**1. Introduction**

The term hyperammonemia denotes an elevated ammonia level in the blood, however, it is often used in clinical practice to refer to a toxic accumulation of ammonia in the blood with its associated serious complications. The normal reference range of ammonia level in adults is 10 to 80 mcg/dL or 6 to 47 μmol/L (SI units) [1], but this range may vary slightly among different laboratories. Ammonia is most damaging to the brain, and this applies to both acute and chronic hyperammonemia [2, 3]. Cerebral edema and brain herniation are more common in patients with acute hyperammonemia, but patients with chronic hypernatremia (e.g., chronic liver disease patients) may develop encephalopathy and have a different mechanism of neurotoxicity caused by hyperammonemia [2, 3]. This serious and potentially fatal condition must be promptly recognized, evaluated, and treated. Although the role of RRT in the management of patients with hyperammonemia is more evident in the pediatric population [4], it is less clear in the adult population. This chapter will give a brief overview of hyperammonemia pathophysiology, causes, manifestations, and general management, but will discuss in detail the available data about the role of RRT in adult patients with hyperammonemia.

### **2. Pathophysiology of hyperammonemia**

Ammonia is normally produced *via* the metabolism of nitrogen-containing compounds [2]. The main sites of ammonia production in the body are the intestine, and to a lesser extent, the kidneys and the muscles [2]. In the intestine, the ammonia is produced *via* the digestion and metabolism of dietary proteins by the mucosal bacteria, *via* urease-producing bacteria and microbial proteolysis, as well as *via* the uptake of glutamine from the systemic circulation with subsequent deamination to glutamate and ammonia [2]. In the kidneys, ammonia is produced by the catabolism of glutamine in the proximal convoluted tubules (ammoniagenesis) [2]. In the muscles, ammonia is the product of muscle metabolism, and this production is increased in certain situations such as seizures, intense exercise, or in catabolic states [2].

The liver is responsible for clearing 90% of the ammonia in the body, and it converts ammonia to urea *via* the urea cycle [2]. If the liver fails or becomes overwhelmed by the excess production of ammonia, the kidneys will decrease the ammonia production in the proximal tubules, and will also increase the urinary excretion of ammonia. Additionally, the brain and the muscles will try to help by metabolizing ammonia to glutamine [2].

Ammonia metabolism is regulated by the extracellular pH, potassium level, and mineralocorticoids and glucocorticoid secretion in the body [2].

With severe hyperammonemia, the osmotic stress is increased in the astrocytes of the brain, which may lead to astrocyte swelling with subsequent cerebral edema and brain herniation. Additionally, the accumulation of glutamine in the astrocytes will affect the energy delivery to neurons, increase oxidative stress, and increase the production of inflammatory cytokines. Together will lead to cellular apoptosis, dysfunction of neurotransmitters, mitochondrial dysfunction, neuronal irritability, and alteration of blood-brain barrier [2]. All cell types of the brain are affected by these changes [2].

### **3. Causes of hyperammonemia in adults**

Hyperammonemia occurs when there is increased production or decreased clearance of ammonia. In the adult population, liver failure is responsible for the majority of cases of hyperammonemia, while non-hepatic causes are rare and account for the minority of cases [2, 5–8]. With non-hepatic causes of hyperammonemia, there is excessive production of ammonia which may exceed the handling capacity of the liver or may bypass the liver to enter directly into the systemic circulation [5–8].

The causes of hyperammonemia in adults are summarized in **Table 1**.

### **4. Clinical manifestations**

In mild cases, symptoms may include headache, vomiting, irritability, behavioral changes, ataxia, and gait abnormalities [2, 7, 8]. Severe hyperammonemia may present with seizures, encephalopathy, coma, and even death [2, 7, 8].

In addition to the severity of hyperammonemia, the clinical manifestations depend on the onset (acute versus chronic). Patients with chronic hyperammonemia (e.g., chronic liver disease patients) have a gradual accumulation of ammonia, allowing for compensatory mechanisms to decrease osmolarity. Additionally, patients with chronic hyperammonemia may have compensatory increase in the ammonia metabolism by other organs (e.g., muscles), which may blunt some of the symptoms.


#### **Table 1.**

*Causes of hyperammonemia in adults.*

Therefore, they are less like to present with cerebral edema and herniation than patients with acute conditions [5, 8].
