Adult liver disease - neoplasms, infections and cirrhosis

Question 1

What are the three malignant adult liver neoplasms we are to know?

Answer 1

• Hepatocellular carcinoma (HCC)
	• Cholangiocarcinoma
	• Metastatic disease to liver
What is the epidemiology/etiology of HCC?
	• 90% of patients are cirrhotic

Question 2

What are the gross findings in a case of cholangiocarcinoma?

Answer 2

• Densely fibrotic mass in the hilar region with infiltrative edges
  
  • Tan-white in color

Question 3

What are the gross findings in a case of HCC?

Answer 3

• Hepatocellular carcinoma
  
  • Distinct mass in a cirrhotic liver
  • Invasion of main branch of portal vein or hepatic artery
  • May have green-yellow color (like bile)

Question 4

What is the epidemiology/etiology of cholangiocarcinoma?

Answer 4

• May be intra or extra hepatic
  
  • PSC is major risk factor
  • Usually presents at an advanced stage
  • Survival is 25% at one year and 13% at 2 years

Question 5

What does a biopsy show in a case of HCC (microscopic)

Answer 5

• Thickened hepatic plates
  
  • Invasion of fibrous tissue/vessels
  • Unpaired arteries
  • No true portal areas

Question 6

What does a biopsy show in a case of cholangiocarcinoma (microscopic)

Answer 6

• Invasive gland forming tumor with abundant desmoplastic response

Question 7

What are the three benign liver neoplasms we are supposed to know?

Answer 7

• Hemangioma
  
  • Focal nodular hyperplasia (FNH)
  • Hepatocellular adenoma

Question 8

What is the epidemiology/etiology of Hepatocellular adenoma?

Answer 8

• Occurs in women of child-bearing age
  
  • 1:9 male to female ratio
  • Associated with oral contraceptive use
  • Present with RUQ pain, most are asymptomatic
  • Risk of ruptor into abdome with hemorrhage
  • Low risk of malignant transformation

Question 9

What is the epidemiology/etiology of Focal nodular hyperplasia (FNH)?

Answer 9

• Second most common primary hepatic mass
  
  • Presumed hyperplastic parenchyma due to vascular anomaly
  • Commonly found in association with hemangiomas
  • More common in women than men 4 to 1
  • Diagnosed in 30s or 40s usually
  • Usually asymptomatic

Question 10

What is the epidemiology/etiology of Hemangioma?

Answer 10

• Benign neoplasm of dilated vascular spaces
  
  • Most common primary hepatic tumor
  • Incidence of 2%
  • More common in females 1:4
  • Most common presentation is vague RUQ pain, early satiety, nausea, vomiting

Question 11

What are the gross characteristics of the benign hemangioma?

Answer 11

• Well circumscribed mass in a non-cirrhotic liver

* Spongy hemorrhagic cut surface with areas of infarction and thrombosis

Question 12

What are the gross characteristics of the benign hepatocellular adenoma?

Answer 12

• Well circumscribed mass in a non-cirrhotic liver
• Soft fleshy cut surface
○ As opposed to spongy in the hemangioma

Question 13

What are the gross characteristics of the benign focal nodular hyperplasia?

Answer 13

• Central stellate scar

* KNOW THIS PATHOGNOMONIC

Question 14

What are the microscopic biopsy findings in the setting of benign hemangioma?

Answer 14

• Dilated thin walled vascular spaces
  
  • Infarction
  • Thrombosis
  • Benign appearing endothelial cells

Question 15

What are the microscopic biopsy findings in the setting of benign hepatocellular adenoma?

Answer 15

• Proliferation of benign hepatocytes
  
  • Normal hepatocyte plate thickness
  • Numerous unpaired arteries
  • No bile ducts or portal areas
  • May be difficult to distinguish between adenoma and well differentiated HCC

Question 16

What are the microscopic biopsy findings in the setting of benign focal nodular hyperplasia?

Answer 16

• Central stellate scar
  
  • Aberrant malformed vascular structures
  • Ductular reaction
  • No true portal areas

Question 17

What are the 5 examples of cellular accumulation to keep in mind with liver pathology?

Answer 17

• Fat
		○ steatosis
	• Bile
		○ cholestasis
	• Iron
		○ hemosiderosis
	• Copper
		○ Wilson's disease or cholestasis
	• Viral particles
		○ Viral hepatitis

Question 18

What are the two types of hepatocyte death, what do they look like and what do they suggest is going on?

Answer 18

• Ballooning degeneration and necrosis/apoptosis
• Ballooning
○ Hepatocyte swelling with clumping of hepatocyte organelles and keratin filaments with clearing of cytoplasm
○ Most common in steatohepatitis
• Necrosis/apoptosis
○ Characterized by decreasing cell size with increased eosinophilia of the cytoplasm and a small dark nucleus
○ Often seen in ischemia and chronic viral hepatitis
○ Called acidophils, councilman bodies, or single necrotic hepatocytes
• Wide spread ischemia typically shows confluent zone 3 ischemic necrosis
• Autoimmune hepatitis and viral hepatitis often show acidophils at the interface zone

Question 19

Though the simple presence of an inflammatory infiltrate is not very specific for a given disease, what are the clues given by the types of inflammation?

Answer 19

• Neutrophils - steatohepatitis
• Eosinophils - drug reaction
• Plasma cells - autoimmune hepatitis
• LOCATION
○ In the lobule is a major factor in lobular disarray
○ Portal based - biliary disease
○ Interface inflammation - autoimmune and viral hepatitis
○ Zone 3 - autoimmune hepatitis or acute cellular rejection (transplant)

Question 20

What kind of hepatocyte death does cholestasis usually result in?

Answer 20

• Ballooning degeneration

Question 21

What is the bile ductular reaction?

Answer 21

• Obstructive cholestasis, bile outflow is impaired and there is build up
○ Zone 1
• Hepatocytes undergo metaplasia to become similar to bile duct cells to take care of increased bile
• Result is lots of bile duct-esque structures at the interface zone
• Usually also has edema and neutrophilic inflammation

Question 22

Where does fibrosis happen?

Answer 22

• Common end result of inflamamtion and injury
  
  • From the activated stellate cells in the space of Disse depositing collagen
  • Progressive fibrosis leads to cirrhosis

Question 23

What is acute hepatitis and what are the common etiologies?

Answer 23

• New onset of symptomatic disease that has lasted less than 6 months and is associated with laboratory evidence of hepatocyte injury with elevations of AST and ALT
• Common causes
○ Viral
○ Autoimmune
○ Adverse drug reaction
○ Idiopathic
• Usually the liver shows marked lovular disarray and inflammation with numerous single necrotic hepatocytes and cholestasis
• The background architecture of the liver should not contain significant fibrosis
○ Suggestive of more chronic disease

Question 24

what are the Characteristic Signs of Severe Hepatic Dysfunction

Answer 24

Characteristic Signs of Severe Hepatic Dysfunction
Jaundice and cholestasis
Hypoalbuminemia
Hyperammonemia
Hypoglycemia
Palmar erythema
Spider angiomas
Hypogonadism
Gynecomastia
Weight loss
Muscle wasting

Question 25

what are the signs of portal hypertension associated with cirrhosis?

Answer 25

Portal Hypertension Associated with Cirrhosis Ascites with or without spontaneous bacterial peritonitis Splenomegaly Esophageal varices Hemorrhoids Caput medusae—abdominal skin

Question 26

What are the important complications of hepatic failure?

Answer 26

Complications of hepatic failure: Coagulopathy Hepatic encephalopathy Hepatorenal syndrome *Hepatorenal syndrome (HRS) is the development of renal failure in patients with advanced chronic liver disease[1] and, occasionally, fulminant hepatitis, who have portal hypertension and ascites. Estimates indicate that at least 40% of patients with cirrhosis and ascites will develop HRS during the natural history of their disease. Portopulmonary hypertension Hepatopulmonary syndrome

Question 27

What tests do you order to investigate hepatocyte integrity?

Answer 27

Cytosolic hepatocellular enzymes: Serum aspartate aminotransferase (AST) Serum alanine aminotransferase (ALT) Serum lactate dehydrogenase (LDH)

Question 28

What is chronic hepatitis?

Answer 28

• Evidence of injury/inflammation for greater than 6 months • Common causes ○ Viral hepatitis ○ Autoimmune hepatitis ○ Adverse drug reactions • Specimens show: ○ Lobular disarray, less prominent inflammation, ○ Rare single necrotic hepatocytes and the slow progression of fibrosis over time ○ Grade in this context = necroinflammatory activity ○ STAGE in this context = degree of fibrosis

Question 29

When worried about biliary execretory function, what labs do you order?

Answer 29

``` Look at the substances in bile *Substances secreted in bile † Serum bilirubin Total: unconjugated plus conjugated Direct: conjugated only Delta: covalently linked to albumin Urine bilirubin Serum bile acids Plasma membrane enzymes † (from damage to bile canaliculi) Serum alkaline phosphatase Serum γ-glutamyl transpeptidase Serum 5′-nucleotidase ```

Question 30

when worried about hepatocyte function what tests do you order?

Answer 30

look at the Proteins secreted into the blood (by hepatocytes) Serum albumin ‡ Prothrombin time † (factors V, VII, X, prothrombin, fibrinogen) Hepatocyte metabolism Serum ammonia † Aminopyrine breath test (hepatic demethylation) Galactose elimination (intravenous injection)

Question 31

What are the stages of the Batts-Ludwig grading system?

Answer 31

* Stage 0 - no fibrosis * Stage 1 - portal fibrosis * Stage 2 - periportal fibrosis * Stage 3 - bridging fibrosis * Stage 4 - cirrhosis

Question 32

What are the GRADES in the Batts-Ludwig system?

Answer 32

* As opposed to stages * Has to do with interface and lobular activity * 1 - focal inflammation, no necrosis * 2 - focal necrosis with mild inflammation * 3 - confluent necrosis without bridging and moderate inflammation * 4 - bridging necrosis with severe inflammation

Question 33

What is cirrhosis?

Answer 33

• The end stage of any liver disease • Dx is made pathologcially • Bridging fibrous septa with distortion of the architecture and regenerative nodules • Clinical ○ Portal hypertension and poor synthetic function ○ Increased risk for hepatocellular carcinoma

Question 34

What are the important virus specific information to know about the hepatitis virus agents?

Answer 34

• B - dsDNA ○ All the others are ssRNA • A - fecal oral route, contaminated food or water • E - fecal oral route • A - NEVER causes chronic liver disease • C- 80% of the time causes chronic liver disease • B - 10% of time causes chronic liver disease • E - NEVER causes chronic liver disease

Question 35

Which two hepatitis viruses are essentially the same?

Answer 35

• E and A. fecal oral route, both are ssRNA viruses and both are tested by looking for IgM and igG antibodies

Question 36

What's up with HBV?

Answer 36

Hepatitis B virus • Only DNA virus of the hepatotropic viruses • Can integrate into host genome • Blood and body fluids transmission • Look for ground glass hepatocytes and sanded nuclei ○ Viral particles within hepatocytes

Question 37

What's up with HCV?

Answer 37

• Hepatitis C virus • Increasing problem - 80% of exposed develop chronic liver disease • Transmission is via blood and body fluids (parenteral) • Look for ongoing infection with PCR • Rarely present as acute hepatitis • Non-specific histology ○ Nodular aggregates of lymphocytes in portal areas are a common finding

Question 38

What's up with autoimmune hepatitis?

Answer 38

• Hepatic inflammation and damage usually associated with prominent plasma cells on histology • Often presents with acute flare • Then settles into a chronic hepatitis • 78% of patients are females • Increased AST and ALT with normal ALP • Usually at least one positive autoantibody in serum (80% of cases) ○ ANA, ASMA, anti-LKMB • Treatment = steroids • Disease is active, histology shows ongoing interface and centrolobular necroinflammatory stuff with zones of confluent hepatocyte necrosis and a prominent plasma cell component

Question 39

What is PBC?

Answer 39

• Primary biliary cirrhosis = PBC • Autoimmune disease primarily involving the intrahepatic bile ducts with inflammatory bile duct destruction • Usually insidious presentation pruritus before jaundice • Again, heavily female with 85% of cases • Liver tests ○ Elevated ALP, GGT, bilirubin ○ Normal AST and ALT (or barely elevated) ○ Positive AMA antibody test 90% and elevated IgM

Question 40

What are the histological signs of PBC?

Answer 40

• PBC = primary biliary cholangitis • Acute or chronic changes can be seen • Acute - lymphohistiocytic and plasma cell rich inflammation of the portal areas with active lymphocytic cholangitis and bile duct destruction ○ These go together to form a "florid duct lesion" • Chronic - bile duct loss and ductular reaction and periportal copper accumulation • Fibrosis will begin to develop in the periportal regions with eventual bridging fibrosis and cirrhosis

Question 41

What is primary sclerosing cholangitis?

Answer 41

• PSC is an idiopathic disease characterized by patchy inflammation and eventual obliterative fibrosis of the bile ducts • Usually affects the extrahepatic bile ducts but may also involve intrahepatic ducts • Common presentation: ○ Persistently elevated alkaline phosphatase and no other signs/symptoms ○ Over time, as the disease progresses patients experience increasing fatigue, pruritus, jaundice • Strong association with IBD and UC more than crohns • Huge increase in cholangiocarcinoma risk • Increased ALP, GGT and bilirubin

Question 42

How do you diagnose PSC?

Answer 42

• Other liver diseases are clinicopathologic correlation, but PSC is clinicoradiologic correlation ○ Endocopic or MR scanning ○ ERCP or MRCP • Cholangiography shows beading of the extra and intra hepatic bile ducts with multiple biliary strictures alternating with areas of dilation (string of pearls) • Histologic ○ Lymphocytic periductular inflammation around the larger bile ducts with progressive fibrosis ○ Peri-ductular fibrosis is concentric around the ducts creating an onion skin pattern ○ "onion skin fibrosis"

Question 43

What is secondary sclerosing cholangitis?

Answer 43

• Several disease processes can increase the risk ○ Cholelithiasis, biliary atresia, choledochal cysts, and cystic fibrosis • These other processes RESULT in sclerosis/fibrosis of the biliary tree • End stage, both primary and secondary sclerosing diseases can be indistinguishable

Question 44

What has to happen to make you think "drug induced liver disease"?

Answer 44

• Wide variety of drugs have been reported to cause liver injury and elevated liver function testing • Of all adverse drug reactions - 10% affect liver (which is high or low depending on how you think about it) • Presentations VARY, so it should ALWAYS be on your differential • Histologic changes may show necrosis, cholestasis, biliary injury, autoimmune-like hepatitis, acute hepatitis or chronic hepatitis • MOST COMMON - acetaminophen is most common cause ○ Represents a large proportion of cases of acute liver failure leading to liver transplant in US ○ Causes confluent coagulative necrosis beginning in zone 3 (centrolobular) ○ Dose dependent progression to pan-lobular necrosis

Question 45

What are the four metabolic liver diseases in adults you need to know by sight and sound?

Answer 45

* Steatosis/steatohepatitis * Hereditary hemochromatosis (AR) * Wilson's disease (AR) * Alpha-1-antitrypsin deficiency (AR)

Question 46

What is the histologic triad of steatohepatitis?

Answer 46

• Steatosis, lobular inflammation and hepatocyte ballooning degeneration ○ Unfortunately these histologic changes are non-specific and are seen in many conditions

Question 47

Describe the two different clinical subtypes of steatohepatitis

Answer 47

• Alcohol - ○ Clinical history of alcohol exposure and the histologic triad on liver biopsy (dx criteria) ○ Lab - AST:ALT ratio greater than 2, and normal ALP with increased GGT ○ IHC /Histology- mallory hyaline and lots of neutrophils in the infiltrate • NASH ○ Common picture in obesity, diabetes, hypertriglyceridemia and adverse drug reaction ○ Increasing prevalence of this disease with increasing obesity

Question 48

What's up with steatohepatitis?

Answer 48

• Remember the histological triad, and match that to an alcoholic clinical picture ○ Steatosis, lobular inflammation and hepatocyte ballooning degeneration • Clinically separated into alcoholic and non-alcoholic forms ○ ASH and NASH • NASH is usually seen in patients with diabetes, metabolic syndrome, obesity, or adverse drug reaction • END RESULT - hepatic fibrosis over time and a 20% risk of cirrhosis • Fibrosis begins in the centrolobular region (3) and shows a prominent sinusoidal pattern (chicken wire) • Cirrhosis pattern = micronodular pattern secondary to fine sinusoidal fibrosis

Question 49

What is HH in the context of liver disease?

Answer 49

* HH - hereditary hemochromatosis * C282Y and H63D mutations * Autosomal recessive inheritance pattern * Symptoms manifest in males more than females who don't handle the iron overload as well * Main problem = iron overload from messed up iron absorption pathway, eventual deposition of iron in tissues (liver) leading to oxidation and cell death * Iron absorption is in small intestine

Question 50

How can you differentiate secondary from primary hemosiderosis?

Answer 50

* Secondary comes from excessive ingestion, repeated transfusions, hemolysis and underlying liver disease * Secondary causes lead to iron deposition in Kupffer cells more than hepatocytes

Question 51

What are the histologic features of HH?

Answer 51

* Progressive iron depositions within the cytoplasm of hepatocytes * Begins in periportal region first * Iron acts an an oxidant and results in hepatocyte injury and fibrosis * Dx is primarily genetic testing for mutations that cause the disease

Question 52

What is the inheritance pattern of HH?

Answer 52

* Autosomal recessive inheritance pattern * C282Y and H63D mutations * Symptoms manifest in males more than females who don't handle the iron overload as well

Question 53

What are the clinical and histological features of wilson's disease?

Answer 53

* Main problem is too much copper * See the particular Kayser-fleischer rings on ophthalmologic examination * See patchy copper accumulation in hepatocytes on histology * Rest of parenchyma shows steatosis and acute/chronic hepatitis changes

Question 54

What is wilson's disease?

Answer 54

* AR disease b/c of mutations in ATP7B gene on chromosome 13 * Copper transport protein that is involved in the biliary excretion of copper * Lots of different mutations have been described so it's not just one exon and one point mutation, it's many places along that gene

Question 55

What is the inheritance pattern of wilson's disease?

Answer 55

• AR disease b/c of mutations in ATP7B gene on chromosome 13

Question 56

What's up with alpha-1-antitrypsin?

Answer 56

• If there is a mutation in this gene the resulting disease has liver, pancreas and lung manifestations • Characterized by decreased production of a protease inhibitor • AR inheritance pattern • Protease inhibitor usually keeps the secretions of neutrophils in check and limits tissue damage • Nomenclature - ○ PiMM - normal ○ PiMZ - heterozygote/carrier ○ PiZZ - homozygous and disease phenotype • Lab - levels less than 10% of normal • Pulmonary emphysema is primary clinical manifestation and 10% patients have liver disease • Histologic features - intracytoplasmic accumulation of PAS positive, diastase resistant hyaline globules with progressive fibrosis ○ Represent abnormally folded A1A

Question 57

What are the important causes of bad hepatic blood flow?

Answer 57

• Very acute hepatic artery thrombosis can cause ischemic infarcts ○ But since there is dual artery supply, this is rare • Portal vein thrombosis is an important cause of non-cirrhotic portal hypertension ○ 50% of cases are idiopathic ○ Shows prominent congestion of the sinusoids with associated hepatocyte atrophy

Question 58

What can a problem in hepatic blood flow look like in the liver?

Answer 58

• Shows marked centrolobular sinusoidal dilation, congestion, and hemorrhage • Grossly - enlarged and tense liver • Budd - Chiari syndrome ○ Liver enlargement ○ Pain ○ Ascites ○ Main hepatic vein occlusion is the cause • End result ○ Subsinusoidal fibrosis and cirrhosis if not corrected ○ Heart failure patients - "cardiac sclerosis"

Question 59

What laboratory evidence points to cholestasis?

Answer 59

A characteristic laboratory finding (in cholestasis) is elevated serum alkaline phosphatase, an enzyme present in bile duct epithelium and in the canalicular membrane of hepatocytes. * (why it isn't especially specific) A different alkaline phosphatase isozyme normally is expressed in many other tissues such as bone, and so hepatic origin must be verified. * Reduced bile flow also causes intestinal malabsorption including inadequate absorption of the fat-soluble vitamins A, D, and K.

Question 60

What might a changed INR indicate?

Answer 60

Since some of the clotting factors produced by the liver have half lives in hours, that is used to indicate acute liver injury *albumin is more of a chronic liver injury marker

Question 61

Alk phos elevation is specific or not?

Answer 61

Not super specific, you need to make sure it's coming from the liver itself. *can use GGT to correlate and make sure liver origin for alk phos

Question 62

Alk phos elevation is specific or not?

Answer 62

Not super specific, you need to make sure it's coming from the liver itself. *can use GGT to correlate and make sure liver origin for alk phos