LIVER PATHOLOGY
I.
Anatomy/Biochemistry
a. Blood supply: majority from portal v. (rest from hepatic a.)
b. Parenchymal Cells: hepatocytes, “Ito cells” in Space of Disse, Kupffer cells, perisinusoidal
stellate cells
c. Bilirubin Metabolism:
1. Heme----(heme oxygenase)----> Biliverdin
2. Biliverdin----(biliverdin reductase)---> Bilirubin unconjugated
3. Unconjugated Bilirubin binds Albumin and is taken to the liver, then
taken up by an “Anion Binding Protein” which can be blocked by
Rifampin
4. Glucuronidation Rxn:
a. Unconjugated Bilirubin----(UGT)--->Conjugated Bilirubin
i. UGT = UDP-Glucuronosyltransferase-1
ii. UGT Attached to ER
iii. Gene = UGT1A1
5. Conjugated bilirubin secreted in bileduodenum/intestine
6. C-bilirubin transformed into Urobilinogen by flora
7. Urobilinogen is excreted (dark color to poop) or goes back into blood
and excreted in kidneys (urine yellow) or back to liver
II.
Lab Evaluation of Liver Disease (better one in 1st Aid)
Test
Category
Hepatocyte
Integrity
Hepatocyte
Function
Biliary
Excretory
Function
III.
Serum Measurement
Intracellular hepatocyte enzymes
AST
ALT
LDH
Proteins Secreted in Blood
Albumin, Prothrombin Time (Factors 5, 7, 10, porthrombin,
fibrinogen)
Hepatocyte metabolism
Ammonia
Aminopyrine breath test (hepatic demethylation)
Substances normally secreted in Bile
Bilirubin (total & direct)
Urine Bilirubin
Bile acids
Plasma membrane enzymes (from damage to bile canaliculus)
Serum alkaline phosphatase (ALP)
GGT (gamma-glutamyl transpeptidase)
5’-nucleotidase
Liver Failure
a. Acute hepatic failure (does she mean fulminant hepatitis? Basically same thing)
1. Definition = Massive necrosis of liver
2. Cause:
a. Drugs: Acetaminophen (Tylenol), Halothane, Rifampin, Aspirin
(Reye’s Syndrome)
b. Toxins: Mushrooms, Carbon Tetrachloride (CCl4)
c. Infections: Viral Hepatitis A and B (don’t understand this. Why just these
two….whatever.)
b. Chronic hepatic failure
1. Cause: Cirrhosis = Endstage liver damage characterized by disruption of
the normal hepatic parenchyma by bands of fibrosis that separate
parenchymal nodules.
a. Cirrhosis Etiology, Pathogenesis, and Clinical Features (1st Aid,
Pathoma)
c. Clinical Features
1. Jaundice—scleral icterus; increased serum bilirubin
2. Hypoalbuminemia—edema
3. Hyperammonemiahepatic encephalopathy (from elevated ammonia)
4. Hyperestrogenemia
a. Palmar erythema (local vasodilation)
b. Spider angiomas
c. Hypogonadism & Gynecomastia in Males
5. Coagulopathies
6. Hepatorenal syndrome (Renal failure due to liver failure)
a.
IV.
V.
VI.
VII.
HOW? = Portal HTN triggers systemic arterial vasodilation leading to
decreased perfusion of the kidneys despite RAAS activation (pre-renal
azotemia)
Hereditary Hyperbilirubinemias
a. Increase in UC-Bilirubin —absent or decreased activity of UGT1 enz
1. Crigler-Najar Syndrome Type I
a. Absent activity; fatal
2. Crigler-Najar Syndrome Type II
a. Decreased activity; Autodominant
3. Gilbert’s Syndrome
a. Decreased activity
b. Increase in C-Bilirubin—impaired biliary excretion of bilirubin
1. Dubin-Johnson Syndrome
2. Rotor Syndrome
Infectious Hepatitis (A, B, C, D, E)
a. Clinical Course
i. Incubationpreicteric phasesymptomatic/ictericconvalescence (recovery)
b. Carrier State
i. No clinical symptoms but infectious to others; can dx with serology/lab values
c. Morphology
1. Drop-out necrosis
2. Periportal necrosis
3. Fatty change (in Hep C)
4. Ballooning degeneration
Hepatitis A
a. ssRNA virus (naked icosahedral)
b. Incubation: up to 6wks
c. Fecal-oral transmission
d. Mild, self-limiting
e. DX: IgM Ab in acute phase; IgG Ab later indicating immunity
Hepatitis B
a. Hepadnaviridae = dsDNA virus (enveloped)
b. incubation: up to 6months
VIII.
IX.
X.
XI.
XII.
XIII.
c. Parenteral transmission
d. Outcomes
1. Subclinical disease with remission (majority)
2. Acute hepatitis
3. Chronic hepatitis (carrier or chronic cirrhosis)
4. Fulminant hepatitis
e. Predispose to Hepatocellular Carcinoma
f. Markers
1. HBsAg: + = you have it (except window)
2. HBsAb: protective (you defeated it, or are immunized)
3. HBeAg: + = you’re infectious
4. HBcAb: IgM (acute), IgG (chronic or resolved)
5. HBV-DNA: same as HBeAg; indicates infectivity
Hepatitis C
a. Flaviviridae = ssRNA (enveloped)
b. incubation: up to 6months
c. parenteral and close contact transmission
d. Outcomes
1. Recovery
2. Chronic heptatitis (majority)
3. Fulminant (rare)
e. DX: PCR for HCV RNA in acute phase for 1-3wks; HCV Ab after 3-6wks
Hepatitis E
a. Water borne infectionHigh mortality among pregos!
b. DX: PCR for HEV RNA; IgM & IgG Ab’s
Hepatitis D
a. Co-infection with acute HepB (looks like HepB alone)
b. Superinfection in chronic HepB carrier (looks like acute hepatitis in previously
unrecognized HBV carrier)
c. DX: IgM & IgG Ab’s, HDV RNA, HDAg in Liver
Chronic Viral Hepatitis
a. Definition = symptomatic or serological evidence of continuing or relapsing hepatic
disease > 6months (+histologic documentation)
Fulminant Hepatitis
a. Definition = (acute liver failure) when hepatic insufficiency progresses from onset of
symptoms to hepatic encephalopathy within 2-3 weeks
Autoimmune Hepatitis
a. Indistinguishable from viral hepatitis
b. Tx = anti-inflammatory drugs
c.
Assoc with autoimmune disease 60% of the time (but most autoimmune diseases are associated with other autoimmune
diseases)
d. Classification
1. Type 1 Ab’s—Associated with HLA-DR3
a. Anti-ANA Ab
b. Anti-Smooth muscle Ab (SMA)
c. Anti-actin Ab (AAA)
d. Anti liver & pancrease Ab’s (SLA/LP)
2. Type 2 Ab’s
a. Anti-KLM-1 (kidney-liver-microsome-1)
i. A.k.a. Anti-LKM-1
ii. Binds to CYP2D6!
b. Anti-Liver Cytosol-1 (ACL-1)
XIV.
XV.
XVI.
Metabolic Liver Diseases
a. Non Alcoholic Fatty Liver Disease (NAFLD), Steatohepatitis-Steatonecrosis (NASH)
i. Principle cause of Cryptogenic Cirrhosis (unknown cause)
ii. Two Hit Hypothesis—Pathogenesis
1. (hit 1) Hepatic Fat accumulation + (hit 2) Hepatic Oxidative Stress 
2. Lipid Peroxidation  Reactive Oxygen Species  Cell damage
b. Hemochromatosis
i. Excess Fe leads to deposits/free radical damage of organs including liver
ii. Deficiency of Hepcidin (no longer can stop release of Fe into blood from
Macrophages nor Intestinal cell)
iii. Mutation of HFE gene on chrom 6
1. Cysteine  Tyrosine Mutation on AA 282 = C282Y
iv. Clinical Fx’s (“Bronze Diabetes”)
1. Joint pain
2. Bronze Skin
3. Diabetes
4. Erectile dysfunction/atrophy of testicles
5. Arrhythmias (& CHF)
v. Hemosiderosis = Fe deposition in tissues due to transfusions; see iron in Kupffer
cells; NO cirrhosis
c. Wilson’s Disease
d. Alpha-1 Antitrypsin Deficiency
i. Results in hepatitis/cirrhosis and emphysema (esp. PiZZ genotype)
ii. PAS+ cytoplasmic inclusions in liver
iii. Hepatitis presents neonatally or late onset
Intrahepatic Biliary Disease
a. Secondary Biliary Cirrhosis
i. Extrahepatic biliary obstruction (gallstone, biliary stricture, chornic pancreatitis,
carcinoma of pancreatic headj
ii. Sx’s = Pruritis, jaundice, dark urine, light stools, hepatosplenomegaly
iii. Lab = increase in C-bilirubin, cholesterol, bile acids and ALP
iv. Histo: bile ductular proliferation with surrounding PMNs and portal tract edema
b. Primary Biliary Cirrhosis—autoimmune
i. Labs & Sx’s same as secondary; + anti-mitochondrial IgM Ab
ii. Histo: See dense lymphocytic infiltrate in portal tracts + granulomatous
destruction of bile ducts
c. Primary Sclerosing Cholangitis
i. Inflammation of bile ducts (both inside and outside liver)
ii. Labs & Sx’s same as secondary; + IgM increase (Hyper IgM gammaglobulinemia)
iii. Assoc with Ulcerative Colitis and can lead to secondary biliary cirrhosis and
cholangiocarcinoma (cancer of bile ducts)
iv. Histo: periductal portal tract fibrosis & stenosis of ducts
Drug Induced Liver Disease—Chart pg 158
a. Cholestasis—Anabolic & Contraceptive Steroids; Estrogen replacement therapy
b.
XVII.
XVIII.
XIX.
XX.
(Bland/Pure Cholestasis)—condition in which the flow of bile from the liver slows or
stops; http://livertox.nih.gov/Phenotypes_bland.html
c. Cholestatic hepatitis—many antibiotics, phenothiazines
d. Steatosis—Ethanol, methotresxate, corticosteroids, total parenteral Nutrition
i. Reversible “Macrovesicular” fatty change of the liver
e. Steatohepatitis—Amiodarone; Ethanol
f. Fibrosis & Cirrhosis—Methotrexate, isoniazind, enalapril
g. Granulomas—Sulfonamides
h. Vesicular Lesions
i. Sinusoidal obstruction syndrome (veno-occlusive disease); obliteration of
central veinschemotherapy, herbal teas
ii. Budd Chiari Syndrome—oral contraceptives
iii. Sinusoidal Dilatation—oral contraceptives
iv. Peliosis hepatis—blood filled cavities not lined by endothelial cellsanabolic
steroids, Tamoxifin
i. Neoplasms
i. Hepatic Adenoma—oral contraceptives, anabolic steroids
ii. Hepatocellular Carcinoma, Cholangiocarcinoma—Thorotrast
iii. Angiosarcoma—Thorotrast, vinyl chloride
Alcoholic Liver Disease
a. Etiology: 8 beers or more a day
b. Pathenogenesis:
i. Induce cyt P450 and immunologic attack on liver
ii. Free Radical Formation
iii. Alcohol directly toxic to mitochondria and microtubules
iv. Acetaldehyde by-produce induces lipid peroxidation and damage
c. Hepatic Steatosis—Why Alcohol makes you fat
i. Alcohol Dehydrogenase uses up NAD+ (needed for FA-Oxidation; if FA-Oxidation
is “off” then concomittently FA-Synthesis is “on”)
ii. Acetaldehyde metabolized into Acetyl-CoA (building block for FA); increased
levels lead to FA-Synthesis
iii. High NADH/NAD ratio decreases glycolysis (NAD needed) and increases
gluconeogenesis and glycerol 3 phosphate which is shunted into lipid synthesis
(glycerol backbone)
d. Alcoholic Hepatitis
e. Alcoholic Cirrhosis
Side Note: according to http://www.brown.edu/Courses/Digital_Path/systemic_path/hepatobiliary/cardiacsclerosis.html,
Passive Congestion leads to…Cardiac Sclerosis = Cardiac Cirrhosis = Congestive Hepatic Fibrosis
Impaired Blood Flow into The Liver
a. Passive Congestion and Centrilobular Necrosis (leads to cardiac cirrhosis if severe)
b. Peliosis Hepatitis = primary dilatation of sinusoids (drug induced)*see above
Hepatic Venous Outflow Obstruction
a. Veno-occlusive Disease = Sinusoidal Obstruction Syndrome (small veins of liver are
occluded; due to chemotherapy and herbal teas *see above)
b. Budd Chiari Syndrome—Hepatic v. thrombosis; can be acute, subacute, chronic;
heptomegaly, weight gain, ascites, abdominal pain. May develop varices and visible back
& abdominal veins. Absence of JVD. Assoc with hypercoaguable states, polycythemia
vera, pregnancy and hepatocellular carcinoma.
XXI.
XXII.
XXIII.
XXIV.
c. Passive congestion = stasis of blood in liver (“Nutmeg Liver”) due to impaired hepatic v.
drainage caused by heart failure (right sided usually); can progress to cardiac sclerosis
and can also get centrilobular congestion and necrosis
Hepatic Diseases in Pregnancy
a. Pre-eclampsia = (gestational hypertension) new-onset of HTN in pregnant woman; or
increase in BP in prego who was previously hypertensive
b. Eclampsia = Hypertensive emergency (severe elevation of BP >180/120)
c. HELLP Syndrome: Hemolysis, Elevation of Liver enzymes, Low Platelets; considered by
some an extension of severe pre-eclampsia. Complication = DIC.
Neoplasms
a. Benign Tumors
i. Cavernous Hemangiomas
1. Present age 30-50; biopsy contraindicated!! (risk of hemorrhage)
ii. Adenomas
1. Related to estrogen and anabolic steroid use; risk of rupture (abdominal
pain and shock)
b. Malignant Tumors
i. Hepatoblastoma: mixed epithelial and mesenchymal; caused by chromosomal
deletions
ii. Angiosarcoma
1. Endothelial origin; assoc with arsenic, vinyl chloride exposure with long
latent period.
Primary Carcinoma of the liver = Hepatocellular Carcinoma
a. Risk Factors: HBV, HCV, Wilson Disease, Hemochromatosis, alpha-1-antitrypsin
deficiency, alcoholic cirrhosis, aflatoxins from Aspergillus.
b. Marker = elevated alpha-fetoprotein
Metastatic Tumors
a. Most common type of tumors in liver; Multiple; commonly come from breast, lung,
colon and pancreas metastases.
b. Lesions outgrow blood supply leading to necrosis