Kupffer cell

**Location/histology:** Kupffer cells sit within the lumen of the hepatic sinusoids (zone 1/periportal enrichment), attached to the endothelium. They are separate from the space of Disse, which contains hepatic stellate (Ito) cells. They derive mainly from embryonic yolk-sac/fetal liver progenitors and self-renew, with some replenishment from circulating monocytes during injury.

**Functions:** - Phagocytosis of gut-derived bacteria and endotoxin delivered by the portal vein. Gut bacteria and LPS are cleared on first pass. - Clearance of senescent or damaged RBCs (with the splenic red pulp macrophages). They recycle heme to bilirubin and iron to ferritin/hemosiderin. - Antigen presentation (MHC II) and cytokine release (TNF-α, IL-1, IL-6, IL-12). They also release ROS and prostaglandins. - Clearance of immune complexes and debris. - Immune tolerance to portal antigens (IL-10, TGF-β).

**Pathophysiology/clinical significance:** - **Alcoholic and non-alcoholic steatohepatitis:** Gut-derived LPS binds TLR4/CD14 on Kupffer cells, which release TNF-α, IL-1, and ROS. This causes inflammation and hepatocyte injury. - **Fibrosis/cirrhosis:** Kupffer cell TGF-β and PDGF activate hepatic stellate cells (Ito cells), which lay down collagen. This is the key pathway to fibrosis. - **Viral hepatitis:** They contribute to inflammation, antigen presentation, and cytokine signaling. - **Infection clearance:** Kupffer cells capture blood-borne pathogens such as *Listeria*, *Salmonella*, and *Plasmodium* sporozoites and merozoites. Their clearance of pathogens is a major protection against bacteremia. Impaired function (e.g., cirrhosis) increases the risk of bacteremia and SBP. - **Storage/granulomatous disease:** They are involved in Gaucher disease (macrophages with glucocerebroside accumulation, "crumpled tissue paper" appearance), though the classic Gaucher cell is more prominent in spleen and marrow. They are also involved in sarcoidosis and other granulomas. - **Hemochromatosis/hemosiderosis:** Iron is deposited in hepatocytes in hereditary hemochromatosis, but in Kupffer cells in secondary iron overload (e.g., transfusions). - **Drug-induced injury:** Acetaminophen toxicity and other hepatotoxins can activate them.

**High-yield board points:** - Kupffer cell = liver macrophage (the "macrophage" of the liver; microglia in CNS, osteoclasts in bone, alveolar macrophages in lung, histiocytes in connective tissue, Langerhans cells in skin, mesangial cells in kidney). - Do not confuse them with stellate (Ito) cells (vitamin A storage, fibrosis) or sinusoidal endothelial cells (fenestrated, no basement membrane). - Stain: Positive for CD68 and CD14. Highlight them with PAS-diastase in some storage diseases and with Prussian blue for iron. - The liver contains the largest population of tissue macrophages in the body.