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GI- Week 3 > Cholestatic Disease > Flashcards

Cholestatic Disease Flashcards

1
Q

What is cholestasis?

A

cholestasis = when there is systemic retention of not only bilirubin but also other solutes eliminated in bile.

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2
Q

What are the main functions of bile?

A

(1) the emulsification of dietary fat in the lumen of the gut through the detergent action of bile salts, and
(2) the elimination of bilirubin and other waste products

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3
Q

When does jaundice occur?

A

Jaundice occurs when there is bilirubin overproduction, hepatitis, or obstruction of the flow of bile

Disruption of the equilibrium between bilirubin production and clearance.

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4
Q

What are some pathologies that lead to jaundice via excess production of bilirubin?

A

Hemolytic anemias

Resorption of blood from internal hemorrhage (e.g., alimentary tract bleeding, hematomas)

Ineffective erythropoiesis (e.g., pernicious anemia, thalassemia)

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5
Q

What are some pathologies that lead to jaundice via reduced hepatic uptake of bilirubin?

A

Drug interference with membrane carrier systems

Some cases of Gilbert syndrome

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6
Q

What is Gilbert Syndrome?

A

Gilbert’s syndrome (GS) is a common genetic liver disorder found in 3-12% of the population.

It produces elevated levels of unconjugated bilirubin in the bloodstream (hyperbilirubinemia), but this normally has no serious consequences, although mild jaundice may appear under conditions of exertion or stress.

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7
Q

What causes the hyperbilirubinemia in Gilbert syndrome?

A

The cause of this hyperbilirubinemia is the reduced activity of the enzyme glucuronyltransferase (UGT1A1), which conjugates bilirubin in the liver and a few other lipophilic molecules. Conjugation renders the bilirubin water-soluble, after which it is excreted in bile into the duodenum. There are a number of variants of the gene for the enzyme, so the genetic basis of the condition is complex.

Similar to Type II Crigler-Najjar Syndrome

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8
Q

What are some pathologies that lead to jaundice via impaired bilirubin conjugation?

A

Physiologic jaundice of the newborn (decreased UGT1A1 activity, decreased excretion)

Breast milk jaundice (β-glucuronidases in milk)

Genetic deficiency of UGT1A1 activity (Crigler-Najjar syndrome types I and II)

Gilbert syndrome

Diffuse hepatocellular disease

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9
Q

What is the function of UGT1A1?

A

The UGT1A1 gene belongs to a family of genes that provide instructions for making enzymes called UDP-glucuronosyltransferases. These enzymes perform a chemical reaction called glucuronidation, in which a compound called glucuronic acid is attached (conjugated) to one of a number of different substances.

The protein produced from the UGT1A1 gene, called the bilirubin uridine diphosphate glucuronosyl transferase (bilirubin-UGT) enzyme, is the only enzyme that glucuronidates bilirubin, a substance produced when red blood cells are broken down. This enzyme converts the toxic form of bilirubin (unconjugated bilirubin) to its nontoxic form (conjugated bilirubin), making it able to be dissolved and removed from the body.

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10
Q

Describe Type I Crigler Najjar syndrome

A

AR genetic disease marked by absence of UGT1A1 activity that is fatal to neonates

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11
Q

Describe Type II Crigler Najjar syndrome

A

AD disease (with variable penetrance) that is marked by decreased UGT1A1 activity causing mild kernicterus

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12
Q

What is kernicterus?

A

bilirubin-induced brain dysfunction

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13
Q

What is Dubin Johnson Syndrome?

A

An AR disorder marked by Impaired biliary excretion of bilirubin glucuronides due to mutation in canalicular multidrug resistance protein 2 (MRP2)

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14
Q

What is Rotor Syndrome?

A

An AR disorder marked by increases in conjugated bilirubin levels and non-itching jaundice

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15
Q

How is Rotor Syndrome differentiated from Dubin-Johnson Syndrome?

A
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16
Q

What is this?

A

Dubin-Johnson Syndrome- impaired excretion due to canalicular membrane-carrier defect, have darkly pigmented cytoplasmic globules in liver

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17
Q

What is this?

A

•Cholestasis - caused by impaired bile formation and bile flow that gives rise to accumulation of bile pigment in the hepatic parenchyma.

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18
Q

What is this showing?

A

Acute large duct obstruction- There is marked edema of the portal tract stroma (white spaces) and a ductular reaction with admixed neutrophils at the interface between portal tract and hepatocellular parenchyma.

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19
Q

Describe ascending cholangitis

A
  • Individuals with large bile duct obstruction risk bacterial infections of the static bile within the biliary tree.
  • Enteric organisms such as coliforms and enterococci are common culprits.
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20
Q
A
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21
Q

What is the result of untx ascending cholangitis/duct obstruction?

A

•Ductular reactions initiate periportal fibrosis, eventually leading to hepatic scarring and nodule formation, generating secondary or obstructive biliary cirrhosis.

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22
Q

What is this?

A

biliary cirrhosis- Unlike other forms of cirrhosis, nodules of liver cells in biliary cirrhosis are often not round but irregular, like jigsaw puzzle shapes

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23
Q

What are the histo features of chronic biliary obstruction?

A
  • feathery degeneration of periportal hepatocytes
  • cytoplasmic swelling often with Mallory-Denk bodies (differing from those in alcohol-induced liver disease and non-alcoholic fatty liver disease by their periportal predominance), and
  • formation of bile infarcts
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24
Q

Cholestasis is also seen in sepsis most often due to in response to circulating microbial products. What is the most common form?

A

•The most common form is canalicular cholestasis, with bile plugs within predominantly centrilobular canaliculi.

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25
Q

What is this?

A
  • Ductular cholestasis - ominous
  • dilated canals of Hering and bile ductules at the interface of portal tracts and parenchyma become dilated
  • contain obvious bile plugs (Fig).

Not a typical feature of biliary obstruction, but septic shock

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26
Q

What is Hepatolithiasis?

A

is the presence of gallstones in the biliary ducts of the liver.

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27
Q

What does primary hepatolithiasis lead to?

A
  • repeated bouts of ascending cholangitis,
  • progressive inflammatory destruction of hepatic parenchyma, and
  • predisposes to biliary neoplasia
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28
Q

What does this show?

A

atrophic right hepatic lobe with characteristic findings of primary hepatolithiasis including markedly dilated and distorted bile ducts containing large pigment stones and broad areas of collapsed liver parenchyma.

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29
Q

What does this show?

A

Neonatal Cholestasis caused by neonatal hepatitis - persisting conjugated hyperbilirubinemia in the newborn with conjugated bilirubin levels exceeding 15% (5.0 mg/dL) of total bilirubin level.

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30
Q

What are the major causes of neonatal cholestasis?

A
  • Biliary Atresia = major cause
  • Neonatal hepatitis - a variety of disorders causing conjugated hyperbilirubinemia
31
Q

Describe the histology seen in this pic of neonatal hepatitis induced cholestasis

A

Lobular disarray

Apoptosis and necrosis

Multinucleated giant hepatocytes

32
Q

What is biliary atresia defined as?

A

defined as a complete or partial obstruction of the lumen of the extrahepatic biliary tree within the first 3 months of life

33
Q

How does biliary atresia appear?

A

•inflammation and fibrosing stricture of the hepatic or common bile ducts

34
Q

What is Primary biliary cirrhosis?

A

Primary biliary cirrhosis, also known as primary biliary cholangitis (PBC), is an autoimmune disease of the liver. It is marked by slow progressive destruction of the small bile ducts of the liver, with the intralobular ducts and the Canals of Hering (intrahepatic ductules) affected early in the disease and progressive destruction as the disease progresses

35
Q

Who gets PBC?

A

90% females around 50 yo

36
Q

What are some associations with PBC?

A

Sjogren syndrome (70%)

Scleroderma

Thyroid disease

37
Q

What ABs are seen in PBC?

A

95% AMA-positive

50% ANA-positive

40% ANCA-positive

38
Q

What part of the biliary system is affected by PBC?

A

Florid duct lesions and loss of small ducts only

39
Q

What is Primary Sclerosing Cholangitis?

A

Primary sclerosing cholangitis (PSC) is a disease of the bile ducts that causes inflammation and obliterative fibrosis of bile ducts inside and/or outside of the liver. This pathological process impedes the flow of bile to the intestines and can lead to cirrhosis of the liver, liver failure, and other complications, including bile duct and liver cancer. The underlying cause of the inflammation remains unknown, but elements of autoimmunity and microbial dysbiosis have been described and are suggested by the observation that approximately 75% of individuals with PSC also have inflammatory bowel disease (IBD), most often ulcerative colitis.

40
Q

Who gets PSC?

A

70% male, at around 30 yo

41
Q

What is the predominant association with PSC?

A

IBD

42
Q

What ABs are seen in PSC?

A

0-5% AMA-positive (low titer)

6% ANA-positive

65% ANCA-positive

43
Q

What parts of the biliary tree are affected by PSC?

A

Inflammatory destruction of extrahepatic and large intrahepatic ducts; fibrotic obliteration of medium and small intrahepatic ducts

44
Q

What is this?

A

PBC - an autoimmune disease characterized by:

nonsuppurative, inflammatory destruction of small and medium-sized intrahepatic bile ducts

45
Q

Describe what you see here

A

PBC showing:

Lymphocytic inflammation and damage to a medium-sized bile duct in a portal tract (long arrow).

poorly-formed granuloma on the right side of the bile duct (curved arrow).

46
Q

What does the inflammation of PBC cause?

A

With inflammatory damage to the bile ducts, further flow of bile fluid distal to the damaged bile duct is impeded resulting is cholestasis and damage to hepatocytes.

47
Q

What is the natural course of untx PBC?

A

Portal fibrosis with eventual development of cirrhosis

Below: Trichrome stain shows concentric collagen fibrosis in a portal tract.

48
Q

How does the bile duct compensate in PBC?

A

Compensatory bile ductular proliferation (long arrow) in portal tracts proximal to obstructed regions.

49
Q

What is a telltale sign of bile duct damage distal in the biliary tree?

A

The presence of multiple bile ductules in the periphery of a portal

50
Q

The extent and geography of reactive bile ductular proliferation in PBC can be highlighted by what?

A

immunostaining for CK-7 since normal bile ducts are positive for this antigen.

Note the absence of any medium-sized bile ducts inside the portal tract and a rather brisk bile ductular proliferation at the portal border.

51
Q

PBC

A
52
Q

What is this showing?

A

Characteristic “beading” on radiographs with PSC

characterized by inflammation and obliterative fibrosis of intrahepatic and extrahepatic bile ducts with dilation of preserved segments.

53
Q

What is this?

A

PSC-

Large duct inflammation - acute, neutrophilic infiltration of the epithelium superimposed on a chronic inflammation

Smaller ducts, have little inflammation and show a striking circumferential “onion skin” fibrosis around an atrophic duct lumen (Fig), with eventual obliteration

54
Q

What does PSC culminate in?

A

Culminates in biliary cirrhosis much like that seen with chronic obstruction and primary biliary cirrhosis.

55
Q

One issue with PSC is the development of _____

A

Biliary intraepithelial neoplasia may develop and cholangiocarcinoma appears usually with a fatal outcomes.

56
Q
A
57
Q

What are some common structural anomalies of the biliary tree?

A
  • Choledochal Cysts
  • Fibropolycystic Disease
  • Congenital hepatic fibrosis
58
Q

What are Choledochal cysts?

A

Congenital dilations of the common bile duct.

59
Q

How do Choledochal cysts present?

A

Children before age 10 in FEMALES as jaundice and/or recurrent abdominal pain, symptoms that are typical of biliary colic

60
Q

What is Caroli disease?

A

In some cases choledochal cysts occur in conjunction with cystic dilation of the intrahepatic biliary tree (Caroli disease).

61
Q

What are sequelae of choledochal cysts?

A

Choledochal cysts predispose to stone formation, stenosis and stricture, pancreatitis, and obstructive biliary complications within the liver. In older patients the risk of bile duct carcinoma is elevated

62
Q
A
63
Q

What is Fibropolycystic disease of the liver?

A

A heterogeneous group of lesions in which the primary abnormalities are congenital malformations of the biliary tree including:

  • Von Meyenburg complexes
  • Single or multiple, intrahepatic or extrahepatic biliary cysts
64
Q

Persons with fibropolycystic liver disease have an increased risk for ________

A

cholangiocarcinoma.

65
Q

What is this?

A

Von Meyenburg complex, a bile duct hamartoma always associated with portal tracts.

Note the dilated and irregularly shaped bile ducts.

66
Q

What is this?

A

Single or multiple, intrahepatic or extrahepatic biliary cysts

Ducts may be cystically dilated, but true cysts are also present.

These may be intrahepatic cysts or choledochal cysts.

67
Q

What is the difference between Caroli disease and Caroli syndrome?

A

When present in isolation intra- or extrahepatic cysts may be symptomatic due to ascending cholangitis and are referred to as Caroli disease. When biliary cysts occur along with congenital hepatic fibrosis, the term Caroli syndrome is used (Fig).

68
Q

Describe congenital hepatic fibrosis

A

•An autosomal recessive disorder, linked with mutations in the PKHD1 gene on chromosome 6, resulting in a ductal plate malformation of intralobular bile ducts.

69
Q

What is this?

A

Congenital hepatic fibrosis

•Not truly cirrhotic, despite the serpiginous scarring separating the hepatic parenchyma, but they may still face complications of portal hypertension, particularly bleeding varices.

Image: Portal tracts are enlarged by irregular, broad bands of collagenous tissue, form­ing septa that divide the liver into irregular islands.

70
Q
A
71
Q

What is Budd-Chiari Syndrome?

A

Condition of portal HTN caused by occlusion of the hepatic veins that drain the liver.

72
Q

How does Budd-Chiari Syndrome present?

A

It presents with the classical triad of abdominal pain, ascites, and liver enlargement. The formation of a blood clot within the hepatic veins can lead to Budd–Chiari syndrome. The syndrome can be fulminant, acute, chronic, or asymptomatic.

73
Q

What are some causes of Budd-Chiari Syndrome?

A

-polycythemia vera/myeloproliferative diseases,

pregnancy, OCP, abdominal cancer (especially within the liver itself)

74
Q

What is this?

A

Budd-Chiari

•Severe centrilobular congestion/necrosis, progressing to centrilobular fibrosis

GI- Week 3 (15 decks)

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