Exocrine, pancreas, gallbladder and liver pathology Flashcards
1
Q
Pancreatic carcinoma - why is there obstructive jaundice with pale stools?
A
Carcinoma blocks the bile duct from emptying –> bilirubin backup and eventual leakage into the blood stream –> jaundice
Bilirubin is also what gives the stool its color so lack of bilirubin being secreted into duodenum will also result in pale stools
2
Q
How does cirrhosis increase the risk of cholesterol stones?
A
Production of bile salts by hepatocytes
Cirrhosis –> decreased bile acid production –> decreased solubility of cholesterol
3
Q
What diseases are associated with a deficiency of bilirubin canalicular transport protein?
What laboratory findings will you see?
A
Dubin-Johnson syndrome and Rotor syndrome
Both will result in increased serum conjugated bilirubin (transport protein responsible for transport of CB into the bile, w/o which will result in backup and leakage into the blood)
4
Q
Bilirubin gallstones
A
Pigmented stones composed of bilirubin (what gives the stone its color)
Usually radiopaque
Risk factors
- extravascular hemolysis (increased bilirubin in bile)
- biliary tract infection (ie E coli, Ascaris lumbricoides, Clonorchis sinensis) – bacteria can de-conjugate bilirubin
5
Q
Causes of viral hepatitis (3)
A
Mainly by hepatitis virus (1)
Can also be caused by EBV (2) and CMV (3)
6
Q
Cirrhosis - what results from decreased detoxification?
A
- mental status changes, asterixis, and eventual coma (due to increased serum ammonia) – metabolic, hence reversible
- gynecomastia, spider angiomata, and palmar erythema due to hyperestrinism
- liver plays an important role in removing estrogen from the blood
- jaundice (remember liver hepatocytes conjugate bilirubin - cirrhosis –> damage to hepatocytes)
7
Q
Wilson disease - what is the gene defect? Inheritance pattern?
A
Autosomal recessive defect in ATP7B gene (responsible for ATP-mediated hepatocyte copper transport)
- can’t transport copper into bile and can’t incorporate into ceruloplasmin –> stored in tissues
8
Q
Acute hepatitis
A
Inflammation of liver parenchyma
- inflammation involves lobules of liver and portal tracts and is characterized by apoptosis of hepatocytes
- some cases may be asymptomatic with elevated liver enzymes
- symptoms lasts
9
Q
Most cholesterol gallstones are radiolucent, what would make it radiopaque?
A
Associated with calcium binding
10
Q
Chronic pancreatitis
A
Fibrosis of pancreatic parenchyma – most often secondary to recurrent acute pancreatitis
- Most commonly due to alcohol (adults) and cystic fibrosis (children) – however, many cases are idiopathic
Clinical features
- epigastric abdominal pain that radiates to the back
- pancreatic insufficiency – results in malabsorption w/ steatorrhea and fat-soluble vitamin deficiencies
- dystrophic calcification of pancreatic parenchyma on imaging – “chain of lakes” due to dilatation of pancreatic ducts
- secondary diabetes mellitus (due to destruction of islets in the body and tail)
- increased risk of pancreatic carcinoma
11
Q
Nonalcoholic fatty liver disease - how is it diagnosed?
A
Diagnosis of exclusion
ALT > AST
12
Q
How does Crohn disease increase the risk of cholesterol stones?
A
Most common effected location is the terminal ileum –> decreased uptake of bile salts/acids –> decreased solubilization of cholesterol
13
Q
How can alcohol cause chronic pancreatitis?
A
Many causes of acute pancreatitis are one-time events (ie trauma, scorpion stings, rupture, etc…)
Alcohol is one of the few causes that is chronic and won’t likely to be stopped. Recurrent bouts of acute pancreatitis –> fibrosis and chronic pancreatitis
14
Q
Chronic pancreatitis - clinical features
A
- epigastric abdominal pain that radiates to the back
- pancreatic insufficiency – results in malabsorption w/ steatorrhea and fat-soluble vitamin deficiencies
- dystrophic calcification of pancreatic parenchyma on imaging – “chain of lakes” due to dilatation of pancreatic ducts
- secondary diabetes mellitus (due to destruction of islets in the body and tail)
- increased risk of pancreatic carcinoma
15
Q
Normal bilirubin metabolism
A
- RBCs when they are unhealthy or about to die are consumed by macrophages of the reticuloendothelial system (mainly located in the spleen)
- Protoporphyrin (from heme) is converted to unconjugated bilirubin (UCB)
- Albumin carries UCB to the liver
- Uridine glucuronyl transferase (UGT) in hepatocytes conjugates bilirubin
- Conjugated bilirubin (CB) is transferred to bile canaliculi to form bile, which is stored in the gallbladder
- Bile is release into the small bowel to aid in digestion
- Intestinal flora convert CB to urobilinogen, which is oxidized to stercobilin (makes stool brown) and urobilin (partially reabsorbed into blood and filtered by kidney, making urine yellow)
16
Q
Gallbladder carcinoma
A
Adenocarcinoma arising from the glandular epithelium that lines the gallbladder wall
- Gallstones are a major risk factor, especially when complicated by porcelain gallbladder*
- Classically presents as cholecystitis in an elderly woman*
- Poor prognosis*
17
Q
Complication(s) associated with chronic hepatitis
A
risk of progression to cirrhosis
18
Q
Chronic cholecystitis - treatment
A
Cholecystectomy – especially if porcelain gallbladder is present
19
Q
Reye syndrome
A
Fulminant (severe and sudden in onset) liver failure and encephalopathy in children with viral illness who take aspirin
- likely related to mitochondrial damage to hepatocytes
Presents with:
- hypoglycemia
- elevated liver enzymes
- nausea with vomiting
- may progress to coma and death
20
Q
Hepatocellular carcinoma
A
malignant tumor of hepatocytes
Risks:
- Chronic hepatitis (HBV, HCV)
- Cirrhosis (ie alcohol, nonalcoholic fatty liver disease, hemochromatosis, Wilson disease, A1AT deficiency)
- Aflaxtoxins derived from Aspergillus (induce p53 mutations)
Increased risk for Budd-Chiari syndrome
- liver infarction secondary to hepatic vein obstruction
- presents with painful hepatomegaly and ascites
21
Q
Wilson disease - characteristic finding on physical exam
A
Kayser-Fleisher rings in cornea
22
Q
Alcoholic hepatitis - when is it usually seen?
What mediates the damage?
A
Seen with binge drinking
Damage mediated by: acetaldehyde (metabolite of alcohol)
23
Q
Most common metastatic sources of liver cancer?
A
- colon
- pancreas
- lung
- breast carcinomas
24
Q
Gallstones - possible complications (5)
A
Usually asymptomatic, but certain complications can arise:
- biliary colic
- acute and chronic cholecystitis
- ascending cholangitis
- gallstone ileus
- gallbladder cancer
25
Nonalcoholic fatty liver disease
Same classic 3 symptoms w/o exposure to alcohol
* Fatty change
* Hepatitis
* Cirrhosis
Associated with obesity
Diagnosis of exclusion ALT \> AST
26
Hallmark of chronic cholecystitis
Rokitansky-Aschoff sinus (herniation of gallbladder mucosa into the muscular wall)
27
Cirrhosis - why is there hyperestrinism? (elevated estrogen)
What is a result of this?
Liver plays important role in removing estrogen. Increased levels results in
* gynecomastia
* spider angiomata
* palmar erythema
28
Hemochromatosis
Excess body iron leading to deposition in tissues (hemosiderosis) and organ damage (hemochromatosis)
* Tissue damage mediated by generation of free radicals (via the fenton reaction)
29
Chronic hepatitis
Characterized by symptoms that lasts \> 6 months
Inflammation predominantly involves portal tract
risk of progression to cirrhosis
30
Hepatitis C - how is the infection confirmed?
HCV-RNA test confirms infection
Decreased RNA levels indicate recovery
RNA persistence despite treatment indicates chronic disease
31
Pancreatic carcinoma
Adenocarcinoma arising from pancreatic ducts
Most commonly seen in the elderly (average age is 70 years)
Major risk factors: smoking and chronic pancreatitis
32
What are the stones made of in cholelithiasis? (2)
Cholesterol or bilirubin stones
33
Nonalcoholic fatty liver disease - what is it associated with?
Associated with obesity
34
Gallstone ileus - cause
Due to cholecystitis with **fistula** formation between the gallbladder and small bowel (which would allow the passage of larger stones which can pass and then obstruct the small bowel)
35
Gallbladder carcinoma - risk factor(s)
**Gallstones** are a major risk factor, especially when complicated by porcelain gallbladder
36
Key marker of hepatitis B infection
Hep B surface antigen (first serologic marker to rise)
37
Bilirubin gallstones - risk factors
* extravascular hemolysis (increased bilirubin in bile)
* biliary tract infection (ie *E coli*, *Ascaris lumbricoides*, *Clonorchis sinensis*) -- bacteria can de-conjugate bilirubin
38
Acute cholecystitis
Acute inflammation of the gallbladder wall
Impacted stone in the cystic duct results in dilatation with:
* pressure ischemia
* bacterial overgrowth (*E coli*)
* inflammation
Presents with:
* right upper quadrant pain often radiating to _right scapula_
* fever with elevated WBCs
* N&V
* increased serum alkaline phosphatase (from duct damage)
Risk of rupture if untreated
39
Hepatocellular carcinoma - what is the prognosis? why?
Poor prognosis mainly because the tumors are often detected very late (symptoms are often masked by cirrhosis)
40
Hepatic adenoma
Benign tumor of hepatocytes
Associated with oral contraceptive use -- regresses upon cessation of drug
Risk of rupture and intraperitoneal bleeding, especially during pregnancy
* tumors are subcapsular and grow with exposure to estrogen
41
Jaundice in newborns -- complications? treatments?
Complication: kernicterus (deposition of UCB in the basal ganglia)
Treatment: phototherapy -- does not cause conjugation, but it does increase the solubility of UCB so it can be excreted into the water
42
Wilson disease - laboratory findings (Urinary copper, serum ceruloplasmin, copper)
Urinary copper -- increased (can't dump into bile so stays in blood stream)
Serum ceruloplasmin -- decreased (defective transport --\> can't put into ceruloplasmin)
Copper -- increased in tissues (especially liver hepatocytes)
43
Primary sclerosing cholangitis - clinical presentation
obstructive jaundice
cirrhosis is a late complication
44
Trousseau syndrome - what is it associated with?
pancreatic and lung cancer
45
Primary sclerosing cholangitis - etiology
unknown but associated with ulcerative colitis; p-ANCA is often positive
46
Hepatitis B (HBV) - mode of transmission
How is it most commonly obtained?
Parenteral transmission (via piercing of the skin or the mucosa)
* childbirth
* unprotected intercourse
* IV drug abuse
* needle stick
47
Where is inflammation seen in chronic hepatitis?
Predominantly involves the portal tract
Figure: notice how there is inflammation in the portal tracts, but the hepatocytes (representing the liver lobules) is relatively clear
48
Gilbert syndrome - how does it present clinically?
Patients are usually normal, because UGT activity is still present, just decreased.
Jaundice occurs during stress (ie severe infection) otherwise, not clinically significant
49
Where is bile made? Where is it stored?
Made in liver. Stored in gallbladder
50
Wilson disease - presentation
Presents in childhood with
1. Cirrhosis
2. Neurologic manifestations (behavioral changes, dementia, chorea, and Parkinsonian symptoms due to deposition of copper in basal ganglia)
3. Kayser-Fleisher rings in the cornea
51
Ascending cholangitis - most common organisms
enteric gram-negative bacteria
52
Primary biliary cirrhosis - what population does this disease classically affect?
Remember autoimmune -- will classically affect women of childbearing age.
Average age is 40 years
53
Lipofuscin - what is it? where is it found? What is its function?
a brown pigment that is a by-product of the 'wear-and-tear' of peroxidized lipids that piles up in lysosomes
Typically found in neurons (because they live essentially throughout your whole life)
54
Role of anti-virus IgG in hepatitis infection
IgG is protective
Its presence indicates prior infection or immunization (immunization is ONLY available for hep A)
55
Hemochromatosis - what does it increase the risk of?
increased risk of hepatocellular carcinoma (due to damage to DNA from the free radicals)
56
Primary sclerosing cholangitis
Inflammation and fibrosis of intrahepatic and extrahepatic bile ducts
* periductal fibrosis with an 'onion-skin' appearance
* uninvolved regions are dilated resulting in a 'beaded' appearance on contrast imaging
presents with obstructive jaundice -- cirrhosis is a late complication
increased risk for cholangiocarcinoma
57
HEV infection - major complication?
HEV commonly acquired from contaminated water or undercooked seafood
HEV infection in pregnant women is associated with **fulminant hepatitis** (liver failure with massive liver necrosis)
58
How does alcohol cause acute pancreatitis?
causes contraction of sphincter of Oddi at the ampulla where the pancreatic/bile ducts drain into the duodenum
59
Most common type of stones in cholelithiasis?
Cholesterol stones (yellow) -- most common (90%) especially in the West
* radiolucent (10% are radiopaque due to associated calcium)
* risk factors
* age (40s)
* estrogen (female gender, obesity, multiple pregnancies, oral contraceptives)
* clofibrate
* Native American ethnicity
* Crohn disease
* cirrhosis
60
Pancreatic carcinoma - what results if the cancer is in the body or tail?
secondary diabetes mellitus -- due to destruction of islets
61
Wilson disease - complications
Increased risk of hepatocellular carcinoma -- same concept as hemochromatosis (production of hydroxy radicals can cause damage to DNA)
62
Ceruloplasmin
The key molecule that carriers copper in the blood (just like how transferrin/ferritin is for iron)
63
If a stone is being passed and is lodged in the common bile duct, what are some complications that may result? (2)
1. acute pancreatitis -- backup of pancreatic enzymes, more prone to unwarranted activation
2. obstructive jaundice -- backup of bile results in bilirubin backflow into the blood --\> jaundice
64
Primary sclerosing cholangitis - what disease is it associated with?
ulcerative colitis; pANCA is often positive
65
Primary sclerosing cholangitis - why is there a beaded appearance on contrast imaging?
Areas of inflammation and fibrosis creates the divets while uninvolved regions are dilated
66
hemochromatosis - liver biopsy
Accumulation of brown pigment in hepatocytes
Prussian blue stain distinguishes iron (blue) from lipofuscin
67
hemosiderosis
deposition of iron in tissues (without the organ damage)
characterized by repeated episodes of intra-alveolar bleeding that lead to abnormal accumulation of iron as hemosiderin in alveolar macrophages and subsequent development of pulmonary fibrosis and severe anemia.
68
Why is a fatty liver seen in alcoholics? Is it reversible?
Alcohol inhibits the oxidation of fatty acids (FAs) resulting in more FAs to be stored in the liver. However, if you remove the alcohol, the liver can continue to process the FAs hence why it is **reversible**.
69
3 main toxic effects of alcohol
1. fatty liver
2. alcoholic hepatitis (chemical injury by the alcohol)
3. cirrhosis
70
Hepatocellular carcinoma - serum marker
alpha-fetoprotein
71
Hemochromatosis - cause (primary vs secondary)
Primary - autosomal recessive defect in iron absorption
Secondary - chronic transfusions
72
Acute pancreatitis - cause
autodigestion of pancreatic parenchyma by pancreatic enzymes
73
Cirrhosis - why is there mental status changes?
Due to decreased detoxification of almost all drugs/toxic compounds (liver is responsible for detoxification)
* primarily caused by the decreased detoxification of serum ammonia (results in increased levels in the blood)
74
Amylase and lipase markers in chronic hepatitis
They are an indicator of damage in acute pancreatitis but not useful serological markers in chronic pancreatitis. The pancreas has suffered a lot of damage level already --\> doesn't make enough of these enzymes to be useful
75
Whipple procedure
en bloc (all together at the same time) removal of the head and neck of pancreas, proximal duodenum and gallbladder
Used for the treatment of pancreatic carcinoma
76
Acute pancreatitis - what is the first enzyme to be classically activated?
**Trypsin**
Activation of which will lead into the activation of other pancreatic enzymes
77
Biliary colic
Waxing and waning right upper quadrant pain
Due to **gallbladder contracting against a stone lodged in the cystic duct**
* If stone lodges in common bile duct, may result in acute pancreatitis or obstructive jaundice
Symptoms are relieve if stone passes
78
Most common causes of chronic pancreatitis (children vs adults)
Alcohol -- adults
Cystic fibrosis -- children
79
How does clofibrate increase the risk of cholesterol stones?
Fibrates are lipid lowering agents that:
* increase Hmg-CoA reductase --\> increases cholesterol synthesis
* decrease conversion of cholesterol to bile acids --\> decreased solubility + increased cholesterol in bile
Overall same effect as estrogen to increase cholesterol levels that will increase likelihood of precipitation
80
Pancreatic carcinoma - clinical features
* Epigastric abdominal pain and weight loss
* Obstructive jaundice with pale stools and palpable gallbladder -- associated with tumors that arise in the head of the pancreas (most common location)
* Secondary diabetes melltius -- associated with tunmors that arise in the body or tail
* pancreatitis
* migratory thrombophlebitis (Trousseau syndrome) -- presents as swelling, erythema, and tenderness in the extremities (seen in 10% of patients)
* serum tumor marker is CA 19-9 (CA = cancer antigen)
81
Cholelithiasis
Gallstones -- solid, round stones in the gallbladder
Due to precipitation of cholesterol (cholesterol stones) or bilirubin (bilirubin stones) in bile
Arises due to:
1. supersaturation of cholesterol or bilirubin
2. decreased phospholipids (ie lecithin) or bileacids, both of which increase the solubility of cholesterol
3. stasis
82
Solubility: conjugated vs unconjugated bilirubin
Conjugation makes bilirubin soluble in water
Unconjugated bilirubin is much more prone to precipitation
83
Primary biliary cirrhosis - clinical presentation
Presents with features of obstructive jaundice (due to the knockout of the bile ducts --\> backup of bile/bilirubin into the blood)
84
Annular pancreas
developmental malformation in which the pancreas forms a ring around the duodenum
risk of duodenal obstruction
85
Pancreatic carcinoma - major risk factors
Smoking
Chronic pancreatitis
86
Acute cholecystitis - clinical presentation
Remember infection is typically due to a bug so you will get typicaly symptoms associated with an infection.
* right upper quadrant pain often radiating to _right scapula_
* fever with elevated WBCs
* N&V
* increased serum alkaline phosphatase (from duct damage)
87
Wilson disease - mechanism of damage
Copper and iron both catalyze the fenton reaction generating hydroxy radicals.
If copper cannot be dumped into the bile and then out of our bodies, it accumulates within tissues inducing free radical damage
88
Hepatic adenoma - cause?
Associated with oral contraceptive use -- regresses upon cessation of drug
89
Acute pancreatitis - clinical features
* epigastric abdominal pain that radiates to the back
* nausea and vomiting
* periumbilical and flank hemorrhage (necrosis spreads into the periumbilical soft tissue and retroperitoneum)
* elevated serum lipase and amylase -- lipase more specific for pancreatic damage
* hypocalcemia (calcium is consumed during saponification in fat necrosis)
90
How long do symptoms in acute hepatitis last?
91
If an elderly woman presents with cholecystitis, what is at the top of your differential?
Carcinoma -- cholecystitis classically affects 40-50 year olds... not elderly
92
Alcoholic hepatitis - characteristic findings on histology
* Swelling of hepatocytes with formation of **Mallory bodies** (damage cytokeratin filaments)
* necrosis
* acute inflammation
93
How does viral hepatitis cause jaundice?
What other clinical findings would be present?
Via inflammation that disrupts hepatocytes and small bile ductules
* disruption/death of hepatocytes --\> inability to conjugate --\> **increased serum UCB**
* disruption/death of small bile ductules --\> inability to excrete the CB --\> **increased serum CB**
There will also be **dark urine** due to increased urine bilirubin (increased CB can be filtered by the kidney and excreted resulting in a pigmentation of the urine)
Urine urobilinogen is normal if not decreased (damage to the ductules will result in decreased released of bile into the gut --\> less formation of urobilinogen)
94
Acute pancreatitis - pancreatic abscess
Often due to *E. coli*
presents with abdominal pain, high fever and persistently elevated amylase
95
Primary sclerosing cholangitis - appearance on histology?
periductal fibrosis with an 'onion-skin' appearance
uninvolved regions are dilated resulting in a 'beaded' appearance on contrast imaging
96
What gallstones are normally radiolucent? Radiopaque?
Cholesterol -- radiolucent unless associated with calcium
Bilirubin -- radiopaque
97
Why is hypercalcemia a risk factor for acute pancreatitis?
calcium is an enzyme activator
increased calcium --\> increased chance of premature/random activation of pancreatic enzymes before they are secreted into the duodenum
98
Hepatitis viral infections - which ones can result in chronic hepatitis?
Hep A and Hep E -- no risk for chronic hepatitis
Hep B -- 20% of chronic
Hep C -- chronic disease occurs in most cases
99
What is the molecular cause of jaundice?
Increased serum bilirubin, usually \> 2.5mg/dL
100
Primary biliary cirrhosis
Autoimmune granulomatous destruction of intrahepatic bile ducts
* classically arises in women (average age is 40 years)
* associated with other autoimmune diseases
Etiology is unknown; antimitochondrial antibody present
101
Where are bile acids reabsorbed?
Ileum
102
Primary biliary cirrhosis - cause?
unknown. However, there is an anti-mitochondrial antibody present
103
Cirrhosis - what is the fibrosis mediated by?
Fibrosis mediated by TGF-β from stellate cells which lie beneath the endothelial cells that line the sinusoids
104
Which hepatitis is immunization available for?
ONLY available for hepatitis A
105
pancreatic carcinoma - prognosis
very poor; 1-year survival is
106
How does rupture of a posterior duodenal ulcer increase risk for acute pancreatitis?
Head of pancreas sits posterior to the duodenum.
107
Gallstone ileus
* Gallstone enters and obstructs the small bowel
* Due to cholecystitis with fistula formation between the gallbladder and small bowel (which would allow the passage of larger stones which can pass and then obstruct the small bowel)
108
Generally, never give a child with a viral illness aspirin. However, there is one disease that may mimic a viral illness but requires the use of aspirin. What is that disease?
Kawasaki Syndrome -- vasculitis that preferentially involves the coronary arteries, but presents with symptoms that mimic a viral illness such as N&V, fever, pain in abdomen or joints, etc...)
109
How does _ineffective erythropoiesis_ cause jaundice?
What are some laboratory findings?
Same reasons as extravascular hemolysis. The BM creates ineffective RBCs that are lysed either intravascularly (in the vessels) or extravascularly (in the spleen)
* High levels of hemolysis overwhelms the conjugating ability of the liver.
* Results in:
* Increased UCB
* Dark urine (despite having increased UCB, the liver is working at maximum efficiency for conjugating meaning there will be increased CB being filtered resulting in a darker urine)
* increased risk for pigmented bilirubin gallstones (increased UCB results in increased risk for stone formation -- pigmented because it bilirubin)
110
Primary biliary cirrhosis - complication(s)
cirrhosis is a late complication
acutely, it causes obstructive jaundice
111
Rotor syndrome
Dubin-Johnson syndrome without the liver discoloration
Deficiency of bilirubin canalicular transport protein --\> increased serum conjugated bilirubin
112
Porcelain gallbladder
Shrunken, hard gallbladder due to chronic inflammation, fibrosis and dystrophic calcification -- makes it very easily visible on xray
A late complication of chronic cholecystitis
Also an indicator for increased risk for carcinoma
113
Cirrhosis - what does portal HTN result in?
1. ascites (fluid in the peritoneal cavity)
2. congestive splenomegaly/hypersplenism (consumption of RBCs by an enlarged spleen)
3. portosystemic shunts (esophageal varices, hemorrhoids, and caput medusae)
* all caused by obstruction
4. hepatorenal syndrome == rapidly developing renal failure secondary to cirrhosis
114
How do you distinguish between metastatic and primary liver tumors?
Metastatic -- multiple nodules
Primary -- most often a single nodule
115
Chronic cholecystitis - clinical presentation
RUQ pain especially after eating
Porcelain gallbladder is a late complication
116
hemochromatosis - laboratory findings (ferritin, TIBC, serum iron, % saturation)
Ferritin -- increased
TIBC -- decreased
serum iron -- increased
% saturation -- increased
117
What is the origin of pancreatic carcinoma?
They arise from the ducts NOT the acinar cells
118
Trousseau syndrome
Episodes of vessel inflammation due to blood clot which are recurrent or appearing in different locations over time (thrombophlebitis migrans or migratory thrombophlebitis)
* Location of the clot is tender and can be felt as a nodule under the skin
* Presents as: swelling, erythema, and tenderness in extremities
Particularly associated with pancreatic and lung cancer
119
What hepatitis infection(s) is(are) associated with only acute hepatitis with no risk for chronic state?
Hep A (HAV)
Hep E (HEV)
120
**Cirrhosis**: end-stage liver damage characterized by disruption of the normal hepatic parenchyma by bands of fibrosis and regenerative nodules of hepatocytes
* Fibrosis mediated by TGF-β from stellate cells which lie beneath the endothelial cells that line the sinusoids
121
Annular pancreas - major concern/complication
duodenal obstruction (remember it wraps around the duodenum -- contraction of pancreas can cause obstruction)
122
How does trauma cause acute pancreatitis? What trauma is most common?
What population is this mostly associated with?
Most common trauma is automobile accidents with children.
Seat belt in children is over the abdomen. Compression of abdominal structures can cause premature release of enzymes resulting in possible premature activation
123
What happens to conjugated bilirubin? How is it excreted out of our bodies?
First is transfered to bile canaliculi to form bile which is stored in gallbladder
When bile is released into the duodenum, intestinal flora convert CB to urobilinogen, which is oxidized to stercobilin (makes stool brown) and urobilin (partially reabsorbed into blood and filtered by kidney, making urine yellow)
124
What factors results in cholelithiasis? (3)
1. supersaturation of cholesterol or bilirubin
2. decreased phospholipids (ie lecithin) or bileacids, both of which increase the solubility of cholesterol
3. stasis
125
Acute vs chronic hepatitis
Acute:
* Inflammation of lobules of liver AND portal tracts w/ apoptosis of hepatocytes
* symptoms
Chronic
* Inflammation predominantly of portal tract
126
Dubin-Johnson syndrome
Deficiency of bilirubin canalicular transport protein (normally responsible for transport of CB into the bile; if it doesn't work, CB will backup and leak into the blood)
Autosomal recessive
Presents with:
* increased conjugated bilirubin
* liver is dark (can't empty via bile duct --\> leakage of bile into to bloodstream and liver --\> pigmentation of liver due to excess bilirubin)
* otherwise NOT clinically significant
127
Acute hepatitis - clinical presentation
* jaundice (mixed CB and UCB)
* dark urine (due to CB)
* fever
* malaise
* nausea
* elevated liver enzymes (ALT \> AST)
* remember AST \> ALT is highly associated with alcohol induced liver damage (alcohol is a direct mitochondrial toxin)
128
What gives urine its yellowish color?
urobilin (a breakdown product of urobilinogen)
129
CB vs UCB
What is more soluble in water?
If urine has a color, what it is due to?
UCB is NOT water soluble. It will stay in the blood until it can be conjugated causing jaundice in the meanwhile.
CB is water soluble. It is what gives urine its color. After it is conjugated, it can finally be filtered by the renal system and secreted which gives urine its color
130
Acute pancreatitis - complications
1. **shock** -- due to peripancreatic hemorrhage and fluid sequestration (from tissue damage)
2. **pancreatic pseudocyst** -- formed by fibrous tissue surrounding liquefactive necrosis and pancreatic enzymes
* presents as an abdominal mass w/ persistent elevated serum amylase
* rupture is associated w/ release of enzymes into the abdominal cavity and hemorrhage
3. **pancreatic abscess** -- often due to *E. coli* -- presents with abdominal pain, high fever and persistently elevated amylase
4. **DIC** -- pancreatic enzymes in blood can activate coagulation factors
5. **ARDS** -- enzymes chewing up the alveolar-capillary interface
131
Jaundice by acute hepatits -- what is it due to?
Mixed CB and UCB
* remember that acute hepatitis causes damage to both the bile ductules and the hepatocytes
* dmg to ductules --\> increased CB
* dmg to hepatocytes --\> increased UCB
132
Clinical causes of jaundice?
1. Extravascular hemolysis or ineffective erythropoeisis
2. Physiologic jaundice of the newborn
3. Gilbert syndrome
4. Crigler-Najjar syndrome
5. Dubin-Johnson syndrome
6. Biliary tract obstruction (obstructive jaundice)
7. Viral hepatitis
133
Breakdown products of urobilinogen
Oxidation into:
* stercobilin (makes stool brown)
* urobilin (makes urine yellow, partially reabsorbed)
134
Cirrhosis - what happens to protein synthesis?
What is a result of this?
Liver makes albumin and a lot of other proteins. Cirrhosis --\> damage to liver --\> decreased protein synthesis
Results in:
* hypoalbuminemia with edema
* coagulopathy due to decreased synthesis of clotting factors --\> increased PT and PTT
* degree of deficiency is followed by PT
* liver makes majority of coagulation factors and responsible for vitamin K epoxide reductase activity
135
Ascending cholangitis - what prevents this from normally happening? What would make some more prone to it?
Increased incidence with choledocholithiasis (presence of 1 or more gallstones in the common bile duct)
* Normally, bile secretions will wash away any bacteria trying to climb up the ducts. If there is an obstruction, the ascending infection is much more feasible because the flow is blocked
136
Ascending cholangitis - clinical presentation
* Sepsis -- high fever and chills (remember it is still an infection by bacteria)
* jaundice (blockade of bile duct --\> bile backup into blood)
* abdominal pain
137
How does estrogen increase the risk of cholesterol stones?
Estrogen:
* increases the activity of Hmg-CoA reductase --\> increased synthesis of cholesterol
* increase lipoprotein receptors on hepatocytes --\> increased cholesterol uptake
Increased cholesterol in liver (where bile synthesis occurs) --\> increased cholesterol in bile --\> stored in gallbladder (where stones can form)
138
Hemochromatosis - treatment
Phlebotomy -- drain blood (essentially just drains iron)
139
Hepatic adenoma - complications?
Risk of rupture and intraperitoneal bleeding, especially during pregnancy
* tumors are subcapsular (right underneath the capsule so it can easily bleed out into the peritoneum) and grow with exposure to estrogen
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Chronic cholecystitis - what finding is classically associated with an increased risk for carcinoma?
Porcelain gallbladder on imaging
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Ascending cholangitis
* Bacterial infection of the bile ducts
* Usually due to an ascending infection with enteric gram-negative bacteria
* Presents as sepsis (high fever and chills), jaundice and abdominal pain
* Increased incidence with choledocholithiasis (stone in common bile duct)
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hepatorenal syndrome
rapidly developing renal failure secondary to cirrhosis
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What helps to keep cholesterol solubilized (2)? (removal of which will likely result in cholesterol stones)
phospholipids (ie lecithin)
bile acids
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How does jaundice in newborns occur?
Newborn liver has transiently low UGT (uridine glucuronyl transferase) activity --\> insufficient conjugating capability --\> Increased UCB --\> jaundice
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Why does biliary tract infection result in gallstones? What type of stones will most likely result?
**bilirubin gallstones** will result from infection -- due to ability of certain bacteria to de-conjugate bilirubin
* Deconjugated bilirubin is much less soluble (esp in water) and will have much higher chance of precipitating out
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Pancreatic carcinoma - most common age group
elderly (average age is 70)
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Association of Budd-Chiari syndrome with hepatocellular carcinoma?
Increased risk for Budd-Chiari syndrome
* liver infarction secondary to hepatic vein obstruction
* presents with painful hepatomegaly and ascites
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Reye syndrome - what is the likely cause of the disease?
Unknown mechanism but it is thought to be related to mitochondrial damage of hepatocytes
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Hepatitis E (HEV) - mode of transmission
How is it most commonly obtained?
fecal-oral transmission
Commonly acquired from contaminated water or undercooked seafood
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Acute pancreatitis - what enzymes would you expect to find in blood?
Elevated lipase and amylase
lipase is more specific for pancreas. Amylase can be from any of the salivary glands
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Chronic cholecystitis
* Chronic inflammation of the gallbladder
* Due to chemical irritation from longstanding cholelithiasis _w/ or w/o_ superimposed bouts of acute cholecystitis
* Characterized by herniation of gallbladder of mucosa into the muscular wall (Rokitansky-Aschoff sinus)
* Presents as vague RUQ pain, especially after eating
* Porcelain gallbladder -- late complication
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Acute pancreatitis - most common causes
Most common:
* **alcohol** -- causes contraction of sphincter of Oddi at the ampulla where the pancreatic/bile ducts drain into the duodenum
* **gallstones** -- obstruction
Other causes:
* trauma -- automobile accidents where compression of the abdominal cavity (esp in children) --\> premature release and activation of enzymes
* hypercalcemia
* hyperlipidemia
* drugs
* scorpion stings
* mumps
* rupture of a posterior duodenal ulcer (head of pancreas sit slightly posterior to the duodenum)
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What does iron look like on biopsy? How do you distinguish it out?
Looks like lipofuscin (a brown pigment that is a by-product of the 'wear-and-tear' of peroxidized lipids that piles up in lysosomes)
Prussian blue can be used to distinguish iron (blue) from lipofuscin (does not stain)
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Alcoholic hepatitis: what happens to AST and ALT? Which one is higher?
Both increase due to damage to liver
AST \> ALT
* AST is located in the mitochondria. Alcohol is a mitochondrial poison --\> preferentially increases AST over ALT, but both will increased due to damage to hepatocytes
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Biliary atresia
Failure to form OR early destruction of extrahepatic biliary tree
Leads to biliary obstruction within the first 2 months of life
presents with jaundice and progresses to cirrhosis (due to back pressure into liver which over time will cause damage to liver cells)
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Biliary atresia - clinical presentation
Jaundice -- leakage of bile (containing conjugated bilirubin) into blood
cirrhosis -- backup/pressure into liver over time causing damage to liver cells
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Hepatocellular carcinoma - risk factors?
* Chronic hepatitis (HBV, HCV)
* Cirrhosis (ie alcohol, nonalcoholic fatty liver disease, hemochromatosis, Wilson disease, A1AT deficiency)
* Aflaxtoxins derived from Aspergillus (induce p53 mutations)
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What type of necrosis is associated with acute pancreatitis?
Liquefactive hemorrhagic necrosis (lot of blood vessels in the pancreas)
Fat necrosis of peripancreatic fat
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Alcoholic hepatitis - clinical presentation
* Painful hepatomegaly
* elevated liver enzymes (AST\>ALT)
* AST is located in the mitochondria. Alcohol is a mitochondrial poison --\> preferentially increases AST over ALT, but both will increased due to damage to hepatocytes
* May result in death
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What is the association between cystic fibrosis and pancreatitis?
Thick secretions from pancreas --\> slower motility (more travel time) --\> increased chance of premature activation
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What cells are responsible for extravascular hemolysis? What are the breakdown products?
splenic macrophages in the reticuloendothelial system.
hemolysis of RBCs results in heme, iron and globin
* Globin --\> broken down into amino acids
* Iron --\> recycled
* Heme --\> broken down into unconjugated bilirubin
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viral hepatitis - what happens to the levels of urine urobilinogen?
The gut bacteria is responsible for forming urobilinogen.
Urine urobilinogen levels should be normal, if not less.
* If hepatocytes are damaged, then there is less CB to release into the gut.
* If the bile ductules are damaged then can't put the CB into the gut
* Either way, likely will result in less urobilinogen (and thus less in the urine) if not normal
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How does _extravascular hemolysis_ cause jaundice?
What are some laboratory findings?
High levels of hemolysis overwhelms the conjugating ability of the liver.
Results in:
* Increased UCB
* Dark urine (despite having increased UCB, the liver is working at maximum efficiency for conjugating meaning there will be increased CB being filtered resulting in a darker urine)
* increased risk for pigmented bilirubin gallstones (increased UCB results in increased risk for stone formation -- pigmented because it bilirubin)
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what enzyme is responsible for bilirubin conjugation?
where does this occur?
Uridine glucuronyl transferase (UGT)
Occurs in the liver
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What is the marker that indicates an active hepatitis infection?
Anti-virus IgM
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If dark urine is due to bilirubin, what type of bilirubin is it associated with? Why?
Conjugated bilirubin. CB in the blood is filtered by the renal system resulting in pigmentation in the urine
UCB is not water soluble and will NOT be dumped into the urine.
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Pancreatic carcinoma - treatment
Whipple procedure -- en bloc (all together at the same time) removal of the head and neck of pancreas, proximal duodenum and gallbladder
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Acute pancreatitis
* Inflammation and hemorrhage of the pancreas
* Due to autodigestion of pancreatic parenchyma by pancreatic enzymes
* Results in liquefactive hemorrhagic necrosis of the pancreas and fat necorsis of the peripancreatic fat
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Wilson disease - treatment
D-penicillamine (chelates copper)
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What age group does cholecystitis classically affect?
40-50 year olds
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What is a long-term complication of alcohol-induced liver damage?
Cirrhosis - occurs in 10-20% of alcoholics
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Primary hemochromatosis
Most commonly due to mtuations in the HFE gene (C282Y mutation -- cysteine is replaced by tyrosine)
* puts the intestinal iron absorption into overdrive
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Metastatic liver tumors -- what is the physical exam finding?
Hepatomegaly with a nodular free edge of the liver
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Earliest sign of jaundice
Scleral icterus (yellow discoloration of the sclera)
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Why are iron and copper associated with hepatocellular carcinoma?
Both induce the fenton reaction. If there is too much iron (hemochromatosis) or copper (Wilson disease) then there will be an increase in generation of hydroxy radicals which can cause damage to DNA
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thrombophlebitis
vessel inflammation due to a blood clot
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Where is inflammation in acute hepatitis?
* involves lobules and liver AND portal tracts
* characterized by apoptosis of hepatocytes
* Figure: inflammation pretty much everywhere, both in the tracts and within the lobules in the liver (surroundings the hepatocytes)
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Hepatitis C (HCV) - mode of transmission
How is it most commonly obtained?
Parenteral transmission (via piercing of the skin or the mucosa)
* IV drug abuse
* unprotected intercourse
Risk of transfusion is almost nonexistent due to the screening for the blood supply
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Acute pancreatitis - how does hypocalcemia occur?
Fat necrosis --\> release of free fatty acids --\> saponification (fat binding to calcium)
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Pancreatic carcinoma - serum tumor marker
CA 19-9 (CA = cancer antigen)
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pancreatic pseudocyst
* pseudocyst because it lacks an epithelial lining (remember it surrounds pancreatic enzymes, very likely that the enzymes just ate up the cells and left behind the fibrotic material)
* formed by fibrous tissue surrounding liquefactive necrosis and pancreatic enzymes
* presents as an abdominal mass w/ persistent elevated serum amylase
* rupture is associated w/ release of enzymes into the abdominal cavity and hemorrhage
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What kind of coagulopathy do you expect with cirrhosis? Why?
1. Decreased coagulability due to decreased synthesis of clotting factors --\> increased PT and PTT
* degree of deficiency is followed by PT (just like how warfarin is used -- blocks epoxide reductase)
2. liver is responsible for vitamin K epoxide reductase activity
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Wilson disease
Autosomal recessive defect (ATP7B gene) in ATP-mediated hepatocyte copper transport
* Results in lack of copper transport into bile and lack of copper incorporation into ceruloplasmin
* Copper builds up in hepatocytes, leaks into serum, and deposits within tissues
* Copper-mediated production of hydroxy free radicals --\> tissue damage
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Kernicterus
deposit of UCB in the basal ganglia resulting in neurological deficits and death
Increased risk when there is elevated in UCB in neonates or fetus
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If a patient with hepatocellular carinoma presents with painful hepatomegaly and ascites, what would you expect?
Likely liver infarction secondary to hepatic vein obstruction (Budd-Chiari syndrome)
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What organ does mumps virus classically affect? What other organs does it hit?
Mainly infects the parotid
Also classically hits:
* testicles (orchitis)
* pancreas (pancreatitis)
* meninges (meningitis)
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When there is fat necrosis in acute pancreatitis, what comes to mind? (Severity of disease? Complications?)
* Since the fat is surrounding the pancreas, when there is fat necrosis, it is a sign of how bad the damage has gotten that it is now destroying the fat that surrounds the pancreas.
* Additionally, the release of fatty acids in fat necrosis results in saponification (binding to calcium) which can induce a hypocalcemia.
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Acute cholecystitis - Why is there an increase in serum alkaline phosphatase levels?
What other cancer(s) would you think of when you see an elevated alkaline phosphatase?
The surface epithelium of gallbladder and biliary tract contain alkaline phosphatase
This is also characteristically seen in bone cancer
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If a patient recovers from a bout of acute pancreatitis but has persistently elevated serum amylase, what do you think of? (2)
How would you distinguish them apart?
Possible pancreatic pseudocyst or pancreatic abscess
Can be distinguish by other symptoms. Pseudocyst will have relatively nothing else besides an abdominal mass while pancreatic abscess (often due to *E. coli* ) will have high fever and abdominal pain
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Hallmark of cirrhosis
broad bands of fibrosis that separates nodules of liver parenchyma
* these nodules are regenerative attempts to heal itself, but is impeded by the fibrosis present
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Cholestyramine -- what is it used for? Mechanism?
What is its association with cholelithiasis?
Bile acid sequestrant --\> prevents recycling of bile acids by the ileum
Decreases bile acids in the body. Bile acids normally help to solubilize cholesterol so that stones do not form
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What 2 syndromes are associated with decreased UGT (uridine glucuronyl transferase) activity?
Gilbert syndrome -- mildly low UGT activity
Crigler-Najjar syndrome -- absence of UGT
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What is the common principle in causes of acute pancreatitis?
**Obstruction** --\> stops the flow of enzymes out of the pancreas. Enzymes are secreted only when needed (ie upon eating). The longer the enzymes sit in the ducts, the more likely they can be randomly activated.
Activation of trypsin will start a chain reaction that activates all the other digestive enzymes.
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Crigler-Najjar syndrome
Absence of UGT
Results in kernicterus and is usually fatal
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Metastatic cancers in the liver
More common than primary liver tumors
Most common sources include:
* colon
* pancreas
* lung
* breast carcinomas
Results in multiple nodules in the liver
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A patient presents with obstructive jaundice. Biopsy of the liver shows autoimmune granulomatous destruction of the intrahepatic bile ducts. Labs show the presence of an antimitochondrial antibody. What is at the top of the Dx?
Primary biliary cirrhosis
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Hepatitis D (HDV) - mode of transmission
How is it most commonly obtained?
Dependent on HBV for infection
* superinfection = hep D superimposed on a hep B infection (hep B then hep D)
* coinfection = hep D + hep B together
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Biliary tract infections -- what bugs are most commonly seen to cause stone formation?
1. *E coli*
2. *Ascaris lumbricoides*
* common roundworm that infects 25% of the world's population
* especially affects areas with poor sanitation (fecal-oral transmission)
3. *Clonorchis sinensis*
* endemic in China, Korea, and Vietnam (Chinese liver fluke)
* infects biliary tract, increasing risk for gallstones, cholangitis and cholangiocarcinoma
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Gilbert syndrome
Mildly low UGT activity
autosomal recessive
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What compound gives stool its color?
Stercobilin -- breakdown product (via oxidation) of urobilinogen
201
Pancreatic carcinoma - most common location
head of pancreas
202
Cirrhosis - clinical features
1. Portal HTN leads to
* ascites (fluid in the peritoneal cavity)
* congestive splenomegaly/hypersplenism (consumption of RBCs by an enlarged spleen)
* portosystemic shunts (esophageal varices, hemorrhoids, and caput medusae)
* hepatorenal syndrome (rapidly developing renal failure secondary to cirrhosis)
2. Decreased detoxification results in
* mental status changes, asterixis, and eventual coma (due to increased serum ammonia) -- metabolic, hence reversible
* gynecomastia, spider angiomata, and palmar erythema due to hyperestrinism
* jaundice (remember liver hepatocytes conjugate bilirubin - cirrhosis --\> damage to hepatocytes)
3. Decreased protein synthesis leads to
* hypoalbuminemia with edema
* coagulopathy due to decreased synthesis of clotting factors; degree of deficiency is followed by PT
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Reye syndrome - clinical presentation
* hypoglycemia
* elevated liver enzymes
* nausea with vomiting
* may progress to coma and death
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Hepatitis A (HAV) - mode of transmission
How is it most commonly obtained?
fecal-oral transmission
Commonly acquired by travelers
205
hemochromatosis - clinical presentation
Classic triad -- all due to iron deposits resulting in damage due from radical formation
1. cirrhosis (iron deposits in the liver)
2. secondary diabetes mellitus (iron deposits in the islets)
3. bronze skin (iron deposits in the skin)
