Hepatic Encephalopathy & Acute Liver Failure PDF

1 1 HEPATIC ENCEPHALOPATHY AND ACUTE LIVER FAILURE By Prof. Hoda El Aggan...

1 1 HEPATIC ENCEPHALOPATHY AND ACUTE LIVER FAILURE By Prof. Hoda El Aggan Professor of Internal Medicine (Hepato-Biliary Pancreatic Unit) Faculty of Medicine, Alexandria University ILOs At the end of this session, the student will be able to: ▪ Know the definition, staging and classifications of hepatic encephalopathy (HE). ▪ Understand the pathogenesis and precipitating factors of HE. ▪ Describe the clinical presentation and diagnosis of HE. ▪ Outline the treatment of HE. ▪ Review acute liver failure as regards definition, causes, pathogenesis, clinical presentation, diagnosis, and treatment of acute liver failure. HEPATIC ENCEPHALOPATHY Definition Hepatic encephalopathy (HE) is broadly defined as brain dysfunction caused by liver insufficiency and/or portal-systemic shunting, which manifests as a wide spectrum of neurological or psychiatric abnormalities ranging from subclinical alterations to coma. Acute liver failure (ALF), although under the umbrella of HE, will be considered separately as discussed later. West Haven criteria According to West Haven criteria, the clinical spectrum of HE is graded into 5 grades based on changes in behavior, consciousness, intellectual function, and neuromuscular function (Table 1). El Aggan H  1 2 Table 1: West Haven criteria for grading of hepatic encephalopathy. Grade Features Grade 0, Minimal No clinical evidence of mental change Abnormal psychometric and neurophysiological tests Grade I Trivial lack of awareness Euphoria or anxiety Shortened attention span Impairment of addition or subtraction Grade II Lethargy or apathy Disorientation for time Obvious personality change Inappropriate behavior Grade III Somnolence to semi‐stupor Responsive to stimuli Confused Gross disorientation Bizarre behavior Grade IV Coma, unable to test mental state Grade 0 or minimal HE Grade 0 or minimal HE describes patients who have normal neurological status on clinical examination but have significant abnormalities on specialized psychometric and neurophysiological tests. Patients with MHE have already deficits in attention, visual perception, memory function, and learning impairment. The clinically inapparent impairment in mental functions is present and sufficient to cause disruption in the routine of everyday living. Simple activities of daily life are impaired, such as the ability to drive a car with consequent increased risk of travel accidents. MHE is present in approximately 30–70% of patients with cirrhosis. Classification HE should be classified as a combination of the following four factors or axes: (1) the type of underlying disease, (2) the severity of manifestations, (3) time course, and (4) the existence of precipitating factors. However, this classification is not clinically relevant in patients with ALF. (1) According to the type of underlying disease, HE is subdivided into: - Type A resulting from Acute liver failure (ALF). - Type B resulting predominantly from portosystemic Bypass or shunting with no intrinsic liver disease. - Type C resulting from Cirrhosis. The clinical manifestations of types B and C are similar, whereas type A has distinct features. El Aggan H  1 3 (2) According to the severity of manifestations, HE is graded into: - Unimpaired (normal mental status). - Covert HE includes West Haven grade 0/minimal HE and grade I HE - Overt HE includes West Haven grade II-IV HE with clinically manifest neurological-psychiatric abnormalities. As the distinction between minimal HE and grade I HE may not be clinically appareny, both can be combined under a single category “covert HE”. In contrast, grade I can be distinguished from grade II by the appearance of disorientation and asterixis that are chosen as initial marker symptoms of overt HE. (3) According to the time course, HE is subdivided into: - Episodic HE denotes bouts occurring more than 6 months apart. - Recurrent HE denotes ≥2 bouts occurring within 6 months or earlier. - Persistent HE denotes a pattern of behavioral alterations that are always present and interspersed with relapses of overt HE. (4) According to the existence of precipitating factors, HE is subdivided into: - Non-precipitated (spontaneous) - Precipitated (the precipitating factors should be specified). Precipitating factors can be identified in nearly all bouts of episodic and recurrent HE type C (Table 2). The presence of portosystemic shunts (PSS) facilitates the occurrence of HE and is associated with more severe forms. Table 2: Precipitating factors of hepatic encephalopathy. Infection Constipation Gastrointestinal bleeding Excess protein intake Electrolyte imbalance Alcohol misuse Hyponatremia Renal dysfunction Hypokalemia Centrally active drugs Dehydration TIPS insertion Fluid restriction Surgery Excessive diuresis Unidentified Paracentesis Diarrhea/vomiting A fifth classification, according to whether or not the patient has acute-on- chronic liver failure (ACLF), has recently been suggested (Refer to Cirrhosis). Example of hepatic encephalopathy classification Example of a recommended description of a patient with HE: ‘‘The patient has HE, Type C, Grade III (overt HE), Recurrent, Precipitated (by urinary tract infection).’’ El Aggan H  1 4 Pathogenesis The basic processes of HE is failure of hepatic clearance of gut-derived substances (neurotoxins), either due to hepatocellular failure or the presence of portosystemic shunting results in their accumulation in the systemic circulation and passage to the brain leading to an imbalance between excitatory and inhibitory neuronal activity. The end result is a brain with abnormal neurotransmitter function, which is unduly sensitive to insults (Figure 1). Alterations in the microbiota (dysbiosis) may be responsible for the formation or release of gut-derived substances (neurotoxins) such as ammonia from Microbiota dietary proteins and blood in the gut. Microbiota Figure 1: Pathogenesis of hepatic Gut bacterial translocation aggravates encephalopathy. systemic inflammation, which in turn produces blood brain barrier (BBB) dysfunction and drives neuroinflammation. Oxidative stress can also compromise BBB permeability. inflammation and oxidative stress exacerbate the deleterious effects of hyperammonaemia on the brain. Several neurotoxins and neurotransmitter systems are thought to be involved in HE including ammonia, mercaptans, amino acid imbalance, gamma aminobutyric acid (GABA), endogenous benzodiazepines, neurosteroids and manganese. 1) Ammonia Ammonia remains the most important factor in the pathogenesis of HE. Ammonia is mainly produced in the gut (by bacterial degradation of nitrogenous components of the diet) and as a small amount in the kidney. Ammonia detoxification takes place mainly in the liver and more in the skeletal muscle and kidney. In liver, ammonia is converted to urea through urea cycle that is excreted through the kidneys and also binds glutamate to form glutamine by glutamine synthetase. In skeletal muscle and kidney, ammonia is converted to glutamine thus enzymatically removing the ammonia. Normally, a small amount of non-ionized ammonia (NH3) crosses the BBB by diffusion. As there is no urea cycle in the brain, ammonia detoxification takes place in the astrocytes, where glutamine synthetase converts glutamate plus ammonia to glutamine. Glutamine is exported from astrocytes by a specific El Aggan H  1 5 transporter and reaches the presynaptic neuronal region where it is transformed by glutaminase into glutamic acid (Figure 2). Figure 2: Ammonia metabolism in the astrocyte. Hyperammonemia in patients with cirrhosis results from increased intestinal production of ammonia, decreased ammonia removal by the liver and/or the presence of PSS as well as reduced skeletal muscle mass (sarcopenia). The excess ammonia passing the BBB results in an increase in glutamine in atrocytes causing an osmotic shift of water into astrocytes and astrocyte swelling. In addition, the accumulation of glutamine in astrocytes results in loss of other osmolytes such as choline and myoinositol from astrocytes as a compensatory response to the increase in intracellular osmolality (osmolar adaptation). The change in the state of cellular hydration is responsible for brain edema and for the neurological manifestations of HE. Moreover, increased glutamine synthesis results in consumption of glutamic acid, which is an excitatory neurotransmitter. Thus, hyperammonemia leads to astrocyte dysfunction with impaired astrocyte-neuronal communication, which forms the basis of neuropsychiatric alterations in HE. 2) Mercaptans Mercaptans, formed by bacterial action on sulfur containing amino acids are also neurotoxic and possibly increase ammonia-induced neurotoxicity. They are probably responsible for fetor hepaticus. 3) Amino acid imbalance and false neurotransmitters Amino acid imbalance is present in patients with HE. Plasma aromatic amino acids (AAA) (tyrosine, phenylalanine and tryptophan) are increased probably due to failure of hepatic deamination while branched-chain amino acids (BCAA) (valine, leucine and isoleucine) are decreased, perhaps due to El Aggan H  1 6 increased metabolism by skeletal muscle and kidneys, secondary to the hyperinsulinemia of chronic liver disease. The two groups of amino acids compete for uptake into the brain. The imbalance in plasma levels allows more AAA to pass the abnormal BBB. Decreased serum BCAA/AAA ratio in the serum (especially BCAA/AAA