protein
Brain – Basal ganglia
(putamen) shows atrophy
and cavitation
Eye – Kayser-Fleischer
rings
Aka hepatolenticular
degeneration

27. Clinical Features





Manifestations rare before 6 yrs
Acute or chronic liver disease – most common
Neuropsychiatric manifestations
Copper chelation therapy with D-penicillamine
Liver transplantation

28. α1-Antitrypsin Deficiency



Autosomal recessive disorder
AAT is a protease inhibitor, particularly
neutrophil elastase released at sites of
inflammation
AAT gene on chr 14


M allele normal, Z allele abnormal → misfolding of
the nascent polypeptide in the hepatocyte ER,
accumulation, degradation
Leads to pulmonary emphysema due to tissue
destructive enzymes

29. Morphology

Round to oval
cytoplasmic inclusions of
retained AAT





Periodic acid-Schiff (PAS)
positive
Marked cholestasis with
hepatocyte necrosis in
newborns
Childhood cirrhosis
Chronic hepatitis or
cirrhosis later in life
Tx: liver transplantation

30. Neonatal Hepatitis


Not a specific entity
Not necessarily inflammatory



Extrahepatic biliary atresia (20%), toxic, metabolic
diseases, AAT deficiency (1.5%), idiopathic (50% to
60%)
Neonatal cholestasis (prolonged conjugated
hyperbilirubinemia)
Present with jaundice, dark urine, light or acholic
stools, hepatomegaly

31. 
Marked bilirubin
stasis in
hepatocytes,
canaliculi, and
Kupffer cells in
neonate with
extrahepatic bile
duct atresia.

32. Reye Syndrome



Rare disease characterized by fatty change in the
liver and encephalopathy
Children < 4 yo
3 to 5 days after a viral illness





Associated with salicylate (aspirin) use
Present with vomiting, irritability or lethargy,
hepatomegaly
25% progress to coma
Death due to progressive neurologic
deterioration or liver failure
Tx: symptomatic, supportive

33. Morphology

Liver – microvesicular steatosis


Brain – cerebral oedema


EM – mitochondrial enlargement with disruption of
cristae
Astrocytes swollen, mitochondrial changes
Skeletal muscles, kidneys, and heart may have
microvesicular steatosis.

34. Obstructive Biliary
Tract Disease

35. Secondary Biliary Cirrhosis





Most common cause is extrahepatic
cholelithiasis
Biliary atresia, malignancies of the biliary tree
and head of the pancreas, and strictures
Cholestasis
Bile duct proliferation with surrounding
neutrophils
Periportal fibrosis

36. Primary Biliary Cirrhosis



Middle-aged women
M:F = 1:10
Possibly autoimmune




Autoantibodies to mitochondrial pyruvate
dehydrogenase 90%
Insidious onset, usually presenting with pruritus
Hyperbilirubinemia, jaundice, cirrhosis late
↑ alkaline phosphatase, cholesterol

37. 
Nonsuppurative,
granulomatous
destruction of
medium-sized
intrahepatic bile
ducts = florid duct
lesion

38. Primary Sclerosing Cholangitis







Inflammation, obliterative onion-skin fibrosis,
and segmental dilatation of the obstructed
intrahepatic and extrahepatic bile ducts
String of beads on ERCP
70% associated with inflammatory bowel
disease, particularly ulcerative colitis
M:F = 2:1, third through fifth decades
Progressive fatigue, pruritus, jaundice
Chronic course
Increased risk for cholangiocarcinoma

40. Circulatory Disorders

41. Hepatic Artery Inflow


Liver has dual blood supply.
Thrombosis of hepatic artery in transplanted
liver → loss of organ

42. Portal Vein Obstruction

Extrahepatic
Peritoneal sepsis leads to phlebitis
 Lymphatic metastases to hilar lymph nodes
 Pancreatitis leads to splenic vein thrombosis
 Postsurgical thromboses
 Banti syndrome umbilical vein catheterization


Intrahepatic thrombus does not cause an
ischemic infarction but results in an area of redblue discoloration (infarct of Zahn).
Invasive carcinoma
 Hepatoportal sclerosis


43. Impaired Blood Flow Through the
Liver






Cirrhosis
Sickle cell disease
DIC – disseminated intravascular coagulation potentially fatal subcapsular haematoma in pts with
eclampsia
Right-sided heart failure → congestion of centrilobular
sinusoids
Left-sided heart failure → hypoperfusion and hypoxia
→ centrilobular necrosis
Peliosis hepatis – primary sinusoidal dilation associated
with anabolic steroids, danazol, and oral contraceptives

44. Hepatic Vein Thrombosis





Aka Budd-Chiari syndrome
Hepatomegaly, weight gain, ascites, abdominal
pain
Polycythaemia vera or other myeloprolifera-tive
disorders, pregnancy, the postpartum state, oral
contraceptive use, PNH, intra-abdominal
cancers, esp. HCC
Massive intrahepatic abscess or parasitic cyst
Centrilobular congestion and necrosis

45. Veno-Occlusive Disease




Shortly after bone marrow transplantation
25% incidence
Subendothelial swelling and reticulated collagen
Due to toxic endothelial injury secondary to
chemotherapy and radiation therapy

46. Hepatic Neoplasms

Metastatic carcinomas – most common
Colon
 Lung
 Breast



Benign tumors
Primary liver carcinoma
Hepatocellular carcinoma
 Cholangiocarcinomas
 Hepatoblastoma – children
 Angiosarcoma – associated with vinyl chloride,
arsenic, or Thorotrast exposure


47. Benign Tumors

Cavernous hemangioma – most common


Well-circumscribed, subcapsular, < 2 cm
Focal nodular hyperplasia
Young to middle aged adults
 Poorly encapsulated
 Central fibrous scar
 Response to local vascular injury


48. Focal Nodular Hyperplasia

49. Liver Cell Adenoma






Women of childbearing
age who have used oral
contraceptives
Often subcapsular
Sheets and cords of
hepatocytes
Portal tracts are absent
Prominent vessels
throughout
Risk for rupture, esp
during pregnancy

50. Hepatocellular Carcinoma

Annual incidence
Americas, Northern Europe, Australia 3-7
cases/100,000
 Southern Europe 20 cases/100,000
 Southeast China, Taiwan 150 cases/100,000





HBV carrier since infancy = 200 fold risk
Cirrhosis in 85% to 90% vs 50%
M:F = 3:1 vs 8:1
Sixth to seventh decades vs third to fifth

51. Pathogenesis

Infection with HBV
Genomic instability with integrated HBV DNA
 Integration pattern is clonal
 HBV X-protein disrupts cell cycle control
 Certain HBV proteins inactivate p53


Chronic liver disease, esp HCV and Etoh



Cirrhosis plays an important role.
Hepatocarcinogens in food (aflatoxins from the
fungus Aspergillus flavus)
Repeated cycles of cell death and regeneration,
i.e., chronic hepatitis, with possible mutations

52. Morphology


Unifocal, multifocal, or infiltrative
Strong propensity for vascular invasion





Portal vein or IVC involvement
Well-differentiated – intracellular bile
Scant stroma → soft
Metastasizes to LN, lung, bone, adrenal
Fibrolamellar carcinoma
20-40 yo, M=F
 No assoc. with cirrhosis or other risk factors
 Tumor cells separated by dense collagen
 Better prognosis


53. HCC

54. Clinical Features







Rapid increase in liver size
Sudden worsening of ascites
Appearance of bloody ascites, fever, pain
↑ serum AFP, esp if > 1000 ng/ml
Median survival 7 months
Death due to GI or esophageal variceal bleeding
or liver failure with hepatic coma
Surgical resection for smaller tumors


Recurrence rate 60% at 5 yrs
Liver transplantation

55. Disorders of the
Gallbladder

56. Cholelithiasis


Very common
Cholesterol stones
Bile is supersaturated with cholesterol
 Gallbladder stasis
 F>M
 Obesity
 Advancing age


Pigment stones – calcium bilirubinate salts
Asian more than Western
 Chronic hemolytic syndromes


57. Clinical Features




Asymptomatic
Biliary colic
Cholecystitis
Gallstone ileus

58. Cholecystitis

Acute calculous
Obstruction of GB neck or cystic duct
 RUQ pain radiating to right shoulder
 Fever, nausea, leukocytosis
 Potential surgical emergency



Acute acalculous – seriously ill pts
Chronic
Recurrent attacks of pain
 Nausea and vomiting
 Associated with fatty meals


60. Choledocholithiasis




Stones within the biliary tree
West – from gallbladder
Asia – primary ductal and intrahepatic stone
formation
Symptoms due to:
Biliary obstruction
 Pancreatitis
 Cholangitis
 Hepatic abscess


61. Cholangitis



Acute inflammation of bile ducts
Due to biliary obstruction, usually
choledocholithiasis
Bacterial infection from gut, i.e., gram negative
aerobes




Fever, chills, abdominal pain, jaundice
Latin America and Near East: Fasciola hepatica,
schistosomiasis
Far East: Clonorchis sinensis, Opisthorchis
viverrini
AIDS: cryptosporidiosis

62. Biliary Atresia








1/3 of cases of neonatal cholestasis
1 in 10,000 live births
Complete obstruction of bile flow caused by
destruction or absence of all or part of the
extrahepatic bile ducts
Acquired inflammatory disorder
Normal stools to acholic stools
Bile ductular proliferation on liver bx
Cirrhosis by 3 to 6 months of age.
Require liver transplantation

63. Gallbladder Carcinoma







Seventh decade
F>M
Discovered at late stage, usually incidental
Exophytic and infiltrating types
Adenocarcinoma
Local extension into liver, cystic duct,
portahepatic LNs
Mean 5 yr survival 1%

65. Cholangiocarcinoma








Older pts
M>F
Painless jaundice, N/V, weight loss
Opisthorchis sinensis (liver fluke), PSC,
inflammatory bowel disease
Tumors usually small at dx yet not resectable
Klatskin tumor – arises at bifurcation
Adenocarcinoma
Mean survival 6 to 18 months

67. Questions?