Brain edema in acute liver failure and chronic liver disease: Similarities and differences

doi:10.1016/j.neuint.2013.01.015

Neurochemistry International

Volume 62, Issue 4, March 2013, Pages 446-457

https://doi.org/10.1016/j.neuint.2013.01.015 Get rights and content

Abstract

Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome that typically develops as a result of acute liver failure or chronic liver disease. Brain edema is a common feature associated with HE. In acute liver failure, brain edema contributes to an increase in intracranial pressure, which can fatally lead to brain stem herniation. In chronic liver disease, intracranial hypertension is rarely observed, even though brain edema may be present. This discrepancy in the development of intracranial hypertension in acute liver failure versus chronic liver disease suggests that brain edema plays a different role in relation to the onset of HE. Furthermore, the pathophysiological mechanisms involved in the development of brain edema in acute liver failure and chronic liver disease are dissimilar. This review explores the types of brain edema, the cells, and pathogenic factors involved in its development, while emphasizing the differences in acute liver failure versus chronic liver disease. The implications of brain edema developing as a neuropathological consequence of HE, or as a cause of HE, are also discussed.

Highlights

► Brain edema is a common feature in ALF and CLD. ► HE is inconsistently associated with the presence of brain edema. ► Fibrous and protoplasmic astrocytes are differentially implicated in the pathogenesis of HE. ► The pathogenesis of HE is multifactorial causing an array of neurological symptoms.

Introduction

Loss of liver function occurs as a consequence of either acute liver failure (ALF) or chronic liver disease (CLD). ALF is defined as a rapid hepatocellular necrosis that leads to the severe deterioration of liver function, which occurs within hours up to 6 months after the onset of jaundice, and in the absence of a pre-existing liver disease (Lee, 2012). The most frequent cause of ALF is drug intoxication and hepatotoxicity (58%), with acetaminophen overdose being the most frequently observed (46%). Other etiologies include autoimmune hepatitis, acute viral hepatitis (A and B), drug-induced, with a large proportion (15%) remaining indeterminate. The mean survival rate (spontaneous liver regeneration) of patients with ALF is 45%, but this can vary significantly depending on the etiology of ALF. The highest recovery rate (55–65%) is reported in patients following acetaminophen overdose or hepatitis A infection (Lee, 2012).

CLD develops due to a chronic deterioration of liver function resulting from a persisting, long-term hepatic insult. After 10–20 years of continuous aggression, cirrhosis evolves, and is characterized by the progressive replacement of normal liver architecture by fibrosis, scar tissue and regenerative nodules (Fauci et al., 2011). The most common etiologies of cirrhosis are: (1) alcoholism, as 8–20% of long-term heavy drinkers develop cirrhosis (Sanyal et al., 2010), (2) chronic viral hepatitis, where approximately 30% of infected patients become cirrhotic (Rosen, 2011), and (3) the accumulation of fat deposits in the liver, which cause non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Given that obesity is on course of becoming a worldwide epidemic condition (in the USA, 66% of adults are overweight or obese; this is predicted to increase to 75% by 2015 (Wang and Beydoun, 2007)), the number of cases of NASH-related cirrhosis is expected to rise.

To date, the only curative treatment for patients with liver failure or disease is liver transplantation. Since the number of patients awaiting a liver transplantation surpasses the number of available livers (from both living and cadaveric donors), managing liver failure/disease-related complications remains the primary challenge.

Section snippets

Hepatic encephalopathy

Hepatic encephalopathy (HE), a major complication of both ALF and CLD, is a metabolic neuropsychiatric syndrome that comprises a spectrum of symptoms, ranging from mild cognition and attention deficits to coma and death. HE has been categorized into 3 types, based on the type of hepatic abnormality (Ferenci et al., 2002):

Brain edema in liver disease/failure

Brain edema is defined as an accumulation of water in the brain, which occurs in the setting of an osmotic gradient. It is commonly associated with HE in both ALF and CLD. Since the brain is contained within a non-compliant skull, an increase in brain volume can progressively result in an increase of intracranial pressure (ICP) and detrimentally lead to brain stem herniation and death.

Components involved in the development of brain edema in liver disease/failure

Brain edema can arise due to cytotoxic or vasogenic mechanisms, with the first occurring as a result of alterations in cellular metabolism, and the latter due to a physical breakdown of the BBB (Klatzo, 1967). The BBB is a physical and metabolic barrier that helps regulate brain homeostasis and protects the brain from endogenous and exogenous toxins arising from systemic circulation. The BBB is a multicellular vascular structure, composed of endothelial cells with tight intercellular junctions

Ammonia

The neurotoxic effects of ammonia have long been considered the main pathogenic factor in HE (Cooper and Plum, 1987). Ammonia is a neurotoxin whose homeostasis is maintained primarily by the liver. It is produced by a number of different metabolic reactions, with phosphate-activated glutaminase (PAG) being an important enzyme catalyzing the deamination of glutamine to glutamate. The gut is a primary source of ammonia production through ammonia-generating intestinal bacteria and PAG activity in

Role of brain edema in HE

In ALF, intracranial hypertension is the primary cause to brain stem herniation and death. Brain edema undoubtedly is linked to a rise of cerebral water in ALF, however aside from its physical contribution to brain volume and ICP, its role in the severe deterioration of neurological function remains unresolved. Brain edema in CLD patients is associated with MHE; not clinically obvious deterioration of neurological function. However, since patients with MHE have an 4-fold increased risk of

Conclusion

In summary, brain edema is present in both ALF and CLD, and a combination of multiple factors can lead to its development (vasogenic or cytotoxic). In ALF, a rapid development of brain edema contributes to an increase in ICP, which physically stresses the brain and causes sudden neurological deterioration. However, in CLD, during which an increase in ICP is rarely observed, the role of brain edema in the pathogenesis of HE remains elusive; brain edema (astrocyte swelling) can lead to

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In patients with greater degrees of cerebral atrophy, as might occur with age or chronic cirrhosis, there is a greater amount of CSF available for displacement and, therefore, a greater buffer against intracranial hypertension [32]. Several authors have proposed differences in intracranial buffering capacity as an explanation for why CE formation in CLD has a less dramatic clinical presentation than in ALF [4,33]. However, it remains unknown whether CE that does not progress to intracranial hypertension (so called “low-grade” CE) is benign.
Liver disease is a growing public health concern. Hepatic encephalopathy, the syndrome of brain dysfunction secondary to liver disease, is a frequent complication of both acute and chronic liver disease and cerebral edema (CE) is a key feature. While altered ammonia metabolism is a key contributor to hepatic encephalopathy and CE in liver disease, there is a growing appreciation that additional mechanisms contribute to CE. In this review we will begin by presenting three classic perspectives that form a foundation for a discussion of CE in liver disease: 1) CE is unique to acute liver failure, 2) CE in liver disease is only cytotoxic, and 3) CE in liver disease is primarily an osmotically mediated consequence of ammonia and glutamine metabolism. We will present each classic perspective along with more recent observations that call in to question that classic perspective. After highlighting these areas of debate, we will explore the leading contemporary mechanisms hypothesized to contribute to CE during liver disease.
Pathogenesis of Hepatic Encephalopathy in Chronic Liver Disease
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In the past, the presence of brain edema was believed to be restricted to cases of acute liver failure, primarily because of the fact that patients with acute liver failure developed increased intracranial pressure (ICP). Because increased ICP is rarely observed in CLD, brain edema was less suspected.4 However, advanced and sensitive magnetic resonance imaging (MRI) techniques have detected water changes in brains of patients with CLD (without an increase in ICP), which has been found to be associated with HE.8
Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome that occurs during chronic liver disease (CLD). While ammonia and other precipitating factors in liver disease including inflammation, bile acids, oxidative stress, and lactate play a role in the pathogenesis of HE, the exact mechanism that leads to HE is not fully understood. Notably, accumulating evidence points toward a synergic effect rather than independent actions among precipitating factors that contributes to the development and severity of HE in CLD. Hence, this review is aimed to briefly discuss the single and synergic interplay of pathological factors in the progression and severity of HE.
Intravenous BCAA Infusion Does Not Lead to a Sustained Recovery From Overt HE in ACLF – An Open Label Randomized Clinical Trial
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Hepatic encephalopathy (HE) in acute-on-chronic liver failure (ACLF) is associated with significant morbidity and mortality. We conducted a prospective, randomized controlled clinical trial to study the efficacy of intravenous branched chain amino acids (IV-BCAA) with lactulose versus lactulose alone for improvement in HE at 24 h, day 3, and day 7. The primary outcome was an improvement in encephalopathy by ≥ 1 grade at 72 h.
European association for study of liver (EASL) defined ACLF patients with overt HE were assessed and randomized into the experimental arm (IV-BCAA - 500 mL/day for 3 days + Lactulose; n = 39) and the comparator arm (Lactulose alone; n = 37). Six patients developed COVID-19 after randomization and were excluded (4-experimental arm and 2-comparator arm).
Of 222 screened patients, 70 (35 in each arm) were included in the analysis. Baseline characteristics, including HE grade (2.9 ± 0.7 vs 2.8 ± 0.7; P = 0.86) and (chronic liver failure) CLIF-C ACLF score (54.2 ± 5.6 vs 54.8 ± 5.7; P = 0.65), were similar. Overall survival was 40% at 28 days (48.5% vs 31.4%; P = 0.14). Improvement in hepatic encephalopathy scoring algorithm (HESA) by ≥ 1 grade at 24 h occurred in 14 patients (40%) in the BCAA arm and 6 patients (17.1%) in the control group (P = 0.03) which translated to a shorter intensive care unit (ICU) stay. The median change in HESA at 24 h was greater in the BCAA arm than the control arm (P = 0.006), which was not sustained at days 3 or 7. Ammonia levels did not correlate with the grade of HE (Spearman's correlation coefficient (ρ) = - 0.0843; P = 0.29).
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Therefore, no longitudinal measurements on the same animal are possible. Table 1 presents a summary of the results published to date on type C HE animal models, while more details on these two techniques can be found in the published literature.1,2 The gravimetry technique appears to be most widely used and to have some advantages, such as a better specificity, together with the possibility of being able to use a smaller quantity of samples.1,2
Brain edema is a common feature associated with hepatic encephalopathy (HE). In patients with acute HE, brain edema has been shown to play a crucial role in the associated neurological deterioration. In chronic HE, advanced magnetic resonance imaging (MRI) techniques have demonstrated that low-grade brain edema appears also to be an important pathological feature. This review explores the different methods used to measure brain edema ex vivo and in vivo in animal models and in humans with chronic HE. In addition, an in-depth description of the main studies performed to date is provided. The role of brain edema in the neurological alterations linked to HE and whether HE and brain edema are the manifestations of the same pathophysiological mechanism or two different cerebral manifestations of brain dysfunction in liver disease are still under debate. In vivo MRI/magnetic resonance spectroscopy studies have allowed insight into the development of brain edema in chronic HE. However, additional in vivo longitudinal and multiparametric/multimodal studies are required (in humans and animal models) to elucidate the relationship between liver function, brain metabolic changes, cellular changes, cell swelling, and neurological manifestations in chronic HE.
Lessons on brain edema in HE: from cellular to animal models and clinical studies
2024, Metabolic Brain Disease

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ReviewBrain edema in acute liver failure and chronic liver disease: Similarities and differences

Abstract

Highlights

Introduction

Section snippets

Hepatic encephalopathy

Brain edema in liver disease/failure

Components involved in the development of brain edema in liver disease/failure

Ammonia

Role of brain edema in HE

Conclusion

Biochem. Pharmacol.

Dig. Liver Dis.

Neurochem. Int.

Free Radic. Biol. Med.

Neurochem. Int.

Gastroenterology

Gastroenterology

Cell

Gastroenterology

Gastroenterology

J. Hepatol.

Hepatology

J. Hepatol.

Neurochem. Int.

Neurochem. Int.

Hepatology

Clin. Liver Dis.

Neurochem. Int.

Am. J. Gastroenterol.

J. Hepatol.

Gastroenterology

J. Hepatol.

Gastroenterology

Gastroenterology

J. Hepatol.

Neuroscience

Neurochem. Int.

Neurosci. Lett.

Clin. Biochem.

J. Hepatol.

Inflammatory mediators and modulation of blood-brain barrier permeability

Cell. Mol. Neurobiol.

Ammonium action on post-synaptic inhibition in crayfish neurones: implications for the mechanism of chloride extrusion

J. Physiol. (Lond.)

Glutamine: a Trojan horse in ammonia neurotoxicity

Hepatology

A quantitative evaluation of the permeability of the blood brain barrier of portacaval shunted rats

Metab. Brain Dis.

Cerebral blood flow and liver function in patients with encephalopathy due to acute and chronic liver diseases

Scand. J. Gastroenterol.

Health related quality of life and minimal hepatic encephalopathy. It is time to insert “quality” in health care

J. Gastroenterol. Hepatol.

Aquaporins in cerebrovascular disease: a target for treatment of brain edema?

Cerebrovasc. Dis.

Observation of cerebral metabolites in an animal model of acute liver failure in vivo: a 1H and 31P nuclear magnetic resonance study

J. Neurochem.

Arterial ammonia and clinical risk factors for encephalopathy and intracranial hypertension in acute liver failure

Hepatology

Neuropathological analysis of pathological forms of astroglia in Wilson’s disease

Folia Neuropathol.

Astrocyte-specific protein and neuroglial differentiation. An immunofluorescence study with antibodies to the glial fibrillary acidic protein

J. Comp. Neurol.

AST-120 (spherical carbon adsorbent) lowers ammonia levels and attenuates brain edema in bile duct-ligated rats

Hepatology

Identifying the direct effects of ammonia on the brain

Metab. Brain Dis.

Oxidative stress: a systemic factor implicated in the pathogenesis of hepatic encephalopathy

Hepatic encephalopathy

N. Engl. J. Med.

Does liver-disease aetiology have a role in cerebral blood-flow alterations in liver cirrhosis?

Eur. J. Gastroenterol. Hepatol.

Hepatic encephalopathy and brain edema in acute hepatic failure: does glutamate play a role?

Hepatology

Neuronal cell death in hepatic encephalopathy

Metab. Brain Dis.

Experimental models of hepatic encephalopathy: ISHEN guidelines

Liver Int.

Ammonia and proinflammatory cytokines modify expression of genes coding for astrocytic proteins implicated in brain edema in acute liver failure

Metab. Brain Dis.

Review
Brain edema in acute liver failure and chronic liver disease: Similarities and differences