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GI 2 Pathology--Chapt. 18 and 19 > Chapter 18 part 4: Cholestatic diseases > Flashcards

Chapter 18 part 4: Cholestatic diseases Flashcards

1
Q

Two functions of bile

A
  • 1) emulsification of dietary fat and
  • 2) elimination of bilirubin, excess cholestrol, and other hydrophobic waste products that cannot be excreted into urine
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2
Q

Excess bilirubin (the end product of heme degradation) leads to?

A
  • jaundice and icterus (yellow skin and sclera discoloration respectively)
  • common causes are bilrubun overproduction, hepatitis, and bile outflow obstruction
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3
Q

Cholestasis

A

-systemic retention of all bile solutes, including bilirubin, bile salts and cholestrol

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4
Q

Bilirubin and bile formation

A
  • Degredation of heme throughout the body progresses from biliverdin to bilirubin; bilirubin is bound to albumin delivered to liver
  • After carrier mediated uptake, bilirubin is conjugated with 1-2 molecules of glucuronic acid by the hepatic endoplasmic transferase UGT1A1
  • Resulting water-soluble bilirubin glucuronides are excreted in bile and deconjugated by gut bacteria and degraded to urobilinogens that are primarily fecally eliminated
  • 20% of urobilinogens are resorbed and recycled to the liver with a small fraction excreted in the urine
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5
Q

Bile acids

A
  • water soluble modifications of cholesterol (mostly cholic acid and chenodeoxycholic acid) that act as detergents to solubilize dietary and biliary lipids
  • Bile salts (bile acids conjugated to taurine or glycine) constitue 2/3 of bile organic compounds
  • More than 95% of bile acids and salts are reabsorbed from gut and recirculate back to liver (enterohepatic circulation)
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6
Q

Pathophysiology of Jaundice

A

-occurs when bilirubin production exceeds hepatic uptake, conjugation, and and/or excretion

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7
Q

Unconjugated vs. conjugated hyperbilirubinemia

A
  • Excess production or diminished uptake and/or conjugation causes UNCONJUGATED HYPERBILIRUBINEMIA
  • defective excretion (intrahepatic or bile flow related) causes CONJUGATED HYPERBILIRUBINEMIA
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8
Q

Unconjugated bilirubin

A
  • insoluble in water
  • circulates tightly bound to albumin and cannot be excreted in urine
  • small amount circulates as free anion that can diffuse into tissues (esp neonatal brain) and cause injury–this unbound fraction can increase with severe hemolysis or when drugs displace bilirubin from albumin
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9
Q

Conjugated bilirubin

A

-water-soluble, non-toxic and only loosely bound to albumin; excess conjugated bilirubin can be renally excreted

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10
Q

Neonatal jaundice (Physiological Jaundice of the newborn)

A
  • Since hepatic metabolic machinery is not matue until 2 weeks, every newborn develops transient, mild unconjugated hyperbilirubinemia
  • can be exacerbated by breast-feeding due to bilirubin-deconjugating enzymes in breast milk
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11
Q

Heriditary Hyperbilirubinemias can be of what two types

A
  • conjugated hyperbilirubinemia

- unconjugated hyperbilirubinemia

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12
Q

Heriditary hyperbilirubinemia–unconjugated

A
  • Crigler-Najjar syndrome type I
  • Crigler-Najjar syndrome type II
  • Gilbert syndrome
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13
Q

Heriditary hyperbilirubinemia-conjugated

A
  • Dubin-Johnson syndrome (autosomal recessive)

- Rotor Syndrome

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14
Q

Crigler-Najjar type I

A
  • unconjugated
  • autosomal recessive
  • total absence of UGT1A1 causes jaundice with high serum levels of unconjugated bilirubin and a histologically normal liver
  • without liver transplantation, fatal neurological damage (kernicterus) occurs
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15
Q

Crigler-Najjar type II

A
  • unconjugated
  • autosomal dominant
  • Less severe UGT1A1 deficiency
  • Although kernicterus can occur, condition is not usually lethal
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16
Q

Gilbert syndrome

A
  • unconjugated
  • autosomal recessive
  • Mild fluctuating unconjugated hyperbilirubinemia, with 30% reduction in UGT1A1 activity attributable in most cases to a mutation that affects gene transcription
  • Hyperbilirubinemia (and jaundice) may be exacerbated by infection, strenuous exercise or fasting
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17
Q

Dubin-Johnson syndrome

A
  • conjugated
  • autosomal recessive
  • Defective hepatocyte secretion of bilirubin conjugates due to absent bilirubin glucuronide transport protein (multidrug resistant protein 2)
  • Liver is brown, with accumulated pigment granules (polymers of epinephrine metabolites, not bilirubin pigment)
  • Patients are jaundiced but have normal life expectancy
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18
Q

Rotor syndrome

A
  • conjugated
  • autosomal recessive
  • defective hepatocellular bilirubin uptake or excretion
  • liver is not pigmented; patients are jaundiced with normal life spans
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19
Q

Cholestasis

A
  • impaired bile formation or flow, leading to accumulation of intrahepatic bile pigments
  • can be extrahepatic (due to obstruction) or intrahepatic (due to hepatocellular dysfunction or canalicular obstruction)
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20
Q

Consequences of cholestasis

A
  • jaundice, pruritus from bile salt retention, xanthomas (skin accumulations of cholestrol) and intestinal malabsorption with nutritional deficiencies due to poor uptake of fat soluble vitamins (A, D, and K)
  • serum alkaline phosphatase and y-glutamyl transpeptidase (GGT) are elevated!!
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21
Q

Morphology of cholestasis

A

-both intra or extrahepatic cholestasis= bile pigment accumulates in hepatic parenchyma leading to dilated bile canaliculi and hepatocyte degeneration

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22
Q

Large bile duct obstruction

A

-most commonly due to extrahepatic cholelithiasis (gallstones), followed by pancreatic or biliary malignancies and post-surgical strictures

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23
Q

Causes of large bile duct obstruction in children

A
  • biliary atresia, cystic fibrosis, choledochal cysts, or insufficient intrahepatic bile duct formation
  • Initial morphologic features of cholestasis are reversible with correction of obstruction but prolonged obstruction can lead to billiary cirrhosis
  • Cholestasis may lead to feathery degeneration of periportal hepatocytes, cytoplasmic swelling with Mallory-Denk bodies and infarcts caused by detergent effects of extravasated bile
24
Q

Chlestasis of sepsis–how sepsis affects the liver

A
  • Direct effects of intrahepatic infection (abscess formation or cholangitis)
  • Ischemia due to hypotension
  • Respose to circulating microbial products: canalicular cholestasis and Ductular cholestasis
25
Q

Canalicular cholestasis

A
  • with canalicular bile plugs

- associated with activated Kupffer cells and mild portal inflammation

26
Q

Ductular cholestasis

A

-more ominous finding with dilated canals of Hering and bile ductules and often accompanies septic shock

27
Q

Primary Hepatolithiasis

A
  • disorder of intrahepatic gallstone formation causing recurrent ascending cholangitis, progressive inflammatory destruction of hepatic parenchyma, and increased incidence of biliary neoplasia
  • high prevalence in east Asia
  • stones are pigmented calcium bilirubinate
28
Q

Neonatal Cholestasis

A
  • prolonged conjugated hyperbilirubinemia

- present w/ jaundice, dark urine, light stools and hepatomegaly

29
Q

Major causes of neonatal cholestasis

A
  • cholangiopathies (primarily biliary atresia)
  • disorders collectively called neonatal hepatitis (but not all are inflammatory)
  • Neonatal infections, a1-AT deficiency, toxic exposures and metabolic diseases (Niemann-Pick) may be responsible
  • No cause identified in 10-15% of cases
  • Establishing etiology is important bc biliary atresia requires surgical intervention
30
Q

Biliary atresia

A
  • causes 1/3 of neonatal cholestasis
  • is extrahepatic biliary tree obstruction within 1st 3 months of life
  • single most frequent cause of death from liver disease in early childhood and accounts for majority of children referred for liver transplants
31
Q

Pathogenesis of Biliary atresia–what are the two forms?

A
  • severe early fetal form (20%)

- perinatal form

32
Q

Pathogenesis of Biliary atresia–severe early fetal form

A

-due to aberrant intrauterine development of biliary tree and is frequently associated with other anomalies

33
Q

Pathogenesis of Biliary atresia–perinatal form

A

-presumed secondary to viral infections and/or autoimmunity–results from postnatal destruction of a normal biliary tree

34
Q

Morphology of biliary atresia

A
  • both forms= inflammation and fibrosing stricture of extrahepatic biliary tree, progressing into intrahepatic biliary system
  • Liver shows features of duct obstruction: marked bile duct proliferation, portal tract edema and fibrosis progressing to cirrhosis within 6 months
35
Q

Clinical features of Biliary atresia

A
  • Neonatal cholestasis is seen in an infant of normal birth weight and post natal weight gain
  • if untreated (liver transplantation), death occurs within 2 years of birth
36
Q

Autoimmune cholangiopathies

A
  • 2 main autoimmune disorders of intrahepatic bild ducts:
  • Primary Biliary Cirrhosis
  • Primary Sclerosing Cholangitis
37
Q

Table 18-5 PBC

A
  • median age: 50 (30-70)
  • gender: 90% female
  • Clinical course: progressive
  • Associated conditions: Sjogren syndrome, scleroderma, thyroid disease
  • Serology: 95% AMA positive, 50% ANA positive, 40% ANCA positive
  • Radiology: Normal
  • Duct lesions: Florid duct lesions and loss of small ducts only
38
Q

Table 18-5 PSC

A
  • median age: 30
  • gender: 70% male
  • Clinical course: Unpredictable but progressive
  • Associated conditions: IBD, Idiopathic fibrosing diseases (retroperitoneal fibrosis)
  • Serology: 0-5% AMA positive (low-titer), 6% ANA positive, 65% ANCA positive
  • Radiology: Strictures and beading of large bile ducts; pruning of smaller ducts
  • Duct lesions: Inflammatory destruction of extrahepatic and large intrahepatic ducts; fibrotic obliteration of medium and small intrahepatic ducts
39
Q

Primary Biliary Cirrhosis

A
  • disorder causing nonsuppurative inflammatory destruction of small and medium sized intrahepatic bile ducts
  • middle aged women and does not lead inexorably to cirrhosis
40
Q

Primary Biliary Cirrhosis–autoimmunity

A
  • antimitochondrial Abs that recognize the E2 component of the pyruvate dehydrogenase complex (PDC-E2) occur in 90% to 95% of patients and are most characteristic lab finding!!
  • PDC-E2-specific T cells and Abs against other cellular components (nuclear pore proteins and centromeric proteins) also present
41
Q

Morphology of PBC

A
  • lesions of varying severity throughout liver
  • dense chronic portal tract inflammation with focal non-caseating granulomas–associated with interlobular bile duct obstruction and generalized cholestasis
  • Intrahepatic biliary obstruction leads to progressive secondary upstream damage with ductular proliferation and inflammation and necrosis of periportal hepatocytes often with prominent Mallory-Denk bodies
  • At end stage, PBC is indistinguishable from other forms of cirrhosis
42
Q

Clinical features of PBC

A
  • insiduous onset with pruritis, hepatomegaly, jaundice and xanthomas (from retained cholestrol)
  • with progression to cirrhosis, see variceal bleeding and encephalopathy
  • increase in alkaline phosphatase, y-glutamyltransferase and cholestrol levels
43
Q

Extrahepatic autoimmune manifestations of PBC

A

-Sjogren syndrome, scleroderma, thyroiditis, Raynaud phenomenon, and membranous glomerulonephritis

44
Q

Consequences for untreated patients with PBC

A

-either hyperbilirubinemia or portal hypertension

45
Q

Tx of early stage PBC

A

-oral ursodeoxycholic acid–greatly slows progression presumably through altering biochemical composition of bile

46
Q

Primary sclerosing cholangitis

A
  • chronic cholestatic disease distinguished by inflammation and obliterative fibrosis of both the extrahepatic and intrahepatic biliary tree
  • dilation of the preserved segments yields a characteristic “beading” of injected radiologic contrast material
47
Q

PSC–facts that suggests it is an autoimmune condition

A
  • associated with ulcerative colitis (70%)
  • presence of circulating autoantibodies (ANA, anti-SMA, rheumatoid factor and atypical p-antineutrophil cytoplasmic Ab (p-ANCA) against a nuclear evelope protein
48
Q

Morphology of Primary scelorsing cholangitis

A
  • Bile ducts exhibit periductular inflammation and concentric (onion-skin) fibrosis with progressive atrophy and eventual luminal obliteration
  • obstruction culminates in biliary cirrhosis and hepatic failure
49
Q

Clinical features of Primary sclerosing Cholangitis

A
  • most common in middle aged men
  • follows protracted course (5-15 years)
  • severe disease associated with weight loss, ascites, variceal bleeding and encephalopathy
  • increased incidence of chronic pancreatitis and HCC
  • 7% of patients will develop CCA
  • Definitive Tx=liver transplant
50
Q

Structural anomalies of Biliary Tree

A
  • Choledochal cysts

- Fibropolycystic Disease

51
Q

Choledochal cysts

A
  • congenital dilations of the common bile duct present in most often in children under 10 with non-specific symptoms of jaundice and recurrent colicky abdominal pain
  • female to male ratio is 3 to 4:1
  • cysts predispose to stone formation, stenosis and stricture, pancreatitis, obstructive biliary complications and bile duct carcinoma in adults
52
Q

Fibropolycystic disease

A
  • heterogenous group of lesions where primary abnormalities are congenital malformations of biliary tree
  • lesions only found incidentally or can present as hepatosplenomegaly and portal HTN
53
Q

All lesions of Fibropolycystic disease are related to what?!?

A
  • persistence of fetal periportal ductal plate!!!
  • the caliber of involved portal tracts determines the different size, morphology and distribution of lesions
  • often occurs with autosomal recessive polycystic renal disease involving protein polycystin
  • increased risk for CCA!!
54
Q

Fibropolycystic disease–Disease list

A
  • Von Meyenberg complexes (bile duct hamartomas)
  • Intrahepatic or extrahepatic biliary cysts
  • Congenital hepatic fibrosis
55
Q

Von Meyenberg complexes (bile duct hamartomas)

A

-small clusters of dilated bile ducts or cysts within a fibrous stroma; extremely common but usually clinically insignificant

56
Q

Intrahepatic or extrahepatic biliary cysts

A
  • In isolation these may lead to ascending cholangitis, so called Caroli disease
  • When biliary cysts occur in association with congenital hepatic fibrosis, the lesion is called CAROLI syndrome!
  • Congenital hepatic fibrosis–caused by incomplete involution of embryonic ductal structures with ensuing portal tract fibrosis, which can cause portal HTN

GI 2 Pathology--Chapt. 18 and 19 (8 decks)

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