patoloji-ders-notlari

Title

Serdar Balcı

Circulatory and Cholestatic Disorders of Liver

Serdar BALCI, MD

CHOLESTATIC LIVER DISEASES

Cholestasis

• Impaired bile flow
• Accumulation of bile pigment in the hepatic parenchyma
• Causes:
  • Mechanical obstruction
  • Inflammatory obstruction
  • Destruction of the bile ducts
  • Metabolic defects in hepatocyte bile secretion

Robbins and Cotran Pathologic Basis of Disease

Robbins Basic Pathology

Robbins and Cotran Pathologic Basis of Disease

Robbins and Cotran Pathologic Basis of Disease

Robbins Basic Pathology

Robbins Basic Pathology

Cholestatic Liver Diseases

• Primary hepatocellular dysfunction
  • neonatal cholestasis, drug cholestasis, sepsis
• Bile duct injuries
  • Mechanical
    • obstruction of large ducts by stones or tumor
  • Inflammatory
    • autoimmune diseases
• Diseases may affect both intra- and extrahepatic segments
• Exclusively extrahepatic biliary disorders may still cause secondary changes within the liver

Cholestatic hepatocytes are enlarged with dilated canalicular spaces.

Apoptotic cells.

Kupffer cells frequently contain regurgitated bile pigments

Robbins and Cotran Pathologic Basis of Disease

Intracellular cholestasis showing the bile pigments in the cytoplasm

Robbins and Cotran Pathologic Basis of Disease

Bile plug showing the expansion of bile canaliculus by bile

Robbins and Cotran Pathologic Basis of Disease

Autopsy Pathology: A Manual and Atlas

Large bile duct obstruction

• Associated with
  • Gallstones
  • Malignancies involving the head of the pancreas
• Complications
  • Chronic obstruction can lead to cirrhosis
  • Ascending cholangitis may develop

Acute large duct obstruction. Marked edema, ductular reaction, neutrophils

Ascending cholangitis

Large bile duct obstruction → static bile → bacterial infections within the biliary tree

Primary hepatolithiasis

Disorder of intrahepatic gallstone formation

Most common in East Asia

Causes repeated bouts of ascending cholangitis and inflam­matory parenchymal destruction

Predisposes to cholangiocarcinoma

Neonatal Cholestasis

• Mild transient elevations in serum unconjugated bilirubin are common in normal newborns
• Neonatal cholestasis
  • Prolonged conjugated hyperbilirubinemia
  • Lasts beyond the first 14 days of life
• Causes
• Extrahepatic biliary atresia
• Neonatal hepatitis
  • not a specific entity, nor are the disorders necessarily inflammatory
  • Idiopathic neonatal hepatitis
    • 10-15% of cases of neonatal hepatitis

Neonatal hepatitis. Multinucleated giant hepatocytes

• Clinical presentation
  • Jaundice
  • Dark urine
  • Light or acholic stools
  • Hepatomegaly
  • Hypoprothrombinemia
• Extrahepatic biliary atresia
  • surgery
• Idiopathic hepatitis

Cholestasis of Sepsis

• Intrahepatic bacterial infection
  • Abscess formation
  • Bacterial cholangitis
• Ischemia
  • Septic shock
• In response to circulating microbial products
  • gram-negative organisms

Cholestasis of SepsisCanalicular cholestasis

Bile plugs within predominantly centrilobular canaliculi

Prominent activated Kupffer cells

Mild portal inflammation

**Hepatocyte necrosis is scant or absent **

Robbins Basic Pathology

Cholestasis of SepsisDuctular cholestasis

Canals of Hering and bile ductules at the interface of portal tracts and parenchyma become dilated and contain prominent bile plugs

Not a typical feature of biliary obstruction

Accompanies or even precedes the development of septic shock

Ductular cholestasis. Large, dark bile concretions within markedly dilated canals of Hering and ductules at the portal-parenchymal interface. This feature, indicative of current or impending severe sepsis, is related to endotoxemia.

Robbins Basic Pathology

AUTOIMMUNE CHOLANGIOPATHIES

Robbins Basic Pathology

PRIMARY BILIARY CIRRHOSIS (PBC)

Primary Biliary Cirrhosis (PBC)

• Autoimmune disease
• Inflammatory, often granulomatous
• Chronic, progressive, and sometimes fatal cholestatic liver disease
• Destruction of intrahepatic bile ducts
  • Nonsuppurative destruction of small and medium-sized intrahepatic bile ducts
• Portal inflammation and scarring
• Development of cirrhosis and liver failure over years to decades
• Disease of middle-aged women, peak incidence 40-50 years
• Autoantibodies (AMA)
• Associated with other autoimmune diseases Sjögren syndrome and Hashimoto thyroiditis

Primary Biliary Cirrhosis

• High titers of autoantibodies directed against several mitochondrial acid dehydrogenases
• Interlobular bile ducts are actively destroyed by lymphocytic or plasmacytic inflammation
• With or without granulomas (the florid duct lesion)
• Portal tracts lacking bile ducts, ductopenia
• Ductular reaction
  • Bile ductular proliferation
• Inflammation and necrosis of the adjacent periportal parenchyma
• Portal-portal septal fibrosis
• Mild interface and lobular hepatitis also may be present

Biliary cirrhosis. Sagittal section through the liver demonstrates the nodularity and bile staining of end-stage biliary cirrhosis.

Robbins and Cotran Pathologic Basis of Disease

Unlike other forms of cirrhosis, nodules of liver cells in biliary cirrhosis are often not round but irregular, like jigsaw puzzle shapes

Robbins and Cotran Pathologic Basis of Disease

Primary biliary cirrhosis. A portal tract is markedly expanded by an infiltrate of lymphocytes and plasma cells. Granulomatous reaction to a bile duct undergoing destruction (florid duct lesion)

Robbins Basic Pathology

• Ductular reaction
• Earlier stages of disease
  • help maintain bile flow
• Later stages
  • **contribute to subsequent scarring **

ductular reaction in a fibrotic septum

Robbins Basic Pathology

• Overlap syndrome
  • The features sometimes overlap with those of autoimmune hepatitis
  • When the hepatitic component is very prominent and there are serologic findings typical for autoimmune hepatitis

Primary Biliary CirrhosisTwo paths to end-stage liver disease

• Prominent portal hypertension
  • Widespread nodularity without the surrounding scar tissue seen in cirrhosis
    • nodular regenerative hyperplasia
  • Liver larger than normal and may show a vague nodularity that differs from the obvious nodules of cirrhosis
• Increasingly widespread duct loss
  • Cirrhosis and profound cholestasis
  • Bile accumulation periportal/periseptal
  • feathery degeneration marked by ballooned, bile-stained hepatocytes, often with prominent Mallory-Denk bodies
    • not centrilobular, as in drug-induced or sepsis-associated cholestatic syndromes
    • similar to those seen in alcoholic hepatitis, differ by their periportal rather than centrilobular location
• Cirrhosis and vivid green discoloration, matching the patient’s general icteric state
• There is little hepatocyte loss
  • regenerative nodular hyperplasia, hepatomegaly
  • different from shrunken livers of chronic hepatitis or alcoholism

Primary biliary cirrhosis, end stage. This sagittal section demonstrates liver enlargement, nodularity indicative of cirrhosis, and green discoloration due to cholestasis

Robbins Basic Pathology

PRIMARY SCLEROSING CHOLANGITIS (PSC)

Primary Sclerosing Cholangitis (PSC)

• Autoimmune disease

• Progressive inflammatory and sclerosing destruction of bile ducts of all sizes

  • intrahepatic and extrahepatic

• Diagnosis is made by radiologic imaging of the biliary tree

• Most often in younger men

• Strong associations with inflammatory bowel disease, particularly ulcerative colitis

• Chronic cholestatic disorder

• Progressive fibrosis and destruction of extrahepatic and intrahepatic bile ducts of all sizes

• Patchy

• Cholangiography shows a characteristic beading in the affected segments of the biliary tree

  • narrow strictures alternating with normal sized or dilated ducts

Robbins and Cotran Pathologic Basis of Disease

Primary Sclerosing Cholangitis

• Seen in association with inflammatory bowel disease

  • Ulcerative colitis coexists in approximately 70% of affected patients
  • **Prevalence of PSC among persons with ulcerative colitis is about 4%. **

• Linkage with certain HLA-DR alleles

• Antinuclear cytoplasmic antibodies with a perinuclear localization

• Largest ducts

  • Chronic inflammation with superimposed acute inflammation
  • Similar to the mucosal lesions of ulcerative colitis
  • Narrowing of the larger ducts
    • edema and inflammation
    • scarring

• Smaller ducts

  • little inflammation
  • striking circumferential fibrosis
    • onion skinning around an increasingly atrophic duct lumen
  • Lumen disappears, dense button of scar tissue, tombstone scar

• Diagnosis depends on radiologic imaging of the extrahepatic and largest intrahepatic ducts

Primary sclerosing cholangitis. A bile duct undergoing degeneration is entrapped in a dense, “onion-skin” concentric scar.

Robbins Basic Pathology

• In response to duct loss;
  • bile ductular proliferation
• portal-portal septal fibrosis
• cirrhosis
• The end-stage liver is usually cirrhotic and green
• Biliary intraepithelial neoplasia may appear
  • cholangiocarcinoma,10-15% in 5 years

Drug/Toxin-Induced Cholestasis

• May be seen alone or in combination with hepatitic features
  • Alkylated anabolic or contraceptive steroids
  • Total parenteral nutrition
  • Antibiotics
• Loss of bile ducts
  • chlorpromazine, amitryptyline, and organic arsenicals

CIRCULATORY DISORDERS

Robbins Basic Pathology

Impaired Blood Flow into the Liver

Hepatic Artery Inflow

• Liver infarcts are rare
  • double blood supply
• Interruption of the main hepatic artery
  • does not always produce ischemic necrosis
  • retrograde arterial flow through accessory vessels
  • portal venous supply sustain the liver parenchyma
• Hepatic artery thrombosis in the transplanted liver
  • leads to loss of the organ
• Localized parenchymal infarct
  • Thrombosis or compression of an intrahepatic branch of the hepatic artery
  • polyarteritis nodosa
  • embolism
  • neoplasia
  • sepsis

Autopsy Pathology: A Manual and Atlas

Acute centrilobular hemorrhage and necrosis

Shock from acute blood loss or sepsis causes centrilobular hemorrhage and necrosis

Autopsy Pathology: A Manual and Atlas

Portal Vein Obstruction and Thrombosis

• Extrahepatic portal vein obstruction may arise from:
  • Peritoneal sepsis
    • acute diverticulitis, appendicitis leading to pylephlebitis in the splanchnic circulation
  • Pancreatitis initiating splenic vein thrombosis, propagates into the portal vein
  • Thrombogenic diseases and postsurgical thromboses
  • Vascular invasion by primary or secondary cancer in the liver that progressively occludes portal inflow to the liver
  • Banti syndrome
    • subclinical thrombosis of the portal vein, fibrotic, partially recanalized vascular channel
    • splenomegaly or esophageal varices years later
  • Cirrhosis
    • reduces the flow of blood in the portal veins
    • leads to extrahepatic portal vein thrombosis
• Intrahepatic thrombosis of a portal vein
  • Acute
  • No ischemic infarction
  • Sharply demarcated area of red-blue discoloration (infarct of Zahn)
  • Hepatocellular atrophy
  • Marked congestion of distended sinusoids
• Hepatoportal sclerosis
  • Chronic
  • Idiopathic (autoimmune?)
  • Progressive portal tract sclerosis
  • Impaired portal vein inflow
  • Myeloproliferative disorders associated with hypercoagulability
  • Peritonitis
  • Exposure to arsenicals

Impaired Blood Flow Through the Liver

Cirrhosis

Sickle cell disease

Disseminated intravascular coagulation

Eclampsia

Sickle cell crisis in liver

Passive Congestion and Centrilobular Necrosis

• Right-sided cardiac decompensation

  • Passive congestion of the liver
  • Centrilobular necrosis and perivenular fibrosis in the areas of necrosis

• Liver is slightly enlarged, tense, and cyanotic, with rounded edges

• Congestion of centrilobular sinusoids

• Centrilobular hepatocytes become atrophic

• Markedly attenuated liver cell cords

• Sustained, chronic, severe congestive heart failure → cardiac sclerosis

• Rarely bridging fibrous septa and cirrhosis develop

• Left-sided cardiac failure or shock

  • Hepatic hypoperfusion and hypoxia
  • Two areas most dependent on arterial flow, centrilobular hepatocytes and bile ducts, undergo ischemic necrosis

• Combination of left-sided hypoperfusion and right-sided retrograde congestion acts synergistically to generate centrilobular hemorrhagic necrosis

• Mottled appearance

  • hemorrhage and necrosis in the centrilobular regions, alternating with pale midzonal areas
  • nutmeg liver

http://www.pathguy.com/lectures/nutmeg3.jpg

Autopsy Pathology: A Manual and Atlas

Centrilobular hemorrhagic necrosis (nutmeg liver)

Robbins Basic Pathology

Robbins Basic Pathology

Hepatic Vein Outflow Obstruction

Hepatic Vein Thrombosis(Budd-Chiari Syndrome)

• Thrombosis one or more major hepatic veins
• Associated with
  • Myeloproliferative disorders (polycythemia vera)
  • Pregnancy
  • Postpartum state
  • Oral contraceptives
  • Paroxysmal nocturnal hemoglobinuria
  • Intra-abdominal cancers, hepatocellular carcinoma
• Liver is swollen and red-purple, with a tense capsule
• Severe centrilobular congestion and necrosis
• Centrilobular fibrosis
• Major veins may contain completely or incompletely occlusive fresh thrombi or organized adherent thrombi

Budd-Chiari syndrome. Thrombosis of the major hepatic veins has caused profound hepatic congestion.

Robbins Basic Pathology

Cholestasis and hepatic vein thrombosis (Budd-Chiari syndrome)

Autopsy Pathology: A Manual and Atlas

Sinusoidal Obstruction Syndrome

Venoocclusive disease

Toxic injury to sinusoidal endothelium

Damaged endothelial cells slough, leading to formation of thrombi that block sinusoidal flow

Endothelial damage allows red cells to spill into the space of Disse, causes proliferation of stellate cells and fibrosis of terminal branches of the hepatic vein

Sinusoidal obstruction syndrome. A central vein is occluded by cells and newly formed collagen. There is also fibrosis in the sinusoidal spaces.

Robbins Basic Pathology