Path slide set 4 Flashcards
1
Q
accumulation of fat
A
steatosis
2
Q
accumulation of bilirubin
A
cholestasis
3
Q
when injury is not reversible, hepatocytes die principally by what 2 mechanisms
A
- apoptosis
- necrosis
4
Q
This form of hepatocyte injury is the predominate mod of death in ischemic/hypoxic injury and a significant response to oxidative stress
A
necrosis
5
Q
councilman bodies
A
apoptotic hepatocytes
6
Q
apoptotic hepatocytes in acute and chronic hepatitis
A
acidophil bodies due to deeply eosinophilic staining characteristics
7
Q
severe, zonal loss of hepatocytes
A
confuent necrosis from widespread parenchymal loss
8
Q
Regeneration of lost hepatocytes occurs primarily by what?
A
mitotic replication of hepatocytes adjacent to those that have died
9
Q
in the most severe forms of acute liver failure, there is activation of the primary intrahepatic stem cell niche, called what
A
canal of Hering
10
Q
principal cell type involved in scar deposition in liver
A
hepatic stellate cell
11
Q
a hepatic stellate cell does what in quiescent form
A
lipid (vitamin A) storing cell
12
Q
in several forms of acute and chronic injury, the stellate cell can become activated and are converted into what?
A
highly fibrogenic myofibroblasts
13
Q
Proliferation of hepatic stellate cells and activation into myofibroblasts is initiated by increase expression of what
A
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
Q
myofibroblast contraction is stimulated by what
A
endothelin-1 (ET-1)
15
Q
If injury persists, where does scar deposition often begin?
What diseases is this important
A
space of Disse
alcoholic and NAFLD
16
Q
if chronic injury ceases, what can break down the scar, potentially reversing the formation
A
metalloproteinases
17
Q
Adaptive immunitey plays a big role in what
A
viral hepatitis
18
Q
Antigen specific and CD8+ cells are involved in what
A
eradication of hepatitis B and C
19
Q
What percent of hepatic functional capacity must be lost before failure
A
80 to 90
20
Q
definition of Acute liver failure
A
-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
Q
another term for acute liver failure
A
fulminant liver failure
22
Q
What causes acute liver failure
A
massive hepatic necrosis
-most often by drugs or toxins
23
Q
What accounts for almost 50% of acute liver failure in US
A
Acetaminophen
24
Q
what predominantly causes acute liver failure in Asia
A
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
