Joseph Gastala, MD; Aristides Capizzano, MD; Patricia Kirby, MD; Toshio Moritani, MD, PhD

University of Iowa Hospitals and Clinics

IMAGING FINDINGS, PATHOLOGY AND PATHOPHYSIOLOGY OF HEPATIC ENCEPHALOPATHY WITH EMPHASIS ON DIFFUSION-WEIGHTED IMAGING

eEdE-03

DISCLOSURES• The authors have no financial or nonfinancial relationships to disclose

OUTLINE• Introduction

• Etiology and epidemiology

• Categorization

• Diagnosis

• Pathophysiology

• Imaging Findings

• Summary

INTRODUCTION• Hepatic encephalopathy is a neuropsychiatric manifestation of chronic and acute liver

disease seen in patients with liver dysfunction and/or portosystemic shunting

• It is a clinical condition with structural and functional abnormalities which can manifest with neuroimaging

• It is important for the radiologist to recognize findings of hepatic encephalopathy as neuroimaging is frequently used to rule out other causes for the encephalopathy and the radiologist can aid in the diagnosis

ETIOLOGY AND EPIDEMIOLOGY• Liver failure is central to the neurologic alterations of hepatic encephalopathy, and this is caused by

different types of liver disease of different chronicity and magnitude [1]

• Hepatic encephalopathy is secondary to decompensated cirrhosis (most common), acute liver failure or other metabolic encephalopathies such as renal or respiratory

• Acute liver failure incidence is low (2000 people per year), but with high mortality rate. A number of etiologies can cause acute liver failure [1]

• In the United States, the most common causes of liver failure from 1998 to 2007 are acetaminophen overdose (46%), indeterminate (14%) idiosyncratic drug reactions (12%), hepatitis B virus (7%), and hepatitis A virus (3%) [2].

• Chronic liver disease, however, has been estimated to have an incidence of 150000 per year [3].

• The most common causes of cirrhosis in the United States are alcohol use (60-70%), chronic hepatitis B or C (10%), NAFLD (10%) biliary obstruction (5-10%) [4].

• Hepatic encephalopathy occurs at a rate of approximately 2-3 % per year in patients with cirrhosis. When associated with cirrhosis it is of gradual onset and rarely fatal, ranging from subtle cognitive impairment to deep coma [5].

CATEGORIZATION• The 11th World Congress of Gastroenterology recommended a standardized nomenclature from

which classification of hepatic encephalopathy has been proposed [6]Type Nomenclature

A Hepatic encephalopathy occurring in the setting of Acute liver failure

B Hepatic encephalopathy occurring in the setting of portal-systemic Bypass with no intrinsic hepatocellular disease

C Hepatic encephalopathy occurring in the setting of Cirrhosis with portal hypertension or systemic shunting

• The severity of hepatic encephalopathy is based on clinical manifestations, known as the West Haven Criteria [7]

Grade ManifestationsI Trivial lack of awareness, euphoria or anxiety, shortened attention span, impaired performance of

additionII Lethargy or apathy, minimal disorientation for time or place, subtle personality change, inappropriate

behavior, impaired performance of subtractionIII Somnolence to semistupor but responsive to verbal stimuli, confusion, gross disorientation

IV Coma; unresponsive to verbal or noxious stimuli

DURATION AND TIME COURSE• Further classification of hepatic encephalopathy in chronic liver disease (Type C) is related to the time course

and duration

• Episodic hepatic encephalopathy

• Precipitated - precipitating factors include gastrointestinal hemorrhage, uremia, psychoactive medication, infection, constipation, dehydration, hypo- or hyperkalemia, hyponatremia

• Spontaneous - overt hepatic encephelopathy with exclusion of precipitating factors

• Recurrent – 2 episodes of episodic HE occur in 1 year

• Persistent hepatic encephalopathy

• Pattern of behavioral alterations are always present, but are interspersed with episodes of overt hepatic encephalopathy

• Minimal hepatic encephalopathy

• Neurologic alterations include attention deficits, mild cognitive impairment, psychomotor slowing, impaired bimanual coordination and visuomotor coordination; these alterations are not overt and must be unveiled using psychometric tests

• Diagnosis of minimal hepatic encephalopathy should be made using a psychometric hepatic encephalopathy score (PHES) [8].

DIAGNOSIS• Diagnosis of hepatic encephalopathy is clinical based on the history and physical exam

• Alterations in consciousness and behavior

• Constructional apraxia – inability to draw a five-pointed star or write legibly in a fully conscious patient is a typical finding of hepatic encephalopathy

• Presence of asterixis – series of extensor and flexor wrist movements elicited by having patients extend the arms with dorsiflexion of the wrists while separating the fingers for at least 15 seconds

• Findings of fetor hepaticus, sweet-smelling breath

• Measurements of blood ammonia are sometimes used to confirm a diagnosis of hepatic encephalopathy and to monitor the success of therapy, but the correlation of ammonia levels with the degree of encephalopathy is only approximate

• Important precipitants of hepatic encephalopathy in a cirrhotic patient include [5]:

• Gastrointestinal bleeding

• Bacterial infection

• Electrolyte imbalance

PATHOPHYSIOLOGY

LIVER FAILURE HYPERAMMONEMIA NEUROTOXICITY BRAIN EDEMA

LIVER FAILURE• The liver is a vital organ that performs a number of functions including glycogen storage,

protein synthesis, and detoxification of many endogenous and exogenous toxic compounds in the blood

• Much of the understanding of the effects of liver failure on cerebral function and subsequent encephalopathy are derived from animal studies, and these animal models may not precisely effect human disease. However, these models have provided a rudimentary understanding of the disease process and have identified therapeutic targets [1].

• With liver failure there is abnormal accumulation of certain substances in the blood normally removed by the liver, including ammonia and manganese [9]. Additionally, there are other alterations in homeostatic mechanisms, all of which contribute to the development of hepatic encephalopathy

• The most implicated substance in the pathogenesis of hepatic encephalopathy is ammonia

LIVER FAILURE HYPERAMMONEMIA NEUROTOXICITY BRAIN EDEMA

HYPERAMMONEMIA• The gastrointestinal tract is the primary source of nitrogenous wastes from glutamine

metabolism in the intestinal epithelium

• The intact liver clears almost all of portal vein ammonia, normally metabolizing it to urea. With liver failure, these mechanisms are not in place leading to hyperammonemia

• Ammonia is able to enter the brain by diffusion and transport through ion channels [10,11].

LIVER FAILURE HYPERAMMONEMIA NEUROTOXICITY BRAIN EDEMA

NEUROTOXICITY• Ammonia excess is toxic to the central nervous sytem and has many affects including modulation of

neurotransmission, astrocyte dysfunction, oxidative stress, and neuroinflammation

HYPERAMMONEMIA

Neurotransmitter Modulation/ alteration

Neuroinflammation

Astrocyte swellingNEUROTOXICITYLIVER FAILURE BRAIN EDEMA

LIVER FAILURE HYPERAMMONEMIA NEUROTOXICITY BRAIN EDEMA

ASTROCYTE SWELLING

Astrocyte

+ glutamate

Glutamine

Glutamine synthetase

• Once ammonia reaches the brain, removal of ammonia relies almost exclusively on glutamine synthetase, largely located within astrocytes [12].

• Glutamine synthetase takes place in astrocytes and maintains glutamate homeostasis in the brain

• Synthesis of glutamine from glutamate and ammonia in the brain is an important step for detoxication of ammonia in hepatic failure with hyperammonemia [13].

• One hypothesis is that glutamine acts as an organic osmolyte increasing osmolarity resulting in an influx of water into the cell [14,15].

• Swelling of astrocytes may be a key event in the development of hepatic encephalopathy. There are a few mechanisms that have been postulated that result in astrocyte swelling from hyperammonemia

Capillary

NH3

Mitochondria

NH3NH3

NH3

H2O

Astrocyte Swelling

LIVER FAILURE HYPERAMMONEMIA NEUROTOXICITY BRAIN EDEMA

• Hyperammonemia has also been shown to generate free radicals, such as superoxide (O2-), nitric oxide (NO), and peroxynitrite [17].

• This oxidative and nitrosative stress subsequently induces the mitochondrial permeability transition (MPT) [18].

• MPT is associated with movement of metabolites across the inner mitochondrial membrane, swelling of matrix, defective oxidative phosphorylation and ATP production and energy failure as well as generation of free radicals [19].

• Excess glutamine synthesized within astrocytes is also transported into the mitochondria where it is metabolized by phosphate activated glutaminase to ammonia and glutamate, the “Trojan Horse” hypothesis [16]. This describes the transport of ammonia into the mitochondria as glutamine.

Astrocyte

Ammonia + glutamate

Glutamine

Glutamine synthetase

GlutamineAmmonia + glutamate

Phosphate-activated glutaminase

Capillary

Mitochondria

NH3NH3

NH3

Reactive oxygen species

Membrane Permeability Transition

Astrocyte Swelling

• A critical consequence of this is astrocyte swelling [20].

• A positive feedback cycle results with the production of free radicals by the MPT further inducing the MPT and worsening of astrocyte swelling [21].

ASTROCYTE SWELLING

NEUROTOXICITY

ALTERED GLUTAMATERGIC TRANSMISSION

Astrocyte

Ammonia + glutamate

Glutamine

Glutamine synthetase

Glutamine Ammonia + glutamate

Phosphate-activated glutaminase

MitochondriaGlutamate

Neuronal Presynaptic terminal

Postsynaptic terminal

NMDA

Glutamate

• Another mechanism implicated in the development of hepatic encephalopathy is altered glutamatergic function.

• However, extracellular glutamate concentrations are elevated in HE [22]. This may be due to excessive release of glutamate from astrocytes depolarized by ammonia, or due to impaired reuptake by neurons [23, 24].

• This excess extracellular glutamate results in an excitotoxic overstimulation of NMDA receptors. Glutamate causes excessive formation of nitric oxide and cGMP from downstream pathways. The effect is similar to mechanisms involved in cerebral ischemia, ultimately causing neuronal degeneration and cell death [25].

Glutamate

Neuronal death

• Total brain glutamate has been shown to be decreased in various models of hepatic encephalopathy, presumably due to the consumption from glutamine formation during ammonia detoxification [22]

NEUROTOXICITY

ALTERED NEUROTRANSMISSION

• Acute elevation in ammonia leads to excessive activation of NMDA and ammonia-induced cell death. • Chronic elevation in ammonia, however, induces adaptive responses resulting in impairment of signal

transduction associated with NMDA receptors and leading to cognitive and motor impairments [26].• Other neurotransmitters have been studied showing alterations in the setting of hepatic encephalopathy.

• Chronic hyperammonemia has various effects on GABAergic neurotransmission, increasing GABAergic tone [27].

• Neurosteroids, metabolites of progesterone, are endogenous neuroactive compounds that cause behavioral effects including sedation, and these have been shown to be increased in brains of hepatic coma patient [28].

NEUROTOXICITY

NEUROINFLAMMATION• There is a synergistic role of hyperammonemia and

inflammation that contributes to the pathogenesis of hepatic encephalopathy [49].

Activation of microglial cells

Systemic inflammatory

mediators• Ammonia upregulates allograft inflammatory factor which

directly activates microglial cells [29].

• The neuroinflammatory response is involved in vasodilation; this is mediated by prostanoids and COX [30]. These cytokines may also influence the permeability of the blood brain barrier [31], subsequently contributing to vasogenic edema.

• Ammonia may also induce neuroinflammation through expression of other pro-inflammatory cytokines .This may occur through direct transport of cytokine to the brain or by induced release within the CNS. These factors include TNF-α, IL-6, and IL-8 [30].

Neuroinflammation

LIVER FAILURE NEUROTOXICITY BRAIN EDEMA

HYPERAMMONEMIA

CEREBRAL EDEMA

• One of the end results of acute fulminant liver failure is increase in cerebral edema and this is thought to be closely related to the development of hepatic encephalopathy

• Vasogenic edema occurs due to increase in blood brain barrier permeability.

• It has been shown that hyperammonemia can induce an increase in blood-brain barrier permeability, favoring capillary water influx to the brain [34].

• Breakdown of BBB causes water and plasma constituents to accumulate in the extracellular space [35].

• Cytotoxic edema is primarily related to astrocyte swelling as previously described

• Ischemia may also cause astrocyte swelling due to disruption of the Na+/K+ ATPase [45] and diffuse ischemia may be a contributing factor in cytotoxic edema apart from mechanisms described with ammonia and glutamine [46] .

• Other factors contributing to cytotoxic edema may be disruption in ion hemostasis [47].

Cerebral Edema

Vasogenic edema

Cytotoxic edema

LIVER FAILURE HYPERAMMONEMIA NEUROTOXICITY BRAIN EDEMA

TEMPORAL RELATIONSHIP OF EDEMA• Vasogenic edema has been shown to be the predominant source of

cerebral edema in early grades of hepatic encephalopathy, while cytotoxic edema predominates in more severe grades [48].

• In acute liver failure, abrupt loss of hepatic function leads to rapidly progressing hepatic encephalopathy, cerebral edema, and increased intracranial pressure. Many patients eventually die of increased intracranial pressure and herniation [32]. However, death from intracranial hypertension is a rare complication in chronic liver failure.

• In chronic liver failure, there is time for osmolar adaptation with the accumulation of glutamine; this is due to the loss of other organic osmolytes from astrocytes including myo-inositol, taurine, and choline [33]. These compensatory metabolic changes counteract the osmotic unbalance induced by intraastrocytic glutamine accumulation.

• The time course of changes in liver failure and subsequent variation in intracellular and extracellular edema leads to different findings on diffusion weighted imaging

Cerebral Edema

Cerebral Edema

Increased intracranial pressure

BRAIN EDEMA

Low grade brain edema

IMAGING FINDINGS• T1 weighted MRI

• The most consistent finding is presence of T1 hyperintensity in basal ganglia including globus pallidus, substantia nigra, reticulate and striatum

• Most widely accepted explanation for basal ganglia hyperintensities is presence of manganese at high concentrations [37].

• T2 weighted MRI

• High diffuse signal intensity along hemispheric white matter in or around the corticospinal tract [38]. This may be due to mild brain edema [39] and the selective involvement of white matter within or close to the corticospinal tract may be due to abnormal expression of Glu transporters [40]

• Patients with acute encephalopathy due to acute or acute-on-chronic liver failure show regions of involvement in thalamus, posterior limb of internal capsule, periventricular white matter, cerebellar white matter, and diffuse cortical involvement [41]. The extension of the lesions correlates with the maximum plasma ammonia level.

• Other focal T2-weighted white matter lesions have been described in patients with hepatic encephalopathy [42].

DIFFUSION WEIGHTED IMAGING FINDINGS• The diffusion weighted imaging findings are related to the chronicity of the hepatic failure and

the amount of intracellular and extracellular water.

• Many characteristic imaging findings have been described [38,41,42,43]

• Symmetrical bilateral diffusion restriction of the insular and cingulate cortices, which has also been reported in several conditions resulting in hyperammonemia

• Sparing of the peri-rolandic and occipital cortices

• Thalamus and posterior limb of internal capsule

• Corticospinal tracts

• Periventricular white matter, cerebellar white matter, and brain stem involvement have also been reported

• These particular regions may be affected because of variations in metabolism or regional blood flow or predominance of astrocytes in the tissue

• Some of these regions of the brain have been hypothesized to have increased metabolic demands, predisposing to the development of cytotoxic edema [51].

• It has been shown that there is decreased cerebral oxygen metabolism rate is in the thalamus, striatum, frontal cortex, and frontal part of cingulate gyrus. These findings suggest a dysfunction in brain energy metabolism in these areas in patients with hepatic encephalopathy [50].

• Hypoperfusion in the frontal lobe and basal ganglia has also been shown in patients with fulminant hepatic failure [52]

CHRONICITY WITH RESPECT TO DIFFUSION RESTRICTION• Patients with acute HE due to acute hepatic failure or acute-on-chronic hepatic failure

show ADC decrease in characteristic regions of involvement on DWI, including the thalamus, posterior limb of the internal capsule, periventricular white matter, cerebellar white matter, and diffuse cortical involvement [41].

• In fulminant acute hepatic failure, there are lower ADC or MD values in the affected locations, suggesting intramyelinic edema, intracellular edema, acute astrocytic swelling, or oligodendroglial injury [41].

• In chronic hepatic failure, several studies have found increased ADC or MD values in the thalami, basal ganglia, and periventricular white matter, which may represent chronic astrocytic swelling, increased interstitial fluid, or chronic demyelination [41].

• It has been shown that ADC values are increased in cirrhotic patients with minimal hepatic encephalopathy, and an increased ADC value may predict the development of overt HE [44].

76 YO M WITH HEPATITIS C CIRRHOSIS PRESENTING WITH DELIRIUM

A

A) Axial T1 weighted image at the level of the basal ganglia demonstrates hyperintensity of the basal ganglia (green arrows)

C, D) Axial FLAIR images demonstrate periventricular white matter changes related chronic small vessel ischemic disease, but no other abnormalities

B

C D

B) DWI images are normal

The patient had mild hepatic encephalopathy from medicine noncompliance. Ammonia level was 57 µmol/L at the time of the exam and the patient was later discharged.

61 Y FEMALE WITH A H/O OF ETOH ABUSE ADMITTED WITH ALTERED MENTAL STATUS

A B C

D E F

G

A, B, C) Axial DWI and D, E, F) ADC maps demonstrate diffusion restriction of the corticospinal tracts.

G) Axial T1 weighted image demonstrates hyperintense T1 signal of the globus pallidi.

The patients ammonia level was 128 µmol/L at the time of the scan.

51 YO FEMALE WITH ETOH CIRRHOSIS ADMITTED WITH DECOMPENSATED CIRRHOSIS AND ALTERED MENTAL STATUS

A) Axial slices T1 weighted image demonstrates hyperintense signal within the thalamiB) Axial FLAIR image demonstrates hyperintense signal within insular cortex and thalami

A B

C D

C) DWI and D) ADC map demonstrate no diffusion restriction

ADC value of the right insular cortex and left thalamus were measured to be 1114 and 987 µm2/s, respectively

This patient had mild acute on chronic hepatic encephalopathy showing edema without diffusion restriction. ADC values are elevated compared to other cases with fulminant hepatic failure. Ammonia level was 80 µmol/L.

57 Y M WITH HEPATITIS C CIRRHOSIS ADMITTED WITH ACUTE HEPATIC ENCEPHALOPATHY AND HYPERAMMONEMIA

A) Axial slices T1 weighted image demonstrates hyperintense signal within the basal ganglia

A B

C D

B) Axial FLAIR image demonstrates hyperintense signal within insular cortex, cingulate cortex, and posterior limb of the internal capsule, and

C) DWI and D) ADC map demonstrate diffusion restriction within the same areas as the FLAIR hyperintensities

ADC values were of the cingulate cortex, insular cortex, and posterior limb of the internal capsule were measured to be 565, 572, and 627 µm2/s respectively

57 Y M WITH HEPATITIS C CIRRHOSIS ADMITTED WITH ACUTE HEPATIC ENCEPHALOPATHY AND HYPERAMMONEMIA

E F

This case demonstrates a case of severe acute hepatic encephalopathy resulting in the patient’s death. This case presents typical imaging findings. Plasma ammonia level was 81 umol/L at the time of the scan and 216 umol/L near the time of death

E) DWI and F) ADC map more superiorly demonstrate diffusion restriction of the cingulate cortex with sparing of the central sulcus and occipital lobe

56 YO MALE WITH NASH LIVER FAILURE, ALPHA 1 ANTITRYPSIN DEFICIENCY ADMITTED WITH ALTERED MENTAL STATUS

A) Axial T1 weighted image demonstrates hyperintense signal within the globus pallidi

C) Diffusion weighted images and D) ADC map also demonstrate diffusion restriction within the splenium

B) Axial T2 weighted images demonstrate high signal intensity within the splenium

This finding is not characteristic of encephalopathy, but can be suggestive of a toxic or metabolic process.

Gross pathology of this patient post mortem shows discolored corpus callosum

Luxol fast blue stain of the corpus callosum demonstrates loss of myelin and vacuolation

Histology of the globus pallidus in this patient demonstrates marked spongiosis

Luxol fast blue stain of normal control

31 Y F WITH ACUTE FULMINANT LIVER FAILURE AFTER TYLENOL OVERDOSE, NO PRIOR HISTORY OF CIRRHOSIS

A B

C D

A) Axial T1 weighted image at the level of the basal ganglia demonstrates no abnormalityB) Axial FLAIR image demonstrates hyperintense signal within the putamen and thalami

C) DWI and D) ADC map demonstrate diffusion restriction within the putamen and thalami

07882238

ADC values were of the putamen and thalami were measured to be 518 and 575 µm2/s respectively

This case demonstrates acute fulminant liver failure, without underlying liver disease to cause manganese deposition within the basal ganglia. Ammonia levels came back as “icteric” at the time of the exam, and near the time of death

31 Y F WITH ACUTE FULMINANT LIVER FAILURE AFTER TYLENOL OVERDOSE, NO PRIOR HISTORY OF CIRRHOSIS

E F

E) DWI and F) ADC map demonstrate restricted diffusion within the pons

ADC value of the pons was measured to be 586 µm2/s

58 YO M FOUND DOWN, AMMONIA FOUND TO BE 2091 UMOL/L ON ADMISSION

A B

C D

A) DWI image and B) ADC map demonstrate diffuse diffusion restriction of the cortex and basal ganglia

C) DWI image and D) ADC map performed the day after admission demonstrate diffuse diffusion restriction now with effacement of the sulci

58 YO M FOUND DOWN, AMMONIA FOUND TO BE 2091 UMOL/L ON ADMISSION

E

F

E) Sagittal T1 weighted image demonstrates tonsillar herniationF) Axial T2 weighted image demonstrates loss of flow voids within the cavernous ICAs

This is a case of acute fulminant hyperammonemic encephalopathy leading to brain death.

SUMMARY• Hepatic encephalopathy is a neuropsychiatric condition related to liver failure with

hyperammonemia and other metabolic alterations implicated in its pathogenesis

• Cerebral edema and manganese deposition lead to some of the characteristic imaging findings on magnetic resonance imaging

• Findings on diffusion weighted imaging are related to the distribution of intracellular and extracellular water in different regions of the brain which are related to the time course and severity of liver failure

• Imaging findings with diffusion weighted imaging in hepatic encephalopathy are characteristic and the radiologist should be able to recognize the diagnosis

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