Consider Muscle Disease in Children with Elevated Transaminase
==============================================================

* Melissa A. Wright
* Michele L. Yang
* Julie A. Parsons
* John M. Westfall
* Audrey S. Yee

## Abstract

The transaminases alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are markers of hepatocellular injury but are highly concentrated in muscle cells. Consequently, muscular dystrophies such as Duchenne muscular dystrophy, lead to hypertransaminasemia. Elevation in ALT and AST is most striking during the early stages of disease, before onset of or when only subtle signs of muscle disease are present. Thus, the incidental finding of elevated ALT/AST may be the presenting sign of muscle disease in many children and provides an opportunity for early diagnosis. Many physicians, however, pursue extensive workup for liver disease in children who present with the incidental finding of elevated ALT/AST. This results in delayed diagnosis and initiation of treatment and increased expense and may lead to unnecessary invasive procedures. We report 12 patients with muscle disease who presented with a variety of symptoms and were found to have an incidental finding of elevated ALT/AST. We propose a rapid screening process for evaluating children with the incidental finding of elevated ALT/AST to shorten the time to diagnosis of muscle disease.

*   Case Reports
*   Children
*   Muscle Weakness
*   Muscular Dystrophy
*   Neurology
*   Transaminases

Serum creatinine kinase (CK) is markedly elevated with breakdown of muscle and is considered a diagnostic marker of muscular dystrophies.1⇓⇓⇓–5 However, it also has long been recognized that alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are present in high concentrations in muscle; elevation of ALT and AST can signal disruption of the muscle membrane.1,4,6 ALT and AST also are found, to a lesser extent, in cardiac muscle, the pancreas, and the kidneys.7,8 Nevertheless, these transaminases frequently are considered to be specific indicators of liver injury and are included in the complete metabolic panel routinely used to screen patients for evidence of liver disease.

Although the majority of patients with chronic hypertransaminasemia ultimately will demonstrate evidence of liver disease, the finding of elevated AST/ALT in the absence of other laboratory abnormalities typically associated with liver disease can pose a diagnostic challenge. Several case reports demonstrate isolated hypertransaminasemia as an initial finding of muscle disease in children.9⇓⇓–12 Despite this, many children with muscle disorders continue to undergo costly and invasive workups for liver disease in the face of the incidental finding of elevated ALT and AST. Here, we report 12 patients with muscle disorders who presented to our muscle clinic only after extensive investigation for liver disease. We propose a rapid screening process for evaluating children with elevated ALT/AST.

## Results

Twelve patients ultimately diagnosed with muscle disorders first presented with a variety of clinical symptoms. Initial blood work showed that they had elevated transaminase levels (ALT/AST). Patients ranged in age from 7 months to 16 years at initial presentation (Table 1). A wide variety of complaints prompted evaluation of a complete metabolic panel in these children, including infection in 4, failure to thrive/poor growth in 4, prolonged diarrhea in one, abdominal pain in one, and splenomegaly in one. ALT levels ranged from 99 to 477 IU/L and averaged 266 IU/L, whereas AST levels ranged from 50 to 497 IU/L and averaged 249 IU/L (Table 1). Serum gamma-glutamyl transferase (GGT) was only checked in 4 patients, but was found to be normal in all (data not shown).

View this table:
[Table 1.](http://www.jabfm.org/content/25/4/536/T1)

Table 1. Patient Characteristics at Presentation and Follow-up

Eight of the 12 children already had exhibited signs or symptoms of muscle disease (eg, calf hypertrophy, toe walking, and muscle weakness) at initial presentation to the neuromuscular clinic. Despite these early signs and symptoms, the average time from identification of elevated ALT/AST to discovery of elevated CK levels was 7 months. The majority of patients had undergone extensive workup for liver disease before a serum CK was checked. In addition to an abundance of serum testing, abdominal ultrasound was performed on 10 of the12 patients and an abdominal MRI was performed on 2 (Table 2). Of particular concern, 4 patients underwent liver biopsies, and only one yielded abnormal pathology. Serum CK testing was ultimately ordered by specialized gastroenterology clinics for 11 patients and an inpatient pediatrics team for the 12th patient.

View this table:
[Table 2.](http://www.jabfm.org/content/25/4/536/T2)

Table 2. Clinical Evaluation for Elevated AST/ALT and Time to Diagnosis of Muscle Disease

When these patients first presented to the muscle clinic, serum CK levels averaged 12,078 IU/L (range, 4867–22,009) (Table 1). The majority (8 of 12) displayed subtle signs of muscle disease, including calf hypertrophy, mild weakness, and hypotonia. Two more patients became symptomatic within 1 year of presenting to muscle clinic. Subsequently, 8 patients were diagnosed with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy by genetic testing, one of whom was identified as a manifesting (symptomatic) female carrier of a dystrophin mutation and one of whom was diagnosed with a dystroglycanopathy. Two patients remain undiagnosed on a genetic basis but carry a clinical diagnosis of muscular dystrophy (Table 1).

## Discussion

DMD is estimated to affect one in 3500 live male births.13 A recent multistate study indicates that signs and symptoms of DMD appear, on average, at age 2.5 years.14 However, because the initial signs and symptoms are mild, there is an average delay of 1 year before children receive medical attention. An additional year-long delay occurs before serum CK levels are measured or children are sent to a neurologist for formal evaluation and treatment.14 Furthermore, although the majority of children first present to their family physician or pediatrician, the primary care provider was the first to check a serum CK in only one third of cases.14

In the past, life expectancy was poor; however, because of improved respiratory therapy, physical therapy, and supportive measures, life expectancy now has improved greatly and boys are living well into their mid-20s. Because of newer clinical and pharmaceutical interventions, early diagnosis has become even more important. Corticosteroids have been shown to slow disease progression and are emerging as a standard treatment for DMD.15⇓⇓⇓–19 Some authors suggest that initiation of steroid treatment as early in the disease process as possible may prolong functionality during later treatment.17 Interestingly, in our study and others, elevated ALT/AST may be seen in early stages of the disease before symptoms of muscle weakness are noted by the family.10,11,20 Further molecular and pharmaceutical advances are on the horizon, and true disease-modifying agents are in early trials.21,22

Many children with muscle disease remain undiagnosed for extended periods after the finding of elevated transaminases. In our study, a primary muscle etiology for elevated ALT/AST was not considered for more than a year in a quarter of the patients, and one patient waited 2 years before evaluation of serum CK. In addition, testing for liver disease involved invasive liver biopsy in one third of patients. To prevent delays in diagnosis, as well as unnecessary invasive testing, it is important to maintain a high index of suspicion for extrahepatic sources of ALT and AST.

We propose a simplified process for rapid screening in patients with elevated ALT/AST on the basis of the recommendations of the DMD Care Considerations Working Group.16 Children with elevated ALT/AST who also have elevated bilirubin or alkaline phosphatase on the metabolic panel should be evaluated for gastrointestinal disease. Elevated serum GGT can be used to identify patients with liver disease.9 A CK level should be obtained in patients with elevated ALT/AST without clear gastrointestinal disease and could be done at the same time as serum GGT. The patient also should be evaluated for symptoms of gait disturbance, falls, or muscle pain and be examined for calf hypertrophy or muscle weakness. A quick developmental screen should be performed and questions regarding gross motor milestones (onset of independent walking) should be asked. Gower sign is common in children with proximal muscle weakness; because of poor hip and thigh strength, it is characterized by using hands and arms to push on thighs to raise the body from a supine position to a standing position. Family history regarding the presence of muscle disease should be obtained. If signs or symptoms are positive, the patient should be evaluated by a neurologist for muscle disease. In the absence of findings suggestive of either liver or muscle disease, other causes of elevated transaminases, such as those with a renal, pancreatic, or cardiac origin, must be addressed.

## Notes

*   This article was externally peer reviewed.

*   *Funding:* none.

*   *Conflict of interest:* none declared.

*   Received for publication May 26, 2011.
*   Revision received August 25, 2011.
*   Accepted for publication September 2, 2011.

## References

1.  1. Pearson CM, Chowdhury SR, Fowler WM Jr., Jones MH, Griffith WH. Studies of enzymes in serum in muscular dystrophy. II. Diagnostic and prognostic significance in relatives of dystrophic persons. Pediatrics 1961;28:962–70.
    
    [Abstract/FREE Full Text](http://www.jabfm.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTA6InBlZGlhdHJpY3MiO3M6NToicmVzaWQiO3M6ODoiMjgvNi85NjIiO3M6NDoiYXRvbSI7czoyMDoiL2phYmZwLzI1LzQvNTM2LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

2.  2. Somer H, Donner M, Murros J, Konttinen A. A serum isozyme study in muscular dystrophy. Particular reference to creatine kinase, aspartate aminotransferase, and lactic acid dehydrogenase isozymes. Arch Neurol 1973;29:343–5.
    
    [CrossRef](http://www.jabfm.org/lookup/external-ref?access_num=10.1001/archneur.1973.00490290083012&link_type=DOI) 
    
    [PubMed](http://www.jabfm.org/lookup/external-ref?access_num=4743886&link_type=MED&atom=%2Fjabfp%2F25%2F4%2F536.atom) 
    
    [Web of Science](http://www.jabfm.org/lookup/external-ref?access_num=A1973R175500012&link_type=ISI) 

3.  3. Thomson WH. Serum enzyme studies in inherited disease of skeletal muscle. Clin Chim Acta 1971;35:183–91.
    
    [PubMed](http://www.jabfm.org/lookup/external-ref?access_num=5126991&link_type=MED&atom=%2Fjabfp%2F25%2F4%2F536.atom) 

4.  4. Munsat TL, Baloh R, Pearson CM, Fowler W Jr.. Serum enzyme alterations in neuromuscular disorders. JAMA 1973;226:1536–43.
    
    [CrossRef](http://www.jabfm.org/lookup/external-ref?access_num=10.1001/jama.1973.03230130024009&link_type=DOI) 
    
    [PubMed](http://www.jabfm.org/lookup/external-ref?access_num=4800933&link_type=MED&atom=%2Fjabfp%2F25%2F4%2F536.atom) 
    
    [Web of Science](http://www.jabfm.org/lookup/external-ref?access_num=A1973R569500005&link_type=ISI) 

5.  5. Sibley JA, Lehninger AL. Aldolase in the serum and tissue of tumor-bearing animals. J Natl Cancer Inst 1949;9:303–9.
    
    [FREE Full Text](http://www.jabfm.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6MzoiUERGIjtzOjExOiJqb3VybmFsQ29kZSI7czo0OiJqbmNpIjtzOjU6InJlc2lkIjtzOjc6IjkvNC8zMDMiO3M6NDoiYXRvbSI7czoyMDoiL2phYmZwLzI1LzQvNTM2LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

6.  6. Thomson WH. Serum enzyme studies in acquired disease of skeletal muscle. Clin Chim Acta 1971;35:193–9.
    
    [PubMed](http://www.jabfm.org/lookup/external-ref?access_num=5126992&link_type=MED&atom=%2Fjabfp%2F25%2F4%2F536.atom) 

7.  7. Wroblewski F. The clinical significance of transaminase activities of serum. Am J Med 1959;27:911–23.
    
    [CrossRef](http://www.jabfm.org/lookup/external-ref?access_num=10.1016/0002-9343(59)90175-5&link_type=DOI) 
    
    [PubMed](http://www.jabfm.org/lookup/external-ref?access_num=13846130&link_type=MED&atom=%2Fjabfp%2F25%2F4%2F536.atom) 
    
    [Web of Science](http://www.jabfm.org/lookup/external-ref?access_num=A1959WC16900005&link_type=ISI) 

8.  8. Wroblewski F, Ladue JS. Serum glutamic pyruvic transaminase in cardiac with hepatic disease. Proc Soc Exp Biol Med 1956;91:569–71.
    
    [Abstract/FREE Full Text](http://www.jabfm.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NToic3BlYm0iO3M6NToicmVzaWQiO3M6ODoiOTEvNC81NjkiO3M6NDoiYXRvbSI7czoyMDoiL2phYmZwLzI1LzQvNTM2LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

9.  9. Rosales XQ, Chu ML, Shilling C, Wall C, Pastores GM, Mendell JR. Fidelity of gamma-glutamyl transferase (GGT) in differentiating skeletal muscle from liver damage. J Child Neurol 2008;23:748–51.
    
    [Abstract/FREE Full Text](http://www.jabfm.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NToic3BqY24iO3M6NToicmVzaWQiO3M6ODoiMjMvNy83NDgiO3M6NDoiYXRvbSI7czoyMDoiL2phYmZwLzI1LzQvNTM2LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

10. 10. Urganci N, Arapoglu M, Serdaroglu P, Nuhoglu A. Incidental raised transaminases: a clue to muscle disease. Ann Trop Paediatr 2006;26:345–8.
    
    [CrossRef](http://www.jabfm.org/lookup/external-ref?access_num=10.1179/146532806X152872&link_type=DOI) 
    
    [PubMed](http://www.jabfm.org/lookup/external-ref?access_num=17132300&link_type=MED&atom=%2Fjabfp%2F25%2F4%2F536.atom) 
    
    [Web of Science](http://www.jabfm.org/lookup/external-ref?access_num=000242714600010&link_type=ISI) 

11. 11. Zamora S, Adams C, Butzner JD, Machida H, Scott RB. Elevated aminotransferase activity as an indication of muscular dystrophy: case reports and review of the literature. Can J Gastroenterol 1996;10:389–93.
    
    [PubMed](http://www.jabfm.org/lookup/external-ref?access_num=9193775&link_type=MED&atom=%2Fjabfp%2F25%2F4%2F536.atom) 
    
    [Web of Science](http://www.jabfm.org/lookup/external-ref?access_num=A1996VP62800008&link_type=ISI) 

12. 12. Rutledge J, Andersen J, Fink CW, Cook J, Strickland A. Persistent hypertransaminasemia as the presenting finding of childhood muscle disease. Clin Pediatr (Phila) 1985;24:500–3.
    
    [Abstract/FREE Full Text](http://www.jabfm.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NToic3BjcGoiO3M6NToicmVzaWQiO3M6ODoiMjQvOS81MDAiO3M6NDoiYXRvbSI7czoyMDoiL2phYmZwLzI1LzQvNTM2LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

13. 13. Emery AE. Population frequencies of inherited neuromuscular diseases–a world survey. Neuromuscul Disord 1991;1:19–29.
    
    [CrossRef](http://www.jabfm.org/lookup/external-ref?access_num=10.1016/0960-8966(91)90039-U&link_type=DOI) 
    
    [PubMed](http://www.jabfm.org/lookup/external-ref?access_num=1822774&link_type=MED&atom=%2Fjabfp%2F25%2F4%2F536.atom) 

14. 14. Ciafaloni E, Fox DJ, Pandya S, et al. Delayed diagnosis in Duchenne muscular dystrophy: data from the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet). J Pediatr 2009;155:380–5.
    
    [CrossRef](http://www.jabfm.org/lookup/external-ref?access_num=10.1016/j.jpeds.2009.02.007&link_type=DOI) 
    
    [PubMed](http://www.jabfm.org/lookup/external-ref?access_num=19394035&link_type=MED&atom=%2Fjabfp%2F25%2F4%2F536.atom) 
    
    [Web of Science](http://www.jabfm.org/lookup/external-ref?access_num=000269427400019&link_type=ISI) 

15. 15. Balaban B, Matthews DJ, Clayton GH, Carry T. Corticosteroid treatment and functional improvement in Duchenne muscular dystrophy: long-term effect. Am J Phys Med Rehabil 2005;84:843–50.
    
    [CrossRef](http://www.jabfm.org/lookup/external-ref?access_num=10.1097/01.phm.0000184156.98671.d0&link_type=DOI) 
    
    [PubMed](http://www.jabfm.org/lookup/external-ref?access_num=16244521&link_type=MED&atom=%2Fjabfp%2F25%2F4%2F536.atom) 
    
    [Web of Science](http://www.jabfm.org/lookup/external-ref?access_num=000232930300003&link_type=ISI) 

16. 16. Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol 2010;9:77–93.
    
    [CrossRef](http://www.jabfm.org/lookup/external-ref?access_num=10.1016/S1474-4422(09)70271-6&link_type=DOI) 
    
    [PubMed](http://www.jabfm.org/lookup/external-ref?access_num=19945913&link_type=MED&atom=%2Fjabfp%2F25%2F4%2F536.atom) 
    
    [Web of Science](http://www.jabfm.org/lookup/external-ref?access_num=000273199700026&link_type=ISI) 

17. 17. Merlini L, Cicognani A, Malaspina E, et al. Early prednisone treatment in Duchenne muscular dystrophy. Muscle Nerve 2003;27:222–7.
    
    [CrossRef](http://www.jabfm.org/lookup/external-ref?access_num=10.1002/mus.10319&link_type=DOI) 
    
    [PubMed](http://www.jabfm.org/lookup/external-ref?access_num=12548530&link_type=MED&atom=%2Fjabfp%2F25%2F4%2F536.atom) 
    
    [Web of Science](http://www.jabfm.org/lookup/external-ref?access_num=000180792600012&link_type=ISI) 

18. 18. Moxley RT 3rd., Ashwal S, Pandya S, et al. Practice parameter: corticosteroid treatment of Duchenne dystrophy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2005;64:13–20.
    
    [Abstract/FREE Full Text](http://www.jabfm.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6OToibmV1cm9sb2d5IjtzOjU6InJlc2lkIjtzOjc6IjY0LzEvMTMiO3M6NDoiYXRvbSI7czoyMDoiL2phYmZwLzI1LzQvNTM2LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

19. 19. Manzur AY, Kuntzer T, Pike M, Swan A. Glucocorticoid corticosteroids for Duchenne muscular dystrophy. Cochrane Database Syst Rev 2008;(1):CD003725.
    
    

20. 20. Morse RP, Rosman NP. Diagnosis of occult muscular dystrophy: importance of the “chance” finding of elevated serum aminotransferase activities. J Pediatr 1993;122:254–6.
    
    [PubMed](http://www.jabfm.org/lookup/external-ref?access_num=8429443&link_type=MED&atom=%2Fjabfp%2F25%2F4%2F536.atom) 
    
    [Web of Science](http://www.jabfm.org/lookup/external-ref?access_num=A1993KL32800016&link_type=ISI) 

21. 21. van Deutekom JC, Janson AA, Ginjaar IB, et al. Local dystrophin restoration with antisense oligonucleotide PRO051. N Engl J Med 2007;357:2677–86.
    
    [CrossRef](http://www.jabfm.org/lookup/external-ref?access_num=10.1056/NEJMoa073108&link_type=DOI) 
    
    [PubMed](http://www.jabfm.org/lookup/external-ref?access_num=18160687&link_type=MED&atom=%2Fjabfp%2F25%2F4%2F536.atom) 
    
    [Web of Science](http://www.jabfm.org/lookup/external-ref?access_num=000251964500006&link_type=ISI) 

22. 22. Kinali M, Arechavala-Gomeza V, Feng L, et al. Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, dose-escalation, proof-of-concept study. Lancet Neurol 2009;8:918–28.
    
    [CrossRef](http://www.jabfm.org/lookup/external-ref?access_num=10.1016/S1474-4422(09)70211-X&link_type=DOI) 
    
    [PubMed](http://www.jabfm.org/lookup/external-ref?access_num=19713152&link_type=MED&atom=%2Fjabfp%2F25%2F4%2F536.atom) 
    
    [Web of Science](http://www.jabfm.org/lookup/external-ref?access_num=000270111200014&link_type=ISI)