Detailed Mechansims Of Liver Injury

DETAILED MECHANSIMS OF LIVER INJURY Causes of liver injury • Infections o Hepatotropic viruses o Other viruses e.g. CMV, EBV o Other infections – bacteria, fungi, parasites • Immune mediated o Autoimmunity o Transplant rejection o Graft versus host disease • Drugs, ingested toxins • Metabolic abnormalities o Inherited o Acquired • Obstruction to bile flow • Vascular alterations/disorders • Environmental exposure o Toxins o Heat stroke • Trauma Basic pathologic processes • Inflammation • Hepatocellular injury o Sublethal • • • • • o Cell death Bile duct injury Regeneration Fibrosis Vascular remodelling Cirrhosis Inflammation • Innate immune system o Kupffer cells and dendritic cells o NK cells and NKT cells • Adaptive immune system o Various T-lymphocyte subtypes ▪ CD4+ T-helper cells ▪ CD8+ cytotoxic T-cells ▪ Regulatory T cells (T-regs) o B-lymphocytes – plasma cells • Aberrant expression of antigens on native liver cells via class I and class II MHC antigens o Hepatocytes e.g. viral components, cell components altered by alcohol Morphologic patterns of inflammation • Parenchymal (lobular) accumulation o Focal (spotty) or diffuse sinusoidal infiltrates • Portal tract inflammatory cell infiltrates o Interface hepatitis – disrupting the limiting plate (interface between portal tract stroma and hepatocytes) o Surrounding +/- infiltrating the bile duct (ductocentric) • Granulomas → collections of large activated histiocytes (‘epithelioid’ cells) • Localized acute inflammation within the liver → abscess Hepatocellular injury morphology • Steatosis: accumulation of TAGs as droplets within cytoplasm o Macrovesicular → vesicles are large enough to distort the nucleus o Microvesicular • Ballooning degeneration – cell swelling, loss of structure, clumping of cytoplasmic filaments, mitochondrial swelling • Mallory-Denk bodies – condensed clumps of cell components Hepatocyte death • Apoptosis – active cell death induced by T-cells with cell degradation • Necrosis – drop out of single cell or larger groups of cells (confluent necrosis) • Confluent necrosis: o Periportal confluent necrosis o Perivenular necrosis (around central vein) o Bridging necrosis o Linking of portal tracts and central veins o Panacinar and multiacinar necrosis o Submassive necrosis Fibrosis • Patterns of fibrosis o Portal/periportal o Zone 3/perivenular – perisinusoidal/pericellular o Bridging – ‘septa’ connecting portal tracts to portal tracts and to terminal hepatic venules Regeneration • Liver is stable in adulthood (doesn’t degenerate naturally) • Following injury or surgical resection it converts to proliferative state • Reserve capacity • Potential to replace 75% of its mass in 6 months • Replication possible by: o Hepatocytes – replace single cells or small groups o Cholangiocytes o Mesenchymal cells o Stem cells after large losses → ductular reaction Patterns of liver disease/injury (1) • Acute hepatitis • Submassive hepatic necrosis/fulminant hepatitis • Chronic hepatitis • Cholestatic/bile duct diseases • Fatty liver disease → steatosis/steatohepatitis – alcoholic liver disease, NAFLD, NASH • Granulomatous hepatitis/suppuration/unusual infections • Vascular abnormalities – zone 3 necrosis, veno-occlusive lesions, thrombus Patterns of liver disease/injury (2) • Metabolic/overload → accumulation of iron, copper, alpha-1-antitrysin etc. • Cirrhosis → end stage of liver disease • Neoplasms (tumours) and nodules • Malformations Pathologic disease patterns • Somewhat characteristic histologic patterns but with overlap between categories e.g. Chronic hepatitis and cholestatic disease, steatosis prominent in some hepatitis C • Correlate with a relatively limited range of specific diseases or insults (flare up) • Some types of injury/disease may manifest a range of different patterns at different times, in different people → drug reaction may have a range of patterns (acute hepatitis, confluent necrosis, steatohepatitis, cholestatic disease, chronic hepatitis) • Liver is subject to many insults → more than one disease with different patterns may be present at the same time Acute hepatitis • Clinically defined as a significant increase in serum ALT &/or AST (2x N limit) in a patient with no history of liver disease o No markers of cholestatic injury (Alk phos, GGT) • Often asymptomatic but may have flu-like symptoms, jaundice, fatigue, nausea • Workup includes viral hepatitis serology (A,B,C,D,E), autoimmune hepatitis serology, drug and toxin history • Biopsy not usually necessary o Used when there is ssuspicion of a second independent process ▪ Underlying chronic liver disease ▪ Immunocompromised patients → unusual infections are likely and biopsies are used to determine degree of hepatocyte necrosis Histopathologic pattern of acute hepatitis • Lobular disarray o Hepatocyte ballooning o Lobular and sinusoidal inflammatory cell infiltrates → diffuse, mostly lymphocytes, with or without plasma cells (AIH, hep A) o Scattered apoptotic bodies o Kupffer cell hyperplasia o Foci of hepatocyte dropout o Sometimes more confluent or bridging necrosis • Variable, often minor portal tract inflammatory cell infiltrate • No portal tract fibrosis • More limited range of diseases cause this pattern than fall within the clinical definition: o Acute hepatitis C (HCV) o Acute hepatitis B (HBV) o Acute hepatitis A (HAV) o Acute hepatitis E (HEV) o Autoimmune hepatitis (AIH) o Drug, herbal remedy or toxin induced hepatitis o Wilson’s disease – copper overload Fulminant hepatitis and acute liver failure • Most common causes of acute liver failure o Acute fulminant HAV o Acute fulminant HBV o Acute fulminant autoimmune hepatitis o Drug or toxin o Ischaemia (portal vein, hepatic vein obstruction) o Wilson’s disease (copper overload) o Idiopathic • Others are rare: HCV, other viruses including herpes virus, adenovirus, massive tumour infiltration Submassive necrosis • Acute necrosis across multiple confluent lobules o Loss of hepatocytes o Large amount of inflammatory cell infiltrates including macrophages o Large bile ductular reaction • Acute necrosis >30-40% suggests liver may not be recoverable • Possible outcomes = death, transplant, recovery to normal liver or recovery with fibrosis and regenerative nodules (post necrotic cirrhosis)