Although it would have been desirable to study this patient on a low-cholesterol diet as well as on his customary diet of 25 eggs per day, it was impossible to do so. Therefore, we compared his cholesterol metabolism with that of our other subjects who were being studied by the same techniques. The results explain in dramatic fashion the apparent paradox of an enormous dietary cholesterol intake and longevity to the age of 88 without clinically important atherosclerosis. The patient had extremely efficient compensatory mechanisms — namely, a marked reduction in the efficiency of cholesterol absorption, greatly increased synthesis of bile acids, and apparently reduced cholesterol synthesis relative to his cholesterol absorption.

The decrease in the efficiency of cholesterol absorption to only 18 percent of the unusually large intake played an important part in maintaining a normal plasma cholesterol level. Approximately 10,622 of the 12,953 μmol of cholesterol ingested each day passed through the patient's gastrointestinal tract to be excreted in the feces. Although he still absorbed 2331 μmol of cholesterol per day (2032 and 941 μmol per day more than the mean amount absorbed by the normal subjects during the low- and high-cholesterol diets, respectively), he compensated further, primarily by doubling the usual rate of bile-acid synthesis.

Cholesterol absorption is a complex process involving a number of steps. Although the rate-limiting step is not known with certainty, it is currently believed to be the transport of micellar free cholesterol from the intestinal lumen through the unstirred water layer20 and, in molecular form, across the cell membrane of the enterocyte. This has classically been thought to occur by passive diffusion, but several studies21 , 22 suggest a role for an as yet unidentified brush-border protein. The other processes — luminal hydrolysis of dietary cholesterol esters, reesterification in the enterocyte, incorporation into chylomicrons and intestinal very-low-density lipoprotein cholesterol, and transport in the lymph — are not normally rate-limiting. The efficiency of cholesterol absorption in animal species ranges from 35 to 85 percent23 and is usually 50 to 60 percent in humans over a wide range of dietary intake.4 Decreased absorption in the presence of increased dietary cholesterol serves as a major control mechanism in cholesterol homeostasis,15 but there is a great individual heterogeneity.3 In this patient it was extraordinarily effective. Since it is likely that much of the reduction in the efficiency of absorption is simply due to the physical barrier to diffusion of micelles, reduced absorption cannot be considered a regulatory process. On the other hand, the additional down-regulation of a putative brush-border transport protein by excess cholesterol cannot be excluded.

The rate of sterol synthesis by peripheral-blood mononuclear leukocytes (primarily monocytes) accurately reflects hepatic and whole-body synthesis of cholesterol.5 , 24 25 26 Physiologic and metabolic perturbations that increase or decrease hepatic cholesterol synthesis have similar effects on the synthesis of sterols by these cells. Cholesterol biosynthesis by the liver and other cells is down-regulated by the uptake of both chylomicron remnants and LDL cholesterol, probably mediated at least in part by endogenous synthesis of hydroxylated sterols, such as 25-hydroxy cholesterol, which are byproducts of cholesterol biosynthesis that inhibit the activity of hydroxymethylglutaryl-CoA reductase,27 the rate-limiting enzyme of cholesterol synthesis. The finding of a rate of cholesterol synthesis in this patient that was equal to the mean synthesis rate in the normal subjects ingesting the high-cholesterol diet is surprising, since other studies suggest that inhibition of synthesis can have a more prominent regulatory role in response to dietary cholesterol.28 , 29 It may, however, reflect the fact that the patient absorbed only 941 μmol of cholesterol more than the normal subjects did during the period of high cholesterol intake and converted about 750 μmol of that to bile acids.

The rate of bile-acid synthesis in the patient was greater than in any of the 200 subjects we have studied during the past 13 years, and it was a major compensatory response. An increase in the excretion of bile acids in some subjects on a high-cholesterol diet has been well documented in balance studies,28 but bile-acid synthesis itself has not often been measured. It is of interest that persons with the same apolipoprotein E phenotype (E 2/2 , E 2/3 , E 2/4 ) have diminished cholesterol absorption and increased synthesis of bile acids.30 In rats, some studies suggest that the availability of substrate, microsomal cholesterol, is a major regulator of the rate-limiting enzyme cholesterol 7α-hydroxylase.31 Since the conversion of cholesterol to bile acids accounts for approximately 70 percent of the cholesterol disposed of daily,32 increased bile-acid synthesis is clearly a major means of maintaining cholesterol homeostasis.

It was not possible in our patient to measure biliary cholesterol secretion, a procedure requiring 8 to 10 hours of nasoduodenal intubation, but in view of the greatly expanded bile-acid pool circulating through the patient's liver and the known regulation of biliary cholesterol secretion by the secretion of bile acids, it is very likely that biliary cholesterol secretion was similarly increased. As we found in a recent study, however, when the secretion of bile acids is increased by increasing dietary cholesterol, cholesterol secretion often increases proportionately, and supersaturated bile, a precursor of cholesterol gallstones, is not secreted.18

In summary, most of the physiologic processes involved in cholesterol balance and in maintaining a normal plasma cholesterol level were studied in an unusual patient, an 88-year-old man who for psychological reasons had eaten about 25 eggs per day, in addition to regular meals, for many years. His almost complete freedom from clinically important atherosclerosis and its complications may be explained in part by a great reduction in the efficiency of cholesterol absorption from the intestine and by a marked increase in the conversion of cholesterol to bile acids. In addition, his cholesterol synthesis was probably reduced moderately, and his biliary cholesterol secretion may have been increased. These physiologic adaptations would leave little if any of the dietary cholesterol to elevate plasma cholesterol levels and be deposited in arterial walls.