Liver Path 1 part 2

Question 1

Acute vs Chronic Hepatitis

Time Course

Answer 1

Acute: New liver disease
within 26 weeks of initial injury
Usually heals completely due to hepatic regeneration

Chronic: Persistent liver disease
> 26 weeks

May evolve through fibrosis to:
Cirrhosis
Complications of cirrhosis
Hepatocellular carcinoma

acute hepatitis is NOT acute liver failure

Question 2

Symptoms of Acute Hepatitis

Answer 2

Asymptomatic (abnormal LFTs only)

Nonspecific constitutional symptoms

• Fever
• Nausea/vomiting
• Fatigue

Physical findings

• Jaundice
• Tender liver
• Altered mental status/coma (hepatic encephalopathy)
• Bleeding, thombosis

Uncommon

• Headaches, myalgias, arthritis
• Rash, urticaria, arthritis

Question 3

Acute Hepatitis: Correlation of Clinical Symptoms

to Degree of Hepatocyte Necrosis

Answer 3

mild hepatitis- asymptomatic, under 500 AST/ALT

Moderate hepatitis: fatigue, nausea, moderate jaundice, normal PT- over 1,000 AST/ALT

Acute liver failure- fatigue, nausea, vomiting, abd pain, severe jaundice, elevated PT, coma/ death

Question 4

ALT and AST

Answer 4

Aminotransferases

AST: liver, muscle, RBC: Enzyme in amino acid metabolism.

ALT: primarily Liver; glutamate and pyruvate metabolism in the alanine cycle

Question 5

Chronic Liver Disease

Answer 5

Liver injury tests (AST/ALT) tend to be low to moderate but persist for months/years

Daily symptoms often mild or even absent

Hepatic regeneration occurs but may or may not equal injury

Long-term: new symptoms may arise due to liver dysfunction and/or as consequences of cirrhosis

Question 6

Numerous etiologies of Chronic Liver Disease

Answer 6

Hepatitis C is called “the silent epidemic.”

Three-quarters of people infected with hepatitis C don’t know they have it because they can have no symptoms for years.

There are usually no symptoms of cirrhosis in its early stage

Autoimmune hepatitis can present insidiously or be rapidly progressive

Up to 10 percent of all children in the nation have non-alcoholic fatty liver disease. NAFLD is the leading cause of chronic liver disease in childrenand adultsin the United States.

(Obesity major cause of NAFLD)

Question 7

Histological Manifestations of Liver Injury

Answer 7

Inflammation (Portal tracts, Interface between portal tracts and parenchyma, Within the parenchyma), cholestasis

Hepatocellular injury (Ballooning degeneration, Steatosis, Cholestasis, Inclusions) (reversible)

Necrosis (the cell swells due to defective osmotic regulation. This form of injury is the predominant mode of death in ischemic/hypoxic injury and a significant part of the response to oxidative stress.) and apotosis (cell death) (an active form of “programmed” cell death (pyknosis), fragmentation (karyorrhexis), and cellular fragmentation into acidophilicapoptotic bodies.)

Regeneration

Fibrosis

Neoplasia

Question 8

Hepatic Injury–> Limited Repertoire of Responses :

Answer 8

Degenerative, but potentially reversible changes, (steatosis) and bilirubin (cholestasis).

Question 9

When injury is not reversible, hepatocytes die principally by two mechanisms

Answer 9

necrosis or apoptosis.

Question 10

Steatosis- causes

Answer 10

Non-alcoholic
fatty liver

Alcohol

Drugs

Viruses

Question 11

Steatosis- def’n, how it comes about

Answer 11

Steatosis is abnormal accumulation of triglycerides in the liver.

EtOH, NASH, Drugs

Defects in fatty acid metabolism are responsible for pathogenesis of fatty liver disease, which may be due to imbalance in energy consumption and its combustion, resulting in lipid storage, or can be a consequence of peripheral resistance to insulin, whereby the transport of fatty acids from adipose tissue to the liver is increased

Hepatocytes are distended by single large fat droplets, which displace the cell nucleus to the side. As fat is dissolved during routine tissue processing, a clear space only remains. (H&E).

Steatosis is very common and once thought to be indicative of excess alcohol. It is now known that steatosis and steatohepatitis are commonly found in patients with type 2 diabetes mellitus, obesity and the metabolic syndrome. Can progress to fibrosis and cirrhosis

This whole spectrum has been referred to asnon-alcoholic fatty liver disease(NAFLD) and the hepatitis subset asnon-alcoholic steatohepatitis(NASH).

Question 12

Microvesicular steatosis - causes

Answer 12

Reye Syndrome

Tetracycline toxicity

Fatty change of pregnancy

Numerous drugs including
Ectasy
Aflatoxins

Acute liver failure WITHOUT necrosis

Question 13

Microvesicular steatosis

Answer 13

generally a serious condition with hepatic dysfunction and coma and one which is often associated with impaired β-oxidation of lipids.
Associated with aspirin use in children (Reye syndrome)

Question 14

Alcoholic hepatitis

Answer 14

which many hepatocytes are markedly ballooned, with rounded plasma membrane contours, cleared-out cytoplasm and clumped strands of intermediate filaments (some of which would qualify as Mallory–Denk bodies).

Interspersed among the ballooned hepatocytes are neutrophils and lymphocytes cells and fibrous tissue.

Mild injury to hepatocytes, cholangiocytes, or the endothelium and mesenchyme may be met with complete recovery of the organ.

There may also be complete recovery of the liver following massive hepatocellular death provided that inflammatory and fibrogenic pathways are not initiated.

Question 15

What does acute hepatitis look like?

Answer 15

lobular disarray

Apoptosis = active form of cell death: cytoplasmic shrinkage, cell membrane blebbing, chromatin condensation), nuclear fragmentation , and cellular fragmentation into small membrane-bound ‘apoptotic bodies’

These characteristic changes (Apoptosis) are the result of activation of caspases and endonucleases Hep C, apoptosis recent cell death, apoptotic bodies cleared quickly

Question 16

In the liver, hepatocellular apoptotic bodies have long been referred to as

Answer 16

acidophilic bodies or Councilman bodies.

Question 17

Identification of apoptotic bodies indicates

Answer 17

current and ongoing hepatocellular apoptosis, since apoptotic hepatocytes are engulfed within a matter of hours by Kupffer cells or other macrophages.

Question 18

good indicator of cholestatic liver disease

Answer 18

Alkaline phosphatase

Question 19

Hepatocellular Biliary Injury: Cholestasis

Answer 19

Necrosisper seis not necessarily a feature of cholestatic liver disease, but hepatocellular apoptosis with appearance of acidophilic bodies is often present, attributed to the * direct toxic effect of retained bile acids on hepatocytes.

Pigmentation includes * accumulation of bilirubin and its glucuronides in hepatocytes, inspissated bile in swollen canaliculi, and bile regurgitation into the sinusoidal space with phagocytosis by Kupffer cells.

Such pigmentation occurs predominantly in the * perivenular region of the hepatic lobule, as does dilatation of bile canaliculi.

During severe cholestasis of long duration, bilirubin deposition and * canalicular dilatation may extend into the * periportal region.

Question 20

A patient with distended bile canaliculus

Answer 20

Theyellow-green globular materialseen within small bile ductules in the liver is bilirubin pigment. This is hepatic cholestasis.

A problem with excretion of bile, or an obstruction to flow of bile, could cause this appearance.

This patient would exhibit jaundice

Question 21

Portal Inflammation

Answer 21

Chronic viral hepatitis. Mononuclear portal inflammation is variable; lymphoid aggregates, sometimes with germinal centers, are common in hepatitis C.

Different forms of peri- portal chronic inflammation sometimes the mononuclear inflammatory cells will infiltrate the bile duct epithelium as seen in some autoimmune diseases and sometimes a chronic inflammatory cells can cause the hepatocytes adjacent to the portal zone to be injured and show early signs of necrosis
this is called piecemeal piecemeal necrosis, correlates with active cellular injury while in other cases there is just increased numbers of inflammatory cells without obvious cell injury.

Question 22

Interface hepatitis in chronic viral hepatitis.

Answer 22

Previously referred to as ‘piecemeal necrosis’, this lesion can often be observed at low power, evidenced by irregular contours of a portal tract containing a dense mononuclear cell infiltrate eroding the limiting plate of hepatocytes in a piecemeal fashion.

Question 23

Liver After Hepatocellular Injury: Progression to Cirrhosis

Answer 23

This trichrome stain of the liver demonstrates bridging fibrosis.

While regeneration may be viewed as a beneficial step to recovery, a central and perhaps defining detrimental process in progressive chronic liver disease is fibrosis.

However, if the hepatic injury persists, liver regeneration may fail to restore lost tissue and matrix deposition becomes more extensive, akin to the formation of scar in the liver.

As chronic liver disease advances, excess type I and III collagens are laid down not only in portal tracts but also in the lobule, creating both fibrous septal tracts and severe alterations to sinusoidal ultrastructure.

Question 24

Liver Fibrogenesis

Answer 24

Hepatic stellate cells, residing in the space of Disse, normally are quiescent, fat-storing cells (Vitamin A). Ito cells

In several forms of acute and chronic injury, the stellate cells can become activated and are converted into highly fibrogenic myofibroblasts.

If injury persists, scar deposition begins, often in the space of Disse.

This is particularly important in alcoholic and nonalcoholic fatty liver diseases, but is also a generalized mechanism of scar formation in other forms of chronic liver injury.

Question 25

What makes HSCs undergo the transition from a quiescent to activated
state.

Answer 25

multiple injurious insults and/or exposure to
inflammatory cytokines such as platelet-derived growth
factor (PDGF), transforming growth factor (TGF)-β,
tumor necrosis factor (TNF)-α, and interleukin (IL)-1

Question 26

HSC activation is a pivotal event in

Answer 26

initiation and
progression of hepatic fibrosis and a major contributor
to collagen deposition[30,31]. Activation of HSCs is characterized
by cell proliferation and migration, contraction
after transforming into myofibroblasts, generation of a
large amount of collagen and other extracellular matrix
(ECM), ultimately leading to liver fibrosis

Question 27

strongest known inducer of fibrogenesis in hepatic fibrosis

Answer 27

TGF-beta

Given the critical role of
TGF-β1 in the pathogenesis of liver cirrhosis, specific
blockade of TGF-β1/Smad3 signaling has shown some
therapeutic value for liver fibrosis

Question 28

Current Thinking on Cirrhosis

Answer 28

Activation of stellate cells is the pivotal event in the initiation and progression of cirrhosis

Animal and clinical evidence has confirmed that any degree of fibrosis and even cirrhosis are potentially reversible by reasonable therapeutic strategies

In clinical circumstances where an effective treatment for the underlying insult is available, remodelling of the scar tissue can occur and a return towards architectural normality has been documented even in advanced fibrosis and cirrhosis.

Question 29

Galectin-3

Answer 29

is a protein that binds to terminal galactose residues on glycoproteins and is highly expressed in macrophages

Question 30

Mouse experiments have shown that galectin-3 is

Answer 30

a critical protein in fibrogenesis in multiple organs, including liver fibrosis due to toxins and NASH

**GR-MD-02 is a complex carbohydrate drug containing terminal galactose residues that binds to galectin-3 and inhibits its function

Question 31

The key features of stellate cell activation are:

Answer 31

(1) robust mitotic activity in areas developing new parenchymal fibrosis
(2) a shift from the resting-state ‘lipocyte’ phenotype to a transitional myofibroblast phenotype
(3) increased capacity for synthesis and secretion of extracellular matrix.

It is predominantly the cytokines secreted by activated Kupffer cells and other inflammatory cells that stimulate the stellate cells to divide and to secrete large amounts of extracellular matrix.

Question 32

End result of myofibroblast activation.

Answer 32

cirrhosis

Question 33

parenchymal extinction

Answer 33

the loss of parenchyma due to microscopic areas of ischemia after vascular inflammatory injury and occlusion

Scarring in areas of hepatocyte dropout and collapse of the lobular unit (PV and CV come close together)

Hepatocyte hyperplasia of viable cells elongate the scars into fibrous septae and bridging fibrosis

Question 34

Parenchymal extinction results from

Answer 34

the presence of widespread imbalance of hepatic blood flow where inflow exceeds the outflow capacity

Question 35

Cirrhosis is characterized by

Answer 35

diffuse nodular regeneration surrounded by dense fibrotic septae with subsequent parenchymal extinction

and collapse of liver structures causing pronounced distortion of hepatic vascular architecture which leads to increased resistance to portal blood flow and subsequent portal hypertension

Question 36

Cirrhosis classifications and most common causes of death

Answer 36

compensatedordecompensated

Most common cause of death in compensated cirrhosis is cardiovascular disease, followed by stroke, malignancy, and renal disease.

Complications of portal hypertension, hepatocellular carcinoma, and sepsisare the usual causes of mortality in patients with decompensated cirrhosis.

Question 37

Most deaths in patients with cirrhosis occur as a result of

Answer 37

hepatic decompensation

Decompensated cirrhosis has complications of variceal hemorrhage, ascites, encephalopathy, jaundice, or hepatocellular carcinoma characterizes.

Compensated cirrhosis does not have the above complications.

Question 38

Hepatic Venous Wedge Pressure

Answer 38

is a strong independent prognostic indicator in compensated and decompensated cirrhosis in predicting complications and mortality.
The pressure gradient between the portal vein and the inferior vena cava represents the liver portal perfusion pressure

Moreover, HVPG changes parallels changes in histology after effective antiviral therapy and showed a significant HVPG reduction after effective antiviral therapy in patients with advanced chronic HCV hepatitis.

Thus, serial HVPG measurements allow evaluating progression/regression in chronic hepatitis C and evaluating the response to antiviral treatment.

Question 39

Child-Turcotte-Pugh Classification

Answer 39

Assessment of Prognosis of Cirrhosis

points for each parameter: encephalopathy, ascites, bilirubin, albumin, PT (see proonged) or INR

Question 40

Portal Hypertension- prehepatic causes

Answer 40

Increased Resistance to Portal Blood Flow

Portal vein thrombosis

Narrowing of the portal vein

Question 41

portal hypertension- intrahepatic causes

Answer 41

Cirrhosis, accounts for most cases of portal hyper­tension

Sinusoidal obstruction

Question 42

portal hypertension- posthepatic causes

Answer 42

Severe right-sided heart failure

Constrictive pericarditis

Hepatic vein outflow obstruction

Question 43

Portal Hypertension in Cirrhosis Mechanisms

Answer 43

Increased resistance to portal flow at the level of the sinusoid

Compression of the central vein by perivenular fibrosis and parenchymal nodules

Anastomoses between arterial and portal systems imposing high pressure on a low pressure system

Question 44

Clinical Consequences of Portal Hypertension

Answer 44

Portosystemic venous shunts

• Congestive splenomegaly
• Ascites
• Hepatic encephalopathy

Question 45

If obstruction is predominantly intrahepatic the major clinical consequences are

Answer 45

ascites and hepatic encephalopathy

Question 46

Portosystemic venous shunts develop

Answer 46

wherever the systemic and portal circulation share common capillary beds

Congestive splenomegaly leads to Thrombocytopenia

Hepatic encephalopathy correlates with accumulation of ammonia

Chronic liver failure complications estrogen, etc

Question 47

Portacaval

Anastomoses

Answer 47

Para-umbilical

Esophageal

Retroperitoneal

Rectal

Question 48

One of the most common causes for splenomegaly is

Answer 48

portal hypertension with cirrhosis of the liver.

Micronodular cirrhosis from chronic alcoholism is more common in the U.S. than macronodular cirrhosis following hepatitis B or C infection. (Lots of overlap between micronodular and macronodular)

Note that this spleen also shows irregular tan-white fibrous plaques over the purple surface.

This “sugar icing” has the name hyaline perisplenitis. (Significance ?? Multiple episodes of peritonitis)

Question 49

Pathophysiology

of ascites

Answer 49

Sinusoidal hypertension drives fluid into the space of Disse where lymph flow exceeds thoracic duct capacity

Splanchnic vasodilation and hyperdynamic circulation leads to increased perfusion pressure of interstitial capillaries causing fluid extravasation in peritoneum

Decreased plasma oncotic pressure

Increased aldosterone leads to increased sodium reabsorption and increased intravascular volume

Question 50

Chronic Liver Failure Syndromes

Answer 50

Hepatopulmonary syndrome

Portopulmonary hypertension

Question 51

Hepatopulmonary Syndrome:

Answer 51

30% of patients with cirrhosis
Intrapulmonary vascular dilation–> rapid blood flow–> poor Hb oxygenation–> Hypoxia
Unknown pathogenesis

Question 52

Portopulmonary hypertension

Answer 52

Related to portal hypertension
?Excessive pulmonary vasoconstriction
Dyspnea on exertion (DOE)
* Clubbing of fingers