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D&T 4, Exam 3 (Liver) > Limjoco - Congenital and Pediatric Liver Diseases > Flashcards

Limjoco - Congenital and Pediatric Liver Diseases Flashcards

1
Q

What enzyme conjugates bilirubin in the liver?

A

Glucuronyl-Bilirubin Transferase

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2
Q

Where does conjugation of bilirubin occur? Where is the newly conjugated bilirubin secreted?

A
  • Hepatocyte
  • Bile
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3
Q

What disease state?

  • 50% of term, 80% of preterm affected
  • Unconjugated bilirubinemia
  • Physiologic jaundice – harmless unless higher level (>20 mg/dL)
  • Conjugation & excretion mechanisms in liver immature until 2 weeks of age (low UDPG transferase activity, low levels of ligandin-binding protein in cytosol)
A

Neonatal hyperbilirubinemia

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4
Q

Why do neonates have more bilirubin than normal ?

(3 reasons)

Bonus: What treats neonatal hyperbilirubinemia?

A
  • Shorter RBC lifespan
  • Higher RBC mass
  • Birth trauma

Bonus: Treatment

Phototherapy (blue wavelength) converts to water-soluble isomers Z-lumirubin, E-bilirubin thru conformational change –> excreted into bile w/o conjugation –> excreted into stool, urine

Most resolve in 14 - 21 days

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5
Q

What type of jaundice occurs by beta-glucuronidase
deconjugating conjugated bilirubin?

  • Lasts longer than physiologic jaundice
  • Treat with phototherapy
  • Discontinue breastfeeding temporarily- if serum bilirubin reaches 20 mg/dL
  • Increase frequency of feedings to increase excretory process
A

Breastmilk Jaundice

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6
Q

What other conditions can lead to neonatal hyperbilirubinemia?

A
  • G6PD deficiency
  • Spherocytosis (increased hemolysis leads to increased bilirubin)
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7
Q

What condition:

  • Excessive levels of unconjugated bilirubin crosses blood-brain-barrier - toxic to brain
  • 0.4-2.7/100,000 births (US)
A

Kernicterus

Bilirubin moves from bloodstream into brain tissue

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8
Q

Which hereditary hyperbilirubinemia?

  • AR, severe UGT1A1 (UDGPT) deficiency
  • Kernicterus - hypotonia, deafness, oculomotor palsy, lethargy
  • FATAL- unless gets transplant
A

Crigler Najjar Syndrome Type 1

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9
Q

What gene?

  • Gene for bilirubin-UDP-glucuronosyl- transferase
  • conjugates bilirubin w/ mono- or diglucuronides
A

UGT1A1 Gene

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10
Q

What hereditary hyperbilirubinemia?

  • AD decreased UGT1A1 activity (monoglucuronide only)
  • Mild jaundice, non-fatal
  • Diagnosis by HPLC/liver biopsy enzyme assay
  • Treatment (if Type I survives infancy) is lifelong phototherapy; liver transplantation for some
A

Crigler-Najjar syndrome Type 2

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11
Q

What hereditary hyperbilirubinemia?

  • Rare (3-12% of population)
  • AR genetic condition
  • Characterized by intermittent unconjugated hyperbilirubinemia
  • Precipitated by stress, calorie restriction, fasting, drug intake
  • 30% of normal activity of UDPGT

Lab findings:

  • Isolated increase in unconjugated bilirubin
  • Increase in the ratio of urinary coproporphyrin I to coproporphyrin III
  • No treatment needed - asymptomatic, or mild jaundice in stress, infection, fasting
A

Gilbert syndrome

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12
Q

What hereditary hyperbilirubinemia?

  • AR
  • Mutated gene for MRP2 (transports glucuronate conjugated bilirubin from liver cell to canaliculi)
  • BENIGN relapsing conjugated hyperbilirubinemia
  • Normal liver transaminases + conjugated hyperbilirubinemia
  • Non-pruritic jaundice in teens, asymptomatic

* Pigmented liver *, melanin pigment

A

Dubin-Johnson syndrome

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13
Q

What hereditary hyperbilirubinemia?

  • AR
  • Clinically similar to Dubin-Johnson syndrome – BUT liver is NOT pigmented
  • Increased urinary coproporphyrin excretion
  • NO gene has been identified yet
A

Rotor Syndrome

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14
Q

What disorder?

  • Accumulation of bile pigment in hepatic parenchyma due to impaired bile formation or bile flow
  • Cause - extrahepatic or intrahepatic obstruction of bile ducts, or defects in hepatocyte bile secretion
A

Liver Cholestasis

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15
Q

Clinical manifestations of what disorder?

  • Jaundice, pruritus, xanthomas of the skin
  • Intestinal malabsorption symptom - deficiency of fat-soluble vits A, D, K
  • Elevated ALP and GGT
  • Enzymes on bile duct cells, apical canalicular membranes of hepatocytes,

Extrahepatic or intrahepatic obstruction of bile ducts, OR
Defects in hepatocyte bile secretion

A

Liver Cholestasis

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16
Q

What duct is formed from hte fusion of the R and L hepatic bile ducts?

What duct is formed from the fusion of the cystic and hepatic ducts?

A
  • Common Hepatic Duct
  • Common Bile Duct
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17
Q
  • Gallstones (extrahepatic cholelithiasis)
  • Malignancies (biliary tree or head of pancreas)
  • Strictures from surgery

Can cause what disorder?

A

Large Bile Duct Obstruction

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18
Q

How does treatment differ for large bile duct obstruction depending on the location of the obstruction?

A
  • Surgical correction of extrahepatic obstruction to reverse obstruction; otherwise, may develop biliary cirrhosis
  • If cause of obstruction is in intrahepatic biliary tree or intrahepatic cholestasis, surgery NOT helpful (unless for transplantation)
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19
Q
  • _____________ - subtotal/intermittent obstruction [ball and valve stone, stricture]
    • Secondary bacterial infection
    • Coliforms, enterococci from gut (retrograde ascent from gut?)
    • Fever, chills, abdominal pain, jaundice
  • ___________ - severe form
    • Bile pus fills bile ducts
    • SEPSIS dominates
A
  • Ascending Cholangitis
  • Suppurative Cholangitis
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20
Q

Two possible routes by which enteric bacteria can reach biliary tract in acute cholangitis?

1.

2.

A
  1. Common bile duct
  2. Portal vein
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21
Q

What disease state?

  • Response to microbial products in blood, especially in systemic Gram-negative infection
  • Conjugated bilirubin, non-obstructive cholestasis
  • Increased bilirubin load from:
    • Hemolysis
    • Hepatocellular injury
  • Cholestasis from:
    • Cytokines (TNF-alpha), endotoxin
    • Drugs used for the treatment of sepsis
A

Sepsis-associated Cholestasis

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22
Q

Types of sepsis-associated cholestasis:

  • Centrilobular canalicular bile plugs, Kupffer cell activation, mild portal inflammation, Scant/absent hepatocyte
  • Worse pathology of the two, dilated canals of Hering and bile ductules

Bonus: Treatment for both?

A
  • Canalicular cholestasis
  • Ductular cholestasis

Bonus: correct fluid and electrolyte imbalances, treat underlying infection

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23
Q

What disorder?

  • Prolonged conjugated hyperbilirubinemia in newborn
  • Affects 1/2500 live births
  • If have jaundice beyond 14 to 21 days -> evaluate for this
  • Causes: Neonatal hepatitis (toxic, metabolic, infectious causes), Cholangiopathies - biliary atresia
A

Neonatal cholestasis

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24
Q

Facts: Neonatal Hepatitis

  • Etiologies - toxic, metabolic, infectious
  • Can determine in 90% clinically
  • 10-15% idiopathic
  • Need liver biopsy in 10%
  • Pathogenesis
    • Immature bile synthesis and secretion pathways
    • decompensated by injury
  • ​Liver biopsy: see Giant cell transformation, Unique response of young liver to injury

? via mitotic inhibition of young growing liver by injury

? dissolution of cell membranes by adjacent cells)

* ​**Necrosis**
A
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25
Q

What is seen on liver biopsy of neonatal hepatitis?

1.

2.

3.

4.

A
  1. Giant cell transformation
  2. Necrosis
  3. Apoptotic, Acidophil bodies
  4. Extramedullary hematopoiesis
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26
Q

What is the most common cause of pathologic neonatal jaundice?

  • Complete/partial obstruction extrahepatic biliary tree in first 3 months (stenosis/atresia)
    • 1/3 of neonatal cholestatic cases
    • 50-60% of childhood transplantation
  • Clinical Manifestations
    • Asymptomatic
    • Jaundice, dark urine, pale stools
A

Biliary atresia

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27
Q

What form of biliary atresia occurs due to aberrant intrauterine development of extrahepatic biliary tree?

  • Associated with other anomalies such as sinus anomalies of abdominal organs, polysplenia, etc.
A

Fetal/embryonal form (20%)

28
Q

What form of biliary atresia occurs due to destruction of the biliary tree at birth?

Associated with viruses (rotavirus, reovirus, echovirus, CMV) causing continual inflammation.

A

Perinatal form (80%)

29
Q

Pathology of what disorder?

  • Fibrosing stricture of hepatic or common bile duct with inflammation, which may involve intrahepatic bile ducts.
  • Gross: enlarged, hard liver, dark green, micronodular cirrhosis; dilated intrahepatic bile ducts with inspissated bile
  • Liver biopsy: changes of extrahepatic biliary obstruction, see fibrosis, increased ductules, neutrophils, bile plugs
A

Liver Biliary Atresia

30
Q

What procedure can be done to bypass the atretic ducts to achieve bile flow with liver biliary atresia?

A

Kasai Procedure (Roux-en-Y, hepatoportoenterostomy)

can also do a liver transplant

31
Q

What disorders?

  1. Iron overload in tissues, organs such as liver due to autosomal recessive genetic mutations.
  2. Iron accumulates from known sources of excess iron - multiple transfusions, ineffective erythropoiesis (thalassemias, sideroblastic anemia), increased iron intake
A
  1. Hereditary (Primary) Hemochromatosis
  2. Secondary Hemochromatosis/Iron Overload/Acquired
32
Q

What disorder?

  • Condition arising from mutations in HFE gene - “human factor engineering” gene
  • HFE gene regulates hepcidin (“iron hormone” in liver)
  • Decreased hepcidin leads to increased iron absorption
  • Defect in regulation of intestinal absorption of dietary iron
A

HFE Hemochromatosis

33
Q

HFE Hemochromatosis:

  • Mutation discovered in 1996 – codes for HFE protein
  • Carrier: 1/70 Homozygous: 1/200; 80% of patients are homozygous
  • (Other mutation: H63D, at amino acid 63, histidine to aspartate substitution)

What mutation?

A

C282Y Mutation in HFE gene: at amino acid 282, nucleotide 845, with Cysteine to tyrosine substitution

34
Q

HFE Hemochromatosis:

Deposition of iron in parenchymal tissues when 20g storage iron accumulated

  • Due to defective regulation of iron absorption 0.5 - 1.0 g/yr net accumulation
  • ____________ inhibits iron entry into plasma
  • Decreased _________ –> increased iron absorption leads to more iron released into bloodstream and deposited in tissues
A

Hepcidin

Hepcidin

35
Q

HFE Hemochromatosis - Abnormal handling of iron is directly toxic to cells in various organs, including: (what do you see in each?)

Pancreas - in acinar and islet cells: _________

Heart: _____________

Pituitary gland, adrenal gland, thyroid, parathyroid, joints: ________

Skin: _______________

A

Pancreas: interstitial fibrosis

Heart: myocytes enlarge, interstitial fibrosis

Pituitary gland, adrenal gland, etc: pseudogout

Skin: increased melanin in melanocytes, iron deposition in dermal macrophages, slate grey skin

36
Q

What cells are seen in HFE hemochromatosis?

  • Hepatic Iron Index (HII)
    • Iron concentration in liver biopsy measured tissue iron in micromole/g dry wt divided by age of patient in yrs (or microg/g dry wt divided by [55.8 x age in yrs)
    • Index of > 1.9 in HH (and also alcoholic liver dis.)
    • Can also confirm with genetic testing
A

Iron deposits in normal liver (L) and in severe pericanalicular deposition - Kupffer cells, biliary cells, periportal hepatocytes

  • Stainable iron in periportal hepatocytes in homozygous HFE HH – an early sign
37
Q

What are some clinical manifestations of HFE hemochromatosis?

Liver:

Skin:

Heart:

Pancreas:

***Classic Triad?

  • *-** Death due to cirrhosis, cardiac failure
  • Death due to ______, 200X the normal risk! (not deacreased by treatment of iron overload)
A

Hepatomegaly, abdominal pain

Skin pigmentation (bronze, slate grey skin)

Cardiac dysfunction (arrhythmias, cardiomyopathy)

Pancreas (diabetes mellitus)

***Bolded are the classic triad

  • Death due to Hepatocellular carcinoma
38
Q

How can hemochromatosis be treated?

** Treatable, can expect normal life expectancy - to diagnose, check serum iron, ferritin, total iron binding capacity

A
  • Regular phlebotomy (blood-letting) to reduce iron stores
  • Monitored via serum ferritin level
39
Q

Fact:

Secondary Iron Overload Disorders

  • Multiple transfusions
  • Thalassemia
  • Ineffective erythropoiesis (thalassemia, myelodysplastic syndrome)
  • Chronic liver disease (viral, ASH, NASH, etc)
  • Cirrhosis
  • Increased iron intake (Bantu siderosis)
A
40
Q

What disorder?

  • Autosomal recessive disorder due to mutation of ATP7B gene (much less common that HH)
  • Copper-transporting ATPase in trans-Golgi network in canalicular area of hepatocyte = absent or dysfunctional ATPase expressed in liver, kidney, placenta
  • Impaired copper excretion into bile
  • Copper not incorporated into ceruloplasmin
  • Results in accumulation of copper at toxic levels in liver, brain, eye
A

Wilson’s Disease

41
Q

Wilson’s Disease:

  • Daily diet has 2-5 mg copper
  • Mostly absorbed in stomach, duodenum
  • Newly absorbed copper complexed with ______ and ______, transported to liver via ________, stored as free copper and excreted into _____ (no enterohepatic circulation)
  • Deficient/defective ATPase:
    • Absorption normal, but not excreted in bile or incorporated into _______, accumulation of copper in hepatocytes, overflow copper into bloodstream
A
  • Albumin, histidine; portal circulation; bile
  • ceruloplasmin
42
Q

Wilson’s Disease:

  • _______ moves from the Golgi to lysosomes in response to elevated copper levels
  • ATP7B promotes storage of _______ in lysosomal lumen
  • By interacting with _______, ATP7B promotes polarized exocytosis of lysosomes
  • Lysosomal exocytosis allows hepatocytes to release excess copper into the bile
A
  • ATP7B
  • copper
  • p62/dynactin
43
Q

Facts for Wilson’s disease:

  • Many, diverse mutations
  • NO genetic testing (unlike HH)
  • Liver biopsy for histological diagnosis, monitoring
  • Copper concentration
  • Determined from liver biopsy
  • Typically > 4 micromole/g dry wt (> 250 microgm/g dry wt)
  • Histological lesions appear before clinical manifestations

Clinical Manifestations - Diagnosis may be easily missed, nonspecific manifestations

  • 2nd to 3rd decades (teens, 20s)
  • Child, young adult with liver abnormalities
  • Neuropsychiatric abnormalities in young adults
A
44
Q

What disorder? (AKA?)

  • Liver changes resemble viral hepatitis and fatty changes (acute and chronic hepatitis, cirrhosis, fulminant hepatitis)
  • Kayser-Fleischer Rings in the Eye
  • Glycogenated nuclei
  • Copper granules
  • Quantitative hepatic copper concentration
  • Use Rhodamine, rubeanic stains for histology, Biochemical assay on fresh tissue
  • Treatable: copper chelation (D-penicillamine, Trientine, zinc acetate), transplantation
A

Wilson’s Disease - Hepatolenticular degeneration

45
Q

Clinical manifestations of what disorder?

  • Liver: acute liver failure, chronic hepatitis, cirrhosis
  • Neuropsychiatric: depression, behavioral abnormalities
  • Neurologic: asymmetrical tremor, ataxia, excess salivation gait disturbances, etc.
  • Ophthalmologic: Kayser-Fleischer rings
  • Joints: arthritis
  • Renal: tubular

Diagnosed with urinary copper excretion, serum ceruloplasmin, liver biopsy (quantitation of copper)

A

Wilson’s Disease

46
Q

What disorder?

  • AR disorder characterized by low levels of alpha1-antitrypsin (AAT)
  • AAT protein inhibits proteases (neutrophil elastase, cathepsin C, proteinase 3)
  • AAT is a serine protease inhibitor (serpin) -> SERPINA1 gene on chromosome 14 mutated in AAT deficiency
A

Alpha-1 Antitrypsin Deficiency

47
Q

What can occur in the lung and liver with alpha-1 antitrypsin deficiency?

Lung:

Liver:

A

Lung: COPD (destruction of lung tissue by proteases)

Liver: chronic liver disease, cirrhosis, HCC

48
Q

Alpha-1 Antitrypsin Deficiency:

Nomenclature - need to know designations -

  • ____ (protease inhibitor) - designates gene locus of A1AT
  • ____ - represents protein and position in the gel (proteins separated by relative migration in isoelectric gel)
  • Each letter represents genotype of each allele
    • ___ - homozygous for M, most common (“wild-type” 90%)
    • ___ - homozygous for Z, have 10% A1AT levels only
    • ___ - intermediate (codominant expression)
A
  • Pi
  • M or Z
  • Genotype:
    • PiMM
    • PiZZ
    • PiMZ
49
Q

Clinical manifestations of which genotype of alpha-1 antitrypsin deficiency:

  • Neonatal hepatitis, cholestasis, fibrosis
  • Chronic hepatitis
  • Childhood or adult cirrhosis
  • A few adults may develop HCC
  • Histology - PAS-D globules, non-specific liver changes (rarely, Mallory bodies, steatosis)
A

PiZZ

50
Q

Pathogenesis of Alpha-1 antitrypsin deficiency:

  • Alpha1-AT-Z protein made in ______
  • AAT deficiency due to defect in migration of _________ synthesized normally from mRNA
  • Migration from _____ to ______ apparatus is defective
A
  • liver
  • protein Pi (protease inhibitor)
  • ER to Golgi
51
Q

Fact: Alpha-1 Antitrypsin Deficiency

PiZ polypeptide

Glu to Lys at amino acid 342

  • Mutant polypeptide (alpha-1AT-Z) folds abnormally -> polymerization -> ultimately causes apoptosis
  • Polypeptide (alpha-1AT-Z) accumulates in ER -> triggers autophagocytosis, mitochondrial dysfunction, inflammation, hepatocyte destruction
  • PiZZ genotype - only 10-15% develop overt liver disease (other environmental/genetic factors at play?)
A
52
Q

Facts: Alpha-1 Antitrypsin deficiency

  • Among possible etiologies of chronic hepatitis, cirrhosis, HCC (2-3% of PiZZ adults)
  • Pulmonary disease (disease may present as pulmonary signs/symptoms, e.g. emphysema in person under 45)
  • Unexplained liver disease, familial liver disease

Treatment

  • Liver transplantation
  • Stop smoking, treat asthma, infections
A
53
Q

What disorder?

  • Autoimmune non-suppurative inflammation and destruction of medium-sized intrahepatic bile ducts
  • Results in chronic progressive, often fatal cholestatic liver disease
  • Unclear why bile ducts are targets
A

Primary Liver Cirrhosis

54
Q

Manifestations of what disease?

  • Increasing incidence, like many other autoimmune diseases
  • Prevalence 40/100,000
  • 90% female, 25 - 65 yo
  • Pruritus, fatigue
  • Associated with celiac, Sjogren’s syndrome, multiple sclerosis, Raynaud’s phenomenon
  • May be asymptomatic, but with elevated ALP
  • May present with advanced state
A

Primary Biliary Cirrhosis

55
Q

Stages of Primary Biliary Cirrhosis:

______: Portal inflammation, BD damage, +/- florid duct lesion

______: Ductular proliferation, periportal inflammation, fibrosis

______: Bridging fibrosis, ductopenia

______: Biliary cirrhosis

A

Portal

Peripheral

Septal

Cirrhosis

56
Q

What stage of primary biliary cirrhosis?

A

Portal Stage: Florid Duct Lesion

57
Q

What stage of primary biliary cirrhosis?

A

Peripheral stage: ductular proliferation, inflammation

58
Q

What stage of primary biliary cirrhosis?

A

Septal Stage: Ductopenia, inflammation

59
Q

What stage of primary biliary cirrhosis?

A

Cirrhosis Stage: Regenerative Nodule

60
Q

What are elevated in the serum in primary biliary cirrhosis?

1.

2.

3.

A
  1. Alkaline phosphatase (ALP),
  2. Gamma-glutamyltransferase (GGT)
  3. Antimitochondrial antibodies (AMA)
61
Q

Facts: Primary Biliary Cirrhosis

  • Treatable
  • Ursodiol (ursodeoxycholic acid, a natural bile acid)
  • Liver transplant if advanced state
    • Cirrhosis in 15 - 20 yrs
    • Low risk for HCC
A
62
Q

What disorder?

  • Chronic cholestatic disorder characterized by inflammation and fibrosis that obliterates intrahepatic and extrahepatic bile ducts up to ampulla of Vater, with dilation of preserved segments - creates “beading”
  • Coexists with inflammatory bowel disease esp. ulcerative colitis (70%)
  • (Conversely, ~4% of UC patients with this)
A

Primary Sclerosing Cholangitis

63
Q

Pathogenesis of what disorder?

“Onion-skin” scar: concentric periductal fibrosis –> fibrous obliteration –> duct disappearance

  • Preserved duct segments dilated due to obstructed downstream ducts
  • “beading” on imaging
  • Persistent asymptomatic elevated ALP
  • Cholestatic symptoms - jaundice, pruritus
  • Chronic liver disease – weight loss, ascites, variceal bleeding, encephalopathy
  • Cirrhosis
A

Primary Sclerosing Cholangitis (Fibrosing cholangitis)

64
Q

Pathogenesis of Primary Sclerosing Cholangitis:

  • Immune-mediated injury to bile ducts, suggested by:
    • ?
    • ?
    • ?
  • Etiology
    • Activated T cells in gastrointestinal tract go to liver and cross-reacts with antigen in bile duct
A
  • T cells present in stroma
  • Circulating autoantibodies
  • Association with IBD (UC)
65
Q

With what disorder are patients at risk for developing:

  • Cholangiocarcinoma (7%)
  • Hepatocellular carcinoma
  • Chronic pancreatitis
  • Autoimmune pancreatitis (IgG4 elevated)

Treatment – progresses to cirrhosis

  • Liver transplant
  • Symptomatic - cholestyramine for pruritus
A

Primary Sclerosing Cholangitis

D&T 4, Exam 3 (Liver) (19 decks)

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