From the Guidelines
Hyperammonemia causes asterixis primarily through ammonia's neurotoxic effects on the central nervous system, leading to disruptions in motor control and neurotransmission, as evidenced by the most recent study 1. The pathophysiological mechanism by which hyperammonemia causes asterixis involves the conversion of ammonia to glutamine in astrocytes, resulting in astrocyte swelling, cerebral edema, and disruption of neurotransmission.
- Ammonia interferes with glutamate-glutamine cycling between neurons and astrocytes,
- alters GABA-ergic neurotransmission,
- and disrupts cerebral energy metabolism. These changes affect the motor control centers in the brain, particularly the thalamus and motor cortex. The resulting abnormal neuronal firing patterns in motor pathways cause the characteristic lapses in sustained muscle contraction that define asterixis - the irregular flapping tremor most commonly observed when patients hold their arms outstretched with wrists extended. This manifestation represents a form of negative myoclonus, where there is a brief lapse in muscle tone rather than an excessive contraction. Asterixis typically appears when blood ammonia levels exceed 150-200 μg/dL and often accompanies other signs of hepatic encephalopathy, as described in the 2014 practice guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver 1. Treatment focuses on lowering ammonia levels through addressing the underlying cause, restricting protein intake, and administering medications like lactulose or rifaximin to reduce ammonia production and absorption from the gut. However, the most recent study on consensus guidelines for management of hyperammonaemia in pediatric patients receiving continuous kidney replacement therapy 1 provides the most up-to-date information on this topic. Key points from this study include:
- Hyperammonaemia is defined as >100 µmol/l (170 µg/dl) in neonates or ≥50 µmol/l (85 µg/dl) in term infants, children, and adolescents.
- The clinical features of an acute hyperammonaemic episode depend on the age of the patient and the cause of the elevation in plasma ammonia levels.
- Management of hyperammonaemia is challenging in pediatric populations given the non-specific clinical symptoms, the age-specific aetiologies, and the lack of consensus in the treatment plan. Given the complexity of hyperammonemia and its effects on the central nervous system, the most effective approach to managing asterixis is to prioritize the reduction of ammonia levels, as supported by the most recent and highest-quality study 1.
From the Research
Pathophysiological Mechanism of Hyperammonemia-Induced Asterixis
The pathophysiological mechanism by which hyperammonemia causes asterixis is complex and involves multiple factors. Key points include:
- Hyperammonemia is a condition characterized by elevated levels of ammonia in the blood, which can be toxic to the brain 2.
- Ammonia can alter the function of astrocytes, leading to changes in the expression of key proteins and the accumulation of excitatory and inhibitory substances 3.
- The brain relies on glutamine synthesis for the removal of excess ammonia, and the enzyme responsible, glutamine synthetase, has a predominantly astrocytic localization 3.
- Hyperammonemia can lead to alterations in cerebral blood flow and metabolism, as well as changes in astrocyte morphology, including cell swelling and Alzheimer Type II astrocytosis 3.
Clinical Signs and Symptoms
Clinical signs of hyperammonemia include:
- Anorexia
- Irritability
- Lethargy
- Vomiting
- Somnolence
- Disorientation
- Asterixis
- Cerebral edema
- Coma
- Death 2 These signs are generally proportional to the free ammonia concentration and are progressive, regardless of the primary etiology.
Underlying Causes
Hyperammonemia can result from various causes, including: