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Peds GI RC > Biliary and Liver > Flashcards

Biliary and Liver Flashcards

1
Q

abnormal development of intrahepatic bile ducts due to ductal plate malformation are likely the underlying cause of which

A
  1. congenital hepatic fibrosis with cystic kidney disease

2. ciliopathies- joubert, meckel-gruber, ivermark syndrome

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2
Q

What direction do bile duct develop occur

A

-start at the hilum and progress to the periphery of the liver

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3
Q

How does bile get from the liver to the duodenum

A
  • Bile passes from canaliculi to canals of Hering
  • Canals of Hering empty into the interlobular bile ducts
  • Interlobular biliary ducts join larger portal tract bile ducts
  • Portal tract bile ducts join to form right and left hepatic ducts which form the common hepatic duct at porta hepatis
  • Cystic duct joins common hepatic duct to form common bile duct
  • common bile duct and pancreatic duct join at ampulla of vater at 2nd portin of duodenum
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4
Q

What is the vascular supply of the intrahepatic biliary ducts

A

-the hepatic artery

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5
Q

What conditions does intrahepatic bile duct occur

A
  • chronic biliary tract obstruction
  • primary sclerosing cholangitis
  • primary biliary cirrhosis
  • ischmia, hepatic artery thrombosis
  • chronic GVHD
  • Chronic graft rejection
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6
Q

Paucity of intrahepatic bile duct

A
  • Premature neonates

- Alagille syndrome

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7
Q

What are the 3 tissue layers of the gallbladder

A
  • mucosa
  • muscular propria
  • serosa

No muscularis mucosa or submucosa

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8
Q

Risk factors for gallstones

A
  1. Age: bimodal distribrution in peds
  2. Gender: 3:1 female:male
  3. Obesity: responsible for majority of recent increase in nonhemolytic cholelithiasis
    - related to increase dietary intake and hypersecretion of cholesterol into bile a well as gallbladder (GB) dysmotility
    - insulin resistance may increase cholesterol synthesis
  4. Hemolytic disease: sickle cell, thalassema, hereditary spherocytosis, Gilbert syndrome and wilsons
  5. Meds
  6. Genetics/ethnicity: PFIC - heterozygous mutations in ABCB4
  7. TPN/biliary stasis
  8. bowel resection/ileal disease
  9. Other: down syndrome, hypertriglyceridemia and pregnancy
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9
Q

Medications that result in choledocholithiasis

A
  • OCP : cholesterol hypersecretion
  • Ceftriaxone: secreted in bile and then precipitates with Ca2+ into an insoluble salt to form sludging and pseudoliths
  • Lasix
  • Cyclosporine
  • Octreotide: biliary sludging though to be due to GB dysmotility
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10
Q

What are the steps in the bile cycle

A

a. breakdown of RBC = formation of lipid-soluble bilirubin
b. bilirubin (water insoluble) binds to albumin and picked up by hepatocytes
c. bilirubin conjugated in liver to glucuronic acid (water soluble) and secreted into ductules (3% of bile)
d. oxidation of cholesterols in hepatocytes to produce bile acids (cholic and chendeoxycholic acid)
e. BA conjugated with taurine and glycine to make them more soluble at acidic pH and less likely to preceipitate with Ca when secreted into bile (61% of bile)
f. other main components of bile:
- fatty acids (12%)
- cholesterol (9%)
- protein (7%)
- inorganic salts/metals (5%)
- phospholipids (3%)

  • GB absorbs water, Cl- and H2O and concentrates bile 5-10x
  • intestinal bacteria create 2dary bile salts by 7 alpha-dehyroxylation
  • bile salts are reabsorbed TI and colon to help maintain BA pool via enterohepatic circulation
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11
Q

How are cholesterol stones formed

A
  • increased secretin of cholesterol and/or decrease secretion of bile = supersaturated bile
  • usually from increased dietary intake
  • to much cholesterol can’t be solublized into micelles = cholestrol crystals and microliths
  • leads to frank gallstones intra- or extra-hepatically
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12
Q

Risk factors for cholesterol stones

A
  • female
  • pregnancy
  • obesity
  • hypertriglyceridemia
  • OCP use
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13
Q

Characteristics of cholesterol stones

A
  • yellow/white
  • > 50% cholesterol by weight
  • radiolucent due to decrease Ca content
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14
Q

What are the characteristics of black pigment stones

A

increased unconjugated bilirubin combined with ionized Ca2+ to form calcium bilirubinate

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15
Q

What are the etiologies of Black Pigment stones

A
  • decreased conjugation activity of uridine diphosphate glucuronosyltransferase (UGT1-A1) in Gilbert syndrome
  • excessive bilirubin load overwhelming bilirubin conjugation as in hemolytic anemia
  • decreased bile pool (ileal disease)
  • TPN use (decrease BA reabsorption, stasis, decreased acidification of bile = decreased solubility of bile
  • increase beta-glucoronidase activity = increased deconjugation of previous conjugated bilirubin
  • CF/pancreatic insufficiency: via increased enterohepatic circ of bili and decreased bile reabsorption
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16
Q

Characteristics of black pigment stones

A
  • brown/black color
  • > 50% are radiopaque due to increased Ca content
  • usually > 1 stone
  • no female preponderance
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17
Q

How are brown pigment stones formed

A

-increased microbial beta-glucuronidase activity in bacterial or helminthi infections = increased deconjugation of bilirubin in bile

  • infection and stasis = increased mucin production, the nidus for stone formation
  • increased unconjugated bilirubin in bile = calcium bilirubinate stones
  • also contain large amounts of fatty acids
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18
Q

Risk factors for brown pigment stones

A

-bile stasis and bile duct abnormalities = form stone w/n CBD

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19
Q

Characteristics of brown pigment stones

A
  • brown to orange in color due to increase Ca2+ bilirubinate concentration
  • usually Ca2+ content still too low to be radiopaque
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20
Q

What are microlithiasis stones formed from

A
  • < 3 mm
  • from precipitation of cholesterol monohydrate crystals, Ca 2+ bilirubinate, Ca2+ phosphate, Ca2+ carbonate and Ca2+ salts of fatty acids
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21
Q

Risk factors for microlithiasis

A
  • PN
  • fasting
  • rapid weight loss
  • systemic infection
  • biliary stasis
  • GB dysfunction
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22
Q

How can urso work for gallstones

A

-decrease cholesterol saturation in bile and may dissolve cholesterol stones

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23
Q

Etiology/pathogenesis of acute calculous cholecystitis

A

-gallbladder stasis common to all causes

1 Cholelithiasis
2. external compression of biliary tree with stasis
3. trauma
4 Structural duct abnormalities
5. Microlithiasis may be underdiagnosed causse of cholecystitis

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24
Q

Songraphic findings of acute calculous cholecystitis

A
  • Gallbladder wall thickening: > 3.0-3.5 in some pediatric reports and > 4-5 in adults
  • Gallstones
  • Pericholecystic fluid
  • Sonagraphic murphy’s sign
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25
Q

What HIDA scan finding is consistent with cholecystitis

A
  • Technetium 99m labeled IDA given IV taken up in the liver, secreted into bile and concentrated into GB
  • normal IDA hepatic uptake with decrease conc in GB bile after 60 mins consistent with cholecystitis
  • morphine administration reduces fall positives by increaesing sphincter of oddi pressure - back pressure in CBD and force more radionuclide into GB
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26
Q

False positives for HIDA scan for cholecystitis

A
  • obstruction of cystic duct by stone, inflammation or tumor
  • hyperbili
  • severe parenchymal liver disease
  • prolonged fasting or TPN - full gallbladder resists further filling
  • prior sphincterotomy - decrease resistance to bile out of the gallbaldder
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27
Q

Complications of acute calculous cholecystitis

Complications of cholecystectomy

A
  • Gallbladder perf
  • abscess
  • empyema
  • gangrene of GB
  • Perforation of GB
  • pancreatitis
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28
Q

Conditions associated with acute acalculous cholecystitis

A
  • sepsis
  • gastroenteritis
  • abdominal trauma/surgery
  • extensive burns
  • shock/cardiac resus
  • IV nutrition and prolonged fasting
  • systemic inflammatory disease- SLE, kawasaki, Polyarteritis nodosa
  • Congestive heart failure
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29
Q

Pathophys of acalculous cholecystitis

A

-gallbladder stasis and/or ischemia

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30
Q

Risk factors for acalculous cholecystisis

A
  • prolong fasting
  • TPN
  • IV opiate narcotics
  • volume depletion
  • multiple transfusions
  • sepsis
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31
Q

What is chronic acalculous cholecystitis/biliary dyskinesia

A

-abnormal gallbadder contractility as measured by decreased GB ejection fraction (EF) on HIDA

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32
Q

Clinical features of biliary dyskinesai

A
  • chronic RUQ pain in absence of other findings with normal imaging of GB
  • fatty food causes abdo pain
  • normal LFT

-surgery often shows chronic inflammatory changes of GB

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33
Q

How do you dx biliary dyskinesia

A
  • HIDA scan before and after CCK or fatty meal stimulation used to calculate GB EF
  • GB EF = difference btw amount of tracer in GB before and after CCK or fatty meal stimulation/ amount of tracer in GB before stim

HIDA EF in adults < 35% considered abnormal

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34
Q

Is unconjugated bili hydrophobic or hydrophili

A
  • hydrophobic

- circulates bound to albumin preventing toxicity of free (unbound) bilirubin)

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35
Q

how is bilirubin made water solube

A

-conjugated to glucuronic acid to make water soluble by UDP-glucuronyl transferase (UGT)

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36
Q

How does conjugated bili get into the bile

A

-secreted into bile by ATP dependent transporter ABCC2/MRP2 on the hepatocyte canalicular membrane

reabsorbed by SI, circulates back into liver and imported into hepatocytes by transport protein OATP1B

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37
Q

What is Rotor Syndrome

A

-defective hepatocyte “reuptake” of circulating conjugated bili
SLCO1B encoding OATP1B

  • Episodic jaundice otherwise Asymptomatic
  • histology = normal liver absent OATP1B
  • no treatment required
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38
Q

Dubin-Johnson Syndrome

A

-defective “secretion” of conjugated bili into bile canaliculi
defective ABCC2 gene - encoding ABCC2/MRP2 transporter that couples with ATP hydrolysis to actively pump organic anions into bile canaliculus

  • low grade, nonpruritic jaundice; increased in pregnancy and with use of oral contraceptives or other steroid hormones
  • jaudice, scleral icterus +/- mild hepatomegaly

Histology: liver black with pigment deposits
Treatment: none necessarily

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39
Q

Gilbert Syndrome

A
  • defect in UGT1A1 - encodes UGT1A1 bilirubin-conjugating enzyme < 50% normal enzyme activity
  • Episodic jaundice often during fasting, nonspecific viral illness, poor sleep or physically strenuous activity

Histo: normal liver with decreased UGT staining

Treatment: non necessary -, phenobarb lowers serum bili often to normal levels

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40
Q

Crigler-Najjar

A

defect in UGT1A encodes UGT1A1 bilirubin-conjugating enzyme- completely absent (type I) or severely reduced (type II)

-Type 1: most severe form: progressive jaundice for first few days of life - high risk of kernicterus
Type II: less severe: lower levels of kernicterus

Histology: normal liver, decrease UGT staining

Treatment:
Type 1 - lifelong phototherapy for 8-12 hrs per day, exchange transfusions to < threshold for kernicterus, consider liver txt

Type II- lifelong phenobarbital thearpy to induce remaining UGT1A! activity (only works for type II). Oral binding agents (cholestyramine, caclium phosphate and agar) to prevent enterohepatic reuptake of bili

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41
Q

What are the most common types of choledocyl cysts

A
  • 5 subtypes
  • Most common: type 1 and 4

Type 1: saccular dilatation of extrahepatic duct
Type 4: saccular dilation of intra- and extrahepatic biliary tree

if untreated - risk of cholangiocarcinoma

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42
Q

What is Inspissated bile syndrome

A
  • impaired bile flow= cholestasis
  • neonates on chronic TPN or severe intestinal disease at risk

-Urso can improve bile flow

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43
Q

Histological findings of Biliary atresia

A
  • proliferation of bile ducts
  • bile plugs of intrahepatic bile ducts
  • fibrosis
  • cirrhosis
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44
Q

What are the stats for timing and successful Kasai

A

-bile driainage if portoenterostomy is preformed before

60 days = 70%
60-90 days = 40-50%
90-120 days = 25%
120 days = 10-20%

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45
Q

What is the first line diuretic in ascites managaement

A
  • K sparing diuretics

- often require adding furosemide

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46
Q

What features in a neonate outside of cholestasis would make you think of galacatesomia

A
  • E. coli sepsis

- absent red reflux = cataracts

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47
Q

Key features of Tyrosinemia?

A
  • can present in fulminant liver failure in neonates
  • degree of coagulopathy out of proportion of mild increase of liver enzymes
  • increased urine succinylacetone is diagnostic

Treatment: NTBC- an inhibitor of an enzyme in the tyrosine degredation pathway

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48
Q

In bile acid synthesis defects what is the level of the serum bile acids

A

-below normal compared to all other cholestatic diseases

confirm BSAD by fast atom bombardment
-also low GGT

Treat: oral bile acid supplementation

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49
Q

What organ systems are involved in Alagille

A
  • Liver: cholestasis- paucity of bile duts
  • Eyes; posterior embryotoxin
  • Cardiac: Congenital heart disease with pulmonic stenosis
  • Skeletal: butterfly or hemivertebrae
  • Renal: common to have renal disease
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50
Q

Features of PFIC 1

A

FIC1 disease - defect in canalicular surface protein FIC1

  • low/normal GGT
  • growth failure/diarrhea
  • neonatal period or later
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51
Q

Features of PFIC 2

A
  • BSEP (bile salt export pump) mutation - mutation in bile transport into the canaliculus
  • low/normal GGT
  • pruritis can be severe
  • high risk of hepatocellular carcinoma
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52
Q

Features of PFIC 3

A

-MDR3 deficiency
- mutation in gene coding transporter MDR3 - affecting phosphatidylcholine secretion into bile canaliculus
High GGT
-can present later in life

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53
Q

What are the characteristic findings of PSC on ERCP

A
  • irregular narrowing and stricture of hepatic and common bile ducts
  • areas of stenosis diffuse or multifocal
  • characteristic “beaded appearance” resulting from areas of stricture with intervening areas of normal or minimally dilated segments
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54
Q

What are the histological findings of PSC

A

-Fibrous obliteration of small bile ducts with concentric fibrous tissue rings in an “onion skin” appearance

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55
Q

What happens in congenital hepatic fibrosis

A
  • AR disease
  • ductal plate malformation of small inter lobular bile ducts
  • biliary stricture and periportal fibrosis
  • can be associated with ARPKD
  • 3 different forms - portal hypertensive, cholangitic, latent
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56
Q

What is the difference btw Caroli disease and syndrome

A

-congenital disorder resulting in dilation of intrahepatic biliary tree

Disease:

  • less common
  • sporadic inheritance
  • ectasia or segmental dilatin of the large intrahepatic bile ducts
  • no other hepatic disease present

Caroli syndrome

  • more common
  • AR
  • biel duct dilation of small or large intrahepatic ducts
  • congenital hepatic fibrosis present
  • often associated with ARPKD
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57
Q

Liver Biopsy of Caroli syndrome

A
  • show broad bands of fibrosis and distorted, dilated bile ducts often in whorls.
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58
Q

Liver bx findings of Alagilles

A
  • paucity of intrahepatic bile ducts
  • 15-20% with periportal and centrilobular fibrosis
  • progressive liver disease with fibrosis and cirrhosis in 10-15%
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59
Q

What are the different types of choledochal cysts

A

Type 1: Cystic dilation of CBD - 90%
A: large saccular cystic dilation
B: small localized segmental dilation
C: diffuse cylindric fusiform dilation

Type 2: diverticulum of CBD and/or GB

Type 3: Choledochocele (intraduoadenal)

Type 4: Multiple cysts
A: cysts both intral and extra hepatic
B: isolated extrahepatic

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60
Q

What is the treatment for choledochal cyst

A
  • Complete surgical resection of cyst with a Roux-en-Y choledochojejunostomy proximal to the mist distal lesion
  • risk of malignancy in residual cyst tissue and increases with age - adenocarcinoma of bile duct or GB most common
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61
Q

Pathophysiology behind pruritus in cholestasis

A

thought to be mediated by opioid neuttransmission

  • opioid peptides = mast cells to release histamine
  • exogenous opiods cause pruritis relieved by only opiod antagonists
  • cirrhotic adults of increase endogenous opioids such as enkephalins
  • opioid antagonists in cholestatic individuals may cause a withdarwal response simialr to opiod abusers
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62
Q

Medications for Pruritis

A

-diphenhydramine
-hydorxyzine
-UDCA
-Cholestyramine
-Rifampin
Naloxon and naltrexone

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63
Q

How do antihistamines prevent itching

A
  • block H1-receptors on peripheral noiceptors = decrease sensation and itching
  • compete with histamine for H1-receptor sites
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64
Q

How does UDCA work

A
  • hydrophilic bile acids stimulates hepatic bile production and protects hepatocytes against cytotoxicity by hydrophilic bile acids
  • reduces toxicity of endogenous bile acids but competitively inhibiting intestinal absorption
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65
Q

How does cholestyramine work

A

-binds bile acids in intestine forming nonabsorable complex, preventing enterohepatic reuptake of bile salts

UDCA not effective in dissolving radio-opaque stones, bile pigment stones and calcified cholesterol stones

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66
Q

How does naloxone and naltrexone work

A

-bind competitively with opioid receptors with high affinity but without activating receptors

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67
Q

Where is AST found outside of the liver

A
  • heart muscle
  • skeletal muscle
  • kidney
  • brain
  • pancreas
  • lung
  • leukocyte
  • RBCs
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68
Q

Where is ALP found outside the liver

A
  • bone
  • placenta
  • intestine
  • WBCs
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69
Q

What is low ALP suggestive of

A
  • zinc deficiency

- Wilsons disease

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70
Q

Where is GGT found outside of the liver

A
  • kidney
  • pancreas
  • spleen
  • brain
  • breas
  • small intestine
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71
Q

What is the half life of Albumin

A

-20 days

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72
Q

AST:ALT ratios suggestive of

a) NASH
b) ETOH liver disease
c) Fulminant wilsons

A

a) <1 : NASH
b) > 2: ETOH liver disease
c) > 4: fulminant wilson disease

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73
Q

DDX for increase transaminase in post liver txt pt

A
  • acute/chronic rejection
  • AIH
  • infection
  • biliary complications
  • vascular complications
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74
Q

What are the 5 mechanisms of hepatomegaly

A
  • inflammation
  • excessive storage
  • infiltration
  • congestion
  • obstruction
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75
Q

What is the definition of portal pressure

A

-portal pressure > 10 mmHg
OR
-HVPG > 5mmHg

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76
Q

How does PHTN affect circulation

A
  • results in hyperdynamic circulation with:
  • increased cardiac output
  • decreased splanchnic tone
  • decreased splanchic vasconstrictor responsiveness
  • leads to vasodilation = Na retention and increased vascular volume due to renal response to vasodilation
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77
Q

Prehepatic causes of PHTN

A
  • PV thrombosis
  • AV fistula
  • Splenic vein thrombosis
  • Congenital stenosis or external compression of the PV
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78
Q

Posthepatic causes of PHTN

A
  • Budd-chiari
  • congestive heart failure
  • constrictive pericarditis
  • inferior vena cava obstruction
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79
Q

What type of hepatic flow indicates worse PHTN

A

-heaptofugal flow - flow away from the liver

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80
Q

What is the HVPG

A
  • Hepatic venous pressure gradient

- difference between wedge hepatic venous pressure (indicates PV pressure) and free hepatic venous pressure

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81
Q

What HVPG is associated with

1) Varices
2) Variceal bleed/ascities

A

1) HVPG > 10

2) HVPG > 12

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82
Q

What cause a variceal to bleed

A

-when the wall tension exceeds the variceal wall strength

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83
Q

Definition of Hepatopulmonary syndrome

A

-oxygen partial pressure < 70 mm Hg
OR
-increase in alveolar-arterial oxygen gradient > 15 mm Hg

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84
Q

What is portopulmonary hypertension

A

-Pulmonary artery HTN in pt with PHTN

  • fatigue, chest pain, syncope and dyspnea with activity
  • tricupsid reurge
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85
Q

How does octreotide work in variceal bleed

A

-decreases splanchnic flow which decreased PV inflow and decreases PV pressure

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86
Q

How do you treat gastric varices

A
  • endoscopic variceal obturation with cyanoacrylate is first line therapy for gastric variceal bleed
  • Balloon-occluded retrodgrade transveous obliteration eliminates gastric varices in the fundus
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87
Q

Indication for surgical management of varices

A
  • extrahepatic PV thrombosis
  • variceal bleed refractory to medical/endoscopic management and does not meet criteria for transplantation
  • refractory ascities
  • complications due to hypersplenism (severe pain, plts < 10000, recurrent infections)
  • medical refractory portosystemic encephalopathy
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88
Q

What is a mesorex shunt

A
  • mesenteric left PV bypass
  • 1st opt for pts with extrhepatic PV thrombosis - must have normal liver architecture

-jugular venous autograft to shunt blood from superior mesenteric vein into intrahepatic PV

restores hepatopetal flow, decompreses varices, improves spleen size

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89
Q

What is a distal splenorenal shunt

A
  • decompresses esophageal and gastric varices through the short gastric vein, spleen and splenic vein to the left renal vein
  • lower risk of portosystemic encephalopathy than mesocaval shunt
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90
Q

What is TIPS

A
  • communication between hepatic and PV
  • decreases portal pressure
  • recurrent variceal bleeding not responsive to medical/endoscopic therapy, refractory ascities, Budd-chiari syndrome, VOD, HRS, HPS
  • can use as bridge to transplant
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91
Q

Complications of TIPS

A
  • encephalopathy
  • PV leakage
  • restenosis
  • peforation
  • infection
  • hemolysis
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92
Q

What factors lead to ascites development in cirrhosis

A
  • splanchnic vasodilation
  • hyperadosteronism
  • PHTN
  • disturbed hydrostatic and oncotic forces that regulate splanchnic portal and hepatic blood and lymphatic flow
  • increased Na retention via RAS system and secretion of antidiuretic hormone
  • Na retention = expansion of extracellular volume and accumulation of ascities
  • PHTN contributes to increased splanchnic capillary pressure = excessive lymph formation
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93
Q

What is the SSAG

A
  • serum ascites albumin gradient
  • difference between serum and ascitic fluid albumin

SAAG < 11 = not PHTN as cause fo ascites

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94
Q

What are treatment strategies for ascites

A

Strategies focus on mobilizing intraperitoneal fluid and correcting the relative systemic hypovolemia

  1. Na restriction
  2. Diuresis:
    a. spironolactone: counters hyperaldosterone. Competitive inhibitor of aldosterone at distal renal tubules: increase Na, CL and H2O excretion and conserve K and H
    b. Loop diuretic: directly inhibits reabsorption of Na and Cl in the ascending loop of Henle and distal renal tubules; excretion of Mg, Na, Cl, H2O and Ca
  3. Fluid restrictionp
  4. IV albumin
  5. Paracentesis
  6. Surgical management: shunts
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95
Q

Definition of Acute Liver Failure

A
  1. biochemical evidence of injury to the liver
  2. no history of known chronic liver disease
  3. Coagulopathy not corrected by vit K
  4. INR > 1.5 if the pt has HE or > 2 if the pt does not have HE
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96
Q

Features of tyrosinemia

A

-profound coagulopathy and normal or near normal serum aminotransferase

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97
Q

Factors that play a central role in the pathogenesis of HE

A
  • hyperammonemia: - associated with increase levels of glutamine in astrocytes = cell swelling
  • increased central blood flow may contribute to the development of cerebral edema
  • enhanced inflammatory response and inflammatory cytokines such as TNFalpha
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98
Q

What is the histology of CMV liver infection

A

-large intranuclear inclusion bodies in bile duct epithelium and occasionally in hepatocytes or kupffer cells and intracytoplasmic inclusion bodies in hepatocytes

Treat with gancyclovir or foscarnet

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99
Q

Histology of HSV liver bx

A

-necrosis with characteristic intranuclear acidophilic inclusions in hepatocytes and multinucleated giant cells

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100
Q

What are the two different forms of Acute Hep D infection

A
  • coinfection: simultaneous acquisition of HBV and HDV

- superinfection:

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101
Q

Perihepatitis (Fitz-Hugh-Curtis syndrome)

A
  • Associated with salpingitis/history of pelvic inflammatory disease
  • infection from genital tract or hematologic spread
  • “violin string” adhesions between hepatic capsule, abdominal wall and diaphragm
  • hemorrhagic spots and white fibrous plaques on liver surface
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102
Q

Which Ab are found in Type 1 AIH

A
  • ANA

- SMA

103
Q

Which Ab is found in Type 2 AIH

A
  • Anti LKM1

- Anti liver cytosol type 1 ab (LC1)

104
Q

Which does Soluble liver antigen (SLA) mean

A

-signifies worse disease and may be seen in type 1 or 2 AIH

105
Q

What Ab is seen in overlap AIH and PSC

A

p-ANCA

106
Q

Syndromes associated with AIH

A

-Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APCED

  • IPEX
  • CIVD
  • Hyper IgM
107
Q

Histology of AIH

A
  • interface hepatitis with lymphocytic and plasma cell infiltration of the portal tracts spilling into the liver lobules
  • bridging inflammation/necrosis
  • bridging fibrosis or cirrhosis
108
Q

Histology of overlap AIH with pSC

A
  • interface hepatitis
  • bile duct changes including ductular proliferation
  • onion skin appearance
109
Q

Which type of AIH is more likely to over lap with PSC

A

-Type 2

110
Q

What are the 4 types of granulomas described

A

Caseating granuloma: central necrosis- associated with infectino

Noncaseating granuloma: no central infection: associated with non infectious cause

Fibrin-ring granuloma: fibrin ring surroundng epithelioid cell - Q fever

Lipogranulomas: central lipid vacuole and associated with mineral oil ingestion

111
Q

Causes of Granulomas

A
  1. Autoimmune:
    - Sarcoidosis
    - PBC
    - Crohns
    - Wegener
  2. Systemic infection:
    -TB
    -Brucellosis, Q fever, Lime disease
    -AIDS
    -Fungal
    Viral: Hep C and B
    -Parasitic
  3. Drugs:
    - Sulfa
    - allopurinol
    - isoniazide
    - quinidine
    - chlorpropamide
    - etanercept
  4. Malignancy:
    - Hodgkin lymphoma
  5. Idiopathic - noncaseating
112
Q

Definition of Budd-Chiari Syndrome

A
  • thrombotic or nonthrombotic postsinusoidal hepatic venous outflow obstruction
  • may occur anywhere from venules to right atrium
    3. Does not include cardiac, pericardial or sinusoidal disease
113
Q

Pathophysiology of Budd-Chiari Syndrome

A
  • Primary: venouse disease (thrombosis/phlebitis)
    a. acquired prothrombotic disease
    b. inherited prothrombotic diease

-Secondary: compression or invasion external venous system (expanding tumor, cystic structure, abscess)

114
Q

Definition of VOD

A
  • obstruction of sinusoid (small terminal venules) of liver
  • toxic injury followed by occlusion and obliteration of the sinusoids

Classically with HSCT
-also chemotherapy, radiation, transplantation, herbal remedies, hepatectomy, VOD with immunodeficiency

115
Q

Presentation of VOD

A
  • usually w/n 1 month of HSCT
  • RUQ abdo pain, hepatomegaly, ascites, weight gain, evidence of liver injury (hyperbili and transaminitis), coagulopathy and PHTN
116
Q

Liver bx of VOD

A
  • sinusoidal dilation and congestion
  • lack of terminal hepatic veins
  • collagen deposition and fibrosis
117
Q

what is the pathogenesis of Hepatic Hemangioma

A
  • abnormal proliferation of endothelial cells during fetal development
  • vascular endothelial growth factor is a key pathway component
118
Q

What endocrine abnormality occurs with Hemangiomas

A
  • Hypothryoidism

- Iodothyronine deiodinase type 3 = is expressed by tumor and inactivates thyroid hormone

119
Q

Treatment for systomatic hepatic hemangiomas

A
  • propanolol
  • corticosteroids
  • vincristine

may require embolization, resection, irradiation or transplantation

120
Q

What is FNH

A

-benign epithelial tumor
-well circumscribed, lobulated lesions with central stellate scar
can present with HCC

121
Q

What is the presentation of FNH

A
  • usually in toddlers but can be any age
  • more common in females
  • typically on routine physical exam
  • normal AFP
  • may have abdo pain
122
Q

What is the imaging finding of FNH

A

-well-demarcated, hyperechoic homogenous lesion +/- central scar

123
Q

What is the management for FNH

A
  • nonoperative management for asymptomatic pts

- exceision of tumor may improve abdo pain associated with FNH

124
Q

what is Hepatic Adenoma associated with

A
  • young women on OCP
  • pregnancy
  • GSD

-carries risk of transformation to HCC

125
Q

What are the CT findings for hepatic adenoma

A
  • nonspecific
  • homogenous enhancement in the arterial phase,
  • hemorrhage
  • fat deposition
  • calcification
  • lack of central scar
126
Q

What is the management of Hepatic Adenoma

A
  • surgical resection

- radiofrequency ablation

127
Q

What are the different histological patterns of Hepatoblastoma

A

-embryonic - most common

  • fetal and embryonal
  • small cell undifferentiated
  • mixed
  • teratoid
  • rhabdoid
128
Q

What are risk factors for hepatoblastoma

A

-FAP
-Beckwith-Wiedemann
-Metabolic/genetic: tyrosinemia and GSD
-low brith weight
parental occupational exposures and cigarette smoking

129
Q

Lab findings in Hepatoblastoma

A
  • anemia
  • thrombocytopenia
  • increased AFP
130
Q

CT findings of hepatoblastoma

A

-low attenuation mass +/- discrete calcifications

131
Q

How do you manage Hepatoblastoma

A

-based on PRETEXT:

PRETEXT I/II = surgical resection followed by chemotherapy

PRETEXT III/IV = chemotherapy followed by delayed primary research

132
Q

Important prognostic factors for Hepatoblastoma

A

-decreasing tumor size or reduction in AFP after chemo

133
Q

Risk factors for HCC

A
  • most are de novo tumors but can be associated with CLD
  • viral hepatitis
  • inborn errors of metabolism
  • biliary atresia and fanconi syndrome
  • adrogenic steroids
  • OCP
  • MTX
134
Q

What is the CT findings of HCC

A

-areas of arterial phase hyperenhancement with rapid wash out on delayed phase imaging

135
Q

What are the two different types of NAFLD

A 
Type 1 (51%): 
Hepatic steatosis with ballooning and fibrosis of perisinusoidal areas without portal involvement (similar to adults)
Type 2 (17%)
Hepatic steatosis with both portal inflammation and fibrosis without ballooning hepatocytes
136
Q

Which Omega fatty acids increase inflammation and which omega fatty acids decrease inflammation

A
  • Omega 6= increase inflammatino

- Omega-3= decrease inflammation

137
Q

What are limitations of transient elastography

A
  • operator dependent
  • does not evaluate entire liver
  • limitation with increased body habitus
  • less able to distinguish degrees of intermittent fibrosis
138
Q

What are the 2 primary BA

A
  • cholic acid
  • chenodexocholic acids

-extensively conjugated to the AA glycine and taurine

139
Q

How are secondary BA made

A
  • primary BA enter the intestine and colon
  • portion deconjugated and dehyroxylated by bacterial enzymes
  • produce secondary BA: deoxycholic and lithocholic acid
  • highly insoluble and most excreted in the feces
  • some carried back to liver
140
Q

What important functions do BA preform

A
  • major catabolic pathways, for elimination of cholesterol form body
  • primary driving force for promotion and secretion of bile
  • Essentail biliary excretory route for elimination of endogenous and exogenous toxic substances - including bilirubin and drug metabolites
  • within lumn, detergent action of BA facilitates absorptiono f fat and FSV
  • signaling molecules in metabolic process including preservation of body mass and glucose metabolism
141
Q

What do the enzyme defects in the BA synthetic pathway result in

A
  • blocked production of normal BA
  • creation of hepatotoxic BA intermediaries
  • accumulation of unusual BAs and intermediary metabolites
  • reduced bile flow
  • decreased intraluminal solubility of fat and FSV
142
Q

What are the clinical features of

A
  • serum BA are usually low or normal (usually high in cholestatic infants)
  • absence ofpruritis
  • GGT normal or minimally elevated
143
Q

How do you diagnose Bile Acid Deficiency

A
  • if serum BA are normal or low, urine BAs should be measured by fast atom bombardment ionized mass spectromtery
  • can establish in urine, bile or serum absence or reduction of primary BAs in conjunction with the presence of atypical BA and sterols that are synthesized as a result of enzymatic deficiency
144
Q

Where is glucose stores

A

-stored as a branched glucose polymer (glycogen) in the liver and the muscle (for local use)

145
Q

What are the main symptoms of inborn erros of carbohydrate metabolism

A
  • hypoglycemia
  • acidosis
  • growth failure
  • hepatic dysfunction
146
Q

Consequences of Galactasemia outside of liver failure

A
  • mental retardation
  • premature ovarian failure
  • cataracts due to accumulation of galactitol
147
Q

What is Hereditary Fructose intolerance caused by

A
  • aldolase B deficiency
  • catalyzes fructose 1-phosphate to dihydroxyacetone phosphate
  • aldolase B in liver, kidney and intestines

-causes lack of ATP intracellularly as a result of accumulated fructose 1-phosphate and depletion of inorganic phosphate

148
Q

What are the 6 types of GCSD that primary affect the liver

Which are the 2 types of GSD that have mixed hepatic and myopathic presentaiton

A

Primarily liver:
I, IIIb, IV, VI, IX and XI

MIxed types:
II and IIIa

149
Q

Which enzyme is affected in tyrosonemia

A
  • Fumarylacetoacetate hydrolase (FAH)
  • mainly expressed in hepatocytes and proximal tubules of the kidney
  • also in lymphocytes, erythrocytes, fibroblasts and chorionic villa
150
Q

What is unique about the coagulation in tyrosonemia

A
  • unresponsive to Vit K
  • low normal factor V
  • very low vit K dependent factors = II, VII, IX, X
  • normal VIII
151
Q

Features of chronic tyrosonemia

A
  • growth failure
  • renal tubular dysfunction from Fanconi syndrome with phosphaturia and renal rickets = from maleylacetoacetate accumulation
  • neurological crisis
152
Q

Diagnosis of Tryosenima

A
  • elevated urine succinyl acetone is most diagnostic
  • Coagulopathy (normal V and VII), hypoalbuminemia and hypoglycemia out proportion to milder elevation of bilirubin and transaminases
153
Q

Management of tyrosenima

A

-dietary restriction of phenylalanine and tyrosine

NTBC:
-inhibits 4HpPD (2nd step in tryosine degredation)

-monitor for HCC

154
Q

What is transient tyrosinemia of the newborn

A
  • immaturity of 4HpPD causes self-limited elevation of tyrosine
  • treat lower protein diet and vitamin C
155
Q

What is the most common FAOD

A
  • MCAD deficiency
  • 1 point mutation

-AR

156
Q

Features of prsentation of FAOD

A

-marked hepatomegaly
-NO splenomegaly
-hypotonia
gallop rhythm/poor perfusion
-1/3 will have family hx of sudden infant death
-ALF rare

-moms of LCHAD-deficient fetuses at risk for Acute fatty liver of pregnancy and HELLP

157
Q

Diagnosis of FAOD

A

-urine OA and serum acylcarnitine profile have best diagnostic yield

-increase ammonia
-mild increase transaminases
-normal or mild increase bili
-urine ketones
serum FFA and beta-hydroxybutyrate
-tissue assys
-genetic screening

158
Q

Treatment for FAOD

A

Acute:

  • reverse hypoglycemia, dextrose infusions
  • avoid drugs that inhibit FAO (VPA, NSAIDS, ASA) and drugs that increase release of FFA (epinephrine)
  • avoid fat emulsions
  • carnitine

Chronic

  • avoid fasting
  • carnitine supplementation
159
Q

Common Mitochondrial defects leading to neonatal liver failure

A
  • mtDNA depletion syndrome (MDS)
  • DGUOK
  • MPV17 (navajo neurohepatopathy)
  • POLG1 (alpers-huttenlocker syndreom)
  • SULG1
160
Q

What are the 3 different types of MDS (Mitochondrial depletion syndrome)

A
  • hepatocerebral
  • myopathic
  • encephalomyopathic
161
Q

Lab findings in Mitochondrial defects

A
  • increased lactate > 2.5
  • increased lactate/pyruvate 25
  • hypoglycemia (ketotic)
  • increased prothrombin
  • increase AST, ALT, bili
162
Q

Features of Pearson syndrome (mtDNA deletion)

A

-mostly affecting complex I
-affects bone marrow (sideroblastic anemia), pancreas and liver
-adrenal insufficiency, renal Fanconi, DM, proximal muscle weakness
some have villous atrophy

163
Q

What states increasing ammonia production

A
  • fasting

- stress

164
Q

Causes of hyperammonemia

A
  • UCD- increased NH3 and metabolic alkalosis
  • FOAD: acidosis, no ketones
  • Organic acidemias (increase ketones, metabolic acidosis)
  • transient hyperammonemia of the newborn
  • Reye’s syndrome
  • liver failure
  • Severe systemic illness
  • pyruvate carboxylase deficiency
  • lysinuric protein intolerace
  • drugs
165
Q

How is urea excreted

A
  • 75% in urine by kidneys

- 25% in gut - bacteria transform some urea back to ammonia again which is reabsorbed

166
Q

Management of Acute UCD

A

Acute:

  • reduce NH3 levels
  • discontinue protein intake
  • IV glucose, insulin +/- Fatty acids
  • gentle fluid resus
  • provide alternative for nitrogen excretion:
    1) sodium benozate
    2) phenylbutyrate
    3) dialysis and hemofiltration
167
Q

What is the function of A1AT

A

-inhibitor of neutrophil protease and elastase

168
Q

What other diseases does A1AT predispose to

A
  • ANCA positive vasculitis
  • glomerulonephritis
  • neutrophilic panniculitis
  • chronic pancreatitis
169
Q

What is the pathogenesis of A1AT deficiency

A
  • accumulation of A1AT protein in the hepatocyte due to protein misfolding and lack of autophagy leading to cellular injury
  • defective autophagy (method used by cells to dispose of polymers and A1AT aggregates) leas to accumulation of the mutant protein in the ER = hepatotoxicity
170
Q

What is the histology findings of A1ATD

A
  • periodic acid-shift positive , diastase-resistant globules in the periportal region
  • globules have clear halo surrounding them in zone 1
171
Q

What is Wilson’s disease

A
  • hepatolenticular degeneration
  • copper accumulation in various tissues of the body
  • decrease secretin of copper into the bile
172
Q

What organs are affected in Wilsons disease

A

-liver
-basal ganglia
-cornea
-endocrine = sex hormone dysfunction and thryoid dysfunction
-kidneys =proximal tubular defect
-cardiac= cardiac arrythmias, LVH, carditis
-bone= bone demineralization, rickets, osteomalacia and stiffness of larger joints
heme= coombs negative hmolysis

173
Q

What is the function of ATP7B

A
  • export copper into bile and incorporate it into ceruloplasmin
  • defect causes:
  • accumulation of copper in hepatocytes and brain tissue
  • decrease synthesis of ceruloplasmin
174
Q

What does accumulation of copper lead to

A

causes oxidative stress leading to:

  • mitochondrial damage
  • changes in antiapoptotic proteins = lower threshold for cell death
  • inhibited polymerization of tubulin
  • collagen gene expression and fibrosis
175
Q

Histological findings of Wilsons

A
  • cirrhosis
  • periportal glycogenated nuceli
  • micro/macro steatosis
176
Q

Neurologic manifestations of

A

motor symptoms: dystonia, worsening of handwriting, ataxia, tremor and dysarthria
-behavior changes - depression- psychosis

-intelligence and sensory function unaffected

177
Q

Diagnosis of Ceruloplasim

A

No single test:

  • AST>ASL and low ALP
  • AST/ALT: 2.2 and ALP/bili < 4

24 hour urine copper > 100ug/24 hours (if > 30-50 ug/24 hours = requires additional testing)

  • Ceruloplasm low
  • Hepatic copper concentration > 250 ug dry weight
  • Serum copper usually low - can be high in acute hepatitis
  • Genetic testing is available and should be done if diagnosis questioned
178
Q

Management of Wilsons disease

A

-Chelating agents:
1) D-penicillamine: chelates copper and induces cupruria - needs supplemental Vit B6
AE: fever, rash, lupus, lymphadenopathy, thrombocytopenia, nephrotoxicity

2) Trientine: chelates copper and induces cupruria
3) Ammonium tetrathiomolybdate- blockers copper absorption
4) Zinc: interferes with uptake of copper from the GI and induces enterocyte metallothionein - binds copper and traps in the enterocyte
5) Antioxidants: Vitamin E may have role, interferes with vit K dependent clotting factor synthesis so need to monitor

Dietary avoidance of food with high copper content
-shellfish, nuts, chocolate, mushrooms and organ meet

Liver txt

179
Q

What are the functions of peroxisomes

A
  • present in all cells except erythrocytes
  • higher conc in liver and kidney

Catabolic function

  • Beta-oxidation of VLCFA
  • Oxidation of phytanic acid, pepecolic, pristanic and many other dicarboxylic acids
  • degredation of hydrogen peroxide

Anabolic function
-biosynthesis of ether lipids isoprenoids, cholesterol and bile acids

180
Q

General clinical feature of peroxisomal disorder

A
  • Neurologic; encephalopathy, hypotonia, seizures and deafness
  • Skeletal: short limbs, calcific stippling and craniofacial abn
  • Ocular: retinopathy, corneal clouding, cataract, blindness
  • Hepatic: neonatal hepatitis, hepatomegaly, cholestasis and cirrhosis
181
Q

Lab findings of Peroxisomal disorders

A

-increased VLCFA
-normal cholesterol
-increased pristanic acid and phytanic acid
-bile acid intermediates typically abnormal
decrease erythrocyte concentration of plasmalogen

182
Q

PFIC 1

A

AR, ATP8B1
apical membrane of hepatocytes, colon, intestine and pancreas

  • bland cholestasis with coarse granular canalicular bile on EM
  • low GGT, increase serum BA, lower biliary bile acids

progressive cholestasis, severe pruritis, diarrhea, steatorrhea, pancreatic involvement, growth failure and hearing loss

183
Q

What is biliary diversion

A

-procedure that interrupts the enterohepatic circulation and decrease the load of bile salts to the liver by diverting bile from the gallbladder through a jejunal lope that connects to the gallbladder to the skin

184
Q

PFIC2

A
  • AR ABCB1
  • located on canalicular membranes of hepatocytes
  • histology: neonatal giant cell hepatitis and amorphous canalicular bile on EM
  • low GGT, increase serum BA, lower biliary bile acids
  • rapidly progressing cholestatic giant cell hepatitis, pruritis, growth failure and severe FSV deficiency

RIsk of PHTN: PFIC2> PFIC1
-risk of HCC or cholangiocarcinoma

185
Q

PFIC3

A

AR ABCB4/MDR3

Located on canalicular membrane of hepatocytes

increase GGT, normal biliary bile acid concentrations

Onset of cholestasis later than PFIC1/PFIC2, minimal pruritis, pHTN and gallstones

186
Q

Findings consistent amongst PFIC diseaes

A
  • absence of xanthomas
  • near normal serum cholesterol
  • severe FSV deficiency
  • growth failure
  • progression to cirrhosis
187
Q

What are the phases of hepatic drug metabolism

A

Activation (phase I):

  • transformation of drug into a more polar or reactive metabolite
  • Cytochrome P450 are associated with most phase I reactions

Detoxification (phase II)
-formation of polar conjugate that can be readily excreted in urine or bile

polymorphisims in these enzymes make individual either rapid or slow metabolizers - important factors in drug hepatotoxicity

188
Q

How are zones related to hepatotoxicity

A

-Hepatocytes in zone 3 of the Rappaport acinus have the greatest potential for producing toxic metabolites b/c of the highest conc of Cyto P450

189
Q

What is the histopathology of Tylenol Hepatotoxicity

A

-zonal hepatocellular necrosis in a centrilobular pattern (zone 3) with minimal to no inflammatory response

190
Q

What are the different types f drug hepatotoxicity by clinical features

A
  1. hepatitic
  2. cholestatic
  3. mixed hepatitic-cholestatitc
  4. Drug hypersensitivity syndrome (drug rash with eosinophilia and systemic symptoms syndrome): fever, inflammation of various organ systems (hepatitis, SJS, renal dysfunction, myocarditis), lymphadenopathy, eosionphilia and atypical lymphocytosis
  5. Chronic active hepatitis (AIH like) subacute/chronic course, variable extrahepatic findings (lupoid rash and arthralgias) increase serum IgG, detectable nonspecific autoantibodies
191
Q

How does NAC help in tylenol OD

A

-restores hepatic glutathione stores to reduce the toxic intermediate metabolites of tylenol

192
Q

What are the 2 patterns of liver injury in VPA

A

1) Dose-responsive hepatitis: resolves when dose is decreased

2) liver failure that progresses despite stopping drug
a) like reye syndrome
b) hepatitic prodromeL malaise, anorexia, N/V

Histology: microvesicular steatosis and zonal hepatocellular necrosis

193
Q

What is the type of liver injury with AZA

A

-cholestatic or mixed

centrilobular hepatocyte ballooning, canalicular cholestasis, endothelial cell damage and nodular regenerative hyperplasia

194
Q

What is the histology of MTX liver injury

A
  • hepatic fibrosis

- macrovasicular steatosis

195
Q

What is the pathophysiology of HH

A
  • increase intestinal iron absorption
  • decreased expression of iron reg hormone hepcidin
  • altered function of HFE protein leads to iron-induced tissue injury and fibrogenesis
196
Q

How to diagnose HH

A
  • TS > 45% or increased serum ferritin
  • obtain HFE mutation analysis
  • If AST/AT or Ferritin ? 1000 then liver bx to stage fibrosis
  • perls prussian blue stain to evaluate the degree of hepatic iron stores
197
Q

Treatment of HFE-related HH

A
  • normal ferritin = surveillance yearly
  • increased ferritin = treat with phlebotomy to maintain ferritin 50-100 ug/L - may reverse fibrosis, skin pigmentaiton, fatigue and hypogonadism but cirrhosis, DM and cardiomyopathy may not be reversible
  • Iron chelators (deferasirox) may be helpful if phlebotomy poorly tolerated
  • no need for iron restriction but avoid vit C - increase iron mobilization and free radical activity
  • screen for HCC
198
Q

What is GALD

A

severe fetal liver disease associated with extrahepatic siderosis
-mediated by maternal IgG crossing placenta and targeting fetal hepatocyte Ag = leads to complement-mediated hepatocyte injury

-b/c liver controls flow of iron from mother to fetus, extrahepatic siderosis seen in pancreas, myocardium, thryoid, salivary glands and resp system

199
Q

Diagnosis of GALD

A
  • demonstrating extrahepatic siderosis
  • bx of salivary gland - minimally invasive, demonstrates iron deposition
  • T2 weighted MRI= shows extrahepatic tissue = pancreas, heart and adrenal glands
  • liver bx not recommended b/c hepatic siderosis also seen in other neonatal liver disease - absence of iron siderosis does not exclude
200
Q

Histology of GALD

A
  • subacute/chronic injury with loss of hepatocyte mass, giant cells, pseudoacini, fibrosis and collapsed reticulum
  • MAC-mediated heptocyte injury - positive stain for C5b-9 complex
201
Q

Treatment for GALD

A
  • double-volume exchange transfusion - remove existing reactive ab
  • then high dose IVIG to block Ab-induced complement activation
  • liver txt for those who fail medical management
202
Q

How to prevent GALD in subsequent pregnancies

A

Recurrent GALD in mother’s subsequent pregnancies can be ameliorated/prevented with IVIG administration during gestation

  • 14 wk
  • 16 wk
  • then weekly from 18 weeks until end of gestation
203
Q

What are lipid storage disease

A

-inherited metabolic disorder that results in harmful accumulation of lipids in lysosomes of organs including brain, liver, peripheral nerves ,spleen and bone marrow

204
Q

Common presentations of lipid storage disease

A

Infants: HSM, FTT, emesis, DD, ALF

Older children: Massive HSM, growth problems, lung disease, neurological issues, DD

205
Q

Niemann Pick type A and B

A
  • SMPD1 gene affected
  • deficiency of aicd sphingomyelinase (ASM)
  • accumulation of lipids, sphingomyelin in reticuloendothelial cells, ganglion cells and other cell types

NPD-A: Infantile onsent neuronopathic with death by 3 yrs
NPD-B: later onset, visceral

206
Q

Niemann-PIck Type C

A
  • defect in cholesterol transport from lysosomes
  • accumulation of sphingolipids and LDL cholesterol in lysosomes due to impaired efflux of these compounds from the lysosome
  • neonates: cholestasis, HSM, ascots, hypotonia
    childhood: ataxia, seizures, gaze disturbances and dementia
207
Q

Gaucher disease

A
  • GBA1 gene
  • Deficiency of acid beta-glucosidase
  • most common lipid storage disorder
  • accumulation of glucosylceramide in marcophages in visceral organs mostly derived from turnover of cell membranes of leukocytes, erythrocytes and plts
208
Q

What are gaucher cells

A
  • engoraged macrophages containing tubular inclusions that resemble wrinkled tissue paper on liver and BM bx
  • results in inflammation and fibrotic changes
209
Q

What are the 3 types of Gaucher disease

A
  1. Type 1 (nonneuropathic type:
    - massive organomegaly, bone disease, lung disease
    - childhood to adulthood
  2. Type 2 (acute neuronopathic and infantile type)
    - w/n 3 months of life
    - massive organomegaly, abnormal eye movements, seizure
  3. Type 3 (chronic neuronopathic type)
    - milder andmore slowly progresisve neurological symptoms, organomeagly and skeletal abnor.
210
Q

Histology of Gauchers

A

-kupffer cells and portal macrophages containing weakly PAS-positive material with distinctive “crinkled paper” appearance

211
Q

Lysosomal acid lipase (LAL) deficiency

A

-accumulation of cholesteryl esters and triglycerides in organs = damage to cells and tissues

Wolman’s disease
Cholesterol ester storage disease (CESD)

212
Q

Presentation of LAL deficiency

A

-Wolman’s fatal by age 1 :
massive HSM, mental deterioration, distended abdo, steatorrhea, jaundice, anemia, vomiting

Deposition of Ca in adrenal glands

CESD - more slow progression

individuals usually have hypercholesterolemia and at risk for developing athersclerosis

213
Q

Dx of LAL deficiency

A
  • LAL enzymes activity in peripheral blood cells or liver tissue
  • LIPA gene sequency
214
Q

Histology of LAL deficiency

A
  • lipid containing membrane bound vesicles

- seen better under polarized light

215
Q

management of LAL deficiency

A
  • treatment of hyperlipidemia with diet and/or meds (cholestyramine and statins)
  • management of complications of progressive liver fibrosis
216
Q

Congestive hepatopathy

A

-results from passive hepatic congestion from right sided heart failure or chronically increased central venous pressures from post-fontan circulation

217
Q

Histology of Congestive hepatopathy

A
  • “nutmeg liver”
  • hemorrhagic centrilobular area (zone 3) alternating with either areas of steatosis or normal liver in zones 1 and 2
  • sinusoidal dilation without inflammation on histology
218
Q

Hereditary hemorrhagic telangiectasia (osler-weber-rendu syndrome)

A
  • Autosomal Dominant
  • characterized by vascular malformations of the skin, mucous membranes and internal organs
  • liver involvement in 75% but < 10% symptomatic
  • noncirrhotic pHTN and complications - cause arterioportal shunting due to increased sinusoidal blood flow
  • Biliary ischemia and resultant strictures, cholestasis and cholangitis result from diversion of blood flow from the hepatic artery in A-V or arterioportal malformation
219
Q

Sarcoidosis

A

-characterized by noncaseating granulomas most often in lungs and lymph nodes - also can occur w/n in the liver

  • PHTN- from a-v shunts around granulomas
  • intrahepatic choleatsis- can be confused with PBC and PSC which can also occur in sarcoidosis

-Budd-chiari syndrome - due to narrowing of intrahepatic veins from compression by granulomas or occlusion by secondary thrombosis

220
Q

Chronic granulomatous disease

A
  • primary immunodeficiency due to defects in nicotinamide ADP oxidase characterized by recurrent bacterial/fungal infections and tissue granuloma formation
  • Liver involvement: granulomas and abscesses, lobular hepatitis, rarely ascites and noncirrhotic pHTN
221
Q

Sjogren syndrome

A
  • autoimmune disease that primarily effects salivary and lacrimal ducts
  • liver involvement is common, non exocrine feature of sjogren syndrome - can present with increased AST/ALT or ALP
  • AIH and PBC can be seen
  • Positive AMA sensitive indicator of liver disease in Sjogrens
222
Q

Features of Scleroderma

A

-autoimmune disease leading to
-tissue fibrosis
-vasculopathy of multiple organ systems
-calcinosis
-raynauds phenomenon
-esophageal dysmotility
-sclerodactyly
-telangectasia
CREST

-PBC associated with scleroderma - AMAs

223
Q

Histology of acute GVHD

A
  • active inflammatory bile duct damage with lobular hepatitis and endothelitis
  • similar to ACR
224
Q

Histology of chronic GVHD

A

-bile duct loss and absence of actue inflammation (as well as chronic rejection)

225
Q

What is sickle cell inrahepatic hcolestasis

A

-rare but severe complication of SCD- can be lethal

  • RUQ pain, hepatomegaly, fevers, leukocytosis - jaundice despite mild-mod increase transaminases and direct bili, renal impairment, encephalopathy
  • hepatic sickling, vascular stasis, hepatocyte ballooning and intracanalicular cholestasis

treatment = exchange transfusions and correction of coagulopathy with products such as FFP

226
Q

What is an acute hepatic sickle crisis

A
  • up to 10% of pts
  • RUQ pain, hepatomegaly, jaundice and fevers
  • increase transaminases and bili
  • supportive care - hydration and pain management
227
Q

What is hepatic sequestration crisis

A
  • similar to splenic sequestration
  • large number of RBC sequestered in liver
  • RUQ pain and progressive hepatomegaly but with noticeably declining hematocrit and can lead to hypovolemic shock

Treatment: cautious transfusions w attention to post transfusion Hgb level
-pt may autotransfuse after and develop hyperviscosity syndrome

228
Q

What is the overall graft survival for a liver transplant

A

1 yr - 92%
5 yr - 85%
10 yr - 68%

229
Q

What is involved in the MELD and PELD scores

A

-Scale of disease severity designed to prioritize allocation of organs based on 3-month mortality risk

MELD = (12-18 yrs) Bili, INR, and creatinine
PELD (< 12 yrs) Bili, INR, albumin, growth failure and age (<1 yr)

230
Q

Difference btw acute and late HAT/stenosis

A

Acute:

  • massive hepatic necrosis and liver failure
  • recurrent fever and bacteremia as a result of cholangitis
  • biliary tract ischemia with bile duct necrosis and leak

Late (>6 months)
-Pts with hepatic artery stenosis can develop late HAT
pts can have chronic indolent course with biliary strictures, biochemical evidence of bile duct damage and recurrent cholangitis

231
Q

Three types of treatment for Hepatic venous outflow obstruction

A
  1. medical= antithrombolytics
  2. surgical = shunt, anastomotic revision and retransplantation
  3. interventional radiology = angioplasty and stent placement
232
Q

Biliary complications post transplant

A
  1. Anastomatic stricture
    a. surgical/technical complication
    b. ischemia
    c. history of preceding bile leak
  2. Nonanastomotic stricture (diffuse intrahepatic stricture)
    a. early or late HAT/stenosis
    b. ABO incompatible graft (ABO Ags expressed on biliary epithelial cells)
    c. Chronic rejection
    d. recurrent PSC
    e. steatosis in the graft
  3. Bile leak (immediately postop)
    a. anastomatoic origin due to thenical complications
    b. cut surface leak in partial/split grafts
    c. presentation = bilious fluid drainage noted post op or fluid collection/abscess
233
Q

What is the triad histological features of ACR

A
  • lymphocyte portal inflammation
  • cholangitis and bile duct damage
  • endothelialitis
234
Q

Risk factors of chronic rejection

A
  • recurrent acute rejection episodes; particularly > 1 year after transplant
  • transplant for autoimmune liver disease
  • decreased risk with living related donor
  • association with viral infection (EBV, CMV, PTLD) with required reduction of immunosuppression
235
Q

Histologic features of Chronic rejection

A
  • biliary epithelial changes affecting most bile ducts
  • bile duct loss (ductopenia) affecting > 50% of portal tracts
  • foam cell obliterative arteriopathy
236
Q

What are the periods of infections post transplatn

A
  1. Early (0-30 days) - bacterial
    often associated with technical issues
  2. Intermediate (31-180) - viral
    EBV/CMV
  3. Late infections (> 180) bacterial or viral
237
Q

Risk factors for PTLD

A
  • high level of immunosuppression/multiple episodes of rejection
  • EBV-naive recipient and EBV-positive donor
  • high or rising viral load
238
Q

Presentation of PTLD

A
  • fever
  • lymphadenopathy
  • tonsillar enlargement
  • anemia
  • splenomegaly
  • hepatitis
  • diarrhea
  • mass
239
Q

Treatment for PTLD

A
  • reduction/discontinuation of immunosuppresion
  • +/- rituximab
  • chemotherapy
240
Q

What are the immunosuppression-related morbidity in post transplant

A
  1. Renal function
    a. CKI from vasoconstriction of afferent and efferent glomerular arterioles
    b. decreased renal blood flow and GFR
    c. abnormal tubular function - can lead to hyperkalemia, hypomagnesemia, hyperuricemia, hypercalciuria and decreased conc capacity
    d. hypertension
  2. Diabetes
    - exposure to steroids
    - CNI exposure= insulin resistance and pancreatic beta-cell toxicity
  3. Cardiovascular health
    - CNI related hyperlipidemia
    - obesity
    - metabolic syndrome
241
Q

What are the phases of immunsuppresion in liver txt

A
  1. induction (< 30 days)
  2. Maintenance (> 30 days)
  3. txt of rejection (augmentatin of immunosuppresion with dx of rejection)
242
Q

What is the MOA for Corticosteriods in rejection

A
  • complex with intracellular receptors that bind intranuclear regulatory elements and prevent activation of genes needed for immune response, particularly IL-2 and INF-gamma
  • suppress proliferation of helper and cytotoxic T cells and B cells
  • inhibit migration and activity of neutrophils
243
Q

Adverse effects of steroids

A
  • infection
  • hyperglycemia
  • hyperlipidemia
  • suppression of pituitary-adrenal axis
  • acne and hirsutism
  • skeletal growth retardation, osteopenia, fracture and AVN of femoral head
  • irritability, mood disturbance and sleep disturbance
  • increase appetitive and weight gain
  • GI tract irritation
244
Q

What is the MOA of calcineurin inhibitors

A
  • bind to intracellular immunophilin and decrease calcineurin activation
  • inhibit translocation of NF of activated cells (NFAT) and prevent expression of cytokine genes (IL-2)
  • leads to decrease T cell response to Ag stimulation
245
Q

How are CNI’s metabolized

A
  • by Cytochrome p450A enzyme system

- most important drug interactions are caused by drugs that affect Cytochrome p450 system

246
Q

Adverse effects of cyclosporin A

A

A. dose-dependent HTN- activates the sympathetic nervous system - upregulates endothelin and inhibits inducible NO = potent vasoconstriction
B. nephrotoxicity = reducing effective renal plasma flow and GFR
C. Neurotoxicity: tremors and seizure
D. Endocrine: decrease insulin secretion and abnormal glucose tolerance
E. Hypertrichosis
F. Gingival hyperplasia
G. Hyperuricemia and gout
H. hyperlipidemia

247
Q

Tac level goals post transplant

A

1) 0-3 months = 10-15
2) 4-12 months = 8-10
3) > 12 months = 3-8

248
Q

Adverse effects of Tac

A
  • dose dependent nephrotoxicity, neurotoxicity and HTN
  • hyperkalemia, hypomagnesemia from renal tubular effects
  • hypertrophic cardiomyopathy with chronic high-dose tac
  • hyperglycemia - reversible dose dependent cytotoxicity to Beta cells with decreased insulin secretion
  • hyperlipidemia and hypercholesterolemia
  • hyperuricemia and gout
249
Q

MMF (mycophenylate mofetil) MOA

A

-used as adjunctive therapy to reduce CNI toxicity/adverse effects, refractory rejection or chronic rejection

  • active metabolite = mycophenolic acid
  • selective inhibitor of inositol monophosphate dehydrogenase = essential enzyme in de novo synthesis of purines
  • inhibition depletes guanosine nucleotides and arrests lymphocyte proliferation
250
Q

Adverse effects of MMF

A
  • dose dependent BM suppression
  • diarrhea
  • doesn’t cause neurotoxicity or nephrotoxicity
  • no effect on glucose metabolism
251
Q

MOA of Sirolimus/rapamycin

A
  • inhibits activation of the mammalian target of rapamycin

- key regulatory kinase involved in T cell proliferation

252
Q

What is Basiliximab

A
  • nonlymphocyte-depleting agent that targets proteins on immune cell surface = IL-2 high-affinity receptor (CD25) on activated T cells
  • can be used as induction agent
253
Q

What are lympocyte-depleting agents

A
  • Monoclonal (OKT3 and alemtuzumab/Campath)
  • polyclonal (antithymocyte globulin/thymoglobulin)
  • can produce systemic symptoms due to cytokine release
  • may result in prolong T cell depletion

-increased risk factors for infection, BM suppression, PTLD

Peds GI RC (12 decks)

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