What Causes Ammonia To Build Up In The Body

What Causes Ammonia To Build Up In The Body – Soluble receptor for advanced glycation end products and their forms in COVID-19 patients with and without diabetes mellitus: a pilot study on their role as disease biomarkers

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What Causes Ammonia To Build Up In The Body

What Causes Ammonia To Build Up In The Body

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Renewable Ammonia: The Future Of Fuels?

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Submission received: 11 October 2020 / Revised: 19 November 2020 / Accepted: 20 November 2020 / Published: 23 November 2020

Transjugular intrahepatic portosystemic shunt (TIPS) is an established treatment tool in decompensated liver cirrhosis that has been shown to prolong transplant-free survival. Hepatic encephalopathy (HE) is a frequent complication of decompensated cirrhosis, ultimately induced and/or exacerbated by TIPS, which remains a clinical challenge, especially in these patients. Therefore, patient selection for TIPS requires careful assessment of risk factors for HO. TIPS procedural parameters related to stent size and invasive portosystemic pressure gradient measurements thereby play an important role. Endovascular shunt modification, in combination with a conservative medical approach, often results in a significant reduction of symptoms. This review summarizes HO molecular mechanisms and pathophysiology as well as diagnostic and therapeutic approaches targeting shunt-induced HO.

Transjugular intrahepatic portosystemic shunt (TIPS) placement is an established method in the management of complications of portal hypertension [ 1 , 2 ]. With technical progress and increasing evidence, TIPS has improved graft-free survival and TIPS-related complications have been significantly reduced [ 1 , 3 , 4 , 5 ]. However, hepatic encephalopathy (HE) occurs frequently after TIPS procedures with an incidence of 20% to 50% [ 6 , 7 ]. The mechanism of HE is complex, including reduced hepatic filter function in liver dysfunction and slunk blood entering the systemic circulation, as well as an overproduction of enteric neurotoxins and increased cerebral inflammation and neurotoxins [8, 9, 10, 11, 12]. Yet hyperammonemia remains the central underlying cause [8, 9, 10, 11, 12]. The clinical effects range from mild cognitive alteration to coma, and are usually graded using the West Haven criteria [13, 14].

What Causes Ammonia To Build Up In The Body

Historically, post-TIPS HE pharmacological approaches have been aimed at reducing enteric neurotoxin production and absorption, which today is increasingly questioned [12, 15, 16, 17]. However, up to 8% of TIPS patients develop refractory HE, which is often associated with further deterioration of liver disease [ 18 , 19 ]. In these cases, endovascular shunt modification is the only therapeutic option besides liver transplantation [ 18 , 20 ]. TIPS modification reduces the portosystemic shunt volume and may improve HE [21].

Hyperammonemia: High Ammonia Levels And What’s Considered Normal

Despite these advances, there are still uncertainties about the appropriate workup for TIPS patients [22]. Moreover, prevention and management of post-TIPS HE still needs to be improved [ 1 , 22 ]. Correct patient selection for TIPS requires careful assessment of risk factors for HE to prevent complications that may impair the improved hemodynamic results and worsen the patient’s quality of life or expectancy [ 22 , 23 , 24 ]. Furthermore, the history of HE with increased severity is itself one of the most important risk factors for HE recurrence in cirrhosis, and also an important predictor of post-TIPS HE [ 25 , 26 , 27 ].

Understanding the underlying pathophysiology and molecular mechanisms of HO is essential for targeted management. Several new pathogenetic mechanisms have recently been identified while neurotoxicity of hyperammonemia remains the central underlying cause of HE [ 10 , 11 , 28 , 29 ].

Figure 1 illustrates the gut-liver-brain axis pathway considering portosystemic hemodynamics. Under physiological conditions, ammonia enters the portal circulation and is cleared by the urea cycle in the liver which is then excreted by the kidneys and metabolized in skeletal muscle ( Figure 1A ) [ 10 , 30 ]. In chronic liver disease or liver failure, blood flow becomes hepatofugal and retrograde in the portal vein, resulting in splanchnic blood moving into the systemic circulation (Figure 1B) [30]. Brain and muscle tissue use the enzyme glutamine synthetase to detoxify ammonia by synthesizing glutamine from glutamate [31]. The kidneys are able to release ammonia from the glutamine taken up by the brain and muscles into the urine with the help of the enzyme glutaminase, but this mechanism is oversaturated in severe or chronic hyperammonemia [31].

Astrocytes are of central importance for maintaining adequate neuronal function and play a central role in the pathophysiology of HE [ 10 ]. They are the only central nervous system (CNS) cells capable of detoxifying ammonia by synthesizing glutamine from the excitatory neurotransmitter glutamate [ 32 , 33 ]. Glutamine increases the permeability of the blood-CSF barrier [33]. Acute HE, e.g. post-TIPS, is caused by a rapid rise in ammonia levels and is often associated with generalized swelling of the astroglia, which may present clinically as cerebral edema ( Figure 1C ) [ 9 , 33 , 34 , 35 ]. In contrast, a long-term increase in serum ammonia levels usually does not show clinical signs of cerebral edema [9, 36]. CNS cells exhibit osmotic adjustment mechanisms that may explain the lower frequency of brain edema in chronic liver failure [ 36 ]. Here, hyperammonemia results in direct neuronal toxicity and altered neurotransmission leading to HE ( Figure 1B ) [ 9 , 37 ].

The Chicken Whisperer: Tackling Ammonia Levels In Backyard Flocks

Among TIPS patients, there is predominantly hepatopetal blood flow to the low-pressure shunt rather than liver parenchyma, whereas intrahepatic portal vein flow is hepatofugal and to the shunt ( Figure 1C ) [ 30 ]. Furthermore, following TIPS there is an up-regulation of glutaminase activity in the intestine leading to increased intestinal ammonia production [30, 38]. On the other hand, the body composition may change among TIPS patients, leading to the reversal of sarcopenia and thus improving ammonia metabolism in skeletal muscles [ 39 , 40 ]. However, acute post-TIPS HE is caused by a rapid short-term increase in ammonia levels and is often associated with cerebral edema [ 9 , 33 , 34 , 35 ]. In contrast, chronic/late post-TIPS HE with a long-term rise in serum ammonia levels usually does not present as cerebral edema [ 9 , 36 ]. Endovascular shunt modification reduces the shunt flow and achieves hepatopetal flow reversal in the portal vein (Figure 1D) [30]. Consequently, the gut-derived ammonia shunt is reduced and perfusion to the hepatocytes is increased, thereby improving HE [ 30 ].

In addition to the direct correlation between blood ammonia levels and the degree of HE, further mechanisms in HE have recently been discussed [ 41 , 42 ]. An increased inhibitory neurotransmission by γ-aminobutyric acid (GABA) is another possible factor [11]. GABA can be formed in the colon by bacterial decarboxylation of glutamate, and, in the case of liver failure due to reduced hepatic clearance via the blood-CSF barrier, it can reach the CNS [ 43 ]. The GABA receptor on the postsynaptic membrane contains binding sites for benzodiazepines [44]. By binding them, the affinity of the receptor for GABA itself is significantly increased [11, 44]. This explains why benzodiazepines can cause or worsen HE in cirrhosis of the liver [45]. It has also been shown that cirrhosis of the liver can lead to an increase in the concentration of so-called endogenous benzodiazepines [46]. A systemic inflammatory response with inflammatory cytokines and oxidative stress is assigned an important role [47]. Moreover, magnetic resonance imaging shows an increased deposition of manganese in the basal ganglia of patients with HE, which is neurotoxic and usually hepatobiliaryly excreted [ 10 ]. In contrast to the aromatic amino acids, the branched chain amino acids in serum are reduced in cirrhosis of the liver, as the former are degraded less in the liver and the latter are more catabolized in extrahepatic tissues [48, 49]. The increased concentrations of aromatic amino acids are said to inhibit the intracerebral synthesis of dopamine and norepinephrine, while inactive false neurotransmitters are increasingly produced [48, 50]. In the large intestine, there are toxic short- and medium-chain fatty acids as well as free, unconjugated phenols, toxic para-hydroxyphenolic acids and mercaptans (metabolites of the amino acids tyrosine, phenylalanine and methionine), which enter the CNS as a result of liver insufficiency and via portosystemic shunts, where they also have neurotoxic effects [50, 51].

With an incidence of 20–80%, HE

What Causes Ammonia To Build Up In The Body

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