Hyperammonemia: Is It the Liver or Something Else?

A review of the cirrhotic and non-cirrhotic causes of hyperammonemia that may be encountered in the emergency department.

Sol volatile, or “smelling salts,” are ammonium salts that release ammonia gas, and were frequently used in Victorian England to revive the alarmingly-prevalent swooning woman. Ammonia causes mucosal irritation in the nasal passages and lungs, triggering inhalation. Aromatic ammonia spirits are still listed as a medication in many places, but are rarely used in practice, perhaps due to the relative infrequency of swooning. Instead, we more often come across ammonia when it manifests its neurotoxic properties in patients with liver disease. However, there are a number of non-hepatic causes of elevated ammonia levels, termed non-cirrhotic hyperammonemic encephalopathy (NCHE). This Rx Pad will review the cirrhotic and non-cirrhotic causes of hyperammonemia that we may encounter in the ED, and their management.

Physiology
Ammonia (NH3) is produced as a byproduct of amino acid catabolism. Bacteria in the small intestines produce ammonia from glutamine, and urease-containing bacteria in the colon produce ammonia from breakdown of proteins and urea. Ammonia is taken up from portal blood by hepatocytes and converted to urea through the Krebs-Henseleit cycle (which is also less formally but more aptly known as the “urea cycle”).

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The liver is highly efficient at removing ammonia from the blood. The urea cycle takes place within the mitochondria and the cytosol of hepatocytes. It relies on a number of enzymes that you may recall from medical school, such as ornithine transcarbamylase and carbamoyl phosphate synthase. Other organs, particularly the kidneys, are also involved in ammonia production and excretion, and most tissues can reduce local ammonia levels by converting glutamate and ammonia into glutamine, which can also feed into the urea cycle. Despite its natural and prosaic origin, ammonia is a deadly neurotoxin at high levels, so it is closely regulated by a number of mechanisms and interweaving chemical cycles. Unfortunately, when these systems are disrupted, hyperammonemia and the accompanying encephalopathy result.

Pathophysiology
When all systems are go, the body is very efficient at quickly shuttling excess ammonia through the urea cycle. Urea is then excreted by the kidneys. Even in the presence of severe kidney disease, when urea levels rise, the urea cycle continues to function to detoxify ammonia. As with any metabolite, there are two ways that ammonia can build up in the blood: excess production or impaired elimination. Let’s look at both of these and how they are clinically relevant in the ED.

Impaired Elimination of Ammonia

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1. Hepatic encephalopathy (HE) – The most important, and far and away the most common cause of hyperammonemia that we will see in the ED is caused by liver disease. It is responsible for about 90% of hyperammonemia in adults. Since the primary means of ammonia detoxification is through the urea cycle in the liver, patients with acute or chronic liver failure can accumulate ammonia. About 30-70% of patients with cirrhosis will develop HE. It can also occur in acute liver failure, such as following acetaminophen overdose, or in Wilson’s disease. 
2. Portosystemic shunts – If blood from the GI tract bypasses the liver, it avoids the detoxyfying hepatocytes. This may be congenital due to an intrahepatic or extrahepatic shunt. It can also occur following TIPS (transjugular intrahepatic portosystemic shunt) procedures, as the ammonia-containing blood is intentionally shunted away from the liver to reduce portal hypertension.
3. Medication-induced hyperammonemia – Many different medications can cause (NCHE). The most well documented is valproic acid. NCHE can occur in patients taking valproic acid who have normal liver function, and even when valproic acid levels in the blood are within the target range. In fact, hyperammonemia occurs in 35-45% of patients taking valproic acid. In most cases, it is mild and patients are asymptomatic. When symptoms develop, they may be gradual or rapid in onset, and may include worsening dementia in elderly patients, or changes in behavior such as irritability or aggressiveness, as well as cognitive dysfunction. The mechanism is thought to be due to toxic valproic acid metabolites that inhibit carbamoyl phosphate synthetase I. Valproic acid also increases carnitine excretion, again inhibiting the urea cycle. Other medications such as phenobarbital, phenytoin, and topiramate can potentiate the hyperammonemic properties of valproic acid. Carbamezapine, ribavirin, sulfadiazine/pyrimethamine, and high dose aspirin can also impair ammonia excretion.
4. Inborn errors of metabolism – There are many different inborn errors that can lead to elevated ammonia levels, most importantly, urea-cycle disorders. The X-linked ornithine transcarbamylase deficiency is the most common urea cycle disorder. However, hyperammonemia can also occur with defects in fatty acid oxidation, organic acidemias, and disorders of pyruvate metabolism. The vast majority of these will manifest, and hopefully be detected, in the neonatal period. However, individuals who are heterozygous, or who have partial deficiencies, may present later in life. Patients with underlying subclinical urea-cycle disorders may develop hyperammonemia at times of increased muscle catabolism, such as extreme exercise, starvation, trauma, GI bleed, seizures, or TPN use, or at times of infection with or without urease-producing bacteria, or when taking one of the medications listed above.
5. Ureterosigmoidostomy – Patients who have had cystectomies sometimes have the ureters directly connected to the sigmoid colon, where urease-containing bacteria can break down urea and release ammonia, some of which is absorbed into the portal system, but some of which may be absorbed by the hemorrhoidal veins directly into the systemic circulation. Fortunately this is a rare complication.

Excess Production of Ammonia

1. Urease-producing UTIs – Urease breaks urea down into ammonia. This ammonia can then diffuse back into the urothelial cells, and into the systemic circulation, thus bypassing the liver’s detoxification mechanisms. Proteus mirabilis is the main culprit, although a number of other urinary pathogens also contain urease. The ammonia buildup usually only becomes clinically relevant when there is severe urinary stasis as well, such as in children with GU abnormalities, or patients with neurogenic bladder.
2. Miscellaneous heme-onc complications – Advanced multiple myeloma can lead to hyperammonemia, possibly due to increased ammonia production by the malignant cells. It can also occur in patients with leukemia who are undergoing chemotherapy, and in patients after a bone marrow transplant.

Symptoms
Symptoms of hyperammonemic encephalopathy are the same regardless of the underlying cause. They can range from mild confusion, sleep disturbance, and irritability (Grade 1) to the final common pathway in most of toxicology, which is seizure, coma (Grade 4), and death.

The Liver, or Not the Liver?
There are typical physical exam and laboratory clues to prompt a clinician to send an ammonia level, and to diagnose hepatic encephalopathy. In addition to the symptoms and exam findings of the encephalopathy itself, there are often stigmata of liver disease, ascites, or a known history of liver disease. In acute liver failure, such as acetaminophen toxicity, lab tests such as elevated LFTs and INR can help point to a hepatic source of the pathology and prompt further evaluation. A more difficult diagnostic challenge arises when patients present with altered mental status but no history of liver disease and normal LFTs. In these cases, an awareness of some of the medications and hereditary disorders that can cause NCHE will be critical to making the diagnosis and sending an ammonia level.

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Treatment
Ammonia is neurotoxic, and can ultimately lead to intracerebral edema and death. In severe cases, supportive care with endotracheal intubation and mannitol or hypertonic saline may be needed. Mannitol can reduce mortality in patients with severe hyperammonemic encephalopathy with acutely elevated ammonia levels. In addition to supportive care, other treatments reduce ammonia production or absorption: Lactulose works by increasing GI transit and fecal excretion of nitrogenous compounds. Antibiotics such as neomycin and rifaximin can be used to eliminate gut bacteria and reduce ammonia production. Ammonia can also be removed by dialysis if other efforts have failed. Medications such as sodium benzoate can be used to increase renal glutamine excretion. Patients with inborn errors of metabolism may require supplementation with specific metabolites to supply missing links in the urea cycle. For patients with valproic acid-induced NCHE, L-carnitine, which helps increase ammonia excretion through the urea cycle, has been found to improve symptoms and survival. Ultimately, liver transplantation may be a final treatment option for patients with cirrhosis or with inborn errors of metabolism.

Take Home points

1. Hepatic encephalopathy (HE) is common among patients with cirrhosis. Have a high suspicion for HE in patients with known liver disease or acute liver failure, who present with confusion, and check an ammonia level. The degree of elevation may not correlate well with the clinical severity, however.
2. There are many causes of non-cirrhotic hyperammonemic encephalopathy (NCHE). For example, consider checking an ammonia level in any patient on valproic acid with unexplained altered mental status. Hyperammonemia can occur even with normal valproic acid levels.
3. Rarely, inborn errors of metabolism can present in teenagers and adults. Hyperammonemia may be triggered by an infection or by increased catabolism of nitrogen-containing compounds such as in patients with a GI bleed. Consider checking a level in patients with otherwise unexplained altered mental status, particularly in patients with a family history of inborn errors of metabolism.

REFERENCES

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