Abstract
Ketoacidosis is an important but under-recognized complication of neuromuscular disease, in particular spinal muscular atrophy. This easily treatable condition is largely overlooked in best practice guidelines, and lack of awareness contributes to adverse outcomes in this patient population. Neuromyopathy associated ketosis should be considered in all patients with severe muscle wasting presenting with an elevated anion gap metabolic ketoacidosis. Treatment is simple, effective, and should be instituted early. Our report of a 50-year-old patient with type 2 spinal muscular atrophy who presents with recurrent ketoacidosis aims to increase awareness of neuromyopathy associated ketosis as a clinical entity, and to enhance its early recognition and timely treatment in order to improve patient outcomes.
INTRODUCTION
Ketoacidosis is a common cause of metabolic acidosis with elevated anion gap. It is most commonly encountered in the setting of diabetes, starvation or alcohol excess. Ketoacidosis is also an under-recognized complication of neuromuscular diseases such as spinal muscular atrophy (SMA). In this setting, causative factors include a reduction in muscle mass, abnormal glucose and fatty acid metabolism, and possibly changes in endocrine function and the autonomic nervous system. We report the case of a 50 year-old man with type 2 spinal muscular atrophy who presents with recurrent episodes of stress-induced ketoacidosis.
CASE REPORT
A 50 year-old man with genetically confirmed spinal muscular atrophy type 2 (homozygous deletion of the SMN1 exon 7 sequence but three copies on exon 7 and exon 8 of the SMN2 gene) presented to the emergency department with 1 day of nausea, two vomits and generalized abdominal discomfort. He had severe generalized weakness and loss of muscle mass, required assistance with all activities of daily living and used a hoist for transfers. His last calculated BMI in 2003 (10 years prior) was 16.4. Most of his days were spent in bed. He could not walk but would feed himself on a soft diet and had adequate nutritional intake, with an albumin of 36 g/L (normal 35–50 g/L). His cough was poor and he had marked respiratory muscle weakness with maximum inspiratory pressures of 43% of predicted and maximum expiratory pressures of 13% of predicted.
Two days prior to presentation, he experienced dysuria and had been treated with trimethoprim for a suspected urinary tract infection (no urine testing had been performed). Blood testing revealed a severe metabolic ketoacidosis with mild hypoglycemia (see Table 1). He was treated with intravenous 50% dextrose and started on ceftriaxone for a presumed partially treated urinary tract infection. By the next morning, his pH was 7.49 and blood glucose was normal.
Further history revealed that he had experienced a similar event five years previous where, following an uncomplicated right external fronto-ethmoidectomy, routine postoperative blood testing detected a marked metabolic ketoacidosis and mild hypoglycemia, which rapidly responded to glucose supplementation.
DISCUSSION
Spinal Muscular Atrophy (SMA) is a progressive neurodegenerative disorder caused by deficiency of the survival motor neuron protein encoded by SMN1 and SMN2 genes on chromosome 5. Without functioning proteins, spinal motor neuron loss, muscle denervation and loss of muscle mass occur [1]. The spectrum of SMA is quite broad and is classified according to the degree of muscle weakness, age of onset and genetic testing [2]. Ketosis is an important but under-recognized complication of this neuromuscular disease which is often overlooked in best practice guidelines [3].
Reductions in muscle mass, defects in fatty acid metabolism, and endocrine changes may all contribute to this predisposition (see Figs. 1 and 2). We report a case of recurrent severe ketoacidosis in a patient with SMA, the early recognition and appropriate treatment of which avoided unnecessary over-investigation, inappropriate treatment and adverse patient outcomes.
Ketoacidosis is an elevated anion gap metabolic acidosis that results from the accumulation of ketone bodies (acetoacetate, 3-B-hydroxybutyrate and acetone) in the blood. It is most commonly encountered in the setting of diabetes, starvation and alcohol excess. Individuals with spinal muscular atrophy (SMA) and other patients with severe muscle wasting are at increased risk for ketoacidosis [4–6].
Ketone bodies are generated in the mitochondria of liver cells by conversion fatty acids into acetoacetate and beta-hydroxybutyrate (acetone is generated by spontaneous decarboxylation of acetoacetate). They are a vital energy source for the brain, heart and kidneys during times of relative glucose scarcity. By day 3 of starvation, ketone bodies provide up to 40% of the body’s energy needs [7].
When looking at the impact of metabolic pathways and glucose handling on the predisposition to ketosis in SMA patients, an understanding of ketogenesis is paramount. Ketogenesis is tightly regulated by the balance between the pro-ketotic hormones glucagon, adrenaline and growth hormone and the ketone-limiting hormone, insulin. Pro-ketotic hormones increase free fatty acid release from adipose tissue, whereas insulin reduces the availability of free fatty acids for ketogenesis [7]. Under conditions of stress or starvation, a paucity of insulin relative to pro-ketotic hormones stimulates fatty acid release from stores. These fatty acid are transported primarily to the liver where they then undergo beta-oxidation to form acetyl-CoA [7]. Under normal circumstances, acetyl-CoA then condenses with oxaloacetate and enters the citric acid cycle [7], but under hypoglycaemic conditions, oxaloacetate gets shunted to the process of gluconeogenesis. The extra acetyl-CoA then cannot enter the citric acid cycle and is instead diverted to ketone body formation (see Fig. 2).
Episodes of ketoacidosis in SMA patients occur when several factors converge to create a perfect storm of metabolic instability. Reductions in muscle mass, abnormal fatty acid and glucose metabolism, hormonal imbalance, physiologic stress and autonomic changes may all have a role to play.
Loss of muscle mass favors ketosis in many ways (see Figs. 1 and 2).
Firstly, skeletal muscle is the primary user of ketones in the body. A direct effect of less muscle mass is less ketone body extraction, and therefore elevated blood ketone levels [8].
Secondly, reduced muscle mass decreases the availability of amino acids for gluconeogenesis. Under conditions of stress, those with low muscle mass (SMA patients and those with other neuromyopathies) [8, 9] are predisposed to hypoglycemia, as was seen in our patient (Table 1). This relative hypoglycemia promotes ketone body formation both by shunting oxaloacetate to gluconeogenesis (forcing acetyl-CoA into ketone body production as described above) [5, 10], and by making these patients more dependent on switching to fatty acids as a source of energy, promoting ketone body formation. In-vivo experiments have shown that with equal duration of fasts, myopathic patients develop more ketosis than normal subjects [8].
Defects in fatty acid metabolism may also render SMA patients prone to ketosis [4, 12]. Infants with severe SMA evaluated in a fasting state develop a distinctive and marked dicarboxylic aciduria, comparable in severity to that seen in children with primary defects of beta-oxidation [4]. It is postulated that the observed defects in fatty acid metabolism in SMA may relate to changes in cellular physiology resulting from absence of the SMN gene product, defects in neighboring genes or the absence of a neural ‘trophic factor’ [13, 14].
Hormonal changes in SMA also predispose to ketosis. As previously discussed, the insulin:glucagon ratio is a critical regular of ketone body formation. Interestingly, both human and animal models of pancreatic islet constituents in SMA demonstrate progressive loss of insulin-producing beta cells as the disease progresses [15]. The resulting increase in alpha (glucagon producing):beta cell ratio favors ketosis.
There is increasing recognition of the importance of the autonomic nervous systemic in the control of hepatic metabolic functions [16, 17]. Patients with SMA have recently been found to have problems with autonomic regulation [18]. More work is needed to determine whether autonomic dysregulation contributes to ketosis in SMA patients [19].
Once diagnosed, ‘neuromyopathic’ ketosis is easily treated, requiring only carbohydrate replacement and avoidance of hypoglycemia. This reverses the body’s drive towards ketosis and will restore pH and serum ketones to normal levels within hours to days. Intercurrent illness must also be sought and appropriately managed.
In conclusion, although the main manifestations SMA are neuromyopathic in nature, these individuals are also at increased risk of developing ketoacidosis. Reductions in muscle mass, alterations in fatty acid metabolism and endocrine imbalance all provide stimuli to ketosis, especially during times of stress. Ketoacidosis in spinal muscular atrophy patients is simply treated with enteral or parenteral glucose. Early recognition and treatment of ketoacidosis corrects metabolic parameters within hours to days, improving patient outcomes.
CONFLICT OF INTEREST
The authors have no conflict of interest to report.