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1

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





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

2

What are the gross findings in a case of cholangiocarcinoma?

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

3

What are the gross findings in a case of HCC?

• 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)

4

What is the epidemiology/etiology of cholangiocarcinoma?

• 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

5

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

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

6

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

• Invasive gland forming tumor with abundant desmoplastic response

7

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




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

8

What is the epidemiology/etiology of Hepatocellular adenoma?

• 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

9

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

• 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

10

What is the epidemiology/etiology of Hemangioma?

• 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

11

What are the gross characteristics of the benign hemangioma?


• Well circumscribed mass in a non-cirrhotic liver
• Spongy hemorrhagic cut surface with areas of infarction and thrombosis

12

What are the gross characteristics of the benign hepatocellular adenoma?

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

13

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

• Central stellate scar
• KNOW THIS PATHOGNOMONIC

14

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



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

15

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

• 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

16

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

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

17

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

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

18

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

• 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

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?

• 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)

20

What kind of hepatocyte death does cholestasis usually result in?

• Ballooning degeneration

21

What is the bile ductular reaction?

• 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

22

Where does fibrosis happen?

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

23

What is acute hepatitis and what are the common etiologies?

• 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

24

what are the Characteristic Signs of Severe Hepatic Dysfunction

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

25

what are the signs of portal hypertension associated with cirrhosis?

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

26

What are the important complications of hepatic failure?

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

27

What tests do you order to investigate hepatocyte integrity?

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

28

What is chronic hepatitis?

• 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

29

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

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

30

when worried about hepatocyte function what tests do you order?

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)

31

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

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

32

What are the GRADES in the Batts-Ludwig system?

• 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

33

What is cirrhosis?

• 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

34

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

• 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

35

Which two hepatitis viruses are essentially the same?

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

36

What's up with HBV?

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

37

What's up with HCV?

• 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

38

What's up with autoimmune hepatitis?

• 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

39

What is PBC?

• 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

40

What are the histological signs of PBC?

• 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

41

What is primary sclerosing cholangitis?

• 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

42

How do you diagnose PSC?

• 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"

43

What is secondary sclerosing cholangitis?

• 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

44

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

• 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

45

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

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

46

What is the histologic triad of steatohepatitis?

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

47

Describe the two different clinical subtypes of steatohepatitis

• 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

48

What's up with steatohepatitis?

• 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

49

What is HH in the context of liver disease?



• 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

50

How can you differentiate secondary from primary hemosiderosis?

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

51

What are the histologic features of HH?

• 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

52

What is the inheritance pattern of HH?

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

53

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

• 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

54

What is wilson's disease?

• 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

55

What is the inheritance pattern of wilson's disease?

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

56

What's up with alpha-1-antitrypsin?

• 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

57

What are the important causes of bad hepatic blood flow?


• 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

58

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

• 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"

59

What laboratory evidence points to cholestasis?

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.

60

What might a changed INR indicate?

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

61

Alk phos elevation is specific or not?

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

62

Alk phos elevation is specific or not?

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