Invited commentary: Low cholesterol and nonatherosclerotic disease risk: Apersistently perplexing question

In contrast to clinical trials using statin drugs, which suggest that chole sterol lowering from high to moderate levels is safe, many, but not all, pr ospective studies report higher nonatherosclerotic disease rates in people with low serum total cholesterol, even after deleting deaths in the 5 years after cholesterol determination. A perplexing and unanswered question is w hether low cholesterol is causally related to nonatherosclerotic disease ri sk. Cholesterol is reduced during the acute phase reaction; a stale of immu ne activation that persists for more than 5 years may explain the prospecti ve observations. Higher cholesterol may be a marker for other protective su bstances such as fat-soluble antioxidants. Low cholesterol might mark poor nutrition, for example, during depression. Alternatively, higher cholestero l levels may result in enhanced delivery of lipids to cells during the immu ne response or tissue repair or may enhance defense against endotoxins and viruses. Although we believe that populationwide efforts to lower cholester ol should continue, we think that important biology may be reflected in the repeatedly observed associations of low cholesterol with nonatheroscleroti c disease, The authors urge that research continue to elucidate any biologi c bases of these relations.