Cholestasis: pathogenesis

The pathogenesis of cholestasis with mechanical stone obstruction or stricture of the ducts is obvious. Drugs, hormones, sepsis cause damage to the cytoskeleton and the membrane of the hepatocyte.

As is known, the process of bile formation includes the following volatile transport processes:

• seizure by hepatocytes of bile components (bile acids, organic and inorganic ions);
• transfer them through the sinusoidal membrane into the hepatocytes;
• Excretion through the tubular membrane into the bile capillary.

Transport of bile components depends on the normal functioning of special protein-carriers of the sinusoidal and tubular membranes.

At the heart of the development of intrahepatic cholestasis are violations of transport mechanisms:

• violation of the synthesis of transport proteins or their functions under the influence of etiological factors;
• violation of the permeability of membranes of hepatocytes and bile duct;
• violation of tubular integrity.

With extrahepatic cholestasis, the leading role belongs to the violation of outflow of bile and increased pressure in the bile ducts.

As a result of these processes, cholestasis occurs and the components of bile are able to flow excessively into the blood.

Changes in fluidity of the membrane and the activity of Na ⁺, K ⁺ -ATPase can be accompanied by the development of cholestasis. Ethinyl estradiol reduces the fluidity of sinusoidal plasma membranes. In an experiment on rats, the effect of ethinylestradiol can be prevented by the administration of S-adenosylmethionine, a donor of the methyl group, which influences the fluidity of the membranes. Endotoxin Esherichia coli inhibits the activity of Na ⁺, K ⁺ -ATPase, apparently acting like ethinyl estradiol.

The integrity of the tubular membrane may be compromised by damage to microfilaments (responsible for tone and tubule cuts) or tight junctions. Cholestasis when exposed to phalloidin is due to the depolymerization of actin microfilaments. Chlorpromazine also affects the polymerization of actin. Cytochalasin B and androgens have a damaging effect on microfilaments, reducing the contractile ability of the tubules. The rupture of dense contacts (under the influence of estrogens and phalloidin) leads to the disappearance of the dividing barrier between hepatocytes and the direct ingress of large molecules from the bloodstream into the tubules, regurgitation of the solutes of bile into the blood. It should be noted that the same agent can influence several mechanisms of bile formation.

[1], [2], [3], [4], [5], [6], [7]

Possible cellular mechanisms of cholestasis

Lipid composition / fluidity of membranes	Change
Na +, K + -ATPase / other transport proteins	Inhibited
Cytoskeleton	Destroyed
Integrity of tubules (membranes, tight junctions)	Violated

Vesicular transport depends on microtubules, the integrity of which can be disturbed by the action of colchicine and chlorpromazine. With inadequate excretion of bile acids in the tubules or leakage from the tubules, the bile current, dependent on bile acids, is disrupted . This also contributes to the violation of enterohepatic circulation of bile acids. Cyclosporin A inhibits the ATP-dependent transport protein for the bile acids of the tubular membrane.

Changes in bile flow are observed in the defeat of ducts caused by inflammation, destruction of the epithelium, but these changes are secondary rather than primary. The role of disorders of the regulator of transmembrane conduction of ductal epithelial cells in cystic fibrosis requires further study. At primary sclerosing cholangitis, gene mutations are observed no more often than in the control group.

Some bile acids that accumulate in cholestasis can damage cells and increase cholestasis. The intake of less toxic bile acids (taurusodoseoxycholic) has a protective effect. When exposed to hepatocytes rats hydrophobic bile acids (taurohenodeoxycholic acid), formation of anoxic radicals in the mitochondria is observed. The damage to hepatocytes decreases when the tubular transport proteins move for bile acids to the basolateral membrane, as a result of which the polarity of the hepatocyte and the directionality of the transport of bile acids change, and the accumulation of bile acids in the cytoplasm is prevented.

Pathomorphology of cholestasis

Some changes are caused directly by cholestasis and depend on its duration. Morphological changes characterizing certain diseases accompanied by cholestasis are given in the relevant chapters.

Macroscopically the liver with cholestasis is enlarged, green, with a rounded edge. At later stages, nodes are seen on the surface.

When light microscopy, pronounced bilirubinostasis is observed in hepatocytes, Kupffer cells and tubules of zone 3. "pinnate" dystrophy of hepatocytes (caused, apparently, by the accumulation of bile acids), foamy cells surrounded by clusters of mononuclear cells can be detected. Necrosis of hepatocytes, regeneration and nodal hyperplasia are expressed minimally.

In the portal tracts of zone 1, the proliferation of the ductules is detected due to the mitogenic influence of bile acids. Hepatocytes are transformed into cells of bile ducts and form a basal membrane. Reabsorption of bile components by duct cells may be accompanied by the formation of microliths.

With obstruction of the bile ducts, changes in hepatocytes develop very rapidly. Signs of cholestasis appear after 36 hours. Initially, proliferation of bile ducts is observed, later fibrosis of portal tracts develops. Approximately 2 weeks later, the degree of changes in the liver no longer depends on the duration of cholestasis. Yellow lakes correspond to ruptures of interlobular bile ducts.

With ascending bacterial cholangitis, clusters of polymorphonuclear leukocytes in the bile ducts, as well as in sinusoids, are detected.

Fibrosis develops in zone 1. In resolving cholestasis, fibrosis undergoes reverse development. With the expansion of fibrosis of zone 1 and the fusion of areas of fibrosis of adjacent zones, zone 3 is located in the ring of connective tissue. The relationship between the hepatic and portal veins in the early stages of the disease has not changed, with biliary cirrhosis disrupted. Continued periductal fibrosis can lead to the irreversible disappearance of the bile ducts.

Edema and inflammation of zone 1 is associated with gall-lymphatic reflux and the formation of leukotrienes. Mallory's calves can also form here. In periportal hepatocytes, coloring with orsein reveals copper-binding protein.

HLA class I antigens are normally expressed on hepatocytes. Reports of hepatocyte expression of HLA class II antigens are contradictory. These antigens are absent on the surface of hepatocytes in healthy children, but are detected in some patients with primary sclerosing cholangitis and autoimmune liver damage.

With prolonged cholestasis, biliary cirrhosis is formed . The fields of fibrous tissue in the portal zones merge, leading to a decrease in the size of the lobules. Bridging fibrosis connects portal tracts and central areas, nodular regeneration of hepatocytes develops. With biliary obstruction, true cirrhosis is rarely formed. With complete compression of the common bile duct with a cancerous tumor of the pancreas head, patients die before nodal regeneration develops. Biliary cirrhosis associated with partial biliary obstruction is formed with strictures of the bile ducts and primary sclerosing cholangitis.

With biliary cirrhosis, the liver is larger and more saturated green than with other types of cirrhosis. Nodules on the surface of the liver are clearly delineated (do not have the form of "eaten moth"). With the resolution of cholestasis, the fibrosis of the portal zones and the accumulation of bile slowly disappear.

With electron microscopy, changes in the bile ducts are non-specific and include dilation, edema, thickening and tortuosity, loss of microvilli. Vacuolization of the Golgi apparatus, hypertrophy of the endoplasmic reticulum, proliferation of lysosomes containing copper in combination with the protein are observed. Vesicles around the tubules containing bile give the hepatocytes a "feathery" appearance with light microscopy.

All these changes are nonspecific and do not depend on the etiology of cholestasis.

Changes in other organs with cholestasis

The spleen is enlarged and compacted due to hyperplasia of the reticuloendothelial system and an increase in the number of mononuclear cells. At a late stage of cirrhosis, portal hypertension develops.

The contents of the intestine are voluminous and have a bold appearance. With total obstruction of the bile ducts discoloration of feces is observed.

Kidneys are edematous, colored with bile. In the distal tubules and collecting tubes, cylinders containing bilirubin are found. Cylinders can be abundantly infiltrated by cells, the tubular epithelium is destroyed. Expressed edema and inflammatory infiltration of connective tissue. Scar formation is not observed.

[8], [9], [10], [11], [12], [13], [14],