Liver Path 5 Flashcards
Hepatocellular disease
Predominantly attack/destroy hepatocytes
Laboratory test abnormalities are increased AST/ALT (transaminases)
Cholestatic diseases
Bile production is impaired (hepatocyte)
Bile flow is blocked (ducts and ductules)
Alkaline phosphatase
Mechanisms of cholestasis:
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
Unconjugated hyperbilirubinemia
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)
Conjugated hyperbilirubinemia
Decreased canalicular transport
- Dubin Johnson syndrome
- Autoimmune cholangiopathies
Sepsis Associated Cholestasis
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
Biliary Tract Disease (Cholestatic Pattern) - Large duct obstruction
causes in adults and children
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
Large Bile Duct Obstruction- prognosis
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
Hepatolithiasis
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*
Ascending Cholangitis
- 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
Major Causes of Neonatal Cholestasis
Extra-hepatic biliary atresia
Infectious hepatitis
Alpha-1 antitrypsin deficiency
Idiopathic neonatal hepatitis
- Diagnosis of exclusion
Perinatal Biliary AtresiaPerinatal Form
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
Key Concepts (Robbins) Cholestasis
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.
Key Concepts (Robbins) Large bile duct obstruction
is most commonly associated with gallstones and malignancies involving the head of the pancreas. Chronic obstruction can lead to cirrhosis. Ascending cholangitis may develop
Key Concepts (Robbins) Cholestasis in sepsis
may arise through direct effects of intrahepatic bacterial infection, ischemia relating to hypotension caused by sepsis, or in response to circulating microbial products.
Key Concepts (Robbins) Primary hepatolithiasis
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.
Key Concepts (Robbins) Neonatal cholestasis
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.
Hereditiary Fibropolycystic Liver Disease in general
Describes a heterogeneous group of genetic disorders with segmental dilatations of the intrahepatic bile ducts and associated fibrosis.
Cysts and/or Fibrosis
**
Fibropolycystic Liver Disease
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
Fibropolycystic Liver Disease Pathogenesis
- 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
Fibropolycystic Liver Disease Congenital Malformations
Polycystic liver disease
Congenital hepatic fibrosis
Caroli disease & Caroli Syndrome
Choledochal cysts
Biliary hamartoma (Von Meyenburg complexes)
Polycystic liver disease - associations
Associated with autosomal dominant* polycystic kidney disease
(most common)
Associated with autosomal * recessive polycystic kidney disease
No renal cysts (Least common)
Von Meyenburg Complexes
Peripheral bile duct malformations (bile duct hamartoma)
Multiple von Meyenburg complexes are called polycystic liver disease
Congenital Hepatic Fibrosis
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
Congenital hepatic fibrosis histology
characterized by presence of numerous residual biliary channels with widely patent lumens arranged around the periphery of the portal tract
Caroli Disease
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
Caroli Disease
histology
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.
Choledochal Cysts
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)
Liver Disease Associated with Pregnancy
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)
Intrahepatic Cholestasis of Pregnancy Clinical Presentation
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
Acute Fatty Liver of Pregnancy
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%
Acute Fatty Liver of Pregnancy Initial Symptoms
Nausea or vomiting (75%)
Epigastric abdominal pain (50%)
Signs of preeclampsia (50%)
Jaundice (90%)
Anorexia
Acute Fatty Liver of Pregnancy Laboratory Tests
Elevated aminotransferases (less than 500 U/L)
Serum bilirubin usually elevated
Evidence of hepatic insufficiency may be present
Hypoglycemia
Encephalopathy
Abnormalities in coagulation studies
Preeclampsia- Characterized by:
Hypertension
Proteinuria
Peripheral edema
Coagulation abnormalities
Preeclampsia and the Liver
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
Pre-Eclampsia Related Liver Disease
HELLP syndrome is the most common form of preeclampsia related liver disease
Hemolysis
Elevated liver tests (AST/ALT)
Low Platelets
Pre-Eclampsia Liver Pathology
Periportal fibrin and hepatocellular coagulative necrosis
AST/ALT 100-300U/L, may exceed 1000 U/L
Hyperbilirubinemia in 5-40%
HEPATIC VENOUS OUTFLOW OBSTRUCTION
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
Budd-Chiari syndrome
Thrombosis of the major hepatic veins has caused extreme blood retention in the liver
Impaired Blood Flow Through the Liver- causes
Cirrhosis most common cause
Sinusoid occlusion
- Sickle cell disease
- Right sided heart failure
- Eclampsia
- Stellate cells
When heart failure is persistent
collagen is deposited around the terminal hepatic venules and within the sinusoidal spaces (trichrome)
Impaired Blood Flow Into the Liver
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
Key Concepts (Robbins) Circulatory Disorders
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.
