Decreased Muscle Strength in Patients With Alcoholic LiverCirrhosis in Relation to Nutritional Status, Alcohol Abstinence,

Liver Function, and Neuropathy

HENNING ANDERSEN,1 METTE BORRE,2 JOHANNES JAKOBSEN,1 PER HEDEN ANDERSEN,2 AND HENDRIK VILSTRUP2

To study motor function quantitatively in alcoholic livercirrhosis muscle strength, liver function, peripheral nervefunction, and nutrition were assessed in 24 patients.Isokinetic strength of flexion and extension at elbow, wrist,hip, knee, and ankle and of shoulder abduction and adduc-tion was evaluated and compared with findings in 24matched healthy subjects. Degree of liver disease wasassessed with the Child-Pugh score and the galactoseelimination capacity (GEC). Nutritional status was evalu-ated with an estimation of lean body mass (LBM) from24-hour urinary creatinine excretions. Peripheral nervefunction was evaluated with neurological symptom anddisability scores, nerve conduction studies, and quantita-tive sensory tests summed to obtain a neuropathy rank-sumscore (NRSS) for each patient. Combined muscle strength athip, knee, ankle, shoulder, elbow, and wrist were weakenedwith 34% (P F .005), 35% (P F .001), 35% (P F .01), 34%(P F .01), 29% (P F .01), and 29% (P F .02), respectively.The median Child-Pugh score was 7 (range, 5-12), and themedian duration of alcohol abstinence was 90 days (range,5-960 days). After multiple linear regression analysis includ-ing LBM, Child-Pugh score, GEC, duration of alcoholabstinence, and NRSS, only LBM was correlated to thestrength at the knee (r 5 .79; P F .0001) and at the ankle(r 5 .63; P F .01). It is concluded that muscle strength isweakened substantially in alcoholic patients with livercirrhosis and that weakness is related to the severity ofmalnutrition but not to the severity of liver disease,duration of alcohol abstinence, or neuropathy. (HEPATOLOGY

1998;27:1200-1206.)

It is a classical clinical observation that patients with livercirrhosis waste muscle mass. The wasting probably leads tomotor dysfunction and disability, but the functional conse-quences are sparsely documented. It is likely that reducedprotein intake and malnutrition contribute to the wasting,

but loss of muscle mass also occurs in patients with normaldietary intake.1 Decreased muscle protein synthesis andincreased myofibrillar degradation in cirrhotic patients couldplay a role as well.2,3 Furthermore, the physical inactivityassociated with severe liver disease probably contributes tothe wasting. In addition to loss of muscle mass, motordysfunction could result from biochemical and physiologicalabnormalities of the contractile properties and the character-istics of the sarcolemma. Thus, lowered concentrations ofenergy-rich phosphagens and magnesium have been reportedin studies of biopsy tissues of cirrhotic patients.4,5 At present,it is unknown whether these abnormalities lead to motordysfunction.

In chronic alcoholics, some studies have reported a pre-dominant type 2 fiber atrophy, indicating the existence of achronic alcoholic myopathy.6,7 In other studies, mitochon-drial alterations were observed, whereas fiber-type propor-tions and dimensions remained normal.8 Considering the fewand unspecific histological abnormalities, the existence of theentity alcoholic myopathy is not generally accepted. Further-more, some investigators suggest that chronic impairment ofmuscles in alcoholic patients is caused exclusively by neuro-genic atrophy.9 Alcoholic polyneuropathy is a predominantsensory disturbance during the initial stages. Later on,degeneration of motor nerves can result in denervation and,consequently, in wasting and weakness.10 In chronic alcohol-ics, a relation between motor neuropathy and muscle atrophyhas not been established.

In patients with alcoholic liver cirrhosis, it is unknownwhether muscle wasting and motor dysfunction are caused bymetabolic, nutritional, or neuropathic abnormalities. There-fore, the aim of the present study was to evaluate themuscular performance in patients with alcohol-induced livercirrhosis with standardized quantitative techniques in rela-tion to nutritional status, liver function, duration of alcoholabstinence, and peripheral nerve function.

PATIENTS AND METHODS

Patients and Control Subjects

During a 14-month period, 24 patients with alcohol-induced livercirrhosis who were referred to the Department of Hepatology andGastroenterology were included in the study. Ten patients werestudied shortly after the initial admission, and the other 14 patientswere studied at subsequent hospitalizations. In 17 patients, thediagnosis of liver cirrhosis was based on biopsy findings. Liverbiopsy was not possible in the remaining 7 patients, and conse-quently, diagnosis was made from clinical (ascites or hematemesis)and laboratory findings (hypoalbuminemia or hypoprothrombin-emia). Patients were not included if they had encephalopathy at the

Abbreviations: GEC, galactose elimination capacity; MNCV, motor nerve conductionvelocity; MAP, motor nerve action potential; SNCV, sensory nerve conduction velocity;SAP, sensory nerve action potential; MAC, mid-arm circumference; LBM, lean bodymass; NRSS, neuropathy rank sum score.

From the Departments of 1Neurology and 2Medicine V (Hepatology and Gastroenter-ology), Aarhus University Hospital, Aarhus, Denmark.

Received June 13, 1997; accepted January 6, 1998.Address reprint requests to: Henning Andersen, M.D., Department of Neurology,

Aarhus University Hospital, Nørrebrogade 44, 8000 Aarhus C, Denmark. Fax: 45-8949-3300.

Copyright r 1998 by the American Association for the Study of Liver Diseases.0270-9139/98/2705-0003$3.00/0

1200

time of study, severe cardiopulmonary disease, diabetes mellitus,other endocrine disorders, acute or chronic musculoskeletal disease,or any other neurological or psychiatric disturbances. For compari-son, the motor performance of 24 healthy age-, sex-, height-, andweight-matched controls was recruited among hospital employees,blood donors, friends, and relatives. To calculate a predictive valueof muscle strength at the ankle and knee, the performances of anadditional 65 healthy subjects were included. All patients andcontrol subjects gave informed consent to the study, which wasapproved by the local ethics committee.

Methods

Clinical Evaluation and Biochemical Measures. To exclude patientswith encephalopathy and dementia, all patients were assessed withthe Mini Mental State Examination.11 Patients were not included ifthe score was ,27 (maximum score, 30). The clinical status of thepatients was assessed according to the Child-Pugh classification(group A, B, and C), using measures of plasma bilirubin, plasmaalbumin, prothrombin time, and the presence or absence of ascitesand hepatic encephalopathy.12 Plasma bilirubin values of ,34µmol/L, between 34 and 51 µmol/L, and greater than 51 µmol/L gavescores of 1, 2, and 3, respectively. Correspondingly, plasma albuminvalues of greater than 35 g/L, between 28 and 35 g/L, and ,28 g/Lresulted in scores of 1, 2, and 3. Prothrombin time of greater than50%, between 30% and 50%, and ,30% of normal scored 1, 2, and 3,respectively. No ascites resulted in a score of 1, and scores for mildand severe ascites were 2 and 3, respectively. Patients with encepha-lopathy were excluded from the study, and therefore, all patientsscored 1 for encephalopathy. As described elsewhere, patients with atotal score of 5 to 6 were categorized as group A, scores of 7 to 9 weregroup B, and scores of greater than 9 were group C.

The 24-hour urinary excretion of creatinine was determined fromtwo collections. Serum levels of albumin, creatinine, magnesium,sodium, potassium, total calcium, iron, phosphate, bilirubin, methylmalonate, hemoglobin, leukocytes, thrombocytes, glucose, alanineaminotransferase, alkaline phosphatase, g-glutamyl transferase, pro-thrombin, thyreotropin-stimulating hormone, erythrocyte folate,immunoglobulin G, carbamide, M-component, and amylase weremeasured with standard laboratory techniques. Galactose elimina-tion capacity (GEC)13 was determined at the time of the studyexcept for a few patients. Eventually, all patients were evaluated by atrained neurologist according to a neuropathy symptom score14 anda neurological disability score.15 The neuropathy symptom scoreincludes symptoms of motor, sensory, and autonomic disturbances.Motor symptoms are complaints about weakness of proximal anddistal muscle groups of upper and lower extremities. In addition,complaints of facial and eye muscle palsy and difficulties in chewingand swallowing are noted. Sensory symptoms include difficulties inidentifying objects with hand and in the mouth, unsteadiness duringwalking, numbness or paresthesia, and pain of neuropathic origin.Autonomic symptoms are postural fainting, male impotence, loss ofurinary control, and nightly diarrhea. The neurological disabilityscore is obtained from the neurological examination and includesscores of muscle strength, tendon reflexes, and sensory functions.The strength of all major muscle groups of upper and lowerextremities is evaluated semiquantitatively and classified as 0, 25%,50%, 75%, and 100% of weakness, resulting in scores of 0 to 4,respectively. Activity of tendon reflexes including the biceps, triceps,brachioradialis, patellar, and achilles reflexes are evaluated andcategorized as normal, decreased, or absent, with the correspondingscores being 0, 1, and 2. Eventually, touch, pricking pain, vibration,and joint position on great toe and index finger are categorized asnormal, decreased, or absent using scores of 0, 1, and 2, respectively.

Electrophysiological Studies and Quantitative Sensory Examination Tests.Nerve conduction studies were performed with standard surfacestimulation and recording techniques using an electromyograph(DANTEC Counterpoint; Skovlunde, Denmark) with standard filtersettings.16 Motor nerve conduction velocity (MNCV) and amplitudeof the compound muscle action potential (MAP) were measured

from the dominant median nerve and the nondominant peronealnerve. Sensory nerve conduction velocity (SNCV) and amplitude ofthe sensory nerve action potential (SAP) were measured from thenondominant sural nerve and the dominant median nerve. ForMNCV and MAP, Z-scores were calculated from values of healthyvolunteers obtained with similar techniques.16 For SNCV and SAP,values previously determined in age-matched healthy controls wereadopted.

Vibratory perception thresholds were determined at pulp of thedominant index finger and at nondominant dorsum of the great toeusing forced choice techniques (Case IV; WR Medical ElectronicsCo., Stillwater, MN). Cooling perception thresholds were assessed atdorsum of the dominant hand and nondominant foot. The thresh-olds were obtained with the 4, 2, and 1 stepping algorithm.17 Theperception thresholds for each patient were compared with thecorresponding percentiles of a large group of healthy subjects.

Isokinetic Muscle Testing. The maximal isokinetic muscle strength(peak torque) of flexion and extension at ankle, hip, knee, elbow,and wrist, as well as abduction and adduction at shoulder, wasevaluated with an isokinetic dynamometer (Lido Active MultijointII; Loredan Biomedical, Inc., West Sacramento, CA). The nondomi-nant leg and the dominant arm were tested with standardizedprocedures as described elsewhere.18,19 After a presession, thesubjects were instructed to push and pull as hard and fast as possiblethrough the full available range of motion. Every test included eightreciprocal trials with a 10-second rest period between each trial. Toexclude submaximal performance, data were accepted if the coeffi-cient of variation for torque values was ,10%. In experiments inwhich the coefficient of variation was greater than 10%, the subjectwas retested once. If the coefficient of variation still was greater than10% at the second test, data were excluded if no out-layer torquecurve could be identified.

For the ankle, knee, and wrist tests, subjects were positioned asdescribed previously.19 At the elbow test, subjects were positioned ina semisupine position, and the axis of the dynamometer was alignedwith an axis perpendicular to the lateral epicondylus. At the hip test,subjects were supine, and the axis of the dynamometer was alignedwith an axis perpendicular to the major trochanter. At the shouldertest, subjects were lying on their nondominant side, and the axis ofthe dynamometer was aligned with an axis perpendicular to theacromion.

Nutritional Status. All patients were examined by a trained dieti-cian. Triceps skinfold thickness was measured with a skin caliper.20

The values were compared with those of a large group of healthysubjects in the literature.21 The mid-arm circumference (MAC) wasmeasured, and the mid-arm muscle area was calculated from thetriceps skinfold thickness as described by Frisancho.22 Lean bodymass (LBM) was determined from two 24-hour urinary creatinineexcretions (LBM 5 24-hour creatinine (in mmol) 3 3.29 1 7.38).23

Results are percentages of the expected values using formulasprovided by Shizgal.24 Eventually, the total lifetime dose of ethanolwas estimated on the basis of an interview.

Calculations and Statistical Analysis. For each patient, predictedvalues for strength of knee and ankle flexors and extensors werecalculated by the use of multiple regression analysis including thevariables of age, height, and weight for each sex. Hereby the actualmuscle strength of each patient was expressed as a percentage of thepredicted strength. To quantify the degree of neuropathy, anindividual neuropathy rank sum score (NRSS) was calculated. TheNRSS was a summation of the rank scores from the neuropathysymptom score, neurological disability score, sensory perceptionthresholds, conduction velocities, and amplitudes of motor andsensory nerves. Scores of symptoms and signs of muscular weaknesswere excluded from the total neuropathy symptom and neurologicaldisability scores. The sensory perception thresholds were rankedaccording to the sum of the two percentiles obtained from the handand foot. The conduction velocities and amplitudes were ranked foreach of the four nerves investigated, and the mean sum score of thefour conduction studies was included in the total rank sum.

HEPATOLOGY Vol. 27, No. 5, 1998 ANDERSEN ET AL. 1201

The primary study parameters were peak torque of flexion andextension at the ankle, knee, hip, elbow, and wrist and at shoulderabduction and adduction. To test the statistical significance ofmuscular strength differences between the cirrhotic patients andcontrol subjects, unpaired t tests were applied. The relationshipsbetween the muscle strength and the measures of nutrition andneuropathy or laboratory findings were estimated with linearregression analysis. Eventually, multiple linear regression analysiswas applied to disentangle the effect on muscle strength of neuropa-thy, stage of liver disease, duration of alcohol abstinence, andmalnutrition.

RESULTS

The cirrhotic patients, aged 51 6 4.6 years (average 6 SD),had a body weight of 66 6 14.6 kg and a height of 168 6 8.5cm. The control subjects, aged 53 6 9.6 years, had a bodyweight of 68 6 9.5 kg and a height of 170 6 7.6 cm. At theinitial admission for medical care, 19 patients had ascites, and10 patients had edema, whereas 3 patients had neither edemanor ascites. Seven and 10 patients had a history of hemateme-sis and encephalopathy, respectively.

At the day of testing the median Child-Pugh score was 7(range, 5-12). Seven patients had ascites. Thirteen weregroup A patients, 9 were group B patients, and 2 were group Cpatients. At the clinical examination, 11 patients had symp-toms of muscle weakness, and 9 had sensory symptoms,primarily paresthesias. The interval between last alcoholintake and the time of study was 90 days (range, 5-960 days).The amount of alcohol ingested was 67 g/d (range, 1.4-140g/d) during a period of 18.5 years (range, 5-40 years),resulting in an estimated total lifetime alcohol consumptionof 460 kg (range, 5-1,073 kg). In 4 patients, a reliable historyfor alcohol consumption could not be obtained. The clinicalexamination resulted in a median neurological disabilityscore of 13 (range, 0-30). Eighteen patients obtained scoresfor muscle weakness and 18 for abnormalities of tendonreflexes and/or sensory function. The Mini Mental StateExamination resulted in a median score of 29 (range, 27-30).No patient was excluded from the study because of a lowMini Mental State Examination score.

The patients had an LBM of 35.6 kg (range, 23.0-52.0 kg),corresponding to 79% (range, 48%-109%) of the expectedvalue. In 2 patients, the LBM could not be determinedbecause 1 subject refused 24-hour urine collection and, inone case, the creatinine determination failed. The body massindex for all patients was 21.2 (range, 15.2-36.1). Moredetailed information about nutritional status including mid-arm muscle area and MAC is given for each sex in Table 1.The median GEC was 1.4 mmol/min (range, 0.85-2.54mmol/min). Laboratory findings for the patients are shown inTable 2. In all patients, the methyl malonate level was withinnormal values. Furthermore, no patient had erythrocytefolate values below the lower limit, and no patient had an

M-component. Sixteen patients had lowered serum albuminlevels.

Abnormal thresholds of vibratory and cooling perceptionthresholds at foot as well as hand were found in 8 and 5patients, respectively. The MNCV and MAP of the mediannerve were 51.2 m/s (range, 39.6-56.3 m/s) and 6.0 mV(range, 1.8-11.0 mV), respectively. For the peroneal nerve,the MNCV was 39.5 m/s (range, 29.6-46.7 m/s), and the MAPwas 3.2 mV (range, 0.3-6.5 mV). In 4 patients, nerveconduction studies of the peroneal nerve could not beperformed because of atrophy of the extensor digitorumbrevis muscle. SNCV and SAP of the median nerve were 50.5m/s (range, 36.9-56.4 m/s) and 9.3 µV (range, 2.9-31.0 µV),respectively. SNCV of the sural nerve was 42.3 m/s (range,38.0-50.0 m/s), and the SAP was 4.0 µV (range, 0.8-9.6 µV).In 10 patients, no action potential could be obtained from thesural nerve.

The isokinetic strength of all evaluated muscle groups wasreduced in the patients compared with their matched controlsubjects (Figs. 1 and 2). For all muscle groups, a significantcorrelation between muscle strength and LBM was found(Table 3). In Fig. 3 the relationship between LBM and themaximal strength of knee extension is shown. In patientswith symptomatic muscle weakness, the strength of kneeextension was 54% 6 22% of the expected value comparedwith a value of 71% 6 17% in asymptomatic patients (P ,.05).

The muscle strength was related to the nutritional status.For the strength at the knee, significant correlations were

TABLE 1. Clinical Data for Cirrhotic Patients

SexBody Mass

IndexLBM(kg)

LBM(% of expected value)

MAC(% of reference)

Mid-ArmMuscle Area

(% of reference)

Women (n 5 15) 21.1 (15.2-31.6) 32.6 (23.0-46.4) 79 (60-109) 82 (66-108) 97 (60-155)Men (n 5 9) 23.2 (18.3-36.1) 41.4 (24.8-52.0) 78 (48-94) 85 (71-116) 60 (38-93)

NOTE. Values are expressed as medians with ranges in parentheses.

TABLE 2. Laboratory Findings for Cirrhotic Patients

Galactose elimination capacity (% of expected) 59 (32-86)Albumin (g/L) (37-48) 33 (23-48)Creatinine (µmol/L) (55-120) 72 (47-122)Magnesium (mmol/L) (0.70-1.10) 0.70 (0.52-1.01)Sodium (mmol/L) (136-146) 138 (127-144)Potassium (mmol/L) (3.2-5.0) 4.1 (2.5-4.7)Calcium (total) (mmol/L) (2.20-2.55) 2.33 (1.66-2.74)Phosphate (mmol/L) (0.80-1.50) 1.20 (0.48-1.50)Bilirubin (µmol/L) (,22) 20 (5-82)Hemoglobin (mmol/L) (7.4-9.6) 7.7 (5.8-11.0)Thrombocytes (109/L) (150-450) 164 (66-415)Alanine aminotransferases (U/L) (10-40) 29 (13-101)Alkaline phosphatases (U/L) (80-270) 259 (107-544)g-Glutamyl transferase (U/L) (,80) 140 (44-778)Prothrombin (arbitrary units) (0.80-1.20) 0.58 (0.34-1.00)Thyreotropin stimulating hormone (mU/L) (0.1-4.0) 1.37 (0.40-4.61)Immunoglobulin A (g/L) (0.7-4.3) 5.0 (2.6-10.1)Carbamide (mmol/L) (2.5-7.8) 3.3 (1.3-9.9)Amylase (U/L) (100-350) 239 (120-478)

NOTE. Values on the right are expressed as medians with ranges inparentheses. Reference values are given in parentheses on the left.

1202 ANDERSEN ET AL. HEPATOLOGY May 1998

found with MAC as well as with LBM (Fig. 4). Significantcorrelations were also found between the strength at theankle and the LBM (r2 5 .40; P , .005) and MAC (r2 5 .52;P , .0005). In contrast, no correlation could be establishedbetween the GEC or the Child-Pugh score and the strength atthe knee or the ankle. None of the laboratory findings givenin Table 2 was related to the strength at the knee. A significantpositive correlation was found between the strength at theknee and the interval between last alcohol intake and the dayof testing (interval between last alcohol intake and the day oftesting) (r2 5 .35; P , .003), whereas no correlation wasobserved at the ankle (r2 5 .02; NS). Interval between lastalcohol intake and the day of testing was also related to theLBM (r2 5 .20; P , .04). No relationship could be establishedbetween the severity of neuropathy expressed as the NRSSand the strength at the knee (Fig. 5), whereas a weakcorrelation was present for the ankle (r2 5 .18; P , .05).Multiple linear regression analysis including LBM, GEC,Child-Pugh score, interval between last alcohol intake and

the day of testing, and NRSS as independent variables resultedin a significant effect only of the LBM at the knee (r2 5 .62;P , .0001) as well as at the ankle (r2 5 .40; P , .01). Norelation was found between the LBM and the NRSS (r2 5 .10;NS). Total lifetime alcohol consumption also did not relate tostrength at the knee (r2 5 0; NS) or at the ankle (r2 5 0; NS).

DISCUSSION

Muscle wasting is a well-known complication of livercirrhosis in patients referred for medical care. Studies ofmotor performance and functional disability in patients withalcoholic liver cirrhosis are few. This is the first quantitativestudy of motor function in alcohol-induced cirrhotic patients.The study includes the relation of muscle strength to nutri-tional status, degree of liver disease, duration of alcoholabstinence, and nerve function. The main finding is asubstantial impairment of the strength of all muscle groups inpatients with alcohol-induced liver cirrhosis. The severity ofweakness closely relates to malnutrition, whereas severity ofperipheral neuropathy and liver disease and interval betweenalcohol intake and testing are not related to the musclestrength.

Population-based studies on elderly people have shown aclose relation between muscle strength and functional abil-ity,25 emphasizing the relevance of quantitative assessment ofmotor function. In the present study, the patients hadconsiderable muscle weakness, which clearly impaired dailyactivities. Isokinetic dynamometry enables sensitive monitor-

FIG. 2. Isokinetic muscle strength of the lower extremity for the cirrhoticpatients and the matched healthy controls. Numbers of patients are given inparentheses. *P , .01; and **P , .001.

FIG. 3. Isokinetic muscle strength of knee extension in relation to LBMfor the cirrhotic patients (r2 5 .62; P , .0005).

TABLE 3. Correlation Coefficient Between LBM (in kg) and CombinedMuscle Strength (in Nm) at Ankle, Knee, Hip, Shoulder, Elbow, and Wrist

Ankle 0.81*Knee 0.80*Hip 0.86*Shoulder 0.74†Elbow 0.69†Wrist 0.78*

*P , .0001.†P , .001.

FIG. 1. Isokinetic muscle strength of the upper extremity for the cirrhoticpatients and the matched healthy controls. Numbers of patients are given inparentheses. *P , .05; and **P , .01.

HEPATOLOGY Vol. 27, No. 5, 1998 ANDERSEN ET AL. 1203

ing of motor deficits and of the effect of medical treament,including liver transplantation. In healthy subjects, musclestrength varies in relation to weight, height, age, and sex.26

Other factors such as occupational status and physicalactivity have a significant impact on muscle strength, al-though the relationship is rather complex. Manual workresults in increased strength in younger subjects but de-creased strength in older subjects.27 Therefore, to evaluatequantitatively the strength of a patient, incorporation ofweight, height, age, and sex is necessary.

In cirrhotic patients, quantitative estimation of total musclemass is difficult because of disturbed body composition withfluid retention. LBM and MAC more closely reflect thenutritional status compared with body weight and serumprotein levels.28,29 Recently, it has been reported that anestimation of total body muscle mass based on 24-hourcreatinine excretion in cirrhotic patients resulted in falselylow values in patients with renal dysfunction caused byextrarenal excretion and recycling of creatinine to creatine.30

Nevertheless, in our study, a close correlation was foundbetween strength of all muscle groups and the LBM estimatedon the basis of renal creatinine excretion (Table 3 and Fig. 3),whereas neither laboratory findings nor the stage of liverdisease was related to the muscle strength. Also the LBMgiven as a percentage of the expected value was closely relatedto the muscle strength expressed as a percentage of theexpected value (Fig. 4). The expected muscle strength of theindividual patient was calculated on the basis of body weight,height, and sex. If a patient has loss of muscle mass withoutretention of fluid, this will result in a decrease of body weightand a lower predicted strength value. Consequently, thisadjustment could result in normal relative strength. However,some of the cirrhotic patients had fluid retention; therefore,the decrease in relative muscle strength could partly be aconsequence of overestimation of the predicted strengthcaused by alterations in body composition.

In addition to loss of muscle mass, motor dysfunction incirrhotic patients could also be caused by qualitative impair-ment of the muscles. This can be evaluated by quantitativeassessment of motor performance in relation to LBM enablingthe calculation of intrinsic muscle strength (force productionper unit muscle mass). In our study, LBM was not determinedin the control subjects, and it is not clear whether theobserved motor dysfunction is only caused by muscle wastingor by additional biochemical alterations of muscle function.A qualitative impairment can in fact be suspected becauseeven the well-nourished patients had some muscle impair-ment, i.e., a strength of ,100% of the expected value (Fig. 4).

Ethanol can induce changes in muscle function by inhibi-tion of muscle membrane channels and pumps, as well asdisturbances of protein synthesis and mitochondrial func-tion.31 In our study, the interval between last alcohol consump-tion and testing was correlated inversely with the musclestrength at the knee, suggesting a direct effect of ethanol perse. However, including all relevant variables, only the nutri-tional status was correlated with the muscle strength. Thus,the relationship between the interval and muscle strengthcould be a consequence of the more recent insufficientnutritional intake during heavy alcohol drinking, resulting ina more malnourished state at the day of study. Decreasedmuscular content of energy-rich phosphagens observed

FIG. 5. Averaged isokinetic muscle strength of knee extension andflexion (r2 5 .02; NS) expressed as a percentage of the predicted strength inrelation to the NRSS for the cirrhotic patients.

FIG. 4. Averaged isokinetic muscle strength of knee extension andflexion expressed as a percentage of the predicted strength in relation to the(A) MAC, given as a percentage of the reference value (r2 5 .56; P , .0001),and to the (B) LBM, expressed as a percentage of the predicted LBM (r2 5 .62;P , .00005), for the cirrhotic patients.

1204 ANDERSEN ET AL. HEPATOLOGY May 1998

in cirrhotic patients could contribute to impaired motorfunction.4 Also cirrhotic patients are insulin insensitive withconcomitant abnormal glycogen deposition in striatedmuscles.32 In addition, accelerated protein degradation and adecreased content of magnesium in striated muscles havebeen reported.3,5 All these abnormalities can contribute to themuscle impairment. Further studies are needed, however, toassess their exact influence on motor function.

In this study, the motor conduction velocities were moreimpaired than the amplitudes. Because proximal and distalparts of the nerves are affected equally, the impaired conduc-tion velocity most likely is caused by metabolic impairmentof the axolemma caused by collateral shunting and hepatocel-lular damage.33,34 It is noteworthy that, in the majority ofpatients in this study, the amplitudes of the motor nerveswere considerably less impaired than the conduction veloci-ties. Considering the severity of weakness, the amplitudeswere well preserved, which is in accordance with findings ofother studies.35 The well-preserved amplitudes suggest thatloss of muscle strength is not primarily caused by axonaldegeneration and neurogenic muscle atrophy. This is furthersupported by the absence of a correlation between theseverity of neuropathy and the strength at the knee (Fig. 5).This conclusion is in accordance with a recent study byEstruch et al.36 In 250 alcoholics, nearly 50% had myopathydefined as decreased muscle strength of shoulder abduction,whereas ,20% had electrophysiological signs of peripheralneuropathy.

The prevalence of neuropathy depends on the definition ofthe condition. No single clinical or electrophysiologicalvariable reliably reflects the degree of peripheral nervedamage in a patient partly because nerve pathology is widelyspread in the peripheral nervous system. To allow a mutualand reliable grading of the severity of neuropathy, wecalculated a NRSS for each patient based on the scores fromthe clinical examination, the quantitative sensory testing, andthe electrophysiological studies. This NRSS has been found tobe useful in other studies of motor function.19 It is notewor-thy that this NRSS was not closely related to motor functionin cirrhotic patients. Neurogenic atrophy in axonal polyneu-ropathies is located distally in the extremities. Also, thepresent finding of generalized weakness favors a metabolicmuscle dysfunction. It is unlikely that the slight changes ofperipheral nerve function found in the present study play animportant role in the development of the severe muscleweakness of cirrhotic patients.

In conclusion, patients with alcoholic liver cirrhosis havesubstantial generalized weakness of both proximal and distalmuscle groups. The weakness is related to malnutrition butnot to degree of liver disease, duration of alcohol abstinence,total life dose of alcohol, or peripheral neuropathy. Furtherstudies are warranted to assess whether muscles from cir-rhotic patients are weak because of factors other than loss ofmass and to decide whether hyperalimentation can improvemotor function.

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