Sverre Skrede

Abstract: Evidence was recently presented that an essential part of the accumulation of cholestanol in patients with cerebrotendinous xanthomatosis is due to acceleration of a novel pathway, involving 7 alpha-hydroxylated intermediates in bile acid biosynthesis as precursors (J. Clin. Invest. 1985; 75:448-456). Such intermediates accumulate in patients with cerebrotendinous xanthomatosis due to lack of the mitochondrial 26-hydroxylase involved in the major pathway for bile acid biosynthesis. The new pathway may involve the following steps: 7 alpha-hydroxycholesterol----7 alpha-hydroxy-4-cholesten-3-one----cholesta-4,6- dien-3-one----4-cholesten-3-one----cholestanol. Accurate methods have been developed for assay of 7 alpha-hydroxy-4-cholesten-3-one and cholesta-4,6-dien-3-one in serum, based on isotope dilution-mass spectrometry. The serum levels of 7 alpha-hydroxy-4-cholesten-3-one as well as those of cholesta-4,6-dien-3-one were found to be markedly elevated in the three patients with cerebrotendinous xanthomatosis. Treatment of two of the patients with chenodeoxycholic acid reduced the serum levels of the two steroids by more than 80%. The concentration of cholestanol was reduced by 72% in one patient and by 48% in the other. The possibility is discussed that accumulation of cholestanol in patients with cerebrotendinous xanthomatosis is secondary to accumulation of 7 alpha-hydroxy-4-cholesten-3-one and cholesta-4,6-dien-3-one.

Abstract: This edition has been revised to include new data on genetics, molecular biology, and the role of cellular structures on one side and the growing experience with MR patterns of less common myelin disorders on the other. In addition, chapters have been added on disorders of which the white matter involvement was previously unclear.

Abstract: Material dealing with the chemistry, biochemistry, and biological activities of oxysterols is reviewed for the period 1987-1995. Particular attention is paid to the presence of oxysterols in tissues and foods and to their physiological relevance.

Abstract: Serum cholestanol was studied in relation to fecal cholestanol excretion and cholesterol metabolism in a random middle-aged population of 61 men. The serum concentrations of cholestanol ranged from 1.6 to 10.8 mumol/L and were positively correlated with those of serum total LDL and HDL cholesterol. In terms of millimole per mole of cholesterol, these correlations disappeared; inverse associations were found with VLDL cholesterol and triglyceride levels, the P/S ratio of dietary fat, and the amount of fecal plant sterols, but not with fecal cholestanol. The serum contents of cholestanol (1) were also closely positively associated with those of serum plant sterols (campesterol and sitosterol) and fractional cholesterol absorption, (2) were inversely related to the fecal excretion of neutral sterols and cholesterol synthesis which were measured either by the sterol balance technique or serum cholesterol precursor sterols (desmosterol and lathosterol), and (3) were unrelated to bile acid synthesis. Fecal cholestanol (mean = 12.5 mg/d) was (1) clearly higher than the dietary cholestanol intake (less than 2 mg/d), (2) unrelated to serum cholestanol, and (3) positively correlated with the intestinal cholesterol (dietary plus endogenous) flux as well as fecal plant sterols, neutral sterols, and bacterial products of cholesterol. The study emphasizes that, in normal men, high serum cholestanol levels reflect high efficiency of intestinal sterol absorption and low cholesterol synthesis. Thus, the changes in the serum contents of cholestanol are parallel with those of plant sterols and opposite to those of cholesterol precursor sterols.

Abstract: Cerebrotendinous xanthomatosis (CTX) OMIM#213700 is a rare autosomal-recessive lipid storage disease caused by mutations in the CYP27A1 gene; this gene codes for the mitochondrial enzyme sterol 27-hydroxylase, which is involved in bile acid synthesis. The CYP27A1 gene is located on chromosome 2q33-qter and contains nine exons. A CYP27A1 mutation leads to decreased synthesis of bile acid, excess production of cholestanol, and consequent accumulation of cholestanol in tissues. Currently there is no consensus on the prevalence of CTX, one estimate being <5/100,000 worldwide. The prevalence of CTX due to the CYP27A1 mutation R362C alone is approximately 1/50,000 in Caucasians. Patients with CTX have an average age of 35 years at the time of diagnosis and a diagnostic delay of 16 years. Clinical signs and symptoms include adult-onset progressive neurological dysfunction (i.e., ataxia, dystonia, dementia, epilepsy, psychiatric disorders,peripheral neuropathy, and myopathy) and premature non-neurologic manifestations (i.e., tendon xanthomas, childhood-onset cataracts, infantile-onset diarrhea, premature atherosclerosis, osteoporosis, and respiratory insufficiency). Juvenile cataracts, progressive neurologic dysfunction, and mild pulmonary insufficiency are unique symptoms that distinguish CTX from other lipid storage disorders including familial dysbetalipoproteinemia, homozygous familial hypercholesterolemia, and sitosterolemia, all of which might also present with xanthomas and cardiovascular diseases. Brain magnetic resonance imaging (MRI) shows bilateral lesions in the dentate nucleus of the cerebellum and mild white matter lesions. The classical symptoms and signs, namely elevated levels of cholestanol and bile alcohols in serum and urine, brain MRI, and the mutation in the CYP27A1 gene confirm the diagnosis of CTX. Early diagnosis and long-term treatment with chenodeoxycholic acid (750 mg/d) improve neurological symptoms and contribute to a better prognosis.

Abstract: Current emphasis on cholesterol as agency if not cause of human atherosclerosis and subsequent cardiovascular disease ignores the essentiality of cholesterol in life processes. Additionally ignored is the ubiquitous presence of low levels of oxidized cholesterol derivatives (oxysterols) in human blood and select tissues, oxysterols also implicated in atherosclerosis. Whereas such oxysterols may be regarded putatively as agents injurious to the aorta, an alternative view of some of them is here proposed: that B-ring oxidized oxysterols of human blood represent past interception of blood and tissue oxidants in vivo by cholesterol as an ordinary aspect of oxygen metabolism. Such interception and subsequent efficient hepatic metabolism of oxysterols so formed, with biliary secretion and fecal excretion, constitute as in vivo antioxidant system. Whether cholesterol, oxysterols, oxidized lipoproteins, or oxidants in blood, singly or in concert, cause or exacerbate human atherosclerosis remains to be understood.