Psychosomatics 47:188-205, June 2006
doi: 10.1176/appi.psy.47.3.188
© 2006 Academy of Psychosomatic Medicine
An Overview of Psychiatric Issues in Liver Disease for the Consultation–Liaison Psychiatrist
Catherine C. Crone, M.D.,
Geoffrey M. Gabriel, M.D., MAJ, MC, USAR, and
Andrea DiMartini, M.D.
Received January 17, 2005; revised September 7, 2005; accepted October 10, 2005. From the Inova Transplant Center, Falls Church, VA, and the Georgetown Univ. Medical Center; the 121st General Hospital, Seoul, Korea; and the Univ. of Pittsburgh Medical Center, Western Psychiatric Institute and Clinic, Pittsburgh, PA. Send correspondence and reprint requests to Dr. Crone, Inova Transplant Center, Inova Fairfax Hospital, Falls Church, VA. e-mail: cathy.crone{at}inova.com
© 2006 Academy of Psychosomatic Medicine
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ABSTRACT
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Liver disease is a common cause of morbidity and mortality in the United States and elsewhere. Arising from infectious, hereditary, or toxin-induced sources, the detection of liver disease often requires a high index of suspicion. Clinical presentations are highly variable and are often accompanied by neuropsychiatric symptoms. This fact, along with an increased incidence of liver disease among patients with primary psychiatric disorders and the presence of varied drug use, complicates the tasks of providing care to patients with liver disease. To assist the consultation–liaison psychiatrist, the authors present the first of a two-part series focused on psychiatric issues in liver disease.
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INTRODUCTION
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The liver is a vital organ responsible for a number of physiological processes, including the synthesis of essential proteins, the handling of various nutrients, and the metabolism of drugs and other compounds (e.g., ammonium ions).1 Because of the breadth of functions dependent on the functioning of an intact liver, diseases causing hepatic impairment have repercussions throughout the body. Abnormal blood clotting, variceal bleeding, muscle wasting, renal dysfunction, extrapyramidal movements, cognitive decline, and coma are just some of the complications we see. Early detection and treatment of liver disease may halt the development of serious complications, but overt early signs of hepatic dysfunction may be lacking.1 Jaundice, ascites, palmar erythema, and spider angiomata may be preceded by nonspecific symptoms such as fatigue, pruritus, personality change, mood disturbances, and memory loss.1 Because some of these symptoms may initially lead to referral to mental health specialists, clinicians need to be alert to the idea that potential liver diseases may mimic primary psychiatric and neurologic disorders. Also, given the prevalence of substance use disorders and the high comorbidity of affective disorders and substance abuse in the United States, psychiatrists will be caring for patients at higher risk for liver disease (e.g., hepatitis C, alcoholic cirrhosis).2
In order to assist the consultation–liaison psychiatrist in the diagnosis and care of patients with liver disease, we present the following article as the first of a two-part overview. This section reviews psychopharmacologic issues in hepatic dysfunction and provides information regarding hepatitis C, hepatic encephalopathy, and acquired hepatocerebral degeneration. The second part will then review Wilson’s disease, porphyria, and alcoholic liver disease.
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Psychopharmacology in End-Stage Liver Disease
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For patients with end-stage liver disease, psychiatric symptoms may evolve from complex and co-occurring psychologic and physiologic processes (e.g., organ failure, hepatic encephalopathy, emotional stress of terminal illness, etc.). Effective treatment is needed, but this population is medically frail and at risk for medication-induced side effects. To assist in the task of treating them, we will review the fundamental pharmacokinetic alterations caused by end-stage liver disease. This knowledge, combined with attention to medication dosing and side effects, can provide a basis for the use of psychotropic medications in these complex patients. (See Trzepacz et al.3 and Crone and Gabriel4 for comprehensive reviews.) We include clinical guidelines to help in medication dosing, as well.
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Changes In Pharmacokinetics
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Liver failure affects basic elements of medication pharmacokinetics, from absorption to metabolism, distribution to elimination, changing drug levels, duration of action, and efficacy. Many processes in pharmacokinetics are interdependent (see Figure 1), and sometimes compensatory, as discussed below.
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FIGURE 1. Interactions Between Pharmacokinetic Processes
Used by permission: Dr. Judy Wong, Univ. of California, Berkeley
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Absorption
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As the liver becomes cirrhotic, portal hypertension, with resulting splanchnic vascular congestion, can develop and delay medication absorption through the small-intestinal vasculature. Patients with hepatic encephalopathy might also require administration of non-absorbable disaccharides (e.g., lactulose) that act as osmotic laxatives to flush out ammonia. This cathartic treatment reduces ammonia absorption by mechanically shortening small-bowel transit time and lowering the pH of the bowel, and it may similarly reduce medication absorption.6
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Distribution
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The amount of drug in the body and its concentration in the plasma is expressed as the apparent volume of distribution (Vd). Increased Vd due to fluid retention (i.e., ascites, peripheral edema) can lower effective levels of both water-soluble and highly protein-bound drugs (particularly if there is concomitant hypoalbuminemia).7,8
With persistent portal hypertension or the development of a portal vein thrombus, collateral blood vessels develop, circumventing the liver. In addition to these intrahepatic and extrahepatic physiologic shunts, therapeutic surgical and angiographic shunts (i.e., splenorenal, portacaval, intrahepatic) may also be created to relieve portal hypertension. Shunts reduce liver perfusion and particularly affect first-pass metabolism since less drug is delivered to hepatic enzymes before systemic distribution (see the Hepatic Metabolism section, below, for flow-limited drugs).
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Protein Binding
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Most psychotropic drugs are highly protein-bound—except, for example, lithium, gabapentin, venlafaxine, and methylphenidate. In liver failure, a reduction in albumin and alpha1-acid-glycoprotein production, along with altered protein-binding, leads to higher levels of free pharmacologically-active drug.9,10 This is offset by a compensatory increase in the rate of hepatic metabolism, and this is especially important for drugs with low intrinsic clearance.11 Nevertheless, for some drugs (e.g., benzodiazepines), very low serum albumin is related to increased side effects (i.e., increased sedation).12
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HEPATIC METABOLISM
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Many lipid-soluble agents do not undergo appreciable renal elimination; thus, plasma clearance of parent compounds and active metabolites primarily consist of hepatic clearance. Few psychotropic medications are dependent on renal excretion (these include lithium, gabapentin, and topiramate); most are highly lipid-soluble and require hepatic metabolism (biotransformation into more polar compounds) to allow them to be cleared from the body in urine or bile. Drugs can be divided into two major categories of clearance, determined by their enzyme affinity. Flow-limited drugs have high hepatic extraction, and their hepatic clearance is dependent on the rate of delivery of the drug to the liver. For example, tricyclic antidepressants undergo significant first-pass metabolism of greater than 50% after oral administration.13 (See Table 1 for a list of drugs with extensive first-pass metabolism.14–19) Drugs with low hepatic-enzyme affinity (e.g., diazepam, paroxetine, phenytoin) are metabolized more slowly, as enzyme saturation is the rate-limiting step.11
Hepatic metabolism occurs in two phases: Phase I is oxidation, hydrolysis, or reduction, and Phase II is conjugation (e.g., glucuronidation, acetylation, and sulfation). Phase I enzymes (the cytochrome P450 isoenzyme families) are located on the smooth endoplasmic reticulum, predominantly in the peri-central region of the portal triad. Phase I metabolites can be active or inactive. Examples of drugs with active metabolites include some benzodiazepines (e.g., diazepam, chlordiazepoxide), tertiary amine antidepressants (e.g., amitriptyline, imipramine), antipsychotics (e.g., chlorpromazine, thioridazine, risperidone), and opioid analgesics (e.g., morphine, meperidine, propoxyphene).20 Phase II enzymes are located in the peri-portal region of the portal triad and can metabolize parent compounds or metabolites from Phase I activity. Glucuronidation (a conjugation pathway) is preserved in cirrhosis.21 Choosing a psychotropic that does not require Phase I biotransformation or only requires glucuronidation (e.g., temazepam, oxazepam, lorazepam) may be advantageous.11
Translation Into Clinical Practice
Changes in drug kinetics in liver disease cannot be fully explained by any one of these disordered mechanisms. Also, evidence suggests that the reduction in hepatic extraction is a consequence of disordered cellular membrane function (i.e., pharmacodynamics),22 and that membrane-bound transport systems (i.e., P-glycoprotein) may also play a role in drug disposition.23
Adjusting for Decreased Metabolism
The clinician using psychotropic medications for patients with liver disease will need to carefully consider the severity of the disease, whether hepatic encephalopathy is present, and the margin between therapeutic and toxic plasma concentrations of the medication being considered. To rate the severity of liver disease, the Child-Pugh score (CPS), is a semi-quantitative measure of liver functioning frequently used by hepatologists.24 The CPS score is easily calculated from several commonly assessed laboratory values and clinical symptoms (Table 2). The CPS provides a readily reproducible and standardized method for assessing the degree of liver failure, and it is generalizable to patients with liver disease regardless of the etiology. Although the CPS may overgeneralize the complexities of drug pharmacokinetics, the CPS total score provides a useful guideline for dosing psychotropic medications. Also, prescribers should consult the pharmaceutical companies’ detailed information on drug dosing and suggested guidelines for prescribing for patients with hepatic disease (these guidelines often use the CPS). Also, although the severity of hepatic encephalopathy is one item in the CPS, the presence of severe encephalopathy requires more careful consideration of pharmacotherapy because drug toxicity and/or anticholinergic side effects can significantly worsen the symptoms of delirium.
From our clinical experience, we have found that patients rated with CPS Class A liver failure are early in the disease process and can usually tolerate 75%–100% of a standard initial dose. Those with CPS Class B disease should be dosed more cautiously, starting with a 50%–75% reduction in the normal starting dose. Because of the prolongation of the elimination half-life and the subsequent delay in reaching steady-state, more gradual increments in dosing are required. Patients with CPS Class B illness can often obtain relief or remission of symptoms with 50% of a typical psychotropic medication dose. Those with CPS Class C illness commonly have some degree of hepatic encephalopathy (HE), and medication usage must be cautiously monitored so that HE symptoms do not worsen. Several studies have demonstrated significant changes in psychotropic pharmacokinetics for patients with varying degrees of liver disease, as compared with normal-control subjects. However, standardized definitions of the severity of liver disease, such as the CPS, are not consistently used or reported (see Table 3 [A] and Table 3 [B] for pharmacokinetic data in patients with mild-to-severe liver disease and recommendations for drug dosing25–35).
Finally, the use of drugs eliminated by glucuronidation (e.g., lorazepam, oxazepam) may be preferable to drugs eliminated by oxidation, since there is often a selective sparing of glucuronidation even in the presence of severe liver disease.22 Also, drugs with high first-pass metabolism may be more likely to yield high and less predictable steady-state levels, and these should be avoided whenever possible.22
Renal Clearance and Fluid Status
Lithium and other drugs distributed in total body water can be especially complex to manage in cirrhotic patients with fluid overload. Maintaining therapeutic serum levels with changes in fluid status can become difficult, if not impossible. Even patients with mild cirrhosis can have decreased renal functioning, including a decreased glomerular filtration rate. In addition to possible abnormal renal hemodynamics, any rapid reduction in fluid status, which may occur as a part of routine hepatologic management (i.e., paracentesis, aggressive diuresis, excessive diarrhea from medications used for the treatment of hepatic encephalopathy) could result in severe drug toxicity. As the volume of total body fluid contracts, a previously therapeutic drug level can become acutely and dangerously toxic. This may be due to the slow equilibrium between intracellular and extracellular fluid compartments.36 If it is necessary to use such drugs, exact coordination between the patient and his or her various medical caregivers is highly recommended so as to avoid any untoward events or drug side effects.
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SPECIFIC HEPATIC DISORDERS: HEPATITIS C
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Disease Characteristics
Infection with the hepatitis C virus (HCV) is one of the leading causes of progressive liver disease in the United States, and it has become the most common indication for orthotopic liver transplantation in most Western countries. Although the rate for acute infection with HCV has been dropping, the prevalence of HCV-related cirrhosis will increase in the next two decades because of the slowly progressive nature of the disease and the large pool of infected individuals.37,38 It is currently estimated that 170 million individuals are infected worldwide, with 3.1 to 4.8 million in the United States alone.39
HCV is a single-stranded, positive-sense ribonucleic acid (RNA) virus belonging to the Flaviviridae family, which are neurotropic by nature. Hepatitis C has been detected in both central and peripheral nervous systems in vulnerable populations.40,41 The work of Radkowski et al.42 suggests that HCV may replicate in the central nervous system after HCV-infected lymphocytes cross the blood–brain barrier. Hepatitis C may also infect glial and macrophage cells, causing release of neurotoxic cytokines and subsequent neuronal death. At present, it remains unclear whether HCV can directly infect neurons.
Six viral genotypes are currently recognized, with 1a and 1b being the most common in patients in the United States.43 The ability of HCV to establish chronic infection is likely due to the development of immunologically distinct variants, termed quasispecies. Quasispecies develop from mutations occurring during the replication process.44,45 Approximately 85% of patients develop chronic infection (i.e., persistent viremia) after a bout of acute hepatitis, with 65%–80% progressing to chronic hepatitis.46 Fulminant hepatitis is a rare event, although co-infection with hepatitis A increases the risk.47 Of those with chronic hepatitis, 7%–20% eventually develop cirrhosis, and 1%–5% develop hepatocellular carcinoma (HCC).48 African Americans have higher rates of HCV infection and progression to HCC.49
Factors that may contribute to a rapid progression of HCV disease are listed in Table 4. Co-infection with HIV allows for increased HCV viral load and reduced response to interferon therapy, and it may hasten progression to cirrhosis and HCC.50 Active alcohol use during treatment is also associated with diminished treatment response to interferon-alpha (IFN- ).51,52
Risk Factors
The most common route of transmission in the United States is intravenous drug use (IVD).53 The prevalence rates of HCV seropositivity among IVD users are between 65% and 80%, with rates being uniformly high in other regions of the world.54 Less common parenteral routes include dialysis and tattooing.55,56 Maternal-to-infant transmission is estimated to be from 0% to 10%.52 Maternal co-infection with HIV and maternal HCV viral load may double this risk. Independent of other risk factors, sexual activity is not a significant mode of transmission.57 The post-transfusion risk of HCV is estimated to be 0.06% per unit of blood.58,59 The majority of studies suggest that route of transmission is independent of the progression of HCV disease.
Screening/Diagnosis
Screening should be considered for all patients with a history of substance abuse or dependence, especially IVD use and alcohol use. After a positive screening test for HCV antibodies, confirmation is obtained by detection of HCV RNA via polymerase chain reaction.60,61 Measurement of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are not specific or sensitive for detection of HCV status. Genotyping of HCV can help predict response to treatment with INF- and ribavirin. Although it is not universally performed or recommended, liver biopsy provides clinical data concerning degree of histological change, especially fibrosis.52
High-Risk Populations
High rates of substance abuse and dependence exist among patients with severe psychiatric disorders, likely contributing to the higher rates of HCV infection in this population. Various studies have found that approximately 10% to 20% of adults with severe mental illnesses were infected with HCV.62,63 El-Serag et al.64 identified at least one psychiatric diagnosis in 85% of HCV-seropositive veterans hospitalized between 1992 and 1999 within the Veterans Administration medical system. High rates of depression and anxiety were found among veterans with or without substance use disorders.64 Personality disorders, especially borderline and antisocial, have also been reported as increased.65 It is estimated that approximately one-third of Americans who are incarcerated are HCV-seropositive, the rate of HCV infection being much higher in the correctional system than in the general population.66 Higher rates of HCV infection have also been discovered among homeless veterans.67
The treatment of high-risk HCV-seropositive psychiatric populations has been a source of controversy, with specific concerns raised regarding risks for noncompliance and re-infection among active substance abusers. Of note, patients who abuse alcohol have increased viral loads and reduced response to IFN-.68 Concerns led to recommendations for 6 to 12 months of abstinence from drugs and alcohol before starting treatment. However, recent studies suggest that effective treatment is possible with coordinated efforts by addiction-medicine specialists and hepatologists (Table 5).69,70 In 2002, these results contributed to the NIH’s eliminating active drug abuse as an absolute contraindication for IFN- therapy.52
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TREATMENT ISSUES
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The current recommended treatment for HCV-seropositive adults with compensated liver disease is subcutaneous IFN- combined with oral ribavirin.71 This combination yields a sustained viremic response (SVR) of between 40%–50%. Use of the pegylated form of IFN- (PEG) allows once-weekly dosing and provides the highest SVR when combined with ribavirin.72,73 If treatment fails to clear the virus after 3 months, the patient is considered to be a non-responder, and medications may be stopped. Lack of detectable HCV RNA 6 months after treatment is completed is considered to represent viral eradication. Treatment tolerability is a particular concern with IFN- because of its side-effect profile (Table 6).74,75 With ribavirin, side effects include cough, dyspnea, pruritus, skin rash, hemolytic anemia, insomnia, anorexia, depression, and teratogenicity.75
Various neuropsychiatric side effects have been attributed to IFN-, including a pattern of subcortical cognitive impairment.76,77 Symptoms include decreased motivation, increased apathy, impaired executive functions, and memory loss.78 The mechanism of interferon-induced cognitive impairment may be related to prefrontal cortical hypometabolism in addition to damage to hippocampal cells.76 Frank delirium secondary to IFN- is considered a rare event.
Depression associated with IFN- therapy has been reported to occur in 10%–50% of patients, with differences in reported rates affected by choice of diagnostic criteria, screening tools, and study population.75,79 Risk of depression has not been linked to previous history of mood disorder, but has been associated with subclinical depressive symptoms at baseline.80,81 IFN- may exert its depressive effects through induction or amplification of other cytokines, including interleukins (IL), IFN- , and tumor-necrosis factor (TNF).82 IFN- may also reduce serotonin levels by inducing indolamine 2,3-dioxygenase, an enzyme responsible for metabolizing tryptophan and serotonin.82,83 The hypothalamic-pituitary-adrenal (HPA) axis may be affected through IFN-’s effects on IL-6. Capuron et al.84 postulated that a sensitized stress response, as demonstrated by hyperresponsiveness of the HPA axis after an initial IFN- injection, might be connected to later onset of interferon-induced depression. Finally, depression may rarely be secondary to thyroid dysfunction developing while patients are on IFN-.85
Management of IFN-Related Neuropsychiatric Side Effects
There should be a low threshold for initiating antidepressant therapy if depressive symptoms appear while patients are on IFN- (Table 7). Screening tools can aid in the assessment, particularly the Beck Depression Inventory (BDI) and the Center for Epidemiologic Studies Depression Scale (CES–D), which have been previously examined in this patient population.86,87 If antidepressant treatment is initiated, patients should be maintained on medications for several weeks after interferon treatment is completed so as to minimize risk of depression relapse. Studies have suggested that prophylactic antidepressant therapy for patients with a history of depression may be warranted before starting IFN- treatment. Musselman et al.80 used paroxetine in a double-blinded, placebo-controlled trial of prophylactic treatment for IFN-–induced depression in melanoma patients. Of the paroxetine-treated group, 11% developed depression, versus 45% of the placebo group.80 Sertraline, fluoxetine, and citalopram have also been reported to be effective treatment options.88–92 Selective serotonin reuptake inhibitor (SSRI) agents also treat comorbid anxiety disorders and may help patients curb alcohol consumption. However, paroxetine has also been associated with retinal hemorrhages and cotton-wool spots in one study.80
In addition to targeting depressive symptoms and nicotine dependence, bupropion can help to alleviate fatigue, cognitive impairment, and psychomotor retardation associated with IFN- therapy. Recently, a 43-year-old woman was successfully treated for IFN-induced depression with sustained-release bupropion.93 Because of the risk of lowered seizure threshold from bupropion and IFN- combined, dosing was started at 150 mg qd and slowly raised to 350 mg qd.93 Venlafaxine lacks significant drug–drug interactions and demonstrates low protein-binding, but case reports of hepatotoxicity suggest the need for added caution and close monitoring.94
Mirtazapine can be useful in treating insomnia, anorexia, nausea, and pruritus often associated with IFN-. Caution must be exercised because of the rare development of agranulocytosis associated with mirtazapine.95 Nefazodone should have a limited role in the treatment of HCV patients because of inhibition of cytochrome P450 3A4 and association with acute hepatic failure.96 Tricyclic anti-depressants (TCAs) and monoamine oxidase inhibitors are problematic because of multiple side effects and potential lethality in overdose. Anticholinergic effects of TCAs can compound cognitive impairment caused by interferon therapy.
Psychostimulants can help to manage fatigue, apathy, and cognitive slowing related to IFN- treatment in those patients without a history of substance abuse. Modafinil, a novel non-amphetamine psychostimulant, has demonstrated positive effects on fatigue associated with multiple sclerosis, fibromyalgia, HIV disease, and depression.97–101 Dosages of 200 mg/day have been reported to cause few, if any, side effects in these groups.97 Its low abuse potential and limited drug–drug interactions make it a viable alternative to the other psychostimulants. Modafinil may also have a role in augmenting other antidepressants when a partial response is present.101,102 Atomoxetine, a selective norepinephrine reuptake inhibitor approved as a non-stimulant treatment for attention-deficit hyperactivity disorder, has also been used in fatigue and antidepressant augmentation.103–105 Although limited experience suggests benefits, there is a risk of serious hepatotoxicity with atomoxetine.106
Several reports exist concerning the development of psychotic and manic or hypomanic symptoms in the presence of IFN- therapy.107–118 Symptoms may be part of a medication-induced delirium or a psychotic mood disorder. However, these are actually rare events and usually reverse upon termination of IFN- or appropriate psychotropic treatment. Valproate, with careful attention to possible hepatotoxicity and thrombocytopenia, may be used to treat manic or hypomanic symptoms in these patients.119
Monitoring of ALT levels in HCV-seropositive patients treated with valproate is clearly indicated. Lithium may be more problematic because of the potential for hypothyroidism, although it has been used safely in some patients.110 Carbamazapine has drug–drug interactions and a side-effect profile that limits its use among patients treated with IFN-. The risk of thrombocytopenia, aplastic anemia, and agranulocytosis bears particular consideration because of hematologic side effects with IFN- and ribavirin. Both typical and atypical antipsychotics have been utilized for management of psychotic, manic, or hypomanic symptoms.102–118 Atypical antipsychotic medications are likely the treatment of choice, given their safety, efficacy, and tolerability.
Hepatic Encephalopathy
Hepatic encephalopathy is a neuropsychiatric syndrome characterized by disturbances in consciousness, mood, behavior, and cognition, that primarily occurs in the setting of advanced liver disease.120,121 The clinical presentation and symptom severity of hepatic encephalopathy varies widely, from minor cognitive impairment to gross disorientation, confusion, agitation, and coma (Table 8). Among patients with chronic liver failure, hepatic encephalopathy is estimated to occur in 50%–70%.120 Mostly, this appears in the form of episodic or recurrent bouts of impairment. Spontaneous or surgical portosystemic shunts often accompany chronic liver failure, and contribute to the onset of hepatic encephalopathy. In the setting of fulminant (acute) liver failure, hepatic encephalopathy occurs in nearly all patients and is accompanied by cerebral edema and intracranial hypertension.120,122,123 Although hepatic encephalopathy is recognized as a common complication of liver failure, efforts to better understand it have been hampered by the lack of consistent terminology and diagnostic criteria.124 Recent efforts, however, have sought to establish a consensus viewpoint.125 Greater understanding of hepatic encephalopathy is needed because evidence suggests that it not only impairs daily functioning and quality of life but is also associated with reduced patient survival.126,127
Pathophysiology Although the exact pathophysiology behind hepatic encephalopathy is unknown, ammonia appears to play a significant role in altering cerebral functioning. Under normal circumstances, ammonia is produced via the action of colonic bacteria and the deamination of glutamine in the small intestine, with a lesser portion coming from kidneys and skeletal muscle.122,128 Ammonia is subsequently absorbed by passive diffusion, followed by a significant first-pass effect.122 Upon reaching the liver, ammonia is detoxified by conversion to glutamine and urea, which is excreted in urine.123 If liver failure is present, impairment of the hepatic enzymes responsible for ammonia detoxification causes hyperammonemia to develop.124,129 Portosystemic shunting and reduced ammonia uptake by skeletal muscle contributes to this build-up.122 Higher amounts of ammonia reach the brain, partly because of increased uptake, as well as altered blood–brain permeability.130–132 Unlike the liver, the brain relies solely on astrocytic glutamine synthesis to maintain normal ammonia levels.122,129 This pathway becomes overwhelmed during liver failure, and the excess ammonia causes astrocytes to undergo cellular swelling and Alzheimer Type II changes.121,129 Ammonia also alters the gene expression of several of the astrocytic proteins and enzymes, including peripheral benzodiazepine receptors, glutamine and glutamate transporters, MAO–A, and nitric oxide synthase.122,124,129,132–133 This results in changes to glutamatergic, monoaminergic, and GABAergic neurotransmission.124,129 Also, ammonia affects excitatory and inhibitory neurotransmission directly by modifying the expression of cellular ion channels and postsynaptic receptor functioning.129
Although ammonia is believed to play a key role in the pathophysiology of hepatic encephalopathy, additional research has suggested the involvement of other mechanisms. Manganese is a neurotoxic agent capable of altering the structure and function of astrocytes, producing Alzheimer Type II changes.122,132 Manganese deposits are also thought to be responsible for producing the basal-ganglia hyperintensities seen on brain magnetic resonance images (MRIs) of cirrhotic patients.132 Although blood and brain manganese levels do correlate with these hyperintensities, they do not correlate with the severity of hepatic encephalopathy.134 Endogenous benzodiazepines (BZ) acting on GABA–BZ receptors have been thought to be another causative factor for encephalopathy.129 Indeed, elevated benzodiazepine levels have been found in cirrhotic patients, but they correlate more closely with the degree of liver function present than the grade of hepatic encephalopathy.135–138 Also, the BZ-receptor antagonist, flumazenil, has only been effective in reversing encephalopathy in a minority of patients studied.134,139,140 Increased concentrations of tryptophan and serotonin, along with evidence of increased serotonergic turnover, have been detected in the blood, brain, and cerebrospinal fluid of encephalopathic patients.123,129,134,141 Accompanied by changes in serotonin-receptor binding, alterations in this neurotransmitter system may play a role in hepatic encephalopathy.124 Limited data also suggest involvement of the dopaminergic system.124 Heliobacter pylori, a gut bacterium with strong urease activity, have been hypothesized to contribute to encephalopathy by raising ammonia production.142–144 However, results from antibiotic therapy to eradicate Heliobacter pylori have not produced the improvements expected.142–144 Finally, animal models of hepatic encephalopathy indicate possible roles for endogenous opioids and nitrous oxide, although further study is needed.124,134
Diagnosis The diagnosis of hepatic encephalopathy is based on the exclusion of other causes for mental status change in patients with advanced liver disease.145 Delirium secondary to infections, metabolic abnormalities, medications, substance abuse, intracranial hemorrhage, and tumor needs to be ruled out.145 Psychometric testing is often used diagnostically, especially when cognitive impairment is subtle.146,147 The digit-symbol test, line-tracing test, and Trailmaking tests A and B have been particularly helpful, as they are all age-normed, validated, and quantifiable.123,148 Although fetor hepaticus may accompany the clinical presentation of hepatic encephalopathy, neurologic examination may show asterixis, as well as extrapyramidal, pyramidal, or cerebellar signs.145,149 Seizures and multifocal twitching may develop during fulminant hepatic failure.124,150 EEG findings mostly involve generalized slowing.123 Triphasic waves may be present, but they are not specific to hepatic encephalopathy.123,151 Impaired cognitive processing is reflected by abnormal event-related (P300) evoked potentials.152,153 Venous ammonia levels are frequently elevated, but they do not correlate with severity of encephalopathic symptoms, and normal ammonia levels are found in approximately 10% of patients.123 Arterial and partial-pressure ammonia measurements do not appear to offer greater sensitivity or specificity in detecting hepatic encephalopathy.154 MRI of the brain reveals bilateral symmetrical hyperintensities of the globus pallidus on T1-weighted images in the majority of patients.155,156 However, these images are not specific to hepatic encephalopathy, as they occur in some patients without cirrhosis.157,158 MRI reveals altered cerebral metabolite levels, with increases in glutamine, glutamate, and aspartate, and reductions in myoinositol, choline, and hypotaurine.123,159–161 Changes in cerebral metabolism correlate with degree of encephalopathy, but these changes also occur in non-encephalopathic patients.161 Positron-emission tomography (PET) scans demonstrate altered cerebral glucose utilization, with decreases noted in the anterior cingulate gyrus, bifrontal, and biparietal regions.162,163
Treatment Management of hepatic encephalopathy primarily calls for identification and correction of factors that precipitate accumulation of ammonia and other toxins (Table 9).123,145 Surgical and spontaneous portosystemic shunts cause blood flow to be redirected around the liver, reducing the amount of substances removed. Shunts are associated with increased incidence of hepatic encephalopathy, with rates varying according to the type of shunt involved.123 With transjugular intrahepatic portosystemic shunts (TIPS), the incidence of encephalopathy normally ranges from 20% to 40%.164,165 Advanced age, Childs-Pugh score, and low post-TIPS portosystemic gradient contribute to a higher rate of hepatic encephalopathy.166 About 10% of patients develop severe encephalopathy after TIPS placement and require modification or occlusion of the shunt.134 Other precipitating factors of hepatic encephalopathy are responsible for raising ammonia production, as with infections, gastrointestinal hemorrhage, transfusions, increased protein intake, constipation, azotemia, metabolic alkalosis, and hypokalemia.123,145 Metabolic acidosis, anemia, hypoxia, and dehydration also act as precipitants, impairing hepatic function and reducing the liver’s ability to metabolize ammonia and other toxins.123,145 Alcohol, sedatives, hypnotics, and opiates are additional precipitants of hepatic encephalopathy that require consideration.123,145
Recommendations regarding the use of various agents to treat hepatic encephalopathy have been hampered by the lack of placebo-controlled trials and the challenge of determining whether improvements are due to specific treatments or the removal of precipitating factors (e.g., infection, GI hemorrhage). Despite this, non-absorbable disacharides and antibiotics remain commonly prescribed treatments. Lactulose and lactitol are thought to reduce manufacture and absorption of ammonia. However, a recent comprehensive review of randomized trials concluded that evidence to support their use in encephalopathic patients was lacking.167 Non-absorbable antibiotics such as neomycin reduce ammonia-producing bowel flora but carry the risk of ototoxicity and nephrotoxicity with sustained use.123 Studies have shown some benefits, although results have not always been positive.168,169 Low-protein diets were used as another therapeutic approach for many years, until research demonstrated that patients needed high protein intake to maintain positive nitrogen balance.170–172 Thus, protein restriction is no longer advised, except during acute episodes of hepatic encephalopathy.170,172 Branched-chain amino acids have been given to patients intolerant to protein, but randomized therapeutic trials have shown mixed results.173,174 Oral ornithine aspartate has benefited patients with overt symptoms of hepatic encephalopathy, but was ineffective in those with mild dysfunction.175–177 Unavailable in the United States, ornithine is believed to reduce ammonia levels by stimulating hepatic urea and glutamine synthesis.120,134,175 Flumazenil, a BZ-antagonist, has produced short-term improvement in a subset of patients, but long-term benefits have not been found.140 Additional approaches showing potential benefits include probiotics, zinc acetate, L-carnitine, sodium benzoate, and phenylacetate, but further study is needed.122,124,173,178,179 Liver transplantation is the definitive treatment for hepatic encephalopathy, with clear cognitive improvement reported.120 Unfortunately, current listing criteria for transplantation do not allow the severity of encephalopathy to raise a patient’s eligibility for a new organ.180
Minimal Hepatic Encephalopathy
Minimal hepatic encephalopathy (mHE) has been found in cirrhotic patients with normal clinical and neurological exams, but impairment on neuropsychological testing. Previously referred to as latent, subclinical, or Stage 0 hepatic encephalopathy, a recent consensus agreed upon the term minimal hepatic encephalopathy.125 Depending on the diagnostic criteria and approach utilized, the prevalence of mHE has been reported to range from 30%–84%.181 Cognitive disturbances are subtle, but typically involve psychomotor speed and visual attention and perception, with verbal ability intact.182,183 These are felt to be responsible for the impairments in work performance and driving ability and the reduced quality of life found in this population.184–187 Patients may also be at greater risk for developing overt encephalopathy.188–190 Various psychometric tests have been used to help detect mHE, including the PSE test (PSE: portosystemic encephalopathy), which offers both high sensitivity and specificity.146 The PSE test is brief and consists of a combination of established tests, including Trailmaking A and B, as well as Digit Symbol.146 P300 event-related potentials can also be used, and some researchers believe this approach offers greater sensitivity than neuropsychological testing.153,191 Recommendations to treat mHE are controversial because the significance of its presence is yet to be fully understood.192 Nonetheless, similar approaches as those used in typical hepatic encephalopathy may help to optimize a patient’s daily functioning and reduce the likelihood of developing overt encephalopathy.
Acquired Hepatocerebral Degeneration
Background Acquired hepatocerebral degeneration (AHCD) is an uncommon but chronic progressive neurological disorder that was first described by van Woerkem, in 1914.193,194 It is also known as chronic progressive hepatic encephalopathy or non-Wilsonian hepatocerebral degeneration. Most of the published literature consists of case reports and small case series. Patients typically exhibit cognitive impairment, along with an array of extrapyramidal and cerebellar movement disorders.193–196 Most patients have a history of recurrent or prolonged episodes of hepatic encephalopathy, which predisposes them to AHCD.193,196 Hepatic dysfunction is normally present, although the degree of impairment can vary.196 Portosystemic shunting also accompanies the clinical picture, causing some patients without liver disease to develop AHCD.193,194,197 Although symptoms seen in AHCD can also occur in hepatic encephalopathy, they differ in that they are persistent and do not necessarily respond to treatments such as lactulose, neomycin, or dietary modification.196 In some cases, AHCD can be difficult to discriminate clinically from Wilson’s disease or Huntington’s chorea. However, the presence of choreoathetosis but absence of Kayser-Fleischer rings, abnormal copper metabolism, and hereditary component helps to discriminate it from Wilson’s disease.193,196 Compared with Huntington’s chorea, patients with AHCD have earlier |
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ABSTRACT
INTRODUCTION