Reversal of a skeletal myopathy with selenium supplementation in a patient on home parenteral nutrition

CLINICAL

SHORT

NUTRITION (1987) 6: 17%183 c Longman Group UK Ltd

PAPER

Reversal of a Skeletal Myopathy with Selenium Supplementation in a Patient on Home Parenteral Nutrition P. I. Mansell*,J. Rawlings *, S. P. Allison*, A. Shenkint, G. Compton$, S. Beck$ and E. J. Basseys *Department of Medicine, University Hospital, Nottingham. t Department of Biochemistry, Royal Infirmary, Glasgow. $ Department of Life Science, Trent Polytechnic, Nottingham. § Department of Physiology & Pharmacology, Queen’s Mecical (Reprint requests to P.I.M.)

Centre,

Nottingham.

There is evidence that selenium deficiency is associated with a fatal specific heart ABSTRACT muscle disorder and with a reversible skeletal myopathy. This paper describes a man who became selenium deficient after several years of intractable malabsorption and 15 months of parenteral nutrition at home. Clinically, he developed muscular weakness and tenderness without evidence of heart disease; deficiencies other than selenium were excluded. The patient’s muscle strength was measured at weekly intervals by hand-grip dynamometry and by a technique involving voluntary and electrically-stimulated abduction of the right index finger. With selenium repletion, the patient’s strength improved with a two-fold increase in force during an involuntary muscle contraction. The patient’s complaint of muscle pain resolved. This study provides further information concerning the essential role of selenium in human nutrition.

INTRODUCTION

1983 he underwent a right hemicolectomy for caecal volvulus. He presented again in March 1984 with small bowel obstruction which was managed conservatively including a 2-month period of intravenous nutrition. A second jejunal biopsy confirmed the histology to be consistent with coeliac disease. A further episode of obstruction ensued necessitating surgical division of adhesions around the ileum. There was no evidence of lymphoma at laparotomy. A further attempt at enteral nutrition merely induced diarrhoea and weight loss. In August 1984 he began permanent home-based total parenteral nutrition (TPN) and this has proved largely successful. In addition to TPN, he takes a small (maximum 400 kcal) amount of food orally on some days. In the summer of 1985 he began to complain of muscle weakness and discomfort, particularly in his thighs.

It has only recently been established that the element selenium has an essential role in human nutrition [l]. Selenium deficiency is associated with a specific heart muscle disease and, seemingly independently, a skeletal myopathy. Little is known about the pathology of these two conditions. This paper concerns a man with severe malabsorption maintained on long-term parenteral nutrition who developed a moderate degree of muscle weakness,

fatigue and myalgia was suspected.

THE

and in whom

selenium

deficiency

PATIENT

A man aged 46 years with a 7-year history of severe malabsorption was referred to the Nutrition Unit, University Hospital, Nottingham in 1984 with a view to parenteral nutrition. Coeliac disease was initially diagnosed by jejunal biopsy but proved unresponseive to a gluten-free diet. A low-fat diet, prednisolone, azathioprine and pancreatic supplements were added in turn but even with various combinations of these therapies, the malabsorption was only partly alleviated. In May 179

METHODS The daily TPN regime consisted of 1500ml Vamin* glucose, 500ml 50% dextrose, 1 vial Addamela, 1 vial Solvito@ and additional sodium, potassium and phosphate. To this was added, on 3 days of the week, 500 ml Intralipidm 20% and 1 vial Vitlipide, and on the remaining 4 days 500 ml of glucose 20s~. This regimen

180

REVERSAL OF A SKELETAL MYOPATHY

WITH SELENIUM SUPPLEMENTATION

provided daily a volume of 2500 ml; 2600 kcal (3 days per week) or 2000 kcal (4 days per week); 14.1 g nitro125 mm01 sodium; 102 mm01 potassium; gen; 8.75 mm01 calcium; 3.75 mm01 magnesium; 20mmol phosphate and 20umol zinc, and met or exceeded the daily requirement for manganese, fluorine and iodine. The iron and zinc content were perhaps sub-optimal. Parenteral nutrition fluids have been shown to contain only a trace of, or no detectable selenium [2,3]. Full blood count, serum urea and electrolytes, liver function tests, calcium, magnesium and phosphate were checked regularly and remained within normal limits on this feeding regime. In September 1985 the serum zinc was marginally low at 7umol/l (reference range 8-18umol/l). Blood samples sent to Glasgow for a comprehensive trace mineral [4] and vitamin [5] analysis confirmed the low serum zinc and showed gross selenium depletion with serum selenium less than 0.05 umol/l (reference range 0.8-2.0 umol/l). The activity of a selenium dependent enzyme, red cell glutathione peroxidase, was 3 units/ gram Hb (reference range 13-25 U/gHb). Serum selenium was measured by carbon furnace atomic absorption [6] and red cell glutathione peroxidase by reaction rate analysis using tertiary butyl hydroperoxide as substrate [7]. Serum concentrations of the essential minerals copper, iron, chromium and manganese, and of vitamins A and E, and the activities of enzymes depending on vitamins Bl, B2 and B6 were all shown to be within or above the reference ranges. Before treating for selenium depletion, the serum zinc concentration was restored to normal by adding 200 umol of zinc sulphate to the TPN fluid for 7 days. Zinc supplementation was continued at 100 umol/day thereafter and selenium repletion begun at the rate of lOOOnmol/day as sodium selenite. After 1 month of selenium supplementation both trace elements were added in the form of lOm1 Addamel-Na per day-a preparation which, in addition to other trace minerals, contains 400nmol selenium and 100 pmol zinc per 10 ml. These levels of provision meet the daily requirements for these trace minerals in most patients on longterm TPN [4]. Serum zinc and selenium concentrations and red cell glutathione peroxidase activities have been estimated on several occasions (see Fig. 1). Before and during both zinc and selenium replacement, we performed serial estimations of muscle strength by two techniques. Voluntary muscle contraction was measured by hand-grip dynamometry using a strain gauge system developed in our laboratory [8, 91. On each occasion, three recordings were made of the maximum force exerted by voluntary grip using right and left hand. The highest of the three recordings was taken as the maximum force. In addition, we assessed the maximum strength of the first dorsal interosseous

muscle of the right hand in both voluntary and involuntary electrically stimulated contractions [lo]. The patient’s right hand and forearm were placed in a supine position with the elbow flexed. The thumb was fixed against a stop in a fully abducted position and the lateral aspect of the proximal interphalangeal joint of the index finger was placed against the input of an isometric transducer. The remaining fingers of the hand were held in position on the baseboard using a shaped ‘plasticine’ mould. The orientation of the transducer and mounting was such that the force recorded was solely due to the activity of the first dorsal interosseous (FDI) muscle. The electrical output from the transducer was amplified and recorded on an FM instrumentation tape-recorder for later analysis. Electrical stimulation of the FDI muscle was carried out transcutaneously via aluminium foil/conducive gel electrodes shaped individually so as to maximise contact area without prejudicing selectivity. The anode was placed over the metacarpo-phalangeal joint of the index finger, whilst the cathode was placed over the motor point of the muscle. At the start of each test period, the stimulation parameters were adjusted for maximal tetanit contractile force. The stimulating pulses were of 200 ps duration at an intensity of 80-100 V and a frequency of 100 Hz in trains lasting for 3 s. During each test period, the patient performed four maximal voluntary contractions and four electrically stimulated contractions of the FDI muscle against the force transducer. Each contraction was of 3 s duration and was followed by 2 min rest. The force finally recorded as the maximum for each test (voluntary and electrical stimulation) was the average of the four trials on that test occasion. These measurements were made before selenium replacement and at weekly intervals thereafter. On electrical stimulation the force generated arises almost solely from the action of the FDI. The force obtained on voluntary contraction is typically 50-709b greater, presumably due to the action of synergists [lo]. Throughout the period of study the subject’s weight increased from 62.0-64.0 kg (lightly clad). Before selenium supplementation there were no signs of heart failure and the 12-lead electrocardiogram was normal excluding overt heart muscle disease.

RESULTS The results are shown graphically in Figure 1. This shows the changes in muscle strength associated first with zinc and then selenium repletion. The maximal force exerted in hand-grip dynamometry did not increase with zinc supplementation but showed an overall increase, with some fluctuation, during selenium replacement. The maximal force induced by involuntary,

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Fig. 1 Changes in maximum force generated by hand-grip dynamometry and during voluntary and electrically stimulated contractions of the right first dorsal interosseous (PDI) before and during zinc and selenium replacement therapy. The zinc and selenium content of the daily TPN infusion is shown with serial estimations of the serum zinc and selenium concentrations in umol/L and the activity of the enzyme glutathione peroxidase (IU/gHb).

18 1

182

REVERSAL

OF A SKELETAL

MYOPATHY

WITH

SELENIUM

electrically stimulated contractions shows a progressive rise amounting to a two-fold increase over 8 weeks of treatment with selenium. This was associated with a subjective increase in muscle strength and a loss of muscle pain on exercise.

DISCUSSION We have demonstrated an objective improvement in muscle strength with selenium supplementation in a subject with an isolated deficiency of this element. This improvement in muscle strength is disproportionate to the small increase in weight over the period of study (2 kg in 8 weeks). Indeed, the weight gain may have been related to selenium replenishment which improves appetite and increases the efficiency of conversion of food to energy in selenium depleted rats [ 111. In each of three prior cases of skeletal muscle dysfunction associated with selenium deficiency, the main complaints were of muscular pain and tenderness rather than of weakness [12-141. In two of these cases muscle enzymes were raised and returned to normal with selenium supplementation [ 12, 131 and in one case an electromyogram showed non-specific muscle irritability. Muscle strength has not, however, been assessed objectively in selenium deficiency. Neither has the vitamin E level been determined to exclude a contribution from deficiency of this vitamin [ 11. In certain areas of the world, a low selenium content of soil is reflected in low levels of the mineral in the locally produced food. New Zealand residents in Otago have plasma selenium concentration half that of visitors but show no associated disease [15]. However, the local sheep are prone to a myopathy termed white muscle disease which is preventable by daily selenium supplementation [ 141. Inhabitants of a certain area of China have the losest selenium intake and are at risk of Keshan disease, an endemic specific heart muscle disease of children and young women [ 161. Keshan disease is preventable by selenium supplementation but when established, is not responsive to treatment. There is one debatable case of heart muscle disease in a young girl associated with moderate selenium deficiency assumed to be dietary in origin [ 171. Apart from this and Keshan disease, the few sporadic cases of overt selenium deficiency in man have all been reported in patients on TPN. In two such cases a specific heart muscle disorder associated with selenium deficiency has been demonstrated. As in Keshan disease, these were unresponsive to selenium replacement and both patients died [18, 191. It is not clear why the skeletal myopathy induced by selenium depletion resolves with selenium replacement whereas the heart muscle disease, once established,

SUPPLEMENTATION

does not. Nor it is known why some selenium deficient patients develop skeletal and others heart muscle disease. Possibly the aetiology of these disorders is multifactorial with selenium deficiency a necessary, but not sufficient cause. Indeed, the exact role of selenium in human nutrition has yet to be determined and the mechanism of the pathology of selenium deficiency is even more obscure. Selenium is an essential component of the enzyme glutathione peroxidase (GPX) which is present in the cytosol and mitochondria of most animal cells. This enzyme catalyses the degradation of hydrogen peroxide and organic hydroperoxides. Although other non-selenium dependent enzymes have a degree of similar activity, e.g., glutathione-5transferases and catalase, it is probable that in selenium deficiency the intracellular concentration of hydrogen peroxide is raised [ 111. A reduced rate of hydrolysis of hydrogen peroxide by red cells has been demonstrated in an asymptomatic selenium depleted subject [20]. Peroxides promote the oxidation and lysis of cell membranes and this is a possible mechanism of the pathology caused by selenium deficiency [ 111. The effects of depletion of selenium and of vitamin E may be linked. Both have a role in the degradation of peroxides; selenium deficiency causes an increase in vitamin E turnover [ 111 and vitamin E deficiency facilitates the development of diseases associated with selenium depletion in some animals [ 181. It is relevant to determine the vitamin E level when assessing disorders which may be related to selenium depletion. Each of the cases of clinically overt selenium deficiency have been associated with gross depletion and serum selenium concentrations less than 0.12 umol/l or 12:.;, of normal. The rapid subjective improvement in muscle pain with selenium supplementation is associated with a much slower rise in the serum selenium and red cell GPX, the latter being dependent on erythropoiesis [21]. The average body selenium content is 14 mg (180 umol) in New England, USA [22]. Urinary selenium loss averages 200 nmol/day in normal subjects and this accounts for 5O-8600 of the total daily loss [ 14, 23, 241. Assuming a total daily loss of 300nmo1, the time to deplete selenium levels to loo,, of normal with no intake would be approximately 18 months and would exceed this figure if the rate of loss of selenium diminished with depletion [14, 211. Clinically overt selenium deficiency is therefore unlikely in previously well nourished patients undergoing several months TPN, although falls in serum selenium and GPX can be demonstrated after 21 days of TPN without appropriate mineral replacement [3, 141. All reported cases of clinical selenium deficiency have occurred in patients with either a long history of intestinal disease or after an extended period of TPN or, more usually, both. To prevent the development of a myopathy or a

CLINICAL

potentially fatal heart muscle disorder it is therefore reasonable to measure blood levels of selenium with a view to appropriate supplementation in any patient undergoing prolonged TPN, particularly if this is associated

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REFERENCES Lancet i: 685 111 Leading article 1983 Selenium perspective. PI Lane H W, Barroso A 0, Englert D et al 1982 Selenium status of seven chronic intravenous hyperalimentation patients. Journal of Parenteral and Enteral Nutrition 6: 426-431 of selenium 131 Jacobsen S, Plantin L-O 1985 Concentration in plasma and erythrocytes during total parenteral nutrition in Crohn’s disease. Gut 26: 50-54 141 Shenkin A, Fell G S, Halls D J et al 1986 Essential trace element provision to patients receiving intravenous nutrition in the United Kingdom. Human Nutrition, Clinical Nutrition 5: 91-97 P, Shenkin A, Campbell R A et al 1981 151 Stromberg Vitamin status during total parenteral nutrition. Journal of Parenteral and Enteral Nutrition 5: 295-299 of 161 Alexander J, Kofstad J, Saeed K 1982 The application direct electrothermal atomic absorption spectrophotometric determination of selenium in clinical chemistry. Trace Element Analytical Chemistry in Biology and Medicine 2: 729-743 171 Beutler E, Blume K G, Kaylan J C et al 1979 Recommended methods for red cell enzyme analysis. British Journal of Haematology 35: 331-339 of 181 Bassey E J, Harries U J, Short AH 1986 Calibration an isometric hand-grip dynamometer using a platform weighing-machine. Journal of Physiology 373: 7 191 Bassey E J, Dudley B R, Harries U J 1986 A new portable strain gauged hand-grip dynamometer. Journal of Physiology 373: 6 M J N, White M J .lOl Davies C T M, Dooley P, McDonagh 1985 Adaptation of mechanical properties of muscle to high force training in man. Journal of Physiology 365: 277-284 Submission

date: 17 August

1986. Accepted after revision: 27 January

NUTRITION

183

1111 Burk R F 1983 Biological activity of selenium. Annual Review of Nutrition 3: 53-70 1121 Watson R D, Cannon R A, Kurland G S et al 1985 Selenium responsive myositis during prolonged home total parenteral nutrition in cystic fibrosis. Journal of Parenteral and Enteral Nutrition 9: 58-60 of chronic 1131 Kien C L, Ganther H F 1983 Manifestations selenium deficiency in a child receiving total parenteral nutrition. American Journal of Clinical Nutrition 37: 319-328 1141 Van Rij A M, Thomson C D, McKenzie J M, Robinson M F 1979 Selenium deficiency in total parenteral nutrition, American Journal of Clinical Nutrition 32: 2079-2085 1151 Rea H M, Thomson C D, Campbell D R, Robinson M F 1979 Relationship between erythrocyte selenium concentrations and glutathione peroxidase activities of New Zealand residents and visitors to New Zealand. British Journal of Nutrition 42: 201-208 1161 Leading article 1979 Selenium in the heart of China. Lancet ii: 889-890 and 1171 Collipp P J, Chen S Y 1981 Cardiomyopathy selenium deficiency in a two year old girl. New England Journal of Medicine 304: 1304-l 305 1181 Johnson R A, Baker S S, Fallon J T et al 1981 An occidental case of cardiomyopathy and selenium deficiency. New England Journal of Medicine 29: 1210-1211 1191 Fleming C R, Lie J T, McCall J T et al 1982 Selenium deficiency and fatal cardiomyopathy in a patient on home parenteral nutrition. Gastroenterology 83: 689-693 1201 Baker S S, Lerman R H, Krey S H et al 1983 Selenium deficiency with total parenteral nutrition: reversal of biochemical and functional abnormalities by selenium supplementation: a case report. American Journal of Clinical Nutrition 38: 769-774 1211 Van Rij A ‘M, McKenzie J M, Thomson CD, Robinson M F 1981 Selenium supplementation in total parenteral nutrition. Journal of Parenteral and Enteral Nutrition 5: 120-124 1221 Schroeder H A, Frost D C, Balassa J J 1970 Essential trace metals in man: selenium. Journal of Chronic Diseases 23: 227 CD, 1231 Stewart R D H, Griffeths N M, Thomson Robinson M F 1978 Quantitative selenium metabolism in New Zealand women. British Journal of Nutrition 40: 45-54 ~41 Fleming C R, McCall J T, O’Brien J F et al 1984 Selenium status in patients receiving home parenteral nutrition. Journal of Parenteral and Enteral Nutrition 8: 258-262 1987