WEEK 2: Pathology of the liver

Question 1

Describe the location of the liver using quadrants.

Answer 1

located in the Right hypochondrium and epigastric region extending into the left hypochondrium.

Question 2

The liver has dual supply. Describe the 2 main supplies and their percentages.

Answer 2

Has dual blood supply with portal vein (60-70% of blood supply and hepatic artery remaining 30-40% of blood).

Portal vein and hepatic artery enter the inferior aspect of the liver through hilum or porta hepatis.

Within the liver, the branches of the portal veins, hepatic arteries and bile ducts travel in parallel within portal tracts ramifying variably through 17 to 20 orders of branches.

Abdominal aorta, celiac trunk, common hepatic artery, hepatic artery proper, right hepatic artery, left hepatic artery, intermediate hepatic artery

Question 3

How much bile is secreted by the liver daily?

State the storage capacity of an adult gall bladder.

Why is the gall bladder not essential for biliary function?
State the cause of more than 95% of biliary tract disease.

Answer 3

As much as 1 L of bile is secreted by the liver daily.
Between meals, bile is stored in the gallbladder, where it is concentrated.

The adult gallbladder has a capacity of about 50 mL.

The organ is not essential for biliary function, since humans do not suffer from indigestion or malabsorption of fat after cholecystectomy.

More than 95% of biliary tract disease is attributable to cholelithiasis (gallstones).

Question 4

Compare the lobes of the liver.

State the function of the porta hepatis.

Answer 4

The Right lobe of the liver is the largest lobe whereas the left lobe of the liver is smaller.

The porta hepatis serves as the point of entry into the liver for the hepatic arteries and portal vein and the exit point for the hepatic ducts

Question 5

Describe the vasculature of the liver.

Answer 5

Vascularization is from the Hepatic Artery

Abdominal aorta»> Celiac trunk&raquo_space;> Common hepatic artery&raquo_space;> Proper hepatic artery

Question 6

Describe the venous drainage of the liver.

Answer 6

Venous drainages come into liver from portal hepatic vein, receiving drainage from intestines (mesenteric veins & splenic veins)

Within the liver, the portal vein branches extensively, forming smaller vessels known as portal venules. These portal venules penetrate into the liver parenchyma (liver tissue) and ultimately terminate in tiny blood vessels called sinusoids, which are lined by hepatocytes (liver cells).

Within the sinusoids, blood from the portal vein comes into close contact with hepatocytes, allowing for the exchange of nutrients, metabolic products, and toxins. The hepatocytes carry out numerous metabolic functions, including the processing and detoxification of substances absorbed from the digestive tract.

From liver the sinusoids united into hepatic veins, that drains into Inferior Vena Cava.

The IVC then carries the deoxygenated blood back to the heart for recirculation.

Hepatic portal vein&raquo_space;> Portal venules»» Hepatic vein»> IVC»>Right atrium

Question 7

Name blood vessels that make up the hepatic portal vein.

Answer 7

Superior mesenteric vein
Inferior mesenteric vein
Splenic vein
Gastric vein

Question 8

Discuss Microstructure of the liver (Lobule).

Answer 8

The Lobule model: hexagonal lobules oriented around the terminal tributaries of the hepatic vein (terminal hepatic veins) with portal tracts at the peripheral of the lobule.
The hepatocytes in the vicinity of terminal hepatic vein are called “centrilobular”, those near the portal tract are “periportal”.

The acinar model: the hepatocytes near the terminal hepatic veins are the distal apices of roughly triangular acini whose bases are formed by penetrating septal venules from portal vein extending out from portal tracts.

In the acinus, the parenchyma is divided into 3 zones, zone 1 being closest to vascular supply, zone 3 abutting the terminal hepatic venule(central vein) and most remote from the afferent blood supply and zone 2 being intermediate.

Question 9

The liver is vulnerable to a variety of metabolic, toxic, microbial, circulatory and neoplastic insults.

Outline the major primary diseases of the liver.

Answer 9

Viral hepatitis
Alcoholic liver disease
Non alcoholic fatty liver disease (NAFLD)
Hepatocellular carcinoma

Question 10

The liver has an enormous functional reserve and this tends to mask minor insults to it, however, with progressive or diffuse disease and disruption in bile flow, the consequences of deranged liver function may become life threatening.

Outline major causes of Hepatic injury/damage.

Answer 10

May result from many common diseases:
-cardiac decompensation
-Disseminated cancer
-And extrahepatic infections

Question 11

Q: How does liver disease typically manifest in terms of clinical detection and symptoms of hepatic decompensation?
Q: What might be the case regarding symptoms and detection of liver abnormality in some patients with liver disease?
Q: What is the most common presentation of liver injury in patients?
Q: How often does acute fulminant hepatic failure occur in the context of liver disease?

Answer 11

A: Liver disease is often insidious, with clinical detection and symptoms of hepatic decompensation potentially occurring weeks, months, or even many years after the onset of injury.
A: Some patients with liver disease may not exhibit symptoms, and abnormalities may only be detected through abnormal laboratory tests.
A: Most patients with liver injury present with chronic liver disease.
A: Acute fulminant hepatic failure is rare in the context of liver disease.

NOTE: Acute fulminant hepatic failure, also known as fulminant hepatic failure or fulminant liver failure, is a rare and severe form of liver injury characterized by rapid and extensive loss of liver function within a short period, typically occurring over days to weeks.

Question 12

Describe Pattern of hepatic injury.

Answer 12

-Hepatocyte degeneration and intracellular accumulations
-Hepatocyte necrosis and apoptosis
-Inflammation
-Regeneration
-Fibrosis

Question 13

Outline examples of Liver syndromes.

Answer 13

Hepatic failure
Cirrhosis
Portal hypertension
Disturbances in bilirubin metabolism leading to jaundice and cholestasis

Question 14

When does hepatic failure usually occur?

State two things that can cause End stage liver disease.

Answer 14

Is the most severe consequence of liver disease. Occurs when there is 80-90% loss of functional capacity.

May result from sudden and massive liver destruction (fulminant hepatic failure).

It is also the end stage of progressive chronic damage to the liver.

End stage liver disease may result from:
*Insidious destruction or hepatocytes or
*Repetitive discrete wave of parenchymal damage

Question 15

State the 3 categories of liver failure.

Answer 15

Acute Liver failure
Chronic liver disease
Hepatic dysfunction without overt necrosis

Question 16

Define acute liver failure.

Compare fulminant and sub-fulminant liver failure.

Answer 16

Is acute liver disease associated with encephalopathy within 6 months of initial diagnosis.

Is described as fulminant when the encephalopathy develops rapidly within 2 weeks of onset of jaundice and as sub-fulminant when it develops within 3 months of onset of jaundice.

Question 17

Discuss the causes of acute liver failure.

Answer 17

1. Massive hepatic necrosis most often due to drugs or toxins
   *Accidental or deliberate ingestion of acetaminophen (Aspirin).
   *Exposure to halothane
   *Antimycobacterial drugs (Rifampin, Isoniazid)
   *Antidepressant monoamine oxidase inhibitors
   *Industrial chemicals such as carbon tetrachloride (CCL4).
   *Mushroom poisoning (Amanita phalloides).
2. Hepatitis A virus
   Hepatitis B virus
   Autoimmune hepatitis
   Unknown causes
   Rarely hepatitis C

Question 18

Discuss the Mechanism of liver damage in acute hepatitis.

Answer 18

1. Direct toxic damage
   -Acetaminophen and mushroom toxins
2. Variable combination of toxicity and immune mediated hepatocyte damage
   -Hepatitis virus infection

Question 19

Define Chronic hepatic failure.

Answer 19

Is the most common route of hepatic failure

Is the end point of persistent chronic hepatitis ending in cirrhosis

Question 20

Define Hepatocyte destruction without overt necrosis.

Answer 20

Hepatocytes may be viable but unable to perform normal metabolic function. This occurs in;
-Tetracycline toxicity
-Acute fatty liver of pregnancy

Question 21

Outline clinical features of Hepatocyte destruction without overt necrosis

Answer 21

Result from hepatocytes failing to perform their homeostatic function
-Jaundice
-Hypoalbuminemia, peripheral oedema
-Hyperammonemia, cerebral dysfunction
-Palmar erythema: Liver Failure Connection: The liver metabolizes hormones, including estrogen. In liver failure, the decreased ability to metabolize these hormones leads to elevated levels of circulating estrogens.
Estrogen Effects: Increased estrogen levels cause vasodilation (widening of blood vessels), which can result in the characteristic redness of palmar erythema.
Other Factors: Increased circulating levels of nitric oxide and other vasodilatory substances due to liver dysfunction can also contribute to the condition.
-Hypogonadism: Hormonal Imbalance: Elevated levels of estrogen relative to testosterone in men can suppress the hypothalamic-pituitary-gonadal axis, leading to decreased testosterone production.
Clinical Manifestations: Symptoms in men include reduced libido, erectile dysfunction, muscle loss, fatigue, and in women, irregular menstrual cycles, or amenorrhea.
-Gynecomastia: Liver Failure Connection: Similar to hypogonadism, the impaired metabolism of estrogen by the liver in liver failure leads to elevated estrogen levels.
Estrogen Effects: High levels of circulating estrogens stimulate breast tissue growth in men.
-Coagulopathy

Question 22

Chronic venous congestion (Passive hepatic congestion).

Define Passive hepatic congestion.

Describe the 2 main conditions associated with this and how it comes about.

Answer 22

Passive hepatic congestion is caused by stasis of blood within theliver parenchyma due to compromise of hepatic venous drainage.

It is a common complication ofcongestive heart failureandconstrictive pericarditis where elevatedcentral venous pressure is directly transmitted from theright atrium to thehepatic veinsbecause of their close anatomic relationship.

The liver becomes tensely swollen as thehepatic sinusoidsengorge and dilate with blood.

Question 23

Discuss Pathogenesis of Chronic venous congestion.

Answer 23

Moderate or severe right-sided heart failure increases central venous pressure, which is transmitted to the liver via the inferior vena cava and hepatic veins.

Chronic congestion leads to atrophy of hepatocytes, distension of sinusoids, and centrizonal fibrosis which if severe progresses to cirrhosis (cardiac cirrhosis).

The basis for liver cell death is probably sinusoidal thrombosis that propagates to the central veins and branches of the portal vein causing ischemia.

Question 24

Describe Chronic Venous Congestion of Liver Gross appearance.

Answer 24

1. The liver is enlarged and tender
2. The cut surface shows characteristic alternate dark areas representing congested centre of each lobule, and light areas being the fatty peripheral part, so called nutmeg liver.

Question 25

Describe Chronic congestion of the Liver Microscopy appearance.

Answer 25

Microscopy
-The central vein and the sinusoids in the centrilobular region are distended with blood.

-The hepatocytes in the centrilobular region undergo degeneration and atrophy, probably as a result of anoxia.

-Eventually, the centrilobular zone shows central haemorrhagic necrosis.

-The peripheral hepatocytes are either normal or may show fatty change.

Question 26

Define Fatty change in Liver (Steatosis).

Answer 26

Fatty liver diseaseis a condition in whichfatbuilds up in theliver.

Question 27

State the two main types of Fatty change in Liver (Steatosis).

Answer 27

1. Non-alcoholicfatty liver disease(NAFLD)
2. Alcoholic fatty liver disease, also calledalcoholicsteatohepatitis.

Question 28

Name Special stains that can be employed to demonstrate fat in the tissue.

Answer 28

Special stains such as Sudan III, Sudan IV, Sudan Black and Oil Red O can be employed to demonstrate fat in the tissue.

Question 29

Excessive alcohol (ethanol) consumption is the leading cause of liver disease in most countries.

Alcohol accounts for 3.8% of deaths globally, making it the eighth highest risk factor for death (fifth in middle-income countries and ninth in high-income countries).

State the three forms of alcoholic liver injury.

Answer 29

(1) hepatocellular steatosis or fatty change,
(2) alcoholic (or steato-) hepatitis, and
(3) steatofibrosis (patterns of scarring typical for all fatty liver diseases including alcohol) up to and including cirrhosis in the late stages of disease.

Question 30

Discuss the Pathogenesis of ALD.

Answer 30

All these changes begin and are usually most prominent in the centrilobular region of the hepatic lobule.

The centrilobular hepatocytes are enzymatically prepared to metabolize alcohol through, for example, cytosolic alcohol dehydrogenase and the induction of cytochrome p450 enzymes.

Such pathways produce the fatty acids accumulating in steatotic hepatocytes and create the toxic metabolites causing inflammation, hepatocyte injury, and fibrosis.

Question 31

Characterized by the presence of small (micro-vesicular) or large (macro-vesicular) lipid droplets inside the hepatocytes

Initial centrilobular involvement followed by entire lobule involved

Reversible if there is abstinence from alcohol

Name the disease.

Answer 31

Hepatic steatosis also called fatty liver disease

Question 32

There is hepatocyte swelling and necrosis (ballooning degeneration)

Neutrophilic infiltration in lobule

Perivenular and periportal fibrosis

Some hepatocytes show the presence of eosinophilic, cytokeratin filaments called “Mallory Hyaline Bodies”

Name the disease.

Answer 32

Alcoholic hepatitis

Question 33

Irreversible form of alcoholic liver disease

Initially, liver is enlarged and later there is presence of micronodules and macronodules

Later, the whole liver has tough, pale scar tissue (Laennec Cirrhosis).

Name the disease.

Answer 33

Alcoholic cirrhosis

Question 34

Describe liver cirrhosis.

Answer 34

Is diffuse transformation of the entire liver into regenerative parenchymal nodules surrounded by fibrous bands and variable degrees of vascular (often portosystemic) shunting.

This is secondary to liver injury.

It is the end stage of liver disease characterized by disruption of the liver architecture by fibrotic bands that divide the liver into nodules of regenerating liver parenchyma.

It can be
may be micronodular (if nodule is <3mm)
or
macronodular (if nodule is >3mm)

Question 35

Outline causes of Cirrhosis of the Liver.

Answer 35

Alcoholic liver disease (most common cause)

Viral hepatitis

Biliary tract disease

Hemochromatosis: Is a disorder in which the body can build up too much iron in the skin, heart, liver, pancreas, pituitary gland, and joints

Cryptogenic/idiopathic(non alcoholic fatty liver diseases is its commonest cause)

Wilson disease: a rare, autosomal recessive disorder caused by abnormal copper accumulation in the body particularly involving the brain, liver, and cornea.

Alpha-1-antitrypsin deficiency

Question 36

Describe Macro-nodular Cirrhosis

Answer 36

Cirrhosis is morphologically categorized by the size of nodules.

Ongoing liver damage with liver cell necrosis followed by fibrosis and hepatocyte regeneration results in cirrhosis. This produces a nodular, firm liver. The nodules seen here are larger than 3 mm and, hence, this is an example of “macronodular” cirrhosis.

Question 37

Describe Micronodular cirrhosis

Answer 37

The regenerative nodules are quite small, averaging less than 3 mm in size.

The most common cause for this is chronic alcoholism.

The process of cirrhosis develops over many years.

Question 38

Discuss the Pathogenesis of Cirrhosis.

Answer 38

The central pathogenic process includes:
1. Death of hepatocytes,
2. Deposition of the extracellular matrix and
3. Vascular reorganization

In normal liver, interstitial collagens (types I & III are concentrated in portal tracts and around central veins, and thin strands of type IV in space of Disse.

In cirrhosis, types I and III collagen are deposited in space of Disse, creating fibrotic septal tracts with scarring and parenchymal damage which disrupts the vasculature.

There is creation of new vascular channels connecting hepatic arteries and portal veins to terminal heptatic veins , shunting blood from parenchyma.

Deposition of collagen in space of Disse is accompanied by loss of fenestrations of sinusoidal endothelial cells, impairing function of sinusoids as channels that permit exchange of solutes between hepatocytes and plasma.

The proliferation of hepatic stellate cells and their activation into highly fibrogenic cells is the predominant mechanism of fibrosis. Cytokines or growth factors are also involved.

Question 39

Discuss portal hypertension.

Answer 39

Increase in pressure in the portal system follows obstruction to portal blood flow anywhere along its course.

Portal veins have no valves and so obstruction anywhere raises pressure in all the veins.

There is increased resistance to portal blood flow due to; prehepatic, hepatic and post-hepatic causes.

1. Prehepatic- due to obstructive thrombosis, massive splenomegaly and increased splenic blood flow.
2. Post hepatic: severe right sided heart failure, constrictive pericarditis and hepatic vein outflow obstruction.
3. Most common intrahepatic cause is cirrhosis, accounting for the majority of cases.

Question 40

Describe the 4 main complications of portal hypertension.

Answer 40

1. Ascites:
   *Accumulation of excess fluid within peritoneal cavity.

*Results from systemic and local factors

-Systemic (decreased plasma colloid oncotic pressure, hyperaldosteronism, impaired renal excretion)

-Local (increased portal pressure, increased hepatic lymph formation)

2. Varices
   Development of collateral blood channels e.g., esophageal varices

Enlarged or dilated blood vessels in the esophagus. Are prone to bleeding.

3. Splenomegaly
   Congestive splenomegaly, may be up to 1000gm
4. Hepatic encephalopathy
   Is a complex metabolic and organic syndrome; there is disturbed consciousness, neurologic signs, and flapping tremors.

Question 41

Define cholelithiasis.

Gallstones afflict to how many % of adult populations in developed countries?

How many % of gallstones are “silent,” and most individuals remain free of biliary pain or other complications for decades?

Describe the 2 general classes of gallstones.

Answer 41

Formation of gall stones.

Gallstones are pieces of solid material that form in your gallbladder.

*Gallstones afflict 10% to 20% of adult populations in developed countries.

*The vast majority of gallstones (>80%) are “silent,” and most individuals remain free of biliary pain or other complications for decades.

There are two general classes of gallstones:

1. cholesterol stones, containing more than 50% of crystalline cholesterol monohydrate.
2. Pigment stones composed predominantly of bilirubin calcium salts.

Question 42

Outline at least 10 Risk Factors for Gallstones.

Answer 42

Cholesterol Stones
1. Multiparity
2. Demography: northern Europeans, North and South Americans, Native Americans, Mexican Americans
3. Advancing age
4. Female sex hormones
5. Female gender
6. Oral contraceptives
7. Pregnancy
8. Obesity and metabolic syndrome
9. Rapid weight reduction
10. Gallbladder stasis
11. Inborn disorders of bile acid metabolism
12. Hyperlipidemia syndromes

Pigment Stones
14. Demography: Asians more than Westerners, rural more than urban
15. Chronic hemolytic syndromes
16. Biliary infection
17. Gastrointestinal disorders: ileal disease (e.g., Crohn disease), ileal resection or bypass, cystic fibrosis with pancreatic insufficiency

Question 43

Discuss cholecystitis.

Answer 43

Inflammation of the gallbladder may be acute, chronic, or acute superimposed on chronic.

Most often occurs in association with gallstones.

Cholecystitis is one of the most common indications for abdominal surgery.

Therefore its epidemiologic distribution closely parallels that of gallstones.

Question 44

Discuss acute cholecystitis.

Answer 44

Acute calculous cholecystitis is precipitated in 90% of cases by obstruction of the neck or the cystic duct by a stone.

It is the primary complication of gallstones and the most common reason for emergency cholecystectomy.

Cholecystitis without gallstones (acalculous cholecystitis) may occur in severely ill patients and accounts for about 10% of patients with cholecystitis.

Question 45

Discuss Chronic cholecystitis.

Answer 45

Chronic cholecystitis may result from repeated bouts of mild to severe acute cholecystitis, but in many instances it develops on its own.

Since it is associated with cholelithiasis in more than 90% of cases, the at-risk patient population is the same as that for gallstones.

Question 46

Outline benign tumors of the liver and biliary tract amd mesoderm.

Answer 46

1. Hepatocellular tumors
   Hepatocellular (Liver cell) Adenoma
2. Biliary tumors
   Bile duct Adenoma
3. Mesodermal tumors
   Hemangioma

Question 47

Outline the malignant tumors of the liver, biliary tract and the mesoderm.

Answer 47

1. Hepatocellular (liver cell) carcinoma
   Hepatoblastoma (Embryoma)
2. Cholangiocarcinoma: bile duct cancer
   Combined hepatocellular and cholangiocarcinoma
   Cystadenocarcinoma: cystic duct cancer
3. Angiosarcoma
   Embryonal Sarcoma

Question 48

State the most common cancers in the liver and biliary tract

Answer 48

Hepatocellular carcinomas (HCCs) and cholangiocarcinomas;
HCCs are the most common.

HCC is a common tumor in regions of Asia and Africa, and its incidence is increasing in the United States.

The main etiologic agents for HCC are;
*chronic hepatitis B and C,
*alcoholic cirrhosis,
*non-alcoholic fatty liver disease, and
*hemochromatosis.

In the Western population, about 90% of HCCs develop in cirrhotic livers; in

Asia, almost 50% of cases develop in noncirrhotic livers.

The liver is the most common site of metastatic cancers

They arise from primary tumors of the colon, lung and breast.

Question 49

Discuss Laboratory evaluation of liver disease.

Answer 49

Laboratory evaluation of liver disease
1. Hepatocyte function:
*Serum albumin
*Serum ammonia
*Prothrombin time

2. Hepatocyte injury (enzymes normally present ide the
   Hepatocytes and released with injury):
   *Serum aspartate aminotransferase(AST)
   *Serum alanine aminotransferase ALT
   *Serum lactate dehydrogenase
3. Biliary excretory function:
   *Serum bilirubin
   *Serum alkaline phosphatase
   *Serum gamma glutamyl transpeptidase