Elevated Serum Aminotransferases Secondary to Rippling Muscle Disease
A 43-year-old male fitness trainer presented to the hepatology clinic after being referred by his general practitioner with elevated serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels (2–3 times the upper limit of normal) over a period of 7 months. Bilirubin, gamma-glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP) were within normal range. On further questioning, the patient gave a history of rippling muscle disease diagnosed when he was 9 years old. Subsequently, he had been lost to further follow-up. There was no other relevant medical history. Specifically he had no history of alcohol abuse or dependency, no history of illicit drug use, no known history of hepatitis and he was not on any regular medications. A detailed family history and research into previous investigations performed on the patient and his family revealed that his father and elder brother had been found to have elevated serum creatine kinase (CK) concentrations. Genetic linkage analysis had pointed to caveolin-3 mutations in all of them.\nOn physical examination, there were no stigmata of chronic liver disease, and gastrointestinal, cardiovascular and respiratory examinations were unremarkable. Positive neuromuscular findings consistent with rippling muscle disease included a long-standing history of activity-related fatigue of upper and lower limb muscle groups. He had obvious symmetrical wasting of pectoralis major muscles bilaterally (fig. ). Characteristic muscle rippling was demonstrated after minimal activity of proximal muscles in the upper limbs and lower limbs bilaterally (online suppl. video clips and ; for all online suppl. material, see www.karger.com/doi/10.1159/000351824). He demonstrated fatigue with repetitive contractions of major skeletal muscle groups (online suppl. video clip ).\nFull blood count examination and serum urea and electrolytes examination were normal. Full liver screen including a liver ultrasound, viral hepatitis, cytomegalovirus screen and autoimmune screen were also normal. There was no evidence of haemochromatosis or Wilson's disease with normal iron studies, serum copper and caeruloplasmin. Thyroid function tests were normal. A Fibroscan® of the liver demonstrated median stiffness of 5.9 kPa consistent with minimal or absent fibrosis.\nPrevious diagnostic studies including a gastrocnemius muscle biopsy when the patient was 9 years of age showed predominance of type 1 fibres, with isolated fibres exhibiting atrophy. There were also degenerative and regenerative changes, suggestive of mild focal necrotising myopathy.\nBlood tests over a 10-month period are shown in table . A consistent elevation of serum aminotransferases and CK is demonstrated.\nALT and AST catalyse the transfer of the alpha-amino groups of alanine and aspartate, respectively, to the alpha-keto group of ketoglutarate. This results in the formation of pyruvate and oxaloacetate [].\nVarious studies have analysed the clinical significance of asymptomatic deranged serum aminotransferases [, ]. In a British study of patients where the diagnosis was not evident with history, physical examination and non-invasive tests including ultrasound scans, the most common diagnoses were found to be non-alcoholic fatty liver disease and alcoholic liver disease []. In another prospective study where patients went on to have a liver biopsy, steatosis and steatohepatitis were the most common diagnoses []. Results have tended to vary depending on the prevalence of liver disease in the population groups studied and the extent to which an underlying cause for these abnormalities was explored. For example, in a study of American blood donors, a diagnosis could not be established in the majority of patients with incidental elevated ALT []. This was partly attributed to the limited investigations and diagnostic algorithm used in the study.\nIn the setting of elevated serum aminotransferases (less than five times the normal range), the following investigative steps can be derived from the American Gastroenterological Association recommendations [, ]: (1) Thorough history and physical examination. (2) Identify medications and supplements that can cause derangement and discontinue them. Assess for alcohol use, viral hepatitis B and C, haemochromatosis and fatty liver disease. (3) Identify non-hepatic causes (primary muscle disease, hypo- and hyperthyroidism, coeliac disease, adrenal insufficiency and anorexia nervosa). (4) Identify rarer liver conditions such as autoimmune hepatitis, Wilson's disease, alpha-1-antitrypsin deficiency and adult bile ductopenia. (5) Proceed to a liver biopsy (patients with greater than two-fold elevation in aminotransferases) or observe over a period of time (patients with less than two-fold elevation in aminotransferases) before liver biopsy.\nHowever, the decision to pursue specific investigations should be based on the pattern of abnormality of liver tests, and be directed by features obtained from history, physical examination and pre-test probability. In this case, elevated serum aminotransferases with a normal serum GGT and ALP indicated a hepatocellular pattern of injury as opposed to cholestasis. Non-invasive investigations performed on the patient did not reveal a hepatic cause, but a detailed history raised the distinct possibility of a non-hepatic cause. The patient gave a history of long-standing muscle fatigue since childhood and consistently exhibited typical signs of rippling muscle disease, such as the rippling phenomenon. Serum aminotransferases were elevated in conjunction with serum CK, which is a known marker of muscle injury.\nSerum aminotransferase levels reflect the rate at which they enter and are cleared from the circulation. They are catabolised by proteolysis in the reticulo-endothelial system and are not excreted in significant amounts in urine and bile []. Hence, derangement is usually related to damage to tissues rich in the aminotransferases, or to changes in cell membrane permeability that permit leakage into the circulation [].\nAlthough hepatocytes contain the highest concentration of ALT and AST, it is well established that they are also present in other tissues such as cardiac and skeletal muscle []. Because their isoenzymes are not tissue-specific, isoenzyme measurements of ALT and AST do not aid in identifying the tissue of origin accurately []. In this clinical setting, chronic degeneration and regeneration of muscle fibres that were demonstrated in the patient's muscle biopsy causing leakage of these enzymes into the circulation explain the chronic low-grade elevation of aminotransferases.