Unit I, week 3 Flashcards
Two types of hepatocyte death
1) Ballooning Degeneration
2) Necrosis and apoptosis
Ballooning degeneration in hepatocytes
What does it look like?
What type of liver disease is it seen in?
Reversible or irreversible?
hepatocyte swelling and clumping of hepatocyte organelles and keratin filaments with clearing of cytoplasm
Most often seen in steatohepatitis
Reversible injury
Necrosis and apoptosis of hepatocytes
What does it look like?
What type of liver disease is it seen in?
Reversible or irreversible?
decrease cell size with increased eosinophilia of cytoplasm with a small dark nucleus
Seen with ischemia and chronic viral hepatitis
Irreversible injury
Common Inflammation/Etiology Associations:
Neutrophils → ?
Eosinophils → ?
Plasma cells → ?
Lymphocytes → ?
Neutrophils → Steatohepatitis
Eosinophils → drug reaction
Plasma cells → autoimmune hepatitis
Lymphocytes → commonly viral (but also in many other hepatitises)
Location of infiltrate in liver and etiology:
Portal based → ?
Interface inflammation → ?
Zone 3 (around central vein)→ ?
Portal based → biliary disease
Interface inflammation → autoimmune and viral hepatitis
Zone 3 → autoimmune hepatitis or acute cellular rejection (transplant)
Cholestasis causes accumulation of _______ in hepatic parenchyma
This results it ____________
accumulation of BILE in hepatic parenchyma
Cytoplasmic bile in hepatocytes → ballooning degeneration
Can result from obstructive and nonobstructive causes
Fibrosis in the liver:
common end result of ________ within hepatic __________
_______ deposition by __________ in __________
common end result of inflammatory/injury within hepatic parenchyma
Type I Collagen deposition by activated stellate in space of Disse
Pathophysiology of fibrosis in the liver (4)
chronic cycles of injury and regeneration
→ activated stellate cells deposit type I collagen
→ architectural and vascular reorganization
→ cirrhosis
Acute Hepatitis
what is it?
causes? (2)
New onset of symptoms for less than 6 months + elevations in AST/ALT
Causes: acute viral hepatitis, adverse drug reaction
Acute hepatitis
histology
marked LOBULAR DISARRAY and inflammation with numerous necrotic hepatocytes and cholestasis
Does NOT have significant liver fibrosis in background (suggests chronic)
Chronic hepatitis
what is it?
causes? (3)
clinical, serologic, or pathologic evidence of hepatic injury / inflammation for greater than 6 months
Causes: chronic viral hepatitis, autoimmune hepatitis, adverse drug reaction
Histology of chronic hepatitis
less lobular disarray, less prominent inflammation, rare necrotic hepatocytes, slow progression of fibrosis over time - “Patchy”
Chronic hepatitis
Grade represents what?
Stage represents what?
Necroinflammatory activity (GRADE) - amount of inflammation/injury
Degree of fibrosis (STAGE) - cumulative result of injury over time, amount of fibrous tissue deposition
Cirrhosis
end stage histological stage of chronic liver disease of any cause characterized by regenerative nodules surrounded by fibrous tissue
Cirrhosis is characterized by diffuse __________ that divides the liver parenchyma into _______ as a result of _______, _________, and __________
Characterized by diffuse FIBROUS SEPTATION that divides the liver parenchyma into NODULES as a result of:
1) recurring death of hepatocytes
2) deposition of ECM
3) architectural and vascular reorganization
Hepatotropic viruses:
Hepatitis A, B, C, D, E viruses →primary site of infection is hepatocytes
Hepatitis A and Hepatitis E
1) ss/ds RNA/DNA?
2) transmission?
3) can chronic disease occur as a result?
4) Test for by looking for what?
5) HEV has a high mortality rate in who?
1) ssRNA virus
2) Spread via fecal-oral route
3) Never lead to chronic disease - only acute hepatitis
4) Test by looking for IgM and IgG specific antibodies
5) HEV → high mortality among pregnant women
Hepatitis B
1) ss/ds RNA/DNA?
2) transmission?
3) can chronic disease occur as a result?
4) histology - 1 main feature
1) dsDNA virus (integrates into host genome)
2) Blood and bodily fluid transmission - can also get vertical transmission
3) 10% of chronic liver disease - major cause of chronic liver disease worldwide
- Most patients will recover from acute infection, only 5-10% progress to chronic hepatitis
4) Histology: see “ground glass” viral inclusions in hepatocytes
Hepatitis C
1) ss/ds RNA/DNA?
2) transmission?
3) can chronic disease occur as a result? can acute disease result?
1) ssRNA virus
2) Blood and bodily fluid transmission
3) Rarely presents as acute hepatitis
* *Causes 80% of chronic liver disease - MOST patients with Hep C get chronic hepatitis (85% of those infected) (but only 20% of these patients go on to develop cirrhosis)
Histology of Hep C infection
lymphoid aggregates, inflamed portal tract with injury between portal tract and lobule
Hepatitis D
cannot replicate without concurrent HBV infection - can augment HBV infection
→ increases risk of fulminant hepatitis, and faster progression to end stage liver disease
Commonly associated with IV drug abuse
Autoimmune hepatitis: immune mediated attack directed at ________ resulting in ___________
Primary biliary cirrhosis (PBC): autoimmune mediated attack directed at _______________ resulting in ___________
Primary sclerosing cholangitis: autoimmune mediated attack directed at __________ resulting in ___________
Autoimmune hepatitis:
- hepatocytes
- resulting in acute flare that progresses to chronic hepatitis
Primary biliary cirrhosis:
- intrahepatic small caliber bile ducts
- -> inflammatory bile duct destruction
Primary sclerosing cholangitis:
- intrahepatic and extrahepatic LARGE carliber bile ducts
- -> obliterative fibrosis of large caliber bile ducts
Autoimmune hepatitis
Labs (3)
Treatment
More in females or males?
Female > male
Labs:
- Increased AST and ALT, normal ALP
- Positive auto-ab test (ANA, ASMA, anti-LKMB)
- elevated IgG
Treat with steroids
Primary biliary cirrhosis (PBC)
Presentation
more in females or males
insidious onset with pruritus appearing before jaundice
Females»_space; males, middle aged
25% progress to liver failure
Primary biliary cirrhosis (PBC)
Labs
elevated ALP, GGT, and bilirubin with normal/slightly increased AST and ALT
Elevated IgM
Anti-mitochondrial antibody*** = HALLMARK
Primary biliary cirrhosis (PBC)
Histology
lymphocyte mediated bile duct damage, granulomatous duct destruction → no bile ducts left (ductopenia)
Intrahepatic SMALL caliber duct destruction
Primary Sclerosing Cholangitis (PSC)
associated with ________
Increases patients risk for _______
More common in males or females?
Associated with UC
Increased risk for cholangiocarcinoma
Male»_space; female
Primary Sclerosing Cholangitis (PSC)
Presentation
Persistently elevated alkaline phosphatase and no other signs/symptoms
- Serology nonspecific
- Later → fatigue, pruritus, jaundice
Dx with radiology (ERCP or MRCP)
**Causes multiple biliary strictures and areas of dilation (string of pearls)
Primary Sclerosing Cholangitis (PSC)
Histology
periductal “onion-skin” fibrosis → fibrous obliteration of bile duct
Intra and extrahepatic LARGE caliber bile duct involvement
Drug induced liver injury
-intrinsic vs. idiosyncratic
- Relatively common cause of liver injury
- Many patterns of injury mimic other diseases
Intrinsic (dose related - e.g. Acetaminophen) or idiosyncratic (unpredictable)
Acetaminophen Liver Injury
Intrinsic or idiosyncratic?
Pattern of necrosis?
Major cause of ACUTE liver failure that leads to liver transplant in US
Intrinsic (dose-related) hepatotoxin
Centrilobular necrosis (zone 3) - death around central vein -Amount of acetaminophen dictates level of damage
Steatosis
accumulation of fat in hepatocytes, metabolic derangement of hepatocytes
Lipid influx > lipid clearance
Steatohepatitis
hepatocellular injury in association with steatosis +/- overt inflammation
Often chronic and can lead to fibrosis and cirrhosis
TWO TYPES: alcoholic, and non-alcoholic
Causes of Steatohepatitis
alcohol metabolic syndrome, drug injury
Not all causes of steatosis also cause steatohepatitis
Triad of findings in steatohepatitis
steatosis, lobular inflammation, and hepatocyte ballooning degeneration
Alcoholic type Steatohepatitis
AST/ALT ratio > 2, normal ALP, increased GGT
-Alcohol is a large carbohydrate load → liver converts carbs into fats and shuts off B-oxidation of lipids and causes problems with export of lipids → accumulation of lipids in hepatocytes
Histology of Alcoholic vs. non-alcoholic type steatoheptatitis
Alcoholic: MALLORY hyaline and prominent NEUTROPHIL infiltrates
Non-Alcoholic: Fibrosis begins centrilobular (zone 3) → prominent sinusoidal pattern (CHICKEN-WIRE)
Non-Alcoholic type Steatohepatitis
Seen in patients with diabetes, metabolic syndrome, obesity, or adverse drug reaction
Causes hepatic fibrosis over time → cirrhosis
Hereditary hemochromatosis
______ overload due to mutation in _______ on chr ________
inheritance pattern?
Males or females more effected?
iron overload secondary to mutation in HFE gene on chr 6 (autosomal recessive)
Males»_space; females (Northern European descent)
Pathogenesis of injury and damage to the liver in Heridatry Hemochromatosis
→ abnormal regulation of iron absorption in SI → deposition of iron in tissues and hepatocytes
→ injury and fibrosis via oxidative damage
Presentation of Hereditary Hemochromatosis (triad)
Histology?
liver disease, diabetes, heart failure
Histology: iron deposits (Prussian blue stain) in hepatocytes
Wilson’s Disease
______ overload due to mutation in _______ on chr ________
inheritance pattern?
copper overload secondary to mutations in ATP7B gene on chr 13 (autosomal recessive)
Problem with copper transport protein for biliary excretion of copper
Presentation of Wilson’s disease
Histology?
Presentation: neuropsychiatric symptoms + Liver disease and Kayser-Fleischer rings on eye exam
Histology: copper accumulation in hepatocytes
Alpha-1-antitrypsin deficiency
genetic disease characterised by decreased production of ____________
three possible genotypes?
associated with what pulmonary problem?
decreased production of protease inhibitor a1-antitrypsin (autosomal recessive)
PiMM = normal, PiMZ = heterozygote, PiZZ = disease genotype
Associated with pulmonary emphysema
Histology of a1-antitrypsin deficiency
Intracytoplasmic accumulation of PAS +, diastase resistant hyaline globules with progressive fibrosis (abnormally folded A1A)
Budd-Chiari Syndrome
liver enlargement, pain, ascites, with main hepatic vein occlusion
Hepatocellular carcinoma
most common primary MALIGNANT tumor of liver
Malignant neoplasm of hepatocytes
Almost exclusively occurs in patients with chronic liver disease and cirrhosis
-Presents as distinct mass in cirrhotic liver
Prognosis of hepatocellular carcinoma is based on what? (4)
1) size
2) presence of macroscopic and microscopic vascular invasion
3) focality
4) invasion of adjacent structures
Cholangiocarcinoma
malignant neoplasm of _______
major risk factor is _____
prognosis?
malignant neoplasm of bile ducts
Major risk factor is PSC
Poor long-term survival
Hemangioma
benign neoplasm of dilated vascular spaces
Most common primary hepatic tumor
More common in women
Usually small and symptomatic - larger ones may require resection
Focal Nodular Hyperplasia
benign mass-like proliferation of hepatocytes
Arises due to a local vascular flow anomaly
Second most common primary hepatic mass
More common in women
Usually asymptomatic
Hepatocellular adenoma
BENIGN neoplasm of hepatocytes
***Extremely low risk of malignant transformation
Occurs mostly in women of childbearing age
-Associated with contraceptive use
Usually no underlying chronic liver disease
Risk of rupture and abdominal hemorrhage
Usually asymptomatic
AST
- normal function
- Located where?
- Expressed where?
catalyze transfer of amino groups to form hepatic metabolite pyruvate
Located in CYTOSOL and MITOCHONDRIA
Also expressed in NON-HEPATIC TISSUES (heart, skeletal muscle, blood)
When are AST and ALT released?
Released from damaged hepatocytes into blood after hepatocellular injury or death
ALT
- normal function
- Located where?
- Expressed where?
catalyze transfer of amino groups to form hepatic metabolite oxaloacetate
Located in CYTOSOL of hepatocytes
More SPECIFIC FOR HEPATOCELLULAR INJURY than AST, but ALT can still be elevated in nonhepatic conditions
What can cause severe (>15x nml) AST and ALT elevations (7)
1) Acute viral hepatitis (A-E, herpes)
2) medications/toxins
3) ischemic hepatitis
4) autoimmune hepatitis
5) Wilson’s disease
6) Acute Budd-Chiari syndrome
7) hepatic artery ligation or thrombosis
Normal AST/ALT ratio = ______
AST/ALT > 1 –> ?
AST/ALT > 2 –> ?
normal = 0.8
AST/ALT > 1 seen in cirrhosis
AST/ALT > 2 → alcoholic hepatitis
Why is the AST/ALT ratio > 2 in alcoholic hepatitis?
Lower ALT from hepatic deficiency of pyridoxine (B6) in alcoholics which is a cofactor for enzymatic activity of ALT
Higher AST because of damage to mitochondria full of AST
Alkaline phosphatase
normal function
located where?
Removes phosphate groups from nucleotides, proteins and alkaloids
Present in nearly all tissues
(bone, placenta, liver, etc.)
Why would alkaline phosphatase be elevated?
cholestatic or infiltrative disease of the liver, and by disease causing obstruction of biliary system
Also due to bone disease, meds, pregnancy, hepatic and nonhepatic tumors
Where is alkaline phosphatase located in the liver?
how can you differentiate an elevated alk. phos. from liver vs. non-hepatic causes
In liver - isolated to microvilli of bile canaliculus
- Liver alkaline phosphatase more heat stable
- Use y-glutamyltransferase (GGT) or 5’nucleotidase serum levels to confirm liver-specific origin for elevation of alk. phos.
Isolated alkaline phosphatase elevation → (4)
1) Primary biliary cirrhosis (PBC)
- AMA (antimitochondrial antibody) positive → PBC
2) Bile duct obstruction - cholestatic disease (may also have elevated conjugated hyperbilirubinemia)
3) Primary sclerosing cholangitis (PSC)
4) Infiltrative diseases of liver
Bilirubin
Normal heme degradation product, excreted by body via secretion into bile
Requires conjugation (glucuronidation) into water soluble bilirubin forms before biliary secretion
Acts as an antioxidant
Bilirubin is typically elevated due to…
cholestasis, impaired conjugation, or biliary obstruction
Normal bilirubin secretion occurs how? (3 steps)
1) Unconjugated bilirubin taken up into hepatocyte
2) → conjugated into glucuronide form by ER enzyme bilirubin-UGT
3) → water soluble bilirubin (conjugated) secreted across canalicular membrane into bile
Gilbert Syndrome
causes _________ hyperbilirubinemia
diminished production of bilirubin-UGT → unconjugated hyperbilirubinemia
Jaundice occurs during times of stress
Hemolytic Jaundice is due to __________ hyperbilirubinemia
unconjugated hyperbilirubinemia
3 main causes of unconjugated (indirect) hyperbilirubinemia
Gilbert’s syndrome
Hemolysis
Crigler-Najjar syndrome
4 main causes of conjugated (direct) hyperbilirubinemia
Extrahepatic obstruction of bile flow
Intrahepatic cholestasis
Hepatitis
Cirrhosis
How does cirrhosis cause hyperbilirubinemia
Cirrhosis → bilirubin elevation due to increased peripheral RBC destruction and fibrosis of sinusoids
→ jaundice and conjugated hyperbilirubinemia
Prothrombin time and liver function
Assesses the extrinsic clotting pathway
Can asses synthetic function
2 reasons why PTT would be elevated
how do you differentiate these causes?
significant hepatocellular dysfunction, or vitamin K deficiency
How to differentiate?
-Administer subcutaneous vitamin K and assess response
No correction → liver dysfunction
Normalization → vitamin K deficiency
Patterns of liver chemistry tests:
Hepatocellular injury or necrosis → predominant _________ elevation
Cholestatic pattern → predominantly __________ elevation
Hepatocellular injury or necrosis → predominant AST and ALT elevation
Cholestatic pattern → predominantly alkaline phosphatase elevation
What does it mean if you are positive for…
HBsAg
Hepatitis B surface antigen = marker for ACTIVE INFECTION or CHRONIC INFECTION (if present for > 6 months)
What does it mean if you are positive for…
HBsAb
Antibody to HBsAg
Marker of immunity to hepatitis B
**Either vaccinated, or successfully cleared HepB infection
What does it mean if you are positive for…
HBcAb
Hepatitis B core antibody
ONLY in people infected with HepB - marker of ACTIVE or PRIOR INFECTION (not present for vaccinated people)
What does it mean if you are positive for…
HBeAg
Hepatitis B “e” antigen
Marker of high viral load, ACTIVE VIRAL REPLICATION
Goal of treatment is to turn this OFF - E ANTIGEN SEROCONVERSION
What does it mean if you are positive for…
HBeAb
Antibody to hepatitis B “e” antigen
Associated with LOWER VIRAL LOAD
What does it mean if you are positive for…
HBV DNA
presence means active viral replication
Indications for treatment of a Hepatitis B infection (4)
1) HBsAG (+) > 6 months
2) Serum HBV DNA > 10^5 copies/mL
3) Persistent or intermittent elevations in ALT and AST levels
- -> Unlikely to get seroconversion with low ALT
OR if Advanced liver disease (cirrhosis) present
Treatment of HBV infection (2)
1) Interferon (not used anymore - lots of side effects)
2) Nucleoside/nucleotide analogs
Nucleoside/nucleotide analogs used to treat HBV infection (4)
lamivudine, adefovir, entecavir, tenofovir
Fewer side effects
Resistant mutations in some strains
Goal of HBV treatment
achieve HBeAg seroconversion
Goal is NOT to get rid of surface antigen
When is an HCV infection considered chronic and treatment should be initiated?
presence of HCV RNA in blood for > 6 months after infection
Goal of HCV antiviral therapy
clear HCV RNA and remain HCV RNA negative for 12 weeks = Sustained Virological Response (SVR) = CURE
**big difference with HepB - all you are trying to get is seroconversion
Treatment of hereditary hemochromatosis (2)
Therapeutic phlebotomy (1x weekly for one year) + maintenance phlebotomy every 2-4 months
OR chelation therapy with deferoxamine*
Treatment of autoimmune hepatitis
1) Corticosteroids
2) Azathioprine - inhibit T cell replication
- Side effects = reduce WBCs, nausea, pancreatitis
Must continue treatment - 50% chance of flare of AIH with cessation of therapy after achieving 2 year remission
Treatment of primary biliary cirrhosis
Ursodiol (ursodeoxycholic acid)
Treatment of primary sclerosing cholangitis
No effective medical therapy
Treatment = management of complications of biliary obstruction with stenting of strictures and ERCP
Liver transplantation is only long term treatment
Treatment of Wilson’s Disease
chelators (D-penicillamine, trientine)
Zinc can be used once successful chelation of copper has occurred
Treatment of non-alcoholic statohepatitis
Treatment = modify risk factors
-Obesity, type II diabetes, dyslipidemia
How many teeth do adults have?
what age do kids get teeth?
Adult dentition = 8 incisors + 4 canines + 8 premolars + 12 molars = 32 teeth
What age do kids get teeth: age 6 months → full complement of primary teeth by age 3
Periodontal ligament
Periodontal ligament binds tooth to alveolar bone
Early childhood caries (ECC)
3 characteristics
Infectious and transmissible, destroys tooth structure
Etiology of Early Childhood Caries
Bacteria (mutans strep) break down dietary sugars into acids which eat away the tooth
How OFTEN sugar is ingested is more important than how MUCH sugar is eaten at once
First clinical sign of caries
Kids need help brushing teeth until what age?
White spots indicate acids have demineralized enamel (first clinical signs of caries)
Kids need help with brushing until age 6
Oral cancer and precancer
often located in what 3 places
Alcohol and tobacco increase risk of oral cancers
Early lesions may be asymptomatic
MUST LOOK at lateral tongue, floor of mouth, inside of lips = NEGLECTED AREAS
Periodontal disease
etiology
chronic plaque at gum line, bacterial infection, host inflammatory response
Periodontal disease
3 types
Gingivitis: mild gum swelling, tenderness, erythema, bleeding gums with brushing - first most mild stage
Chronic periodontitis: more severe than gingivitis
-Infection and inflammation induce loss of bone and tooth attachment
Aggressive periodontitis: otherwise healthy individual with rapid attachment loss and bone destruction
What makes diabetic glycemic control worse?
Periodontal disease
Poor glycemic control = 3x increased risk of periodontitis and periodontal disease worsens glycemic control → viscous cycle
Periodontal disease and pregnancy
Periodontal disease associated with preterm birth and preeclampsia- dental treatment IS SAFE during pregnancy
Xerostomia
what is it?
what causes it?
Decreased saliva promotes periodontal disease
Typically iatrogenic!
Meds (Steroids, antihistamines, diuretics, anti-HTN, anticholinergic, antidepressants)
Physical exam of patient with cirrhosis (9)
1) Ascites (sign of portal hypertension)
2) Variceal hemorrhage (signs of portal hypertension)
3) Hepatic encephalopathy (sign of portal HTN and liver dysfunction)
4) Jaundice (sign of compromised liver function)
5) Muscle wasting
6) Splenomegaly
7) Enlargement of left lobe of liver
8) Spider angiomata
9) Caput Medusae
Labs in a patient with cirrhosis (4)
1) Hypoalbuminemia
2) Prolonged PTT
3) Hyperbilirubinemia
4) Low platelet count - due to portal HTN and hypersplenism
Radiographic findings in cirrhosis
Nodular liver with caudate lobe hypertrophy, ascites, splenomegaly, venous collaterals, recanalization of umbilical vein, and hepatocellular carcinoma
2 main pathophysiologic causes of portal HTN
portal HTN from
1) increased intra-hepatic resistance (at level of SINUSOIDS in patient with cirrhosis)
2) increased portal venous inflow from splanchnic vasodilation
Increase in intrahepatic vascular resistance (sinusoidal region) in cirrhosis caused by what?
1) Deposition of fibrous tissue and formation of nodules that disrupt architecture of liver → increased resistance to portal blood flow
2) Active vasoconstriction within liver + reduced endothelial NO release → increased resistance
In cirrhosis, portal HTN is at level of sinusoids
What is the mechanism causing splanchnic vasodilation in cirrhosis?
→ Increased shear stress in splanchnic vasculature → increase NO production → splanchnic vasodilation → increased portal blood inflow
→ increases portal HTN
Measurement of Portal Pressure
Hepatic venous pressure gradient (HVPG) = WHVP - FHVP
Wedged hepatic venous pressure (WHVP)
Free Hepatic venous pressure (FHVP) → internal zero (corrects for extravascular, intra abdominal pressure increases)
Patterns of hepatic venous pressure gradient for:
Presinusoidal portal HTN
Sinusoidal portal HTN
Post-sinusoidal portal HTN
Posthepatic portal HTN
Pre-sinusoidal portal HTN (e.g. in schistosomiasis) → no pressure gradient, with portal HTN
Sinusoidal pattern → elevated HVPG (can’t dissipate pressure through liver)
Post-sinusoidal HTN → sinusoids intact, but have outflow obstruction, can’t dissipate pressure → elevated HVPG
Posthepatic portal HTN (e.g in heart failure)
-Have high FHVP - don’t get gradient because the whole system is at higher pressure
Formation of varices
formation of portal systemic collaterals → dilation of coronary and gastric veins → gastroesophageal varices
Variceal hemorrhage
what is the most important predictor of hemorrhage?
occurs when expanding force exceeds its maximal wall tension
Most important predictor of hemorrhage is variceal SIZE
Treatment of varices
1) Pharmacotherapy (vasoconstrictors, venodilators)
2) Endoscopic Variceal Band Ligation - can be used prophylactically
3) Shunt therapy (TIPS)
Octreotide
THIS WILL BE ON TEST
Vasoconstrictor - reduce portal blood inflow
Decreases splanchnic flow by causing splanchnic vasoconstriction → reduce portal pressure
Give to a patient when they come into the ER with variceal bleeding
Transjugular Portosystemic Shunt (TIPS)
corrects portal HTN by creating communication between hypertensive portal system and low pressure systemic veins, bypassing the liver
Connects hepatic vein and portal vein
Can cause complications due to liver bypass → encephalopathy, liver failure
Pathophysiology of ascites
Elevated portal pressure → increase in NO production in splanchnic and systemic circulations → potent vasodilation
→ decreased effective arterial blood volume
→ activate neurohumoral systems (renin, angiotensin, aldosterone), and sodium and water retention → ASCITES
In advanced cirrhosis get translocation of bacteria from gut that further increases NO production
Causes of ascites (3)
how do you differentiate these?
cirrhosis
peritoneal pathology (malignancy or TB)
heart failure
Differentiate with pericentesis (SAAG + total protein)
Complications of ascites (2)
Spontaneous bacterial peritonitis
Hepatorenal syndrome
Paracentesis
used to determine if infected and differentiate between causes of ascites - should be done in anyone with ascites
Assess SAAG, total protein, PMN count, and cultures
Serum-ascites albumin gradient***
SAAG > 1.1 g/dL –> ?
SAAG < 1.1 g/dL –> ?
SAAG = serum albumin - ascites albumin
SAAG > 1.1 g/dL → ascites due to sinusoidal HTN (or Heart failure)
SAAG < 1.1 g/dL → ascites due to peritoneal malignancy
-NOT due to sinusoidal HTN, or HF
Ascites total protein:***
Total protein > 2.5 g/dL →?
Total protein > 2.5 g/dL → Heart failure or peritoneal malignancy
-Loss of protein through normal “leaky” sinusoid as opposed to capillarized sinusoids seen in cirrhosis = Heart failure cause
Total protein < 2.5 and SAAG > 1.1 → ascites due to _______
Total protein > 2.5 and SAAG > 1.1 → ascites due to ______
Total protein > 2.5 and SAAG < 1.1 → ascites due to _______
Total protein < 2.5 and SAAG > 1.1 → ascites due to cirrhosis
Total protein > 2.5 and SAAG > 1.1 → ascites due to heart failure
Total protein > 2.5 and SAAG < 1.1 → ascites due to peritoneal malignancy
Treatment of ascites (4)
1) Diuretics and sodium restriction
2) Albumin
3) Large volume paracentesis
4) TIPS - can be used to deal with ascites refractory to diuretic tx
Hepatorenal Syndrome: (HRS)
Occurs in advanced cirrhosis due to drop in effective arterial blood volume and renal vasoconstriction → renal dysfunction and reduced GFR
Liver transplant is curative if transplant performed within 4-6 weeks before irreversible ischemic damage occurs
Kidney themselves are not damaged, they just get reduced blood flow due to significant systemic vasodilation
Criteria for diagnosis of hepatorenal syndrome
Cr > 1.5 or CrCl l< 40 ml/min
No improvement of renal function after plasma volume expansion
Ascites + Hyponatremia universal in HRS
Spontaneous Bacterial Peritonitis
infection of ascitic fluid
Pathophysiology: migration of viable microorganisms from intestinal lumen to mesenteric lymph nodes and other extraintestinal organs and sites
Typically caused by E. Coli
Treatment and diagnosis of spontaneous bacterial peritonitis
TX: abx (avoid aminoglycosides - nephrotoxic)
Dx: ascites with PMN count > 250 /mm^3
Hepatic encephalopathy
neuropsych manifestations of cirrhosis
Due to portosystemic shunting and failure to metabolize neurotoxic substances
- Astrocytes are only cells in brain that can metabolize ammonia
- Ammonia crosses BBB → dysregulation of GABA-BD receptors
Can’t use ammonia levels to diagnose
Risk factors that worsen hepatic encephalopathy (6)
1) High protein load
2) GI bleeding
3) Infection
4) Over diuresis → azotemia and hypokalemia
5) Narcotics and sedatives
6) TIPS ** commonly causes HE
Treatment of hepatic encephalopathy - reasoning?
Lactulose (laxative that acidifies stool, trapping NH4+ in stool and increases bowel movement)
Model for End-Stage Liver Disease (MELD score)
estimates 3 month mortality in pts with cirrhosis
Used to rank patients on liver transplant list
Derived from total bilirubin, creatinine, and INR (now sodium also)
Th1 T helper cells
2 main functions?
secrete _______ and activate __________
_______ helps CTL get activated when they recognize antigen
recognize antigen, attract macrophages
IFNy → activate M1 (inflammatory, “angry”) macrophages
IL-2 → helps CTL get activated when they recognize antigen
Th17 helper T cells
secrete _______
Dendritic cells can make _______ –> pushes differentiation into Th17
-This is considered a central cytokine in what two diseases?
inflammatory role, more potent than Th1 cells
Secrete IL-17
Dendritic cells can make IL-23 → pushes differentiation into Th17
IL-23 considered a central cytokine in Crohn Disease and UC
Th2 helper T cells
stimulate ______ to promote ___________ and __________
stimulate macrophages to become M2 (alternatively activated) → wall off pathogens, promote healing
Th2 helper cells make ______ to attract ________ and _______
important for _________
Make IL-4 → attract eosinophils and macrophages
Important in parasite immunity if Th1’s M1 macs can’t kill invader
-Typically occurs after pathogen killing Th1 response
Follicular helper T cells (Tfh)
stimulated by antigen and migrate from T cell areas of lymph nodes into B cell follicles → help B cells get activated and make IgM, IgG, IgE, and IgA
Regulatory T cells (Treg)
make cytokines (_____ and _____) –> do what function?
This is the predominant T cell type where?
Make cytokines (IL-10, TGF-B) → suppress activation and function of Th1, Th17, and Th2 cells → keep immune response in check
Predominant T cell type in healthy gut
Cytotoxic killer T cells (CTL)
make ______ –> attract ______
Make IFNy → attract macrophages that eat cells induced to die via apoptosis
Cytotoxic killer T cells (CTL)
destroy any body cell they identify as foreign or abnormal antigen on surface presented on class I MHC
T cell development
Pre T cells in thymus proliferate → express T cell receptor via random V(D)J → use TCR to examine stromal cell surfaces with 3 possible outcomes:
1) Nonselection
2) Negative selection
3) Positive selection
1) Non-Selection
2) Negative Selection
3) Positive Selection
1) Non-Selection: no affinity between TCR and MHC
2) Negative-Selection: high affinity for self peptide in MHC → T cell dies by apoptosis (prevent autoimmunity) OR turns into a Treg
3) Positive selection: low affinity, T cell selected to mature
Th0 cells (undecided precursors) located in _________ –> APC presents correct antigen in lymphoid tissues –> ?
located in PARACORTEX of lymph nodes
→ APC presents correct antigen in lymphoid tissues
→ divide and differentiate into Th1, Th17, Th2, Tfh, or Treg
Determinants of differentiation of Th0 cells
conditions in periphery when APC was stimulated, what TLRs were engaged, and what cytokines/chemokines predominate
Normal Peyer’s Patches
Th0 in gut binds peptide/MHC in presence of TGF-B → ONLY turns into a Treg (iTreg)
Local dendritic cells made IL-10 → favor Treg development
Abundant Tfh cells that drive B cells towards IgA production
Recognition of normal commensal gut organisms
recognition of organisms by innate immunity via pattern recognition receptors that bind PAMPs
→ formation of iTregs (induced by exposure to normal flora) → prevent chronic inflammation
Abnormal Peyer’s Patches
TGF-B + IL-6 → downregulate Treg and upregulate Th1 and Th17
IL-6 produced in response to stress or damage
Th0 cell in gut binds peptide/MHC in presence of TGF-B + IL-6 turns into a Th1, Th2, or Th17
Celiac disease and HLA
HLA-DQ2, HLA-DQ8 → specially present peptides derived from gliadin to Th1 and Th17 cells (MUST have these HLA to get Celiac’s)
→ B cells with anti-TTG2 antibodies activated by Tfh cells to make IgA anti-tTG
Is celiac disease an autoimmunity?
Celiac disease itself is NOT autoimmune, but dermatitis herpetiformis is
Anti-tTG ab (self) only made when gliadin (foreign peptide) also present
Non-celiac gluten sensitivity:
Negative blood tests for celiac disease AND no sign of damage on intestinal biopsy
Symptoms improvement when gluten is removed from diet
Recurrence of symptoms when gluten is reintroduced
No other explanation for symptoms
NOT HLA-DQ2 and 8 associated but may be a food allergy
Cephalic phase:
________ enzyme in saliva digests carbs
_______ sequesters iron to limit bacterial growth
________ neutralizes refluxed gastric acid
_________ pore forming antimicrobial enzyme
Stimulation of pancreatic release of digestive enzymes via the ENS is mediated primarily by _______
AMYLASE
LACTOFERRIN
HCO3-
LYSOZYME
ACH
Salivary innervation:
_________ increased acinar cell secretion and vasodilation of blood vessels surrounding the acini (results in protein rich and fluid/ion rich solution)
_________ increased acinar cell secretion (results in high protein/low fluid solution)
Parasympathetic
Sympathetic
Slow or fast, or both?
Saliva contains less HCO3- → ?
Acinar secretions are isotonic → ?
Ductal cells absorb more Na+ → ?
Ductal cells absorb less Cl- → ?
Ductal cells secrete K+ → ?
Saliva contains less HCO3- → SLOW
Acinar secretions are isotonic → BOTH
Ductal cells absorb more Na+ → SLOW
Ductal cells absorb less Cl- → FAST
Ductal cells secrete K+ → BOTH
Involuntary phase of swallowing begins at ____________
closing of epiglottis
Spasmogen or relaxant:
Substance P → ? VIP → ? ATP → ? Acetylcholine → ? Nitric oxide → ?
Spasmogen or relaxant:
Substance P → Spasmogen VIP → relaxant ATP → relaxant Acetylcholine → Spasmogen Nitric oxide → Relaxant
Stimulation of gastric acid secretin:
Neurocrine → ?
Paracrine → ?
Endocrine → ?
Stimulation of gastric acid secretin:
Neurocrine → ACh (M3 receptors)
Paracrine → Histamine (H2 receptors)
Endocrine → Gastrin
Intestinal phase:
___________ enzymes secreted from __________ cells to break down proteins into AAs
_______ is generated by proton pumps and secreted by parietal cells
________ breaks down the a1-4 bond of amylose and amylopectin yielding maltotriose and glucose
Protease, Acinar
HCl
Amylase (not B-1,4)
Intestinal phase
_______ cells produce bicarbonate solution to liquify and neutralized the _________ in the duodenum that has a low pH
Decreased intestinal pH stimulates release of the enzyme __________ which in turn drives bicarbonate release from the pancreas
Ductal, chyme
Secretin
Duodenal detection:
Fats and AA in the intestine compete for the enzyme trypsin allowing for signaling by ________ and __________ to increase the release of _________ from duodenal I cells
______ then acts back on the pancreas to increase release of digestive enzymes into the duodenal lumen via relaxation of the __________
CCK-RF and Monitor Peptide, CCK
CCK, Sphincter of Oddi
Duodenal detection:
This causes contraction of the __________ to facilitate the release of __________ which aids fat digestion and absorption
It also has a negative effect on _________ motility and __________ emptying
Gallbladder, bile
Gastric, gastric
Salivary vs. Pancreatic
Myoepithelial cells → ? ACh drives secretion → ? Partially hormonally regulated → ? Responds to blood flow → ? Rich in KHCO3 → ?
Myoepithelial cells → salivary
ACh drives secretion → salivary and pancreatic
Partially hormonally regulated → pancreatic
Responds to blood flow → salivary
Rich in KHCO3 → salivary
Fat absorption:
Primary bile acids are produced in the liver from __________
Secondary bile acids are formed by ___________ in the intestines and colon
Bile acids are complexed with glycine or taurine to make ____________
Cholesterol
Bacteria
Bile salts
Bile is recycled during a meal by uptake in the _____________
-Mechanism mediated by _________
Dietary fats are broken down by _________ and ___________ lipase
__________ lipase hydrolyses triglycerides into FFAs
Distal ileum
enterohepatic circulation
Lingual and gastric
Pancreas
Bile salts solubilize fats into _____________ and FFAs are transported into enterocytes
FFA are esterified into triglycerides bound to proteins such as apolipoproteins and exported out of the cells through __________ in the form of ___________
Micelles
Lacteals, chylomicrons
Fat soluble vitamins such as ____________
While water soluble vitamins either use ______________ e.g. biotin or folic acid or are taken up via specific transporters e.g. ______________
ADEK
Simple diffusion, B12
Iron absorption:
Mostly absorbed in the jejunum, ______ absorption is often linked with the transport of other dietary components
Intracellular concentration of _____ is made artificially high by the __________ pump
Secretion of ________ into the lumen draws water with it during secretory diarrhea
Na+
K+, Na+/K+
Cl-
Severe diarrhea or dehydration can cause significant loss of ______ leading to cardiac dysrhythmia
Both ______ and __________ compete for absorption into enterocytes
K+
Mg2+ and Ca2+
________ sphincter is closed to prevent reflux of bacteria
Opened by distention of the distal ________ (local reflex)
Closed by distention of the proximal ________ (local reflex)
The _______ has the lowest paracellular permeability to water in the GIT due to its role in solidifying waste
Ileocecal
Ileum
Colon
Colon
_________ are muscles that run along the colon but are shorter than it
__________ folds allow expansion while supporting the weight of the digesta
The ___________ is a small pouch that give the colon its segmented appearance
The colon does not experience _______________ but rather mass movements which is a good thing
Taenia Coli
Semilunar
Haustrum
MMC
Defecation:
Filling of the _________ with stool causes relaxation of the _________ anal sphincter
This is mediated via intrinsic neuron derived _________ and ______
Rectum, Internal
VIP and NO
This causes automatic contraction of the ________ anal sphincter also known as ___________ reflex
Voluntary relaxation of the _______ anal sphincter and increased ________ pressure result in ___________
External, Rectoanal inhibitory
External, abdominal, defecation
___________= intrinsic hepatotoxin
Causes confluent ________ necrosis in the_________ region (zone ?), with significant inflammatory cell infiltrate
One of the more common causes of __________
Acetaminophen
coagulative
centrilobular (zone 3)
acute liver failure
Hepatitis A (main points from review sesh)
can be from EATING CONTAMINATED STRAWBERRIES
ONLY CAUSES ACUTE HEPATITIS
A and E are fecal/oral - vowels hit your bowels
Hepatitis B (main points from review sesh)
Transmitted in blood/bodily fluids, vertical transmission
DNA virus
Progress to chronic liver disease in only a minority of adult infected patients
There is a vaccine
Hepatitis C (main points from review sesh)
Transmitted by blood/bodily fluids
RNA virus
Most progress to chronic hepatitis
Diagnosis via anti-HCV abs or by serum HCV PCR
NO vaccine
Asymptomatic in acute infection, then can progress to chronic hepatitis 80-85% of time (only 20% then progress to cirrhosis)
Hepatitis D (main points from review sesh)
requires coinfection
Hepatitis E
main points from review sesh
Fecal-oral
RNA virus
Higher mortality with pregnant women
Does not cause chronic disease in otherwise healthy people
PAS-positive diastase resistant globules in hepatocytes
emphysema
what am I?
Alpha-1-antitrypsin
IgM Anti-Mitochondrial abs Mostly middle aged women Female predominance Granulomatous lymphocytic cholangitis/florid duct lesion
what am I?
Primary biliary cholangitis (cirrhosis)
IgG
anti-smooth muscle antibody
Plasma cell rich interface and centrilobular hepatitis
female predominance
what am I?
Autoimmune hepatitis
UC
large bile duct strictures
male predominance
cholangiography is a primary diagnostic test
presents with obstructive/cholestatic labs
what am I?
Primary sclerosing cholangitis
tumor of bile ducts
malignant, gland forming (adenocarcinoma) tumor with marked desmoplasia
associated with PSC
malignant neoplasm of bile duct cells**
what am I?
Cholangiocarcinoma
tumor of hepatocytes
malignant, thickened hepatic plates + trabeculae with unpaired arteries
occurs almost exclusively in cirrhosis
most common malignant primary hepatic tumor
what am I?
Hepatocellular carcinoma
tumor of hepatocytes
benign
female predominance
normal hepatic plate thickness with unpaired arteries
associated with oral contraceptives
what am I?
Hepatocellular adenoma
primary tumor of blood vessels, benign
most common benign hepatic tumor
what am I?
Hemangioma
proliferation of hepatocytes
non neoplastic, benign
*central scar and malformed blood vessels
vascular malformation/anomaly etiology
what am I?
Focal nodular hyperplasia
What is STAGE of cirrhosis?
amount of fibrous tissue deposition which tracks the progression of patient towards cirrhosis
Grade = amount of inflammation
