Glomerular Filtration and determinants of glomerular filtration .pptx
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
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
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
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
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
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.
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
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
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
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
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
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
59.
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