3 - Basic Principles of Liver Pathology Flashcards
The most common cause of abnormal LFTs in the US today!
Fatty liver
Liver Biopsy is used for
Grading & Staging of chronic hepatitis
Workup of possible fatty liver disease (alcoholic or non-alcoholic)
Evaluation of cholestasis & jaundice
Establish a tissue dx of tumor
Determine whether cirrhosis is present
Hepatocellular Diseases
Acute Hepatitis
Chronic Hepatitis
Fatty Liver Diseases
Metabolic Diseases (Genetic mutations: AAT def., Fe, Cu, inherited storage disorders)
Biliary Tract Diseases
Large bile duct obstruction (LBDO)
Intrahepatic bile ducts
Bile canaliculi/hepatocytes (“pure” or intrahepatic cholestasis)
Vascular Diseases
Central veins & sinusoids
Portal veins/hepatic arteries
Hepatitis - Most common etiologies
Infection by the Hepatitis Viruses
Drug Hepatitis
Hepatitis Viruses
HAV (28nm) - RNA (oral-fecal)
HBV (42nm) - dsDNA (genome incorporated into human genome, lead to cancer)
HCV (60nm) - RNA (also causes cancer in the liver)
HDV (30nm) - RNA (delta agent, parasite. Can’t exist without HBV at the same time. You’re a carrier for HBV, and then you shoot up with something contaminated with HDV)
HEV (32nm) - RNA (fecal-oral, meat)
Other viruses (CMV, HSV, etc)
Drug Hepatitis
Predictable (CCl4, acetaminophen)
Unpredictable (INH, aldomet)
Viral Hepatitis - Pathogenesis
Virus enters cell Is encoded Reproduces Viral antigens are expressed on the hepatocyte membrane CD8 cells kill that bitch
Drug Hepatitis - Pathogenesis
Predictable
Metabolite directly damages hepatocyte (Tylenol)
No immune system necessary
OR
Unpredictable
Metabolism in the liver of the drug, producing antigen “hapten” that binds the hepatocyte, causing T-Cells or Eosinophils to KILLLLLLLL
Acute Hepatitis
Does not mean neutrophils Diffuse inflammation (lymphocytes) Lymphocytes come through portal tract, infiltrate and spread towards central vein Lobular disarray Hepatocyte ballooning/apoptosis "Spotty Necrosis"
Spotty Necrosis
Hepatitis, but can’t tell if it’s idiosyncratic or if it’s viral
Massive hepatic necrosis
Seen in Fulminant Hepatitis
Viral causes are HAV & HBV
HEV can do it too in the nondeveloped world
Destroys all the hepatocytes in the damn liver.
Periportal progenitor/steam cell activation leads to formation of bile ductular structures. They tryna make up the difference gurl.
Wrinkled capsule!!!!!!
Occurs within 8 weeks of onset of infection/drug
Sometimes it creeps along for months
Fulminant Hepatitis
Occurs in 1 - 3 % of cases (between all acute viral and acute drug hepatites)
Submassive Necrosis
A thing he didn’t explain
Chronic Hepatitis
Inflammation of the liver continuing without improvement for 6 months or longer
Disease process involving portal tracts/pp regions, lobules
Causes of Chronic Hepatitis
HBV HCV HDV (with co-presence of HBV) Autoimmune hepatitis Drugs (Hx of chronic intake) 2 metabolic diseases (α-1-antitrypsin deficiency, Wilson's)
Presenting Time of Wilson’s
Not 60 years old. Younger? I missed it.
Grade 1
Sometimes modest inflammation only in the portal tracts, intermittently seeding out lymphocytes.
Grade 2
Ground glass Hepatitis B surface antigen inclusions. More inflammation getting out, “interface hepatitis.”
Scarring
Scarring occurs, usually through stellate cells, making irregular portal tracts and thickened plates
Interface Hepatitis
Interface in all the portal tracts leads to increased fibrosis, losing all the hepatocytes.
Chronic Hepatitis - Grade 1
Minimal
Chronic Hepatitis - Grade 2
Mild
Includes interface hepatitis at the edge, some lobular as well
Chronic Hepatitis - Grade 3
Moderate
More circumferential
Chronic Hepatitis - Grade 4
Marked
Extensive interface and extensive lobular involvement
Chronic Hepatitis - Stage 1
Dots
Chronic Hepatitis - Stage 2
Dots with legs
Chronic Hepatitis - Stage 3
Stars
Chronic Hepatitis - Stage 4
Needlepoint
How can you tell on liver biopsy what caused the chronic hepatitis?
We may never know. I was taking notes on other shit
Hepatitis C Hallmarks
Once you have the virus chronically, the lymphoid system knows there is an antigen out there.
Takes over and sets up housekeeping in the portal tracts
Lymphoid aggregates form
Primary lymphoid follicle in the portal tract, essentially.
CLASSIC Hepatitis C
Autoimmune chronic hepatitis
Regenerative liver-cell rosettes
Interface hepatitis
Plasma cells
α-1-antitrypsin deficiency
Mutation in the gene for the gene product
New product doesn’t exit well
Gets stuck in hepatocytes
Visible on DPAS as purple globules!!!
Wilson’s Disease
Copper steigns for copper oh-ver-lode
Liver-Cell Dysplasia (LCD)
Pre-neoplastic lesion associated with HCC
Atypical nuclei
Seen in individuals with years of chronic hepatitis
Nuclear atypia: Hyperchromatic Convoluted contour Prominent nucleoli Multiple nuclei and nucleoli Large hepatocytes
3/4 have cirrhosis first before progressing to cancer
Potential sequelae of acute viral hepatitis
Immune system clears virus
Resolution
Other potential sequelae of acute viral hepatitis (1 - 3%)
Immune system clears virus
Fulminant hepatitis
Other other potential sequelae of acute viral hepatitis (5% with HBV, 80% with HCV)
Poor CD4 response
Chronic hepatitis
Cirrhosis (with liver cell dysplasia)
HCC
Fatty Liver (Steatosis)
Will float in water
Large droplet vs. small droplet
Macrovesicular (large droplet) steatosis
Most common type of fatty liver
Due to alcohol, obesity, diabetes, corticosteroids
Droplets contain triglycerides
Increased Triglyceride synthesis or decreased Triglyceride excretion
Usually begins centrilobular, then moves to other regions
Microvesicular (small droplet) steatosis
Uncommon
Severe mitochondrial injury
Impaired β-FA oxidation: Acute fatty liver of pregnancy Reye's syndrome Tetracycline toxicity Nucleoside analogue toxicity Valproic acid toxicity
Fatty Liver (large vacuole) and possible sequelae
Fatty liver
AFLD - Alcoholic fatty liver disease
NAFLD - Non-alcoholic fatty liver disease
Steatohepatitis (with peroxidation, swelling, fibrosis, etc)
ASH - Alcoholic steatohepatitis
NASH - Non-alcoholic steatohepatitis
Cirrhosis
Steatohepatitis
Fibrosis (activated Ito cells)
Steatosis (large droplet) inflammation
Intrahepatocellular Mallory bodies (or Mallory-Denk bodies)
Hepatocyte swelling (ballooning); cell injury
Fibrosis is “chicken-wire” centrilobular & pericellular/perisinusoidal
Mallory Denk Bodies
Circular inclusions that are like almost the size of a nucleus and they are just red, like a cherry red spot almost
Contents of Mallory Denk Body
Abnormal keratins (8 & 18) specific to hepatocytes. It is hyperphosphorylated or misfolded or crosslinked.
GET IT OUT!!
it’s ubiquitinated, but doesn’t make it out. It is evidence of steatohepatitis
P62 upregulation leads to aggregation
Overwhelms the proteosome/autophagy
Leads to micronodular cirrhosis (ASH or NASH)
Hit 1 - Causes fat
Alcoholics - Acetaldehyde
Non-Alcoholics - Obesity, diabetes, metabolic syndrome, certain drugs
Hit 1 - Causes steatohepatitis
Cytokines
Endotoxin
Large bile duct obstruction (LBDO)
Portal Edema
Neutrophils
Proliferation of bile ductular structures
Causes of LBDO
Gallstone obstruction
Cholelithiasis (gall stones)
Cholecystitis
Ampullary Carcinoma (pancreas) Stricture (from scar) Lymphoma or cancer in portall hepatitits lymph nodes Cholangiocarcinoma (bile duct cancer) Gallbladder cancer Common bile duct cancer
Primary Sclerosing Cholangitis (PSC)
Younger patients Hx of IBD (UC>Crohns) Serum pANCA + 80% Risk of Cholangio carcinoma Periductal concentric "onion skin" fibrosis - diagnostic
Diagnose via ERCP
Primary Biliary Cirrhosis (PBC)
Targeting by antimitochondrial antibody that’s an antigen on the intermitochondrial cristae
90% in females
10% in men
Serum positive antimitochondrial antibody
Partial destruction of interlobular bile ducts (one side but not the other!!!)
Does not affect large ducts
PBC
Middle aged women
+AntiMitochondrial Ab (M2 subtype)
Alk Phos up
It’s like post-strep rheumatic fever! If you’ve had a Gram (-) UTI in the past, there are similar antigens on the inner cristae of the mitochondrial membrane (PDC-E2 - Pyruvate dehydrogenase complex - E2)
IgM up
Associated with other autoimmune diseases (RA, sicca, celiac, scleroderma
4 Stages of PBC
Stage 1 - Florid bile duct lesion
Stage 2 - Bile ductular proliferation
Stage 3 - Scarring
Stage 4 - Cirrhosis
Signs of Chronic Cholestasis
Jaundice + Scleral Icterus
Xanthelasma (eyelids)
Pruritus
Skin excoriations (from scratching)
Cholestasis - Retention of Pruritogen
Pruritis
Cholestasis - Increased serum bilirubin and serum lipids
Jaundice
Xanthomas
Cholestasis - Decreased bile acids entering intestine
Malabsorption of fat and fat-soluble vitamins Steatorrhea bone disease coagulopathy night blindness
Cholestasis - Hepatic accumulation of copper, bile acids, and other compounds
Exacerbation of liver damage
Vascular disease & the liver
Veins - Central/hepatic
Sinusoids
Arteries
Left HF (shock, hypotensive, septic) - Centrilobular Necrosis
Right HF - Centrilobular Congestion (nutmeg liver)
Both HF - Both!!
Budd-Chiari Syndrome
Hepatic Venous Outflow Obstruction
Thrombosis of hepatic vein/IVC
Tumor invasion of hepatic vein/IVC
OCPs
Coagulopathy (protein S, Protein C, Factor V leiden def, anti-cardiolipin Abs)
Tumor invasion (renal cell carcinoma + HCC)
Small vein disease (VOD “bush tea”)
Cirrhosis - Many causes, pathologic features vary, depending on the cause, complications often similar
1 - Liver Failure
2 - Portal HTN
3 - Hepatocellular carcinoma
2 gross types of cirrhosis
Micronodular (nodules 3mm)
Both have diffuse fibrosis + architecturally abnormal regenerative nodules
Causes of cirrhosis
Chronic hepatitis - Chronic HBV, HCV, Autoimmune
Fatty liver disease - AFLD, NAFLD
Chronic biliary tract disease
Metabolic diseases (Hemochromatosis, Wilson’s disease, α-1-antitrypsin deficiency (AAT deficiency))