New findings on cerebral ammonia uptake in HE using functional 13N-ammonia PET

Sørensen, Michael; Keiding, Susanne

doi:10.1007/s11011-007-9066-1

Cited by 35 publications

(25 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Whilst the BBB has been shown to remain anatomically intact in HE, 28 PET studies utilizing 13 N-ammonia have demonstrated an increased uptake and trapping of ammonia in the brains of individuals with CLF, with controversy prevailing over the respective roles that alterations in the permeability of the BBB, and blood ammonia levels, may have in this observation. [29][30][31][32] From the neuropathological standpoint, significant astrocyte swelling and cytotoxic brain edema are cardinal features of human ALF. Using electron microscopy, Kato and colleagues observed marked swelling of astroglial foot processes in samples of cerebral cortex obtained from patients succombing from ALF.…”

Section: Ammonia and The Brain: The Sick Astrocytementioning

confidence: 99%

Pathogenesis of Hepatic Encephalopathy: Role of Ammonia and Systemic Inflammation

Aldridge

Tranah

Shawcross

2015

Journal of Clinical and Experimental Hepatology

237

190

View full text Add to dashboard Cite

The syndrome we refer to as Hepatic Encephalopathy (HE) was first characterized by a team of Nobel Prize winning physiologists led by Pavlov and Nencki at the Imperial Institute of Experimental Medicine in Russia in the 1890's. This focused upon the key observation that performing a portocaval shunt, which bypassed nitrogen-rich blood away from the liver, induced elevated blood and brain ammonia concentrations in association with profound neurobehavioral changes. There exists however a spectrum of metabolic encephalopathies attributable to a variety (or even absence) of liver hepatocellular dysfunctions and it is this spectrum rather than a single disease entity that has come to be defined as HE. Differences in the underlying pathophysiology, treatment responses and outcomes can therefore be highly variable between acute and chronic HE. The term also fails to articulate quite how systemic the syndrome of HE can be and how it can be influenced by the gastrointestinal, renal, nervous, or immune systems without any change in background liver function. The pathogenesis of HE therefore encapsulates a complex network of interdependent organ systems which as yet remain poorly characterized. There is nonetheless a growing recognition that there is a complex but influential synergistic relationship between ammonia, inflammation (sterile and non-sterile) and oxidative stress in the pathogenesis HE which develops in an environment of functional immunoparesis in patients with liver dysfunction. Therapeutic strategies are thus moving further away from the traditional specialty of hepatology and more towards novel immune and inflammatory targets which will be discussed in this review. ( J CLIN EXP HEPATOL 2015;5:S7-S20) H epatic encephalopathy (HE) is the term used to encapsulate the broad spectrum of neuropsychiatric disturbances associated with both acute and chronic liver failure (ALF and CLF, respectively), as well as porto-systemic bypass in the absence of hepatocellular disease. The clinical manifestations of HE can be extremely heterogeneous in nature, with symptoms presenting anywhere on a continuum spanning from seemingly normal cognitive performance, right the way through to states of confusion, stupor and coma. In between these extremes, patients with HE may exhibit signs such as inattentiveness, blunted affect, impairment of memory or reversal of the sleep-wake cycle, as well as physical manifestations such as tremor, myoclonus, asterixis and deep tendon hyperreflexia.ALF is defined by the onset of coagulopathy alongside any degree of encephalopathy in patients with no evidence of pre-existing liver disease. 1 The presence of HE in those with ALF is prognostic, with up to a quarter of cases developing raised intracranial pressure. 2 Patients presenting with ALF are at risk of developing its cardinal, lifethreatening feature, cerebral edema. Left untreated, cerebral edema can rapidly progress to cause herniation of the uncus through the falx cerebri, leading to compression of the brainstem and, ultimately, death. H...

show abstract

Section: Ammonia and The Brain: The Sick Astrocytementioning

confidence: 99%

Pathogenesis of Hepatic Encephalopathy: Role of Ammonia and Systemic Inflammation

Aldridge

Tranah

Shawcross

2015

Journal of Clinical and Experimental Hepatology

237

190

View full text Add to dashboard Cite

show abstract

“…Using 11 C-CSar PET, we demonstrated backflux even in the normal state, not just during cholestasis. Because hepatic blood perfusion was constant throughout each PET recording, the E ss /E 0 ratio was equal to k BSEP /(k backflux 1 k BSEP ) (22). This relationship shows that the physiologic significance of backflux is relative to canalicular secretion and that a decrease in k BSEP can cause an apparent increase in k backflux (22).…”

Section: Discussionmentioning

confidence: 92%

“…In some cases, the analysis yielded K mem values higher than Q, an innate problem with compartmental analysis of PET data (21); in these cases, K mem was calculated as QE 0 (unidirectional extraction fraction) in Equation 3 (22). The hepatic intrinsic clearance of 11 C-CSar, K int (mL blood/min/ mL liver tissue), which is not dependent on flow, was calculated (23) as…”

Section: Calculations From Pet Measurementsmentioning

confidence: 99%

Hepatobiliary Secretion Kinetics of Conjugated Bile Acids Measured in Pigs by ¹¹C-Cholylsarcosine PET

et al. 2016

Self Cite

View full text Add to dashboard Cite

The aim of this study was to develop a method for the quantification of hepatobiliary uptake and secretion of conjugated bile acids with PET and the 11 C-labeled conjugated bile acid analog [N-methyl-11 C] cholylsarcosine ( 11 C-CSar). Methods: Six pigs (13 experiments) underwent dynamic 11 C-CSar PET of the liver with simultaneous measurements of hepatic blood perfusion and 11 C-CSar concentrations in arterial, portal, and hepatic venous blood. In 3 pigs (7 experiments), bile was collected from a catheter in the common hepatic duct. PET data were analyzed with a 2-tissue compartmental model with calculation of rate constants for the transport of 11 C-CSar among blood, hepatocytes, and intra-and extrahepatic bile ducts. PET results were validated against invasive blood and bile measurements. Results: The directly measured rate of secretion of 11 C-CSar into bile was equal to the rate of removal from blood at steady state. Accordingly, hepatocytes did not accumulate bile acids but simply facilitated the transport of bile acids from blood to bile against a measured concentration gradient of 4,000. The rate constant for the secretion of 11 C-CSar from hepatocytes into bile in experiments with a catheter in the common hepatic duct was 25% of that in experiments without a catheter (P , 0.05); we interpreted this result to be mild cholestasis caused by the catheter. The catheter caused an increased backflux of 11 C-CSar from hepatocytes to blood, and hepatic blood flow was 25% higher than in experiments without the catheter. The capacity for the overall transport of 11 C-CSar from blood to bile, as quantified by intrinsic clearance, was significantly lower in experiments with the catheter than in those without the catheter (P , 0.001). PET and blood measurements correlated significantly (P , 0.05). Conclusion: The in vivo kinetics of hepatobiliary secretion of conjugated bile acids can now be determined by dynamic 11 C-CSar PET.

show abstract

“…Increased arterial ammonia is reflected in increased intracerebral ammonia (Sorensen and Keiding 2007). Ammonia is thought to cross the blood brain barrier (BBB) by means of both passive diffusion and active transport (Nagaraja and Brookes 1998).…”

Section: Inter-organ Ammonia and Glutamine Metabolism In Hepatic Encementioning

confidence: 99%

Clinical science workshop: targeting the gut-liver-brain axis

et al. 2015

View full text Add to dashboard Cite

A clinical science workshop was held at the ISHEN meeting in London on Friday 11th September 2014 with the aim of thrashing out how we might translate what we know about the central role of the gut-liver-brain axis into targets which we can use in the treatment of hepatic encephalopathy (HE). This review summarises the integral role that interorgan ammonia metabolism plays in the pathogenesis of HE with specific discussion of the roles that the small and large intestine, liver, brain, kidney and muscle assume in ammonia and glutamine metabolism. Most recently, the salivary and gut microbiome have been shown to underpin the pathophysiological changes which culminate in HE and patients with advanced cirrhosis present with enteric dysbiosis with small bowel bacterial overgrowth and translocation of bacteria and their products across a leaky gut epithelial barrier. Resident macrophages within the liver are able to sense bacterial degradation products initiating a pro-inflammatory response within the hepatic parenchyma and release of cytokines such as tumour necrosis factor alpha (TNF-α) and interleukin-8 into the systemic circulation. The endotoxemia and systemic inflammatory response that are generated predispose both to the development of infection as well as the manifestation of covert and overt HE. Co-morbidities such as diabetes and insulin resistance, which commonly accompany cirrhosis, may promote slow gut transit, promote bacterial overgrowth and increase glutaminase activity and may need to be acknowledged in HE risk stratification assessments and therapeutic regimens. Therapies are discussed which target ammonia production, utilisation or excretion at an individual organ level, or which reduce systemic inflammation and endotoxemia which are known to exacerbate the cerebral effects of ammonia in HE. The ideal therapeutic strategy would be to use an agent that can reduce hyperammonemia and reduce systemic inflammation or perhaps to adopt a combination of therapies that can address both.

show abstract

New findings on cerebral ammonia uptake in HE using functional 13N-ammonia PET

Cited by 35 publications

References 16 publications

Pathogenesis of Hepatic Encephalopathy: Role of Ammonia and Systemic Inflammation

Pathogenesis of Hepatic Encephalopathy: Role of Ammonia and Systemic Inflammation

Hepatobiliary Secretion Kinetics of Conjugated Bile Acids Measured in Pigs by ¹¹C-Cholylsarcosine PET

Clinical science workshop: targeting the gut-liver-brain axis

Contact Info

Product

Resources

About

New findings on cerebral ammonia uptake in HE using functional 13N-ammonia PET

Cited by 35 publications

References 16 publications

Pathogenesis of Hepatic Encephalopathy: Role of Ammonia and Systemic Inflammation

Pathogenesis of Hepatic Encephalopathy: Role of Ammonia and Systemic Inflammation

Hepatobiliary Secretion Kinetics of Conjugated Bile Acids Measured in Pigs by 11C-Cholylsarcosine PET

Clinical science workshop: targeting the gut-liver-brain axis

Contact Info

Product

Resources

About

Hepatobiliary Secretion Kinetics of Conjugated Bile Acids Measured in Pigs by ¹¹C-Cholylsarcosine PET