Cholesterol

DISPOSAL OF CHOLESTEROL

The cholesterol from atherosclerotic plaques is carried to the liver by macrophages and by binding to blood protein. The liver parenchymal cells dispose of the lipid by excretion into the biliary tract. Fig 1 (b) demonstrates modest lipid deposit in hepatic parenchymal cells together with lipid stained cholelithiasis. In scurvy the biliry system cannot handle the load (1), and the entire liver fills with lipid as in Fig (a).

Ginter et al (2) have shown that the activity of the cholesterol 7 alpha-hydroxylating system containing cyto-chrome P-450 is depressed in the liver of guinea pigs with chronic marginal scurvy. The slowing down of this rate-limiting reaction of cholesterol transformation to bile acids causes many of the phenomena associated with atherosclerosis. These include accumulation of cholesterol in the liver, blood plasma, and arteries, increase in the index total:HDL cholesterol, prolongation of plasma cholesterol half-life, increase in the cholesterol:bile acids in the gall bladder bile, cholesterol gall stone formation and coronary atherosclerosis in guinea pigs with long lasting marginal ascorbic acid deficiency.

In scurvy, retardation of the reaction of cholesterol to bile salts results in an accumulation of excess cholesterol in the liver, and a deficiency of the bile salts needed to suspend it in bile. The consequence is cholelithiasis. Ginter et al (2) conclude ‘The most effective means for preventing these changes are vitamin C doses that ensure maximal steady-state levels of ascorbate in the tissues.’

The pathology of liver disease of scurvy was reported in detail in 1957 (1), as was the rapid resorption of lipid with ascorbic acid replacement. There was a consistent association with cholesterol biliary calculi, Fig 1 (b), and biliary sludge. Occasionally there were patches of hepatic necrosis Fig 2 (a), suggesting another mechanism apart from biliary obstruction. The fatty deposit in hepatocytes of scurvy is attributed to biochemical impairment of the reaction cholesterol to bile salt, which in turn, causes failure to suspend cholesterol in the bile; cholelithiasis results.

Conclusion #1: When cholesterol laden macrophages, or other means of lipid transport, deliver cholesterol to the scorbutic liver they overload the capacity of the hepatocytes to excrete the lipid in the bile. Biliary obstruction at a biochemical level precipitates cholesterol calculi and sludge within the liver, making the obstruction mechanical. The biochemical obstruction has been identified by Ginter et al as depressed activity of the cholesterol 7 alpha-hydroxylating system. This biliary obstruction is remedied by ascorbic acid replacement. Additional disruption of liver function in scurvy is suggested by the occasional finding of hepatic necrosis, something not usually caused by biliary obstruction.

As noted in the discussion of the ground substance, ascorbic acid deficiency, besides affecting cholesterol metabolism, also seriously deranges collagen. This is a morphological hall-mark consistently associated with scurvy. There are other reasons for fatty liver apart from scurvy; were it not for the association of the characteristic damage to the hepatic reticulum scurvy produces, it would be difficult or impossible to morphologically distinguish the contribution, if any, of scurvy to these other instances of fatty liver. Fig 3 (a) shows normal hepatic reticulum in the guinea pig, while Fig 3 (b) shows the fragmenting effect upon it of ascorbic acid deprivation. This disintegration is not restored to normal with ascorbic acid replacement, thus making reticular disintegration a permanent marker of hepatic scurvy, past or present (1).

The healing of post- necrotic scarring of the liver, whatever its cause, is followed by fibroblastic scar formation. The reticulum involved in scar has the appearance of matted hair. Fig 3 (b) shows this reticulum scar following ascorbic acid treatment of patchy scurvy- induced hepatic necrosis such as in Fig 3 (a). Ascorbic acid is unable to restore the original architecture. When post-necrotic scarring is related to ascorbic acid depletion, the rest of the reticulum will show the tell-tale reticulum disintegration of scurvy. If this disintegration of reticulum has not occurred, the post-necrotic scarring in question is not ascorbic acid related. The role of hepatic reticulum in the metabolism of cholesterol per se is obscure, and perhaps irrelevant. However as a marker that scurvy has been involved in the pathogenesis of a given case of liver disease, it has major importance.

Conclusion #2: The presence of disintegration of the hepatic reticulum in liver disease identifies ascorbic acid depletion as important in that particular hepatic pathology. This is a permanent marker, not lost when ascorbic acid is replaced. If post-necrotic scarring or fatty infiltration of the liver is not accompanied by the typical reticular disintegration shown in Fig 2 (b), there is no morphological evidence that the lesions are scurvy related.

REFERENCES

1. Willis, G.C., C.M.A.J., 76: 10, 1957

2. Ginter, E., et al, International Journal for Vitamin and Nutritional Research- Supplement 1982; 23: 137-52.

Fig 1. The liver of a guinea pig with acute scurvy. Note the hepatocytes are filled with stainable lipid. (b) Less filling of hepatocytes with lipid in another scorbutic guinea pig allows visualization of a cholesterol calculus in a bile canaliculus.

Fig 2 (a) shows hepatic necrosis in a scorbutic guinea pig. Fig 2 (b) is the reticulum staining of the same area demonstrating the typical matted hair formation of the reticulum produced by fibroblasts in the scars.

Fig 3 (a) The reticulum of a normal guinea pig liver has this architecture; its fibres are not disintegrated. Fig 3 (b) shows the typical disintegration of the hepatic reticulum in scurvy.

Fig 4 This matted hair appearance of the hepatic reticulum is what is found in all forms of post-necrotic scarring of the liver. The critical feature that declares ascorbic acid depletion to be the cause in a specific case of hepatic necrosis is the presence also of disintegration, as in 3 (b), in the rest of the hepatic reticulum.