Postgrad Med J: first published as 10.1136/pgmj.66.773.235 on 1 March 1990. Downloaded from Postgrad Med J (1990) 66, 235 - 237 © The Fellowship of Postgraduate , 1990 Myoglobinuria: the importance ofreaching a firm diagnosis - a patient with defective fatty acid oxidation C.J. Ellis', A.G. Dewhurst', M. Cooper2, D.P. Brenton2 and J.R.E. Dathan' 'Department ofMedicine, Royal South Hants Hospital, Lyon Street, Southampton and2Department of Medicine, University College and Middlesex School ofMedicine, University Street, London, UK.

Summary: A 52 year old man presented with myoglobinuria-induced acute renal failure requiring dialysis. Despite renal biopsy, the cause of the myoglobinuria was not established until he re-presented a year later with a milder episode. At this stage investigations, including a muscle biopsy, demonstrated a defect in fatty acid oxidation amenable to dietary and lifestyle advice. This report emphasizes the importance of reaching a definitive diagnosis in myoglobinuria.

Introduction We report a patient with a rare muscle disorder After 2 days, he was re-admitted with leg muscle (defective fatty acid oxidation) who presented with cramps and red-brown . Investigations revealed two episodes ofmyoglobinuria-induced acute renal visible myoglobinuria (laboratory confirmed), urea failure before the correct diagnosis was made. This 8.8 mmol/l, 138 tmol/l, potassium condition requires dietary treatment and this 3.8 mmol/l, aspartate transaminase > 300 IU/1,

report highlights the importance of making an creatinine kinase > 36 000 IU/I. With bed rest, the copyright. accurate diagnosis in such a patient. symptoms and biochemistry returned to normal. Further history at this stage indicated several episodes during his life of exercise-induced Case report severe muscle cramps, including one as a young army recruit when he had to drop out ofan exercise A previously well 52 year old engineer presented march. Having excluded other commoner causes following a 10-day history of , vomiting of myoglobinuria (see discussion), a muscle and 'chocolate-coloured' urine. Examination defect was An ischaemic fore- enzyme suspected. http://pmj.bmj.com/ was normal. Mid-stream urine revealed no casts, arm test showed a normal rise of lactate after infection or visible , renal ultrasound anaerobic exercise - lactate levels: pre-test 1.3 was normal, urea 52 mmol/l (3.0-6.5 mmol/l), mmol/l (0.6-2.4 mmol/l), immediately post-test creatinine 1224 lmol/l (60-125 ;tmol/l), aspartate 8.0 mmol/l, 20 minutes post-test 2.0 mmol/l - and transaminase > 450 IU/I (5-42 IU/1, potassium a provisional diagnosis of a defect in fatty acid 5.5 mmol/l (3.5-5.0 mmol/l). Two days later the oxidation was made. Muscle biopsy was performed aspartate transaminase had fallen to 103 IU/I when 6 months later (when the muscle would have the creatine kinase was 4880 IU/1 (25-195 IU/1), regained its normal histology) and confirmed this on September 30, 2021 by guest. Protected suggesting a higher peak value of creatine kinase diagnosis. before admission. Peritoneal dialysis followed by haemodialysis was required before the acute renal failure resolved. Renal biopsy showed marked Methods and results tubular damage and a moderate interstitial infil- trate, with immuno-peroxidase evidence of tubules Mitochondria isolated from a quadriceps muscle containing red-brown material, compatible with tissue obtained by needle biopsy demonstrated myoglobin. a decreased oxidation of palmityl carnitine, The patient remained well and the following year 0.02 LAmol min-'. g. tissue-' (normal 0.73 + 0.17 he obtained a postman'sjob in his rural area, which s.e.m., n = 9). Oxidation of pyruvate and the involved 5 miles of walking and cycling daily. activity of succinate cytochrome reductase and cytochrome oxidase were all normal in the same biopsy.' The accumulation in the muscle of short chain Correspondence: A.G. Dewhurst, M.R.C.P. fatty acid carnitine esters 15.3 limol, g protein-' Accepted: 21 July 1989. (normal 0.8-4.0) and of long chain fatty and Postgrad Med J: first published as 10.1136/pgmj.66.773.235 on 1 March 1990. Downloaded from

236 CLINICAL REPORTS carnitine esters 1.17/imol, g protein-' (normal DIET GLYCOGEN TRIGLYCERIDES 0.1-0.7) is consistent with the restricted meta- \ Myophosphorylase J bolism ofthese fatty acid intermediates. This could deficiency arise from a deficiency of carnitine palmityl tran- FREE FATTY ACIDS sferase (CPT) or in beta-oxidation (see below). Phosphofructokinase Organic acid investigations on both urine and deficiency plasma were normal without abnormal dicar- PALMITYL CoA any Outer ====. = boxylic acids. mitochondrial CARNITINE He was advised to have a low fat diet and to membrane CPT-I follow a more sedentary life-style, both treatments Inner Co.ASH reported to prevent further in this mitochondrial ======carrier protein condition,2 and he remains well a year later. membrane membranePALMITYL CARNITINE Discussion PYRUVATE CASH Anaerobic \ CPT-If Anaerobic / V...... Carnitine Rhabdomyolysis is the syndrome resulting from LACTIC ACID , with the release of muscle Aerobic\\ PALMITYL CoA cell contents into plasma. These include enzymes of which creatine kinase is the most sensitive indicator ACETYL CoA of rhabdomyolysis3 and myoglobin. Myoglobin- I uria occurs at the low serum concentration of KREBS CYCLE 1.5 mg/dl. However, the distinctive brown coloura- tion only becomes visible to the naked eye once the myoglobin concentration exceeds 100 mg/dl. There ATP (Energy) are many causes of myoglobinuria: toxins (espec- Figure 1 Lipid and carbohydrate metabolism pathways ially alcohol), infections, drugs, muscle trauma in skeletal muscle: sites of potential enzyme defects. copyright. (including epilepsy), metabolic disorders and immunological diseases (e.g. ) being pathway defects (as in our patient), but not with an among the more common.4 Exercise-induced myo- enzyme deficiency in glycogenolysis.7 There are 2 globinuria may result from defective glycogen distinct currently recognizable deficiencies con- utilization with enzyme abnormalities such cerned with the transfer of fatty acids into as myophosphorylase deficiency (McArdle's dis- mitochondria. In myopathic carnitine deficiency, ease) or muscle phospho-fructokinase deficiency only the skeletal muscle tissues contain low concen-

(Tauri's disease) in the carbohydrate pathway. trations of L-carnitine. The clinical symptoms in http://pmj.bmj.com/ Similarly, deficiencies in lipid metabolism may this condition are those of muscle weakness, and cause an energy (adenosine triphosphate: ATP) muscle biopsy shows a gross lipid storage deficit resulting in muscle breakdown.5 . Depending upon the metabolic state, skeletal Two carnitine palmityl transferase (CPT) muscle uses variable proportions of glucose or free enzymes have been recognized; CPT-I located on fatty acids and as fuel. Integrity of the inner face of the outer mitochondrial memb- both the lipid and carbohydrate metabolic path- rane and CPT-II located on the inner face of the ways is therefore essential for normal muscle inner mitochondrial membrane. Carnitine palmityl on September 30, 2021 by guest. Protected function. Normally more than 50% of the energy transferase deficiency can cause exercise-induced requirement of resting skeletal muscle is supplied muscle cramps and myoglobinuria,8 worsened by from the oxidation of lipids, but this quantity fasting, cold or high fat diet; myopathy is not increases during fasting when glucose is spared. usually a feature.9 During short bursts of strenous activity skeletal Carnitine palmityl transferase deficiency was muscle predominantly uses muscle glycogen.6 first reported by Di Mauro and Bank and collea- Figure 1 demonstrates these enzyme defects in gues'0 " who found 2 brothers with the condition. the pathways of lipid and carbohydrate meta- Cases previously described as 'paroxysmal myo- bolism. A simple test to distinguish between defects globinuria' or the 'Meyer-Betz syndrome' were in the 2 pathways is the 'ischaemic forearm test' but probably also due to carnitine palmityl transferase it carries some risk of contracture formation in deficiency.'2 The genetic basis of inheritance is defects of carbohydrate metabolism. In this the unclear, and although autosomal recessive with forearm is cuffed at above systolic blood pressure, differing expression is likely, sub-groups do seem to and a vigorous hand-squeezing exercise is per- exist.'3'4 Fewer examples of genetic defects in the formed. Venous samples show a normal rise of beta-oxidation pathway have been described. lactate after anaerobic exercise with the lipid It is likely that the patient reported here is Postgrad Med J: first published as 10.1136/pgmj.66.773.235 on 1 March 1990. Downloaded from CLINICAL REPORTS 237

CPT-II deficient but further investigations would determining whether there is a defect in oxidation be required to establish whether the defect in this of carbohydrates and fatty acids. Such metabolic patient is in the CPT-II enzyme or in the beta- defects render the patient at risk of recurrent oxidation of long chain fatty acids. More accurate myoglobinuria and repeated episodes of acute diagnosis would not alter treatment but this report renal failure, yet may respond well to appropriate emphasizes the need to make an accurate diagnosis preventive . in any patient with myoglobinuria, at least as far as

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