Lecture 71/73 - Pathology of Liver Disease Flashcards
what are the different zones of a liver microscopic anatomy? why is this important?
acetaminophen toxicity damages which zone first?
Zone 1 – closest to heaptic arteries – sees the most oxygen
Zone 2 - Intermediate oxygenation
Zone 3 closest to the central Central vein – least amount of oxygen, but this is typically more than sufficient
But becomes oxygen deficient with any ischemic/toxic event
Acetaminophen Tox – Zone 3 toxicity first
but overall, drug toxicities and zone order of damage cannot be predicted
for what reason are liver biopsies taken?
how are they taken?
why: to establish severity of liver disease or evaluate progression. Never (rarely) taken to establish the diagnosis itself
how ? Percutaenous, Transjugular, Laproscopic/operative
Cholestatic pattern of liver injury on histology
- what is the mechanism
- what does it look like
- lab findings
Bile in hepatocytes/canaliculi
Elevated BR and Alk Phosph
Apoptotic pattern of liver injury on histology
- what does it look like ?
- lab findings
small pink cells with white space around them
↑ AST/ALT
Necrotic pattern of liver injury on histology
labs
Loss of hepatocytes (appears blue)
- may have inflammation
↑↑↑ AST/ALT
May ↓ AST/ALT late – -which is very concerning finding; it means all the heaptocytes have been depleted and enzymes exhausted
Steatosis pattern of liver injury on histology
labs
is this reversible?
Steatosis – Fat accumulation within the hepatocytes
§ Appears white fat droplets;
Normal to Mild ↑ AST/ALT
this is reversible
Steatohepatitis pattern of liver injury on histology
– what is a pathognomonic finding here? what do they look like?
labs
is this reversible ?
The more aggressive cousin in Steatosis – fat accumulation with evidence of injury and inflammation
§ Cells balloon up -- leading to Mallory bodies § Mallory bodies -- appear with pink inclusions that are meant to be removed but damaged cells cannot get rid of them
Other signs of inflammation and apoptosis
↑ AST/ALT
fatty changes are reversible, but not the scarring that may occur
Hepatitis pattern of liver injury on histology
labs
Inflammation (mostly lymphocyte)
↑ AST/ALT
what are the 2 types of fatty liver disease ?
how common are they?
can these be distinguised on histology
Alcoholic Fatty Liver disease – 5 to 10 %
Non-alcoholic fatty liver disease – 20 - 30 % of US adults
No – cannot be distinguished on histology
NAFLD / AFLD – at what stages can changes be reversed? how can they be reversed?
describe the progression of disease if not reversed …
Steatosis – very common and reversible.
Steatohepaptitis – fibrosis is not not reversible; fatty changes are.
have patients decreased fat and alcohol consumption; lose weight
Fibrosis(Cirrhosis) –> HCC
Progression of NAFLD:
NAFLD –> NASH –> Cirrhosis –> HCC
what is the difference between grading and staging of chronic hepatitis
Grading – the severity of the current inflammation, this may resolve
Staging – the severity of the fibrosis – this does not regress. Assessing how much damage has already been done
Grading of hepatitis – what are 4 grades?
□ Grade 1 - confined to the interface plate
□ Grade 2 - some leak across the plate into the parenchyma
□ Grade 3
□ Grade 4 - severe inflammation; treat regardless of etiology; can lead to necrosis (lymphocytes killing hepatocytes)
Staging of Hepatitis – what are the 4 stages?
what causes the “nodular/bumpy” appearance
□ Stage 1 - no Bridging
□ Stage 2 – some bridging
□ Stage 3 - bridging fibrosis between portal tracts, but no change in architecture and do not get portal HTN. No compression of the vessels. The fibrosis begins to define curved nodules of the liver
□ Stage 4- extensive bridging fibrosis, nodules and bumpy contour as the liver attempts to regenerate. Full bridging.
what are the etiologies of chronic hepatitis:
Viral Hepatitis – HBV and HCV
Auto-immune –
Drug/Meds/Alcohol
Inherited/Metabolic Diseases – Wilson’s disease, Hereditary hemochromatosis, A1AT Deficiency
what are the two primary viral origins or chronic hepatitis? what percentage of each acute infection leads to chronic hepatitis?
what causes most of the damage to hepatocytes in chronic hepatitis?
HCV – 85% chronic hepatitis (20% of whome develop cirrhosis).
HBV – 4% develop persistent infection; 30% of whom develop chronic hepatitis
The immune repsonse itself is what causes most of the damage in chronic hepatitis. The attempts at repair lead to scarring / cirrhosis
Auto Immune Chronic Hepaptitis –
What are some histological findings:
what labs can be run to help with the dx?
what is a common treatment?
Histo: Lots of plasma cells; +/- multinucleated giant hepatocytes
Labs: IgGs, ANA Titers
Females > Males
Common treatment: steroids
what are three inherited disease that can lead to chronic hepatitis?
Alpha 1 Anti-Trypsin Deficiency – the misfolded protein accumulates in the liver;
Hereditary Hemocrhomatosis
Wilson’s Disease –
Hereditary Hemochromatosis –
what is it ? (what gene)
Dx?
Treatment?
AR mutation in C282Y – There is no negative feedback for iron uptake (enterocyte iron binding complex). In this, the enterocytes and other organs keep taking up iron
Dx - Stains blue; can make definitive dx with genetic testing
Treatment: Phlebotomy/bloodletting
Wilson’s Disease:
What is it? (gene)
Phagonomonic physical exam finding
Definitive Dx:
Treatment;
Autosomal recessive mutation in ATP7B (nomrlaly excretes copper into bile); therefore leads to abnormal copper retention and accumulation
Leads to cirrhosis; decreased cerruloplasmin
Pathog – Kayser Fleischer Rings in the corner
Definitive dx – liver bx
Treatment - Chelation
Alpha 1 Anti Trypsin Deficiency -- what is it? lung findngs? liver findings? Treatment for liver vs lung ??
ALpha 1 anti-trypsin (with either PiZ or PiS mutations) – the protein is misfolded leading to abn accumulation in hepatocytes
Lung findings – panacinar emphysema
Liver findings — Globules (accumulation of misfolded protein); best seen on Immnostain
Treatment:
lungs – infuse the protein
liver – cannot do much except advise patients to avoid alcohol in order to prevent further damage
what is the role of bile?
describe how it is formed?
Bile – helps eliminate waste (bilirubin); fat emulsifier
Bilirubin is formed from heme.
Heme –> Biliverdin –> Bilirubin (not water soluble; travels in blood to the liver bound to albumin)
Conjugated UDP gluconuryl transferase (UDPT1A1) to Glucuronic Acid (water soluble); which is then excrted in bile
what is indirect (unconjugated) vs direct (conjugated) Hyperbilirubininemia
give examples of both
Indirect (unconjugated) – § A defect in the bilirubin metabolism pathway BEFORE the glucuronidation; or there is simply too much bilirubin production
examples: Hemolytic, physiologic, Crigler Najjar (1 and 2), Gilbert’s disease
Conjugated (direct) – Defect in bilirubin metabolism/excretion (AFTER) the gluconuridation step. BIle transport is impared in the haptocytes
examples: Dubin Johnson Syndrome
what are the hereditary unconjugated hyperbilirubinemias ? which is the most severe
which are the most benign
□ Crigler Najjar 1 – AR — Not compatible with life
□ Crigler Najjar II -- AD -- Usually mild and worsened by stress
□ Gilbert (french pronunciation) – 5 to 10%; benign; common and does not correlate to a disease state
® Small Group: mild scleral icterus during periods of stress, starvation, exercise
what are the conjugated hyperbilirubinemias
□ Dubin Johnson — AR – benign; turns liver black; but never biopsied bc its asymptomatic
□ Rotor — AR — benign and even more mild than Dubin Johnson
what is kernicterus?
end organ, including the gray matter in the brain seen in unconjugated bilirubinemias
worse in ped patients
what are the three cholestatic diseases of the biliary tract?
what lab findings would you expect? (what pattern of LFTs)
Physical exam findings/History?
Primary Biliarly Cirrhosis
SEcondary Biliary Cirrhosis
Primary Sclerosing Cholangitis –
Increased conjugated BR, Increased ALP
LFTs c/w Choestatic pattern of LFTs
History: Pruritis, dark urine, light colored stool
Exam: Jaundice, heaptosplenomegaly
Primary Biliarly Cirrhosis –
cause/what is it?
Characteristic histology?
characteristic patient?
Common lab finding ?
Cause: Idiopathic; Lymphocytic, granulomatous destruction of intrahepatic bile ducts; as bile escapes out into parenchyma, there is an immune reaction to it, forming granulomas
Histo: Granulomas; destruction of the ducts
Patient: Middle aged women
Labs: + AMA (anti-mitochondrial antibody)
Secondary Biliary Cirrhosis –
pathology?
Gross pathology?
Histology?
Path – extrahepatic Biliary Obstruction (tumors, stones, pancreatitis, parasites); leading to increased pressure in intrahepatic ducts –> injury/fibrosis and cholestasis
Gross Path – green liver
Histo – Islands of liver parenchyma surrounded by fibrosis; lots of bile ductules
Primary Sclerosing Cholangitis
- Pathology?
- Histology?
- Commonly a/w? typical patient
- whats seen on ERCP?
Treatment?
pathology: unknown cause of inflammation, constriction and fibrosis
Histology – “Onion skinning” bile duct fibrosis; much less inflmmation than Primary Biliary Cirrhosis
Typical patient: young men with IBD (UC or CD)
ERCP: “Skip pattern” or “beading”
Treatment: Transplant
Name three causes of Acute hepatitis
infectious
toxic
Metabolic
Infectious causes of acute hepatitis – hepatotropic vs non hepatocropic
hepatotropic – hepatitis A, B, C, D, E, Yellow Fever
Non hep – EBV, CMV
Liver flukes
Toxic causes: what is the difference between intrinsic hepatotoxicity and idiosyncratic hepatotoxicity
Metabolic causes of hepatitis
intrinsic – cuase injury in everyone (acetaminophen)
Indiosyncratic – causes injury in only vary rare cases (eg 1/100 people get liver toxicity from a specific drug).
Metabolic: A1AT def, Wilsons, hemocrhomatosis etc
What are the three classes of vascular injury to the liver?
Pre hepatic –
Intra hepatic
Post hepatic
Pathology and manifestations of pre - hapatic injury –
transaminase levels normal or elevated?
- Mechanisms: Hepatic artery compromised, portal vein obstruction, thrombosis
* Manifestations – esophageal varices, splenomegaly, intestinal congestion
* The Liver (Usually) does not infarct as it has dual vascular supply
normal transaminases
Etiologies and manifestations of intra - hapatic injury –
transaminase levels normal or elevated?
Cirrhosis – by the far the most common (intrahepatic vessels are compressed by the nodularity of the scarring liver)
Sinusoidal Diseases – DIC, Eclapsia, Tumor, Sickle Cell, Toxins
Can give rise to portal HTN and cirrhosis, even if cirrhosis is not already present
dManifestations – ascites, varices, + hepatomegaly +
some evidence of liver damage (elevated AST, ALT)
Etiologies and manifestations of post - hapatic injury –
transaminase levels normal or elevated?
hepatic venous outflow obstruction
Budd Chiari (hepatic vein thrombosis) — hepatomegaly, pain ascites
□ Causes: malignancies, coagulative disorders (PCV, HCC)
□ The liver can’t get rid of the blood and it swells up; necrosis
Other causes: Veno-occlusive disease (VOD) / Sinusoidal obstruction syndrome (SOS) — less common
Manifestations: Congestive liver disease (ascites, hepatomegaly, varices; no JVD)
name three benign liver tumors?
Hemangioma
Focal nodular hyperplasia
Adenoma
name the malignancies of the liver/biliary tree
what is the most common?
Dysplasia
HCC
Cholangiocarcinoma
HEpatoblastoma
Metastatic disease – most common
Hepatic Hemangioma –
clinical approach?
should you biopsy?
very common — clinically negligible
Bx is contraindicated; risk of bleeding
Focal Nodular Hyperplasia
- clinical approach?
- gross pathology/radiographic appearance
clinically negligible
but can become symptomatic if large enough
radiographic / path – central scar; “focal cirrhosis”
Adenoma
- clinical approach?
- commonaly associated with what type of therapy?
- treatment?
Typically Benign but is a true neoplasm and has the potential to develop into a malignancy
Tumors are hormone response
commonly associated with young women taking OCPs or an athletes taking anabolic steroids
Treat: discontinue steroids; resection
Hepatic Dysplasia
what is it?
risk factors?
indicates that the liver is at risk for developing into HCC
□ Cirrhosis, recurrent injury (inflammation and repair);
□ Viral integration (HBV)
□ Inherited
Sporadic/idiopathic
Hepatocellular Carcinoma
etiologies:
what protein can be used to screen?
pathology/growth patterns?
treatment?
HBV (+/-) cirrhosis; and all other causes of cirrhosis (HCV, alcoholic and non alcoholic FLD, Auto immune, hematochromatosis, A1AT def, Wilson disease)
what protein can be used to screen? – AFP
pathology/growth patterns? – may be single or multiple
treatment? – resection, transplant, chemo-embolization, radiation, etc
Fibrolamellar HCC
- who gets it?
- progonosis?
- histology?
□ Occurs in young patients w/o risk factors
□ Often large at Diagnosis
□ But Good Prognosis
Histology: Fibrous bands passing through tumor; large hepatocytes
Cholangiocarcinoma
- what is it? / where does it arise?
risk factors?
histo?
prognosis?
Tumor arising from the bile duct;
Risk factors: disease of bile duct (PSC, Liver flukes), cirrhosis
Histo: Looks like adenocarcinoma (glandular), likes to travel along nerves, vessels
○ Poorer prognosis
Hepatoblastoma
- who gets it?
morphology?
treatment?
Most common liver malignancy in young children
○ Morphology:
□ Epithelial component, resembling developing liver
Mesenchymal component
○ Treatment: Surgery Or Transplantation; possibly preceded by neoadjuvant therapy
Metastatic disease to the Liver
presentation? pathology
most common primary diseases that like to go to the liver?
Metastatic- by far the most common malignancy in the Liver
* Most common is carcinoma * Colon, stomach, pancreas, breast, lung
Usual: multiple round masses, often near capsule
