Normally, the liver breaks down ammonia into urea, which is safely excreted in urine. Physicians think that excessive ammonia and other toxins play a central role in the debilitating symptoms of encephalopathy, which may range from subtle personality changes to confusion and even coma. Type A is the result of acute liver failure, which occurs when a patient experiences rapid deterioration in liver function. This deterioration may be caused by numerous conditions including but not limited to drugs, medications, viral infection, or autoimmune disease.
Type B occurs in the setting of portosystemic shunting or bypass. In this condition, the circulatory system bypasses the liver, typically the result of either a congenital abnormality or of surgery. Type C is the result of cirrhosis. Individuals with chronic liver disease from viral hepatitis such as hepatitis B or C , non-alcoholic fatty liver disease, alcohol, autoimmune hepatitis, or another cause, may be at risk of developing cirrhosis.
Cirrhosis refers to a specific pattern and extent of scar tissue in the liver, reflective of advanced disease. This tends to develop gradually, with scar tissue slowly replacing healthy tissue over a period of time. Often, a precipitating factor plays a role in an episode of HE, such as infection, gastrointestinal bleeding, diuretic overdose, electrolyte disorders, dehydration, or constipation. Covert HE Subtle signs and symptoms that may require special testing to diagnose.
Overt HE Clinically apparent signs and symptoms on a spectrum from moderate to severe. One important physical examination sign in HE is asterixis, which is a flapping tremor of the hands typically elicited when the arms are outstretched and wrists extended. Hepatic or porto-systemic encephalopathy HE is one of the most serious complications of chronic or fulminant liver failure, associated most commonly with cirrhosis, and encompasses a spectrum of neuropsychiatric symptoms and signs.
Due to differences in etiology and severity, as well as heterogeneity of manifestations, the diagnosis and management of HE remain a difficult challenge for physicians and medical professionals.
Since HE does not clinically differ from encephalopathies of different etiologies, its diagnosis requires the presence of liver disease or a portosystemic shunt. Several factors have been implicated in pathogenesis, with ammonia considered to have a central role, thus prompt recognition of the cause of hyperammonemia can be potentially lifesaving.
Identification and correction of precipitating factors remains the cornerstone of treatment, while morbidity and mortality can be decreased by timely intervention. Overall, treatment of HE consists of the following three directions: modifying factors precipitating hyperammonemia and accumulation of toxic metabolites; decreasing blood and cerebral ammonia levels; and addressing the consequences of hyperammonemia and accumulation of toxic metabolites.
Screening all patients with cirrhosis for MHE and treating those with MHE diagnosis has been recommended to improve quality of life and rate of survival. Finally, liver transplantation is often the most successful long-term therapy for HE. Source of support: Self financing. National Center for Biotechnology Information , U.
Journal List Med Sci Monit v. Med Sci Monit. Published online Feb 1. Giannakis T. Toris , Christos N. Bikis , Gerasimos S. Tsourouflis , and Stamatios E. Author information Article notes Copyright and License information Disclaimer. Asias str. Received Mar 11; Accepted Aug 5.
This article has been cited by other articles in PMC. Summary One of the most serious complications of chronic or fulminant liver failure is hepatic encephalopathy HE , associated most commonly with cirrhosis. Keywords: hepatic encephalopathy, hyperammonemia, minimal hepatic encephalopathy, pathophysiology, treatment. Background Hepatic encephalopathy HE or portosystemic encephalopathy PSE is one of the most serious complications of liver failure, either chronic or fulminant.
Clinical Hepatic Encephalopathy Patients with HE, according to the West Haven Criteria, display a variety of neuropsychiatric abnormalities characterized by four degrees of severity, ranging from disturbances affecting quality of life abnormal sleep patterns, lack of awareness, increased reaction times, impairments in cognitive and mental function, behavior and personality alteration, disturbances in attention and coordination , to transient neurological symptoms, asterixis or flapping tremor, combined with characteristic electroencephalographic abnormalities [ 12 — 15 ].
Table 1 Degrees of severity and neuropsychiatric abnormalities in hepatic encephalopathy. Open in a separate window. Table 2 Precipitating factors for hepatic encephalopathy. Minimal hepatic encephalopathy Coma grade deeper than I is usually defined as overt encephalopathy and grade 0 or less as subclinical or minimal HE MHE , which is the mildest form of HE spectrum.
Etiology of hyperammonemia Ammonia is created primarily from nitrogenous products in the diet, bacterial metabolism of urea and proteins in the colon, as well as deamination of glutamine in the small intestine by glutaminase EC 3. Table 3 Etiology of hyperammonemia. Figure 1. Table 4 Important points in pathogenesis of hepatic encephalopathy. Knowledge at the molecular level Several studies have been performed in order to elucidate the molecular milestones in the pathogenesis of HE.
Figure 2. Figure 3. Table 5 Molecular mediators in hepatic encephalopathy. Treatment of hepatic encephalopathy Treatment of HE consists of the following three goals: a Dealing with precipitating factors of hyperammonemia and accumulation of toxic metabolites, b Lowering blood and cerebral ammonia levels, and c Dealing with the consequences of hyperammonemia and accumulation of toxic metabolites.
Dealing with precipitating factors of hyperammonemia and accumulation of toxic metabolites One of the most important aspects of dealing with HE is the ability to potentially reverse its progress by prompt recognition and treatment of its precipitating factors before a decompensated liver function takes place. Gastrointestinal hemorrhage, renal failure, dehydration, constipation Prompt treatment of upper or lower GI bleeding is essential. Infection Culture from all appropriate body fluids should be received.
Drugs The use of psychoactive medications such as benzodiazepines and narcotics should be evaluated and discontinued if possible. Acute brain injury and seizures The possibility of focal neurological injury must be excluded by a careful history and neurological examination. Lowering blood and cerebral ammonia levels Dietary regulations It has been demonstrated that dietary protein restriction in cirrhotic patients does not ameliorate or reverse the course of HE [ 55 ].
Figure 4. Non-absorbable disaccharides reduce the production and absorption of ammonia. Removing the ammonia from plasma L-ornithine-L-aspartate LOLA is a stable salt of two amino acids, which administered to a hyperammonemic patient effectively lowers the blood and brain ammonia levels [ 70 ].
Novel approaches and strategies under development The spherical adsorptive carbon AST, which is used in the treatment of patients with kidney failure in order to reduce the absorption of uremic toxins, was able to reduce ammonia levels in experimental animal models [ 79 ]. Dealing with the consequences of hyperammonemia and the accumulation of toxic metabolites Regulating neurotransmission in the brain Branched-chain amino acids, benzodiazepine antagonists such as flumazenil [ 82 , 83 ], dopamine receptor stimulators such as bromocriptine [ 84 ], NMDA receptor antagonists and zinc [ 85 ] have been tested as supplementary medication for the treatment of HE-related neurological symptomatology.
Invasive treatments Molecular adsorbent recirculating system MARS Molecular adsorbent recirculating system MARS is a blood detoxification system that removes both protein-bound and water-soluble toxins by means of hemodiadsorption, a combination of hemodialysis and adsorption by the use of albumin [ 86 ]. Surgical treatments The obliteration of any large spontaneous portosystemic anastomoses, surgical shunts, or TIPS, usually by the insertion of a reduction stent, [ 89 ] balloon-occluded retrograde transvenous obliteration BRTO , [ 90 ] or by surgical eradication of shunt vein, should be considered in cases of chronic HE.
Novel approaches and strategies under development Endocannabinoids have been used in animal studies in order to alleviate the symptoms of cerebral dysfunction, by activating the AMP-activated protein kinase [ 99 ]. Conclusions Hepatic or porto-systemic encephalopathy HE is one of the most serious complications of chronic or fulminant liver failure, associated most commonly with cirrhosis, and encompasses a spectrum of neuropsychiatric symptoms and signs.
Footnotes Source of support: Self financing. References 1. Scherlock S, Dooley J. Hepatic encephalopathy Diseases of the Liver and Biliary System. Oxford: Blackwell Scientific; Zieve L. Hepatic encephalopathy Disease of the Liver. Philadelphia, Pennsylvania: Lippincott; Compensated Cirrhosis: natural history and prognostic factors. Hepatic encephalopathy: An update of pathophysiologic mechanisms.
Proc Soc Exp Biol Med. Pomier LG. TIPS and hepatic encephalopathy. Semin Liver Dis. Prognosis assessment in patients with liver cirrhosis. Butterworth R.
Alterations of neurotransmitter-related gene expression in human and experimental portal systemic encephalopathy.
Metab Brain Dis. Complications of cirrhosis III. Hepatic encephalopathy. J Hepatol. Ueber den ammoniakgehalt des blutes under der organe und die harnstoffbildug bei den saugethieren. Arch Exp Pathol Pharmakol. Ammonia and hepatic encephalopathy: the more things change, the more they remain the same.
Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration. Cerebral ammonia metabolism in patients with severe liver disease and minimal hepatic encephalopathy. J Cereb Blood Flow Metab. Albrecht J, Jones EA. Hepatic encephalopathy: Molecular mechanisms underlying the clinical syndrome.
J Neurol Sci. Blei AT, Cordoba J. Am J Gastroenterol. Conn HO. Hepatic Encephalopathy: Syndromes and Therapies. Bloomington, Illinois: Medi-Ed Press; The hepatic encephalopathies; pp. J Neurosci Res. Encephalopathy-definition, nomenclature, diagnosis and quantification: final report of the working party at the 11 th World Congress of Gastroenterology, Vienna, Santiago J, Munoz Hepatic Encephalopathy.
Med Clin N Am. Eroglu Y, Byrne W. Hepatic Encephalopathy. Emerg Med Clin N Am. Scherlock S. Disease of the liver and biliary system.
Boston: Blackwll Sci; Weissenborn K. Diagnosis of subclinical hepatic encephalopathy. Minimal hepatic encephalopathy: diagnosis by neuropsychological and neurophysiological methods. Non-adherence can be a contributing factor to treatment failure.
Therefore, patients and their carers should be given clear advice on how to titrate the lactulose dose to maximize efficacy and reduce side-effects. If individuals are intolerant of lactulose, they should use alternative laxatives or regular enemas, although these will have less impact on ammonia production than lactulose. Rifaximin is a minimally absorbed oral antibiotic that alters the gut flora, leading to reduced ammonia production and absorption.
It is concentrated in the gastrointestinal tract, and despite broad-spectrum activity against gram-positive and gram-negative enteric bacteria, it has a low risk of inducing bacterial resistance [7]. Rifaximin maintained remission from hepatic encephalopathy in a landmark randomized controlled trial of patients [7]. This treatment also significantly reduced the risk of hospitalization for those with overt hepatic encephalopathy over 6 months.
Of note, Another study demonstrated long-term safety with rifaximin and a sustained reduction in hepatic-encephalopathy-related and all-cause hospitalization [8].
At present, rifaximin is recommended by the National Institute for Health and Care Excellence to prevent recurrence of over hepatic encephalopathy. In practice, treatment with rifaximin should be considered in patients with persistent symptoms of encephalopathy despite lactulose or in lactulose-intolerant patients, or in those who have had two or more episodes of over hepatic encephalopathy in the previous 6 months.
Rifaximin and lactulose in combination controls hepatic encephalopathy in most patients. Education of patients with overt hepatic encephalopathy and of their relatives or carers is paramount to reducing recurrence and hospital admissions.
Understanding of hepatic encephalopathy is limited among many of those affected and their caregivers, leading to structured education tools being developed with promising initial results [10]. Key education points include the effects of medication and potential side-effects, the importance of adherence, and early signs of recurrence and appropriate actions eg, laxative administration or, if febrile, seeing a general practitioner or attending hospital.
Other therapies for hepatic encephalopathy are generally less robustly supported by the available evidence, but could be considered in patients with recurrent disease despite lactulose and rifaximin, particularly for those who do not have the option of liver transplantation. L-ornithine-aspartate is a stable salt of the amino acids ornithine and aspartic acid that is thought to lower blood ammonia concentrations in patients with cirrhosis by stimulating urea and glutamine synthesis from hepatocytes and skeletal muscle respectively.
It might also have a directly hepatoprotective effect [11]. It can be administered orally or intravenously. A recent Cochrane review suggested that L-ornithine-aspartate has beneficial effects on mortality and hepatic encephalopathy, but the quality of evidence remains very low [12]. Supplementation with branched-chain amino acids is another potential option. Levels of these amino acids are reduced in patients with cirrhosis, which results in impaired conversion of ammonia to glutamine in skeletal muscle and reduces its detoxification.
Oral supplementation is effective in treating overt hepatic encephalopathy compared with placebo or no intervention, but not compared to lactulose or neomycin [13]. There are no trials examining the efficacy of this treatment in prevention of recurrent hepatic encephalopathy.
Some patients with recurrent severe hepatic encephalopathy have large dominant portosystemic shunts that increase the risk of this disease due to gut-derived toxins bypassing the liver and entering the systemic circulation.
His encephalopathy was likely due to increased absorption of ammonia into the mesenteric blood supply due to very slow transit constipation. Such absorption of ammonia most likely overwhelmed hepatic excretion.
A similar case scenario and hypothesis has been previously described [ 15 ]. We primarily used lactulose, a nonabsorbable disaccharide, to treat hyperammonemia and the patient improved significantly after maintaining three to four bowel movements daily. Lactulose helps decrease endogenous ammonia production, reduces intestinal pH, entraps ammonia as non-diffusible ammonium in the gut lumen and increases fecal nitrogen load by the direct cathartic effect. Absence of pre-existing liver disease may misguide a clinician and cases of non-cirrhotic hyperammonemia may be missed leading to life-threatening outcomes such as cerebral edema and herniation.
Persistent unresolved encephalopathy increases hospital stay, increases morbidity and mortality and leads to significant cognitive and functional decline in the long run. Thus, clinicians must routinely check serum ammonia in patients with acute encephalopathy of unclear etiology and must perform workup to determine potentially treatable causes. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein.
All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. The authors have declared that no competing interests exist.
Consent was obtained by all participants in this study. National Center for Biotechnology Information , U. Journal List Cureus v.
Published online Jan Author information Article notes Copyright and License information Disclaimer. Corresponding author. Salim Surani moc. Received Jan 8; Accepted Jan This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Hyperammonemia is a common cause of encephalopathy encountered in an intensive care unit ICU.
Keywords: acute encephalopathy, non-cirrhotic hyperammonemia, constipation, lactulose. Introduction Acute encephalopathy refers to global cerebral dysfunction in the absence of underlying primary structural disease of the brain [ 1 ].
Open in a separate window. Figure 1. Computed tomography of the head without contrast did not reveal acute intracranial pathology. Figure 2. Figure 3.
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