Chapter 18 - Liver And Bile Ducts Flashcards
1
Q
What lab tests show hepatocyte integrity?
A
Serum aspartate aminotransferase (AST)
Serume alanine aminotransferase (ALT)
2
Q
What tests show biliary excretory function?
A
Total, Direct (conjugated), serum bilirubin
Serum alkaline phosphatase
Serum GGT
3
Q
What tests show hepatocyte synthetic function
A
Serum albumin
Prothrombin Time (PT)
Serum ammonia
4
Q
What are the reversible degenerative changes of hepatocytes?
A
Fat accumulation (steatosis) and bilirubin buildup (cholestasis)
5
Q
When hepatocyte injury is not reversible how do they die?
A
Necrosis: predominant mode in ischemic-hypoxic injury and oxidative stress
Apoptosis: acute and chronic hepatitis, shrinkage, pyknosis, karyorrhexis, acidophil bodies
6
Q
Explain the process of hepatocyte regeneration
A
Primarily occurs by proliferation of hepatocytes adjacent to those that have died
Stem cell replenishment is usually NOT a significant part of parenchymal repair
Hepatocytes are stem-cell like
7
Q
What hepatic cell once activated, is primarily responsible for liver scar deposition?
A
Stellate cells
Lipid (vit A) storing cell when quiescent
Activated: TNF, Kupffer cells, toxins etc -> highly fibrogenic and contractile myofibroblasts
8
Q
If chronic injury leading to scar formation is interrupted (like clearance of hepatitis virus infection, or cessation of alcohol use), then what can lead to scar formation being reversed?
A
Stellate cell activation cease
Fibrosis fragmented by Metalloproteinases produced by hepatocytes
9
Q
When does liver failure occur?
A
When greater than 80-90% of hepatic function is lost
10
Q
What cytokine is fibrogenesis driven by?
A
TGF-B released by Kupffer cells and lymphocytes
11
Q
What cytokine drives Proliferation of stellate cells: Contraction of activated stellate cells: Chemotaxis of activated stellate cells: Fibrogenesis:
A
Proliferation of stellate cells: PDGF, TNF
Contraction of activated stellate cells: ET-1
Chemotaxis of activated stellate cells: MCP-1, PDGF
Fibrogenesis: TGF-B
12
Q
What is acute liver failure defined as?
A
Liver illness associated with encephalopathy and coagulopathy within 6 months of initial diagnosis
Fulminant hepatic failure: encephalopathy develops w/i 2 weeks of jaundice onset
13
Q
What is most acute liver failure caused by?
A
Massive hepatic necrosis attributable to
US: acetaminophen overdose
Asia: Hep B and E, A
14
Q
What is the clinical course of acute liver failure
A
Nausea, vomiting, jaundice
Progressing to encephalopathy and coagulopathy (inadequate hepatic synt of coagulopathy factors)
Liver initially swells d/t edema and inflammation
Liver transaminases elevated - hepatocyte destruction
Liver dramatically shrinks - transaminases decline
Portal HTN
15
Q
What is hepatic encephalopathy
A
Life-threatening disorder of CNS and neuromuscular transmission
Excess ammonia in the blood impairs neuronal fxn and brain edema -> confusion, coma, limb rigidity, hyperrefelxia, asterisks
16
Q
What are the MC causes of chronic liver failure worldwide?
A
Alcohol abuse, viral hepatitis, NASH, hemochromatosis
17
Q
Morphological characteristics of cirrhosis
A
No central vein
Bridging fibrosis
Parenchymal nodules - hepatocyte regeneration encircled by fibrosis
Dense mononuclear infiltrate
Increase portal chronic inflammation gives interface hepatitis appearance
18
Q
Clinical features of Chronic liver failure/Cirrhosis
A
Clinically silent until far advanced in 40% of pts
Anorexia, WL, weakness, and debilitation
Hyperestrogenemia -> palmar erythema in men, spider angiomata, hypogonadism, gynecomastia
Portal HTN + Sx of acute failure
19
Q
Cirrhosis death can be due to what?
A
Progressive liver failure with encephalopaty and coagulopathy
Complications of portal HTN - variceal bleeding
Bacterial infections duet o gut mucosal damage and Kupffer cell dysfunction
HCC
20
Q
What does Portal HTN result from?
A
Combination of increased flow into portal circulation and/or increased resistance to portal blood flow
Prehepatic: thrombosis, portal vein narrowing, massive spenomegaly with increased splenic vein blood flow
Intrahepatic: fibrous tissue (cirrhosis) MC, schistosomiasis, massive fatty change
Posthepatic: RSHF, hepatic vein obstruction
21
Q
What are the major clinical consequences of portal HTN?
A
Ascites
Splenomegaly - caused by long-standing congestion and can cause thrombocytopenia and pancytopenia due to hypersplenism
Esophageal varices
Hepatic encephalopathy
22
Q
Describe ascites
A
Collection of excess serous transudate in the peritoneal cavity
Most often a consequence of cirrhosis
500 ml or more to detect - trunkal obesity
23
Q
Hep A virus
A
ssRNA Causes benign, self limited disease; fulminant HAV is rare Damage d/t CD8 T cells Fecal-oral route Anti-HAV IgM - acute infection IgG - long-term immunity
24
Q
Hep B virus
A
dsRNA, Parenteral, PAS-D stain risk of hepatocellular carcinoma CD8 T cells damage Ground glass hepatocytes**** Acute, self-limited hepatitis - MC Fulminant hepatitis with massive liver necrosis - rare Nonprogressive chronic hepatitis Progressive chronic disease culminating in cirrhosis and increased risk of HCC Asymptomatic carrier
25
Best predictor of chronicity in HBV hepatitis
| Geographic distribution and mode of transmission
Age at time of infection
Younger age at infection has higher probability of chronicity
Africa, Asia: high-prevalence area, transmission during childbirth MC
Europe: intermediate prevalence, horizontal transmission in childhood by minor cuts or breaks MC
US, Western Europe: low-prevalence, IV drug abuse and unprotected intercourse
> 90% HBV infections acquired early in life in endemic areas result in healthy carrier states
26
Antigens and Abs in HBV infection
HBeAG persistence = progression of chronic disease
HBsAG for 6 months = chronic carrier
IgM anti-HBcAg usually first antibody to appear
Anti-HBsAg signifies end of acute disease and persists for years
27
Hep C virus
Ss RNA, parenteral
HCV RNA polymerase low fidelity -> genomic variability
High titers against HCV does not confer effective immunity
Progresssion to chronic disease occurs in most (80-90%) and cirrhosis in 20%
Morph: lymphoid follicle**
28
What are the primary risk groups of HCV infection and how is the infection discovered?
IV drug abusers and multiple sex partners
| Coincidental blood screen detecting elevations of ALT/AST (transaminases)
29
What Hepatitis virus has a high rate of fatal fulminant hepatitis in pregnant women? Where is it prevalent and what is the clinical course in a non pregnant pts?
HEV
HEV epidemics in Asia, Mexico, Africa,
Endemic: India
Usually self limited
30
What are the key features of autoimmune hepatitis (AIH)
Chronic, progressive hepatitis with strong genetic predisposition
Caucasian - DRB1 allele
Female predom
Triggered by viral infections or drugs or component of other autoimmune disorders (RA, Sjogren, UC)
Clusters of periportal plasma cells****
Rosettes
Type I: MC in US; ANA, ASMA; middle aged women; HLA-DR3
Type II: LKM-1, ACL-1; Kids-teens
31
What are the clinical features of autoimmune hepatitis ? Treatment?
```
Acute or indolent paths
Acute fulminant onset of Sx of liver failure in 40% of pts
Early severe fibrosis/scarring
untreated: 6 month mortality in 40%
Survivors: cirrhosis in 40%
Immunosuppression therapy
```
32
What is the leading cause of liver pathology in most Western countries?
Alcoholic liver disease
33
What are the three (overlapping) forms of ALD?
Hepatic steatosis (fatty liver)
Alcoholic (steato-) hepatitis
Alcoholic steatofibrosis
34
Key features of hepatic steatosis
```
Fatty liver
Microvesicular lipid droplets w/i hepatocytes
Can occur with moderate alcohol intake
Enlarged, soft, greasy, yellow
Little-no fibrosis
Reversible
```
35
Key features of alcoholic (steato) hepatitis
Ballooning degeneration and hepatocyte necrosis
Mallory-Denk body (intracellular eosinophilic aggravates of intermediate filaments)
Neutrophilic rxn
Portal and periportal mononuclear inflammation
Fibrosis
36
Key features of alcoholic steatofibrosis
Stellate cell activation
Hepatic dysfunction
Hypoproteinemia
Coagulation abnormalities
37
Pathogenesis of ALD
Quantity and time
15% of alcoholics develop cirrhosis
Gender: women (pharmacokinetics and metabolism, estrogen increases permeability to endotoxins)
Ethnic: AA
Genetic: polymorphism in aldehyde dehydrogenase (metabolizing enzymes) or cytokine promoters
Comorbid conditions: iron overload, viral hepatitis increase severity
38
What are the clinical features of ALD ? What are the causes of death?
Elevation of AST:ALT 2:1 - unique
Hepatic steatosis: hepatomegaly, elevation of serum bilirubin and alk phos, minimal Sx
Alcoholic hepatitis: after heavy drinking acutely, tender hepatomegaly, bilirubin and alk phos elevated ---> cirrhosis in 1/3 pts; slow resolution
Alcoholic cirrhosis: irreversible
Abstained: survival good
Death: hepatic coma, Gi hemorrhage, intercurrent infection, hepatorenal syndrome, and HCC
39
What is the most acquired metabolic disorder of the liver?
NAFLD
40
What is NAFLD and NASH? What is it d/t?
Group of conditions (metabolic syndrome - dyslipidemia, hyeprinsulinemia, insulin resistance) characterized by hepatic steatosis in absence of heavy alcohol consumption
NASH = NAFLD + hepatocyte damage and inflammation
Increasing prevalence of obesity
41
Pathogenesis of NAFLD?
| Morphology?
Probably a consequence of hepatocyte fat accumulation and increased hepatic oxidative stress
2 hit Hypothesis: Hit 1 - insulin resistance -> hepatic steatosis-> NAFLD; Hit 2 - hepatocellular oxidative injury -> necrosis and 2* inflammation -> NASH
Morph: hepatocytes filled with fat vacuoles w or w/o inflammatory infiltrates; microvascular steatosis
42
Clinical features of NAFLD and NASH
| Treatment?
Hispanics>AA>whites
NAFLD only: asymptomatic w little risk of cirrhosis
+ NASH: symptom free or fatique, malaise, RUQ discomfort; serum transaminases levels elevated in 90%
NASH -> possible HCC or cirrhosis
Cardiovascular disease is frequent cause of morbidity and mortality
RX: targeted at obesity, hyperlipidemia, and insulin resistance
43
What is hemochromatosis ?
Multi-organ disease
Excessive iron accumulation in parenchymal cells of liver and pancreas mainly
Hereditary (primary) type: homozygous recessive, excessive iron absorption bc regulation abnormal
Hemosiderosis (secondary) type: parental iron admin (transfusions, ineffective erythropoietin, increase iron intake, chronic liver disease)
44
How is Hemochromatosis screened for? What is the treatment?
Increase serum iron and ferritin
Liver biopsy
Genetic testing
Prussian blue stain
Rx: regular phlebotomy
45
What is the pathogenesis of hemochromatosis ?
Hepcidin (HAMP) mutation (normally lowers plasma iron)
| Adult form: almost always caused by HFE gene mutation (cys-tyr, C282Y); causes reduction in Hepcidin expression
46
Morphology of hemochromatosis
Iron accumulates as hemosiderin in liver, pancreas, myocardium, endocrine glands, joints, and skin
Cirrhosis and pancreatic fibrosis are the chief additional morphological changes
47
What are the clinical features of hemochromatosis ? Death can result from what?
Classic triad; micronodular cirrhosis, DM, and skin pigmentation in sun-exposed areas
Iron->pancreas->DM
Sx appear after age 40 (amenorrhea, m: impotence and loss of libido)
Males predom (women lose iron w menstruation, and pregnancy)
Hepatomegaly
Death: cirrhosis and HCC and cardiac involvement
48
What is Wilson disease
Multi-organ disease (liver, brain, eye)
Autosomal recessive
ATP7B gene mutations (copper transporting ATPase)
Copper excretion into bile reduced
Copper not incorporated into cerulopasmin
Ceruloplasmin secretion into blood inhibited
= copper accumulation in liver ->ROS generation
49
Morphology of wilson disease
```
Liver damage: minor-severe
Fatty change, acute and chronic hepatitis with Mallory-Denk bodies, cirrhosis, rarely massive necrosis
CNS toxicity of basal ganglia
Kayser-Fleischer rings***
Copper toxic to RBC-> hemolytic anemia
```
50
What are the clinical features of Wilson Disease? How is it Dx?
Age of onset and clinical presentation: variable (6-40 YOA; avg 11.4)
MC: acute or chronic liver disease b4 age 40
Mild behavioral changes, psychosis, Parkinson-like symptoms
Dx: decreased serum ceruloplasm, increased hepatic copper content, increased urinary copper excretion
Serum copper lvls are no NO diagnostic value
51
What is the treatment for Wilson disease?
Copper chelation
| Liver transplantation may be necessary
52
Main mutation in Wilson disease
ATP7B
| Majority have compound heterozygotes of different mutations on each ATP7B allele
53
What is A1-Antitrypsin deficiency
MC diagnosed inherited hepatic disorder in infant and child
Autosomal recessive
2 organ disease: liver and lung
Very low serum lvls of this protein that normally inhibits neutrophil protease
-> emphysema bc of destructive proteases and hepatic disease by hepatocellular accumulation of misfolded protein
54
What is the pathogenesis of A1-AT deficiency?
```
Most mutations (PiMM) result in no or only moderate reductions in lvls and have no clinical manifestations
PiZZ homozygotes (Glu->Lys): protein misfolding, ER stress response (UPR) -> autophagy, mitochondrial dysfunction and NF-kB = hepatocyte damage
```
Additional genetic or environmental factors: only 10% PiZZ homozygotes develop overt liver disease
55
Morphology of a1-AT deficiency
PAS positive cytoplasmic globules in periportal hepatocytes
56
Clinical features of a1-AT deficiency
| Treatment
Neonatal hepatitis with cholestatic jaundice in 10-20% newborns
Adolescence: Acute hepatitis, cirrhosis, lung dz
Adults: HCC in 2-3% of homozygous adults, cirrhosis
Smoking accentuates lung emphysematous damage
Rx: liver transplantation
57
What is neonatal jaundice?
Physiologic jaundice
Hepatic metabolic machinery does not mature until 2 weeks of age
Newborn develops transient, mild unconjugated hyperbilirubinemia
Exacerbated by breast-feeding due to bilirubin-deconjugating enzymes in breast milk
Use blue light machine
58
What are the hereditary hyperbilirubinemias unconjugated forms?
Crigler-Najjar syndrome type I: Fatal, autosomal recessive, kernicterus, liver transplant, no UGT1A1
Critter-Najjar syndrome type II: autosomal dominant, UGT1A1 deficiency, not usually lethal
Gilbert syndrome: AR, not symptomatic, hyperbilirubemia exacerbated by infection, exercise, or fasting
59
What are the hereditary hyperbilirubinemias conjugated forms?
Dubin-Johnson syndrome: AR, Black liver - pigment granules, usually not symptomatic, no bilirubin glucuronide transport protein, jaundice
Rotor syndrome: AR, jaundice, not symptomatic, defective uptake or excretion
60
What are the consequences of cholestasis
Intrahepatic: hepatocellular dysfunction or canalicular obstruction
Extrahepatic: d/t duct obstruction
Jaundice, pruritus, xanthomas, intestinal malabsorption with nutritional deficiencies d/t port uptake of A,D,K vitamin
Serum alk phos and gamma-glutamyl transpeptidase (GGT) elevated
61
What is the MC cause of bile duct obstruction in adults?
Extrahepatic choleslithiasis (gallstones)
62
Clinical features of Large bile duct obstruction
Obstruction may promote ascending cholangitis with 2* bacterial infection of biliary tree: fever, chills, abdominal pain, jaundice
Charcot triad: fever, RUQ pain, jaundice
63
MC cause of bile duct obstruction in neonates ?
Biliary atresia: extrahepatic biliary tree obstruction w/i first 3 months of life
64
What is the single most frequent cause of death from liver disease in early childhood and accounts for the majority of children referred for liver transplantation?
Biliary atresia
65
Pathogenesis of biliary atresia
Extrahepatic ducttst
Severe early fetal form (20%): aberrant intrauterine development of the biliary tree and commonly associated with other anomalies
Perinatal form (80%): secondary to viral infections and/ or autoimmunity; results from postnatal destruction of normal biliary tree
66
Morphology and clinical features of Biliary atresia
Inflammation and fibrosing stricture of extrahepatic biliary tree
Fibrosis progressing to cirrhosis in 6 months
Seen in infant of normal birth weight and postnatal weight gain
If left untreated (liver transplantation), death occurs w/i 2 years of birth
67
What is autoimmune cholangiopathy ?
Autoimmune disorder of intrahepatic bile ducts
| PBC and PSC
68
Key features of Primary Biliary Cirrhosis
Age: 50
Gender: F
Clinical course: progressive, insidious, pruritis, hepatomegaly, jaundice, xanthomas -> cirrhosis , variceal bleeding, encephalopaty
Associated conditions: Sjogren
Serology: 95% AMA + for PDC-E2 and 50% ANA +
Florid duct lesions and loss of small ducts only
Alk phos, GGT, cholesterol lvls elevated
Nonsuppurative inflammatory destruction of small bile ducts
69
Treatment of primary biliary cirrhosis
Early-stage disease: oral urosodexycholic acid, slows progression
70
Key features of Primary Sclerosing cholangitis
Age: 30
Gender: Male
Clinical course: unpredictable but progressive, severe - WL, ascites, variceal bleeding, encephalopathy, chronic pancreatitis and HCC
Ass conditions: IBD (UC)
Serology: P-ANCA
Radiology: strictures and beading of large bile ducts; pruning of smaller ducts
Duct lesion: inflammatory destruction of extrahepatic and large intrahepatic ducts; fibrotic obliteration of medium and small intrahepatic ducts
71
what are nodular hyperplasias?
Solitary or multiple benign hepatocellular nodules in the absence of cirrhosis
Focal nodular hyperplasia: young adults, liver normal, single well demarcated mass containing central stellate fibrous scar
Nodular regenerative hyperplasia: diffuse (multiple) nodules without fibrosis, d/t intrahepatic blood flow; can develop portal HTN, ass: HIV, rheumatologic dz and SLE
72
What is the most common benign liver tumor?
Cavernous hemangioma
73
What are cavernous hemangiomas?
Benign neoplasm
Unencapsulated lesions usually 1-2 cm in diameter
Large, thin-walled vascular spaces
Can be locally destructive and generally DO NOT REGRESS
Female predom
Incidental discovery or cause of hemorrhage
74
What are hepatocellular adenomas?
```
Benign neoplasm
30 cm in diameter
Young females
Associated with OC use and anabolic steroids
Incidentally discovered
```
75
What are the three subtypes of hepatocellular adenoma?
HFN1-alpha -inactivated hepatocellular adenoma: mutations responsible for AD maturity-onset of diabetes in young, women, no risk of malignancy
B-catenin-activated: very high risk for malignant transformation, respected when found, OC and anabolic steroid use (women, men)
Inflammatory: men and women, NAFLD associated, small risk of malignant transformation, gp130 mutation (IL-6, jakstat)
76
In the US, the vast majority of tumors involving the liver are benign or metastatic?
Metastatic
77
What is the most common primary liver cancer?
HCC
78
What is the most common liver tumor of early childhood? Key features?
Hepatoblastoma
Rare after age 3
Wnt-B-catenin pathway
Ass.: FAP and Beckwith-Wiedemann syndrome
Epithelial type and mixed epithelial and mesenchymal type
fatal if untreated, good prog if resected
79
HCC predominately found in what people and geography?
Male predom
Developing countries with high rates of HBV
Exposure to aflatoxin (aspergillosis toxin)
Western pop: Increase HCV infection increasing HCC incidence
Chronic alcoholism, NASH, Hemochromatosis, a1-AT def
Background of chronic liver disease
80
Morphology of HCC
Solitary mass, multifocal nodules or diffuse infiltrative cancer with massive liver enlargement in the background of cirrhosis often
Intrahepatic and vascular invasion common
Metastases more likely after 3 cm
Satellite tumor nodules
81
What is a distinctive variant of HCC? Key features?
```
Fibrolamellar carcinoma
5% of HCC
Single scirrhous, hard tumor
20-40 yo (85% under age 35)
ABSENCE of chronic liver disease
Cells in cords or ness separated by dense lamellar collagen bundles
Rich in mitochondria - oncocytes
```
82
Clinical features of HCC and prognosis
Hepatomegaly
RUQ pain
WL
Elevated serum AFP (alpha-fetoprotein) **
Prognosis depends on respectability of tumor
Mortality 2* to cachexia, GI or esophageal variceal bleeding, liver failure with hepatic coma or tumor rupture and fatal hemorrhage
83
What is a cholangiocarcinoma ? Associations?
2nd MC 1* malignant tumor of liver
Chronic inflammation and cholestasis increasse risk
Arise from intrahepatic and extrahepatic biliary tree
Most perihilar (Klatskin tumors)
Can be associated w PSC, stones, NAFLD, HBV, and HCV
84
What is a major risk in Southeast asia for cholangiocarcinoma?
Parasitic infection by Op=isthorchis sinensis
85
Morphology of CCA
Single large mass, multifocal nodules or diffusely infiltrative
Contrast to HCC: typically pale, bc no bilirubin pigment
Desmoplastic w dense collagenous stroma
86
Describe metastasis to the liver
Typically multiple implants are present with massive hepatic enlargement
Large implants tend to have defective vascular supplies and become centrally necrotic
87
What are the congenital anomalies of the gallbladder? What is most common?
Absent
Aberrant location (embedded in hepatic substance)
Folded fundus (phrygian cap) MC***
Duplicated, bilobed
88
More than 95% of biliary tract disease is attributable to what?
Cholelithiasis
89
Majority of calculus are what kind of stones?
Cholesterol (90%)
90
What are the main risk factors for cholesterol gallstones ?
Native americans: 75% of Hopi, Navajo, Pima groups
| Fair, Fat, Female, Fertile, Family History
91
What are the most common gallstones in US and Western Europe?
Cholesterol stones: supersaturation; hard, pale yellow
92
What are the most common stones found in African americans?
Pigment stones, setting of unconjugated bilirubin due to chronic hemolytic conditions
I.e sickle cell disease
Black if sterile or brown with infection, soft
93
What are the clinical features of cholelithiasis?
Majority asymptomatic
Pain = biliary colic (RUQ or right shoulder pain)
Sx: spasmodic, colicky pain d/t passing stones in bile ducts; inflammation causes RUQ pain
More severe complications: emphysema, perforation, fistula, cholangitiss, obstructive cholestasis or pancreatitis
Increased risk for gallbladder carcinoma
94
What is acute cholecystitis and the MC cause?
Acute inflammation of gallbladder mostly d/t gallstone obstruction
95
What is the pathogenesis of acute cholecystitis ?
Acute calculous cholecystitis: gallstones causing irritation -> inflammatory mediators--> gallbladder dysmoltility
Acute Acalculous cholecystitis: d/t ischemia, decrease flow in end-arterial cystic arter circulation; setting of sepsis w hypotension and multiorgan failure, immunosuppression, major trauma or burns, DM or infections
96
What is the morphology of acute cholecystitis?
Enlarged, tense, bright red - blotchy green/black gallbladder with serosal fibrinous exudate
--> gangrenous cholecystitis in severe cases
97
What are the clinical features of acute cholecystitis ?
Mild or surgical emergency
| Sx: RUQ or epigastric pain in 6 hrs, pain, fever, anorexia, tachycardia, diaphoresis, and N/V
98
What is chronic cholecystitis d/t?
Repeated bouts of acute cholecystitis
Often develops w/o antecedent attacks
90% gallstones but do not play a direct role in initiating inflammation
Chronic bile supersaturation with cholesterol-> inflammation
99
What is the morphology of chronic cholecystitis
Contracted (fibrosis)
Normal in size or enlarged (from obstruction)
Gray-white wall -
Cholesterol-laden Mo in lamina propria (Cholesterolosis) and gallstones freq
Rokitansky-Aschoof sinuses
porcelain gallbladder (mural dystrophic calcification - rare) -> risk of cancer
100
What are the complications of acute and chronic cholecystitis?
Bacterial superinfection, gallbladder perforation and abscess formation or peritonitis
Formation of biliary-enteric fistula
101
What is the MC malignancy of extrahepatic biliary tract?
Adenocarcinoma
102
Key feature of carcinoma of the gallbladder
Women predom
Age 70
Gallstones (95%)
Chronic gallbladder inflammation with or without stones is a critical risk factor
Asians: parasitic disease dominate vs stones
Infiltrating (diffuse thickening) or exophytic (cauliflower)
Local invasion of liver, extension to cystic duct and portohepatic LN
Metastatic seeding in peritoneum, viscera and lungs
Sx: insidious and indistinguishable from cholelithiasis - unresectable when discovered = poor prognosis
