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Flashcards in Path slide set 4 Deck (432):
1

accumulation of fat

steatosis

2

accumulation of bilirubin

cholestasis

3

when injury is not reversible, hepatocytes die principally by what 2 mechanisms

-apoptosis
-necrosis

4

This form of hepatocyte injury is the predominate mod of death in ischemic/hypoxic injury and a significant response to oxidative stress

necrosis

5

councilman bodies

apoptotic hepatocytes

6

apoptotic hepatocytes in acute and chronic hepatitis

acidophil bodies due to deeply eosinophilic staining characteristics

7

severe, zonal loss of hepatocytes

confuent necrosis from widespread parenchymal loss

8

Regeneration of lost hepatocytes occurs primarily by what?

mitotic replication of hepatocytes adjacent to those that have died

9

in the most severe forms of acute liver failure, there is activation of the primary intrahepatic stem cell niche, called what

canal of Hering

10

principal cell type involved in scar deposition in liver

hepatic stellate cell

11

a hepatic stellate cell does what in quiescent form

lipid (vitamin A) storing cell

12

in several forms of acute and chronic injury, the stellate cell can become activated and are converted into what?

highly fibrogenic myofibroblasts

13

Proliferation of hepatic stellate cells and activation into myofibroblasts is initiated by increase expression of what

PDGFR-B and TNF

-also Kupffer cells and lymphocytes release cytokine and chemokines that modulated expression of TGF-B and MMP-2 and TIMP-1

14

myofibroblast contraction is stimulated by what

endothelin-1 (ET-1)

15

If injury persists, where does scar deposition often begin?

What diseases is this important

space of Disse

alcoholic and NAFLD

16

if chronic injury ceases, what can break down the scar, potentially reversing the formation

metalloproteinases

17

Adaptive immunitey plays a big role in what

viral hepatitis

18

Antigen specific and CD8+ cells are involved in what

eradication of hepatitis B and C

19

What percent of hepatic functional capacity must be lost before failure

80 to 90

20

definition of Acute liver failure

-an acute liver illness associated with ENCEPHALOPATHY and COAGULOPATHY that occurs within 26 weeks of initial injury in absence of pre-existing liver disease

21

another term for acute liver failure

fulminant liver failure

22

What causes acute liver failure

massive hepatic necrosis
-most often by drugs or toxins

23

What accounts for almost 50% of acute liver failure in US

Acetaminophen

24

what predominantly causes acute liver failure in Asia

hepatitis B and E

25

What does liver look like grossly with acute liver failure

small and shrunken

26

is there scarring in acetaminophen acute liver failure

no. . .usually happens within hours to days, too brief a time period for scarring

27

What viruses can cause acute liver failure in immunocompromised

-CMV
-Herpes
-adenovirus

28

what are elevated in acute liver failure

-at first liver serum transaminases increase
-as parenchyma dies, liver shrinks and transaminases decrease

29

a characteristic sign of acute liver failure, nonrhythmic, rapid extension-flexion movements of the head and extremities, best seen when the arms are held in extension with dorsiflexed wrists

Asterixis

30

What gets elevated in the blood with acute liver failure that correlates with impaired neuronal function and cerebral edema

ammonia

31

Coagulopathy and acute liver failure

-easy bruising
-fatal intracranial bleeding

32

form of renal failure occurring in individuals with liver failure in whom there are no intrinsic morphologic or functional causes for kidney dysfunction

Hepatorenal syndrome

33

leading causes of chronic liver failure worldwide

-chronic hep B
-Chronic hep C
-Non alcoholic fatty liver disease
-alcoholic fatty liver disease

34

Liver failure in chronic liver disease is most often associated with what

cirrhosis

35

diffuse transformation of the entire liver into regerative parenchymal nodules surrounded by fibrous bands and variable degrees of vascular (often portosystemic) shunting

cirrhosis

36

What is the classification of cirrhosis which uses different morphologic features which helps monitor the decline of patients on the path to chronic liver failure

The Child-Pugh classification of cirrhosis

37

cirrhosis when there is no clear cause

cryptogenic cirrhosis

38

in chronic liver disease, what increases with advancing stage of disease and are usually most prominent in cirrhosis

ductular reactions

39

What percent of individuals with cirrhosis are asymptomatic until the most advanced stages of disease

40%

40

The ultimate causes of death in chronic liver failure, whether cirrhotic or not

-those seen in acute liver failure
-multiorgan system failure
-hepatic encepholopathy, bleeding from esophageal varices, and bacterial infections

41

additional grim outcomes associated with chronic liver failure in the context of cirrhosis

hepatocellular carcinoma

42

Additional features of chronic renal failure that are different than acute

-pruritus (intense itching)
-Hyperestrogenemia
-Palmar erythema
-spider angiomas
-hypogonadism
-gynecomastia

43

is portal hypertension more common in acute or chronic liver failure

chronic

44

what are the 3 types of portal HTN

-Pre, intra, and post hepatic

45

the major prehepatic conditions leading to portal HTN

-obstructive thrombosis
-massive spenomegaly

46

main posthepatic causes of portal HTN

-severe right sided heart failure
-constrictive pericarditis
-hepatic vein outflow obstruction

47

The dominant intrahepatic cause, accounting for most cases of portal HTN

cirrhosis

48

in portal HTN, the increased resistance to portal flow is at the level of what?

sinusoids

49

4 major clinical consequences of portal HTN?

-Ascites
-formation of portosystemic venous shunts
-congestive splenomegaly
-hepatic encephalopathy

50

how much fluid is needed for ascites to become clinically detectable

at lease 500 mL

51

This appears in about 40% of individuals with advanced cirrhosis of the liver and causes massive hematemesis and death in about half of them

esophageal varices

52

Each episode of bleeding from esophageal varices has what % mortality

30%

53

2 additional syndromes that occur with chronic liver failure

-hepatopulmonary syndrome
-portopulmonary HTN

54

Hep virus: usually benign, self-limiting disease with an incubation period of 2 to 6 weeks

Hep A

55

Hep virus: does NOT cause chronic hepatitis or a carrier state and only uncommonly causes acute hepatic failure

Hep A

56

the only DNA hep virus

Hep B

57

route of transmission for Hep A

fecal-oral

58

reliable marker of acute infection with HAV

IgM antibody against HAV

59

The Hep virus that can leads to chronic liver disease and is then a precursor for hepatocellular carcinoma even in the absence of cirrhosis

Hep B

60

what is the best predictor of chronicity with HBV

age at time of infection

61

risk factors for HCV infection

-IV drugs
-multiple sex partners
-having surgery within last 6 months
-needle stick injury
-multiple contacts with an HCV infected person
-employment in medical or dental fields
-unknown

62

elevated titers of what after an active infection of HCV do not confer effective immunitiy

anti-HCV IgG

63

what are the hallmarks of HCV infection

persistent infection and chronic hepatitis despite the generally asymptomatic nature of the acute illness

64

what must be measured to confirm diagnosis of HCV infection

HCV RNA

65

in HCV infection, levels of what waxes and wanes but never become normal

serum aminotransferases

66

which hep virus will cause chronic disease in 80-90%

HCV

67

Which hep virus has an association with metabolic syndrome

HCV

68

Which hep virus is dependent for its life cycle on HBV

HDV

69

which hep virus is cocaine use a risk factor

HCV

70

time frame needed for it to be chronic hepatitis

more than 6 months

71

acute or chronic hepatitis?
-portal inflammation minimal or absent
-"spotty necrosis"
-lobular hepatitis

Acute

72

defining histologic feature of chronic viral hepatitis

mononuclear portal infiltration

73

acute or chronic hepatitis?
-interface hepatitis

Chronic

74

"GROUND GLASS" hepatocytes

chronic Hepatitis B

75

diagnostic hallmark of HBV

cells with endosplasmic reticulum swollen by HBsAg

76

which Hep virus: LYMPHOID FOLLICLES

HCV

77

Chronic, progressive hepatitis
-autoantibodies
-therapeutic response to immunosuppression

autoimmune hepatitis

78

gender for autoimmune hepatitis

female predominance (78%)

79

antibodies for type 1 autoimmune hepatitis

-ANA
-SMA
-anti-SLA/LP
-less commonly, AMA

80

antibodies for type 2 autoimmune hepatitis

-anti-LKM-1 (directed against CYP2D6)
-ACL-1 antibodies

81

age for type 1 autoimmune hepatitis

type 2?

middle aged to older

children and teenagers

82

hepatitis with PLASMA cell predominance and hepatocyte "ROSETTES" in areas of marked activity

autoimmune hepatitis

83

What should always be included in the differential diagnosis of any form of liver disease

exposure to a toxin or therapeutic agent

84

toxic agent for hepatocellular necrosis

Acetaminophen

85

toxic agent for periportal and pericellular fibrosis

alcohol

86

Toxic agent for Budd-Chiari syndrome

-Oral contraceptives

87

toxic agent that can cause cholangiocarcinoma

thorotrast

88

toxic agents for peliosis hepatis: blood filled cavities, not lined by endothelial cells

anabolic steroids and tamoxifen

89

toxic agents for hepatocellular adenom

-oral contraceptives
-anabolic steroids

90

Most common cause of acute liver failure necessitating transplantation in the U.S.

Acetaminophen

91

Leading cause of liver disease in most western countries

Excessive alcohol consumption

92

3 distinct forms of alcoholic liver injury

-hepatocellular steatosis
-alcoholic (or steato-) hepatitis
-steatofibrosis

93

This form of alcoholic injury is completely reversible if there is abstention from further intake of alcohol

Fatty change or steatosis

94

What 3 things characterize alcoholic or steato-hepatitis

-hepatocyte swelling and necrosis
-Mallory-Denk Bodies
-Neutrophilic reaction

95

keratins 8 and 18

Mallory Denk bodies

96

chicken wire fence pattern of alcoholic hepatic injury

alcoholic steatofibrosis

97

perisinusoidal scarring leads to a classic micronodular or LAENNEC CIRRHOSIS . . . burned out stage

alcoholic steatofibrosis

98

Mallory-Denk bodies seen in what

-alcoholic hepatitis or steatohepatitis
-Non-alcoholic fatty liver disease
-Wilson disease
-chronic biliary tract disease

99

What percent of alcoholics develop cirrhosis

only 10 to 15%

100

gender for alcoholic hepatic injury?

WhY?

women more susceptible

estrogen increases gut permeability to endotoxins which increase LPS receptor CD14 in Kupffer cells.
This predisposes to increased production of proinflammatory cytokines

101

Ethnicity for alcoholic hepatic injury?

genes involved

AA

ALDH*2

102

comorbid conditions for alcoholic hepatic injury

-iron overload
-infection from HCV and HBV

103

what does alcohol that causes injury

-Acetaldehyde
-ROS
-decreases glutathione
-releases bacterial endotoxin
-contraction of activated myofibroblastic stellate cells (portal HTN)

104

Hepatic steatosis may cause what?

hepatomegaly with mild elevation of serum bilirubin and alkaline phosphatase levels

105

Alcoholic hepatitis tends to appear acutely following what?

a bout of heavy drinking

106

lab findings for alcoholic hepatitis

-hyperbilirubinemia
-elevated serum aminotransferase
-alkaline phosphatase
-neutrophilic leukocytosis

107

ALT:AST ratio for alcoholic hepatitis

other chronic diseases ALT tends to be higher BUT!!!!

AST:ALT ratio is 2:1

108

Lab findings for alcoholic cirrhosis

-elevated serum aminotransferases
-hyperbilirubinemia
-hypoproteinemia
-anemia

109

In the end-stage alcoholic, the proximate causes of death are what

-hepatic coma
-massive GI hemorrhage
-intercurrent infection
-hepatorenal syndrome
-hepatocellular carcinoma

110

most common acquired metabolic liver disorder

Non-alcoholic fatty liver disease (NAFLD)

111

Most common cause of chronic liver disease in the US

NAFLD

112

What term is often used to denote overt clinical features if liver injury in NAFLD

nonalcoholic steatohepatitis (NASH)

113

histologic hallmarks of NAFLD are most consistent with what syndrome?

metabolic syndrome

114

what has resulted in increasing rates of NAFLD

increased obesity in US

115

NAFLD increases risk for what?

hepatocellular carcinoma in ABSENCE of scarring

116

2 hit model for NAFLD

-insulin resistance gives risk to hepatic steatosis
-hepatocellular oxidative injury

117

What are the inherited metabolic liver diseases

-Hemochromatosis
-Wilson disease
-alpha 1 antitrypsin deficiency

118

Criteria for metabolic syndrome:
One the following:

AND

two of the following:

-DM
-impaired glucose tolerance
-Impaired fasting glucose
-insulin resistanct

-BP: >140/90
-Dyslipidemia
-central obesity: waist:hip ratio >.9 for males, .85 for females or BMI >30
-microalbuminuria

119

ethnic groups for NAFLD

Hispanic>AAs>Caucasians

120

Pathologic steatosis is defined as involving more than what percent of hepatocytes?

more than 5%

121

Greater than 90% of previously described "cryptogenic cirrhosis" is now thought to represent what?

"burned out" NAFLD

122

stain for NAFLD

Masson Trichrome stain

123

what is the most reliable diagnostic tool for NAFLD and NASH

-liver biopsy

124

excessive iron absorption, most of which is deposited in parenchymal organs such as the liver and pancreas, followed by hearts, joints, and endocrine organs

Hemochromatosis

125

what causes ssecondary hemochromatosis

usually transfusion

126

Fully developed cases of severe iron overload in the body exhibit what?

-Micronodular cirrhosis in all
-DM in 75-80%
-abnormal skin pigmentation in 75-80%

127

When do symptoms of hereditary hemochromatosis usually first appear

4th to 5th decade of life and later in women wince menstrual bleeding counterbalances the accumulation until menopause

128

Gender for heriditary hemochromatosis

Males 5 to 7:1

129

grams of iron accumulation per year in hereditary hemochromatosis

.5 to 1 gm/year

130

how many grams of iron are stored in hereditary hemochromatosis before the disease manifests

after 20 grams

131

Main regulator of iron absorption?

what gene?

hepcidin

HAMP

132

3 genes in hemochromatosis

Adult form almost always caused by which?
-specific mutation

HFE, HJV, and TFR2

HFE
-C282Y

133

C282Y mutation of HFE gene for hemochromatosis is confined to what race

caucasian

134

penetrance of hemochromatosis

low

135

What mutations cause severe juvenile hemochromatosis

-HAMP
-HJV

136

Which form of hemochromatosis is milder? adult or juvenile

adult

137

what stain for hemochromatosis

prussian blue

138

Classic tetrad of hemochromatosis

-cirrhosis with hepatomegaly
-abnormal skin pigmentation
-DM
-cardiac dysfunction

139

Slate-gray colored skin

hemochromatosis

140

joints and hemochromastosis

acute synovitis . .. psuedogout

141

Testes and hemochromatosis

may be small and atrophic

142

gender and age for hemochromotosis

often males and rarely before 40

143

Death in hemochromostosis is from what

cirrhosis or cardiac disease

144

Risk of hepatocarcinoma in hemochromatosis

200 fold greater . . . . significant cause of death

145

Treatment by what steadily depletes tissue iron stores in hemochromatosis

regular phlebotomy

146

is neonatal hemochromatosis an inherited disease

no . . just congenital

147

in neonatal hemochromatosis, hemosiderin deposition is detected where and needs to be documented for correct diagnosis

buccal biopsy

148

inheritance pattern of Wilson disease

automsomal recessive

149

Gene for Wilson disease

ATP7B

150

Wilson disease principally involves what organs

liver, brain, eyes

151

deposition of copper

Wilson disease

152

Free copper usually binds to what

ceruloplasmin

153

Accumulation of copper in Wilson disease causes toxic liver injury by what 3 mechanisms

-formation of free radicals by the Fenton reaction
-binding to sulfhydryl groups of cellular proteins
-displacing other metals from hepatic metalloenzymes

154

in wilson disease, what increases in urine

Copper

155

Stains for Wilson Disease

-Rhodamine stain for copper
-Orcein stain for copper-associated protein

156

Toxic injury to the brain in Wilson disease affects what areas

-basal ganglia, particularly the putamen which shows atrophy and even cavitation

157

Kayser-Fleischer rings in Wilson disease affect what in the eye

Descemet membrane in the limbus of the cornea

158

Age of onset for Wilson disease

average 11.4 . . . 6-40

159

Neurologic symptoms of Wilson disease

Parkinsonian symptoms

160

Most sensitive and accurate test for Wilson?

most specific screening test?

increase in hepatic copper content

increased urinary excretion

161

Inheritance pattern for alpha 1 antitrypsin deficiency

autosomal recessive

162

disorder of protein folding

a1-antitrypsin deficiency

163

Major function of a1-antitrypsin

inhibition of proteases, particularly neutrophil elastase, cathepsin G, and proteinase 3

164

Gene for a1-antitrypsin on what chromosome

14

165

amino acid substitution for PiZ genotype

Glu342 to Lys342

166

pathogenesis of alpha1-antitrypsin deficiency

abnormally folded protein creates endoplasmic reticulum stress and triggers a signaling cascade (UPR) that leads to apoptosis

167

cytoplasmic globular inclusions in hepatocytes
-PAS positive

a1-antrypsin deficiency

168

what is seen in 10 to 20% of newborns with a1-antitrypsin deficiency

Neonatal hepatitis with cholestatic jaundice

169

presenting symptoms of a1-antitrypsin deficiency in adolescence

hepatitis, cirrhosis, or pulmonary disease

170

2 major functions of hepatic bile

-emulsification of dietary fat in lumen of the gut through detergent action of bile salts
-elimination of bilirubin, excess cholesterol, xenobiotics

171

The metabolism of bilirubin by the liver consists of four separate but interrelated events: what are they

-uptake from circulation
-intracellular storage
-conjugation with glucuronic acid
-biliary excretion

172

bilirubin is the end product of what?

heme degradation

173

what converts heme to biliverdin

intracellular heme oxygenase

174

biliverdin is immediately reduced to bilirubin by what

biliverdin reductase

175

Bilirubin is formed outside of the liver and is released and bound to what

serum albumin

176

Hepatic processing of bilirubin involved carrier-mediated uptake where?

sinusoidal membrane

177

conjugation of bilirubin is done by waht

bilirubin uridine disphosphate (UDP) glucuronyl transferase (UGT1A1)

178

Most bilirubin glucuronides are deconjugated in the gut lumen by what? and degraded to what?

bacterial B-glucuronidases

colorless urobilinogens

179

solubility of unconjugated bilirubin

insoluble at physiologic pH and exists in tight complexes with serum albumin

180

can unconjugated bilirubin be excreted in urine

no . . not soluble

181

What kind of bilirubin can diffuse into tissues, particularly the brain of infants, and produce toxic injury

the albumin free unconjugated bilirubin in plasma

182

Hemolytic disease of the newborn (erythroblastosis fetalis) may lead to accumulation of what in the brain . . .kernicterus

unconjugated bilirubin

183

This type of bilirubin is water-soluble, nontoxic, and can only loosely bind to albumin . .. excreted in urine

conjugated

184

the 2 conditions that result from specific defects in hepatocellular bilirubin metabolism

-neonatal Jaundice
-Hereditary Hyperbilirubinemias

185

Because the hepatic machinery for conjugating and excreting bilirubin does not fully mature until about 2 weeks of age, almost every newborn develops transient and mild unconjugated hyperbilirubinemia termed what?

neonatal jaundice or PHYSIOLOGIC JAUNDICE OF THE NEWBORN

186

mutations of UGT1A1 cause hereditary UNCONJUGATED hyperbilirubinemias . . what ones

-Crigler-Najjar
-Gilbert syndrome

187

these result from defects that lead to CONJUGATED hyperbilirubinemias?

inheritence pattern

-Dubin-Johnson
-Rotor syndrome

autosomal recessive

188

This caused by impaired bile formation and bile flow that gives rise to accumulation of bile pigment in the hepatic parenchyma

Cholestatis

189

Patients with cholestatis may have what symptoms

-jaundice
-pruritis
-skin xanthomas
-malabsorption of A,D, K

190

characteristic lab finding in cholestasis

-elevated serum alkaline phosphatase
-elevated gamma-glutamyl transpeptidase (GGT)

-AST and ALT probably normal

191

"feathery degeneration"

Cholestasis . . droplets of bile pigment that accumulate in hepatocytes and take on a fine, foamy appearance

192

a1-antitrypsin deficiency in middle to late life

cirrhosis with or without HCC

193

Black liver (pigmented cytoplasmic globules)

Dubin-Johnson

194

What hereditary hyperbilirubinemia is fatal

Crigler-Najjar syndrome type 1

195

The 2 cholestasis diseases we need to know

-Large Bile duct obstruction (adults)
-Biliary Atresia (neonatal)

196

most common cause of bile duct obstruction in adult

extrahepatic cholelithiasis (gallstones)

197

subtotal or intermittent obstruction of the bile duct may promote what

ascending cholangitis, a secondary bacterial infection of the biliary tree that aggravates the inflammatory injury

198

Cholangitis usually pressent with what

-fever
-chills
-abdominal pain
-jaundice

199

What is the most severe form of cholangitis

suppurative cholangitis in which purulent bile fills and distends the bile ducts

200

What dominates suppurative cholangitis

sepsis rather than cholestasis

201

Histologic hallmark of ascending cholangitis

influx of periductular neutrophils directly into the bile duct epithelium

202

Which cholestasis is ammenable with surgery?

Extrahepatic

intrahepatic will get worse so proper diagnosis is key

203

Charcots triad

What disease

-Jaundice
-RUQ pain
-Fever

Acute cholangitis

204

The presence of pus in the biliary ducts may result in Reynold's pentad: what is this

Charcot's triad plus hypotension and confusion

205

The single most frequent cause of death from liver disease in early childhood

Biliary atresia

206

Neonates who have jaundice beyond how many days after birth should be evaluated for neonatal cholestasis

14-21 days

207

Kasai procedure

surgical intervention of biliary atresia

208

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

biliary atresia

209

What accounts for 50 - 60% of children referred for liver transplantation

biliary atresia

210

2 forms of biliary atresia

fetal and perinatal

211

Which type of biliary atresia? associated with other anomalies resulting from ineffective establishment of laterality of thoracic and abdominal organ during development

fetal

212

which type of biliary atresia is more common and the normally developed biliary tree is destroyed following birth probably from viral infection or immune reactions

perinatal

213

inflammation and fibrosing stricture of the hepatic or common bile ducts

biliary atresia

214

multinucleate giant hepatocytes

neonatal hepatitis

215

biliary atresia limited to the common duct

type 1

216

biliary atresia of right and/or left hepatic bile ducts

type 2

217

biliary atresia in which there is obstruction at or above the porta hepatis (90%)?

Why is this a problem?

type 3

not surgically correctable by Kasai procedure

218

presentation of biliary atresia

-normal birth weight
-postnatal weight gain
-slight female predominance
-stools change to acholic as disease progresses

219

what remains the primary hope for salvage of biliary atresia patients

liver transplant

220

without surgical intervention, when does death occur in biliary atresia

within 2 years of birth

221

2 main autoimmune disorders of intrahepatic duct

-Primary biliary cirrhosis (PBC)
-Primary sclerosis cholangitis (PSC)

222

autoimmune disease characterized by nonsuppurative, inflammatory destruction of small and medium sized intrahepatic bile ducts

PBC

223

age and gender for PBC

middle aged women with female predominance of 9:1 occurring 30-70. ave of 50

224

geography for PBC

-northern European countries (England and Scotland)
-Northern US (Minnesota)

225

most characteristic Lab finding with PBC

Antimitochondrial antibodies
-recognize E2 compenent of pyruvate dehydrogenase complex (PDC-E2)

226

Florid duct lesion

PBC

227

associated condition with PBC

Sjogren

228

Serology with PBC

AMA-positive and ANA-positive

229

what is elevated in PBC

alkaline phosphatase and GGT

230

PBC is confirmed by what?

Liver biopsy which is considered diagnostic if a florid duct lesion is present

231

in PBC, over a period of two or more decades, untreated patients will follow one of two pathways to end-stage disease . .

-hyperbilirubinemia predominates
-prominent portal HTN

232

With progression of PBC, what secondary features may emerge

-skin hyperpigmentation
-Xanthelasmas
-Steatorrhea
-Vitamine-D malabsorption-related osteomalacia and/or osteoporosis

233

Inflammation and obliterative fibrosis of intrahepatic and extrahepatic bile ducts with dilation of preserved segments

Primary sclerosis cholangitis (PSC)

234

Beading on radiograph

PSC

235

what condition coexists in about 70% of PSC patients

-IBD particularly UC

236

age and gender for PSC

males age 30

237

What HLA in PSC suppports that it is an inherent immunologic process

HLA-B8

238

Autoantibody in 65% of those with PSC

perinuclear antineutrophil cytoplasmic antibodies (pANCA)

239

small duct morphology for PSC

"onion skin" fibrosis leading to a "tombstone" scar

240

Asymptomatic pts with PSC may come to attention only because of what?

persistent elevation of serum alkaline phosphatase, particularly in pts with UC who are being routinely screened

241

Risk for what cancer with PSC

cholangiocarcinoma . . 1.5% annual risk and 20% lifetime

242

A distinctive type of sclerosing cholangitis with elevated IgG4 levels in association with what

autoimmune pancreatitis

243

congenital dilations of the common bile duct

age

gender

choledochal cysts

before 10

female to male 3:1 to 4:1

244

heterogeneous group of lesion in which the primary abnormalities are congenital malformations of the biliary tree

fibropolycystic disease of the liver

245

the most severe forms of fibropolycystic disease manifest as what

hepatosplenomegaly or portal HTN in absence of hepatic dysfunction, starting in late childhood or adolescence

246

3 pathologic findings that may be seen in fibropolycystic Disease

-Von Meyenburg complexes (small bile duct hamartomas)
-Single or multiple intrahepatic or extrahepatic biliary cysts
-congenital hepatic fibrosis

247

when biliary cysts occur along with congenital hepatic fibrosis

Caroli SYNDROME

248

When biliary cysts are in isolation and may be asymtomatic due to ascending cholangitis

Caroli DISEASE

249

Stain for Congenital hepatic fibrosis

Masson Trichrome stain

250

Structural anomalies of the biliary tree are related to abnormal development of what

ductal plate

251

Fibropolycystic liver disease often occurs with what other disease?

gene

autosomal recessive polycystic renal disease

-polycystin

252

Persons with fibropolycystic liver disease have an increased risk for what?

cholangiocarcinoma

253

two conditions where solitary or multiple hyperplastic hepatocellular nodules may develop in the noncirrhotic liver

-focal nodular hyperplasia
-nodular regerative hyperplasia

254

What is the common factor in both focal nodular hyperplasia and nodular regenerative hyperplasia?

focal or diffuse alterations in hepatic blood supply, arising from obliteration of portal vein radicles and compensatory augmentation of arterial blood supply

255

spontaneous mass lesion in an otherwise normal liver
-younger to middle aged adult
-lighter than surrounding liver
-STELLATE scar

focal nodular hyperplasia

256

liver entirely transformed into nodules but without fibrosis

nodular regenerative hyperplasia

257

nodular regenerative hyperplasia can lead to what?

portal HTN

258

most common benign liver tumor

cavernous hemangioma

259

discrete, red-blue, soft nodule usually less than 2 cm in diameter, located directly beneath the capsule

cavernous hemangioma

260

conditions associated with nodular regenerative hyperplasia

-HIV
-rheumatologic diseases/SLE

261

gender for cavernous hemangioma

F>M

262

chief clinical significance of cavernous hemangioma

might be mistaken radiographically or intraoperatively for metastatic tumors

263

Benign neoplasm developing from hepatocytes

hepatocellular adenoma

264

3 subtypes of hepatocellular adenoma

-HNF1-a inactivated hepatocellular adenomas
-B-catenin Activated hepatocellulr adenoma
-Inflammatory hepatocellular adenoma

265

What drugs are associated with development of hepatocellular adenoma

-Oral contraceptives (30-40x increased risk)
-anabolic steroids

266

Hepatocellular adenoma that is responsible for autosomal dominant MODY-3 (maturity onset diabetes of the young type 3)

HNF1-a inactivated

267

Hepatocellular adenoma that has very high risk for malignant transformation

B-Catenin activated

268

Hepatocellular adenoma that is associated with Non-alcoholic fatty liver disease

Inflammatory

269

risk of malignant transformation in inflammatory Hepatocellular adenoma

small but definite risk

270

mutations in inflammatory Hepatocellular adenoma

activating mutations in gp130, a coreceptor for IL-6 that lead to JAK-STAT signaling

271

This hepatocellular adenoma has tumors that are often fatty and devoid of cellular or architectural atypia.
-Almost no risk for malignant transformation
-Liver fatty acid binding protein (LFABP) is ABSENT

HNF1-a inactivated

272

these hepatocellular adenomas have a high degree of cytoogic of architectural dysplasia
-nuclear translocation
-Glutamine synthetase diffusely positive

B-catenin Activated

273

These hepatocellular adenomas have fibrotic stroma, mononuclear inflammtion, ductular reactions, dilated sinusoids, and telangiectatic vessels
-express C reactive protein and serum amyloid

inflammatory

274

hepatocellular adenoma: DAB (brown) stain and hemotoxylin counterstain

inflammatory

275

Most primary liver cancers arise from hepatocytes and are termed what?

hepatocellular carcinoma

276

Much less common carcinomas of bile duct origin

cholangiocarcinoma

277

Most common liver tumor of early childhood?

Age?

Hepatoblastoma

rarely over age 3

278

2 types of hepatoblastoma

-epithelial
-mixed epithelial and mesenchymal

279

Which type of hepatoblastoma: composed of small polygonal fetal cells or smaller embyonal cells forming acini, tubules, or papillary structures vaguely recapitulating liver development

epithelial type

280

Which type of hepatoblastoma: contain primitive mesenchyme, osteoid, cartilage, or striated muscle

mixed epithelial and mesenchymal type

281

What pathway is activated in hepatoblastomas

WNT

282

Patients with what familial disease frequently develop hapatoblastomas

Familial adenomatous polyposis

283

FOXG1, a regulator of the TGF-beta pathway, is highly expressed in some of what type of tumor

hepatoblastoma

284

Beckwith-Wiedemann syndrome

hepatoblastoma

285

another name for HCC

hepatoma

286

More than 85% of cases of HCC occur in countries with high rates of what?

chronic HBV infection

287

when HCC occures in places with high incidence of chronic HBV what is the age?

Cirrhosis?

Toxin associated?

between 20 and 40

50% absence of cirrhosis

Aflatoxin

288

In Western countries, the incidence of HCC is rapidly increasing, largely owing to what?

Hep C epidemic

289

age for HCC in western countries?

cirrhosis?

gender?

-rarely before age 60

almost 90%

Male predominance: 3:1 in low incidence. 8:1 in high

290

What is the most common setting for emergence of HCC

chronic liver disease

291

The most important underlying factors in HCC are what?

-viral infections ( HCV, HBV)
-toxic injury (Aflatoxin, alcohol)

292

what produces aflatoxin

Aspergillus

293

Where can you find Aflatoxin metabolites in affected individuals

-urine
-also aflatoxin-albumin adducts in serum

294

What two (maybe 3) things synergize with HBV to increase risk for HCC

-Aflatoxin
-alcohol
-possibly cigarette smoke

295

What metabolic diseases markedly increase risk of HCC

-Hereditary hemochromatosis
-a1AT deficiency

-More importantly, metabolic syndrome associated with obesity, DM, and NAFLD

296

2 most common early mutational events or HCC

-Activation of B-catenin
-inactivation of p53

297

What mutation is strongly associated with HCC that is associted with aflatoxin

p53

298

What mutation is more likely associated with HCC that is unrelated to HBV

B-catenin

299

signaling pathway implicated in HCC

-IL-6/JAK/STAT
-IL-6 regulates function of HNF-a

300

In chronic liver disease the cellular dysplasias (precursor lesions) are called what?

-which is directly pre-malignant

-Which is thought to at least a marker of increased risk of HCC but in HBV they are also directly pre-malignant

-Large cell change
-small cell change

-Small cell

-Large cell

-MARKERS IN BIOPSY

301

What precursor lesion for HCC is usually detected in cirrhosis

dysplastic nodules

302

What are probably the most important primary pathway for emergence of HCC in viral hepatitis and alcoholic liver disease

High grade dysplastic nodules

303

HCC Precursor lesion: larger than normal hepatocytes, large often multiple pleomorphic nuclei . . . NORMAL nuclei:cytoplasmic ratio

Large cell change

304

HCC precursor lesion: HIGH nuclear:cytoplasmic ratio. mild nuclear hyperchromasia and pleomorphism.
-tiny expansile nodules within single parenchymal lobule

small cell change

305

HCC precursor lesion: devoid of cytologic or architectural atypia. Probably neoplastic.

Low grade dysplasia

306

HCC precursor lesion: small cell change, occasional psuedoglands, trabecular thickening. Overt HCC may arise within and overgrow it

high grade dysplastic nodule

307

3 ways grossly HCC may appear as

1: unifocal (usually large) mass
2: multifocal, widely distributed nodules of variable size
3: diffusely infiltrative cancer

-all three may cause liver enlargement

308

What becomes more likely once HCC tumors reach 3 cm in size

intrahepatic metastases by either vascular invasion or direct extension

309

Variant of HCC
-under age 35
-no gender predilection or predisposing condition
-single, large, hard "scirrhous" tumor with fibrous bands
-Well-differentiated cell rich in mitochondria . . ONCOCYTES growing in nests or cords separated by parallel lamellae of dense collegen bundles
-NO history of cirrhosis

Fibrolamellar carcinoma

310

History of liver disease in HCC where aflatoxin is common?

No

311

Elevated levels of what in serum are found in 50% of HCC

serum alpha-fetoprotein

312

What is most valuable for detection of small HCC tumors

imaging studies

313

what forms the basis for diagnostic imaging of HCC

increasing arterialization in the process of conversion from high grade dysplastic nodule to early HCC then to fully developed HCC. .. bascially vascular changes

314

Death from HCC usually occurs from what?

-cachexia
-GI or esophageal variceal bleeding
-Liver failure with hepatic coma
-rarely, rupture of the tumor with fatal hemorrhage

315

second most common primary malignant tumor of the liver after HCC

chalangiocarcinoma (CCA)

316

malignancy of the biliary tree, arising from bile ducts within and outside of the liver

CCA

317

In Areas where infestation with liver flukes is endemic, what is more common than HCC

CCA

318

All risk factors for CCA cause what

-chronic inflammation
-cholestasis

319

risk factors for CCA

-infestation by liver flukes (Opisthorchis and Clonorchis)
-chronic inflammatory disease of large bile ducts
-Primary sclerosing cholangitis
-hepatolithiasis
-fibropolycystic liver disease

320

Extrahepatic forms of CCA include perihilar tumors known as what?

Klatskin tumor

321

Where are Klatskin tumors located?

at the junction of the right and left hepatic ducts

322

prognosis for CCA regardless of location

dismal

323

Most important premalignant lesion for CCA?

Which is highest grade and highest risk for malignant transformation

biliary intraepithelial neoplasias (low to high grade, BiIIN-1, -2, -3)

-BiIIN-3

324

CCAs are usually what type of cancer

typical adenocarcinomas . . produce mucin

325

What do CCAs usually incite

marked desmoplasia

326

whats more common in liver . . metastasis or primary hepatic neoplasia

Metastasis is far more comfMmon

327

most common sources for metastasis to liver

-colon
-breast
-lung
-pancreas

328

More than 95% of biliary tract disease is attributable to what?

cholelithiasis (gallstones)

329

What is the most common anomaly of the gallbladder?

a folded fundus, creating a phrygian cap

330

Agenesis of all or any portion of the hepatic or common bile ducts and hypoplastic narrowing of biliary channel

true "biliary atresia"

331

2 general classes of gallstones

-cholesterol stones (crystalline cholesterol monohydrate)
-pigment stones (bilirubin calcium salts)

332

Ethnicity that gall stones are really prevalent

-Native American
-more prevalent in US and western europe
-uncommon in developing countries

333

Pigment gallstones are predominent type where?

what settings?

Non-western populations

bacterial infections of biliary tree and parasitic infestations

334

Major risk factors for gallstones

-Age and Sex (middle to older age, females, caucasian women twice as likely) . . .also metabolic syndrome and obesity
-Environmental factors: Estrogen (oral contraceptive use during pregnancy)
-acquired disorders: Gallbladder stasis
-Hereditary: ABC . . ATP-binding cassette transporters

335

ABCG8 gene

Cholesterol Gallstones

336

Four conditions that contribute to formation of cholesterol gallstones

-supersaturation of bile with cholesterol
-hypomotility of the gallbladder
-accelerated cholesterol crystal nucleation
-hypersecretion of mucus in gallbladder

337

Disorders that are associated with elevated levels of unconjugated bilirubin and increase risk of developing pigment stones

-chonic hemolytic anemia
-Severe ileal dysfunction or bypass
-bacterial contamination of biliary tree

338

What organisms increase likelihood of pigment stone formation

-E. coli
-Ascaris lumbricoides
-Liver fluke C. sinensis

339

This gallstone is pale yellow, round to ovoid and exclusively in gallbladder

Cholesterol stone

340

Black pigment stones are found where

sterile gallbladder bile

341

Brown pigment stones are found where

infected large bile ducts

342

What kind of gallstone: laminated and soft and may have soaplike or greasy consistency

Brown pigment stones

343

what is a prominent symptom of gallstones that may be excruciating

biliary colic

344

-constant pain
-follows fatty mean which forces stone against the gall bladder outlet increasing pressure
-Pain in right upper quadrant or epigastrium that may radiate to the right shoulder or back

biliary colic

345

More severe complictions of gallstones

-empyema
-perforation
-fistulas
-inflammation of biliary tree (cholangitis)
-obstructive cholestasis
-pancreatitis

346

What size stones are more dangers

very small or "gravel" stones

347

When a large stone erode directly into an adjacent loop of small bowel, generating intestinal obstruction

"gallstone Ileus" or "Bouveret syndrome"

348

Gallstones increase risk for what

Gallbladder carcinoma

349

Cholecystitis (inflammation of gallbladder) occurs almost always in association with what

gallstones

350

Acute calculous cholecystitis is precipitated in 90% of cases by what

obstructin of the nuck or the cystic duct by a stone

351

What is the primary complication of gallstones and the most common reason for emergency cholecystectomy

Acute cholecystitis

352

What percent of Cholecystitis cases are without (acalculous) gallstones

10%

353

Acute calculous cholecystitis results from what?

chemical irritation and inflammation of a gallbladder obstructed by stones

354

Acute calculous cholecystitis frequently develops in who?

diabetic patients who have symptomatic gallstones

355

Acute acalculous cholecystitis without stone involvement is thought to result from what?

ischemia

356

Risk factors for acute Acalculous cholecystitis

-sepsis with hypotension and multisystem organ failure
-Immunosuppresion
-major trauma and burns
-DM
-infections

357

gallbladder is enlarged and tense. may assume a bright red or blotchy, violaceous to green-black discoloration

Acute cholecystitis

358

An attack of acute cholecystitis begins with progressive right upper quadrant or epigastic pain that lasts for how long?

more than 6 hours

359

Which cholecystitis has higher incidence of gangrene and perforations

Acalculous

360

What infections may cause acute acalculous cholecystitis

-Salmonella typhi
-Staph

361

Rokitansky-Aschoff sinuses (Outpouchings of the mucosal epithelium through wall)

Chronic Cholecystitis

362

Porcelain gallbladder?

why is this notable

chronic cholecystitis

increased incidence of cancer

363

gallbladder has a massively thickened wall and is shrunken, nodular . .triggered by rupture of Rokitansky-Aschoff sinuses

Xanthogranulomatous cholecystitis (a type of chronic)

364

an atrophic, chronically obstructed, often dilated gallbladder that may contain only clear secretions

hydrops of the gallbladder (chronic cholecystitis)

365

most common malignancy of the extrahepatic biliary tract

Carcinoma of the gallbladder

366

Areas with higher risk for carcinoma of the gallbladder

In the US areas with large numbers of Native American or Hispanic populations such as the southwest

367

Gender for Gallbladder cancer

at least twice as common in women than men

368

5 year survivial for gallbladder cancer

less than 10%

369

What is the most important risk factor for gallbladder cancer (besides gender and ethnicity)?

gallstones

370

common thread that ties gallstones or chronic infections together with gallbladder cancer

chronic inflammation

371

overexpression of ERBB2 (Her-2/neu)

Gallbladder cancer

372

mutations of chromatin remodeling genes such as PBRM1 and MLL3

Gallbladder cancer

373

2 patterns of growth for carcinomas of the gallbladder?

which more common

-infiltrating
-exophytic

Infiltrating more common

374

Most carcinomas of the gallbladder are what

adenocarcinomas

375

What is the only effective treatment of gallbladder cancer

surgical resection, often including adjacent liver

376

Murphy's sign

cholecystitis

377

Most common congenital anomaly of the pancreas

Pancreas divisum

378

Failure of fusion of the fetal duct systems of the dorsal and ventral pancreatic primordia

Pancreas divisum

379

What is the result of pancreas divisum

bulk of the pancreas drains into the duodenum through the small-caliber minor papilla instead of the duct of Wirsung through pailla of Vater

380

This congenital anomaly is a band-like ring of normal pancreatic tissue that completely encircles the second portion of the duodenum . . . can produce obstruction

Annular Pancreas

381

Favored sites for extopia of the pancreas

-stomach and duodenum
-followed by jejunum, Meckel diverticula, and Ileum

382

What may ectopic pancreas cause

may cause pain from localized inflammation or rarely incite mucosal bleeding

383

gene for pancreatic agenesis

PDX1

384

Cullen's and Grey Turner's signs

Acute Pancreatitis

385

Both acute and chronic pancreatitis are initiated by what

injuries that lead to autodigestion of the pancreas by its own enzymes

386

Acute pancreatitis: reversible or not

reversible

387

What 2 things account for 80% of cases of acute pancreatitis in Western countries

-Biliary tract disease
-alcoholism
-gallstones also

388

Gender and age predominance of acute pancreatitis based on etiology

-Alcoholism: Males 6:1 and younger
-Gallstones: Females 3:1 and older

389

3 major initiating events that cause activation of pancreatic enzymes in sporadic forms of acute pancreatitis

-Pancreatic duct obsruction
-Primary acinar cell injury
-Defective intracellular transport of proenzymes within acinar cells

390

3 genes implicated in hereditary pancreatitis

-CFTR
-PRRS1
-SPINK1

391

Alcohol increases contraction of what leading to pancreatitis

sphincter of Oddi . .the muscle at the Papilla of Vater

392

recurrent attack of severe acute pancreatitis often beginning in childhood and ultimately leading to chronic pancreatitis

Hereditary pancreatitis

393

The shared feature of most forms of hereditary pancreatitis

a defect that increases or sustains the activity of Trypsin

394

Which gene associated with hereditary pancreatitis is Loss of function and autosomal recessive

SPINK1

395

Hereditary pancreatitis risk for pancreatic cancer

40% lifetime risk

396

Fat necrosis in pancreatitis is due to what

activity of lipase

397

Pancreatic substance that is red-black with interspersed foci of yellow-white chalky fat necrosis

Acute necrotized pancreatitis

398

cardinal manifestation of acute pancreatitis

abdominal pain

399

referred pain for acute pancreatitis

upper back and LEFT shoulder

400

elevated levels of what support at diagnosis of acute pancreatitis

amylase and lipase

401

time frame for elevated serum amylase in acute pancreatitis?

lipase?

first 24 hours

72-96 hours

402

What is the key to managing acute pancreatitis

"resting" the pancreas by total restriction of oral intake and by supportive therapy

403

What may be seen with acute pancreatitis

-Glycosuria in 10%
-Hypocalcemia

404

5% of patients with severe acute pancreatitis may die withing the first week of illness due to what?

-acute respiratory distress syndrome
-acute renal failure

405

possible sequalae of acute pancreatitis

-sterile pancreatic abscess
-pancreatic psuedocyst

406

is Chronic pancreatitis reversible?

NO

407

prolonged inflammation of pancreas associated with destruction of exocrine parenchyma, fibrosis, and in late stages, destruction of endocrine parenchyma

chronic pancreatitis

408

age and gender most common for chronic pancreatitis

middle age males

409

most common cause of chronic pancreatitis

by far long term alcohol abuse

410

What cytokines tend to predominate in chronic pancreatitis?

These induce activation and proliferation of what?

fibrogenic factors like TGF-b and PDGR

periacinar myofibroblasts resulting in deposition of collagen and fibrosis

411

Pathogenically distinct form of chronic pancreatitis that is associated with presence of IgG4-secreting plasma cells

Autoimmune pancreatitis

412

Autoimmune pancreatitis may mimic what?

how do you differentiate?

pancreatic carcinoma

responds to steroid therapy

413

Dropout of pancreatic acinar cells

chronic pancreatitis

414

visualization of calcifications within the pancreas by CT and Ultrasound

chronic pancreatitis

415

long term outlook for chronic pancreatitis

poor

416

What are the things that lead to significant morbidity and contribute to mortality in chronic pancreatitis

-Pancreatic exocrine insufficiency
-chronic malabsorption
-DM

417

localized collections of necrotic and hemorrhagic material that are rich in pancreatic enzymes and lack an epithelial lining

Psuedocyst

418

When do psuedocysts usually arise?

following a bout of acute pancreatitis, particularly one superimposed on chronic alcoholic pancreatitis

can also arise from trauma

419

Where may a psuedocyste be located

-may be within the pancreas
-more commonly in lesser omental sac or in retroperitoneum b/t stomach and transverse colon
-or between liver and stomach

420

invasive pancreatic cancers are believed to arise from what?

well-defined noninvasive precursor lesion in small ducts referred to as pancreatic intraepithelial neoplasia (PanIN)

421

epithelial cells in PanIN show what

dramatic telomere shortening

422

most frquently altered ONCOGENE in pancreatic cancer?

Most common Tumor suppressor gene?

Tumor suppressor gene most specific to pancreatic cancer?

KRAS

CDKN2A -->p16/INK4a

SMAD4

423

age and ethnicity for pancreatic cancer

-older adults . . 60-80
-Black>whites
-Ashkenazi jews slightly more common

424

strongest environmental influence for pancreatic cancer?

other risk factors

smoking

-diets rich in fats
-chronic pancreatitis
-DM

425

Germline mutations in CDKN2A are associated with pancreatic cancer and are almost always observed in individuals from families with increased incidence of what?

Melanoma

426

Most pancreatic cancers arise where

head

427

Inherited diseases that predispose to pancreatic cancer

-Peutz-Jeghers
-HNPCC

428

Pancreatic carcinomas that remain silent for a long time and may be quite large and most are widely disseminated by the time they are discovered?

Why?

body and tail

don't impinge on biliary tract

429

characteristic microscopic feature of pancreatic cancer

intense desmoplastic reaction with dense stromal fibrosis

-also has perineural invasion

430

what is usually first symptom of pancreatic cancer

pain . . . by the time they present, usually beyond cure

431

Migratory thrombophlebitis and Trousseau's sign

pancreatic cancer

432

serum levels that are often elevated in pancreatic cancer

-carcinoembyonic antigen - CEA
-CA19-9