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Pathophysiology of hyperammonemic encephalopathy Ammonia (NH3) is a known powerful neurotoxin, usually associated with the occurrence of hepatic encephalopathy (HE), which is a serious complication of decompensated liver cirrhosis.
Cause a series of neurological or mental abnormalities.
In addition, HE is an important predictor of mortality in patients with liver cirrhosis.
In healthy individuals, ammonia enters the portal circulation from the gastrointestinal tract and is then converted to urea through the urea cycle (Figure 1).
Eventually, urea is excreted from the body through the colon or kidneys.
Figure 1 Urea cycle However, in the case of severe liver dysfunction or portosystemic shunt, the burden of excreting ammonia falls on the kidneys, skeletal muscles and brain.
In these cases, ammonia enters the systemic circulation, suppresses both excitatory and inhibitory postsynaptic potentials, and impairs nerve function (Figure 2).
Figure 2 The pathophysiological mechanism of encephalopathy caused by high ammonia passes through the blood-brain barrier through passive diffusion or mediated transport.
Ammonia can promote the production of glutamine (an osmotic pressure regulator) and further lead to cerebral edema; this complication It is most severe in acute liver failure.
Other factors, such as gastrointestinal bleeding, can promote the transfer of toxins from the portal vein to the systemic bloodstream.
Cerebral edema, brain herniation, and seizures usually occur when acute hyperammonemia (that is, in the case of acute liver failure) results in arterial blood ammonia levels> 200 μmol/L.
Therefore, arterial blood ammonia monitoring (not related to venous ammonia levels) is particularly suitable for patients with acute liver failure.
The etiology of non-cirrhotic hyperammonia encephalopathy In clinical work, elevated blood ammonia levels may not be secondary to cirrhosis.
At this time, it is still necessary to evaluate the exact cause of blood ammonia levels.
A summary of the underlying causes of non-cirrhotic hyperammonemic encephalopathy can be found in Table 1.
Table 1 Etiology of non-cirrhotic hyperammonemic encephalopathy * Often onset in childhood, ammonia clearance decreases 1.
Metabolic disorders caused by congenital metabolic disorders Congenital metabolic abnormalities (IEMs) (such as organic aciduria or carnitine deficiency) ), usually onset in childhood, but urea cycle disorders can affect any enzyme in the urea cycle, and can appear in adult patients.
The lack of ornithine transcarbamylase (OTC) characterized by an X-linked recessive inheritance pattern is the most common cause of urea cycle disorders.
The clinical manifestations of OTC deficiency can range from lethargy and disorientation to deep coma.
This enzyme deficiency limits the liver's ability to convert ammonia into urea, leading to non-cirrhotic hyperammonemia, and can continue to be symptom-free.
2.
Portosystemic shunt Spontaneous portosystemic shunt is common in patients with liver cirrhosis.
Congenital portosystemic shunts may be intrahepatic shunts or extrahepatic shunts, and are often diagnosed in the neonatal period.
Portal vein thrombosis (PVT) that causes portosystemic shunt can also lead to non-cirrhotic hyperammonemia (shunting ammonia into the systemic circulation).
In this case, the encephalopathy is mild and the patient retains some liver function.
3.
Certain drugs Certain drugs disrupt the urea cycle, especially valproic acid, which is known to induce non-cirrhotic hyperammonemia.
Valproic acid increases the level of propionic acid, which can inhibit the rate-limiting enzyme of the urea cycle-carbamoyl phosphate synthase.
According to reports, the prevalence of valproic acid-induced hyperammonemia is 35%-45%, and patients are usually asymptomatic.
Hyperammonemia can also be caused by glycine.
Other drugs that may cause hyperammonemia are carbamazepine, ribavirin and sulfadiazine, but the specific mechanism is not clear.
Increased ammonia production 1.
Increased muscle catabolism.
Seizures, hunger, and trauma are all related to hyperammonemia.
These conditions can lead to hyperammonemic encephalopathy in patients whose liver cannot handle the increased nitrogen load (such as patients with urea cycle disorders).
It is worth noting that a retrospective study of 17 cases of transient hyperammonemia found that hyperammonemia may be related to generalized seizures.
Although its mechanism needs further research, it may be related to the persistent muscles during the seizure.
Shrinkage related.
Compared with the fluctuation of blood ammonia level during HE, the blood ammonia level of patients with seizures will quickly return to normal.
2.
Total parenteral nutrition The high protein load in total parenteral nutrition (TPN) can cause urea cycle disorders.
This phenomenon can also occur when adults take total parenteral nutrients containing only essential amino acids.
In these patients, the lack of ornithine (a substrate in the urea cycle) impairs ammonia detoxification.
Conclusion Evaluation of blood ammonia levels in patients with known liver cirrhosis is unlikely to change clinical management, so it is not recommended.
In the absence of chronic liver disease, elevated blood ammonia levels can be detected to assess other unexplained changes in mental status.
If hyperammonemia is found (especially in patients in the intensive care unit), complications should be monitored immediately, such as Cerebral edema and high pressure in the brain.
Hyperammonemia is associated with high morbidity and mortality in critically ill patients.
In the case of non-cirrhotic hyperammonia encephalopathy, the differential diagnosis should focus on the mechanisms leading to increased ammonia production or decreased ammonia clearance.
After excluding acute liver failure and potential chronic liver disease, a detailed drug/nutrition history review (including total parenteral nutrition), evaluation of epilepsy activity, imaging tests for portosystemic shunt or PVT, and comprehensive evaluation of infection can be performed .
If the cause of hyperammonemia is still unclear, consider evaluating occult urea cycle disorders (Table 2).
Yimaitong compiled and compiled from: Kalra A, Norvell JP.
Cause for Confusion: Noncirrhotic Hyperammonemic Encephalopathy[J].
Clin Liver Dis (Hoboken).
2020;15(6):223-227.
Published 2020 Jun 30.
doi:10.
1002 /cld.
929
Cause a series of neurological or mental abnormalities.
In addition, HE is an important predictor of mortality in patients with liver cirrhosis.
In healthy individuals, ammonia enters the portal circulation from the gastrointestinal tract and is then converted to urea through the urea cycle (Figure 1).
Eventually, urea is excreted from the body through the colon or kidneys.
Figure 1 Urea cycle However, in the case of severe liver dysfunction or portosystemic shunt, the burden of excreting ammonia falls on the kidneys, skeletal muscles and brain.
In these cases, ammonia enters the systemic circulation, suppresses both excitatory and inhibitory postsynaptic potentials, and impairs nerve function (Figure 2).
Figure 2 The pathophysiological mechanism of encephalopathy caused by high ammonia passes through the blood-brain barrier through passive diffusion or mediated transport.
Ammonia can promote the production of glutamine (an osmotic pressure regulator) and further lead to cerebral edema; this complication It is most severe in acute liver failure.
Other factors, such as gastrointestinal bleeding, can promote the transfer of toxins from the portal vein to the systemic bloodstream.
Cerebral edema, brain herniation, and seizures usually occur when acute hyperammonemia (that is, in the case of acute liver failure) results in arterial blood ammonia levels> 200 μmol/L.
Therefore, arterial blood ammonia monitoring (not related to venous ammonia levels) is particularly suitable for patients with acute liver failure.
The etiology of non-cirrhotic hyperammonia encephalopathy In clinical work, elevated blood ammonia levels may not be secondary to cirrhosis.
At this time, it is still necessary to evaluate the exact cause of blood ammonia levels.
A summary of the underlying causes of non-cirrhotic hyperammonemic encephalopathy can be found in Table 1.
Table 1 Etiology of non-cirrhotic hyperammonemic encephalopathy * Often onset in childhood, ammonia clearance decreases 1.
Metabolic disorders caused by congenital metabolic disorders Congenital metabolic abnormalities (IEMs) (such as organic aciduria or carnitine deficiency) ), usually onset in childhood, but urea cycle disorders can affect any enzyme in the urea cycle, and can appear in adult patients.
The lack of ornithine transcarbamylase (OTC) characterized by an X-linked recessive inheritance pattern is the most common cause of urea cycle disorders.
The clinical manifestations of OTC deficiency can range from lethargy and disorientation to deep coma.
This enzyme deficiency limits the liver's ability to convert ammonia into urea, leading to non-cirrhotic hyperammonemia, and can continue to be symptom-free.
2.
Portosystemic shunt Spontaneous portosystemic shunt is common in patients with liver cirrhosis.
Congenital portosystemic shunts may be intrahepatic shunts or extrahepatic shunts, and are often diagnosed in the neonatal period.
Portal vein thrombosis (PVT) that causes portosystemic shunt can also lead to non-cirrhotic hyperammonemia (shunting ammonia into the systemic circulation).
In this case, the encephalopathy is mild and the patient retains some liver function.
3.
Certain drugs Certain drugs disrupt the urea cycle, especially valproic acid, which is known to induce non-cirrhotic hyperammonemia.
Valproic acid increases the level of propionic acid, which can inhibit the rate-limiting enzyme of the urea cycle-carbamoyl phosphate synthase.
According to reports, the prevalence of valproic acid-induced hyperammonemia is 35%-45%, and patients are usually asymptomatic.
Hyperammonemia can also be caused by glycine.
Other drugs that may cause hyperammonemia are carbamazepine, ribavirin and sulfadiazine, but the specific mechanism is not clear.
Increased ammonia production 1.
Increased muscle catabolism.
Seizures, hunger, and trauma are all related to hyperammonemia.
These conditions can lead to hyperammonemic encephalopathy in patients whose liver cannot handle the increased nitrogen load (such as patients with urea cycle disorders).
It is worth noting that a retrospective study of 17 cases of transient hyperammonemia found that hyperammonemia may be related to generalized seizures.
Although its mechanism needs further research, it may be related to the persistent muscles during the seizure.
Shrinkage related.
Compared with the fluctuation of blood ammonia level during HE, the blood ammonia level of patients with seizures will quickly return to normal.
2.
Total parenteral nutrition The high protein load in total parenteral nutrition (TPN) can cause urea cycle disorders.
This phenomenon can also occur when adults take total parenteral nutrients containing only essential amino acids.
In these patients, the lack of ornithine (a substrate in the urea cycle) impairs ammonia detoxification.
Conclusion Evaluation of blood ammonia levels in patients with known liver cirrhosis is unlikely to change clinical management, so it is not recommended.
In the absence of chronic liver disease, elevated blood ammonia levels can be detected to assess other unexplained changes in mental status.
If hyperammonemia is found (especially in patients in the intensive care unit), complications should be monitored immediately, such as Cerebral edema and high pressure in the brain.
Hyperammonemia is associated with high morbidity and mortality in critically ill patients.
In the case of non-cirrhotic hyperammonia encephalopathy, the differential diagnosis should focus on the mechanisms leading to increased ammonia production or decreased ammonia clearance.
After excluding acute liver failure and potential chronic liver disease, a detailed drug/nutrition history review (including total parenteral nutrition), evaluation of epilepsy activity, imaging tests for portosystemic shunt or PVT, and comprehensive evaluation of infection can be performed .
If the cause of hyperammonemia is still unclear, consider evaluating occult urea cycle disorders (Table 2).
Yimaitong compiled and compiled from: Kalra A, Norvell JP.
Cause for Confusion: Noncirrhotic Hyperammonemic Encephalopathy[J].
Clin Liver Dis (Hoboken).
2020;15(6):223-227.
Published 2020 Jun 30.
doi:10.
1002 /cld.
929
