Liver Pathology

Question 1

What are some major liver diseases

Answer 1

Viral hepatitis
NAFLD (non-alcoholic fatty liver disease)
ALD (Alcoholic liver disease)
HCV (Hepatocellular carcinoma)

Question 2

What are some secondary causes of liver damage

Answer 2

Heart failure
Disseminated cancer
Extrahepatic infections

Question 3

What are some major liver diseases

Answer 3

Viral hepatitis
NAFLD (Non-Alcoholic Fatty Liver Disease)
ALD (Alcoholic Liver Disease)
HCC (Hepatocellular Carcinoma)

Question 4

What are some secondary causes of liver damage

Answer 4

Heart failure
Disseminated cancer
Extra-hepatic infections

Question 5

What are some mechanisms of liver damage repair

Answer 5

Hepatocyte and Parenchymal Responses
Scar formation and regression
Inflammation and Immunity

Question 6

Ballooned hepatocytes are a hallmark of ……….. (what condition)

Answer 6

Alcohol-induced or non-alcoholic steato-hepatitis

Question 7

What are some morphological changes the liver can undergo

Answer 7

Fat accumulation (Steatosis)
Bilirubin accumulation (Cholestasis)
Ballooning (cell swelling, cytoplasmic clearing, clumping of intermediate filament, Mallory’s Hyaline)

Question 8

What is the histology of liver steatosis

Answer 8

Multiple vacuoles of fat have been deposited in the liver
The vacuoles did not stain for glycogen nor was hepatocellular glycogenosis observed, although normal amounts of glycogen are apparent in hepatocytes
A chacteristic feature of steatosis is fatty droplets and displaced nuclei.
Steatosis is associated with diabetes and other metabolic diseases.
Alcoholism can also induce steatosis because the metabolism of ethanol produces NADH which shifts the metabolism of hepatocytes toward lipid synthesis.

Question 9

What is the histology of cholestasis

Answer 9

Canaliculi are not visible under normal circumstances but can be seen in cholestasis when they become dilated with inspissated bile plugs

Bile pigment can be identified as golden granular material within hepatocytes or as phagocytosed debris within Kupffer cells.
Cholestasis is characterized by feathery degeneration (cytoplasmic swelling with protein condensation) of hepatocytes

Question 10

What is liver ballooning

Answer 10

Hepatocellular ballooning is a key finding in nonalcoholic steatohepatitis (NASH)

•It is conventionally defined by hematoxylin and eosin (H&E) staining showing enlarged cells with rarefied cytoplasm and by changes in the cytoskeleton
•There is cellular enlargement 1.5-2 times the normal hepatocyte diameter

Ultrastructural Features
• A dilated endoplasmic reticulum sometimes referred to as hydropic change
•Enlarged cells, often with degenerative changes, containing multiple small fat droplets along with a lesser degree of dilated endoplasmic reticulum

•Ballooned cells may come in association with Mallory-Denk bodies

Nb: Immunohistochemical studies have demonstrated that ballooned cells contain oxidized phosphatidylcholine in the phospholipid-rich rim of fat droplets, and show altered expression of fat droplet associated (PAT family) proteins which regulate insulin-sensitive droplet lipase activity

Question 11

What is the histology of liver ballooning

Answer 11

Liver showing ballooning degeneration of hepatocytes and fibrous tissue proliferation around hepatic lobules, HE stain. Magnification × 100

Question 12

What are the two mechanisms through which hepatocytes die

Answer 12

Necrosis and apoptosis

Question 13

Describe how hepatocytes die by necrosis

Answer 13

Na+-K+ pumps fails, causing ionic imbalance
*Osmotic dysregulation-excess H2O enter cell, cell swells and ruptures
*Increased intracellular calcium  mitochondrial dysfunction
Necrosis is the primary cause of cell death in Ischemia, hypoxia and oxidative stress

Also in necrosis:
*Remnants of necrotic cells are phagocytosed by macrophages which tend to cluster and mark sites of necrosis

*Morphologically, necrotic cells contain pas-positive intracellular materials derived from necrotic hepatocytes

Nb: Necrosis, unlike apoptosis, induces an inflammatory response

Question 14

How does necrosis look like under the microscope

Answer 14

Accumulation of macrophages with ingested necrotic materials
Clusters with pas-positive intracellular materials from necrotic hepatocytes

Question 15

Describe apoptosis

Answer 15

•Programmed cell death
•Hepatic shrinkage
•Chromatin condensation (pyknosis)
•Chromatin fragmentation (Karyorrhexis)
•Cell fragments into apoptotic bodies (as implicated in yellow fever and acute chronic hepatitis)

Nb: Apoptosis does not stimulate an inflammatory response

Question 16

In cases of widespread parenchymatous injuries, what happens

Answer 16

Other forms of necrosis take place
•Confluent necrosis
•Bridging necrosis
•Pan-acinar necrosis

Question 17

What is confluence necrosis

Answer 17

Substantial areas of liver-cell death (multilobular)
•May be localized in some infections and viable tissues may remain
•Typically perivenular but it may, if severe and extensive, form bridges linking vascular structures
●Commonest cause in biopsy material is hepatitis, either viral or drug-related, in which case it is accompanied by an inflammatory reaction

Confluent necrosis with little or no inflammation is seen in hypoperfusion of the hepatic parenchyma, as in shock or left ventricular failure, and in heatstroke.

Drug related sources;
•Paracetamol(acetaminophen)-commonest, produces similar lesions

•Ferrous sulphate-typically causes periportal (zone 1) necrosis

CN may induce;
•Disseminated herpes virus infections (e.g. herpes simplex, varicella) and mycobacterial diseases

Nb: A prominent feature of confluent necrosis is the striking proliferation of neocholangioles (ductules) as a reactive process, which over time is followed by fibrous scarring.

Question 18

What is bridging necrosis

Answer 18

Bridging Necrosis

●Confluent necrosis linking terminal venules to portal tracts.

Originally describing necrosis linking any of the vascular structures, but now more often restricted to the linking of terminal hepatic venules (centrilobular veins) to portal tracts (central-portal bridging necrosis).

•BN describes the location rather than the type of necrosis. It usually results from extensive necrosis of confluent necrosis

•BN is a manifestation of severe acute hepatitis

•However its distribution even within a single biopsy may be irregular

•Represents necrosis of acinar zones 3, which touch both the veins and the larger portal tracts

Question 19

What are the types of bridging necrosis

Answer 19

C-C(central-to-central): as seen in parenchymal hypoperfusion and venous outflow obstruction.

•C-P(central-to-portal): a fairly common feature of acute hepatitis of viral type, when the bridges contain few or no elastic fibers. It is also seen in exacerbations of chronic hepatitis. Old bridges contain elastic fibers as well as collagen fibers.

•P-P(portal-to-portal): common in conditions in which portal tracts are widened, for example by chronic hepatitis or biliary tract disease; this is partly because the chance of obtaining a longitudinal section of a widened portal tract is greater than for one of normal width.

Nb:
Necrosis and inflammation linking adjacent portal tracts without involvement of terminal venules should not strictly be called bridging because it almost certainly has different pathogenetic significance; it results from widening of portal tracts, with or without periportal necrosis

Question 20

How is confluent necrosis shown under the microscope

Answer 20

Confluent necrosis (bridging). Large zones of hepatocyte injury and loss are apparent in this trichrome stained tissue. They link the central vein in the middle of the image to the portal tract, upper left, and probably to another portal tract, to the right, but outside of the needle core. These areas of confluent necrosis contain macrophages, mononuclear cells, cellular debris, and, where there is light blue staining, early deposition of collagen (Masson Trichrome, original magnification 10)

Question 21

Describe a pan-acinar/pan-lobular necrosis

Answer 21

Entire liver lobule is obliterated (a single lobule), as opposed to multilobular necrosis, where several adjacent lobules are invaded

•Panacinar necrosis is a more common feature in patients with “fulminant hepatitis“

•In multilobular necrosis, the parenchyma is replaced by collapsed stroma, inflammatory cells and activated macrophages.

•Around the surviving portal tracts, there are prominent duct-like structures, some of which probably represent proliferation of pluripotential progenitor cells.

Question 22

Describe the histology of a pan-acinar necrosis

Answer 22

There is panlobular necrosis with haphazardly scattered islands of viable hepatocytes. Pseudoductular proliferation is prominent in areas of necrosis. The field bracketed is seen at higher magnification in B (H&E, 25 x).

(B)
Clusters of viable hepatocytes are surrounded by a mixed inflammatory infiltrate composed largely of lymphocytes, Occasional bile plugs (arrows) are present (H&E, lOO x)

Question 23

What are the features of necrosis in a viral hepatitis

Answer 23

Features unique to the cause may be present

•Ground‐glass cytoplasmic change with hepatitis B and viral cytopathic changes with herpes simplex virus, cytomegalovirus, and adenovirus.

•The type and extent of necrosis is also variable in autoimmune hepatitis; in typical untreated chronic autoimmune hepatitis there is prominent IH with many plasma cells

Question 24

What are some effects of ischemic liver injury

Answer 24

Ischemic liver injury causes centrilobular necrosis (CLN; often called “centrilobular dropout”) in mild or early cases, and confluent necrosis in more severe cases.
*CLN can also be seen with severe venous outflow impairment, resulting from stasis and ischemic injury

*In these cases, other findings of venous outflow impairment are present, such as sinusoidal dilatation, congestion, and hemorrhage.

Question 25

Describe drug induced liver injury

Answer 25

Vary morphologically, depending on the inciting drug, with patterns of injury including bland cholestasis, cholestatic hepatitis, inflammatory hepatitis, granulomatous hepatitis, steatosis/steatohepatitis, and zonal or confluent necrosis.

•Acetaminophen is a drug well‐known for necrosis in the liver, with the extent of necrosis ranging from centrilobular to massive necrosis, the latter requiring liver transplantation.

•Other common drugs associated with necrosis include isoniazid, ketoconazole, nitrofurantoin, methyldopa, and fluoroquinolones.

Question 26

Describe acute allograft failure

Answer 26

After transplantation, necrosis in the allograft may result from preservation/reperfusion injury, acute nonfunction, rejection, ischemia, and hepatitis, with the extent and pattern of necrosis depending on the severity of the underlying cause.

Acute cellular rejection (ACR) is the most common type of rejection and the most common complication in the early post-transplant period.
The diagnosis is based on three main histopathologic features:
(1) Mixed but predominantly mononuclear portal inflammation containing activated lymphocytes, neutrophils, and eosinophils;
(2) Subendothelial inflammation of portal and/or central veins (i.e., endotheliitis); and
(3) Bile duct inflammation and damage.

•The minimum diagnostic criteria for ACR are generally accepted as the presence of at least two of these features. However, because these findings may vary considerably in different areas of the graft, it is recommended that a minimum of five portal tracts and at least two sections at different levels be examined when evaluating allograft biopsies

Question 27

Describe acute cellular rejection

Answer 27

Acute cellular rejection. The portal inflammatory infiltrate is mixed and consists predominantly of lymphocytes, including large activated immunoblasts with large nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm. Other inflammatory cells include eosinophils, plasma cells, macrophages, and occasional neutrophils. This portal infiltrate may range from mild to severe and can involve a few to all sampled portal tracts. Bile duct injury (arrows) is shown as lymphocytic infiltration of the duct epithelium accompanied by epithelial cell injury with nuclear enlargement, overlapping nuclei, loss of nuclear polarity, cytoplasmic vacuolization, and luminal disruption

Question 28

Ballooned cells may come in association with which bodies

Answer 28

Mallory-Denk bodies

Question 29

But, eventually, however in individuals with chronic diseases, hepatocytes reaches replicative senescence
True or false

Answer 29

True

Question 30

In biliary disease, the stem cell gives rise to what cells

Answer 30

Cholangiocytes

Question 31

The tissue stem cells are mainly present in what canal

Answer 31

Canal of hering

Question 32

What are some characteristics of a ductular reaction

Answer 32

Multiple small ducts
Repair process taken over by actual tissue stem cells

Question 33

Describe scar formation and regression

Answer 33

Principal cell involved in scar formation is hepatic stellate cells
•In quiescent state, act as lipid storage sites(including vitamin A)
•In acute/chronic injury, are activated, differentiating into fibrogenic myofibroblasts

Stimuli for Stellate Cell Activation
•Inflammatory cytokines (mainly TNF-α) produced by Kupffer cells, macrophages etc.
•Altered interactions and ECM
•Toxins and ROS

Conversion of stellate cells to myofibrobasts is mediated by;
•PDGF-β receptor signaling
•Cytokines-TGR-B & IL-17
•Chemokines released from macrophages, Kupffer cells and lymphocytes

The activated stellate cells release chemokines, cytokines, vasoactive factors, as well as growth factors

If injury and inflammatory stimuli persist;

1.Then, there will be eventual ECM deposition and scarring (starting in the space of disse)

2.There is also loss of sinusoidal endothelial cell fenestration (sinusoidal capillarisation)

•Most common in Non-Alcoholic Steato-Hepatitis(NASH)
•Also a feature of abnormal sinusoids classically seen in HCC

Areas of hepatocyte loss in chronic liver disease (features)
•Transformed into dense fibrous septa through collapse of underlying reticular framework & deposition of collagen by myofibroblasts

•Portal myofibroblasts also play a role in scarring in CLDs

Eventually the fibrous septa encircle surviving hepatocytes & give rise to diffused scarring (cirrhosis)

In CLDs, surviving hepatocytes replicate in an effort to restore the parenchyma, forming regenerative nodules that are a predominant feature in most cirrhotic livers

•In chronic injury leading to scar formation is interrupted;
•i.e. as seen when there is clearance of hepatic virus infection or cessation of alcohol use;

•Then stellate cell activation and scarring ceases, and fibrous septa may be broken down by metalloproteases leading to partial resolution and an appearance termed as Incomplete Septal Cirrhosis

•Unfortunately, even after insult has been removed, vascular remodeling and other architectural changes may not revert back to normal

Same case even with extensive scar resorption, which explains why vascular abnormalities such as portal hypertension fails to improve in some patients

Question 34

Describe immunity and inflammation

Answer 34

Large amount of lymphocytes present in the liver  about 22% of cells

Both Innate and adaptive immune systems are involved in all forms of liver injury and repair

Also, antigens in the liver are taken up by APC (Kupffer cells and dendritic cells in the liver) and presented to lymphocytes for degradation

TLR’s (with distinctive capacity to identify antigens from viruses, bacteria and other microbes) also;
•Release inflammatory cytokines
•Causing Hepatocyte injury and scarring
•And even malignant transformation