HPB Patho Flashcards
1
Q
What is cholestasis?
A
Systemic retention of bilirubin and other solutes eliminated in bile, caused by impaired bile formation and flow
2
Q
What is bile?
A
bilirubin and other non-water soluble waste products + bile salts
3
Q
What is the term for yellow discoloration of the sclera?
A
Icterus
4
Q
What are 5 symptoms of cholestasis?
A
1) Jaundice
2) Icterus
3) Pruritis (itch)
4) Skin xanthomas (Fat bumps)
5) Intestinal malabsorption (fat-soluble vit ADEK deficiencies)
5
Q
What are 5 causes of jaundice?
A
Pre-hepatic
1) excess bilirubin prod. (eg. haemolysis, ineffective erythropoeisis)
Hepatic
2) ↓ hepatic uptake (eg. drugs)
3) impaired conjugation (eg. neonatal, genetic, diffuse hepatocellular change)
4) Impaired bile flow (eg. autoimmune cholangiopathies)
Post-hepatic
5) Impaired bile flow (eg. cholelithiasis, cancer)
6
Q
What is the difference between unconjugated and conjugated bilirubin?
A
Unconjugated:
- ↑ in prehepatic jaundice
- water-insoluble, bound to albumin in circulation
- diffuse into tissues (eg. kernicterus)
Conjugated:
- ↑ in hepatic/post-hepatic jaundice
- water-soluble, non-toxic
- excess excreted in urine (“tea-coloured urine”)
7
Q
What are the features of obstructive patterned jaundice?
A
1) ↑ conjugated bilirubin
2) tea-coloured urine
3) Pale stools
(Likely post-hepatic)
8
Q
What are the features of hepatitic patterned jaundice?
A
1) ↑ conjugated bilirubin
2) ↑ unconjugated bilirubin
3) ↑ AST/ALT
4) ±tea coloured urine
5) Normal stools
(likely hepatic)
9
Q
What is the clinical importance of localising the problem precipitating jaundice?
A
Extrahepatic biliary obstruction: surgical alleviation
Intrahepatic cholestasis: does not benefit from surgery/can be worsened
10
Q
What are 3 examples of cholestatic diseases?`
A
1) Large bile duct obstruction
2) Primary hepatolithiasis
3) Neonatal cholestasis & biliary atresia
11
Q
What are 5 common associations of large bile duct obstruction?
A
1) Gallstones (extrahepatic)
2) Malignancies (of biliary tree/pancreas head)
3) Inflammatory bile duct strictures
4) Porta hepatis lymphadenopathy
5) Children: Bile duct malformations/loss
12
Q
What are the categories for large bile duct obstruction etiologies?
A
1) Intraluminal (eg. stones, parasites)
2) Mural (eg. strictures, malignancies)
3) Extramural (eg. HOP cancers, Portal LNs)
13
Q
What are 3 sequelae of large bile duct obstruction?
A
1) Acute: reversible with obstruction removal
2) Subtotal/intermittent obstruction:
- ↑ ascending cholangitis risk → intrahepatic cholangitic abscesses/sepsis
3) Chronic: Biliary cirrhosis
4) Acute on Chronic Liver Failure (by superimposed ascending cholangitis)
14
Q
When is feathery degeneration seen?
A
Hepatocyte damage secondary to cholestasis
15
Q
When are dilated bile ducts seen?
A
Cholestasis
16
Q
What is primary hepatolithiasis?
A
Intrahepatic biliary stone formation
17
Q
What are 3 sequelae of primary hepatolithiasis?
A
Repeated bouts of:
1) Ascending cholangitis
2) Progressive inflammatory destruction/collapse
3) Scarring of hepatic parenchyma (recurrent pyogenic/oriental cholangitis)
18
Q
Primary hepatolithiasis predisposes a px to ___________________________.
A
1) Biliary Intraepithelial Neoplasia (BilIN)
2) Cholangiocarcinoma
19
Q
What kind of jaundice does neonatal cholestasis cuase?
A
Prolonged conjugated hyperbilirubinaemia in neonates (>14-21days after birth)
20
Q
What are 5 major causes of neonatal cholestasis?
A
1) Cholangiopathies (extrahepatic biliary atresia → surgery)
2) Toxins: drugs, parenteral nutrition
3) Metabolic: Tyrosinaemia
4) Infectious: CMV, sepsis
5) Idiopathic
21
Q
What histological changes are expected in neonatal cholestasis?
A
Multinucleated hepatocyte giant cells
22
Q
What is extrahepatic biliary atresia?
A
Complete/partial obstruction of the extrahepatic biliary tree lumen < 1st 3 mths of life
- cause of neonatal cholestasis
23
Q
True or false: Extrahepatic biliary atresia can extend to involve intrahepatic ducts?
A
True, usually requires transplantation
24
Q
How does extrahepatic biliary atresia present?
A
1) Jaundice (↑conj. bil)
2) Pale stools
3) Tea-coloured urine
(obstructive jaundice)
25
True or false: Extrahepatic biliary atresia is the #3 cause of death from liver disease in early childhood.
False. #1 cause (death <2yrs w/o transplant)
26
What are the 2 forms of extrahepatic biliary atresia patheogenesis?
By presumed timing of obstruction:
1) Fetal form
- aberrant intrauterine development of extrahepatic biliary tree (±other abnormalities eg. situs inversus, CHD)
2) Perinatal form
- normal biliary tree destroyed after birth (eg. viral infection, autoimmune)
27
What are 2 types of autoimmune cholangiopathies?
1) Primary biliary cholangitis
- assoc.: Sjogren's, thyroid disease, 50F
- Histo: Florid duct lesions, loss of small/medium bile ducts
2) Primary sclerosing cholangitis
- assoc.: IBS/D, 30M
- histo: Inflammatory destruction of large ducts, fibrotic obliteration of small/medium ducts
- radio: strictures/beading of large ducts, pruning of small bile ducts
28
What are 2 structural anomalies of biliary tree that can lead to cholestasis?
1) Choledochal cyst
2) Fibropolycystic disease
29
What is a choledochal cyst?
Developmental malformation of biliary tree (usually CBD)
- predispose to stones, stenosis, strictures, pancreatitis, cholangiocarcinoma
30
What is fibropolycystic disease?
Heterogenous group of lesions (primary abnormalities are congenital ductal plate malformations)
eg.
1) Von Meyenburg complex (small bile duct hamartomas)
2) Single/multiple intra/extrahepatic biliary cysts
3) Congenital hepatic fibrosis
4) ±polycystic renal disease
↑ risk of cholangiocarcinoma
31
What is the difference between Caroli disease and Caroli syndrome?
Caroli disease: Biliary cysts 2° to fibropolycystic disease
Caroli syndrome: " w congenital hepatic fibrosis
32
What are 3 types of gallstones?
1) Cholesterol
- supersaturation of cholesterol
- radiolucent
- Fat, Female, Forty, Fertile
2) Pigment
- Unconj. bil + insoluble Ca salts
- radio-opaque
- Black: Chronic Haemolytic Anemia; Brown: Biliary infections
3) Mixed
33
What are the clinical presentations of cholelithiasis?
1) >80% asymptomatic
2) Symptomatic:
- RUQ/epigastic pain
- biliary colic
- worse after fatty meal
34
What are 4 sequelae of cholelithiasis?
1) Acute cholecystitis, empyema (pus), hydrops (fluid distension)
2) CBD obstruction/pancreatitis
3) Perforation, fistulas, gallstone ileus (SI obstruction)
4) ↑gall bladder carcinoma
35
What are the features of acute and chronic cholecystitis?
Chronic:
- often asymptomatic, ± antecedent attacks
Acute:
- Progressive pain (>6hrs) ± mild fever
- LOA
- Tachycardia, sweating, nausea, vomiting
- Hx of RUQ/perigastric/biliary colic
36
What are the 2 types/pathogenesis of acutecholecystitis?
1) Calculous (90%)
- obstruction by stone → irritation and inflammation
2) Acalculous (10%)
- severely ill px (eg. septic shock, trauma, burns, immunosuppressed, DM, infections)
- due to ischaemia (cystic artery is end-artery)
37
What is the pathogenesis of calculous cholecystitis?
Mucosal phospholipase hydrolyse luminal lecithins → toxic lysolecithins
→ disrupt protective glycoprotein mucus layer (exposed to detergent action of bile salts)
→ prostaglandin release
→ mucosal and mural inflammation
→ distension + ↑intramural P
→ ↓blood flow to mucosa
38
What is the pathogenesis of acalculous cholecystitis?
Ischaemia to cystic artery
→ inflammation + oedema of wall
→ ↓blood flow
→ gallbladder stasis, biliary sludge, mucus
→ cystic duct obstruction
39
What are 4 gross features of acute cholescystitis?
1) Enlarged, tense edematous and congested
2) Violaceous/green-black
3) Fibrinous/Fibrinopurulent serosal exudates
4) Ulcerated mucosa
± stones
40
What are 4 complications of acute cholecystitis?
1) Gangrene/empyema (eg. C. diff)
2) Pericholecystic/subdiaphragmatic abscesses
3) Ascending cholangitis/Liver abscess
4) Septicaemia
41
What are 2 gross features of chronic cholecystitis?
1) Contracted, thickened wall
2) Smooth mucosa
± calculi
42
What are 4 histological features of chronic cholecystitis?
1) Chronic inflammatory infiltrates
2) Fibromuscular hypertrophy
3) Rokitansky-Aschoff sinuses
4) Subserosal fibrosis
43
What is a porcelain gallbladder?
Form of chronic cholecystitis
- extensive dystrophic calcification in walls
- ↑risk of cancer
44
What is Xanthogranulomatous cholecystitis?
Form of chronic cholecystitis
- rupture of Rokitansky-Aschoff sinuses → accumulation of foamy macrophages
- massively thickened wall
45
What is a hydrops gallbladder?
Form of chronic cholecystitis
- atrophic
- dilated GB containing only clear secretions
46
What are 2 non-neoplastic liver masses?
1) Focal nodular hyperplasia (FNH)
2) Macro-regenerative nodule
47
What are 3 benign neoplasms of liver masses?
1) Hepatocellular adenoma (HCA)
2) Bile duct hamartoma/adenoma
3) Haemangioma
48
What are 3 malignant neoplasms of liver masses?
1) Hepatocellular carcinoma (90%)
2) Cholangiocarcinoma (10%)
3) Angiosarcoma
49
What is focal nodular hyperplasia?
Non-neoplastic liver mass
- due to focal alterations in hepatic blood supply
50
What are 2 gross features of focal nodular hyperplasia?
1) Well-demarcated but poorly encapsulated pale nodule (± central fibrous scar)
2) Background non-cirrhotic liver
51
What are
1) Fibrous scar w radiating fibrous septa containing large, misshapened arterial vessels
2) Ductular reaction
3) Separated hyperplastic hepatocytes
4) No normal ducts
52
What is the most common benign liver tumour?
Cavernous haemangioma
53
What is a cavernous haemangioma?
Benign neoplasm of liver
54
What are the 4 gross features of a cavernous haemangioma?
1) Subcapsular
2) Discrete
3) Red-blue
4) Soft
55
What is 1 histological feature of cavernous haemangioma?
Large vascular channels separated by thin fibrous connective tissue
56
What are 3 complications of cavernous haemangiomas?
Rupture →
1) Intraperitoneal bleeding
2) Thrombosis
3) DIVC
57
What is a hepatocellular adenoma?
Benign tumour arising from hepatocytes
58
What are the risk factors hepatocellular adenoma?
1) Oral contraceptives
2) Anabolic steroids
59
How do px with hepatocellular adenomas present?
Incidental abdo pain (rapid growth of haemorrhage)
60
What are the 3 gross features of a hepatocellular adenoma?
1) Pale
2) Soft
3) Non-cirrhotic background
±haemorrhage
61
What are 2 histological features of a hepatocellular adenoma?
1) 2-3 cell thick hepatocytes cords
2) ± steatosis and haemorrhage
62
What is hepatocellular carcinoma?
#1 malignant neoplasm of liver
63
What are 4 major etiological associations pf HCC?
1) Viral infections (HBV, HCV)
2) Toxins (Aflatoxin: from aspergillus, alcohol)
3) Metabolic diseases (hereditary haemochromatosis, Wilson disease (WD) and alpha1-antitrypsin deficiency (AATD))
4) Non-alcoholic fatty liver disease (NAFLD) w metabolic syndrome
64
What are the 2 most common mutational events in Hepatocarcinogenesis?
1) ß catenin activation (40%) → genetic instability
2) p53 inactivation (esp for aflatoxin)
65
How does chronic liver disease predispose a px to hepatocarcinogenesis?
IL-6/JAK/STAT pathway → hepatocyte proliferation (HNF4a transcription factor)
66
True or false: cirrhosis is a prerequisite for hepatocarcinogenesis.
False
- progression to cirrhosis and hepatocarcinogenesis can be parallel
67
What are 3 clinical presentations of HCC?
1) Asymptomatic
2) Ill-defined upper abdo pain, malaise, fatigue, WL
3) Hepatomegaly, abdominal mass, fullness
4) Rare: jaundice, fever, variceal bleeding
68
What are 2 Ix for suspected HCC?
1) Serum α-fetoprotein
2) Radio imaging w contrast
69
What are the 3 areas of spread in HCC?
1) Intrahepatic (vascular) → satellite lesions
2) Portal/hepatic vein
3) Lymph nodes
70
What are 3 gross findings of HCC?
1) Unifocal (large) mass
2) Multifocal (variable) nodules
3) Diffuse and infiltrative
4) Pale or variegated
71
What are 5 histological features of HCC?
1) Well to poorly differentiated
2) Growth patterns: (i) trabecular-sinusoidal (ii) pseudoacinar (iii) compact
3) Polygonal cells w eosinophilic cytoplasm and central, round, distinct nucleolus
4) Pleomorphism
5) Bile production
72
What is the prognosis for HCC and what are the factors?
Factors:
1) Stage/grade
2) No./size of nodules
3) Vascular spread
4) ±cirrhosis
Poor 5 yr survival (most <2 years)
Death by:
- cachexia
- variceal bleeding
- liver failure/hepatic coma
- rupture → haemorrhage
73
What are 4 treatment options for HCC?
1) Surgical resection
2) Liver transplantation
3) Immunotherapy
4) Locoregional ablation
(transarterial chemoembolisation, transarterial Y90 radioembolisation, radiofrequency ablation)
74
What are 2 ways screening and surveillance is done for HCC?
1) US + serum α-fetoprotein
2) CT + MRI w Contrast
75
What is the most common liver tumour in early childhood?
Hepatoblastoma
76
What are the 2 main histological variants of hepatoblastoma?
1) Epithelial type:
- polygonal fetal/smaller embryonic cells
- vaguely recapitulating liver development
2) Mixed epithelial and mesenchymal type:
- Primitive mesenchyme, osteoid, cartilage, striated muscle
77
What is the hepatoblastoma associated syndrome for FAP?
Beckwith Wiedemann syndrome
78
What are 2 treatment options for hepatoblastoma?
1) Surgical resection
2) Chemotherapy
79
What is the 2nd most common primary malignant tumour of the liver?
Cholangiocarcinoma
80
What are 4 risk factors that predispose to cholangiocarcinoma?
1) Liver fluke infestation
2) Primary sclerosing cholangitis
3) Hepatolithiasis
4) Fibropolycystic liver disease
5) HBV, HCV, NAFLD
6) Premalignant lesions: BilIN, Intraductal papillary biliary neoplasia, Mucinous cystic neoplasms
81
How does the location of cholangiocarcinoma affect presentation?
Extrahepatic:
- present earlier w RUQ pain, smaller biliary obstruction, cholangitis
Intrahepatic:
- detected late
82
What is the prognosis of cholangiocarcinoma?
poor
- ~15% survival @ 2 years
- 6mths median survival after surgery for intrahepatic CCA
83
What are the difference in gross features of a extrahepatic and intrahepatic cholangiocarcinoma?
Intrahepatic: mass-forming, periductal/mixed
Extrahepatic: papillary/polyploid, stricture, diffusely-infiltrative adenocarcinoma, lymphovascular adn perineural infiltration
84
What are 2 vascular malignant primary hepatic tumours?
1) Angiosarcoma
2) Epithelioid haemangioendothelioma
85
What are 3 malignant primary hepatic lymphomas?
1) DLBCL
2) MALT lymphoma
3) Hepatosplenic δ-γ T cell lymphoma
86
True or false: Primary hepatic neoplasms are the most common tumours in the liver
False.
- metastases far more common than primary hepatic
87
Where do secondary hepatic neoplasms usually spread from (3)?
1) Breast
2) Colon
3) Lung
4) Pancreas
88
What are 3 gross features of secondary hepatic neoplasms?
1) Hepatomegaly
2) Multiple pale nodules in non-cirrhotic liver
3) Subcapsular umbilication of nodules (from central tumour necrosis)
89
What is the most common malignancy of the extrahepatic biliary tract?
Gallbladder Carcinoma
90
What are 2 risk factor for gallbladder carcinoma?
1) Gallstones
2) Chronic bacterial and parasitic infections
91
What are the 6 areas of spread for gallbladder carcinoma?
Direct:
- Liver
- Stomach
- Duodenum
Metastasis:
- Liver
- Regional lymph node
- Lungs
92
What 2 gross features of gall bladder carcinoma?
1) Diffuse (70%) / infiltrating
2) Polyploid (30%) / exophytic
93
What are 4 congenital anomalies of the pancreas?
1) Pancreas divisum (failed fusion of dorsal and ventral pancreatic primordia duct systems)
2) Annular pancreas (ring encircling duodenum)
3) Ectopic pancreas (elsewhere eg. stomach, SI)
4) Agenesis (homozygous mutation of PDX1 gene)
94
What is the most common congenital anomaly of the pancreas?
Pancreas divisum
- failed fusion of dorsal and ventral pancreatic primordia duct systems
→ CBD and main pancreatic duct enter duodenum separately
→ predisposition to chronic pancreatitis
95
What are the sequelae of an annular pancreas?
Stenosis and obstruction
96
What are the sequelae of an ectopic pancreas?
Pain from localised inflammation or mucosal bleeding
97
What are the 3 normal mechanisms protecting the pancreas from self-digestion by secreted enzymes?
1) Most digestive enzymes synthesised as zymogens, packaged in secretory granules
2) Intrapancreatic activation of proenzymes are limited to the small bowel (enterokinase→trypsin→proenzymes)
3) Acinar and ductal cells secrete trypsin inhibitors (including serine protease inhibitor SPINK1 → limits intrapancreatic trypsin activity)
98
True or false: Acute pancreatitis is a reversible pancreatic parenchymal injury a/w inflammation.
True
99
What are the etiologies of acute pancreatitis?
I GET SMASHED
Idiopathic
Gallstones
Ethanol
Trauma
Steroids
Mumps and other infections
Autoimmune (SLE, PAN)
Scorpion toxin
HyperCa, HyperTG, Hypothermia
ERCP (endoscopic retrograde cholangiopancreatography)
Drugs (furosemide, azathioprine)
Others: CF, HOP cancers, pancreas divisum
100
What are the 3 mechanisms/pathways for the pathogenesis of acute pancreatitis?
TLDR:
Acinar cell injury → activated enzymes → (i) interstitial inflammation + edema (ii) Proteolysis (iii) fat necrosis (iv) hemorrhage
1) Duct obstruction (eg. stones, chronic alcoholism)
→ interstitial edema → ↓blood flow → Ischemia
2) Acinar cell injury (eg. drugs, trauma, ischemia, viruses)
→ oxidative stress → release + activation of enzymes
3) Defective Intracellular transport
→ proenzymes delivered to lysosome → activation of enzymes
101
How can alcohol consumption lead to pancreatitis?
1) Transient ↑ in contraction of sphincter of Oddi
2) Secretion of protein-rich pancreatic fluid → deposition of inspissated proteins plugs and obstruction of small pancreatic ducts
3) Direct toxicity on acinar cells → oxidative stress
102
What is the typical clinical presentation of acute pancreatitis?
Constant intense epigastric/central abdo pain
- radiates to upper back or left shoulder
- a/w nausea, vomiting, LOA
103
What are the types of acute pancreatitis in order of severity?
Full-blown (SIRS) > Hemorrhagic > Acute necrotising > Acute interstitial
104
How does full-blown acute pancreatitis cause SIRS?
Release of toxic enzymes, cytokines, etc. into circulation → systemic inflammatory response (SIRS)
105
How is acute pancreatitis diagnosed?
1) ↑ serum amylase (1st 24hr) + Lipase (72-96hrs)
2) Glycosuria (10%)
3) Hypocalcemia (Ca soaps deposit in necrotic fat)
4) Leukocytosis, DIC
5) ± jaundice (only if due to gallstones)
106
What are the 5 histological features of acute pancreatitis?
1) Microvascular leak and edema
2) Fat necrosis
3) Acute inflammation
4) Destruction of pancreatic parenchyma
5) Destruction of blood vessels and interstitial hemorrhage
107
In acute pancreatitis,
i) Head of pancreas shows __________
ii) Omental fat shows ____________
iii) Fat necrosis with __________________
i) Head of pancreas shows hemorrhage and necrosis
ii) Omental fat shows necrosis with saponification
iii) Fat necrosis with neutrophilic response "chicken broth" peritoneal fluid
108
What are 3 complications of acute pancreatitis?
1) Systemic organ failure
- Shock (SIRS)
- Acute respiratory distress syndrome
- Acute renal failure (renal tubular necrosis)
- DIVC
2) Sterile pancreatic "abscess"
- can become infected
3) Pancreatic pseudocyst
109
What is chronic pancreatitis?
Prolonged inflammation of pancreas a/w irreversible destruction of exocrine parenchyma, fibrosis and later, destruction of endocrine parenchyma
110
What are 4 etiologies of chronic pancreatitis?
1) Long-term alcohol abuse (#1)
2) Long-standing obstruction of pancreatic duct by calculi/neoplasm
3) Autoimmune (IgG4+ plasma cells, mimic pancreatic carcinoma, responds to steroid therapy)
4) Hereditary pancreatitis
111
What differentiates chronic pancreatitis from acute pancreatitis?
Chronic inflammatory cells
Fibrogenic factors predominate (activation and proliferation of periacinar myofibroblasts/pancreatic stellate cells) → collagen and fibroblast deposition
112
What are the clinical presentations of chronic pancreatitis?
Repeated/persistent epigastric/central abdo pain
- radiates to upper back or left shoulder
- precipitated by alcohol, overeating, opiates, drugs that ↑tone of sphincter of Oddi
or asymptomatic until pancreatic insufficiency (intestinal malabsorption) and DM develop
113
How is chronic pancreatitis diagnosed?
Pancreatic calcifications on CT/US
114
What are 4 complications of chronic pancreatitis?
1) Pancreatic exocrine insufficiency → chronic malabsorption
2) Endocrine insufficiency → DM
3) Sever chronic pain
4) Pancreatic pseudocysts
115
What are 5 histological features of chronic pancreatitis?
1) Variable dilatation of pancreatic ducts w protein plugs/calcified concretion
2) Fibrosis
3) Atrophy, Acini dropout with sparing of islets
4) Pseudocysts
AI: ductocentric inflammation, venulitis, ↑IgG4+ plasma cells
116
What are 3 non-neoplastic pancreatic masses?
Solid:
1) Autoimmune pancreatitis
Cystic:
2) Pseudocysts
3) Congenital
117
What are 4 solid neoplastic pancreatic masses?
1) Ductal adenocarcinoma
2) Acinar cell carcinoma
3) Pancreatoblastoma
4) Neuroendocrine tumours
118
What are 4 cystic neoplastic pancreatic masses?
1) Serous cystadenoma (benign)
2) Mucinous cystic neoplasm (pre-malignant)
3) Intraductal papillary mucinous neoplasm (pre-malignant)
4) Solid pseudopapillary neoplasm (malignant)
119
How are pancreatic masses diagnosed?
Endoscopic ultrasound-guided fine needle aspiration cytology
120
Pseudocysts are (localised/diffuse) collections of necrotic and haemorrhagic material rich in ___________ and (have/lack) an epithelial lining.
And have 3 end-results: ________________
localised collections of necrotic and haemorrhagic material
rich in pancreatic enzymes
NO epithelial lining.
1) Spontaneously resolves
2) Secondary infection
3) Compress/perforate adjacent structures
121
What are the 3 histological features of congenital cystic non-neoplastic pancreatic masses?
1) Unilocular
2) Contain serous fluid
3) Thin fibrous wall lined by single later of variably attenuated uniform cuboidal epithelium
122
In serous cystadenoma,
i) which part of the pancreas in affected
ii) what are the histological features
iii) what are the most commonly associated gene mutation?
i) Tail
ii) Multicystic, lined by glycogen-rich cuboidal cells
iii) VHL inactivation
123
In mucinous cystic neoplasm,
i) which part of the pancreas in affected
ii) what are the histological features
iii) what are the most commonly associated gene mutation?
i) body/tail (not connected to duct)
ii) columnar mucinous epithelium with "ovarian cortical-type" stroma
iii) KRAS mutation
124
In intraductal papillary mucinous neoplasm,
i) which part of the pancreas in affected
ii) what are the histological features
iii) what are the most commonly associated gene mutation?
i) Head (connected to duct)
ii) intraductal papillae lined by columnar mucinous epithelium
iii) KRAS, GNAS mutation
125
In solid-pseudopapillary neoplasm,
i) which part of the pancreas in affected
ii) what are the histological features
iii) what are the most commonly associated gene mutation?
i) body/tail
ii) well-circumscribed, solid vascular nests w pseudopapillae
iii) CTNNB1 (ß-catenin)
126
True or false: Pancreatic carcinoma is very aggressive and have one of the highest mortality rates
True
127
What are 5 risk factors for pancreatic carcinoma?
1) Smoking
2) High-fat diet
3) Chronic pancreatitis
4) DM
5) Genetics (BRCA2, CDKN2A)
128
What are 2 precursors of pancreatic carcinoma?
1) Premalignant neoplasms (IPMN, MCN)
2) Non-invasive small duct lesions (pancreatic intraepithelial neoplasia)
129
What are 4 genes commonly mutated in pancreatic carcinoma?
1) KRAS
2) CDKN2A
3) TP53
4) SMAD4
130
What are 5 clinical presentation of pancreatic carcinoma?
1) Asymptomatic
2) Pain
3) Obstructive jaundice (head of pancreas lesions)
4) Systemic symptoms (advanced: LOW, LOA, lethargy)
5) Migratory thrombophlebitis (trosseau's sign)
131
How is pancreatic carcinoma diagnosed?
1) Serum CEA, CA19-9↑
2) Imaging
3) EUS-FNAC/Core biopsy
132
How is pancreatic carcinoma treated?
1) Surgical resection
2) Chemoradiotherapy
133
What are the 3 gross features of pancreatic carcinomas?
1) Large pale firm mass w infiltrative border
2) Adenocarcinoma w desmoplasia
3) Perineural/lymphatic involvement
134
True or false: All pancreatic neuroendocrine tumours have malignant potential regardless of grade and appearance.
True
135
Which pancreatic neuroendocrine tumour is most commonly benign compared to the rest?
Insulinomas
136
What are 7 types of pancreatic neuroendocrine tumours and their clinical syndromes?
1) Insulinoma (ß-cell) → Whipple triad (hypoglycemia, CNS, relief on glucose)
2) Glucagonoma (α-cell) → mild DM, anemia, necrolytic migratory skin erythema
3) Somatostatinoma (δ-cells) → DM, Cholelithiasis, Steatorrhoea, Hypochlorhydria
4) PP-secreting endocrine tumour → asymptomatic (just mass)
5) VIPoma (D1 cells) → Watery diarrhoea, HypoK+, Achlorhydria
6) Carcinoid (ECF cells) → carcinoid syndrome (flushing, diarrhoea, bronchospasm, heart valve lesions)
7) Gastrinoma (G cells) → Zollinger-Ellison syndrome (diarrhoea, intractable peptic ulceration, hyperchlorhydria)
137
What are the 3 histological features of pancreatic neuroendocrine tumours?
1) Solid pale mass ± cystic change
2) Nests, islands, trabeculae of small round cells w "salt and pepper chromatin
3) Highly vascular
138
How are pancreatic neuroendocrine tumours diagnosed?
1) IHC stain for neuroendocrine and secretory products
2) Ultrastructural image of neurosecretory granules in cytoplasm
139
What are the 3 major genes/pathways for the pathogenesis of sporadic (90%) pancreatic neuroendocrine tumours?
1) MEN1
2) lof mutations in TS genes (eg. PTEN, TSC2), resulting activation of mTOR pathway
3) Inactivating mutations in ATRX and DAXX genes
140
What are 4 example genes for syndromic/familial pancreatic neuroendocrine tumours (10%)?
1) MEN1
2) VHL
3) NF1
4) TSC1/2
141
What are 3 tests that are done to assess hepatocyte integrity?
Cytosolic hepatocellular enzymes:
1) AST
2) ALT
3) LDH
142
What are 5 tests that are done to assess biliary excretory function?
Substances normally secreted in bile:
1) Serum bilirubin: total, unconj, conj
2) Urine bilirubin
3) Serum bile acids
Plasma membrane enzyme (dmg to canaliculi):
1) ALP
2) GGT
143
What are 3 tests that are done to assess hepatocyte synthetic function?
Proteins secreted into blood:
1) Serum albumin
2) PT
3) PTT
144
What are 2 tests that are done to assess hepatocyte metabolism?
1) Serum ammonia (↑ in disease)
2) Aminopyrine breath test (hepatic demethylation)
145
Why are most liver diseases chronic at the time of clinical presentation (except acute liver failure)?
Liver has enormous functional reserve
- Mild liver damage may be clinically masked
- Liver injury and healing may occur without clinical detection
- Liver disease is usually an insidious process
146
What are 3 degenerative but reversible hepatocyte/ parenchymal responses to liver insult?
1) Ballooning degeneration (cellular swelling)
2) Steatosis
3) Cholestasis (accumulation of bilirubin)
147
What are 2 irreversible hepatocyte/ parenchymal responses to liver insult?
1) Necrosis (coagulative)
- ischaemic injury
- cell swelling & rupture → macrophages
2) Apoptosis
- activation of caspases cascade → cell shrinkage and eosinophilia (acidophil bodies)
- spotty → confluent necrosis (zonal → bridging → submassive → massive)
148
What are 2 regenerative hepatocyte/parenchymal responses to liver insult?
1) Primary: hepatocyte mitosis
2) Extensive: activation of primary stem cell niche (canals of hering)
- hepatocyte reach replicative senescence → stem cell activation (ductular rxn)
149
Describe the process of hepatic scar formation and cirrhosis?
Zones of parenchymal loss:
→ Collapse of underlying reticulin
→ Hepatic stellate cells activated → highly fibrogenic myofibroblasts (via cytokines and chemokines from inflammatory cells, endothelial cells, hepatocytes, bile duct epithelial cells)
Or:
- Portal fibroblasts, ductular rxn (epithelial-mesenchymal transition)
Eventually:
Portal / periportal fibrosis → portal-central and portal-portal bridging fibrosis / septa → cirrhosis
150
Can liver cirrhosis be reversed?
Yes? kinda?
- reversal of fibrosis via cirrhosis regression
151
What are 5 consequences of liver failure?
1) Coagulopathy (↓ coag. factors)
2) Hepatic encephalopathy (impaired NH3 metabolism)
3) Cholestasis (impaired bile secretion)
4) Portal HTN (cirrhosis → ascites, congestive splenomegaly, portosystemic venous shunts)
5) Hepatorenal, hepatopulmonary syndrome
152
What are 3 causes of acute liver failure?
1) Drugs / toxins (faster time course e.g. within hours to days)
2) Acute Hepatitis A/B/E
3) Autoimmune hepatitis
153
What is the macroscopic and 5 microscopic features of acute liver failure?
Macro:
- Small shrunken liver with wrinkled liver capsule
Micro:
1) Massive hepatic necrosis
2) Diffuse injury w/o obv cell death (diffuse microvesicular steatosis)
3) Hepatocyte loss
4) RBC extravasation
5) Florid ductular rxn
154
True or false: Cirrhosis is the precursor to chronic liver failure.
False.
- Not all end-stage chronic liver disease is cirrhotic e.g. PBC/PSC
- Not all cirrhosis leads to chronic liver failure
(eg. Child-Pugh clinical classification of cirrhosis: Class A (well compensated), B (partially compensated), C (decompensated))
155
What are 4 causes of chronic liver failure?
1) Chronic Hep B and C
2) NAFLD
3) Alcoholic liver disease
4) Cryptogenic/Idiopathic
156
What is cirrhosis?
Diffuse transformation of the liver into regenerative parenchymal nodules surrounded by fibrous bands (scarring) and accompanied by disturbed vascular architecture (due to variable degrees of vascular (often portosystemic) shunting)
157
What 2 factors influence whether there would be scarring or regression in liver injury?
Persistent disease
→ Synthesis via hepatic stellate cell myofibroblastic activity
Vs
Disease inhibition/elimination
→ Degradation via matrix metalloproteinases
→ degrade collagen and elastin fibres
158
What are 6 clinical features of cirrhosis?
40% asymptomatic until advanced
1) Non-specific manifestations (anorexia, WL, weakness)
2) Liver failure
3) Hepatocellular carcinoma
Terminal events:
4) Hepatic encephalopathy
5) Bleeding from esophageal varices
6) Bacterial infections/sepsis
159
What are 4 main stigmata of chronic liver disease?
1) Cholestasis
→ jaundice → pruritis → scleral icterus
2) Hyperoestrogenemia
- Palmar erythema
- Spider angioma
- Hypogonadism
- Gynaecomastia
3) Coagulopathy
→ easy bruising
4) Portal HTN
- Ascites
- Portosystemic venous shunts (eg. caput medusae, haemorrhoids)
- splenomegaly
- hepatic encephalopathy → asterixis
160
What are 2 pathways for the pathogenesis of portal hypertension?
1) ↑ R to portal flow @ sinusoids
- vasoconstriction (smooth muscle + myofibroblasts)
- disrupted blood flow (scarring/parenchymal nodule formation)
- sinusoidal remodelling → intrahepatic shunts + arterial-portal anastamosis
2) ↑ portal venous flow due to hyperdynamic circulation
- arterial vasodilation (splanchnic circulation)
161
What are 7 causative organisms for viral hepatitis?
Hepatotropic: A-E (5)
Non-hepatotropic: EBV, CMV
162
What are 4 effects of portal HTN?
1) Ascites (↑P in peritoneal capillaries + RAAS)
2) Hepatorenal syndrome (splanchnic vasodilation → RAAS → renal vasoconstriction)
3) Hepatic encephalopathy + collateral channels (Portosystemic shunting of blood)
4) Splenomegaly → pancytopenia
163
What is ascites?
Accumulation of excess fluid in the peritoneal cavity
(500 ml = clinically detectable)
164
What are 4 causes of ascites?
1) Cirrhosis
2) Chronic heart failure
3) Hypoalbuminemia
4) Malignancies
5) Peritonitis
## Footnote
Can seep through trans-diaphragmatic lymphatics
hydrothorax (R>L)
165
How is the etiology of ascites determined?
Ascitic tap:
- Few mesothelial cells, mononuclear inflammatory cells → Normal
- ↑ Neutrophils → infection
- Malignant cells → disseminated intra-abdominal cancer
166
What is hepatic encephalopathy?
Brain dysfunction caused by liver insufficiency and/or porto-systemic shunting manifesting as a wide spectrum of neurological or psychiatric abnormalities ranging from subclinical alterations to coma
(Shunting of ammonia from GIT into general circulation → BBB)
167
How does portal hypertension lead to peripheral cytopenias?
↑venous P → congestive splenomegaly
Retention of a large number of leukocytes, erythrocytes
and platelets in the spleen
facilitates capture, phagocytosis or destruction of blood cells by phagocytes
→ peripheral cytopenia
168
The main sequelae of liver failure are:
A___________________
B___________________
C___________________
D___________________
E___________________
Ammonia – encephalopathy
Bile retention – cholestasis
Coagulopathy
Distension – ascites
Esophageal varices
169
What is acute on chronic liver failure?
1) An unrelated acute injury supervenes on a well-compensated late-stage chronic disease, or
2) The chronic disease itself has a flare of activity that leads directly to liver failure
170
What are 2 hepatic and 2 systemic causes of acute on chronic liver failure?
Hepatic:
1) Chronic hep B + Hep D superinfection
2) Ascending cholangitis in px with primary sclerosing cholangitis
3) Development of malignancy e.g. HCC or metastases
Systemic:
1) Sepsis and hypotension
2) Acute cardiac failure
3) Superimposed drug or toxic injury
171
What is a differential for viral hepatitis?
1) Autoimmune hepatitis
2) Drug/toxin-induced hepatitis
172
What are 3 sequelae of acute viral hepatitis?
1) Asymptomatic
2) Symptomatic w recovery
- incubation → symptomatic pre-icteric → symptomatic icteric → convalescence
3) Acute liver failure with submassive/massive hepatic necrosis
4) Chronic hepatitis ±cirrhosis
173
Which viruses can cause both asymptomatic and symptomatic acute viral hepatitis?
All hepatotropic
Hepatitis A, B, C, D, E
174
Which viruses can cause acute liver failure w submassive/massive hepatic necrosis in viral hepatitis?
HAV, HBV, HDV
(HEV in pregnancy)
175
Which viruses can cause chronic viral hepatitis?
HCV
(some HBV)
## Footnote
HAV and HEV do not unless
immunocompromised
176
Hepatitis A is a (self-limiting/progressive) disease, spread by ________________________.
It causes _________________________.
Hep A:
- self-limiting disease
- spread by fecal-oral
- causes: mild symptoms, acute liver failure (uncommon), transient viraemia (aft 2-6 weeks)
## Footnote
Does not cause chronic hepatitis or carrier state
177
After an infection, a px has immunity against HAV for _____________.
Life
(IgG anti-HAV persists for years → lifelong immunity)
178
What form of hepatitis can result from a hep A infection?
Acute hepatic failure (uncommon)
179
What form of hepatitis can result from a hep B infection?
1) Acute hepatitis
2) Acute hepatic failure
3) Chronic hepatitis
180
True or false:
Hep B often causes direct hepatocyte injury via interruption of protein synthesis.
False.
HBV generally does not cause direct hepatocyte injury; injury is caused by CD8+ cytotoxic T cells attacking infected cells
181
What are 3 modes of Hep B transmission?
1) Vertical
2) Horizontal
3) Sexual/IVdrugs
182
True or false.
Hep B is a risk factor for HCC even w/o cirrhosis and thus vaccination is very important and effective in preventing infection.
True.
Vaccination induces protective anti-HBs response in 95% of infants, children and adolescent
183
What are 3 modes of transmission for Hep C?
1) IVDA
2) Sex
3) Needle-stick injury
4) vertical
183
Which hepatotropic viruses have a carrier state?
Only Hep B
- HBsAg+, HBeAg- but anti-HBe+, low/undetectable HBV DNA
- AST/ALT normal, liver biopsy no significant inflammation
- Probably not a stable state – re-activation may occur e.g. co-infection, immune
changes
184
After an infection, a px has immunity against HBV for _____________.
never.
HCV is inherently genomically unstable → Elevated titers of anti-HCV IgG occurring after an active infection do not confer effective immunity; circulating HCV RNA often persists (90%)
185
How is HCV infection (i) diagnosed (ii) prevented (iii) cured?
i) HCV RNA testing
ii) No vaccine (just limit transmission
iii) Direct-acting antivirals
186
What are 2 sequelae and 1 association of HCV infection?
Repeated bouts of hepatic damage occur
1) Persistent infection and
chronic hepatitis (80-90%)
2) cirrhosis (20%)
a/w: metabolic syndrome (esp. HCV genotype 3) – insulin resistance and NAFLD
187
How does acute and chronic disease of HCV infections differ?
Acute:
Jaundice, symptoms, serum marker, serum transminases all high and present
Chronic:
Intermittent symptoms
- persistent/fluctuating elevations of AST/ALT (wax and wane)
188
What are 2 sequelae of HDV infections?
1) Co-infection → acute hepatitis (self-limited w clearance of both HBV and HDV)
2) Superinfection →
severe acute hepatitis in a previous unrecognised HBV carrier or exacerbation of preexisting chronic Hep B infection
Chronic HDV infection occurs in almost all patients → cirrhosis ± HCC
189
How is HDV transmitted?
Blood-borne
- IVDA
- blood transfusions
190
Can HDV alone cause disease?
No, require co/super-infection w HBV
191
True or false:
Vaccination for HBV prevents HDV infection
True
192
What is the most reliable indicator of recent HDV exposure?
IgM anti-HDV antibody
193
HEV infections are usually self-limiting with which 2 exceptions?
1) High mortality rate in pregnant women (~20%)
2) Chronic infection only in immunosuppressed patients (HIV / transplant)
194
How HEV transmitted?
Fecal-oral
(Zoonotic disease with animal reservoirs: monkeys, cats, pigs, dogs)
195
In a HEV infection, _______________ can be detected by PCR in stool and serum.
IgM replaced by______ anti-HEV (will persist for a few years) when symptoms
start resolving in 2-4 weeks.
HEV RNA and virions can be detected by PCR in stool and serum
IgM replaced by IgG anti-HEV (will persist for a few years) when symptoms
start resolving in 2-4 weeks
196
True or false:
Acute and chronic hepatitis can be differentiated histologically by the inflammatory cell infiltrate.
False.
It is the time course and pattern of injury that distinguishes acute vs chronic
hepatitis, not the inflammatory cell infiltrate (both are mononuclear, mainly T cells)
197
Lobular hepatitis is seen in which form of hepatitis?
Acute viral (<1 mth)
198
Portal hepatitis is seen in which form of hepatitis?
Chronic viral (Symptomatic, biochemical or serologic evidence > 6 months)
199
What are 3 histological features of lobular hepatitis in acute viral hepatitis?
1) Lobular disarray
- Hepatocyte swelling
- Apoptosis, spotty to confluent necrosis
- Kupffer cell hypertrophy
2) Lymphoplasmacytic infiltrate
3) ± Cholestasis
4) ± portal inflammation
200
What are 3 histological features of portal hepatitis in chronic viral hepatitis?
1) Lymphoplasmacytic portal
infiltration
2) Portal and periportal (interface)
hepatitis to bridging hepatic necrosis
3) ± lobular hepatitis in active disease
4) Fibrosis to cirrhosis; regression may
occur
201
"Ground-glass" hepatocytes are seen in which hepatitis infection?
Chronic Hep B
202
Lymphoid follicles and fatty change are seen in which hepatitis infection?
Chronic Hep C
203
How is hepatitis (i) graded and (ii) staged?
Grading: extent of injury and inflammation (Metavir grading)
Staging: progression of fibrosis (Ishak stage)
204
What are 2 non-hepatotropic viruses that implicate the liver?
1) CMV
2) HSV
3) EBV
4) Adenovirus
## Footnote
- Systemic infections with multi-organ
involvement
- Immunocompetent versus
immunocompromised patients
- Opportunistic infections
205
Bacterial, parasitic and helminthic infections of the liver can cause:
Localised disease:
1) __________ (bacterial or amoebic)
2) ___________(Echinococcus)
1) Abscess (bacterial or amoebic)
2) Hydatid cyst (Echinococcus)
206
Bacterial, parasitic and helminthic infections of the liver can cause:
Diffuse disease:
1) Mild hepatic inflammation and varying hepatocellular cholestasis
2) ____________________ – fungal, mycobacterial, parasitic (__________ – ‘pipe stem fibrosis’)
3) ____________________ - liver flukes → high rate of ___________________
1) Mild hepatic inflammation and
varying hepatocellular
cholestasis
2) Granulomatous disseminated disease – fungal, mycobacterial, parasitic (Schistosoma – ‘pipe stem fibrosis’)
3) Dilated intrahepatic ducts - liver flukes → high rate of cholangiocarcinoma
207
What is the characteristic finding of miliary TB affecting the liver?
Granulomas
208
What are 2 histological features of amoebic liver abscess?
1) Abscess contents have lack of inflammatory cells due to process of liquefactive necrosis
2) Trophozoites of Entamoeba histolytica (protozoa)
209
How is autoimmune hepatitis diagnosed (3) ?
1) Autoantibodies
2) Elevated IgG
3) Liver histology
## Footnote
Likely: Portal lymphoplasmacytic infiltrate + interface/lobular
hepatitis, OR Lobular hepatitis + lymphoplasmacytic infiltrates,
interface hepatitis or portal fibrosis, in the absence of features suggestive of other liver disease
Possible: As above, but if there are also other histologic features suggestive of other liver disease
Unlikely: Non-classic histologic features + features of other liver disease
210
How does autoimmune hepatitis present?
1) acutely (40%) / fulminant
presentation within 8 wks of onset, followed rapidly by scarring (40% of survivors will progress to cirrhosis)
2) Indolent, detected incidentally or only when cirrhotic
## Footnote
Female (78%) >> male
211
What is the difference between Type I and II autoimmune hepatitis?
Type I: Middle-aged to older; ANA, SMA
Type II: Young; anti-LKM1
212
What are 3 mechanisms of drug/toxin-induced liver injury?
1) Direct toxicity
2) Hepatic conversion of xenobiotic to an active toxin
3) Immune-mediated mechanisms (e.g. drug acts as a hapten)
213
What should be in the differential diagnosis of any form of liver disease?
Drug/toxin-Induced Liver Injury (DILI)
214
How is Drug/toxin-Induced Liver Injury (DILI) diagnosed?
Diagnosis is on the basis of
1. A temporal association of liver damage with drug/toxin exposure (may be immediate or weeks-months)
2. Recovery (usually) upon removal of inciting agent
3. Exclusion of other potential causes
215
What are 4 factors that affect the development and severity of ALD?
1) Dosage and duration: ≥ 80g/day ethanol (~6 beers) generates significant risk for severe hepatic injury; 10-20 years
2) Gender: females more susceptible
3) Ethnic and genetic differences e.g. in detoxifying enzymes
4) Comorbid conditions e.g. concomitant liver pathologies like viral hepatitis
216
What are 5 mechanisms contributing to the pathogenesis of ALD?
1) Shunting
- ↑NADH → shunt ↑lipid synthesis + ↓lipoprotein export + ↑peripheral fat catabolism
2) Dysfunction of mitochondrial and cellular membranes
- acetaldehyde induces lipid peroxidation and acetaldehyde protein adduct formation
3) Hypoxia and oxidative stress
- CYP450 → ↑ROS
- impaired hepatic methionine metabolism → ↓glutathione levels
4) ↑ inflammation
- bacterial endotoxins from gut
5) ↓ Hepatic sinusoidal perfusion
- endothelin release → vasoconstriction + stellate cell contraction
217
What are 4 histopathological features of ALD?
1) Centrilobular steatosis (reversible with abstention)
2) Hepatocyte swelling (ballooning degeneration) and necrosis
3) Mallory-Denk bodies
4) Neutrophilic reaction
5) Pericellular/perisinusoidal fibrosis (“Chicken-wire fence” pattern)
6) Cirrhosis (micronodular)
218
What are the expected biochemical findings in a px with ALD?
1) AST>>ALT (2:1 ratio)
2) Bil, ALP ↑
3) ↑Neutrophils
219
What is NAFLD?
Spectrum of disorders that have in common the presence of hepatic steatosis in individuals who do not consume alcohol or do so in very small
quantities (< 20g/wk)
220
What is the pathogenesis of NAFLD?
2-hit model:
1) Insulin resistance → dysfunctional lipid metabolism and ↑inflammatory cytokines
2) Oxidative injury → liver cell necrosis as fat laden cells are highly sensitive to
lipid peroxidation products
221
NAFLD is most commonly a/w ___________ and increases the risk of ________
NAFLD is most commonly a/w metabolic syndrome and increases the risk of HCC
222
How is MAFLD diagnosed?
1) Detection of liver steatosis (via liver histology, non-invasive biomarkers or imaging)
2) at least 1/3 criteria of:
- overweight/obesity
- T2DM
- clinical evidence of metabolic dysfunction e.g. increased waist circumference, abnormal lipid or glycaemic profile
223
In which type of liver disease is cryptogenic cirrhosis seen?
Advanced fibrosis "burned out" NAFLD
224
What is Haemochromatosis
Caused by excessive iron absorption, deposited in parenchymal organs e.g. liver, pancreas, heart, joints, endocrine organs, skin
225
What is Wilson's disease?
Autosomal recessive disorder caused by ATP7B gene mutation (chr 13)
→ impaired copper excretion into bile and failure to incorporate copper into caeruloplasmin for secretion into blood.
→ Toxic levels of copper thus accumulate
in many tissues and organs
226
What is A1-antitrypsin deficiency?
Autosomal recessive disorder of protein folding resulting in impaired secretion and very low serum α1AT (important in inhibition of proteases, particularly those released from neutrophils)
227
What is passive liver congestion?
Diffuse venous congestion within the liver that results from right-sided heart failure
→ Dilatation and congestion of
centrilobular sinusoids
→ Centrilobular hepatocytes atrophy with time
228
What is centrilobular hemorrhagic necrosis?
combination of both passive congestion
and hepatic hypoperfusion e.g. left
heart failure
→ “nutmeg liver”
