Liver Path 5

Question 1

Hepatocellular disease

Answer 1

Predominantly attack/destroy hepatocytes

Laboratory test abnormalities are increased AST/ALT (transaminases)

Question 2

Cholestatic diseases

Answer 2

Bile production is impaired (hepatocyte)
Bile flow is blocked (ducts and ductules)
Alkaline phosphatase

Question 3

Mechanisms of cholestasis:

Answer 3

Intrahepatic cholestasis due to decreased bile formation:

- Sepsis
- Estrogens

Intrahepatic cholestasis due to diseases that destroy or compress intrahepatic bile ductules/ducts:

- Primary biliary cirrhosis
- Infiltration of liver with tumor/granulomas	

Intrahepatic cholestasis due to any severe liver disease:
-Viral hepatitis

Extrahepatic/large bile duct obstruction:
-Tumor, gallstones, duct strictures
Primary sclerosing cholangitis

Question 4

Unconjugated hyperbilirubinemia

Answer 4

uncommon finding

Increased bilirubin production i.e. hemolysis*
Decreased hepatocellular uptake i.e. drugs*
Decreased conjugation
– Gilbert’s syndrome
– Crigler-Najjar
– Neonatal jaundice
– Diffuse hepatocellular disease (virus, drugs, cirrhosis)

Question 5

Conjugated hyperbilirubinemia

Answer 5

Decreased canalicular transport

- Dubin Johnson syndrome

- Autoimmune cholangiopathies

Question 6

Sepsis Associated Cholestasis

Answer 6

Linked to infections with gram-negative bacteria*

Canalicular cholestasis* with activated Kupffer cells, fatty change and portal inflammation

Increase in serum bilirubin is out of proportion to the elevation of alkaline phosphatase

Poor prognosis (60-90% mortality)

Cholestasis of sepsis is predominantly conjugated

Question 7

Biliary Tract Disease (Cholestatic Pattern) - Large duct obstruction
causes in adults and children

Answer 7

Causes in Adults:
Obstruction by gallstones (Most Common)
Malignant neoplasms of biliary tree/head of pancreas
Primary sclerosing cholangitis

Causes in Children:
Biliary atresia
Choledochal cysts
Cystic fibrosis

Question 8

Large Bile Duct Obstruction- prognosis

Answer 8

Initial morphologic features of cholestasis are entirely reversible with correction of the obstruction

Prolonged obstruction can lead to secondary biliary cirrhosis

Intermittent obstruction may promote ascending cholangitis

Question 9

Hepatolithiasis

Answer 9

Disorder of intrahepatic gallstone formation

High prevalence in East Asia and rare elsewhere

Associated with *recurrent ascending cholangitis

Progressive inflammatory destruction of parenchyma–> Risk of cholangiocarcinoma*

Question 10

Ascending Cholangitis

Answer 10

• Fever, jaundice and abdominal pain

Suppurative cholangitis can be associated with septic shock and high mortality*

Increased blood neutrophils, alkaline phosphatase and bilirubin

Biliary dilation on imaging studies

Question 11

Major Causes of Neonatal Cholestasis

Answer 11

Extra-hepatic biliary atresia

Infectious hepatitis

Alpha-1 antitrypsin deficiency

Idiopathic neonatal hepatitis
- Diagnosis of exclusion

Question 12

Perinatal Biliary AtresiaPerinatal Form

Answer 12

Jaundice is observed after the period of physiologic hyperbilirubinemia.

Absence of all or a portion of the extrahepatic bile ducts

Most frequent cause of liver disease death in early childhood

Congenital infections have been implicated in * initiating autoimmune reaction

Question 13

Key Concepts (Robbins) Cholestasis

Answer 13

occurs with impaired bile flow, leading to accumulation of bile pigment in the hepatic parenchyma. Causes include mechanical or inflammatory obstruction or destruction of the bile ducts or by metabolic defects in hepatocyte bile secretion.

Question 14

Key Concepts (Robbins) Large bile duct obstruction

Answer 14

is most commonly associated with gallstones and malignancies involving the head of the pancreas. Chronic obstruction can lead to cirrhosis. Ascending cholangitis may develop

Question 15

Key Concepts (Robbins) Cholestasis in sepsis

Answer 15

may arise through direct effects of intrahepatic bacterial infection, ischemia relating to hypotension caused by sepsis, or in response to circulating microbial products.

Question 16

Key Concepts (Robbins) Primary hepatolithiasis

Answer 16

is a disorder ofintrahepaticgallstone formation, most common in East Asia, that leads to repeated bouts of ascending cholangitis and inflam­matory parenchymal destruction. It predisposes to cholangiocarcinoma.

Question 17

Key Concepts (Robbins) Neonatal cholestasis

Answer 17

is not a specific entity; it is variously associated with cholangiopathies such as primarilybiliary atresiaand a variety of inherited or acquired disorders causing conjugated hyperbilirubinemia in the neonate, collectively referred to asneonatal hepatitis.

Question 18

Hereditiary Fibropolycystic Liver Disease in general

Answer 18

Describes a heterogeneous group of genetic disorders with segmental dilatations of the intrahepatic bile ducts and associated fibrosis.

Cysts and/or Fibrosis
**

Question 19

Fibropolycystic Liver Disease

Answer 19

Congenitally acquired conditions that target bile ducts and surrounding portal tracks

Embryogenesis of portal tract formation proceeds from the central portion of the liver toward progressively smaller and more peripheral branches

Phenotype of disease depends upon where embryogenesis of portal tract formation is disrupted

Question 20

Fibropolycystic Liver Disease Pathogenesis

Answer 20

• Primary cilia protein gene mutations cause hereditary fibropolycystic diseases

Complex interrelationship of gene products lead to various disruptions of portal tract embryogenesis and different phenotypes of disease
- Central biliary structures vs peripheral biliary structures

Question 21

Fibropolycystic Liver Disease Congenital Malformations

Answer 21

Polycystic liver disease

Congenital hepatic fibrosis

Caroli disease & Caroli Syndrome

Choledochal cysts

Biliary hamartoma (Von Meyenburg complexes)

Question 22

Polycystic liver disease - associations

Answer 22

Associated with autosomal dominant* polycystic kidney disease
(most common)

Associated with autosomal * recessive polycystic kidney disease

No renal cysts (Least common)

Question 23

Von Meyenburg Complexes

Answer 23

Peripheral bile duct malformations (bile duct hamartoma)

Multiple von Meyenburg complexes are called polycystic liver disease

Question 24

Congenital Hepatic Fibrosis

Answer 24

Associated with autosomal recessive polycystic kidney disease

Complications of portal hypertension including splenomegaly and esophageal varices

Hepatic cystic lesions are rarely identified in patients with congenital hepatic fibrosis by gross inspection

Question 25

Congenital hepatic fibrosis histology

Answer 25

characterized by presence of numerous residual biliary channels with widely patent lumens arranged around the periphery of the portal tract

Question 26

Caroli Disease

Answer 26

Defined by the presence of congenitally dilated intrahepatic bile ducts often involving entire liver When superimposed on congenital hepatic fibrosis called Caroli syndrome Recurrent bacterial cholangitis Risk of cholangiocarcinoma

Question 27

Caroli Disease | histology

Answer 27

cystically dilated bile ducts. The cystic cavities are traversed by fibrous cords, known to contain the portal vessels. Dilated bile ducts have thickened walls due to marked chronic inflammation.

Question 28

Choledochal Cysts

Answer 28

Congenital cystic dilatation of the extrahepatic and intrahepatic bile ducts Complete inflammatory obstruction of the terminal portion of the bile duct is common in infants with choledochal cyst Predispose to stone formation, stenosis and pancreatitis Risk of cholangiocarcinoma** (3-14%, age related)

Question 29

Liver Disease Associated with Pregnancy

Answer 29

Unique liver diseases of pregnancy - Intrahepatic cholestasis of pregnancy - Acute fatty liver of pregnancy - Preeclampsia and liver disease Hepatitis E virus* infection in pregnant patients runs a more severe course (20% fatality)

Question 30

Intrahepatic Cholestasis of Pregnancy Clinical Presentation

Answer 30

Mild cholestatic disease that occurs in less than 2% of pregnancies Also occurs with oral contraceptives May cause intrauterine fetal death Strong genetic component, 10-15% of first degree female relatives affected Onset is usually in the third trimester Pruritus occurs in virtually all patients Jaundice occurs in ~25% Resolves within few days of delivery

Question 31

Acute Fatty Liver of Pregnancy

Answer 31

Usually appears in the third trimester before delivery (~1 in 13,000 pregnancies) Severe cases present as Acute/fulminant failure with modest increase in AST/ALT May occur in subsequent pregnancies Maternal mortality is 5-26% Intrauterine fetal death rate is 9-32%

Question 32

Acute Fatty Liver of Pregnancy  Initial Symptoms

Answer 32

Nausea or vomiting (75%) Epigastric abdominal pain (50%) Signs of preeclampsia (50%) Jaundice (90%) Anorexia

Question 33

Acute Fatty Liver of Pregnancy Laboratory Tests

Answer 33

Elevated aminotransferases (less than 500 U/L) Serum bilirubin usually elevated Evidence of hepatic insufficiency may be present Hypoglycemia Encephalopathy Abnormalities in coagulation studies

Question 34

Preeclampsia- Characterized by:

Answer 34

Hypertension Proteinuria Peripheral edema Coagulation abnormalities

Question 35

Preeclampsia and the Liver

Answer 35

Preeclampsia affects 5-10% of pregnancies Liver is affected and 10-20% of women with preeclampsia Liver disease related to preeclampsia accounts for: ~5% of jaundice ~20% of mortality in pregnancy

Question 36

Pre-Eclampsia Related Liver Disease

Answer 36

HELLP syndrome is the most common form of preeclampsia related liver disease Hemolysis Elevated liver tests (AST/ALT) Low Platelets

Question 37

Pre-Eclampsia Liver Pathology

Answer 37

Periportal fibrin and hepatocellular coagulative necrosis AST/ALT 100-300U/L, may exceed 1000 U/L Hyperbilirubinemia in 5-40%

Question 38

HEPATIC VENOUS OUTFLOW OBSTRUCTION

Answer 38

``` Hepatic Vein Thrombosis (2 or more veins) (Budd Chiari syndrome)** Polycythemia vera Pregnancy Postpartum state ``` Sinusoidal Obstruction Syndrome (obliteration of terminal hepatic venules)** Chemotherapeutic agents and immunosuppressive agents

Question 39

Budd-Chiari syndrome

Answer 39

Thrombosis of the major hepatic veins has caused extreme blood retention in the liver

Question 40

Impaired Blood Flow Through the Liver- causes

Answer 40

Cirrhosis most common cause Sinusoid occlusion - Sickle cell disease - Right sided heart failure - Eclampsia - Stellate cells

Question 41

When heart failure is persistent

Answer 41

collagen is deposited around the terminal hepatic venules and within the sinusoidal spaces (trichrome)

Question 42

Impaired Blood Flow Into the Liver

Answer 42

Liver infarcts are rare because of dual blood supply Hepatic artery compromise - Arteriosclerosis - Thrombosis or emboli Portal vein obstruction and thrombosis - Intra-abdominal sepsis - Hypercoagulable disorders with thrombosis - Cirrhosis (5% to 25% have portal vein thrombosis) - Pancreatitis

Question 43

Key Concepts (Robbins) Circulatory Disorders

Answer 43

Circulatory disorders of the liver can be caused by impaired blood inflow, defects in intrahepatic blood flow, and obstruction of blood outflow. Portal vein obstruction by intrahepatic or extrahepatic thrombosis may cause portal hypertension, esophageal varices, and ascites. The most common cause of impaired intrahepatic blood flow is cirrhosis. Obstructions of blood outflow include hepatic vein thrombosis (Budd-Chiari syndrome) and sinusoidal obstruction syndrome, previously known as veno-occlusive disease.