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Serum enzyme studies in acquired disease of skeletal muscle
CLINICA
CCA
CHIMICA
ACTA
193
4626
SERUM ENZYME STUDIES IN ACQUIRED DISEASE OF SKELETAL MUSCLE
W. H. S. THOMSON Research Laboratory, Knightswood Hospital, Glasgow Wg (U.K.) (Received
April I, 1971)
SUMMARY
Tissue specificity of muscle creatine phosphokinase and liver y-glutamyl transpeptidase was directly demonstrated in a case of chronic hepatitis with acute ischaemic muscle necrosis. Evidence from different patients suggested that in polymyositis the contractile apparatus initially is reversibly affected, with structural damage only later. Riochemical identification of a female Duchenne muscular dystrophy phenocopy with polymyositis was accomplished using corticosteroid therapy with serial serum enzyme assay, and her progress compared with other patients.
INTRODUCTION
The reciprocally exclusive distribution of creatine phosphokinase (CPK) and y-glutamyl transpeptidase (GGTP) in muscle and liver respectively is discussed elsewhere, and clinical application of their serum activities illustrated in a series of patient+. Their diagnostic independence is particularly evident when transient acute disease of one tissue coincides with evolving chronic disease of the other, as in the present case of localised muscle necrosis complicating unsuspected chronic hepatitis. Although extensive reviews of polymyositis have appeared2v3,close studies of single cases continue to give new information. In particular, the rapid and accurate diagnosis essential in Duchenne muscular dystrophy (DMD) phenocopies4 is readily available biochemically without recourse to biopsy. METHODS
Six serum enzymes were assayed. They were creatine phosphokinase (ATP : creatine phosphotransferase; EC 2.7.3.2; CPK), r,6-diphosphofructoaldolase (EC 4.1.2.7; ALD), lactate dehydrogenase (EC 1.1.1.27; LDH), aspartate aminotransferase (glutamic-oxalacetic transaminase; EC 2.6.1.1; GOT), alanine aminotransferase (glutamicpyruvic transaminase ; EC 2.6.1.2 ; GPT) and y-glutamyl transpeptidase (GGTP). The assay methods, apparatus and techniques, normal ranges, and special precautions in the handling of specimens are referred to elsewherel. Clin. Chim. Acta, 35 (1971) 193-199
I94 StJBJECTS
ANI)
IIESI-LTS
Acute ischacrnic nausclc nccvosis with chronic hcjxtitis
Since viral hepatitis for three weeks five years ago a 47-year-old man addicted to alcohol had felt unwell, but still drank as much and continued taking barbiturates. After a major convulsicn he was unruly and semicomatose, and lay inert on his bent right arm partly occluding the forearm blood supply. Next day (day o) the flexor muscles were painful, powerless and swollen from wrist to elbow, though radial pulse and extensors were normal. The swelling diminished (day 16) and went (day zo), but left some induration (day 28) and slight maiwen-gri’z deformity (day 47) with improving flexor power by day 72. On day 85 firm hepatomegaly (4 cm) was noted, and needle biopsy disclosed active chronic hepatitis. Morning blood specimens before rising were taken every 2nd day from days 3 to 20, then every 4th day ambulant at home and finally twice as an outpatient, and assayed forthwith for all six serum enzymes (Fig. I) and for liver functions (Table I).
Fig.
1. Acute
TABLE LIVER ~-.
ischaemic
muscle necrosis with chronic
hepatitis.
I FUNCTIONS
IX
ACUTE
ISCHAEMIC
hfUSCLE
___-__ Serum total bilirubin (mg/Ioo ml) Serum alkaline phosphatase (K.A. units/loo Serum total protein (g/-r00 ml) Serum albumin (g/Ioo ml) Serum globulin (g/loo ml)
KECROSIS
ml)
WITH
CHRONIC
HEPATITIS
Days aftrv awn injury -____ 24 32 39 ~... ~~_ 0.5 0.6 0.5 II.2 16.2 16.5 7.4 3.4 4.0
7.7 3.5 4.2
7.8 3.7 4.’
47 0.8
20.8 7.6 3.7 3.9
54 0.8 24.0
8.2 3.8 1.4
72 1.1 41.6
8.4 3.4 5.0
On day 24 the values of the first five serum enzymes in simultaneous venous specimens from both arms were the same in each; and on day 36 blood from the left Cl&.
Chim.
Acta,
35
(1971)rgyIgg
SERUM ENZYMES IN MUSCLE DISEASE
19.5
arm, just before and IO min after maximal exercise of the injured right flexors for 5 min, showed no change in CPK or ALD and increases of only 5%, 4% and 3% in LDH, GOT and GPT respectively. Normal saline dilutions (2, 4, 6, 9, 12, 15 & 18 times) of the serum on day 3 showed no real increase in CPK, LDH, GOT or GPT, but a progressive 32.6% increase in ALD activity, absent on diluting instead with cell-free, heat-inactivated (30 min at 56”) mixed normal female serum, when ALD activity remained constant,
(A) Sleroid-res$onsive. Case I. Four weeks ago a fit g&year-old man developed an extensive rash on face and limbs, with severe dysphagia and general muscular pain and weakness, especially proximal, so rapidly progressive that he could not sit up in bed. ESR and grossly elevated serum enzymes (Table II) indicated acute dermatomyositis, confirmed by skin histology though that of muscle seemed normal. No other abnormalities were found. TABLE
II
RESPONSETo
CORTICOSTEROIDS
OF POLYMYOSITIS
CASES
A(1)
AND
A(2)
Age
Sex
Dysphagia
ESR
Acute dermatomyositis 4 weeks, bedfast due weakness ; biopsy & ve
57 : I I
M
t+i
33
5.30 Pm
Prednisolone 60 mg/day then I.=, mg/day; revived 48 h, ambulant 24th day
11.45 am
Condition
ym : nzos Case
Time 61ed
CPK
ALD
LDH
a413
23.3
697
2.3
189
8.9
6.8
19.6
447
40.8
14.7
2.0
119
IO.7
6.3
GOT
GPT
1
58:5
M
Nil
5
Case 2 Polymyositis 3 mos, low pyrexia, bedfast due weakness : biopsy + ve 38 : g
F
Nil
98
12.20
pm
522
Prednisolone 20 mg/day then altern. days; apyrexial & ambulant on 9th day -
F
Nil
32
12.15
pm
19.2
39:3
23.4
127
Prednisolone (60 mg daily) gave a rapid and very great return of strength in 48 h. After 15 days, 40 mg daily was given for 5 days, 30 mg daily until discharge ambulant on the 24th day, then 15 mg daily maintenance for slight shoulder weakness at work and a tendency for the rash to return in sunlight. The dysphagia had gone. All serum enzymes except LDH were normal. Case z. Three months ago, after Raynaud phenomena in both hands for r8 months, a woman of 38 years developed generalised muscular weakness and wasting, especially proximal, progressing rapidly until she could not sit up in bed. ESR and serum enzyme elevations (Table II) upheld deltoid histology of polymyositis. Other systems seemed normal. Prednisolone (20 mg daily) restored strength so rapidly that she was discharged ambulant on the 9th day; maintenance was by 20 mg on alternate days since ESR and GOT remained elevated though muscle power was normal. Normal saline dilutions (3,6, g, 12,15,18 & 21 times) of serum before treatment showed no increase in CPK or ALD activities. C&z. Chim. Acta,
35 (1971)
x93-199
52.1
(l3) DMD fihmocofiy with subacute $olywg,ositis. This ro-year-old girl had been fit and active; a year ago limb pains developed, notably in the legs, with weight loss and progressive weakness. Sloe was now thin and lordotic, with marked proximal wasting so that the calves looked swollen. Sire tended to walk on her toes, with a slight roll, and ascended stairs slowly clutching the handrail. She had weak neck flexors without dysphagia, and diminished tendon reflexes. Blood pressure and EC(; in were normal, ESR 5 mm in the first hour, and a buccal smear chromatin-positive the range for normal females (26)‘:,, cells). The maternal grandmother (68 yrs), mother (34 yrs), father (9 yrs) and younger sister (6; yrs---the only sib) were healthy, with repeatedly normal values for all five serum enzymes. No MD history was found in the extensive ancestry. Gastrocnemius histology (Dr. Alex McQueen) was not at all dystrophic (areas of virtually normal fibres with little variation in size) but showed typical active polymyositis (a few foci of active fibre destruction with interstitial inflammatory infiltrate, areas of much new fibre growth, and others of nearly normal fibres with some interstitial fibrous tissue from earlier damage).
SERUM ENZYME VALUES 360
1
ALDr20L 120UPPW NO,lllC#l Limits
#GOT .GPT
s.GGTP 37
66
Ibl
prwiourly
DAYS after stertinp treatment
Fig.
2. Successful
Clin. Chim.
Acta,
corticosteroid
treatment
3.5 (1971) 193-199
of DMD
phenocopy
(13) with subacute
polymyositls.
SERUM ENZYMES IN MUSCLE DISEASE
I97
Ambulant treatment in hospital (days o-24) at age IO years 7 months was by prednisolone in daily divided doses of 60 mg (days o&5), 40 mg (days 7-16), 30 mg (days 17-q), then 20 mg on alternate days as an outpatient (days 24-101). Side effects (Cushing) were minimal and blood pressure normal at day 24, with faint hirsuties at day 66. Morning blood specimens before rising were taken twice weekly throughout, then thrice as an outpatient, and assayed forthwith for all six serum enzymes (Fig. 2). All were haemolysis-free save that on day 14 (+ +). The neck flexors (day 8) and the facial and upper limb-girdle muscles (day 37) regained normal strength in that order, though a timed ascent of stairs remained just as slow and difficult. On day 66 tests showed a marked increase in general strength, and ascent of stairs was almost normal, in half the time and without the handrail. On day IOI the same tests showed no further improvement. Normal saline dilutions (3, 6, 9,12,15, 18 & 21 times) of serum 6 months before treatment had showed no real increase in CPK, ALD, LDH, GOT or GPT activities. (C) Steroid-resistant case. 22 months ago an athletic woman of 28 years developed progressive general weakness and wasting, chiefly proximal, with Raynaud phenomena and eventual dysphagia, until she needed a stick to walk and could scarcely ascend stairs. Serum enzyme elevations (Fig. 3) supported indifferent deltoid histology. There was no other abnormality.
5X
44c SERUM ENZYME VALUES 36C
280
: ‘b ALDx20
200
\
CPK x ‘h
UPPer Normal Limits * *./
: .., -
t
. l
previously
Fig. 3. Corticosteroid
DAYS after starting
treatment
GGTP GOT GPT
treatment
of resistant polymyositis
(C),
Clin. Chim.
Acta,
35 (1971)
193-199
THOXISON
198
Prednisolone dosage, increased stepwise to 30 mg daily by day 32, was maintained to day 83, then reduced to zero over 3 weeks, when the marked hirsuties and side-effects disappeared. by day 14; but though better,
Dysphagia had gone by day 7, and walking improved slightly by day IOO she walked without a stick and ascended stairs
rising from a chair was still as difficult. All five serum enzymes had declined by
half, but were still much elevated. DISCUSSION In Fig. I enzyme tissue specificity circulation
of soluble
muscle
protein
is evident after immediate content,
including
enzymes.
discharge
into the
The initial
great
serum elevations and rapid clearance to normal values of muscle CPK wholly describe the necrosis of this small muscle bulk. No evidence was found of further passive enzyme discharge on day 24, nor after exercise on day 36. The simultaneous lesser elevations of ALD, LDH, GOT and GPT likewise decline but not to normal, and their marked persistence, with normal CPK, indicates disease in tissues other than muscle. Increasing elevations of GGTP and suggest chronic hepatitis 5T6 , finally patient remained symptomless and progressing to irreversible cirrhosis.
progressively abnormal liver functions (Table I) demonstrated by liver biopsy. Throughout, the abnormal and anicteric, though biochemically Conventional
liver functions
became
abnormal
only slowly. Serial serum enzyme assay, particularly of CPK and GGTP, promptly described both muscle and hepatic lesions independently. Polymyositis3 is a sporadic, often chronic myopathy, usually inflammatory but often painless, occurring at any age and characterised primarily by muscular weakness, especially proximal, with late wasting; dermatomyositis has in addition a particular rash. Diagnostic serum elevations of effluent muscle enzymes occur, as in MD; unlike MD successful treatment by corticosteroids reduces these towards normal and restores strength, and serial assay monitors continued suppressive therapy. In this small series the response to corticosteroids is related not to dosage but to muscular weakness, and not to its severity but inversely to its duration, since cases A (I), A (z), B and C recovered in that order. This relation extends to muscle groups in individuals, those weakening last improving first, and conversely, as in Is and C. The very rapid response of A (I), profoundly weak but without obvious wasting, suggests a reversible lesion initially impairing only contractile mechanisms or their energy sources, consistent with the normal biopsy so often found2. Its persistence, as in B and C, may then cause structural damage requiring regrowth time before improvement, affirming a dependence of structure on function. Serial serum enzyme assay, especially of CPK, is by far the best measure of therapeutic efficacy, and can be diagnostic without biopsy, as in B. This case, chromatin-positive and without carrier ancestry, is still clinically and biochemically indistinguishable from the progressive, fatal DMD of boys, recorded only twice in X0 girls though biopsy in one was not obtained’ and in the other was uninformative*, or from the hitherto hypothetical DMD of girls now generally regarded as misdiagnosisg. The rapid decline (Fig. 2) to normal enzyme values on corticosteroid therapy, unknown in MD, is itself diagnostic long before physical improvement in such established cases; and renewed elevations due to too rapid dosage reduction after day 16 herald weakening, despite the continuing recovery of recent regrowth, now liable to regress. Since czin. Chim. Acta, 35
(1971)
rgp199
SERUM
ENZYMES
IN MUSCLE
DISEASE
I99
polymyositis can be treated and is sporadic, while DMD is fatal and implies a pedigree at risklo, this ready diagnosis of such DMD phenocopies, both boys and girls, becomes important. Occasionally patients are steroid-resistantll. In C, undoubted physical improvement is slow despite prolonged therapy with marked side-effects, but persists, perhaps due to regrowth, long after withdrawal. The slow decline of serum enzyme values (Fig. 3), only GPT becoming normal, reflects this; and methotrexate potentiation of steroid actionll may be appropriate. ACKNOWLEDGEMENTS
I wish to thank the patients examined, the medical colleagues who referred them, and Dr. Alex McQueen for the histology report in case B. This study was supported by the Andrew Patrick Trust and the Muscular Dystrophy Group of Great Britain. The Unicam SP 800 B spectrophotometer on which the enzyme assays were performed was kindly donated by Mrs. Kaye Tait of Cheltenham. REFERENCES
Cl&z.Chim. Acta, 35 (1971) 183. A. L. ROSE AND J.N. WALTON,&U~TZ, 89 (1966) 747. C. M. PEARSON, Ann. Rev. Med., 17 (1966) 63. C. E. THOMPSON, CC&. Pediat., 7 (1968) 24. S. B. ROSALKI, D. RAW, D. LEHMANN AND M. PRENTICE, Ann. CZin.Biochem., 7 (1970) '43. M. ZEIN AND G. DISCOMBE, Lancet, ii(Ig7o)748. J.N. WALTON,Ann.HumanGenet., 21 (1956) 40. P.FERRIER, F. BAMATTER AND D. KLEIN,~. Med. Genet.,2 (1965) 38. A. S. PENN, R. P. LISAK AND L. P. ROWLAND, Neurology, 20(1970) 147. W. H. S. THOMSON, C&n. Chim. Acta, 26 (1969) 207. M.C. SOKOLOFF,L. S. GOLDBERG AND C.M.PEARSON,L~~~~~,~(I~~I) 14.
I W. H. S. THOMSON,
2 3 4 5 6 7 8 9 IO II
C&5. Chim. Acta, 35 (1971) 193-199
CCA
CHIMICA
ACTA
193
4626
SERUM ENZYME STUDIES IN ACQUIRED DISEASE OF SKELETAL MUSCLE
W. H. S. THOMSON Research Laboratory, Knightswood Hospital, Glasgow Wg (U.K.) (Received
April I, 1971)
SUMMARY
Tissue specificity of muscle creatine phosphokinase and liver y-glutamyl transpeptidase was directly demonstrated in a case of chronic hepatitis with acute ischaemic muscle necrosis. Evidence from different patients suggested that in polymyositis the contractile apparatus initially is reversibly affected, with structural damage only later. Riochemical identification of a female Duchenne muscular dystrophy phenocopy with polymyositis was accomplished using corticosteroid therapy with serial serum enzyme assay, and her progress compared with other patients.
INTRODUCTION
The reciprocally exclusive distribution of creatine phosphokinase (CPK) and y-glutamyl transpeptidase (GGTP) in muscle and liver respectively is discussed elsewhere, and clinical application of their serum activities illustrated in a series of patient+. Their diagnostic independence is particularly evident when transient acute disease of one tissue coincides with evolving chronic disease of the other, as in the present case of localised muscle necrosis complicating unsuspected chronic hepatitis. Although extensive reviews of polymyositis have appeared2v3,close studies of single cases continue to give new information. In particular, the rapid and accurate diagnosis essential in Duchenne muscular dystrophy (DMD) phenocopies4 is readily available biochemically without recourse to biopsy. METHODS
Six serum enzymes were assayed. They were creatine phosphokinase (ATP : creatine phosphotransferase; EC 2.7.3.2; CPK), r,6-diphosphofructoaldolase (EC 4.1.2.7; ALD), lactate dehydrogenase (EC 1.1.1.27; LDH), aspartate aminotransferase (glutamic-oxalacetic transaminase; EC 2.6.1.1; GOT), alanine aminotransferase (glutamicpyruvic transaminase ; EC 2.6.1.2 ; GPT) and y-glutamyl transpeptidase (GGTP). The assay methods, apparatus and techniques, normal ranges, and special precautions in the handling of specimens are referred to elsewherel. Clin. Chim. Acta, 35 (1971) 193-199
I94 StJBJECTS
ANI)
IIESI-LTS
Acute ischacrnic nausclc nccvosis with chronic hcjxtitis
Since viral hepatitis for three weeks five years ago a 47-year-old man addicted to alcohol had felt unwell, but still drank as much and continued taking barbiturates. After a major convulsicn he was unruly and semicomatose, and lay inert on his bent right arm partly occluding the forearm blood supply. Next day (day o) the flexor muscles were painful, powerless and swollen from wrist to elbow, though radial pulse and extensors were normal. The swelling diminished (day 16) and went (day zo), but left some induration (day 28) and slight maiwen-gri’z deformity (day 47) with improving flexor power by day 72. On day 85 firm hepatomegaly (4 cm) was noted, and needle biopsy disclosed active chronic hepatitis. Morning blood specimens before rising were taken every 2nd day from days 3 to 20, then every 4th day ambulant at home and finally twice as an outpatient, and assayed forthwith for all six serum enzymes (Fig. I) and for liver functions (Table I).
Fig.
1. Acute
TABLE LIVER ~-.
ischaemic
muscle necrosis with chronic
hepatitis.
I FUNCTIONS
IX
ACUTE
ISCHAEMIC
hfUSCLE
___-__ Serum total bilirubin (mg/Ioo ml) Serum alkaline phosphatase (K.A. units/loo Serum total protein (g/-r00 ml) Serum albumin (g/Ioo ml) Serum globulin (g/loo ml)
KECROSIS
ml)
WITH
CHRONIC
HEPATITIS
Days aftrv awn injury -____ 24 32 39 ~... ~~_ 0.5 0.6 0.5 II.2 16.2 16.5 7.4 3.4 4.0
7.7 3.5 4.2
7.8 3.7 4.’
47 0.8
20.8 7.6 3.7 3.9
54 0.8 24.0
8.2 3.8 1.4
72 1.1 41.6
8.4 3.4 5.0
On day 24 the values of the first five serum enzymes in simultaneous venous specimens from both arms were the same in each; and on day 36 blood from the left Cl&.
Chim.
Acta,
35
(1971)rgyIgg
SERUM ENZYMES IN MUSCLE DISEASE
19.5
arm, just before and IO min after maximal exercise of the injured right flexors for 5 min, showed no change in CPK or ALD and increases of only 5%, 4% and 3% in LDH, GOT and GPT respectively. Normal saline dilutions (2, 4, 6, 9, 12, 15 & 18 times) of the serum on day 3 showed no real increase in CPK, LDH, GOT or GPT, but a progressive 32.6% increase in ALD activity, absent on diluting instead with cell-free, heat-inactivated (30 min at 56”) mixed normal female serum, when ALD activity remained constant,
(A) Sleroid-res$onsive. Case I. Four weeks ago a fit g&year-old man developed an extensive rash on face and limbs, with severe dysphagia and general muscular pain and weakness, especially proximal, so rapidly progressive that he could not sit up in bed. ESR and grossly elevated serum enzymes (Table II) indicated acute dermatomyositis, confirmed by skin histology though that of muscle seemed normal. No other abnormalities were found. TABLE
II
RESPONSETo
CORTICOSTEROIDS
OF POLYMYOSITIS
CASES
A(1)
AND
A(2)
Age
Sex
Dysphagia
ESR
Acute dermatomyositis 4 weeks, bedfast due weakness ; biopsy & ve
57 : I I
M
t+i
33
5.30 Pm
Prednisolone 60 mg/day then I.=, mg/day; revived 48 h, ambulant 24th day
11.45 am
Condition
ym : nzos Case
Time 61ed
CPK
ALD
LDH
a413
23.3
697
2.3
189
8.9
6.8
19.6
447
40.8
14.7
2.0
119
IO.7
6.3
GOT
GPT
1
58:5
M
Nil
5
Case 2 Polymyositis 3 mos, low pyrexia, bedfast due weakness : biopsy + ve 38 : g
F
Nil
98
12.20
pm
522
Prednisolone 20 mg/day then altern. days; apyrexial & ambulant on 9th day -
F
Nil
32
12.15
pm
19.2
39:3
23.4
127
Prednisolone (60 mg daily) gave a rapid and very great return of strength in 48 h. After 15 days, 40 mg daily was given for 5 days, 30 mg daily until discharge ambulant on the 24th day, then 15 mg daily maintenance for slight shoulder weakness at work and a tendency for the rash to return in sunlight. The dysphagia had gone. All serum enzymes except LDH were normal. Case z. Three months ago, after Raynaud phenomena in both hands for r8 months, a woman of 38 years developed generalised muscular weakness and wasting, especially proximal, progressing rapidly until she could not sit up in bed. ESR and serum enzyme elevations (Table II) upheld deltoid histology of polymyositis. Other systems seemed normal. Prednisolone (20 mg daily) restored strength so rapidly that she was discharged ambulant on the 9th day; maintenance was by 20 mg on alternate days since ESR and GOT remained elevated though muscle power was normal. Normal saline dilutions (3,6, g, 12,15,18 & 21 times) of serum before treatment showed no increase in CPK or ALD activities. C&z. Chim. Acta,
35 (1971)
x93-199
52.1
(l3) DMD fihmocofiy with subacute $olywg,ositis. This ro-year-old girl had been fit and active; a year ago limb pains developed, notably in the legs, with weight loss and progressive weakness. Sloe was now thin and lordotic, with marked proximal wasting so that the calves looked swollen. Sire tended to walk on her toes, with a slight roll, and ascended stairs slowly clutching the handrail. She had weak neck flexors without dysphagia, and diminished tendon reflexes. Blood pressure and EC(; in were normal, ESR 5 mm in the first hour, and a buccal smear chromatin-positive the range for normal females (26)‘:,, cells). The maternal grandmother (68 yrs), mother (34 yrs), father (9 yrs) and younger sister (6; yrs---the only sib) were healthy, with repeatedly normal values for all five serum enzymes. No MD history was found in the extensive ancestry. Gastrocnemius histology (Dr. Alex McQueen) was not at all dystrophic (areas of virtually normal fibres with little variation in size) but showed typical active polymyositis (a few foci of active fibre destruction with interstitial inflammatory infiltrate, areas of much new fibre growth, and others of nearly normal fibres with some interstitial fibrous tissue from earlier damage).
SERUM ENZYME VALUES 360
1
ALDr20L 120UPPW NO,lllC#l Limits
#GOT .GPT
s.GGTP 37
66
Ibl
prwiourly
DAYS after stertinp treatment
Fig.
2. Successful
Clin. Chim.
Acta,
corticosteroid
treatment
3.5 (1971) 193-199
of DMD
phenocopy
(13) with subacute
polymyositls.
SERUM ENZYMES IN MUSCLE DISEASE
I97
Ambulant treatment in hospital (days o-24) at age IO years 7 months was by prednisolone in daily divided doses of 60 mg (days o&5), 40 mg (days 7-16), 30 mg (days 17-q), then 20 mg on alternate days as an outpatient (days 24-101). Side effects (Cushing) were minimal and blood pressure normal at day 24, with faint hirsuties at day 66. Morning blood specimens before rising were taken twice weekly throughout, then thrice as an outpatient, and assayed forthwith for all six serum enzymes (Fig. 2). All were haemolysis-free save that on day 14 (+ +). The neck flexors (day 8) and the facial and upper limb-girdle muscles (day 37) regained normal strength in that order, though a timed ascent of stairs remained just as slow and difficult. On day 66 tests showed a marked increase in general strength, and ascent of stairs was almost normal, in half the time and without the handrail. On day IOI the same tests showed no further improvement. Normal saline dilutions (3, 6, 9,12,15, 18 & 21 times) of serum 6 months before treatment had showed no real increase in CPK, ALD, LDH, GOT or GPT activities. (C) Steroid-resistant case. 22 months ago an athletic woman of 28 years developed progressive general weakness and wasting, chiefly proximal, with Raynaud phenomena and eventual dysphagia, until she needed a stick to walk and could scarcely ascend stairs. Serum enzyme elevations (Fig. 3) supported indifferent deltoid histology. There was no other abnormality.
5X
44c SERUM ENZYME VALUES 36C
280
: ‘b ALDx20
200
\
CPK x ‘h
UPPer Normal Limits * *./
: .., -
t
. l
previously
Fig. 3. Corticosteroid
DAYS after starting
treatment
GGTP GOT GPT
treatment
of resistant polymyositis
(C),
Clin. Chim.
Acta,
35 (1971)
193-199
THOXISON
198
Prednisolone dosage, increased stepwise to 30 mg daily by day 32, was maintained to day 83, then reduced to zero over 3 weeks, when the marked hirsuties and side-effects disappeared. by day 14; but though better,
Dysphagia had gone by day 7, and walking improved slightly by day IOO she walked without a stick and ascended stairs
rising from a chair was still as difficult. All five serum enzymes had declined by
half, but were still much elevated. DISCUSSION In Fig. I enzyme tissue specificity circulation
of soluble
muscle
protein
is evident after immediate content,
including
enzymes.
discharge
into the
The initial
great
serum elevations and rapid clearance to normal values of muscle CPK wholly describe the necrosis of this small muscle bulk. No evidence was found of further passive enzyme discharge on day 24, nor after exercise on day 36. The simultaneous lesser elevations of ALD, LDH, GOT and GPT likewise decline but not to normal, and their marked persistence, with normal CPK, indicates disease in tissues other than muscle. Increasing elevations of GGTP and suggest chronic hepatitis 5T6 , finally patient remained symptomless and progressing to irreversible cirrhosis.
progressively abnormal liver functions (Table I) demonstrated by liver biopsy. Throughout, the abnormal and anicteric, though biochemically Conventional
liver functions
became
abnormal
only slowly. Serial serum enzyme assay, particularly of CPK and GGTP, promptly described both muscle and hepatic lesions independently. Polymyositis3 is a sporadic, often chronic myopathy, usually inflammatory but often painless, occurring at any age and characterised primarily by muscular weakness, especially proximal, with late wasting; dermatomyositis has in addition a particular rash. Diagnostic serum elevations of effluent muscle enzymes occur, as in MD; unlike MD successful treatment by corticosteroids reduces these towards normal and restores strength, and serial assay monitors continued suppressive therapy. In this small series the response to corticosteroids is related not to dosage but to muscular weakness, and not to its severity but inversely to its duration, since cases A (I), A (z), B and C recovered in that order. This relation extends to muscle groups in individuals, those weakening last improving first, and conversely, as in Is and C. The very rapid response of A (I), profoundly weak but without obvious wasting, suggests a reversible lesion initially impairing only contractile mechanisms or their energy sources, consistent with the normal biopsy so often found2. Its persistence, as in B and C, may then cause structural damage requiring regrowth time before improvement, affirming a dependence of structure on function. Serial serum enzyme assay, especially of CPK, is by far the best measure of therapeutic efficacy, and can be diagnostic without biopsy, as in B. This case, chromatin-positive and without carrier ancestry, is still clinically and biochemically indistinguishable from the progressive, fatal DMD of boys, recorded only twice in X0 girls though biopsy in one was not obtained’ and in the other was uninformative*, or from the hitherto hypothetical DMD of girls now generally regarded as misdiagnosisg. The rapid decline (Fig. 2) to normal enzyme values on corticosteroid therapy, unknown in MD, is itself diagnostic long before physical improvement in such established cases; and renewed elevations due to too rapid dosage reduction after day 16 herald weakening, despite the continuing recovery of recent regrowth, now liable to regress. Since czin. Chim. Acta, 35
(1971)
rgp199
SERUM
ENZYMES
IN MUSCLE
DISEASE
I99
polymyositis can be treated and is sporadic, while DMD is fatal and implies a pedigree at risklo, this ready diagnosis of such DMD phenocopies, both boys and girls, becomes important. Occasionally patients are steroid-resistantll. In C, undoubted physical improvement is slow despite prolonged therapy with marked side-effects, but persists, perhaps due to regrowth, long after withdrawal. The slow decline of serum enzyme values (Fig. 3), only GPT becoming normal, reflects this; and methotrexate potentiation of steroid actionll may be appropriate. ACKNOWLEDGEMENTS
I wish to thank the patients examined, the medical colleagues who referred them, and Dr. Alex McQueen for the histology report in case B. This study was supported by the Andrew Patrick Trust and the Muscular Dystrophy Group of Great Britain. The Unicam SP 800 B spectrophotometer on which the enzyme assays were performed was kindly donated by Mrs. Kaye Tait of Cheltenham. REFERENCES
Cl&z.Chim. Acta, 35 (1971) 183. A. L. ROSE AND J.N. WALTON,&U~TZ, 89 (1966) 747. C. M. PEARSON, Ann. Rev. Med., 17 (1966) 63. C. E. THOMPSON, CC&. Pediat., 7 (1968) 24. S. B. ROSALKI, D. RAW, D. LEHMANN AND M. PRENTICE, Ann. CZin.Biochem., 7 (1970) '43. M. ZEIN AND G. DISCOMBE, Lancet, ii(Ig7o)748. J.N. WALTON,Ann.HumanGenet., 21 (1956) 40. P.FERRIER, F. BAMATTER AND D. KLEIN,~. Med. Genet.,2 (1965) 38. A. S. PENN, R. P. LISAK AND L. P. ROWLAND, Neurology, 20(1970) 147. W. H. S. THOMSON, C&n. Chim. Acta, 26 (1969) 207. M.C. SOKOLOFF,L. S. GOLDBERG AND C.M.PEARSON,L~~~~~,~(I~~I) 14.
I W. H. S. THOMSON,
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C&5. Chim. Acta, 35 (1971) 193-199