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269 Cards in this Set

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  • Back
1. What are the five patterns of hepatic injury?
1. Degeneration and intracellular accumulation
2. Necrosis and apoptosis
3. Inflammation
4. Regeneration
5. Fibrosis
2. What is ballooning degeneration?
With more severe hepatocellular damage, swollen hepatocytes have irregularly clumped cytoplasmic organelles and large clear spaces. This is called ballooning degeneration.
3. What is feather degeneration?
In cholestatic liver injury, retained biliary material may impart a diffuse, foamy appearance to the swollen hepatocyte.

This lesions can be difficult to distinguish from ballooning degeneration, except for the variable yellow discoloration of the cytoplasm.
4. What is microvesicular steatosis?
Multiple tiny droplets that do not displace the nucleus are called microvesicular steatosis, and appear in such conditions as acute fatty liver of pregnancy and valproic acid toxicity.
5. What is macrovesicular steatosis?
A single large droplet that displaces the nucleus, macrovesicular steatosis, may be seen in hepatocytes throughout the livers of obese or diabetic individuals and in scattered hepatocytes in patients w/HCV.
6. What is ischemic coagulative necrosis?

What do hepatocytes look like in apoptotic cell death?
In ischemic coagulative necrosis, the liver cells are poorly stained and "mummified" and often have lysed nuclei.

In apoptotic cell death, isolated hepatocytes round up to form shrunken, pyknotic, and intensely eosinophilic cells containing fragmented nuclei.
7. What is lytic necrosis?
Hepatocytes may also osmotically swell and rupture, so called lytic necrosis, the outcome of ballooning degeneration.

Lytic necrosis leaves neither mummified hepatocytes nor pyknotic cells but rather shards of cellular debris.
8. What is centrilobular necrosis?

What about pure midzonal and periportal necrosis?
The most obvious necrosis of hepatocytes occurs immediately around the terminal hepatic vein (called centriblobular necrosis), an injury that is characteristic of ischemic injury and a number of drug and toxic reactions.

Pure midzonal and periportal necrosis are rare; the latter may be seen in eclampsia.
9. What is bridging necrosis?
With more severe inflammatory injury, necrosis of contiguous hepatocytes may span adjacent lobules in a portal-to-portal, portal-to-central, or central-to-central fashion (bridging necrosis).
10. What is the definition of hepatitis?

What is interface hepatitis?
Injury to the liver associated w/an influx of acute or chronic inflammatory cells is termed hepatitis.

In viral hepatitis, quiescent lymphocytes may collect in the portal tracts as a reflection of mild smoldering inflammation, spill over into the periportal parenchyma as activated lymphocytes (interface hepatitis) causing a moderately active hepatitis, or suffuse the entire parenchyma in severe hepatitis.
11. What is a sign of very recent hepatocyte destruction?
Identification of apoptotic hepatocytes is a sign of very recent hepatocyte destruction.
12. What characterizes hepatocellular proliferation?

What is the ductular reaction?
Hepatocellular proliferation is marked by mitoses, thickening of the hepatocyte cords, and some disorganization of the parenchyma structure.

The canal of Herin-bile ductule unit constitutes a reserve compartment for restitution of severe parenchymal injury; when it is activated, innumerable serpentine profiles resembling bile ductules appear; the so called ductular reaction.
13.What is the most severe clinical consequence of liver disease?
Hepatic failure.

This can result from sudden and massive hepatic destruction, but more often it is the end point of progressive damage to the liver as part of chronic liver disease.

80-90% of hepatic functional capacity must be eroded before hepatic failure ensues. In most cases, liver transplantation is the only hope for survival.
14. What are the three categories of morphological alterations that cause liver failure?
1. Massive hepatic necrosis
2. Chronic liver disease
3. Hepatic dysfunction without overt necrosis
15. What causes massive hepatic necrosis?
This is most often drug or toxin induced, as from acetaminophen, halothane, antituberculosis drugs (rifampin, isoniazid), antidepressant MOAIs, carbon tetrachloride, and mushroom poisoning.

The mechanism may be direct toxic damage to hepatocytes, but more often is a variable combination of toxicity and inflammation with immune mediated hepatocyte destruction.

HepA and HepB also cause massive hepatic necrosis; HepC does not!
16. What causes hepatic dysfunction w/o overt necrosis?
Hepatocytes may be viable but unusable to perform normal metabolic function, as with Reye syndrome, tetracycline toxicity, and acute fatty liver of pregnancy.
17. What are the clinical features of hepatic failure?
These include jaundice, hypoalbuminemia, hyperammonemia, fetor hepaticus, palmar erythema, spider angiomas, hypogonadism, and gynocomastia
18. What is fetor hepaticus?
Fetor hepaticus is a characteristic body odor that is variously described as musty or sweet and sour and occurs occasionally. It is related to the formation of mercaptans by the action of GI bacteria on the sulfur-containing AA methionine and shunting of splanchnic blood from the portal into the systemic circulation (portosystemic shunting).
19. Why does coagulopathy develop in hepatic failure?
This is attributable to impaired hepatic synthesis of blood clotting factors 2, 7, 9, and 10.

The resultant bleeding tendency can lead to massive GI bleeding as well as petechial bleeding elsewhere.
20. What are the two important complications that herald the most grave stages of hepatic failure?
1. Hepatic encephalopathy
2. Hepatorenal syndrome
21. What is hepatic encephalopathy?
Hepatic encephalopathy is a life threatening disorder of CNS and neuromuscular transmission. It is reversible if the underlying liver conditions are corrected. It is caused by loss of hepatocellular function and blood shunting around the liver, leading to an altered metabolic milieu bathing the CNS. *Excess ammonia levels appear to be important.

In a great majority of cases, there are only minor morphologic changes in the brain, such as edema and an astrocytic reaction.
22. What are the symptoms of hepatic encephalopathy?
1. Disturbances in consciousness (e.g. behavioral abnormalities, confusion, stupor, coma)
2. EEG changes
3. Limb rigidity and hyperreflexia
4. Seizures
5. Asterixis (nonrhythmic, rapid extension-flexion movements of the head and extremities)
23. What is hepatorenal syndrome?
Hepatorenal syndrome is life-threatening renal failure (w/o intrinsic renal pathology) in the setting of severe liver disease.

*The cause is decreased renal perfusion pressure, followed by renal vasoconstriction. Although the patients have a drop in urine output (with a corresponding rise in serum creatinine and BUN levels), the concentrating ability of the kidney is maintained. The resulting urine is hyperosmolar, devoid of proteins, and surprisingly low in sodium.

Kidney function promptly improves if hepatic failure is reversed.
24. What causes cirrhosis?
Cirrhosis is among the top 10 causes of death in the Western world. The chief worldwide contributors are EtOH abuse and viral hepatitis. Other causes include biliary disease, and iron overload.
25. Cirrhosis as the end-stage of chronic liver disease is defined by what three characteristics?
1. Bridging fibrous septae in the form of delicate bands or broad scars linking portal tracts w/one another and portal tracts w/terminal hepatic veins.
2. Parenchymal nodules, containing proliferating hepatocytes encircled by fibrosis, with diameters varying from very small (<3mm) to large (several cm).
3. Disruption of the architecture of the entire liver.
26. What are five important features of cirrhosis?
1. The parenchymal injury and consequent fibrosis are diffuse, extending throughout the liver. (Focal injury does not constitute cirrhosis).
2. Nodularity is part of the Dx and reflects the balance between generative activity and constrictive scarring.
3. Vascular architecture is reorganized by the parenchymal damage and scarring, with the formation of abnormal interconnections btw vascular inflow and hepatic vein outflow channels.
5. Fibrosis is the key feature of progressive damage to the liver.
27. What is the pathogenesis of cirrhosis?
The central pathogenetic processes in cirrhosis are progressive fibrosis and reorganization of the vascular microarchitecture of the liver.
28. What is the vascular microarchitecture in the normal liver?
In the normal liver, interstitial collages (types I and II) are concentrated in protal tracts and around central veins. The collagen (reticulin) coursing alongside hepatocytes is composed of delicate strands of type IV collagen in the space of Disse.
29. What is the vascular microarchitecture in the cirrhotic liver?
In cirrhosis, types I and III collagen are deposited in the lobule, creating delicate or broad septal tracts. New vascular channels in the septae connect the vascular structures in the portal region (hepatic arteries and portal veins) and terminal hepatic veins, shunting blood around the parenchyma.

Continued deposition of collagen in the space of Disse w/in preserved parenchyma is accompanied by the loss of fenestrations in the sinusoidal endothelial cells. In the process, the sinusoidal space comes to resemble a capillary rather than a channel for exchange of solutes btw hepatocytes and plasma.
30. What is the major source of excess collagen in cirrhosis?
The perisinusoidal stellate cells, which lie in the space of Disse.

Although normally functioning as vitamin A fat storing cells, during the development of cirrhosis they become activated, a process that includes robust mitotic activity, a shift from the resting lipocyte phenotype to a transitional myofibroblast phenotype, and increased capacity for synthesis and secretion of ECM.
31. What are the four major stimuli for stellate cell activation?
1. Chronic inflammation, w/production of cytokines such as TNF, lymphotoxin, and IL-1.
2. Cytokine production by activated endogenous cells (Kupffer cells, endothelial cells, etc...) including TGF-β, PDGF, and lipid peroxidation products.
3. Disruption of the ECM, as stellate cells are extraordinarily responsive to the status of their substrate.
4. Direct stimulation of stellate cells by toxins.
32. What causes the constriction in the vascular resistance associated w/cirrhosis?
Acquisition of myofibers by perisinusoidal stellate cells also increases vascular resistance w/in the liver parenchyma, since tonic contraction of these "myofibroblasts" constricts the sinusoidal vascular channels.
33. What are the clinical features of cirrhosis?

What are the three mechanisms of death caused by cirrhosis?
Can be clinically silent for years; it ultimately presents w/anorexia, weight loss, weakness, osteoporosis, and debilitation.

Death is caused by:
1. Progressive liver failure
2. A complication related to portal hypertension
3. The development of HCC
34. What are the causes of prehepatic portal hypertension?
The major prehepatic conditions are obstructive thrombosis and narrowing of the portal vein before it ramifies w/in the liver.

Massive splenomegaly may also shunt excessive blood into the splenic vein.
35. What are the causes of posthepatic portal hypertension?
The major posthepatic causes are severe right sided heart failure (cor pulmonale), constrictive pericarditis, and hepatic vein outflow obstruction.
36. What are the causes of intrahepatic portal hypertension?
The dominant intrahepatic cause is cirrhosis, accounting for most cases of portal hypertension.

Fall less frequent are schistosomiasis, massive fatty change, diffuse fibrosing granulomatous disease such as sarcoidosis, tuberculosis, and diseases affecting the portal microcirculation.
37. What is the pathogenesis of portal hypertension?
Portal hypertension in cirrhosis results from increased resistance to portal blood flow at the level of the sinusoids, and compression of terminal hepatic veins by perivenular scarring and expansile parenchymal nodules.

Anastomoses between the arterial and portal systems in the fibrous septa also contribute to portal hypertension by imposing arterial pressure on the low pressure hepatic venous system.
38. What are the four major clinical consequences of portal hypertension?
1. Ascites
2. Formation of portosystemic venous shunts
3. Congestive splenomegaly
4. Hepatic encepalopathy
39. What is ascites?
Ascites refers to the collection of excess fluid in the peritoneal cavity.

It is generally a serous fluid having less than 3 gm/dL of protein (largely albumin). The fluid may contain a scant number of mesothelial cells and mononuclear leukocytes.

Influx of neutrophils suggests secondary infection, whereas red cells point to possible disseminated intra-abdominal cancer. With long standing ascites, seepage of peritoneal fluid thru lymphatics may produce hydrothorax, most often on the right side.
40. What are the four mechanisms involved in the pathogenesis of ascites?
1. Hepatic sinusoidal hypertension (promoted by hypoalbuminemia)
2. Percolation of hepatic lymph into the peritoneal cavity
3. Intestinal fluid leakage
4. Renal retention of sodium and water due to secondary hyperaldosteronism
41.Where are the portosystemic shunts?
1. Veins around and within the rectum (hemorrhoids)
2. Cardioesophageal junction (producing esophagogastric varices)
3. The retroperitoneum
4. The falciform ligament of the liver (involving the periumbilical and abdominal wall collaterals called caput medusae).
42. Can portal hypertension cause splenomegaly?
Yes, in long standing congestion splenomegaly can result.

The degree of enlargement varies widely up to 1 kg and is not necessarily correlated w/other features of portal hypertension.
43. What are the definitions of:



Jaundice and icterus denote yellow skin and sclera discoloration, respectively; they both reflect systemic bilirubin retention.

Cholestasis denotes systemic retention of bilirubin, bile salts, and cholesterol due to inadequate biliary elimination of these solutes.
44. What is the summary of bilirubin metabolism and elimination?

Five main steps...
1. Normal bilirubin production from heme is derived primarily from the breakdown of senescent circulation RBCs, w/a minor contribution from degradation of tissue heme containing proteins.
2. Extrahepatic bilirubin is bound to serum albumin and delivered to the liver.
3. Hepatocellular uptake via carrier mediated transfer.
4. Glucuronidation (UGT1A1) in the ER generate bilirubin monoglucuronides and diglucuronides, which are water soluble and readily excreted into bile.
5. Gut bacteria deconjugate the bilirubin and degrade it to colorless urobilinogens. The urobilinogens and the residue of intact pigments are excreted in the feces, w/some reabsorption and excretion into urine.
45. What is the hepatic conjugating enzyme?
The hepatic conjugating enzyme, UGT1A1 is a member of a family of UGTs that catalyze the glucuronidation of an array of substrates such as steroid hormones, carcinogens, and drugs.

UGT1A1 is located primarily in the sER and rER of hepatocytes; and it catalyzes the glucuronidation of bilirubin to its bilirubin monoglucuronide and diglucuronide form.
46. What is the pathogenesis of jaundice?

How are the two forms of bilirubin distinguished btw one another?
Both unconjugated bilirubin and bilirubin glucuronides may accumulate systemically and deposit in tissues, giving rise to the yellow color of jaundice.

The two forms of bilirubin are distinguished by pathophysiologic differences: unconjugated bilirubin is virtually insoluble in water at physiological pH and is tightly complexed to serum albumin. This form cannot be excreted in the urine even when blood levels are high.

In contrast, conjugated bilirubin is water soluble, nontoxic, and only loosely bound to albumin. This form can be excreted in urine.
47. What are the features of erythroblastosis fetalis?
Hemolytic disease of the newborn, (erythroblastosis fetalis) may lead to accumulation of unconjugated bilirubin in the brain, which can cause severe neurologic damage, referred to as kernitcterus.
48. Why does jaundice occur?

What are the five mechanisms in jaundice formation?
Jaundice occurs when the equilibrium between bilirubin production and clearance is disturbed from any of the following mechanisms:

1. *Excessive production of bilirubin
2. *Reduced hepatocyte uptake
3. *Impaired conjugation
4. Decreased hepatocellular excretion
5. Impaired bile flow

*Produce unconjugated hyperbilirubinemia
49. What causes neonatal jaundice?
B/c the hepatic machinery for conjugating and excreting bilirubin does not fully mature until about 2 weeks of age, almost every newborn develops transient and mild unconjugated hyperbilirubinemia,.

Breast-fed infants tend to exhibit jaundice w/greater frequency, possibly the result of β-glucuronidases present in maternal milk.

These enzymes deconjugate bilirubin glucuronides in the gut, increasing intestinal reabsorption of unconjugated bilirubin.
50. What is Crigler-Najjar syndrome (type I)?
In Crigler-Najjar syndrome (type I - autosomal recessive), the enzyme UGT1A1 is completely absent. The liver is incapable of synthesizing a functional enzyme, and the colorless bile contains only trace amts of unconjugated bilirubin.

The liver is morphologically normal. However, serum unconjugated bilirubin reachs very high levels, producing severe jaundice and icterus.

Without liver transplant, this condition is invariably fatal, causing death within 18 mos of birth secondary to kernicterus.
51. What is Crigler-Najjar syndrome (type II)?

What is the treatment?
Crigler-Najjar syndrome (type II - autosomal dominant) is a less severe, nonfatal disorder in which UGT1A1 enzyme activity is greatly reduced, and the enzyme is capable of forming only monoglucuronidated bilirubin.

Unlike Type I, the only major consequence is extraordinarily yellow skin from high levels of circulating unconjugated bilirubin.

*Treatment is with phenobarbital; it can improve bilirubin conjugation via inducing hypertrophy of the hepatocellular ER.
52. What is Gilbert syndrome?
Gilbert syndrome is a relatively common, benign, somewhat heterogeneous inherited condition presenting w/mild, fluctuating hyperbilirubinemia.

The primary cause is reduction in hepatic bilirubin glucuronidating activity to about 30% of normal levels. In most patients, 2 extra bases (TA) are found which results in reduced expression of UGT1A1.

The mild hyperbilirubinemia may go undiscovered for years and is not associated w/functional problems. When detected in adolescence or adult life, it is typically in association with stress, illness, strenuous exercise, or fasting.
53. What is Dubin-Johnson syndrome?
Dubin-Johnson syndrome results from a hereditary defect in hepatocellular excretion of bilirubin glucuronides across the canalicular membrane.

The defect is due to absence of the canalicular protein, the multidrug resistance protein 2 (MRP2), that is responsible for transport of bilirubin glucuronides and related organic anions into bile.

Apart from chronic or recurrent jaundice of fluctuating intensity, most patients are asymptomatic and have a normal life expectancy.
54. What is the appearance of the liver in Dubin-Johnson syndrome?
The liver is darkly pigmented owing to coarse pigmented granules within the cytoplasm of hepatocytes.

Electron microscopy reveals that the pigment is located in lysosomes, and it i appears to be composed of polymers of epinephrine metabolites, not bilirubin pigment. The liver is otherwise normal.
55. What is Rotor syndrome?
Rotor syndrome is a rare form of asymptomatic conjugated hyperbilirubinemia with multiple defects in hepatocellular uptake and excretion of bilirubin pigments.

The liver is not pigmented. As w/Dubin-Johnson syndrome, patients with Rotor syndrome exhibit jaundice but otherwise live normal lives.
56. What are six signs of cholestasis?
1. Jaundice
2. Pruritus, related to the elevation in plasma bile acids and their deposition in peripheral tissues, particularly skin
3. Skin xanthomas
4. Elevated ALKPHOS
5. Elevated gGTP
6. Malabsorption of fat soluble vitamins
57. What is the morphology of cholestasis (common to both obstructive and nonobstructive cholestasis)?
The morphology can vary depending on the severity, duration and underlying cause.

Common to both obstructive and nonobstructive cholestasis is the accumulation of bile pigment within the hepatic parenchyma. Elongated green-brown plugs of bile are visible in dilated bile canaliculi. Rupture of canaliculi leads to extravasation of bile, which is quickly phagocytosed by Kupffer cells. Droplets of bile pigment also accumulate within hepatocytes, which can take on a fine, foamy appearance (feathery degeneration)
58. What is the morphology of obstructive cholestasis?
Obstruction of the biliary tree, either intra or extrahepatic, induces distention of upstream bile ducts and ductules by bile. Ductular proliferation is confined to portal tracts. The ductules also reabsorb secreted bile salts, serving to protect the downstream obstructed bile ducts from the toxic detergents.

Associated histologic findings include protal tract edema and periductular infiltrates of neutrophils.

Prolonged obstructive cholestasis leads not only to feathery degeneration but to bile lakes fill with cellular debris and pigment.
59. Unrelieved obstruction in cholestasis eventually leads to...?
Portal tract fibrosis, which initially extends into and subdivides the parenchyma w/relative preservation of hepatic architecture.

Ultimately, an end-stage bile-stained, cirrhotic liver is created (biliary cirrhosis).
60. Can cholestasis be corrected?
Extrahepatic biliary obstruction is frequently amenable to surgical alleviation. In contrast, choelstasis due to diseases of the intrahepatic biliary tree or hepatocellular secretory failure cannot be benefited by surgery (short of transplantation) and the patients condition may be worsened by an operative procedure.

Regardless, there is thus some urgency in making a correct diagnosis of the cause of jaundice and cholestasis.
61. What is familial intrahepatic cholestasis?
This group of disorders is characterized by low bile salt secretion into bile. Unlike many other cholestatic condition, the virtual absence of bile salts within the canalicular lumen btwn hepatocytes means that gGTP levels are low for the degree of hyperbilirubinemia.
62. What is benign recurrent intrahepatic cholestasis?
In BRIC, there are intermittent attacks of cholestasis over life w/o progression to chronic liver disease.
63. What is progressive familial intrahepatic cholestasis 1 (PFIC-1)?
In progressive familial intrahepatic cholestasis 1, cholestasis begins in infancy w/severe pruritus due to high serum bile acid levels and relentlessly progresses to liver failure before adulthood.

The first major characterized family w/this syndrome are descendents from amish people. Affected members of this particular family are designated as having Byler syndrome; unrelated individuals w/different mutations have Byler disease.
64. What genetic alterations are common in PFIC-1?
These conditions encompass a spectrum arising usually from mutations in the ATP8B1 gene on chromosome 18q21. The encoded protein is a canalicular P-type ATPase that probably plays a role in secretion of bile salts indirectly thru the maintenance of aminophospholipid polarity in the membrane.
65. Mutations in the canalicular bile salt export pump (BSEP), encoded by the ABCB11 gene are the cause of...?
Progressive familial intrahepatic cholestasis 2 (PFIC-2).

This cholestatic disorder features severely impaired bile salt secretion into bile, w/extreme pururitus, growth failure, and progression to cirrhosis in the first decade of life.
66. What is Progressive familial intrahepatic cholestasis 3?
PFIC-3 is an autosomal-recessive disorder w/high serum GGT and is due to mutations in the ABCB4 gene.

The encoded protein, MDR3, is responsible for flipping phosphatidylcholine from the internal to the external hemileaflet of the canalicular membrane.

In patients w/this disorder, absence of phosphatidylcholine in bile leaves the apical surfaces of the biliary tree epithelia subject to the full detergent action of secreted bile salts, with resultant toxic destruction of these epithelia and release of GGT into the circulation.
67. What is 3β-hydroxysteroid dehydrogenase deficiency?
Children w/severe cholestasis but with absence of elevated serum GGT and absence of pruritus may also have inherited defects in bile acid synthesis.

The most common condition is a deficiency of 3β-hydroxysteroid dehydrogenase, an enzyme located early in the pathway for bile acid synthesis.
68. What three systemic viral infections can involve the liver?
1. EBV (mononucleosis), which may cause a mild hepatitis during the acute phase
2. CMV, particularly in the newborn or immunosuppressed patient.
3. Yellow fever, which has been a major and serious cause of hepatitis in tropical countries.

Less frequently, in children and immunosuppressed patients, the liver is affected in the course of rubella, adenovirus, herpesvirus, or enterovirus infections.
69. What is the hepatitis A virus?
HAV is a self limited disease with an incubation period of 2-6 weeks. HAV does not cause chronic hepatitis or a carrier state and only rarely causes fulminant hepatitis, so the fatality rate is very low.

HAV occurs throughout the world and is endemic in countries with substandard hygiene and sanitation.
70. What are the characteristics of HAV?
HAV is a small, nonenveloped, single-stranded RNA virus that is spread by ingestion of contaminated water and foods and is shed in the stool for 2-3 weeks before and 1 week after the onset of jaundice. Thus, close personal contact w/an infected individual or fecal oral contamination during this period accounts for most cases.

It can also be spread via consumption of raw or steamed shellfish which are contaminated with sewage.
71. How is the serologic Dx of HAV made?
Anti HAV-IgM appears in the blood at the onset of symptoms. Fecal shedding of the virus ends as the IgM titer rises.
The IgM response usually begins to decline in a few months and is followed by the appearance of IgG anti-HAV. The latter persists for years, perhaps for life. Hence, the HAV vaccine is effective.
72. What are the five possible outcomes in HBV?
1. Acute hepatitis with resolution
2. Chronic hepatitis, which may evolve to cirrhosis
3. Fulminant hepatitis with massive liver necrosis
4. The backdrop for HDV infection
5. HCC
73. What are the characteristics of HBV infection?
HBC has a prolonged incubation period (4-26 weeks). Unlike HAV, HBV remains in the blood up to and during active episodes of acute and chronic hepatitis. It is also present in all physiologic and pathologic body fluids, w/the exception of stool. HBC is a hardy virus and can withstand extremes of temp and humidity.

Thus, whereas blood and body fluids are the primary vehicles of transmission, virus may also be spread via contact w/body secretions such as semen, saliva, sweat, tears, breast milk, and pathologic effusions.
74. What are high risks for contracting HBV?
Transfusion, blood products, dialysis, needle-stick accidents, IV drug abuse and homosexual activity constitute the primary risk categories for HBV infection.

Also, spread from an infected mother to a neonate during birth (vertical transmission) is common. These neonatal infections often lead to the carrier state for life.
75. What is the HBV?

What are the four parts of the virus?
HBV is a member of the Hepadnaviridae, a family of DNA containing viruses that cause hepatitis in multiple animal species.

It consists of:
1. A nucleocapsid core protein (HBcAg), with a precore and core region (HBeAg). The precore region directs the HbEAg toward secretion into blood, whereas HBcAg remains in hepatocytes for the assembly of complete virions.
2. Envelope glycoprotein (HBsAg)
3. A DNA polymerase that exhibits reverse transcriptase activity
4. A protein from the X region, which is necessary for virus replication and acts as a transcriptional transactivator of the viral genes and a wide variety of host genes.
76. What are the two phases in HBV infection of a hepatocyte?
1. *Proliferative phase, where HBV-DNA is present in episomal form, with formation of complete virions and antigens. HBsAg and HBcAg in association MHC class I molecules leads to activation of CD8+ cytotoxic T lymphocytes. Hepatocyte destruction occurs if a cytotoxic T lymphocyte interacts w/the infected hepatocyte.

2. For the infected hepatocytes that are not destroyed by the immune system, an *integrative phase may occur in which viral DNA is incorporated into the host genome.
77. What is the pathogenesis of liver injury in HBV?
HBV is not directly toxic to liver cells; instead it is the immune response to viral antigens, expressed on infected hepatocytes, that cause liver cell injury.

HBV evokes both a humoral and cellular immune response, the latter involving both CD4+ helper T cells and CD8+ cytotoxic T cells. Whereas on one hand, cytotoxic T cells mediate hepatocellular injury, on the other hand, they also help clear the infection by destroying the intracellular reservoirs of HBV.
78. When does HBsAg appear?
HBsAg appears before the onset of symptoms, peaks during overt disease, and the declines to undetectable levels in 3-6 months.
79. When does HBeAg appear?
HBeAg, HBV-DNA, and DNA polymerase appear in the serum soon after HBsAg, and all signify active viral replication.
80. When does IgM anti-HBc become detectable?
IgM anti-HBc becomes detectable in serum shortly before the onset of symptoms, concurrent w/the onset of elevation of serum aminotransferases.

Over months, the IgM antibody is replaced by IgG anti-Hbc.
81. When does Anti-HBe become detectable?
Anti-HBe is detectable shortly after the disappearance of HBeAg, implying that the acute infection has peaked and the disease is on the wane.
82. When does IgG anti-Hbs become detectable?
IgG anti-HBs does not rise until the acute disease is over and is usually not detectable for a few weeks to several months after the disappearance of HBsAg.

Anti-Hbs may persist for life, conferring protection; this is the basis for current vaccination strategies using noninfectious HBsAg.
83. What designates the carrier state in HBV?
The carrier state is defined by the presence of HBsAg in serum for 6+ months after initial detection.

The presence of HBsAg alone does not necessarily indicate replication of complete virions, and patients may be asymptomatic and w/o liver damage.
84. What does the serologic profile look like of someone who has a chronic replication of HBV virions?
Chronic replication of HBV virions is characterized by persistence of:

85. What is the HCV?
HCV is a major cause of liver disease. It is the most common chronic blood-borne infection and accounts for almost half of all patients in the US w/chronic liver disease.

The major routes of transmission are inoculations and blood transfusions. IV drug use accounts for 60% of cases, transfusions prior to '91 account for 10%, and hemodialysis patients and healthcare workers make up less than 5%. Sexual transmission is the only presumed risk factor in 15% of cases.
86. What type of liver disease does HCV cause?
Acute HCV infection is generally undetectable. In contrast to HBV, progression to chronic disease occurs in the majority of individuals infected w/HCV, and cirrhosis eventually occurs in approx 20% of patients.

**Persistent infection and chronic hepatitis are the hallmarks of HCV infection.
87. What type of virus is HCV?
HCV is a small, enveloped, single stranded RNA virus. The virus is not that hardy, however, and it is inherently unstable which gives rise to multiple genotypes and subtypes. Over time, several dozen mutant strains can be detected within one individual. THe E2 protein of the envelope is the target of many anti-HCV antibodies but it is also the most variable region of the entire viral genome, enabling emergent virus strains to escape from neutralizing antibodies.
88. Give me more info on this variability of HCV...
In particular, elevated titers of anti-HCV IgG occurring after an active infection do not confer effective immunity. Moreover, HCV is able to actively evade the interferon mediated cellular antiviral response, b/c E2 and NS5A inhibit the interferon induced double-stranded RNA-activated protein kinase, which is involved in the antiviral response to IFN.

A characteristic feature of HCV infection, therefore, is repeated bouts of hepatic damage, the result of reactivation of a preexisting infection or emergence of an endogenous, newly mutated strain.
89. What is the serologic profile for HCV?
HCV RNA is detectable in blood for 1-3 weeks, coincident w/elevations in serum transaminases. In symptomatic acute HCV infection, anti-HCV antibodies are detected in only 50-70% of patients; in the remaining, the anti-HCV antibodies emerge after 3-6 weeks.

In chronic HCV infection, circulating HCV RNA persists in many patients.

*A clinical feature that is quite characteristic of chronic HCV infection is episodic elevations in serum aminotransferases, with intervening normal or near-normal periods.
90. What is HDV?
HDV is a unique RNA virus that is replication defective, causing infection only when it is encapsulated by HBsAg. Thus, HDV is absolutely dependent on the genetic information provided by HBV for multiplication and causes hepatitis only in the presence of HBV.
91. What are the two settings in which HDV arises?
1. Acute coinfection occurs following exposure to serum containing both HDV and HBV. The HBV must become established first to provide the HBsAg necessary for development of complete HDV virions.

2. Superinfection of a chronic carrier of HBV w/a new inoculum of HDV (and HBV) results in disease about 30-50 days later. The carrier may have been previously healthy or may have had underlying chronic hepatitis.
92. What are the clinical symptoms of HDV?
Simultaneous coinfection w/HBV and HDV results in hepatitis ranging from mild to fulminant, fulminant disease being more likely than w/HBV alone.

Chronicity rarely develops. When HDV is superimposed on chronic HBV infection, (1) acute severe hepatitis may result, (2) mild HBV hepatitis may be converted into fulminant disease, and/or (3) chronic, progressive disease may develop (in 80% of patients), often culminating in cirrhosis.
93. How is HDV spread?
HDV infection is uncommon and is largely restricted to drug addicts and hemophiliacs. Other groups at risk for HBV, such as homosexual men and health care workers are at low risk for HDV infection, for unclear reasons.
94. What are the characteristics of the HDV?
HDV is a double-shelled particle that resembles HBV. The external coat antigen of HBsAg surrounds an internal polypeptide assembly, designated HDAg.
95. What is the serologic profile of HDV?
HDV RNA is detectable in the blood and liver just prior to and in the early days of acute symptomatic disease. IgM anti-HDV is the most reliable indicator of recent HDV exposure, although its appearance is late and freq short lived.

Nevertheless, acute coinfection by HDV and HBV is best indicated by detection of IgM against both HDAg and HBcAg.
96. What is HEV?
HEV hepatitis is an enterically transmitted, water-borne infection that occurs primarily in young-to middle-aged adults; sporadic infection and overt illness in children are rare.

A characteristic feature of HEV infection is the high mortality rate among pregnant women, approaching 20%.

In most cases, the disease is self-limiting; HEV is not associated w/chronic liver disease or persistent viremia. The average incubation period following exposure is 6 weeks.
97. What type of virus is HEV?
HEV is an uneveloped, single-stranded RNA virus that is structually similar to the Caliciviridae. A specific antigen (HEV Ag) can be identified in the cytoplasm of hepatocytes during active infection, and virions are shed in stool during the acute illness.
98. What is the serologic profile of HEV?
Before the onset of clinical illness, HEV RNA and HEV virions can be detected in stool and liver. The onset of rising serum aminotransferases, clinical illness, and elevated IgM anti-HEV titers are virtually simultaneous. Symptoms resolve in 2-4 weeks, during which time the IgM is replaced w/a persistent IgG anti-HEV titer.
99. What is HGV infection?
In up to 75% of infections, HGV is cleared from plasma; in the remainder of cases, HGV infection becomes chronic.

The site of HGV replication is most likely in mononuclear cells; hence, HGV is inappropriately names, as it is not hepatotropic and does not cause elevations in serum aminotransferases.

This virus commonly co-infects patients with HIV, and curiously this dual infection is somewhat protective against HIV disease.
100. What are four clinical syndromes that may develop following exposure to hepatitis viruses?
1. Acute asymptomatic infection w/recovery; serologic evidence only
2. Acute symptomatic hepatitis w/recovery; anicteric or iteric
3. Chronic hepatitis; without or with progression to cirrhosis
4. Fulminant hepatitis; with massive to submassive hepatic necrosis
101. What type of people fall into the acute asymptomatic infection w/recovery group?
Patients in this group are identified only incidentally on the basis of minimally elevated serum transaminases or by the presence of antiviral antibodies.
102. What are the four phases of acute symptomatic infection with recovery?
1. An incubation period
2. A symptomatic preicteric phase
3. A symptomatic icteric phase
4. Convalescence
103. What defines the preicteric phase?
The preicteric phase is marked by nonspecific, constitutional symptoms. Malaise is followed in a few days by general fatigueability, nausea, and loss of appetite. Weight loss, low grade fever, headaches, muscle and joint aches, and pains and diarrhea are inconstant symptoms.

About 10% of patients w/acute hepatitis (most often HBV), develop a serum sickness like syndrome, which may be due to elevated transaminases.

Physical exam reveals a mildly enlarged, tender liver. In some patients, the nonspecific symptoms are more severe, w/higher fever, shaking chills and headache, and sometimes accompanied by right upper quadrant pain and tender liver enlargement.
104. What defines the icteric phase?
The icteric phase, if it appears, is caused by conjugated hyperbilirubinemia. Icteric hepatitis is usual in adults (but not children) with acute HAV infection, but it is absent in about 1/2 the cases of HBV and in the majority of HCV cases.

Dark colored urine and light gray colored stools are common. The liver may be mildly enlarged and moderately tender to percussion. Prolonged PT time and hyperglobulinemia is common.

Recovery is heralded by the generation of strong T cell responses against viral antigens expressed on infected liver cells.
105. What defines chronic hepatitis?
Chronic hepatitis is defined as symptomatic, biochemical or serologic evidence of continuing or relapsing hepatic disease for more than 6 mos, with histologically documented inflammation and necrosis.

Chronic viral hepatitis constitutes a carrier state, in that these individuals harbor replicating virus and therefore can transmit an organism.

However, in all instance of chronic hepatitis, etiology is the single most important indicator of likelihood to progress to cirrhosis.
106. What populations develop chronic hepatitis after viral infection?
HAV: none

HBV: over 90% in infected neonates; 10% of adults

HCV: over 60%

HDV: rarely in acute HBV/HDV coinfection but is the most freq outcome of HDV superinfection of HBV-infected patient

HEV: none
107. What are common morphologic features found in acute and chronic hepatitis?
These morphologic changes can be mimicked by drug reactions. Tissue alterations caused by acute infection w/HAV, HBV, HCV, and HEV are similar, as is the chronic hepatitis caused by HBV, HCV, and HBV + HDV.

HBV-infected hepatocytes may exhibit a cytoplasm packed w/spheres and tubules of HBsAg, producing a finely granular eosinophilic cytoplasm "Ground glass hepatocytes".

HCV infected livers freq show lymphoid aggregates within portal tracts and focal sublobular regions of hepatocyte macrovesicular steatosis, which are to be distinguished from the extensive panlobular microvescular and macrovesicular steatosis seen in many forms of toxic hepatitis.
108. What are the morphologic features of acute hepatitis?

With acute hepatitis, hepatocyte injury takes the form of diffuse swelling ("ballooning degeneration"), so the cytoplasm looks empty and contains only scattered eosinophilic remnants of cytoplasmic organelles.

An inconstant finding is cholestasis, with bile plugs in canaliculi and brown pigmentation of hepatocytes. The canalicular bile plugs result from cessation of the contractile activity of the hepatocyte pericanalicular actin microfilament web.
109. What are the two patterns of hepatocyte cell death in acute hepatitis?
1. Rupture of cell membranes leads to cytolysis and focal loss of hepatocytes. The sinusoidal collagen reticulin framework collapses where the cells have disappeared, and scavenger macrophage aggregates mark sites of hepatocyte cell loss.

2. Apoptosis, which is more consipicuous. It is caused by anti-viral cytotoxic T cells. Apoptotic hepatocytes shrink, become intensely eosinophilic, and have fragmented nuceli; effector T cells may still be present in the immediate vicinity.
110. What are the morphologic features of acute hepatitis?

In severe cases of acute hepatitis, confluent necrosis of hepatocytes may lead to bridging necrosis connecting portal-to-portal, central-to-central, or portal-to-central regions of adjacent lobules. Hepatocyte swelling and regeneration compress sinusoids, and the more or less radial array of the parenchyma is lost.
111. What is a prominent feature of acute hepatitis?
Inflammation is a characteristic and usually prominent feature of acute hepatitis. Kupffer cells undergo hypertrophy and hyperplasia and are often laden with lipofuscin pigment due to phagocytosis of hepatocellular debris.

*The portal tracts are usually infiltrated w/a mixture of inflammatory cells. The inflammatory infiltrate may spill over into the adjacent parenchyma to cause necrosis of periportal hepatocytes - interface hepatitis.
112. What are the morphologic features of chronic hepatitis?

The histologic features of chronic hepatitis range from exceedingly mild to severe. In the mildest forms, significant inflammation is limited to portal tracts and consists of lymphocytes, macrophages, occasional plasma cells, and rare neutrophils or eosinophils. Liver architecture is usually well preserved, but smoldering hepatocyte necrosis throughout the lobule may occur.
113. What are the morphologic features of chronic hepatitis?

Common finding are lymphoid aggregates and bile duct damage in the portal tracts and focally mild to moderate macrovesicular steatosis.

In all forms of chronic hepatitis, continued interface hepatitis and bridging necrosis are harbingers of progressive liver damage.

*The hallmark of irreversible liver damage is the deposition of fibrous material. At first, only portal tracts show fibrosis; but with time, periportal septa fibrosis occurs, followed by linking of fibrous septa between lobules occurs (bridging fibrosis).
114. What are the morphologic features of chronic hepatitis?

Continued loss of hepatocytes and fibrosis results in cirrhosis, with fibrous septae and hepatocyte generative nodules.

This pattern of cirrhosis is characterized by irregularly sized nodules separated by variable but mostly broad scars.
115. What is fulminant hepatitis?
When hepatic insufficiency progresses from onset of symptoms to hepatic encephalopathy within 2-3 weeks, it is termed fulminant hepatic failure.

A less rapid course, extending up to 3 months, is called subfulminant failure.
116. What are three major causes of fulminant hepatitis?
1. In the US, fulminant viral hepatitis is responsible for about 12% of cases of fulminant hepatic failure; almost all are due to HAV or HBV.
2. Drug and chemical toxicity account for a substantial remainder (52%).
3. Misc or unknown (18%)
117. What is the morphology of fulminant hepatitis?
The entire liver may be involved or only random areas. The liver may be transformed into a limp, red organ covered by a wrinkled, too-large capsule. On transection, necrotic areas have a muddy red, mushy appearance with blotchy bile staining. Microscopically, complete destruction of hepatocytes in contiguous lobules leaves only a collapsed reticulin framework and preserved portal tracts.

There may be little inflammatory reaction; alternatively, with survival for several days, there is a massive influx of inflammatory cells to begin the phagocytic cleanup process.
118. If a patient with fulminant hepatitis survives for more than a week, what morphologic changes take place?
Survival for more than a week also permits secondary regenerative activity of surviving hepatocytes and bile ducts.

A dormant stem cell population lying alongside the bile ducts and canals of Hering also proliferates, creating a population of small cells with a high nuclear:cytoplasmic ratio (so called oval cells) interspersed with surviving hepatocytes.
119. What morphologic changes take place in the liver when large amts of hepatotoxins are introduced, or during ischemia?
With centrilobular zonal necrosis caused by direct hepatotoxins or ischemia, the parenchymal framework is preserved. Regeneration is directly from hepatocytes, and native liver architecture is restored in time.

With more massive destruction of confluent lobules, regeneration is disorderly, yielding nodular masses of liver cells that produce a more irregular liver on healing.
120. What are the clinical features of fulminant hepatic failure?
Fulminant hepatic failure may present as jaundice, ecephalopathy, and fetor hepaticus.

Life threatening extrahepatic complications include coagulopathy and bleeding, cardiovascular instability, renal failure, ARDS, electrolyte and acid-base disturbances and sepsis.

The overall mortality rate ranges from 25-90% in the absence of liver transplantation.
121. What is the morphology of liver abcesses?
Liver abscesses may occur as solitary or multiple lesions, ranging in size from mm's to massive lesions many cm's in diameter. Bactermic spread thru the arterial or portal system tends to produce multiple small abscesses, whereas direct extension and trauma usually cause solitary large abscesses.

Biliary abscesses, which are usually multiple, may contain purulent material from adjacent bile ducts.

The causative organism can occasionally be identified in the case of fungal or parasitic abscesses. On rare occasion, abscesses located in the subdiaphragmatic region, particularly amebic, may burrow into the thoracic cavity to produce empyema or a lung abscess.
122. What are the clinical features of liver abscesses?
Liver abscesses are associated w/fever and in many instances, right upper quadrant pain and tender hepatomegaly. Jaundice may result from extrahepatic biliary obstruction. Although antibiotic therapy may control smaller lesions, surgical drainage is often necessary for the large lesions.

B/c Dx is freq delayed and b/c patients are often elderly and have serious coexistent disease, the mortality rate w/large liver abscesses ranges from 30-90%. W/early recognition and management, up to 80% can survive.
123. What are the five sources of infection in liver abscesses?
1. Portal vein
2. Arterial supply
3. Ascending infection in the biliary tract (ascending cholangitis)
4. Direct invasion of the liver from a nearby source
5. A penetrating injury

*The majority of hepatic primarily spread thru the biliary tree or the arterial supply in patients suffering from some form of immune deficiency.
124. What is autoimmune hepatitis?
Autoimmune hepatitis is a chronic hepatitis w/histologic features that may be indistinguishable from those of chronic viral hepatitis. This disease may run an indolent or severe course.

Clinical presentation is often similar to other forms of chronic hepatitis, and autoimmune hepatitis may progress to cirrhosis w/o clinical Dx.

In untreated severe disease, as many as 40% of patients die w/in 6 months of Dx, and cirrhosis develops in at least 40% of survivors.
125. What are the important features of autoimmune hepatitis?
1. Female predominance (78%), particularly in the young and perimenopausal women.
2. The absence of viral serologic markers
3. Elevated serum IgG and γ-globulin levels (>1.5x normal)
4. High serum titers of autoantibodies in 80% of cases, including antinucear, antismooth muscles, and/or antiliver/kidney microsomes antibodies
5. Negative antimitochondrial antibody
126. What are the two subgroups of autoimmune hepatitis?
1. The most common, type 1, exhibiting ANA and/or SMA serum markers
2. The type 2 subgroup of younger patients exhibits antibodies to liver/kidney microsomes (anti-LKM1).
127. What are the three types of injuries in drug- and toxin-induced liver disease?
Injury may result from:
1. Direct toxicity
2. Via hepatic conversion of a xenobiotic to an active toxin
3. Through immune mechanisms, usually by a drug or a metabolite acting as a hapten to convert a cellular protein into an immunogen.
128. What are the two types of drug reactions?
1. Predictable (intrinsic)
-Occurs in anyone who accumulates a sufficient dose

2. Unpredictable (idiosyncratic)
-Depends on idiosyncrasies of the host, particularly the rate at which the host metabolizes the agent and the host's propensity to mount an immune response to the antigenic stimulus.
129. What are four important points regarding drug and toxin induced hepatic injury?
1. The injury may be immediate or may take weeks to months to develop, presenting only after severe liver damage has developed.
2. The injury may take the form of hepatocyte necrosis, cholestasis, or insidious onset of liver dysfunction.
3. Drug-induced chronic hepatitis is clinically and histologically indistinguishable from chronic viral hepatitis; hence, serologic markers of viral infection are critical for making the distinction.
4. In EtOH induced liver disease, the microvesicular and macrovesicular steatosis both arise form the same etiology: the production of excess reducing equivalents (NADH + H) owing to the metabolism of ethanol.
130. What are examples of predictable drug reactions?
Hepatic injury is considered predictable from overdoses of acetaminophen, and exposure to Amanita phalloides toxin, carbon tetrachloride, and alcohol.

However, individual genetic differences in the hepatic metabolism of xenobiotics thru activating and detox pathways play a major role in the susceptibility to "predictable" hepatotoxins.
131. What are examples of idiosyncratic drug reactions?
Many other xenobiotics, such as sulfonamides, α-methyldopa, and allopurinol, cause idiosyncratic reactions.
132. What is Reye syndrome, again?
Reye syndrome, a potentially fatal syndrome of mitochondrial dysfunction in liver, brain, and elsewhere, occurs predominantly in children who are given acetylsalicylic acid from the relief of fever.

This disease, which features extensive accumulation of fat droplets within hepatocytes (microvesicular steatosis), is exceedingly rare.
133.What are the three distinctive forms of liver disease due to EtOH?
1. Hepatic steatosis
2. Alcoholic hepatitis
3. Cirrhosis
134. What is the morphology of hepatic steatosis due to EtOH disease?

Following even moderate intake of EtOH, small microvesicular lipid droplets accumulate in hepatocytes. W/chronic intake, lipid accumulates to the point of creating large, clear macrovesicular globules, compressing and displacing the nucleus to the periphery of the hepatocyte. This transformation is initially centrilobular but in severe cases it can involve the entire lobule.
135. What is the morphology of hepatic steatosis due to EtOH disease?

Macroscopically, the fatty liver of an alcoholic is a large, soft organ that is yellow and greasy.

Although there is little or no fibrosis at the outset, w/continued EtOH intake, fibrous tissue develops around the terminal hepatic veins and extends into the adjacent sinusoids.

*The fatty change is completely reversible if there is abstention from further intake of EtOH.
136. What are four important features of alcoholic hepatitis?
1. Hepatocyte swelling and necrosis
2. Mallory bodies
3. Neutrophilic reaction
4. Fibrosis
137. What are mallory bodies?
Scattered hepatocytes accumulate tangled skeins of cytokeratin intermediate filaments and other proteins, visible as eosinophilic cytoplasmic inclusions in degenerating hepatocytes. These inclusions are a characteristic but not specific feature of alcoholic liver disease, as they are also seen in primary biliary cirrhosis, Wilson disease, chronic cholestatic syndromes, and hepatocellular tumors.
138. What is the neutrophilic reaction?
Neutrophils permeate the lobule and accumulate around generating hepatocytes, particularly those having Mallory bodies. Lymphocytes and macrophages also enter portal tracts and spill into the parenchyma.
139. What is the morphologic appearance of the liver in alcoholic hepatitis?
Although steatotic hepatocytes are present, they are interspersed with the inflammatory cells and activated stellate cells.

In macroscopic appearance, the liver is mottled red w/bile-stained areas. Although the liver may be of normal or increased size, it often contains visible nodules and fibrosis, indicative or evolution to cirrhosis.
140. What is alcoholic cirrhosis?
The final and irreversible form of alcoholic liver disease usually evolves slowly and insidiously. At first, the cirrhotic liver is yellow-tan, fatty, and enlarged, usually over 2 kg. Over the span of years, it is transformed into a brown, shrunken, nonfatty organ, sometimes less than 1 kg in weight.
141. What is the morphologic appearance of the liver in alcoholic cirrhosis?
Initially, the developing fibrous septae are delicate and extend thru sinusoids from central to portal regions as well as from portal tract to portal tract.

With time, the nodularity becomes more prominent; scattered larger nodules create a "hobnail" appearance on the surface of the liver.

As fibrous septae dissect and surround nodules, the liver becomes more fibrotic, loses fat, and shrinks progressively in size. *Ischemic necrosis and fibrous obliteration of nodules eventually create broad expanses of tough, pale scar tissue ("Laennec cirrhosis").
142. SUMMARIZE the morphologic appearance of the liver in alcoholic cirrhosis...
Bile stasis often develops; Mallory bodies are only rarely evident at this stage.

Thus, end stage alcoholic cirrhosis comes to resemble, both macroscopically and microscopically, the cirrhosis developing from viral hepatitis and other causes.
143. Why does alcohol cause steatosis?
Steatosis results from (1) shunting of substrates toward lipid biosynthesis, (2) impaired lipoprotein assembly and secretion, and (3) increased peripheral catabolism of fat.
144. Why does alcohol sensitize the liver to oxidative injury?
Alcohol-induced impaired hepatic metabolism of methionine results in decreased intrahepatic glutathione (GSH) levels, thereby sensitizing the liver to oxidative injury.
145. How does alcohol affect cellular function?
As a solute at millimolar levels, alcohol directly affects microtubular and mitochondrial function and membrane fluidity.
146. How does acetaldehyde affect cellular and hepatocellular function?
Acetaldehyde (the major intermediate metabolite of alcohol en route to acetate production) induces lipid peroxidation and acetaldehyde-protein adduct formation, further disrupting cytoskeletal and membrane function.

Alcohol induced and acetaldehyde-induced changes in heaptocellular proteins create new epitopes to which the immune system reacts, producing inflammation and immune-mediated heaptocellular injury.
147. How would you define alcoholic liver disease?
Alcoholic liver disease is a chronic disorder featuring steatosis, hepatitis, progressive fibrosis, cirrhosis, and marked derangement of vascular perfusion.

In essence, alcoholic liver disease can be regarded as a maladaptive state in which cells in the liver respond to an increasingly pathologic manner to a stimulus (EtOH) that was only marginally harmful.
148. What are the five proximate causes of death in the end-stage alcoholic?
1. Hepatic coma
2. A massive GI hemorrhage
3. An intercurrent infection (to which these patients are predisposed)
4. Hepatorenal syndrome following a bout of alcoholic hepatitis
5. HCC in 3-6% of cases
149. What is nonalcoholic fatty liver disease and steatohepatitis?
Nonalcoholic fatty liver disease is a condition that resemble alcohol induced liver disease but occurs in patients who are not heavy drinkers.

There are strong associations w/obesity, dyslipidemia, hyperinsulinemia, and insulin resistance, and overt type 2 DM.

Steatohepatitis, or NASH, is an intermediate form of liver damage.
150. What is the morphology of nonalcoholic fatty liver disease?
This condition features liver biopsy findings of steatosis. Large and small vesicles of fat, predominantly TAGs, accumulate within hepatocytes. At the most clinically benign end of the spectrum, there is no appreciable hepatic inflammation, hepatocyte death, or scarring.
151. What is the morphology of steatohepatitis?
Liver biospy shows steatosis, multifocal parenchymal inflammation, Mallory hyaline, hepatocyte death (both ballooning degeneration and apoptosis), and sinusoidal fibrosis.

Cirrhosis may occur.
152. What is hemochromatosis?
Hemochromatosis is characterized by the excessive accumulation of body iron, most of which is deposited in parenchymal organs such as the liver and pancreas. B/c humans do not have a major excretory pathway for iron, hemochromatosis results either from a genetic defect causing excessive iron absorption or as a consequence of parenteral administration of iron (i.e. transfusions).

Hereditary hemochromatosis is a homozygous-recessive inherited disorder; acquired forms of hemochromatosis w/known sources of excess iron are called secondary hemochromatosis.
153. What features characterize hemochromatosis?
1. Fully developed cases exhibit (1) micronodular cirrhosis in all patients; (2) DM; and (3) skin pigmentation
2. Iron accumulation is lifelong; symptoms usually first appear in the 5th-6th decades of life
3. The hemochromatosis gene is called HFE, and regulates intestinal absorption of dietary iron; a cysteine to tyrosine substitution is the most common and this inactivates HFE
4. Males predominate with slightly earlier clinical presentation
154. What genetic alterations cause hemochromatosis?
The hemochromatosis gene is called HFE, and regulates intestinal absorption of dietary iron.

The most common HFE mutation is a cysteine to tyrosine substitution at amino acid 282 (called C282Y), which inactivates this protein.

The HFE gene is in linkage disequilibrium w/HLA-A3, thus accounting for the association of this haplotype w/hereditary hemochromatosis.
155. How does the body balance iron levels?
The critical site for HFE expression appears to be the basolateral surface of the small intestinal crypt epithelial cells. HFE complexes w/the transferrin receptor, TfR, enabling the binding of plasma transferring and its bound iron.

The TfR-Tf-iron complex is endocytosed into the crypt enterocyte; acidification of the endosome releases iron into the regulatory iron pool of the crypt cell.

This is a sensing mechanism for the systemic iron balance, as increased levels of circulating iron bound to transferrin will lead to an increased iron regulatory pool in enterocytes. This pool sets the level of expression of apical iron uptake systems.
156. What is the pathogenesis in hereditary hemochromatosis?
Crypt cells w/mutant HFE lack the facilitating effect on TfR-dependent iron uptake, thus decreasing the regulatory iron pool in the crypt cell.

As small intestinal crypt cells are the progenitors of villus absorptive cells, these cells are preprogrammed to absorb dietary iron regardless of the systemic iron overload.
157. By what three mechanisms is excessive iron toxic to host tissues?
1. Lipid peroxidation via iron-catalyzed free radical reactions
2. Stimulation of collagen formation
3. Interactions of ROS and iron itself w/DNA, leading to lethal injury or predisposition to HCC.
158. What are the most common causes of secondary hemochromatosis?
Hemolytic anemias associated w/ineffective erythropoiesis. In these disorders, the excess iron may result not only from transfusions, but also from increased absorption.

Transfusions alone, as in aplastic anemias, lead to systemic hemosiderosis in which parenchymal organ injury tends to occur only in extreme cases.
159. What is Bantu-siderosis?
A rather unusual form of iron overload resembling hereditary hemochromatosis occurs in sub-Saharan Africa, the result of ingesting large quantities of alcoholic beverages fermented in iron utensils.
160. What are the three key morphologic features in hereditary hemochromatosis?
1. Deposition of hemosiderin in the liver, pancreas, myocardium, pituitary, adrenal, thyroid, and PTH glands, joints, and skin
2. Cirrhosis
3. Pancreatic fibrosis
161. How does the liver look in hemochromatosis?
In the liver, iron becomes evident first as golden-yellow hemosiderin granules in the cytoplasm of periportal hepatocytes, which stain blue w/the Prussian blue stain.

With increasing iron load, there is progressive involvement of the rest of the lobule, along w/bile duct epithelium and Kupffer cell pigmentation. Since iron is a direct hepatotoxin, inflammation is characteristically absent.

At this stage, the liver is typically slightly larger than normal, dense, and chocolate brown.
162. What is the standard for quantitating hepatic iron content?
Biochemical determination of hepatic iron concentration in unfixed tissue is the standard for quantitating hepatic iron content.

Hepatic iron concentrations above 22,000μg per gram dry weight are associated w/the development of fibrosis and cirrhosis.
163. What other morphologic characteristics occur in other organs in hemochromatosis?
1. The pancreas becomes intensely pigmented
2. The heart is often enlarged and has hemosiderin granules within the myocardial fibers
3. Skin pigmentation due to increased epidermal melanin production, causing a slate-gay color to the skin
4. Hemosiderin deposition in the joint synovial linings causes an acute synovitis and can lead to pseudo-gout
5. The testes may be small and trophic which results indirectly from alterations at the HPA axis.
164. What are the clinical features of hemochromatosis?
Hereditary hemochromatosis presents at age 20 - 30 with hepatomegaly, abdominal pain, skin pigmentation, DM, cardiac dysfunction, arthritis, and hypogonadism.

Potentially fatal complication occur from cirrhosis (incl. HCC) and cardiac involvement.

Regular phlebotomy is sufficient treatment; screening of family members of probands is important.
165. What is Wilson disease?
Wilson disease is an autosomal-recessive disorder marked by the accumulation of toxic levels of copper in many tissues and organs, principally the liver, brain, and eye.
166. What is the pathogenesis of Wilson disease?
The genetic defect is in the ATP7B gene on chromosome 13. This gene encodes a hepatocyte canalicular membrane transmembrane copper-transporting ATPase.

Copper absorption and delivery to the liver is normal, but there is increased hepatic export into the circulation most likely due to defective secretion of copper into bile.
167. What are the common genetic defects in Wilson disease?
Over 30 mutations in ATP7B have been identified. The overwhelming majority of patients are compound heterozygotes containing different mutations of the Wilson disease gene on each allele.
168. How does defective biliary excretion lead to copper accumulation?
Defective biliary excretion leads to copper accumulation in the liver in excess of the metallothionein-binding capacity, causing toxic liver injury thru copper-catalyzed formation of ROS.

Usually by 5 years of age, the non-ceruloplasmin-bound copper spills over from the liver into the circulation, causing hemolysis and pathologic changes in other sites.
169. What is the morphology of Wilson disease?
The liver often bears the brunt of injury in Wilson disease, with hepatic changes ranging from minor to massive damage. Fatty change may be present, with vacuolated nuclei and occasionally focal hepatocyte necrosis. Acute and chronic hepatitis (with Mallory bodies), cirrhosis, and (rarely) massive liver necrosis can occur.

Toxicity in the brain predominantly affects the basal ganglia, which becomes atrophied and even cavitated. *Nearly all patients with neurological involvement develop Kayser-Fleischer rings in the eyes.
170. What is the clinical course of Wilson disease?
Age at onset and clinical presentation are variable; typically there will be some liver disease in the first couple decades of life. Neuropsychiatric disorders are also possible, including mild behavioral changes, frank psychosis, and Parkinson disease-like symptoms.

Dx is suggested by decreased serum ceruloplasmin (a copper binding serum protein), increased hepatic copper content, and increased urinary copper excretion.

Copper chelation therapy (as with D-penicillamine) can help.
171. What is α1-antitrypsin deficiency?

What is the major function of this protein?
α1-antitrypsin deficiency is an autosomal recessive disorder marked by abnormally low serum levels of this important protease inhibitor.

The major function of this protein is the inhibition of proteases, particularly elastase, cathepsin G, and proteinase 3, which are normally released from neutrophils at sites of inflammation.

α1-antitrypsin deficiency leads to the development of pulmonary emphysema and can also cause hepatic disease (cholestasis or cirrhosis).
172. What are the genetic defects in α1-antitrypsin deficiency?

What is the most common clinically significant mutation?
α1-antitrypsin is a 394 AA serum protease inhibitor (Pi) synthesized primarily in the liver. The gene is very polymorphic and at least 75 α1-antitrypsin forms have been identified.

The most common genotype is PiMM, occurring in 90% of individuals with this disorder.

*The most common clinically significant mutation is PiZ; homozygotes for the PiZZ protein have circulating α1-antitrypsin levels that are only 10% of normal.
173. What is the pathogenesis of α1-antitrypsin deficiency?
Deficiency variants exhibit a selective defect in migration of this secretory protein from the ER to Golgi apparatus; this is most marked for the PiZ polypeptide.

The mutant polypeptide α1AT-Z is abnormally folded, and polymerizes, causing its retention in the ER. All individuals w/the PiZZ genotype accumulate α1AT-Z in the ER of hepatocytes.
174. So... is the accumulation of α1AT-Z in the ER of hepatocytes toxic?
No, the accumulated α1AT-Z is not toxic per se, nor does the liver suffer from a lack of protease inhibitor activity.

***Rather, it is the intense autophagocytic response stimulated within hepatocytes, as an alternative degradative pathway, that appears to be the chief cause of liver injury, possibly by autophagocytosis of mitochondria.
175. What is the morphology of α1-antitrypsin deficiency in the liver?
α1-antitrypsin deficiency is characterized by the presence of round-to-oval cytoplasmic globular inclusions in hepatocytes, which in routine H&E stains are acidophilic and indistinctly demarcated from the surrounding cytoplasm.

For the most part, the only distinctive features of the hepatic disease is the PAS-positive globules; infrequently, fatty change and Mallory bodies are absent.
176. What is the clinical course of α1-antitrypsin deficiency?
Neonatal hepatitis w/cholestatic jaundice occurs in 10-20% of newborns with α1-antitrypsin deficiency. Later presentation may be attributable to acute hepatitis or complications of cirrhosis.

HCC develops in 2-3% of PiZZ homozygous adults.

Treatment is liver transplantation; avoidance of smoking is extremely important in patients with α1-antitrypsin deficiency, since smoking accentuates their lung emphysematous damage.
177. What is neonatal cholestasis?
Prolonged conjugated hyperbilirubinemia in the neonate affects 1/2500 live births.

Affected infants have jaundice, dark urine, light or acholic stools, and hepatomegaly. Variable degrees of hepatic synthetic dysfunction may be identified such as hypoprothrombonemia.
178. What causes neonatal cholestasis?
The major conditions causing it are cholangiopathies (primarily biliary atresia) and a variety of other disorders causing conjugated hyperbilirubinemia.

*Neonatal heptitis should be distinguished from the bile duct proliferation seen in obstructive bile duct disease.
179. What are the six morphological features of neonatal hepatitis?
1. Lobular disarray with focal liver cell necrosis
2. Panlobular giant cell transformation of hepatocytes and formation of hepatocyte "rosettes": radially arrayed hepatocytes
3. Prominent hepatocellular and canalicular cholestasis
4. Mild mononuclear infiltration of the portal areas
5. Reactive changes in the Kupffer cells
6. Extramedullary hematopoiesis
180. What is the morphology of neonatal cholestasis?
This predominantly parenchymal pattern of injury may blend imperceptibly into a ductal patter of injury, w/bile ductular proliferation and fibrosis of portal tracts.

Clear distinction from an obstructive cholangiopathy may therefore be impossible. Specific features that point toward a particular etiology include the inclusions of CMV or fatty change w/cirrhosis in galactosemia and tyrosinemia.
181. What are the three disorders of intrahepatic bile ducts?
1. Secondary biliary cirrhosis
2. Primary biliary cirrhosis
3. Primary sclerosing cholangitis.
182. What is secondary biliary cirrhosis?

What is the most common cause?
Prolonged obstruction of the extrahepatic biliary tree results in profound alteration of the liver itself.

The most common cause of obstruction in adults is extrahepatic cholelithiasis, followed by malignancies of the biliary tree or head of the pancreas and strictures resulting from previous surgical procedures.

The initial morphologic features of cholestasis are entirely reversible w/correction of the obstruction; however, secondary inflammation resulting from biliary obstruction initiates periportal fibrosis which then leads to secondary biliary cirrhosis.
183. What is the morphology of secondary biliary cirrhosis?
The end-stage obstructed liver exhibits extraordinary yellow-green pigmentation and is accompanied by marked icteric discoloration of body tissues and fluids. On cut surface, the liver is hard, with a finely granular appearance.

The histology is characterized by coarse fibrous septae that subdivide the liver in a jigsaw like patter. Embedded in the septa are distended small and large bile ducts, which freq contain inspissated pigmented material.

Cholestatic features in the parenchyma may be severe, with extensive feathery degeneration and formation of bile lakes.
184. What is ascending cholangitis?
Subtotal obstruction of the extrahepatic biliary duct may promote secondary bacterial infection of the biliary tree (ascending cholangitis), which aggravates the inflammatory injury.
185. What is primary biliary cirrhosis?

What is a characteristic feature of this disease?
Primary biliary cirrhosis is a chronic, progressive, and often fatal cholestatic liver disease, characterized by the destruction of intrahepatic bile ducts, portal inflammation and scarring, and the eventual development of cirrhosis and liver failure.

*The primary feature of this disease is a nonsuppurative, inflammatory destruction of medium-sized intrahepatic bile ducts.
186. What is the prevalence of primary biliary cirrhosis?

How does it present?
This is primarily a disease of middle-aged women, and has an autoimmune pathogenesis.

Onset is insidious, with pruritus and hepatomegaly; jaundice and xanthomas (from retained cholesterol) develop later, w/progression to hepatic failure after a prolonged clinical course. Liver transplants are required for end stage disease.
187. What labs help Dx primary biliary cirrhosis?
Lab findings include elevated ALKPHOS and cholesterol. Present in 90% of pts ware circulating "antimitochondrial antibodies".

These antibodies are against the E2 subunit of the pyruvate dehydrogenase complex, dihydrolipoamide acetyltransferase. This enzyme is located on the inner face of the inner mitochondrial membrane and hence is well shielded from circulating antibodies in undamaged hepatocytes.
188. What is the pathogenesis of primary biliary cirrhosis?
There is an autoimmune etiology for primary biliary cirrhosis, including aberrant expression of MHC class II molecules on bile duct epithelial cells and accumulation of autoreactive T cells around bile ducts.

Associated conditions include Sjogren syndrome, scleroderma, thyroiditis, RA, Raynaud phenomenon, membranous glomerulonephritis, and celiac disease.
189. What is the morphology of primary biliary cirrhosis?

During the precirrhotic stage, portal tracts are infiltrated by a dense accumulation of lymphocytes, macrophages, plasma cells and occasional eosinophils. Terminal and conducting bile ducts are infiltrated by lymphocytes and may exhibit noncaseating granulomatous inflammation and undergo destruction.

W/time, the obstruction to intrahepatic bile flow leads to secondary hepatic damage. Portal tracts upstream exhibit bile ductal proliferation, inflammation and necrosis of the adjacent periportal hepatic parenchyma, leading to cholestasis and then to cirrhosis.
190. What is the morphology of primary biliary cirrhosis?

Macroscopically, the liver does not at first appear abnromal, but as the disease progresses, bile stasis stains the liver green. The capsule remains smooth and glistening until a fine granularity appears, culminatin gina well-developed, uniform micronodularity.

*In most cases, the end stage picture is indistinguishable from secondary biliary cirrhosis or the cirrhosis that follows chronic hepatitis from other causes.
191. What is primary sclerosing cholangitis?
Primary sclerosing cholagitis is characterized by inflammation and obliterative fibrosis of intrahepatic and extrahepatic bile ducts, w/dilation of preserved segments.

Characteristic "beading" of a barium column in radiographs of the intrahepatic and extrahepatic biliary tree is due to the irregular strictures and dilations of affected bile ducts.

*Primary sclerosing cholangitis is commonly seen in association w/IBD, particularly UC.
192. What is the pathogenesis of primary sclerosing cholangitis?
The cause is unknown. Key events appear to be secretion of proinflammatory cytokines by activated hepatic macrophages followed by infiltration of T cells into the stroma immediately around bile ducts. The stimuli that initiate and perpetuate the characteristic periductal fibrosis remain unknown. An ischemic contribution to bile duct loss has also been postulated.
193. What is the morphology of primary sclerosing cholangitis?
*Primary sclerosing cholangitis is a fibrosing cholangitis of bile ducts, w/a lymphocytic infiltrate, progressive atrophy of the bile duct epithelium, and obliteration of the lumen.

The concentric periductal fibrosis around affected ducts ("onion skin fibrosis") is followed by their disappearance, leaving behind a solid, cordlike fibrous scar.

As the disease progresses, the liver becomes markedly cholestatic, culminating in biliary cirrhosis much like that seen w/primary and secondary biliary cirrhosis.
194. What are the clinical features of primary sclerosing cholangitis?
Asymptomatic patients may come to attention only b/c of persistent elevations in ALKPHOS. Alternatively, progressive fatigue, pruritus, and jaundice may develop.

Autoantibodies are present in less than 10% of pts. There does appear to be an increased risk for cholangiocarcinom.

The disease also follows a protracted course over many years.
195. What are Von Meyeburg complexes?
Von Meyenburg complexes are close to or within portal tracts; they are small clusters of modestly dilated bile ducts embedded in a fibrous, sometimes hyalinized stroma. Although these "bile duct microhamartomas" may communicated w/the biliary tree, they generally are free of pigmented material.

They presumably arise from residual embryonic bile duct remnants. Occasionally, a triangular bile duct hamartoma may lie just under Glisson's capsule.
196. What is polycystic liver disease?
The liver contains multiple diffuse cystic lesions, numbering from a scattered few to hundreds. The cysts are lined by cuboidal or flattened biliary epithelium and contain straw-colored fluid. They do not contain pigmented material and appear to be detached from the biliary tree.

Occasionally, solitary liver cysts of biliary origin are identified, more commonly in women than in men (4:1).
197. What is congenital hepatic fibrosis?
The portal tracts are enlarged by irregular and broad bands of collagenous tissue, forming septa and dividing the liver into irregular islands.

Variable numbers of abnormally shaped bile ducts are embedded in the fibrous tissue and bile duct remnants are distributed along the septal margins.

Sometimes curved bile duct profiles are arranged in a concentric circle around portal tracts. The increased number of bile duct profiles are in continuity with the biliary tree. This anomaly arises b/c of persistence of a malformed embryonic form of the biliary tree, with ensuing portal tract fibrosis.
198. What is Caroli disease?
The larger ducts of the intrahepatic biliary tree are segmentally dilated and may contain inspissated bile.

Pure forms are rare; this disease is usually associated w/portal tract fibrosis of the congenital hepatic fibrosis type.
199. What are the clinical features of Von-Meyenburg complexes?
Von-Meyenburg complexes are rather common and are usually w/o clinical significance, save to avoid mistaking lesions radiographically for metastatic carcinoma.
200. What are the clinical features of polycystic liver disease?
Patients polycystic liver disease may develop abdominal tenderness or pain on stooping, occasionally requiring surgical intervention.

There is a slight female predilection, w/presentation common during pregnancy.
201. What are the clinical features of Caroli disease?
Caroli disease is freq complicated by intrahepatic cholelithiasis, cholangitis, and hepatic abscesses, as well as by portal hypertension.

There is an increased risk of cholangiocarcinoma w/Caroli disease and congenital hepatic fibrosis.
202. What is Alagille syndrome?
Alagille syndrome (syndromatic paucity of bile ducts) is an uncommon autosomal-dominant condition in which the liver is almost normal, but portal tract bile ducts are completely absent.

The syndrome is caused by mutations in the gene Jagged1, a cell-surface protein that functions as a ligand for the Notch transmembrane receptors. The Jagged1:Notch signaling pathway regulates cell fate and is involve din the development of the organ systems affected in Alagille syndrome: liver, heart, skeleton, eye, face, and kidney. Patients also exhibit a number of extrahepatic features, including a peculiar facies, vertebral anomalies, and cardiovascular defects. Patients can survive into adulthood but are at risk for hepatic failure and HCC.
203. What is hepatic artery compromise?
Liver infarcts are rare, thanks to the double blood supply to the liver. Nonetheless, thrombosis or compression of an intrahepatic branch of the hepatic artery by embolism, neoplasia, polyarteritis nodosa, or sepsis may result in a localized infarct that is usually anemic and pale tan, or sometimes hemorrhagic, owing to suffusion of portal blood.

Interruption of the main hepatic artery does not always produce ischemic necrosis of the organ, particularly if the liver is otherwise normal.
204. What is portal vein obstruction?
Blockage of the extrahepatic portal vein may be insidious and well tolerated or may be a catastrophic and potentially lethal event; most cases fall somewhere in between.

Occlusive disease of the portal vein or its major radicles typically produces abdominal pain and, in most instances, ascites and other manifestations of portal hypertension, principally esophageal varices which are prone to rupture. The ascites, when present, is often massive and intractable. Acute impairment of visceral blood flow leads to profound congestion and bowel infarction.
205. What are the causes of extrahepatic portal vein obstruction?

5 of them...
1. Banti syndrome
2. Intra-abdominal sepsis
3. Thrombogenic disorders, including postsurgical thromboses
4. Trauma
5. Pancreatitis that initiates splenic vein thrombosis which propagates into the portal vein
206. What is Banti syndrome?
Banti syndrome- subclinical occlusion of the portal vein (as from neonatal umbilical sepsis or umbilical vein catheterization) presents as variceal bleeding and ascites years later.
207. What are the characteristics of acute thrombosis of an intrahepatic portal vein radicle?
Acute thrombosis of an intrahepatic portal vein radicle does not cause ischemic infarction but instead results in a sharply demarcated area of red-blue discoloration (so-called infarct of Zahn).

There is no necrosis, only severe hepatocellular atrophy and marked hemostasis in distended sinusoids.

Invasion of the portal vein system by primary or secondary cancer in the liver can progressively occlude portal inflow to the liver; tongues of HCC can even occlude the extrahepatic portal vein.
208. What is idiopathic portal hypertension?
Idiopathic portal hypertension is a chronic, generally bland condition of impaired portal vein inflow and noncirrhotic portal hypertension.
209. What is hepatoportal sclerosis?
In those instances when a cause can be identified, it may be associated w/hypercoagulability of the blood, myeloproliferative disorders, peritonitis, or chronic exposure to arsenicals.

The histologic manifestation is termed hepatoportal scleroosis, owing to dense fibrosis of intrahepatic portal tracts w/obliteration of portal vein channels.
210. What are the most common intrahepatic causes of blood flow obstruction into the liver?

What are other causes?
The most common intrahepatic cause of blood flow obstruction is cirrhosis.

In addition, physical occlusion of the sinuoids occurs in a small but striking group of diseases. This includes, sickle cell disease, DIC, and eclampsia, and tumors.
211. What is the morphology of passive congestion and centrolobular necrosis?
Right sided cardiac decomp leads to passive congestion of the liver. The liver is slightly enlarged, tense, and cyanotic, with rounded edges. Microscopically, there is congestion of centrolobular sinusoids. With time, centrolobular hepatocytes become atrophic, resulting in markedly attenuated liver cell cords.

Left sided cardiac failure or shock may lead to hepatic hypoperfusion and hypoxia. In this instance, hepatocytes in the central region of the lobule undergo ischemic coagulative necrosis (centrolobular necrosis).
212. What is centrolobular hemorrhagic necrosis?
The combination of hypoperfusion and retrograde congestion acts synergistically to generate centrolobular hemorrhagic necrosis.

The liver takes on a mottled appearance reflecting hemorrhage and necrosis in the centrilobular regions, known as the nutmeg liver.

By microscopy, there is sharp demarcation of viable periportal and necrotic pericentral hepatocytes, w/suffusion of blood thru the centrilobular region.
213. What is cardiac sclerosis?
An uncommon complication of sustained chronic severe congestive heart failure is so-called cardiac sclerosis.

The pattern of liver fibrosis is distinctive, inasmuch as it is mostly centrilobular.
214.What is peliosis hepatitis?
Sinusoidal dilation occurs in any condition in which efflux of hepatic blood is impeded. Peliosis hepatitis is a rare condition in which the dilation is primary. It is most commonly associated w/exposure to anabolic steroids and rarely, oral contraceptives and danazol.

Clinical signs are generally absent even in advanced peliosis, but potentially fatal intra-abdominal hemorrhage or hepatic failure may occur. Peliotic lesions usually disappear after cessation of drug treatment.
215. What is Budd-Chiari syndrome?
The obstruction of two or more major hepatic veins produces liver enlargement, pain, and ascites (so-called Budd-Chiari syndrome), the result of increased intrahepatic blood pressure and an inability of the massive hepatic blood flow to shunt around the blocked outflow tract.
216. What is hepatic vein thrombosis associated with?
Hepatic vein thrombosis is associated w/primary myeloproliferative disorders, inherited disorders of coagulation, antiphospholipid syndrome, paroxsmal nocurnal hemoglobinuria, and intra-abdominal cancers, particularly HCC.
217. What is the difference between hepatic vein thrombosis and IVC thrombosis?
A separate distinction is made for IVC thrombosis at its hepatic portion (obliterative hepatocavopathy).

While IVC thrombosis may arise from the same thrombogenic disorders as for hepatic vein thrombosis, it is frequently idiopathic.
218. What is the morphology of thrombosis of the major hepatic veins or hepatic portion of the IVC?
W/acutely developing thrombosis of the major hepatic veins or hepatic portion of the IVC, the liver is swollen and red-purple and has a tense capsule.

Microscopically, the affected hepatic parenchyma reveals severe centrilobular congestio and necrosis. Centrilobular fibrosis develops in instances in which the thrombosis is more slowly developing.

**Unlike hepatic vein thrombosis, which heals leaving extensive scarring of the hepatic parenchyma, the thrombosis of obliterative hepatocavopathy may heal to leave only an incomplete membranous web protruding into the lumen of the IVC.
219. What is veno-occlusive disease (Sinusoidal obstruction syndrome)
This veno-occlusive disease now occurs primarily in the immediate weeks following bone marrow transplantation. The incidence approaches25% in recipients of allogeneic marrow transplants, w/mortality rates over 30%.

A Dx of veno-occlusive disease is freq made on clinical grounds only (tender hepatomegaly, ascites, weight gain, and jaundice), owing to the high risk of liver biopsy in these patients.
220. What is the morphology of veno-occlusive disease (sinusoidal obstruction syndrome)
Veno-occlusive disease is characterized by obliteration of hepatic vein radicles by varying amts of subendothelial swelling and fine reticulated collagen. In acute disease, there is striking centrolobular congestions w/hepatocellular necrosis and accumulation of hemosiderin-laden macrophages.

As the disease progresses, obliteration of the lumen of the venule is easily identified by using reticulin stains for connective tissue.

W/chronic or healed veno-occlusive disease, dense perivenular fibrosis radiating out into the parenchyma may be present, frequently w/total obliteration of the venule; hemosiderin deposition is evident in the scar tissue, and congestion is minimal.
221. What is the pathogenesis of veno-occlusive disease?
This disease presumably arises from toxic injury to the sinusoidal endothelium. These cells round up and slough off the sinusoidal wall, embolizing downstream and obstructing sinusoidal blood flow. This is accompanied by passage of RBCs into the space of Disse and downstream accumulation of cellular debris in the terminal hepatic vein.

Proliferation of perisinusoidal stellate cells and subendothelial fibroblasts in the terminal hepatic vein follows, w/deposition of ECM.

*The obliterative changes in the terminal hepatic vein are thus secondary to sinusoidal damage.
222. What is preeclampsia?

What is eclampsia?
Preeclampsia affects 7-10% of pregnancies and is characterized by maternal hypertension, proteinuria, peripheral edema, coagulation abnormalities and varyign degrees of disseminated intravascular coagulation.

*When hyperreflexia and convulsions occur, the condition is called eclampsia and may be life threatening.
223. What is HELLP syndrome?
In pregnancy, subclinical hepatic disease may b ethe primary manifestation of preeclampsia, as part of a syndrome of Hemolysis, Elevated Liver enzymes, and Low Platelets, dubbed HELLP syndrome.
224. What is the morphology of the liver in preeclampsia?
The affected liver in preeclampsia is normal size, firm, and pale, with small red patches due to hemorrhage. Occasionally, yellow or white patches of ischemic infarction can be seen.

***Microscopically, the periportal sinusoids contain fibrin deposits w/hemorrhage into the space of Disse, leading to periportal hepatocellular coagulative necrosis.

Blood under pressure may coalesce and expand to form a hepatic hematoma; dissection of blood under Glisson's capsule may lead to catastrophic hepatic rupture.
225. What is the treatment for severe cases of eclampsia?
Termination of the pregnancy. In mild cases, patients can be managed conservatively.
226. What is acute fatty liver of pregnancy (AFLP)?
AFLP exhibits a spectrum ranging from modest or even subclinical hepatic dysfunction (elevated AST and ALT), to hepatic failure, coma, and death.

Affected women present in the latter half of pregnancy, usually in the third trimester. Symptoms are related to incipient hepatic failure, including bleeding, nausea, and vomiting, jaundice, and coma. 20-40% of cases the presenting symptoms may be those of coexistent preeclampsia.
227. What is the morphology of AFLP?

What two things does the Dx depend upon?
***The Dx of AFLP rests on biopsy identification of the characteristic microvesicular fatty transformation of the hepatocytes.***

Dx depends on:
1. A high index of suspicion
2. Confirmation of microvesicular steatosis using special stains for fat (oil-red-O or Sudan black) on frozen tissue sections.
228. What is the clinical course of AFLP?
While this condition most commonly rusn a mild course, pts w/AFLP can progress w/in days to hepatic failure and death.

*The primary treatment for AFLP is termination of the pregnancy. (Ex: the fetus causes metabolic disease in the mother)
229. What is intrahepatic cholestasis of pregnancy?
The onset of pruritus in the third trimester, folowed by darkening of the urine and ocasionally light stools and jaundice, heralds the development of this ysndrome.

Serum BILI rarely exceeds 5 mg/dL; ALKPHOS may be slightly elevated. Liver biopsy reveals mild cholestasis w/o necrosis.
230. What is the morphology of intrahepatic cholestasis of pregnancy?

What is its clinical course?
The altered hormonal state of pregnancy appears to combine w/biliary secretion defects, as in secretion of bile salts or sulfated progesterone metabolites, to engender cholestasis.

Although this is generally a benign condition, the mother is at risk for gallstones and malabsorption, and the incidence of fetal distress, stillbirths, and prematurity is modestly increased.
231. What is "liver toxicity" following bone marrow transplantation?
Liver toxicity describes a syndrome of hepatic dysfunction following the cytotoxic therapy administered to patients just prior to bone marrow transplantation. It affects up to one half of such patients and is characterized by weight gain, tender hepatomegaly, edema, ascites, hyperbilirubinemia, and a fall in urinary sodium excretion.

The onset is typically on the days immediately following the donor marrow transplantation.
232. What is the morphology of this type of liver toxicity?
A spectrum of centrolobular necrosis and inflammatory changes is encountered,k culminating in veno-occlusive disease.

Clinical outcome is directly related to the severity of liver toxicity. Persistent severe liver dysfunction is a harbinger of a fatal outcome, w/patients succumbing to septicemia, pneumonia, bleeding, and/or multi organ failure.
233. What is graft-vs-host disease and liver rejection?

Why are liver transplants well tolerated by recipients?
The liver can be attacked by g-vs-h and h-vs-g mechanisms in the setting of bone marrow transplantation and liver transplantation, respectively.

Liver transplants are reasonably well tolerated by recipients. One explanation is that the transplanted liver carries many donor lymphocytes, establishing a state of chimerism in the recipient. This prevents the recipient's immune system from reacting against donor alloantigens.
234. What is the morphology of acute graft-vs-host disease?
Liver damage in acute graft-vs-host disease (10-15 days post transplantation) is dominated by direct attack of donor lymphocytes on epithelial cells of the liver. This results in a hepatitis w/necrosis of hepatocytes and bile duct epithelial cells and inflammation of the parenchyma and portal tracts.
235. What is the morphology of chronic graft-vs-host disease?
In chronic hepatic graft-vs-host disease (usually more than 100 days post transplant), there is portal tract inflammation, selective bile duct destruction, and eventual fibrosis.

Portal vein and hepatic vein radicles may exhibit endotheliitis, a process in which a subendothelial lymphocytic infiltrate lifts the endothelium from its basement membrane.

Cholestasis may be observed in both acute and chronic g-vs-h disease.
236. What is the morphology of acute cellular rejection of transplanted livers?
With acute rejection, infiltration of a mixed population of inflammatory cells into portal tracts, bile duct and hepatocyte injury and endothelitis.
237. What is the morphology of chronic cellular rejection of transplanted livers?
With chronic rejection, a severe obliterative arteritis of small and larger arterial vessels results in ischemic changes in the liver parenchyma. Alternatively, bile ducts are progressively occluded, due to either direct attack or obliteration of their arterial supply.
238. What is preservation injury?
Revascularization and perfusion of the donor liver (which may have been kept outside of the body for many hours) may result in preservation injury, attributable to the generation of oxygen radicals in a hypoxic organ w/insufficient reserves of oxygen scavengers to prevent damage.

This leads to sinusoidal endothelial injury and Kupffer cell activation, neutrophil adhesion, platelet aggregation, and local cytokine release.
239. What are some other technical complications associated with rejection?
Technical complications include hepatic artery or portal vein thrombosis leading to occlusion and bile duct obstruction (e.g. stricture).
240. What are focal nodular hyperplasias?
Focal nodular hyperplasia presents as a spontaneous mass lesion, most frequently in young to middle-aged adults, w/a female preponderance.
241. What is the morphology of focal nodular hyperplasias?
Focal nodular hyperplasia appears as a well-demarcated but poorly encapsulated nodule, ranging up to many cm in diameter. The lesion is generally lighter than the surrounding liver and is sometimes yellow.

***Typically, there is a central gray-white, depressed stellate scar from which fibrous septa radiate to the periphery. The central scar contains large vessels, usually arterial, that typically exhibit fibromuscular hyperplasia w/eccentric or concentric narrowing of the lumen.
242. What is nodular regenerative hyperplasia?
Nodular regenerative hyperplasia is associated w/the development of portal hypertension with its attendant clinical manifestations.

This lesion occurs in association w/conditions affecting intrahepatic blood flow, including solid organ (particularly renal) transplantation, bone marrow transplantation, and vasculitic conditions.
243. What is the morphology of nodular regenerative hyperplasias?
Nodular regenerative hyperplasia affects the entire liver with roughly spherical nodules, in the absence of fibrosis.

*Microscopically, plump hepatocytes are surrounded by rims of atrophic cells.

Reticulin stain is required to appreciate the changes in hepatocellular architecture.
244. What is the common factor in both nodular regenerative hyperplasias and focal nodular hyperplasias?
The common factor in both lesions appears to be heterogeneity in hepatic blood supply, arising from focal obliteration of portal vein radicles w/compensatory augmentation of arterial blood supply.
245. What are cavernous hemangiomas?

What is their chief clinical significance?
The most common benign lesions in the liver are cavernous hemangiomas- blood vessel tumors. They appear as discrete red-blue, soft nodules, usually < 2cm in diameter, and often occur directly beneath the capsule.

*Their chief clinical significance is that they not be mistaken for metastatic tumors and that blind percutaneous biopsies not be performed on them.
246. What are liver cell adenomas?
Benign neoplasms developing from hepatocytes are called liver cell adenomas. These tend to occur in young women who have used oral contraceptive and regress on discontinuance of their use.
247. Liver cell adenomas have clinical significance for three reasons...

What are they?
1. When they present as an intrahepatic mass, they may be mistaken for HCC.
2. Subcapsular adenomas have a tendency to rupture, particularly during pregnancy (under estrogen stimulation), causing severe intraperitoneal hemorrhage.
3. Rarely, they may harbor HCC.
248. What is the morphology of liver cell adenomas?
Liver cell adenomas are pale, yellow-tan, and freq bile stained nodules, found anywhere in the hepatic substance but not often beneath the capsule. They may reach 30 cm in diameter!

On microscopic exam, they are composed of sheets and cords of cells that may resemble normal hepatocytes or have some variation in cell and nuclear size. Abundant glycogen may generate a clear cytoplasm.
249. What are the types of malignant tumors in the liver?
Most arise from hepatocytes and are termed HCC. Much less common are the CAs of bile duct origin, cholangiocarcinoomas.

Two rarer forms of primary liver cancer also include hepatoblastomas and angiosarcomas.
250. What is a hepatoblastoma?

What are the two types of hepatoblastomas?
Hepatoblastoma is the most common liver tumor of young childhood, usually fatal within a few years if not resected.

This tumors has two anatomic variants:
1. The epithelial type, composed of small polygonal fetal cells or even smaller embryonal cells forming acini, tubules, or papillary structures vaguely recapitulating liver development.
2. The mixed epithelial and mesenchymal type, which contains foci of mesenchymal differentiation that may consist of primitive mesenchyme, osteoid, cartilage, or striated muscle.
251. What is an important feature of hepatoblastomas?
The frequent activation of the Wnt/β-catenin signaling pathway by stabilizing mutations of β-catenin, contributing to the process of carcinogenesis.

Approx 80% of hepatoblastomas exhibit this change, with chromosomal deletion constituting more than half of such mutations.
252. What is an angiosarcoma?
The primary liver angiosarcoma is of interest b/c of its association w/exposure to vinyl chloride, arsenic, or Thorotrast. The latency period after exposure to the carcinogen may be several decades.

These highly aggressive neoplasms metastasize widely and generally kill w/in a year.
253. What is the prevalence of HCC?
HCC constitute 90% of primary liver cancers; they arise in the middle to late decades. The male-female ratio is 3:1 to 4:1. There is a strong causal relationship btw hepatotropic viral infections (HBV and HCV), and HCC. Additionally, chronic alcoholism and food contaminants (primarily aflatoxins) are associated with HCC. Other conditions include tyrosinemia and hereditary hemochromatosis.

*More than 85% of cases of HCC occur in countries w/high rates of chronic HBV infection.
254. Which disease is most likely to give rise to HCC?
Believe it or not, the extremely rare hereditary tyrosinemia is the disease that is most likely to give rise to HCC.

Almost 40% of pts develop this tumor despite adequate dietary control.
255. What causes preneoplastic changes such as hepatocyte dysplasia?
Preneoplastic changes such as hepatocyte dysplasia can result from point mutations in selected cellular genes, loss of heterozygosity in tumor suppressor genes, DNA methylation changes, and constitutive expression of hepatocyte growth factor (HGF) and transforming growth factor alpha (TGF-α).

These changes and possibly the effect of some viral proteins act to further stimulate the replication of hepatocytes.
256. Genomic instability is more likely in the presence of what...?
Genomic instability is more likely in the presence of HBV DNA, giving rise to chromosomal aberrations such as deletions, translocations, and duplications.
257. What is the role of HBV DNA's X-protein?
The X-protein is a transcriptional activator of many genes and is present in most tumors w/integrated HBV DNA.

It is possible that in liver cells infected w/HBV, the X-protein disrupts normal growth control by activation of host cell proto-oncogenes and disruption of cell cycle control. The core protein of HCV may have oncogenic potential as well, although the pathways through which Hbx and HCV core proteins operate may differ.
258. What is Aspergillus flavus, and where is it found?
In certain regions of the world where HBV is endemic, there is also high exposure to dietary aflatoxins derived from the fungus Aspergillus flavus. These highly carcinogenic toxins are found in moldy grain and peanuts.

Studies reveal that aflatoxin can bind covalently w/cellular DNA and cause mutations in proto-oncogenes or tumor suppressor genes, particularly p53.
259. What are the three gross morphologic patterns of HCC?
HCC may appear grossly as: (1) a unifocal mass; (2) multifocal, widely distributed nodules of variable size; or (3) a diffusely infiltrative cancer, permeating widely and sometimes involving the entire liver.

All three patterns may cause liver enlargement, particularly the unifocal massive and multinodular patterns.
260. What do HCC tumors look like?
HCCs are usually paler than the surrounding liver substance and sometimes take on a green hue when composed of well-differentiated hepatocytes capable of secreting bile.

**All patterns of HCC have a strong propensity for vascular invasion. Extensive intrahepatic metastases ensure and occasionally, long, snakelike masses of tumor invade the portal vein or IVC, extending even into the right side of the heart.
261. What are the morphological differentiations of HCC?
HCCs range from well-differentiated to highly anaplastic undifferentiated lesions. In well-differentiated and moderately well-differentiated tumors, cells that are recognizable as hepatocytic in origin are disposed either in a trabecular patter or in an acinar, pseudoglandular pattern.

In poorly differentiated forms, tumor cells can taken on a pleomorphic appearance w/numberous anaplastic giant cells, can become small and completely undifferentiated cells, or may even resemble a spindle cell sarcoma.
262/. What is the fibrolamellar carcinoma variation of HCC?
This tumor occurs in young male and female adults (20-40 years) with equal incidence, has no association w/HBV or cirrhosis risk factors, and often has a better prognosis.
263. What is the morphology of the fibrolamellar carcinoma variation of HCC?
It usually presents as a single large, hard "scirrhous" tumor w/fibrous bands coursing thru it.

On microscopic exam, it is composed of well differentiated polygonal cells growing in nests or cords and separated by parallel lamellae of dense collagen bundles.
264. What are the clinical features of HCC?
Features include hepatomegaly, right upper quadrant pain, weight loss, and elevated serum α-fetoprotein.

Prognosis depends on the resectability of the tumor; death usually occurs w/in 6 mos of Dx.
265. What is cholangiocarcinoma?

What are the risk factors?
Cholangiocarcinoma arises from elements of the intrahepatic biliary tree. The risk conditions for developing this include primary sclerosing cholangitis, congenital fibropolycystic disease of the biliary system (Caroli disease especially), and previous exposure to Thorotrast.

In the Orient, a major risk condition is chronic infection of the biliary tract by the liver fluke Opisthorchis sinensis.
266. What is the morphology of intrahepatic cholangiocarcinomas?

Intrahepatic cholangiocarcinomas occur in the non-cirrhotic liver and may track along the portal tract system to create a treelike tumorous mass w/in a portion of the liver. Alternatively, a massive tumor nodule may develop. In either instance, lymphatic and vascular invasion may be prominent features and give rise to extensive intrahepatic metastases.

Most are well to moderately differentiated sclerosing adenocarcinomas w/clearly defined glandular and tubular structures lined by cuboidal to low columnar epithelial cells.
267. What is the morphology of intrahepatic cholangiocarcinomas?

Thse neoplasms are ususally markedly desmoplastic, w/dense collagenous stroma separating the glandular elements. Asa result, the tumor substance is firm and gritty.

*Cholangiocarcinomas are rarely bile stained, b/c differentiated bile duct epithelium does not synthesize bile.
268. What are the clinical features of cholangiocarcinomas?
Clinical outlook is dismal b/c they are rarely resectable. The median time from Dx to death is 6 mos.

I miss you, Pops
269. What are the telltale clinical signs of metastases to the liver?
Often, the only telltale clinical sign is hepatomegaly, sometimes w/nodularity of the free edge.

However, w/massive destruction of liver substance or direct obstruction of major bile ducts, jaundice and abnormal elevations of liver enzymes may appear.