Chap 18- Liver and Gallbladder Flashcards
1
Q
what is the functional unit of the liver
A
lobule
2
Q
liver circulation
A
- portal vein supplies 70%
- hepatic artery supplies 30%
3
Q
how does hepatic BF change with aging?
A
significantly declines
4
Q
result of hepatic ischemia/ hypoxia
A
- temporary protection of hepatocytes
- cellular acidosis protects against hepatocyte death
- adenosine is a hepatoprotector against liver damage by CCl4/ ethanol
5
Q
major functions of liver
A
- detoxification
- metabolism of CHO, fats, proteins
- form coagulation factors
- form bile
- filter/ store blood
- store vitamins and Fe
6
Q
kupffer cells
A
- macrophages found in liver
- located in sinusoids
- removes 99% of bacteria from gut that flows to liver
7
Q
glycogenesis
A
excess glucose after meal is converted to glycogen
8
Q
glycogenolysis
A
decreased glucose between meals stimulates breakdown of glycogen
9
Q
gluconeogenesis
A
exhaustion of glycogen reserves stimulates glucose production from AA and sugars
10
Q
liver protein metabolism
A
- deamination of AA
- removal of ammonia by making urea
- formation of plasma proteins
- synthesis of nonessential AA
11
Q
where does ammonia come from?
A
bacterial degradation of amines, AA, purines, and urea in gut
12
Q
liver fat metabolism
A
- conversion of CHO and proteins to fat
- beta oxidation of fatty acids
- synthesis of lipoproteins
- cholesterol
- phospholipids
13
Q
what coagulation factors does the liver make
A
- prothrombin
- VII
- IX
- X
- requires vitamin K to do so
14
Q
effect of abnormal liver function on coagulation factors
A
- abnormal synthesis
- dysfunctional coagulation factors
- increased consumption
- platelet disorders
15
Q
bilirubin
A
- formed from breakdown of heme
- heme found in hemoglobin, myoglobin, cytochromes, catalase, peroxidase
16
Q
what is the role of heme oxygenase
A
convert heme to unconjugated bilirubin
17
Q
where is heme oxygenase found
A
- spleen
- kupffer cells
18
Q
what is the role of bilirubin conjugation?
A
- unconjugated bilirubin is poorly soluble in water and toxic
- conjugation allows for elimination
19
Q
how does bilirubin conjugation occur
A
through glucuronic acid conjugation in liver
20
Q
urobilinogen
A
- produced in intestines by bacterial breakdown of bilirubin
- partially absorbed in bowel
- mainly excreted in urine
21
Q
when is urinary urobilinogen excretion increased?
A
- excessive bilirubin production
- inefficient hepatic clearance of urobilinogen
- excessive exposure of bilirubin to intestinal bacteria
22
Q
when is urinary urobilinogen excretion reduced?
A
- biliary obstruction
- severe cholestasis
23
Q
causes of elevated serum bilirubin
A
- overproduction
- impaired uptake, conjugation, or excretion
- backward leak from damaged hepatocytes or bile ducts
24
Q
beneficial effects of bilirubin
A
- antioxidant
- protective against CV disease and cancer
- heme oxygenase reduces replication of Hep C virus
25
ways to protect against bilirubin toxicity
- binding to plasma albumin
- rapid uptake
- conjugation
- clearance
26
jaundice
- yellowish tint of body tissues
- classified as either hemolytic or obstructive
- occurs when bilirubin concentrations are 3 times normal
27
hemolytic jaundice
- due to increased destruction of RBC
| - rapid release of bilirubin into blood
28
obstructive jaundice
- obstruction of bile ducts or damage to liver cells
| - results in inability to excrete bilirubin into GIT
29
biochemical markers of liver injury
- serum aminotransferases (ALT* and AST)
- bilirubin and bile acids
- alkaline phosphatase
30
liver function markers
- albumin
| - prothrombin time
31
tests to detect injury to hepatocytes
- serum aminotransferases (ALT* and AST)
| - released when hepatocyte gets injured
32
tests for livers capacity to transport organic anions and metabolize drugs
- bilirubin and bile acids
33
tests for the livers biosynthetic capacity
- serum albumin
| - prothrombin time
34
what enzyme reflects cholestasis
alkaline phosphatase
35
hepatic lymphatic vascular system
- 50% of lymph formed in liver
- fenestrations in sinusoidal endothelial cells leak fluid and proteins into space of disse
- lymph flows through space of disse
36
what is the result of increased sinusoidal pressure?
- increases lymph production
| - fluid accumulates in abdominal cavity -> ascites
37
what signals hepatocytes to enter mitosis
- macrophages
- hepatic stellate cells
- liver sinusoidal endothelial cells
- hepatic stellate cells are not active in healthy liver
38
acute liver failure
- occurs suddenly
- also see encephalopathy and elevated prothrombin time
- no cirrhosis or preexisting liver disease
- duration of <26 weeks
39
what are the main cause of acute liver failure?
- viral
| - drug induced- APAP
40
clinical manifestations of acute liver failure
- liver test abnormalities*
- hepatic encephalopathy*
- prolonged prothrombin/INR*
- jaundice
- hepatomegaly
- r upper quadrant tenderness
- coagulopathy
- increased portal HTN
41
hepatic encephalopathy
- impaired brain function
| - reversible
42
pathogenesis of hepatic encephalopathy
- hyperammonemia
- oxidative stress
- oxindole
43
hyperammonemia
- increases brain uptake of AA -> altered synthesis of DA, NE, and serotonin
- increases intracellular osmolarity in astrocytes
- alters neural electric activity
44
oxindole
- tryptophan metabolite
- formed by gut bacteria
- causes sedation, muscle weakness, hypotension, coma
45
how does APAP cause liver injury?
- converted to NAPQI which is cytotoxic
| - NAPQI binds to proteins and DNA to form adducts
46
acute alcohol ingestion and APAP
- protective to liver
| - alcohol competes with APA for CYP enzymes -> decreased NAPQI produced
47
chronic alcohol ingestion and APAP
- increases CYP activity two fold
| - reduces glutathione levels
48
what are the three possible fates of APAP metabolism?
- produce free NAPQI via CYP
- renal excretion
- conjugation of NAPQI urinary excretion
49
cirrhosis
- late stage progressive hepatic fibrosis
- distortion of hepatic architecture
- irreversible
- requires liver transplant
- associated with chronic liver failure
50
etiology of chronic liver failure and cirrhosis
- chronic viral hepatitis (B and C)
- alcoholic liver disease
- hemochromatosis
- nonalcoholic fatty liver disease
51
what is the main source of hepatic fibrosis
stellate cells that become activated
52
portal HTN
- resistance to portal BF
- often develops in cirrhosis
- develop structural and dynamic changes
53
structural changes with portal HTN
- fibrosis
- angiogenesis
- vascular occlusion
54
dynamic changes with portal HTN
- increased production of vasoconstrictors
| - reduced release of endothelial vasodilators
55
main clinical consequences of portal HTN
- ascites
- congestive splenomegaly
- hepatic encephalopathy
56
ascites
- accumulation of excess fluid in peritoneal cavity
- most often caused by cirrhosis
- portal HTN causes changes in splanchnic circulation
57
liver alcohol metabolism
- generates acetaldehyde in liver via alcohol dehydrogenase (ADH)
- acetaldehyde metabolized to acetate via ALDH
- acetaldehyde can produce liver injury
58
gastric alcohol metabolism
- stomach has ADH activity
| - h pylori and gastritis can reduce activity of gastric ADH
59
alcoholic steatosis
- reduced oxidation of hepatic fatty acids
- increased lipogenesis
- chronic consumption of alcohol increases expression of genes like fatty acid synthase
60
alcoholic steatohepatitis
- cytokine release and inflammation
- antigenic adduction formation- acetaldehyde and hydroxyethyl radicals
- immunologic
61
types of alcoholic liver disease
- alcoholic steatosis
| - alcoholic steatohepatitis
62
where are iron stores normally found
- Hb in circulating RBC
- iron containing proteins other than Hb
- iron bound to transferrin in plasma
- storage iron as ferritin or hemosiderin
63
causes of iron overload
- increased intake- blood transfusion
| - increased absorption- hereditary hemochromatosis and chronic liver disease
64
what is the main clinical consequence of iron overload?
- organ damage
- when taken into organs it creates hydrogen peroxide
- OH is a ROS -> damage, inflammation, fibrosis
65
transferrin
protein in the blood that transfers iron throughout body
66
what happens when iron burden increases?
- tranferrin becomes saturated
- iron binds to other molecules - non-transferrin bound iron
- NTBI taken up in liver, heart, endocrine organs
67
cause of hereditary hemochromatosis
mutation in HFE gene
68
what is the clinical outcome of hemochromatosis
- increased absorption of iron from intestine
| - fibrosis and cirrhosis due to iron
69
mechanism of liver injury in hereditary hemochromatosis
- lipid peroxidation due to increased ROS
- interaction of ROS with DNA
- activation of stellate cells
70
hemochromatosis pathogenesis
- hepcidin activity is reduced
- have unchecked iron-export by ferroportin in macrophages
- excess iron -> accumulation in tissues and organ damage
71
hepatitis A virus
- self limited
- does NOT become chronic infection
- can prevent with vaccine, immune globulin, proper hygiene
- complete recovery within 6 mo in most pts
72
how is HAV spread?
- contaminated water and food
- shed in stool
- consumption of raw or steamed shellfish
73
pathogenesis of HAV
- replication occurs in hepatocyte
- damage mediated by CD8+ and NK cells
- interferon-gamma promotes clearance of infected hepatocytes
74
what is the incubation period for HAV
- 28 days
| - contagious during incubation pd and 1 week after jaundice appears
75
symptoms of HAV
- N/V
- anorexia
- fever
- malaise
- abdominal pain
- jaundice
- scleral icterus
- hepatomegaly
76
Hep B virus
- global problem
- clinical manifestations vary from either acute or chronic
- outcome depends on age, level of HBV replication, immune status
77
how is HBV spread?
- blood
- semen
- other bodily fluids
- child birth
- needle sharing
78
pathogenesis of HBV
- CD8 mediated
- HBV mutations can affect severity of liver disease
- development of chronic infection
79
acute hepatitis clinical manifestations
- subclinical or anicteric hepatitis
| - more severe in pts with co-infection or underlying liver disease
80
phases of chronic HBV infection
- immune tolerance
- immune clearance- HBeAg pos
- inactive carrier
- reactivation- HBeAg neg
81
hepatitis C virus
- majority of infected are not clinically ill
- no vaccine
- persistent infection and chronic hepatitis are hallmarks
82
how is HCV spread?
- blood borne
| - mostly through sharing needles
83
pathogenesis of HCV
- acute spread through hepatic a, viral replication and INF increase
- chronic hep c
- liver cirrhosis
- hepatocellular carcinoma
84
HCV associated carcinogenesis
- combo of indirect host mediated and direct HCV mediated mechanisms
- persistant inflammation -> ROS damage
- impaired DNA repair
- repeated cycles of destruction and fibrosis -> cancer field
85
nonalcoholic fatty liver disease
- spectrum of disorders
- nonalcoholic fatty liver (NAFL)
- nonalcoholic steatohepatitis (NASH)
86
effect of visceral adipose and intrahepatic fatty acids
- induce gluconeogenesis
- increase production of FFA
- insulin resistance
87
progression of NAFLD
- simple steatosis -> steatohepatitis -> fibrosis
| - simple steatosis is low risk for significant fibrosis
88
pathogenesis of inflammation in NAFLD
- free cholesterol -> liver injury
- kupffer cells secrete pro-inflammatory mediators
- stellate cells increase liver fibrogenesis
- hepatocytes induce lipid peroxidation and lipotoxicty
- mitochondrial dysfuntion
89
insulin resistance and hepatic steatosis
- increased FFA released from adipose
- accumulation in liver
- decreased glucose uptake
- net result=increase glucose production and decreased uptake
- hyperglycemia and hyperinsulinemia -> lipogenesis
90
clinical features of NAFLD/ NASH
- simple steatosis generally asymptomatic
- clinical presentation related to insulin resistance or diabetes
- AST and ALT elevated
- CVD is frequent cause of death
91
bile
- liver secretes 1L/day
- fat emulsification and absorption
- medium for excretion of bilirubin and cholestrol
92
bile salts
- amphipathic
- emulsification of lipids
- transport of lipids
93
cholelithiasis classifications
- pure cholesterol stones
- pigmented- mainly bilirubin
- mixed- varying cholesterol, bilirubin, calcium carbonate, calcium phosphate
94
major risk factors of cholelithiasis
- age and sex- age >40 and female
- environmental factors- estrogen
- acquired disorders
- hereditary factors- ABC transporters
95
conditions that contribute to formation of cholesterol gallstones
- suppression of bile with cholesterol
- hypomotility of gallbladder
- defective conversion of cholesterol to bile acids
- hypersecretion of mucus in gallbladder
96
pathogenesis of pigmented stones
- elevated unconjugated bilirubin in bile from bacterial contamination
- e coli increases likelihood of stone formation
97
clinical features of cholelithiasis
- most are asymptomatic
- most common sx- biliary colic
- pain in RUQ or epigastrium, can radiate to shoulder
- inflammation
98
cholecystitis
- inflammation of gallbladder
| - either acute, acalculous, or chronic
99
acute calculous cholecystitis
- chemical irritation and inflammation of gallbladder obstructed by stones
- mucus layer is disrupted
- prostaglandins released in wall
100
acute acalculous cholecystitis
- d/t ischemia
| - inflammation and edema of wall, gallbladder stasis and accumulation of biliary sludge causes obstruction
101
chronic cholecystitis
- associated with presence of gallstones
- result of mechanical irritation or recurrent attacks of cholecystitis
- results in fibrosis and thickening of gallbladder
102
carcinoma of gallbladder
- uncommon
- highly fatal
- most are dx at advanced stage
103
risk factors for carcinoma of gallbladder
- pt demographics- age, female
- gallbladder abnormalities
- pt exposure i.e. smoking
- infections- salmonella and h pylori
- common thread= chronic inflammation
104
pathogenesis of gallbladder carcinoma
- cholelithiasis
| - mutations in KRAS and p53
105
cholestatic disease
- decrease in bile flow
| - due to hepatocellular impairment of bile formation or obstruction of bile flow
106
clinical presentation of cholestatic disease
- jaundice
- scleral icterus
- pruritis
107
pathogenesis of pruritis in cholestasis
- retention of bile salts
- release of endogenous opioids
- lysophosphatidic acid and autotaxin
108
risk factors for hepatocellular carcinoma
- cirrhosis
- HBV
- HCV
- hereditary hemochromatosis
