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Liver zonation
The enormous number of different liver functions are carried out by parenchymal and
four main types of nonparenchymal cells, either alone or in cooperation. Although the
liver tissue is uniform on the level of histology, it is heterogenous on the level of
morphometry and histochemistry. This heterogeneity is related to the blood supply; cells
located in the upstream or periportal zone differ from those in the downstream or
perivenous zone in their equipment with key enzymes, translocators, receptors, and
subcellular structures and therefore have different functional capacities. This is the basis
of the model of metabolic zonation, according to which glucose release from glycogen
and via gluconeogenesis, amino acid utilization and ammonia detoxification, protective
metabolism, bile formation, and the synthesis of certain plasma proteins such as albumin
and fibrinogen occur mainly in the periportal area, whereas glucose utilization,
xenobiotic metabolism, and the formation of other plasma proteins such as alpha 1antitrypsin or alpha-fetoprotein occur predominantly in the perivenous zone. The morphologic and functional heterogeneity is the result of zonal differences in the activation of
the cellular genome caused by gradients in oxygen, substrate, hormone, and mediator
levels, in innervation, as well as in cell-to-cell and cell-to-biomatrix interactions.
HEPATIC ENCEPHALOPATHY
Hepatic encephalopathy (HE), also known as porto systemic encephalopathy, is a major
neuropsychiatric complication of cirrhosis and it is the occurrence of confusion, altered level of
consciousness, and coma as a result of liver failure. In the advanced stages it is called hepatic
coma or coma hepaticum and it may ultimately lead to death.
Hepatic encephalopathy: pathophysiology and advances in therapy. 2007
HE comprises a broad range of potentially reversible neuropsychiatric disturbances in patients
with liver dysfunctions after exclusion of other neurological and/or metabolic causes. For that
reason the severity of hepatic encephalopathy is graded with the West Haven Criteria: this is
based on the level of impairment of autonomy, changes in consciousness, intellectual function,
behaviour, and the dependence on therapy.
Grade 2 - Lethargy or apathy, minimal disorientation for time or place, subtle personality
change, inappropriate behaviour;
In acute liver failure, the development of severe encephalopathy strongly predicts short-term
mortality, and is almost as important as the nature of the underlying cause of the liver failure in
determining the prognosis.
Compared to the US general population, the physical and mental component summary scores
were lower in patients with cirrhosis. Among patients with cirrhosis, there were no significant
differences in the physical and mental component summary scores according to age, gender,
ethnicity, and aetiology. Increased severity of liver disease is associated with decreased physical
aspects of quality of life. Patients with encephalopathy (overt and subclinical) had decreased
physical and mental component summary scores compared to patients without encephalopathy.
Compared to patients without encephalopathy, those with subclinical encephalopathy had a lower
mental component summary score.
Flapping tremor
Increasing severity of liver disease is associated with decreased physical aspects of quality of
life: overt hepatic encephalopathy negatively affects both physical and mental aspects of quality
of life, whereas subclinical encephalopathy affects mainly the mental aspects, independently of
age, gender, ethnicity, aetiology and liver disease severity. Widespread cortical and subcortical
network connectivity changements that correlated with neuropsychologic impairment were found
in patients with subclinical HE. In particular, impairment in the basal ganglia-thalamocortical
circuit could play an important role in mediating neurocognitive dysfunction, especially for
psychomotor speed and attention deficits in patients with subclinical HE. Additionally, studies
revealed significantly reduced functional connectivity in the right middle frontal gyrus and left
posterior cingulate cortex in the HE patients.
Encephalopathy often occurs together with other symptoms and signs of liver failure. These may
include jaundice, ascites, and peripheral edema. The tendon reflexes may be exaggerated, and
the plantar reflex may be abnormal, namely extending rather than flexing (Babinski's sign) in
severe encephalopathy. A particular smell (foetor hepaticus) may be detected.
CAUSES
In a small proportion of cases, the encephalopathy is caused directly by liver failure; this is more
likely in acute liver failure. More commonly, especially in chronic liver disease, hepatic
encephalopathy is caused or aggravated by an additional cause, and identifying these causes can
be important to treat the episode effectively. These predisposing factors are common and include:
Excessive nitrogen load, caused by:
- Oral protein load
- Gastrointestinal bleeding
- Renal failure
Electrolyte or metabolic disturbances:
- Hyponatraemia
- Hypokalaemia
- Diuretics abuse (generally used for the treatment of ascites)
- Hypoxia
- Dehydratation
Drugs:
- Sedatives
- Narcotics
- Antipsychotics
- Alcohol intoxication
Infections, especially by HCV
Transjugular intrahepatic portosystemic stent shunts (TIPS)
Poor nutritional status
DM and insulin resistance
Surgery
Unknown: in 2030% of cases, no clear cause for an attack can be found.
PATHOGENESIS
The pathogenesis of HE in cirrhosis is complex and multifactorial, but a key role is thought to be
played by circulating gut-derived toxins of the nitrogenous compounds, most notably ammonia.
In healthy subjects, nitrogen-containing compounds from the intestine, generated by gut
bacteria from food, are transported by the portal vein to the liver, where 8090%
is metabolised through the urea cycle and/or excreted immediately.
The water channel aquaporin IV: astrocytes modulate AQP4 mRNA expression and distribution
and the aggregation status of the ensuing protein depending on ammonia concentration and
duration of exposure, determining a smaller water influx in ammonia-treated astrocytes.
Furthermore, AQP4 gene suppression determines the appearance of a new morphological cell
phenotype associated with a strong reduction in cell growth.
Ammonia induces aquaporin-4 rearrangement in the plasma membrane of cultured astrocytes.
2012
Despite numerous studies demonstrating the central role of ammonia, ammonia levels don't
always correlate with the severity of the encephalopathy. Besides, inflammatory cytokines and
reactive oxygen species appear to play a crucial role in the pathogenesis of HE.
There is evidence to suggest that, in acute liver failure (ALF), brain ammonia and
proinflammatory cytokines may act synergistically to cause brain oedema and its complications
(intracranial hypertension, brain herniation). It seems that ammonia and proinflammatory
cytokines modify the expression of genes coding for astrocytic proteins (AQP4, GFAP, iNOS,
HO-1) and, although modest, these effects are additive, suggesting a synergistic mechanism.
However, the molecular mechanisms involved remain to be established.
Additionally, recent studies indicate that other suspected toxins in HE, such as phenol, produce
comparable effects to that caused by ammonia, particularly on the astrocyte benzodiazepine
receptor.
DIAGNOSIS
In general, it is based on clinical findings, whereas measurement of serum ammonia has no
validated role in HE diagnosis.
The diagnosis is usually made by neuropsychological and/or neurophysiological testing in
cirrhotic patients who are otherwise normal on neurological examination. At present the most
frequently used psychometric methods for diagnosing minimal hepatic encephalopathy are the
Inhibitory Control Test and the Psychometric Hepatic Encephalopathy Score (PHES). Another
frequently used method is Critical Flicker Frequency. Today, no data are available that allow to
decide which of these methods is the most appropriate. Visually evoked potentials (P300 wave)
and critical flicker frequency analysis are also objective and sensitive techniques for detection of
minimal HE.
It is recommended to screen all patients with cirrhosis for minimal hepatic encephalopathy using
psychometric testing because it impairs the health-related quality of life, predicts the
development of overt encephalopathy and is probably associated with a poor prognosis.
[Diagnostics and treatment of hepatic encephalopathy]. 2012 ; Psychometric tests for diagnosing
minimal hepatic encephalopathy. 2012
Additionally, cerebral magnetic resonance imaging reveals that marked loss of brain tissue
density is common in cirrhosis, progresses during the course of the disease, is greater in patients
with history of hepatic encephalopathy and persists after liver transplantation.
Cerebral magnetic resonance imaging reveals marked abnormalities of brain tissue density in
patients with cirrhosis without overt hepatic encephalopathy. 2011 ; Altered brain functional
connectivity in patients with cirrhosis and minimal hepatic encephalopathy: a functional MR
imaging study. 2012 ; Altered resting-state brain activity at functional MR imaging during the
- Use of probiotics;
- Use of inhibitors of phosphodiesterase 5 (PDE-5), such as Zaprinast and Sildenafil, or antiinflammatories, such as Ibuprofen: they increase cGMP levels
Mechanisms of cognitive alterations in hyperammonemia and hepatic encephalopathy:
therapeutical implications. 2009 ;
- Mild hypothermia: it delays in the onset of severe encephalopathy, selectively normalizes
lactate and alanine synthesis from glucose, prevents the impairment of oxidative metabolism and
results in a reduction of brain water content, in a significant reduction of cerebrospinal fluid
(CSF), but not plasma ammonia concentrations and in an inhibition of blood-brain transfer of
ammonia. It seems to offer a potentially useful bridge therapy in patients with acute liver failure
who are awaiting liver transplantation. The impact of potential adverse events, such as infection,
should also be taken into account
Mild hypothermia for acute liver failure: a review of mechanisms of action. 2005 ; Therapeutic
hypothermia for acute liver failure. 2009
Instead, strategies aimed at lowering gut ammonia production are generally ineffective.