Roger J. Williams

Multisystem involvement in chronic liver disease: Studies on the incidence and pathogenesis

Abstract Sjogrens syndrome occurred in 37 per cent, renal tubular acidosis in 32 per cent, pulmonary diffusion defects in 26 per cent and peripheral neuropathy in 10 per cent of patients with active chronic hepatitis, primary biliary cirrhosis or cryptogenic cirrhosis. The incidence of certain other conditions determined from clinical features alone was lower; these included arthropathy in 14 per cent, thyroid disorders in 10 per cent, skin lesions in 17 per cent and colitis in 5 per cent. In the complete series of 218 patients, 125 (57 per cent) had involvement of at least one organ other than the liver, such involvement being significantly more common in those with active chronic hepatitis (63 per cent of cases) and primary biliary cirrhosis (68 per cent) than in those with cryptogenic cirrhosis (38 per cent). In a number of patients, prednisone therapy was followed by both subjective and objective improvement in the features of the multisystem involvement. No correlation could be found between multisystem involvement and the presence of mitochondrial, smooth muscle or antinuclear antibodies in the serum or with the serum levels of immunoglobulins A (IgA), M (IgM) and G (IgG). Histologie examination of the various organs disclosed dense infiltration with small lymphocytes, suggesting that delayed hypersensitivity reactions were involved in the production of tissue damage. In support of this was the demonstration of cell-mediated reactivity in vitro to salivary or renal antigens in 42 per cent of the patients with Sjogrens syndrome and in 62 per cent of those with renal tubular acidosis, respectively. These findings, together with the frequency and similar pattern of multisystem involvement in the three conditions, suggest a common pathogenetic mechanism, and disordered cellular immune reactions directed primarily against the liver could affect other organs as a result of cross antigenicity.

Observations on the pathogenesis, complications and treatment of diabetes in 115 cases of haemochromatosis

Abstract The findings in 115 patients with idiopathic haemochromatosis seen personally by us have been analysed, with particular reference to the incidence, pathogenesis and effects of the diabetes. Clinical diabetes developed in seventy-two patients (63 per cent). The previously held view that the complications of diabetes are rare in haemochromatosis was not supported. Nephropathy, neuropathy and peripheral vascular disease, either singly or together, were found in nine patients (22 per cent). A similar number showed a mild retinopathy with microaneurysms or exudates or both. Unusual features of the diabetes were the frequency of insulin resistance, which occurred in five patients shortly after diagnosis, and the high incidence of insulin fat atrophy. A family history of diabetes was more common in the diabetic group—25 per cent had a first degree relative with diabetes as compared with 4 per cent in the nondiabetic group. An abnormal oral glucose tolerance test was found in one third of the patients without clinical diabetes; in some of them who were further examined by an intravenous glucose tolerance test, elevated serum insulin levels were also found. Such changes, indicative of insulin insensitivity, are described in varieties of cirrhosis not due to iron overload and are also associated with an increased incidence of diabetes. Thus the presence of cirrhosis, a family history of diabetes and direct damage to the pancreas by iron deposition may all be involved in the development of diabetes in haemochromatosis. This might explain why only some of the patients (40 per cent in this series) with diabetes showed improvement in carbohydrate tolerance following venesection therapy.

Distribution of Adiponectin, Leptin, and Metabolic Correlates of Insulin Resistance: A Longitudinal Study in British Children. 1. Prepuberty (EarlyBird 15)

BACKGROUND The emergence of type 2 diabetes in young populations has mirrored a rising prevalence of obesity and insulin resistance during childhood and adolescence. At the same time, the role of adipokines as links between obesity and insulin resistance is becoming more appreciated. We sought to establish age- and sex-specific distributions of metabolic correlates of insulin resistance in healthy prepubertal children. METHODS We collected fasting blood samples from a contemporary cohort of 307 British children at ages 5, 6, 7, and 8 years and measured insulin, glucose, triglycerides, total and HDL cholesterol, urate, glycohemoglobin, sex hormone-binding globulin (SHBG), leptin, and adiponectin. We used homeostasis model assessment (HOMA 2) to estimate insulin sensitivity (HOMA-%S) and beta-cell function (HOMA-%B). Anthropometric measures included body mass index. RESULTS Body mass index increased from age 5 to 8 years (P < 0.001). HOMA-%B decreased (P < 0.001) and HOMA-%S increased (P < 0.05), but glucose also increased (P < 0.001) whereas glycohemoglobin decreased (P < 0.001). Consistent with the rise in insulin sensitivity, HDL cholesterol increased (P < 0.001) and triglycerides decreased (NS), whereas adiponectin decreased (P = 0.02). The patterns were similar in boys and girls, although girls were less insulin sensitive throughout. Accordingly, triglycerides tended to be higher in the girls, and HDL cholesterol and SHBG lower. CONCLUSIONS The metabolic disturbances associated with insulin resistance appear to be more advanced in girls. Markers of metabolic health improve in both sexes from 5 to 8 years, despite rising adiposity.

Urinary amino acids, creatinine and phosphate in muscular dystrophy.

Abstract 1. 1. A study has been made on urinary levels of creatinine, phosphate, glycine, alanine, serine, threonine, valine, leucine, taurine, citrulline, and arginine in a group of young males with muscular dystrophy and a group of young normal males. 2. 2. Threonine, valine, leucine, arginine, and taurine levels in urine have been found to be higher in muscular dystrophy. 3. 3. Creatinine and phosphate have been found to be excreted in smaller quantities in muscular dystrophy. 4. 4. Intra- and inter-individual differences seem to occur in the excretion of all substances studied. The intra-individual variations are almost never as wide as the inter-individual variations. 5. 5. It is proposed that a dietary supplement containing vitamins E, B 12 and folic acid, the sulfur amino acids, arginine, and glycine, with or without other factors, be tested for its efficacy in alleviating the metabolic difficulties in muscular dystrophy.

The significance of the vitamin content of tissues.

Publisher Summary This chapter presents a rather broad view of the problem of vitamin distribution, particularly in animal tissues, which will be suggestive of additional research. A thoughtful study of the data under consideration leads one to realize how manifold the problems related to vitamins are, and how many questions of a fundamental nature are as yet unanswered. One is led to appreciate how fragmentary, inexact, and speculative our knowledge is as to the fundamental roles played by different tissues and organs of the body. It would not be an overstatement to say that vitamin research has the capability of revolutionizing the science of physiology and enriching it in every department. Vitamins may be regarded, from the standpoint of physiology, simply as a miscellaneous and heterogeneous collection of indispensable tissue constituents, which were discovered by nutritional investigation. It took nutritional investigation using guinea pigs and dogs to point the way toward two new constituents of rat tissues, which are of outstanding physiological significance for the rat—namely, ascorbic acid and nicotinamide. Nutritional investigations of yeasts and bacteria have led to the recognition of other highly significant constituents of animal tissues: pantothenic acid, biotin, inositol, p-aminobenzoic acid and folk acid.

Effects of converting enzyme inhibitor on hepatic blood flow in man

The acute effects of the oral angiotension converting enzyme inhibitor captopril on hepatic blood flow and systemic hemodynamics were studied in six patients with essential hypertension. Mean arterial pressure decreased from 141.9 +/- 6.9 mm Hg to 130.2 +/- 6.7 mm Hg (p less than 0.05) one hour after the administration of captopril. There was no significant change in other hemodynamic values, but hepatic blood flow decreased uniformly from 1,127 +/- 115 ml per minute to 841 +/- 93 ml per minute (p less than 0.001).

Effect of Pantothenic Acid on the Longevity of Mice

Summary 1) Thirty-three young male and female C-57 black mice were given approximately 300 μg of calcium pantothenate daily in drinking water. Forty-one control mice did not receive the vitamin supplement. 2) The mean life span for the mice given supplementary calcium pantothenate was 653.1 days and that for the control mice was 549.8 days. The statistical difference between the 2 groups is P = 0.05 (T test) 0.01 (U test). 3) The mice which received the vitamin supplement maintained slightly greater body weight after they were approximately 250 days old.

Pantothenic acid content of animal tissues.

Evidence has been presented 1 for the existence in all types of living tissue of a substance which has been named “pantothenic acid”. A quantitative biological test based upon yeast growth which is specific for this substance has been developed. While marked progress has been made in this laboratory in concentrating and purifying the acid it is unlikely that any chemical method for its determination can be devised for some time to come. In order to learn something of its functions, however, it seemed desirable to obtain approximate information as to the content of various animal tissues. Each of the tissues indicated below was thoroughly ground and extracted with a large volume of hot water, usually 100 times its weight. The pantothenic acid which is not “bound” in the tissues is thus extracted, and that which in some cases, at least, is “bound” is not determined. The numerical values are based upon the pantothenic acid extracted from a unit weight of moist tissue, in comparison with that in a unit weight of an arbitrary standard preparation. This “standard” was prepared by extracting rice bran with 60% methanol and evaporating to dryness. Our most potent concentrate is approximately 8,000 times as effective on a weight basis as this standard. Duplicate or triplicate determinations were made in every case. These usually agreed within about 10%. In order to save space, only averages are given: Skeletal muscle dog No. 1, 0.032, dog No. 2, 0.037, rat, fresh, 0.034, rat autolyzed at 37°, 0.147; smooth muscle, dog, 0.033; heart muscle, dog No. 1, 0.032, dog No. 2, 0.020, sheep 0.053; skin, dog, 0.007; blood vessel, dog, 0.0012; duodenum, dog, 0.020 stomach, antrum, dog, 0.008 fundus, dog, 0.008; lymph gland, dog, 0.011; blood, dog, 0.0021; human, 0.005; spleen, dog, 0.01, ovary, dog, 0.004, testis, dog 0.014, cockerel, 0.09; liver, dog No. 1, not taken at once, 0.153 dog No. 2 (placed in methanol immediately), 0.008, sheep (few hours after butchering), 0.09, same allowed to autolyze at 37°, 0.30, rat taken immediately, 0.036, same in ice box 3 days, 0.20, same autolyzed at 37°, 0.45; human (autopsy), 0.07, cancerous portion, 0.0045, cockerel, not taken at once, 0.19; adrenal, dog, 0.046, beef, 0.058, cortex, beef, 0.063; kidney, dog, 0.036, lung, dog, 0.007; pituitary, whole, dog, 0.027, post, beef, 0.026, ant. beef, 0.025; brain, whole, dog No. 1, 0.081, rat, taken immediately, 0.036, same in ice box 3 days 0.062, sheep, few hours after butchering, 0.054, grey matter, dog No. 2, 0.08, white matter, 0.067; umbilical cord, human, 0.005; thyroid, dog No. 1, 0.013, dog No. 2, 0.008; pancreas dog No. 1, 0.040, dog No. 2, 0.027; fatty tissue, dog, 0.0014.

Microbiological Determination of Amino Acids. IV. Lysine, Histidine, Arginine, and Valine

Summary A method of assay for histidine and lysine employing Leuconostoc mesenteroides as test organism has been developed. This method is compared with those of Dunn et al. 4 5 A method of assay similar to that of Stokes et al. 6 for lysine, arginine, and valine using Streptococcus faecalis as test organism has been independently developed and studied. With few exceptions, the data reported agree closely with those obtained by previous investigators with microbiological or isotope dilution methods.

THE GENETOTROPHIC CONCEPT—NUTRITIONAL DEFICIENCIES AND ALCOHOLISM

A full appreciation of the general and far-reaching significance of the genetotrophic concept1’ requires that we recast, if not revolutionize, our ideas regarding how we should use statistical methods in our attempts to solve biological and human problems. The revolutionary point of view which enters into this concept is in line with the current opinion of geneticists that every genotype determines its “norm of reaction” to the environment3 and that no species can adequately be described in terms of a type specimen. It is also in accord with the idea of partial genetic blocks4, which recent evidence has indicated to be the rule rather than the exceptioa6 In the areas of physiology, psychology, biochemistry, and medicine, as well as in philosophy and the social sciences, we have built into our thinking the concept of the normal man whom we regard as of paramount importance. We have set it as our supreme task to understand how this hypothetical creature functions. In the field of animal biology, the rat, the guinea pig, or the salamander, etc., become the center of our attention. This is the view which is incompatible with the genetotrophic concept. Biological variability is recognized by the biological fraternity as a more or less necessary evil. When it is extreme, it makes very difficult the establishment of norms. However, by proper statistical treatment, its effects are smoothed out and we are, as it were, back on the right track again. The tacit assumption is made that the normal man is normal through and through, and that abnormalities are to be observed only in those who belong in the category of the “abnormals.” This assumption is manifestly false, as will be made clear in our discussion. Nevertheless, it is commonly accepted and underlies the firmly intrenched idea of the normal man (or rat or guinea pig) which appears to be a guiding concept for most monographs, advanced books, and research publications in all of the areas of biological science. This attitude, which centers its attention on those supposed individuals whose attributes always lie within the normal range, is based in part upon another idea which is firmly intrenched in much biological thinking, namely that, on the microscopic level, “the cell” is the center of our interest. If, we say, we can ascertain how “the cell” is constructed and how it works, we will have gone a long way toward understanding biology. The fundamental reason why we construct “the normal man” in our minds is so we can develop generalizations, which in a sense are the essence of science. Scientific progress in the area of biology as well as in other areas may be measured in terms of the number and scope of valid generalizations which exist; the more far-reaching the generalizations, Ihe more advanced the science. It is my broad thesis, however, that biological variability in the human