CASE REPORT
Duchenne and Becker Muscular Dystrophy Presenting as Nonalcoholic Fatty Liver Disease C. Veropalumbo, E. Del Giudice, G. Capuano, C. Gentile, N. Di Cosmo, and P. Vajro
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onalcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of conditions ranging from simple steatosis to steatohepatitis and liver cirrhosis (1). It is the most common liver disorder in the pediatric age group, paralleling the epidemic of obesity (2,3). Duchenne and Becker muscular dystrophy (DBMD) is often characterized in the early stage by central obesity and increased muscular fat content (4). We report on the first case of biopsy-proven NAFLD in a patient with DBMD to emphasize the relation between these 2 conditions as well as the peculiar weightloss management. The patient, a 9-year-old Italian boy, was born at the 32nd week of gestation. His clinical history, including the achievements of motor milestones, was uneventful up to the age of 7 years, when he complained of mild and ill-defined general asthenia. Because of this, he underwent routine laboratory examinations. The only reported abnormal laboratory tests were the increased serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (3 times upper normal values [unv] for both enzymes). He was then hospitalized because of the persistence of isolated hypertransaminasemia for approximately 1 year (levels ranging from 4 to 6 times unv for AST and from 3 to 5 times unv for ALT). Laboratory tests performed to exclude the most common viral and autoimmune causes of liver diseases were within normal limits. Ultrasonography of the liver showed a bright pattern compatible with steatosis, which was also confirmed at histology after needle liver biopsy (Fig. 1). Because of his obesity (both body mass index [BMI] and weight/height [W/H] ratio >95th percentile) and excessive caloric intake, a slimming diet was prescribed. Four months after starting the diet he lost some weight (4.2 kg, 8% of basal weight) and ultrasonographic liver brightness decreased. Hypertransaminasemia, however, remained unchanged (AST and ALT 5 and 4 times unv, respectively). The patient was therefore referred to our pediatric liver unit at the age of 8 years 10 months. His mother and father were obese and overweight, respectively. His mother presented with a pattern of insulin resistance (HOMA 2.9) without other components of the metabolic syndrome, and his father had borderline HOMA (2.4). Both parents had normal serum aminotransferase levels and a recently performed abdominal ultrasonography without liver brightness. At physical examination, the patient appeared obese and anthropometric parameters were as follows: weight 42.1 kg (>95th percentile), height 134 cm Received May 20, 2010; accepted February 3, 2011. From the Department of Pediatrics, University of Naples ‘‘Federico II,’’ Naples, Italy. Address correspondence and reprint requests to Prof Pietro Vajro, Department of Pediatrics, University of Naples ‘‘Federico II,’’ Via S. Pansini 5, 80131 Naples, Italy (e-mail:
[email protected]). The authors report no conflicts of interest. Copyright # 2011 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0b013e318217f5d9
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(50th–75th percentile), weight/height ratio >95th percentile, and BMI 24.1 kg/m2 (>95th percentile). Visceral adiposity was significant (waist circumference 76 cm, >95th percentile). The patient was in good general clinical condition, and his liver and spleen were not enlarged. Blood pressure was 110/60 mmHg. Repeated neurological examination revealed a cooperative patient with no cognitive, behavioral, or language delays. Gait was within normal limits, possible on heels and toes. The ability to climb upstairs and descend downstairs without support was reported by the mother. The bilateral mild increase in the consistency of the gastrocnemius muscle along with a slightly abnormal Gower sign (the boy needed support to pull himself to an upright position), combined with high serum levels of muscle enzymes, was compatible with DBMD. Laboratory findings confirmed increased serum ALT (152 U/L, 4 times unv) and AST (206 U/L, 5 times unv) with no cholestasis or abnormalities of synthetic function. Tests aimed at investigating possible hepatic causes of hypertransaminasemia, namely viral infections (hepatitis B, C, Epstein-Barr and cytomegalovirus serum markers), autoimmune disorders (nuclear, smooth muscle, liver-kidney microsomes, and liver citosol serum antibodies; serum total immunoglobulin [Ig]), genetic-metabolic diseases (a1 antitrypsin, ceruloplasmin, glucose, lactic acid, ammonia, amino acids serum levels, blood gas analysis, urinary-reducing substances and organic acids, sweat test), and celiac disease (anti-tissue transglutaminase and antigliadin IgG and IgM serum antibodies markers) were within normal limits. HOMA was indicative of insulin resistance (3.2). Blood lipid profile was within normal limits. Slight acanthosis nigricans was present on the neck. A repeated liver ultrasonography showed a mild residual liver brightness. To investigate a possible muscular origin of elevated aminotransferases, muscle-specific enzymes (eg, lactate dehydrogenase [LDH], creatine kinase [CK], and aldolase) were also evaluated. LDH was 1181 IU/L (2.5 times unv), CK was 6885 IU/L (30 times unv), and aldolase was 87 IU/L (11 times unv). Cardiologic evaluation provided normal results. Finally, molecular testing for the dystrophin gene revealed a macrodeletion of exons 45 to 48. A total-body dual-energy x-ray absorptiometry (DEXA) study was therefore performed to evaluate body composition and compared with the results of age-matched healthy subjects and patients with DBMD (4). Bone mineral density of whole body (1436.1 g) and mean lean body mass (LBM) value (24,918 g) were between mean values and standard deviation of healthy controls. Conversely, whole-body and trunk fat percentage were above upper normal values of both healthy control subjects and patients with DBMD. Moderate physical activity for habilitation and a diet for gradual weight loss were therefore prescribed to preserve muscular function and LBM, respectively. The patient was then referred to the pediatric neurology unit where he has been followed up.
DISCUSSION During a 2-year period our obese patient with asymptomatic myopathy had been fully investigated and followed up for NAFLD
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Veropalumbo et al
FIGURE 1. Needle liver biopsy showing mild micro/macrovacuolar simple steatosis without inflammation and fibrosis (Brunt score of 1). (Hematoxylin and eosin stain; original magnification 20). and other hepatic causes of his hypertransaminasemia, before a muscular origin of aminotransferases could be detected, because of a cooccurring diagnosis of obesity-related histological and ultrasonographic liver steatosis. It should be stated, however, that even mild symptoms and signs, for example, asthenia, increased bulk of calves, and minor weakness associated with elevated transaminases, should have immediately prompted the search for DBMD. DBMD is a frequently unrecognized cause of increased serum muscular aminotranferases in the pediatric age group (2,5). Patients with DBMD also may present with excess weight gain occurring in the early stage of the disease, which contributes to the progression of muscular injury by exerting extra forces on weak muscles. Obesity may occur from the age of 7 years; its prevalence seems to reach approximately 50% by the age of 13 years. In agreement with other obese populations, DBMD-obese boys show a centralized body fat distribution (6). In adult, onset myotonic dystrophy NAFLD has been reported frequently and related to peripheral insulin resistance rather than to weight excess itself (7). Apart from the case reported here, NAFLD has not hitherto been reported in patients with DBMD. Insulin resistance, however, has been reported to occur in late wheelchaired patients with DBMD (8). We cannot exclude that this metabolic derangement may occur earlier in cases of obesity and be involved in causing NAFLD development. The issue is of particular interest because a timely diagnosis plays a key role in organizing weight management in DBMD. A drastic hypocaloric diet should be avoided similar to what is indicated in obese children with NAFLD. Physical activity should be individually tailored. In fact, it is necessary not only to prevent the progression of liver damage (9) but also to avoid loss of LBM, which does not have the potential to regenerate (10). In our patient, we recommended gradual weight loss, looking at decreasing W/H ratio rather than weight alone. Because there is a risk of increased muscle breakdown from overuse versus increased muscle weakness for disuse (11), our patient started to follow a regular but lowintensity exercise program. DEXA monitoring has been planned for adjusting dietetic and physical activity management to reduce his trunk fat percentage and preserve the LBM (12). Our patient well illustrates that DBMD may be a special item of the ‘‘NASH trash’’ bin (nonalcoholic steatohepatitis) (13,14). We believe that health care providers should be aware that early DBMD is a condition predisposing to overweight and consequently
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also to fatty liver disease (NAFLD). Poor responsiveness of hypertransaminasemia to diet and lifestyle changes is an alarm bell for underlying conditions other than NAFLD alone. Including CK measurements in the initial diagnostic workup would be an easy and inexpensive way to shorten the time to establishing the diagnosis of DBMD. CK levels should be measured in any child with elevated transaminases, even in the presence of a known cause of liver disease and/or in absence of obvious symptoms of myopathy. A high index of suspicion for DBMD is needed because, should DBMD be diagnosed in an obese patient, a careful and personalized management for early and safe weight loss and exercise is mandatory (15). The delayed diagnosis of DBMD is particularly important in light of the subsequent delay in starting corticosteroid treatment and potential lost opportunities for timely genetic counseling. Acknowledgment: We thank Prof R. Vecchione for thoughtful discussion and histological evaluation of liver biopsy.
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