WJG 19 26 PDF
WJG 19 26 PDF
WJG 19 26 PDF
REVIEW
Halina Cicho-Lach, Department of Gastroenterology, Medical University of Lublin, 20094 Lublin, Poland
Agata Michalak, 2nd Faculty of Medicine, Medical University
of Lublin, 20059 Lublin, Poland
Author contributions: Cicho-Lach H and Michalak A contributed equally to this work, they both made substantial contributions to the study conception and design, and the text of
the paper.
Correspondence to: Halina Cicho-Lach, Professor, Department of Gastroenterology, Medical University of Lublin,
Jaczewski Str. 8, 20094 Lublin, Poland. [email protected]
Telephone: +48-60-1377656 Fax: +48-81-4796135
Received: May 11, 2012
Revised: July 25, 2012
Accepted: July 28, 2012
Published online: January 7, 2013
HEPATIC ENCEPHALOPATHY
Introduction and division
Hepatic encephalopathy (HE) continues to be a major
clinical problem. In subjects suffering from acute/chronic liver failure, HE can lead to coma and death. This
medical state causes a broad range of neuropsychiatric
disturbances with variable intensities, including poor
concentration, psychomotor retardation, decreased reaction time, short-term memory impairment and sensory
dysfunction[1,2]. According to the newest data, HE occurs
as one of four types. Therefore, this encephalopathy syndrome might be classified into four groups: A, B, C and
D[3-5]. Type A HE is inseparably associated with acute
liver failure resulting from severe inflammatory and/or
necrotic rapid onset liver disease (e.g., paracetamol overdose, excessive alcohol intake or acute fatty liver caused
by pregnancy or Reyes syndrome). Type B HE is associated with portosystemic bypass in the absence of parenchymal liver disorders and is mainly connected with congenital abnormalities. Type C HE accompanies chronic
liver failure (cirrhosis) and portal hypertension with portosystemic shunts. Type C has three subcategories: episodic (precipitated, spontaneous, or recurrent), persistent
(mild, severe, or treatment-dependent) and minimal. In
2009, the International Society for the Study of Hepatic
Encephalopathy and Nitrogen Metabolism completed
these classifications and added the experimental models
Abstract
Hepatic encephalopathy is a medical phenomenon
that is described as a neuropsychiatric manifestation
of chronic or acute liver disease that is characterized
by psychomotor, intellectual and cognitive abnormalities with emotional/affective and behavioral disturbances. This article focuses on the underlying mechanisms of the condition and the differences between
hepatic encephalopathy and noncirrhotic hyperammonemic encephalopathy. Hepatic encephalopathy is
a serious condition that can cause neurological death
with brain edema and intracranial hypertension. It is
assumed that approximately 60%-80% of patients
with liver cirrhosis develop hepatic encephalopathy.
This review explores the complex mechanisms that
lead to hepatic encephalopathy. However, noncirrhotic
hyperammonemic encephalopathy is not associated
with hepatic diseases and has a completely different
etiology. Noncirrhotic hyperammonemic encephalopathy is a severe occurrence that is connected with multiple pathogeneses.
2013 Baishideng. All rights reserved.
WJG|www.wjgnet.com
26
Hepatic encephalopathy
Astrocyte swelling
Changes in the
blood-brain barrier
Inflammatory mediators
Calcium
Ammonia
Glutamine
Bacterial products
and bacterial infection
Mitochondrial disorders
Oxidative and
nitrosative stress
NMDA receptors
Figure 1 The different factors and mechanisms involved in the pathogenesis of hepatic encephalopathy. GABA: Gamma-aminobutyric acid; NMDA: N-methylD-aspartate.
Pathogenesis
Although the etiology of HE has not been conclusively
established, it is widely agreed to be the result of numerous pathological processes. Research on the pathogenesis of HE is still being conducted, and several theories
have been reported (Figure 1).
The ammonia hypothesis
The neurotoxicity of ammonia is well recognized and
was first thought to play a significant role in the development of HE in the 1890s. In one study, creating
WJG|www.wjgnet.com
27
WJG|www.wjgnet.com
28
glutamate-nitric oxide cyclic GMP pathway. Indomethacin might reduce ICP and cerebral edema independently
of changing the cerebral blood flow (excepting the brain
function modulation). Numerous studies have revealed
the beneficial role of anti-inflammatory agents in the
course of HE. Ibuprofen reportedly reduces locomotor
disorders and increases the learning abilities of rats with
portacaval shunts. Ibuprofen also normalizes blood and
brain ammonia levels[46,55]. Consequently, anti-inflammatory therapy inhibits microglial activation during HE.
The findings in different experimental models provide
new therapeutic targets for HE and require further study.
WJG|www.wjgnet.com
29
tion in the pathogenesis of many CNS disorders (e.g., Alzheimers disease and multiple sclerosis). The pathological appearance of HE is closely related to BBB changes.
Swollen astrocytes constitute a well-known phenomenon
in the course of HE[22,63]. The phenomenon is primarily
caused by cellular and vasogenic edema and aquaporins
(AQP). In CNS structures, elevated values of AQP 1, 4
and 9 are characteristic of brain edema[26]. The increased
expression of these water channels serves an important
role in the movement of water through the BBB and its
pathological result. Moreover, AQPs have been reported
to participate in apoptosis in the CNS[64,65]. Astrocyte
disorders in HE result in changes to the BBB, reflected
by the loss of ion homeostasis and the accumulation of
intracellular water. Nevertheless, increased BBB ammonia permeability during hyperammonemia or HE is still
a matter of controversy among scientists[66]. There are
investigations that support and refute this theory. Several positron emission tomography studies have revealed
elevated brain ammonia concentrations in HE. In addition, transmission electron microscopy demonstrated a
disruption in the junction of BBB capillaries in the hippocampal area in a MHE model[26,35]. According to the
presented data, the structure of the BBB and its connection to systemic hyperammonemia in HE require further
exploration. The large number of studies conducted in
this area indicates that it might be essential for the pathological appearance of HE.
WJG|www.wjgnet.com
30
REFERENCES
1
Av SP. Hepatic encephalopathy: pathophysiology and advances in therapy. Trop Gastroenterol 2007; 28: 4-10 [PMID:
17896602]
Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K,
2
Blei AT. Hepatic encephalopathy--definition, nomenclature,
diagnosis, and quantification: final report of the working
party at the 11th World Congresses of Gastroenterology,
Vienna, 1998. Hepatology 2002; 35: 716-721 [PMID: 11870389
DOI: 10.1053/jhep.2002.31250]
Wakim-Fleming J. Hepatic encephalopathy: suspect it early
3
in patients with cirrhosis. Cleve Clin J Med 2011; 78: 597-605
[PMID: 21885692 DOI: 10.3949/ccjm.78a10117]
4
Quadrennial reviews and working party reports from the
World Congress in Gastroenterology. February 24-March
1, 2002. Bangkok, Thailand. J Gastroenterol Hepatol 2002; 17
Suppl: S1-195 [PMID: 12227330]
Mullen KD. Review of the final report of the 1998 Working
5
Party on definition, nomenclature and diagnosis of hepatic
encephalopathy. Aliment Pharmacol Ther 2007; 25 Suppl 1:
11-16 [PMID: 17295847 DOI: 10.1111/j.1746-6342.2006.03216.x]
Butterworth RF, Norenberg MD, Felipo V, Ferenci P, Albre6
cht J, Blei AT. Experimental models of hepatic encephalopathy: ISHEN guidelines. Liver Int 2009; 29: 783-788 [PMID:
19638106 DOI: 10.1111/j.1478-3231.2009.02034.x]
Leonard JV, Morris AA. Urea cycle disorders. Semin Neonatol
7
2002; 7: 27-35 [PMID: 12069536 DOI: 10.1053/siny.2001.0085]
Panlaqui OM, Tran K, Johns A, McGill J, White H. Acute
8
hyperammonemic encephalopathy in adult onset ornithine
transcarbamylase deficiency. Intensive Care Med 2008; 34:
1922-1924 [PMID: 18651132 DOI: 0.1007/s00134-008-1217-2]
Ben-Ari Z, Dalal A, Morry A, Pitlik S, Zinger P, Cohen J,
9
Fattal I, Galili-Mosberg R, Tessler D, Baruch RG, Nuoffer
JM, Largiader CR, Mandel H. Adult-onset ornithine transcarbamylase (OTC) deficiency unmasked by the Atkins
diet. J Hepatol 2010; 52: 292-295 [PMID: 20031247 DOI:
10.1016/j.jhep.2009.11.014]
10 Cohn RM, Roth KS. Hyperammonemia, bane of the brain.
Clin Pediatr (Phila) 2004; 43: 683-689 [PMID: 15494874 DOI:
10.1177/000992280404300801]
11 Maillot F, Crenn P. [Urea cycle disorders in adult patients].
Rev Neurol (Paris) 2007; 163: 897-903 [PMID: 18033025]
12 Wasant P, Srisomsap C, Liammongkolkul S, Svasti J. Urea
cycle disorders in Thai infants: a report of 5 cases. J Med Assoc Thai 2002; 85 Suppl 2: S720-S731 [PMID: 12403252]
13 Mak CM, Siu TS, Lam CW, Chan GC, Poon GW, Wong
KY, Low LC, Tang NL, Li SK, Lau KY, Kwong NS, Tam
S. Complete recovery from acute encephalopathy of lateonset ornithine transcarbamylase deficiency in a 3-year-old
boy. J Inherit Metab Dis 2007; 30: 981 [PMID: 17922216 DOI:
10.1007/s10545-007-0692-x]
14 Gulati S, Menon S, Kabra M, Kalra V. Intermittent hyperammonemic encephalopathy in a child with ornithine trans-
NONCIRRHOTIC HYPERAMMONEMIC
ENCEPAHALOPATHY
Research shows that approximately 90% of adult hyperammonemia cases are caused by severe liver disease. A
small number of cases have other causes and can be divided into two groups: (1) cases that are connected with
increased ammonia production; and (2) cases that are
caused by decreased ammonia elimination[81].
Increased ammonia production
Hyperammonemic encephalopathy may develop in patients with progressive multiple myeloma[82]. Several studies have demonstrated that malignant cells are able to
produce excess ammonia as the result of increased amino
acid metabolism. During intensive chemotherapy, leukemia patients tend to struggle with hyperammonemia[83].
Idiopathic hyperammonemia is also described among
bone marrow recipients. The other reason for noncirrhotic hyperammonemic encephalopathy might be the
presence of infections caused by urea-producing bacteria
(Proteus mirabilis, Escherichia coli, Klebsiella and Providencia
rettgeri). In extreme cases, the protein load and increased
metabolism might cause the elevated ammonia level.
Therefore, seizures, severe exercise, starvation, total parenteral nutrition or gastrointestinal bleeding can (rarely)
result in encephalopathy.
Decreased ammonia elimination
Metabolic disorders and problems with ammonia elimination might be the source of encephalopathy. Such
disorders include organic acidurias, urea-cycle disorders,
dibasic aminoaciduria, impaired fatty acid oxidation and
mistakes in pyruvate metabolism [7,11,12]. Noncirrhotic
congenital portosystemic shunts can also cause an elevated ammonia level in the blood stream, and the intake
of certain drugs (e.g., valproic acid, glycine, ribavirin and
carbamazepine) may induce noncirrhotic hyperammonemic encephalopathy[84-87].
CONCLUSION
Encephalopathy can be caused by various factors. The
WJG|www.wjgnet.com
31
WJG|www.wjgnet.com
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
32
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
WJG|www.wjgnet.com
33
81
82
83
84
85
86
87
WJG|www.wjgnet.com
34