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An Overview of Psychiatric Issues in Liver Disease for the Consultation–Liaison Psychiatrist

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

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.

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.

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.

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

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

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).

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

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

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TABLE 1. Drugs With Extensive First-Pass Metabolism

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.

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TABLE 2. Calculation of the Child-Pugh Score (CPS)

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 dosing^25–35).

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TABLE 3. Pharmacokinetic Data and Alterations in Metabolism for Specific Psychotropic Medications

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.

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

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TABLE 4. Factors Contributing to Rapid Progression of Hepatitis C Viral Disease

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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TABLE 5. Management of Relationship With Substance-Abusing Hepatitis C Virus Patients

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

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TABLE 6. Side-Effects Associated With IFN-

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

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TABLE 7. Guidelines for Treatment of Depression in Hepatitis C Virus Patients

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

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TABLE 8. Stages of Hepatic Encephalopathy

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

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TABLE 9. Precipitants of Hepatic Encephalopathy

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 onset of cerebellar symptoms, concurrent hepatic dysfunction, and no family history of degenerative neurologic disorder.¹⁹³

Clinical presentation/course The clinical presentation of acquired hepatocerebral degeneration is highly variable, with the appearance of neurological symptoms sometimes preceding overt evidence of hepatic dysfunction.¹⁹⁶ Patients differ from one another regarding the exact combination of their symptoms, along with their severity, speed of onset, and course over time.¹⁹³ Neurological symptoms may develop over months or years, with some patients becoming severely disabled as the disease progresses.^{194–196,198} The most common neurological symptoms include dementia, dysarthria, cerebellar gait ataxia, and choreoathetosis, as well as postural and intention tremor.^193,195,196 Pyramidal tract signs such as brisk reflexes, extensor plantar response, and mild generalized weakness, frequently occur.^193,196 Choreoathetosis primarily involves the head, trunk, and upper limbs, with patients exhibiting facial twitching, grimacing, and tongue movements that may resemble tardive dyskinesia.^195,196 Dysarthria appears in most patients, and is described as slow, monotonous, and slurred, with elements of scanning and explosiveness.¹⁹³ Less often, asterixis, saccadic eye movements, frontal release signs, resting tremor, and intention myoclonus may accompany the clinical presentation.¹⁹³ Myelopathy is infrequent, but can mimic transverse myelitis or spastic paraparesis.¹⁹³ Although AHCD is considered to be rare, evaluation of a consecutive series of 51 patients referred for liver transplantation showed that 22% had evidence of a Parkinson-like subset of AHCD symptoms.¹⁹⁹ Cognitively, patients may demonstrate psychomotor slowing or impaired attention, along with disturbances in executive functioning.¹⁹³ However, cognitive impairment has not been observed in all patients. Disturbances of mood and affect may accompany other symptoms of AHCD, with apathy, depression, or aggressive behavior having been observed.^194,198

Neuropathology/neuroimaging findings EEG and neuroimaging studies involving patients with AHCD show alterations that are the same as those reported in patients with hepatic encephalopathy.^193,196 Generalized slowing is most often found on EEG, whereas MRI of the head shows T₁-weighted bilateral pallidal hyperintensities.^{193,196,199–201} Some patients have shown T₂-weighted hyperintensities of the basal ganglia that cannot be differentiated from those seen in Wilson’s disease.^196,202,203 The MRI findings are thought to reflect the possible underlying role of manganese deposition in causing the neurologic changes seen in AHCD.¹⁹⁹ Results of magnetic-resonance spectroscopy are also the same as in hepatic encephalopathic patients, with reduced myoinositol and choline peaks, but elevated glutamate/glutamine ratios.¹⁹⁶ Neuropathological examination typically reveals diffuse, patchy neuronal cell damage/loss, astrocytosis, and astrocytic intranuclear inclusions.^193,196 The parenchymal changes mainly involve the deeper cortical layers, subcortical white matter, basal ganglia, and cerebellum.¹⁹³ We also see pseudolaminar necrosis, along with microcavitation and degeneration of both nerve cells and myelin sheaths.^193,195,196 The frontal, parietal, and occipital lobes are particularly affected by these degenerative changes.¹⁹⁴ Diffuse proliferation of Alzheimer II astrocytes is also noted, and we also find glycogen inclusions in the nuclei of astrocytes.^193–195 Diffuse loss of Purkinje cells and increased number of Bergmann glial cells may be found in the cerebellum.¹⁹⁸ Spinal cord involvement is uncommon in AHCD but tends to involve degeneration of posterolateral columns.^193,195

Treatment Most often, AHCD has not responded to treatments such as lactulose, dietary changes, or antibiotics commonly used during episodes of hepatic encephalopathy.¹⁹⁶ However, there is a report describing marked improvement by 2 months after administration of branched-chain amino acids intravenously and then orally.²⁰⁴ Branched-chain amino acids have been used in some patients with hepatic encephalopathy, although results have been mixed. Levodopa has been helpful in the subset of AHCD patients who primarily present with parkinsonian symptoms.^195,199 Improvements in clinical symptoms and MR images have also been reported after orthotopic liver transplantation.^196,205,206 Occurring as early as the first few months after transplantation, gradual improvement has been observed over time. Full resolution of symptoms was reported in two cases, but not in others.^196,206 Despite these dramatic cases, Wijdicks points up potential problems in postoperative recovery after transplantation, including poor mobility and aspiration caused by the movement disorders.²⁰⁷

CONCLUSION

TOP ABSTRACT INTRODUCTION Psychopharmacology in End-Stage... Changes In Pharmacokinetics Absorption Distribution Protein Binding HEPATIC METABOLISM SPECIFIC HEPATIC DISORDERS:... TREATMENT ISSUES CONCLUSION REFERENCES

 
Although liver disease complicates the task of diagnosis and management of comorbid psychiatric disorders, safe and effective treatment is possible. Liver-function tests cannot be used alone to guide pharmacotherapy, but combining the use of Childs-Pugh scores with closer monitoring can help to increase safety and tolerability. One of the primary liver diseases with significant psychiatric comorbidity is hepatitis C, which is treated with interferon therapy. Interferon may be able to halt progression to cirrhosis and cancer, but its neuropsychiatric side effects often require use of education, support, and psychotropic medications.

With advanced liver disease of various etiologies, hepatic encephalopathy is a frequent complication that increases mortality and reduces quality of life. Presenting symptoms may be overt or may involve subtle cognitive changes, with more pronounced alterations in mood and personality. Treatment mainly involves correcting precipitating factors for HE and avoidance of medications that may worsen cognitive functioning. Acquired hepatocerebral degeneration is a rare, progressive neuropsychiatric disorder that appears to be related to hepatic encephalopathy. The clinical presentation may mimic Wilson’s or Huntington’s disease, but the absence of a family history helps to distinguish it from these entities.

REFERENCES

TOP ABSTRACT INTRODUCTION Psychopharmacology in End-Stage... Changes In Pharmacokinetics Absorption Distribution Protein Binding HEPATIC METABOLISM SPECIFIC HEPATIC DISORDERS:... TREATMENT ISSUES CONCLUSION REFERENCES

 

1. Powell DW: Approach to the patient with liver diseases, in Cecil Textbook of Medicine, 21st Edition. Edited by Goldman L, Bennett JC. Philadelphia, PA, WB Saunders, 2000, pp 767-768
2. Grant BF, Stinson FS, Dawson DA: Prevalence and co-occurrence of substance use disorders and independent mood and anxiety disorders: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Arch Gen Psychiatry 2004; 61:807–816[Abstract/Free Full Text]
3. Trzepacz PT, DiMartini AF, Gupta B: Psychopharmacologic issues in transplantation, in The Transplant Patient: Biological, Psychosocial, and Ethical Issues in Organ Transplantation. Edited by Trzepacz P, DiMartini A. Cambridge, UK, Cambridge University Press, 2000, pp 187-213
4. Crone CC, Gabriel GM: Treatment of anxiety and depression in transplant patients: pharmacokinetic considerations. Clin Pharmacokinet 2004; 43:361–394[CrossRef][Medline]
5. Wong, Judy MY: Lecture: Pharmacotherapy in the Elderly, from http://mcb.berkeley.edu/courses/mcb135k/Discussion/lecture-Wong.pdf, accessed September 14, 2004
6. Riley SA, Kim M, Sutcliffe F, et al: Effects of a non-absorbable osmotic load on drug absorption in healthy volunteers. Br J Clin Pharmacol 1992; 34:40–46[Medline]
7. George CF, Walt PJ: The liver and response to drugs, in Liver and Biliary Disease, Pathophysiology, Diagnosis, Management. Edited by Wright R, et al. London, UK, Saunders, 1979, pp 344-377
8. Klotz U: Pathophysiological and disease-induced changes in drug distribution volume: pharmacokinetic implications. Clin Pharmacokinet 1976; 1:204–218[Medline]
9. Blaschke TF: Protein binding and kinetics of drugs in liver diseases. Clin Pharmacokinet 1977; 2:32–44[Medline]
10. Adedoyin A, Branch RA: Pharmacokinetics, in Hepatology: A Textbook of Liver Disease, 3rd Edition. Edited by Zakim D, Boyer TD. Philadelphia, PA, WB Saunders, 1996, pp 307-322
11. Howden CW, Birnie GG, Brodie MJ: Drug metabolism in liver disease. Pharmacol Ther 1989; 40:439–474[CrossRef][Medline]
12. Greenblatt DJ, Koch-Weser J: Clinical toxicity of chlordiazepoxide and diazepam in relation to serum albumin concentration: a report from the Boston Collaborative Drug Surveillance Program. Eur J Clin Pharmacol 1974; 7:259–262[CrossRef][Medline]
13. Pond SM, Tozer TN: First-pass elimination: basic concepts and clinical consequences. Clin Pharmacokinet 1984; 9:1–25[Medline]
14. DeVane CL, Savett M, Jusko WJ: Desipramine and 2-hydroxy desipramine pharmacokinetics in normal volunteers. Eur J Clin Pharmacol 1981; 19:61–64[CrossRef][Medline]
15. Schroeder DH: Metabolism and kinetics of bupropion. J Clin Psychiatry 1983; 44:79–81[Medline]
16. Wetzel H, Szegedi A, Hain C, et al: Seroquel (ICI 204 636), a putative "atypical" antipsychotic, in schizophrenia with positive symptomatology: results of an open clinical trial and changes of neuroendocrinological and EEG parameters. Psychopharmacology 1995; 119:231–238[CrossRef][Medline]
17. Klamerus KJ, Maloney K, Rudolph RL, et al: Introduction of a composite parameter to the pharmacokinetics of venlafaxine and its active O-desmethyl metabolite. J Clin Pharmacol 1992; 32:716–724[Abstract]
18. Troy SM, Parker VP, Hicks DR, et al: Pharmacokinetics and effect of food on the bioavailability of orally-administered venlafaxine. J Clin Pharmacol 1997; 37:954–961[Abstract]
19. Product Information: Zoloft®, sertraline hydrochloride. Roerig Division of Pfizer Inc, New York, NY (PI revised 10/2002)
20. Beers MH, Berkow R, et al (eds): The Merck Manual of Diagnosis and Therapy, 17th Edition, Section 22: Clinical Pharmacology, Chapter 304: Drug Therapy in the Elderly. Merck and Co, Inc., West Point, PA, 1999
21. Pacifici GM, Viani A, Franchi M, et al: Conjugation pathways in liver disease. Br J Pharmacol 1990; 30:427–435
22. Huet PM, Villeneuve JP: Determinants of drug disposition in patients with cirrhosis. Hepatology 1983; 3:913–918[Medline]
23. Abramowicz M (ed): Drug Interactions. Medical Letter on Drugs and Therapeutics 2003; 45:46–48[Medline]
24. Albers I, Hartmann H, Bircher J, et al: Superiority of the Child-Pugh classification to quantitative liver function tests for assessing prognosis of liver cirrhosis. Scand J Gastroenterol 1989; 24:269–276[Medline]
25. Trouvin JH, Farinotti R, Haberer JP, et al: Pharmacokinetics of midazolam in anaesthetized cirrhotic patients. Br J Anaesthesia 1988; 60:762–767[Abstract/Free Full Text]
26. MacGilchrist AJ, Birnie GG, Cook A, et al: Pharmacokinetics and pharmacodynamics of intravenous midazolam in patients with severe alcoholic cirrhosis. Gut 1986; 27:190–195[Abstract/Free Full Text]
27. Pentikainen PJ, Valisalmi L, Himberg JJ, et al: Pharmacokinetics of midazolam following intravenous and oral administration in patients with chronic liver disease and in healthy subjects. J Clin Pharmacol 1989; 29:272–277[Abstract]
28. Klotz U, Avant GR, Hoyumpa A, et al: The effects of age and liver disease on the disposition and elimination of diazepam in adult man. J Clin Invest 1975; 55:347–359[Medline]
29. Andreasen PB, Hendel J, Griesen G, et al: Pharmacokinetics of diazepam in disordered liver function. Eur J Clin Pharmacol 1976; 10:115–120[CrossRef][Medline]
30. Bass NM, Williams RL: Guide to drug dosage in hepatic disease. Clin Pharmacokinet 1988; 15:396–420[Medline]
31. Van Harten J, Duchier J, Devissaguet JP, et al: Pharmacokinetics of fluovoxamine maleate in patients with liver cirrhosis after single-dose oral administration. Clin Pharmacokinet 1993; 24:177–182[Medline]
32. Schenker S, Bergstrom RF, Wolen RL, et al: Fluoxetine disposition and elimination in cirrhosis. Clin Pharmacol Ther 1988; 44:353–359[Medline]
33. Dalhoff K, Almdal TP, Bjerrum K, et al: Pharmacokinetics of paroxetine in patients with cirrhosis. Eur J Clin Pharmacol 1991; 41:351–354[CrossRef][Medline]
34. Barbhaiya RH, Shukla UA, Greene DS: Single-dose pharmacokinetics of nefazodone in healthy young and elderly subjects and in subjects with renal or hepatic impairment. Eur J Clin Pharmacol 1995; 49:221–228[Medline]
35. Schroeder DH: Metabolism and kinetics of bupropion. J Clin Psychiatry 1983; 44:79–81[Medline]
36. Anderson RJ, Gambertoglio JG, Schrier RW: Clinical Use of Drugs in Renal Failure. Springfield, IL, Charles C Thomas Publishers, 1976
37. Booth J, O’Grady J, Neuberger J, et al: Clinical guidelines on the management of hepatitis C. Gut 2001; 49(suppl1):1-21
38. Davis G, Albright J, Cook S, et al: Projecting future complications of chronic hepatitis C in the United States. Liver Transpl 2003; 9:331–338[CrossRef][Medline]
39. World Health Organization: Global Surveillance and Control of Hepatitis C. J Viral Hepat 1999; 6:35–47[CrossRef][Medline]
40. Bolay H, Soylemezoglu F, Nurlu G, et al: PCR detected hepatitis C virus genome in the brain of a case with progressive encephalomyelitis with rigidity. Clin Neurol Neurosurg 1996; 98:305–308[CrossRef][Medline]
41. Maggi F, Giorgi M, Fornai C, et al: Detection and quasi-species analysis of hepatitis C virus in the cerebrospinal fluid of infected patients. J Neurovirol 1999; 5:319–323[Medline]
42. Radkowski M, Wilkinson J, Nowicki M, et al: Search for hepatitis C virus negative-strand RNA sequences and analysis of viral sequences in the central nervous system: evidence of replication. J Virol 2002; 76:600–608[Abstract/Free Full Text]
43. Alter M: Epidemiology of hepatitis C in the West. Semin Liver Dis 1995; 15:5–14[Medline]
44. Alter H: To C or not to C: these are the questions. Blood 1995; 85:1681–1695[Free Full Text]
45. Rehermann B: Immunopathogenesis of hepatitis C, in Pathogenesis, natural history, treatment, and prevention of hepatitis C (moderator: Liang TJ). Ann Intern Med 2000; 132:296–305[Abstract/Free Full Text]
46. Iwarson S: The natural course of chronic hepatitis C. FEMS Microbiol Rev 1994; 14:201–204[CrossRef][Medline]
47. Vento S, Garofano T, Renzini C, et al: Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic hepatitis C. N Engl J Med 1998; 338:286–290[Abstract/Free Full Text]
48. Takahashi M, Yamada G, Miyamato R, et al: Natural course of chronic hepatitis C. Am J Gastroenterol 1993; 88:240–243[Medline]
49. Wiley T, Brown J, Chan J: Hepatitis C infection in African Americans: its natural history and histological progression. Am J Gastroenterol 2002; 97:700–706[CrossRef][Medline]
50. Graham C, Baden L, Yu E, et al: Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis 2001; 33:562–569[CrossRef][Medline]
51. Zhang T, Yuan L, Lai J, et al: Alcohol potentiates hepatitis C virus replicon expression. Hepatology 2003; 38:57–65[CrossRef][Medline]
52. National Institutes of Health. National Institutes of Health Consensus Development Conference Statement: Management of Hepatitis C. Hepatology 2002; 36(suppl1):3-20
53. Fireman M: Hepatitis C treatment and substance use disorders. Psychiatr Ann 2003; 33:402–408
54. Crofts N, Thompson S, Kaldor J: Epidemiology of the Hepatitis C Virus. Technical Report Series No. 3. Communicable Diseases Network of Australia and New Zealand, 1999
55. Fabrizi F, Martin P, Dixit V, et al: Acquisition of hepatitis C virus in hemodialysis patients: a prospective study by branched DNA signal amplification assay. Am J Kidney Dis 1998; 31:647–654[Medline]
56. Haley RW, Fischer RP: Commercial tattooing as a potentially important source of hepatitis C infection: clinical epidemiology of 626 consecutive patients unaware of their hepatitis C serologic status. Medicine 2001; 80:134–151[CrossRef][Medline]
57. Collantes R, Younossi Z: How great is the risk of transmitting the hepatitis C virus sexually? Cleveland Clin J Med 2004; 71:160–161[Free Full Text]
58. Lauer G, Walker B: Hepatitis C virus infection. N Engl J Med 2001; 345:41–52[Free Full Text]
59. Alter M, Kruszon-Moran D, Nainan O, et al: The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med 1999; 341:556–562[Abstract/Free Full Text]
60. Pawlotsky J: Use and interpretation of virological tests for hepatitis C. Hepatology 2002; 36(suppl1):65-73
61. Pawlotsky J: Molecular diagnosis of viral hepatitis. Gastroenterology 2002; 122:1554–1568[CrossRef][Medline]
62. Rosenberg S, Goodman L, Osher F, et al: Prevalence of HIV, hepatitis B, and hepatitis C in people with severe mental illness. Am J Public Health 2001; 91:31–37[Abstract]
63. Dinwiddie S, Shicker L, Newman TL: Prevalence of hepatitis C among psychiatric patients in the public sector. Am J Psychiatry 2003; 160:172–174[Abstract/Free Full Text]
64. El-Serag H, Kunik M, Richardson P, et al: Psychiatric disorders among veterans with hepatitis C infection. Gastroenterology 2002; 123:476–482[CrossRef][Medline]
65. Yovtcheva S, Rifai M, Moles J, et al: Psychiatric comorbidity among hepatitis C-positive patients. Psychosomatics 2001; 42:411–415[Abstract/Free Full Text]
66. Allen S, Spaulding A, Osei A, et al: Treatment of chronic hepatitis C in a state correctional facility. Ann Intern Med 2003; 138:187–190[Abstract/Free Full Text]
67. Desai R, Rosenheck R, Agnello V: Prevalence of hepatitis C virus infection in a sample of homeless veterans. Soc Psychiatry Psychiatr Epidemiol 2003; 38:396–401[Medline]
68. Bhattacharya R, Shuhart M: Hepatitis C and alcohol. J Clin Gastroenterol 2003; 36:242–252[CrossRef][Medline]
69. Backmund M, Meyer K, Von Zielonka M, et al: Treatment of hepatitis C infection in injection drug users. Hepatology 2001; 34:188–193[CrossRef][Medline]
70. Sylvestre D: Treating hepatitis C in methadone-maintenance patients: an interim analysis. Drug Alcohol Depend 2002; 67:117–123[CrossRef][Medline]
71. Patel K, McHutchison J: Initial treatment for chronic hepatitis C: current therapies and their optimal dosing and duration. Cleveland Clinic J Med 2004; 71(suppl3):8-12
72. Manns M, McHutchinson J, Gordon S, et al: Peginterferon alpha-2b plus ribavirin compared with interferon alpha-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 2001; 358:958–965[CrossRef][Medline]
73. Perry C, Jarvis B: Spotlight on peginterferon--2a (40KD) in chronic hepatitis C. Drugs 2001; 61:2263–2288[CrossRef][Medline]
74. Weiss K: Safety profile of interferon-alpha therapy. Semin Oncol 1998; 25:9–13[Medline]
75. Gervais A, Boyer N, Marcellin P: Tolerability of treatments for viral hepatitis. Drug Saf 2001; 24:375–384[CrossRef][Medline]
76. Juegling F, Ebert D, Gut O, et al: Prefrontal cortical hypometabolism during low-dose interferon-alpha treatment. Psychopharmacology 2000; 152:383–389[CrossRef][Medline]
77. Pavol M, Meyers C, Rexer J, et al: Pattern of neurobehavioral deficits associated with interferon-alpha therapy for leukemia. Neurology 1995; 45:947–950[Abstract/Free Full Text]
78. Van Gool A, Kruit W, Engels F, et al: Neuropsychiatric side effects of interferon-alpha therapy. Pharm World Sci 2003; 25:11–20[CrossRef][Medline]
79. Davis G, Esteban-Mur R, Rustgi V, et al: Interferon-alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C: International Hepatitis Interventional Therapy Group. N Engl J Med 1998; 339:1493–1499[Abstract/Free Full Text]
80. Musselman D, Lawson D, Gumnick J, et al: Paroxetine for the prevention of depression induced by high-dose interferon-. N Engl J Med 2001; 344:961–966[Abstract/Free Full Text]
81. Loftis JM, Hauser P: Co-management of depression and HCV treatment. Psychiatr Ann 2003; 33:385–391
82. Capuron L, Neurauter G, Musselman D, et al: Interferon-alpha-induced changes in tryptophan metabolism: relationship to depression and paroxetine treatment. Biol Psychiatry 2003; 54:906–914[CrossRef][Medline]
83. Bonaccorso S, Marino V, Puzella A: Increased depressive ratings in patients with hepatitis C receiving interferon-alpha-based immunotherapy are related to changes to interferon-alpha-induced changes in the serotonergic system. J Clin Psychopharmacol 2002; 22:86–90[CrossRef][Medline]
84. Capuron L, Raison C, Musselman D, et al: Association of exaggerated HPA-axis response to the initial injection of interferon-alpha with development of depression during interferon-alpha therapy. Am J Psychiatry 2003; 160:1342–1345[Abstract/Free Full Text]
85. Lisker-Melman M, Di Bisceglie A, Usala S, et al: Development of thyroid disease during therapy of chronic viral hepatitis with interferon-. Gastroenterology 1992; 102:2155–2160[Medline]
86. Dieperink E, Ho SB, Thuras P, et al: A prospective study of neuropsychiatric symptoms associated with interferon-alpha-2b and ribavirin therapy for patients with chronic hepatitis C. Psychosomatics 2003; 44:104–112[Abstract/Free Full Text]
87. Clark CH, Mahoney JS, Clark DJ, et al: Screening for depression in a hepatitis C population: the reliability and validity of the Center for Epidemiologic Studies Depression Scale (CES-D). J Adv Nurs 2002; 40:361–369[CrossRef][Medline]
88. Hauser P, Soler R, Reed S, et al: Prophylactic treatment of depression induced by high-dose interferon-. Psychosomatics 2000; 41:439–441[Free Full Text]
89. Levenson JL, Fallon HJ: Fluoxetine treatment of depression caused by interferon-. Am J Gastroenterol 1993; 88:760–761[Medline]
90. Schramm T, Lawford B, Macdonald G, et al: Sertraline treatment of interferon--induced depressive disorder. Med J Aust 2000; 173:359–361[Medline]
91. Gleason O, Yates WR, Isbell MD, et al: An open-label trial of citalopram for major depression in patients with hepatitis C. J Clin Psychiatry 2002; 63:194–198[Medline]
92. Hauser P, Khosla J, Aurora H, et al: A prospective study of the incidence and open-label treatment of interferon-induced major depressive disorder in patients with hepatitis C. Mol Psychiatry 2002; 7:942–947[CrossRef][Medline]
93. Malek-Ahmadi P, Ghandour E: Bupropion for treatment of interferon-induced depression. Ann Pharmacother 2004; 38:1202–1205[Abstract/Free Full Text]
94. Cardona X, Avila A, Castellanos P: Venlafaxine-associated hepatitis (letter). Ann Intern Med 2000; 132:417[Free Full Text]
95. Anttila S, Leinonen E: A review of the pharmacological and clinical profile of mirtazapine. CNS Drug Reviews 2001; 7:249–264[Medline]
96. Aranda-Michel J, Koehler A, Bejarano P, et al: Nefazodone-induced liver failure: report of three cases. Ann Intern Med 1999; 130:285–288[Abstract/Free Full Text]
97. Rammohan K, Rosenberg J, Lynn D, et al: Efficacy and safety of modafinil for the treatment of fatigue in multiple sclerosis: a two-center, Phase-2 study. J Neurol Neurosurg Psychiatry 2002; 72:179–183[Abstract/Free Full Text]
98. Schaller JL, Behar D: Modafinil in fibromyalgia treatment. J Neuropsychiatry Clin Neurosci 2001; 13:530–531[Free Full Text]
99. Rabkin JG, McElhiney MC, Rabkin R, et al: Modafinil treatment for fatigue in HIV+ patients: a pilot study. J Clin Psychiatry 2004; 65:1688–1695[Medline]
100. DeBattista C, Doghramji K, Menza MA, et al: Adjunct modafinil for the short-term treatment of fatigue and sleepiness in patients with major depressive disorder: a preliminary double-blind, placebo-controlled study. J Clin Psychiatry 2003; 64:1057–1064[Medline]
101. DeBattista C, Lembke A, Solvason HB, et al: A prospective trial of modafinil as an adjunctive treatment of major depression. J Clin Psychopharmacol 2004; 24:87–90[CrossRef][Medline]
102. Nasr S: Modafinil as adjunctive therapy in depressed outpatients. Ann Clin Psychiatry 2004; 16:133–138[Medline]
103. Berigan T: The use of atomoxetine adjunctively in fibromyalgia syndrome. Can J Psychiatry 2004; 49:499–500[Medline]
104. Berigan TR: Atomoxetine used adjunctively with selective serotonin reuptake inhibitors to treat depression. (Primary Care Companion) J Clin Psychiatry 2004; 6:93–94[Medline]
105. Stahl SM, Zhang L, Damatarca C, et al: Brain circuits determine destiny in depression: a novel approach to the psychopharmacology of wakefulness, fatigue, and executive dysfunction in major depressive disorder. J Clin Psychiatry 2003; 64(suppl14):6-17
106. FDA Talk Paper: New Warning for Strattera; Dec 17, 2004, http://www.fda.gov/bbs/topics/ANSWERS/2004/ANS01335.html
107. Iancu I, Sverdlik A, Dannon P, et al: Bipolar disorder associated with interferon- treatment. Postgrad Med J 1997; 73:834–835[Free Full Text]
108. Strite D, Valentine A, Meyers C: Manic episodes in two patients treated with interferon-. J Neuropsychiatry Clin Neurosci 1997; 9:273–276[Abstract/Free Full Text]
109. Howes OD, McKenzie KJ: Manic psychosis induced by long term -interferon treatment for hepatitis C. International Journal of Psychiatry and Clinical Practice 2000; 4:161–162[CrossRef]
110. Onyike CU, Bonner JO, Lyketsos CG, et al: Mania during treatment of chronic hepatitis C with pegylated interferon and ribavirin. Am J Psychiatry 2004; 161:429–435[Free Full Text]
111. Greenberg D, Jonasch E, Gadd M, et al: Adjuvant therapy of melanoma with interferon-_2b is associated with mania and bipolar syndromes: gabapentin may serve as a mood stabilizer. Cancer 2000; 89:356–362[CrossRef][Medline]
112. Monji A, Yoshida I, Tashiro K, et al: A case of persistent manic-depressive illness induced by interferon- in the treatment of chronic hepatitis C. Psychosomatics 1998: 39:562-564
113. Altindag A, Ozbulut O, Ozen S, et al: Interferon--induced mood disorder with manic features. Gen Hosp Psychiatry 2001; 23:166–170[CrossRef][Medline]
114. Malik AR, Ravasia S: Interferon-induced mania. Can J Psychiatry 2004; 49:867–868[Medline]
115. Tamam L, Yerdelen D, Ozpoyraz N: Psychosis associated with interferon- therapy for chronic hepatitis B. Ann Pharmacother 2003; 37:384–387[Abstract/Free Full Text]
116. Bozikas V, Petrikis P, Balla A, et al: An interferon--induced psychotic disorder in a patients with chronic hepatitis C. Eur Psychiatry 2001; 16:136–137[CrossRef][Medline]
117. Prior TI, Chue PS: Psychotic depression occurring after stopping interferon-. J Clin Psychopharmacol 1999; 19:385–386[CrossRef][Medline]
118. Hoffman RG, Cohen MA, Alfonso CA, et al: Treatment of interferon-induced psychosis in patients with comorbid hepatitis C and HIV. Psychosomatics 2003; 44:417–420[Free Full Text]
119. Felker BL, Sloan KL, Dominitz JA, et al: The safety of valproic acid use for patients with hepatitis C infection. Am J Psychiatry 2003; 160:174–178[Abstract/Free Full Text]
120. Diehl AM: Acute and chronic liver failure and hepatic encephalopathy, in Cecil Textbook of Medicine, 21st Edition. Edited by Goldman L, Bennett JC. Philadelphia, PA, WB Saunders, 2000, pp 813-816
121. vom Dahl S, Kircheis G, Haussinger D: Hepatic encephalopathy as a complication of liver disease. World Journal of Gastroenterology 2001; 7:152–156[Medline]
122. Butterworth RF: Complications of cirrhosis, III: hepatic encephalopathy. J Hepatol 2000; 32(suppl1):171-180
123. Gerber T, Schomerus H: Hepatic encephalopathy in liver cirrhosis: pathogenesis, diagnosis, and management. Drugs 2000; 60:1353–1370[CrossRef][Medline]
124. Hazell AS, Butterworth RF: Hepatic encephalopathy: an update of pathophysiologic mechanisms. PSEBM 1999; 222:99–112[Abstract/Free Full Text]
125. Ferenci P, Lockwood A, Mullen K, et al: Hepatic encephalopathy: definition, nomenclature, diagnosis, and quantification: final report of the Working Party at the 11th World Congresses of Gastroenterology, Vienna, Austria, 1998. Hepatology 2002; 35:716–721[CrossRef][Medline]
126. Bustamante J, Rimola A, Ventura PJ, et al: Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol 1999; 30:890–895[CrossRef][Medline]
127. Arguedas MR, DeLawrence TG, McGuire BM: Influence of hepatic encephalopathy on health-related quality of life in patients with cirrhosis. Dig Dis Sci 2003; 48:1622–1626[CrossRef][Medline]
128. Huizenga JR, Gips CH, Tangerman A: The contribution of various organs to ammonia formation: a review of factors determining arterial ammonia concentration. Ann Clin Biochem 1996; 33:23–30[Medline]
129. Felipo V, Butterworth RF: Neurobiology of ammonia. Prog Neurobiol 2002; 67:259–279[CrossRef][Medline]
130. Lockwood AH, Weissenborn K, Butterworth RF: An image of the brain in patients with liver disease. Curr Opin Neurol 1997; 10:525–533[Medline]
131. Butterworth RF: Pathophysiology of hepatic encephalopathy: a new look at ammonia. Metab Brain Dis 2002; 17: 221-227
132. Butterworth RF: Pathogenesis of hepatic encephalopathy: new insights from neuroimaging and molecular studies. J Hepatol 2003; 39:278–285[CrossRef][Medline]
133. Mousseau DD, Baker GB, Butterworth RF: Increased density of catalytic sites and expression of brain monoamine oxidase-A in humans with hepatic encephalopathy. J Neurochem 1997; 68:1200–1208[Medline]
134. Ong JP, Mullen KD: Hepatic encephalopathy. Eur J Gastroenterol 2001; 13:325–334[CrossRef][Medline]
135. Avallone R, Zeneroli ML, Venturini I, et al: Endogenous benzodiazepine-like compounds and diazepam-binding inhibitor in serum of patients with liver cirrhosis with and without overt encephalopathy. Gut 1998; 42:861–867[Abstract/Free Full Text]
136. Dasarthy S, Mullen KD: Benzodiazepines in hepatic encephalopathy: sleeping with the enemy. Gut 1998; 42:764–765[Free Full Text]
137. Sand P, Kavvadias D, Feineis D, et al: Naturally-occurring benzodiazepines: current status of research and clinical implications. Eur Arch Psychiatry Clin Neurosci 2000; 250:194–202[CrossRef][Medline]
138. Venturini I, Corsi L, Avallone R, et al: Ammonia and endogenous benzodiazepine-like compounds in the pathogenesis of hepatic encephalopathy. Scand J Gastroenterol 2001; 36:423–425[Medline]
139. Barbaro G, Di Lorenzo G, Soldini M, et al: Flumazenil for hepatic encephalopathy Grade III and IVa in patients with cirrhosis: an Italian multicenter, double-blind, placebo-controlled, cross-over study. Hepatology 1998; 28:374–378[CrossRef][Medline]
140. Goulenok C, Bernard B, Cadranel JF, et al: Flumazenil vs. placebo in hepatic encephalopathy in patients with cirrhosis: a meta-analysis. Aliment Pharmacol Ther 2002; 16:361–372[CrossRef][Medline]
141. Bengtsson F, Berquist P: Neuropsychiatric implications of brain tryptophan perturbations appearing in hepatic encephalopathy, in Recent Advances in Tryptophan Research. Edited by Fillippini GA. New York, Plenum, 1996, pp 387-395
142. Huber M, Rossle M, Siegerstetter V, et al: Heliobacter pylori infection does not correlate with plasma ammonia concentration and hepatic encephalopathy in patients with cirrhosis. Hepato-Gastroenterology 2001; 48:541–544[Medline]
143. Miquel J, Barcena R, Boixeda D, et al: Role of heliobacter pylori infection and its eradication in patients with subclinical encephalopathy. Eur J Gastroenterol Hepatol 2001; 13:1067–1072[CrossRef][Medline]
144. Zullo A, Hassan C, Morini S: Hepatic encephalopathy and Heliobacter pylori: a critical reappraisal. J Clin Gastroenterol 2003; 37:164–168[CrossRef][Medline]
145. Blei AT, Cordoba J: Hepatic encephalopathy. Am J Gastroenterol 2001; 96:1968–1976[CrossRef][Medline]
146. Weissenborn K, Ennen JC, Schomerus H, et al: Neuropsychological characterization of hepatic encephalopathy. J Hepatol 2001; 34:768–773[CrossRef][Medline]
147. Schomerus H, Hamster W: Neuropsychological aspects of porto-systemic encephalopathy. Metab Brain Dis 1998; 13:361–377[CrossRef][Medline]
148. Weissenborn K, Ruckert N, Hecker H, et al: The Number Connection Tests A and B: inter-individual variability and use for assessment of early hepatic encephalopathy. J Hepatol 1998; 28:646–653[CrossRef][Medline]
149. Wiltfang J, Nolte W, Weissenborn K, et al: Psychiatric aspects of portal-systemic encephalopathy. Metab Brain Dis 1998; 13:379–389[CrossRef][Medline]
150. Ficker DM, Westmoreland BF, Sharbrough FW: Epileptiform abnormalities in hepatic encephalopathy. J Clin Neurophysiol 1997; 14:230–234[CrossRef][Medline]
151. Fisch BJ, Klass DW: The diagnostic specificity of triphasic wave patterns. Electroencephalogr Clin Neurophysiol 1988; 70:1–8[CrossRef][Medline]
152. Kullmann F, Hollerbach S, Holstege A, et al: Visual event-related P300 potentials in early portosystemic encephalopathy. Gastroenterology 1992; 103:302–310[Medline]
153. Saxena N, Bhatia M, Joshi YK, et al: Utility of P300 auditory event-related potential in detecting cognitive dysfunction in patients with cirrhosis of the liver. Neurol India 2001; 49:350–354[Medline]
154. Nicolao F, Efrati C, Masini A, et al: Role of determination of partial pressure of ammonia in cirrhotic patients with and without hepatic encephalopathy. J Hepatol 2003; 38:441–446[CrossRef][Medline]
155. Kreiger S, Jaub M, Jansen O, et al: MRI findings in chronic hepatic encephalopathy depend on portosystemic shunt: results of a controlled, prospective clinical investigation. J Hepatol 1997; 27:121–126[CrossRef][Medline]
156. Skehan S, Norris S, Hegarty J, et al: Brain MRI changes in chronic liver disease. Eur Radiol 1997; 7:905–909[CrossRef][Medline]
157. Genovese E, Maghnie M, Maggiore G, et al: MR imaging of CNS involvement in children affected by chronic liver disease. AJNR 2000; 21:845–851[Abstract/Free Full Text]
158. Lockwood AH: Hepatic encephalopathy. Neurol Clin 2002; 1:241–246[CrossRef]
159. Cordoba J, Hinojosa C, Sampedro F, et al: Usefulness of magnetic resonance spectroscopy for diagnosis of hepatic encephalopathy in a patient with relapsing confusional syndrome. Dig Dis Sci 2001; 46:2451–2455[CrossRef][Medline]
160. Cordoba J, Sanpedro F, Alonso J, et al: 1H-magnetic resonance in the study of hepatic encephalopathy in humans. Metab Brain Dis 2002; 17:415–429[CrossRef][Medline]
161. Geissler A, Lock G, Frund R, et al: Cerebral abnormalities in patients with cirrhosis detected by proton magnetic resonance spectroscopy and magnetic resonance imaging. Hepatology 1997; 25:48–54[CrossRef][Medline]
162. Lockwood AH, Murphy BW, Donnelly KZ, et al: Positron-emission tomographic localization of abnormalities of brain metabolism in patients with minimal hepatic encephalopathy. Hepatology 1993; 18:1061–1068[CrossRef][Medline]
163. Lockwood AH, Weissenborn K, Bokemeyer M, et al: Correlations between cerebral glucose metabolism and neuropsychological test performance in nonalcoholic cirrhosis. Metab Brain Dis 2002; 17:29–40[CrossRef][Medline]
164. Nolte W, Wiltfang J, Schindler C, et al: Portosystemic hepatic encephalopathy after transjugular intrahepatic portosystemic shunt in patients with cirrhosis: clinical, laboratory, psychometric, and electroencephalographic investigations. Hepatology 1998; 28:1215–1225[CrossRef][Medline]
165. Somberg KA, Riegler JL, LaBerge JM, et al: Hepatic encephalopathy after transjugular intrahepatic portosystemic shunts: incidence and risk factors. Am J Gastroenterol 1995; 90:549–555[Medline]
166. Kramer L, Bauer E, Gendo A, et al: Neurophysiological evidence of cognitive impairment in patients without overt hepatic encephalopathy after transjugular intrahepatic portosystemic shunts. Am J Gastroenterol 2002; 97:162–166[CrossRef][Medline]
167. Als-Nielsen B, Gluud LL, Gluud C: Non-absorbable disacharides for hepatic encephalopathy: systematic review of randomized trials. BMJ 2004; 328:1046 (bmj.38048.506134.EE)[Abstract/Free Full Text]
168. Strauss E, Tramote R, Silva EP, et al: Double-blind, randomized clinical trial comparing neomycin and placebo in the treatment of exogenous hepatic encephalopathy. Hepatogastroenterology 1992; 39:542–545[Medline]
169. Dasarthy S: Role of gut bacteria in the therapy of hepatic encephalopathy with lactulose and antibiotics. Indian Journal of Gastroenterology 2003; 22(suppl2):S50-S53
170. Plauth M, Merli M, Kondrup J, et al: ESPEN guidelines for nutrition in liver disease and transplantation. Clin Nutr 1997; 16:43–55[Medline]
171. Lochs H, Plauth M: Liver cirrhosis: rationale and modalities for nutritional support: the European Society of Parenteral Nutrition Consensus and beyond. Curr Opin Clin Nutr Metab Care 1999; 2:345–349[CrossRef][Medline]
172. Seymour CA, Whelan K: Dietary management of hepatic encephalopathy: too many myths persist. BMJ 1999; 318:1365–1366[Free Full Text]
173. Riordan SM, Williams R: Treatment of hepatic encephalopathy. N Engl J Med 1997; 337:473–479[Free Full Text]
174. Als-Nielsen B, Koretz RL, Kjaergard, et al: Branched-chain amino acids for hepatic encephalopathy. Cochrane Database of Syst Rev 2003(2): CD001939
175. Kircheis G, Wettstein M, vom Dahl S, et al: Clinical efficacy of L-ornithine-L-aspartate in the clinical management of hepatic encephalopathy. Metab Brain Dis 2002; 17:453–462[CrossRef][Medline]
176. Kircheis G, Nilius R, Berndt H, et al: Therapeutic efficacy of L-ornithine-L-aspartate infusion concentrate in patients with liver cirrhosis and hepatic encephalopathy: a placebo-controlled, double-blind study. Hepatology 1997; 25:1351–1360[CrossRef][Medline]
177. Stauch S, Kircheis G, Adler G, et al: Oral L-ornithine-L-aspartate therapy of chronic hepatic encephalopathy: results of a placebo-controlled, double-blind study. J Hepatol 1998; 28:856–864[CrossRef][Medline]
178. Cecere A, Ciaramella F, Tancredi L, et al: Efficacy of L-carnitine in reducing hyperammonemia and improving neuropsychological test performance in patients with hepatic cirrhosis: results of a randomized trial. Clin Drug Invest 2002; 22(suppl1):7-14
179. Liu Q, Duan AP, Ha DK, et al: Symbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis. Hepatology 2004; 39:1441–1449[CrossRef][Medline]
180. Yoo HW, Edwin D, Thulavath PJ: Relationship of the model for end-stage liver disease (MELD) scale to hepatic encephalopathy, as defined by electroencephalography and neuropsychometric testing, and ascites. Am J Gastroenterol 2003; 98:1395–1399[CrossRef][Medline]
181. Watanabe A: Cerebral changes in hepatic encephalopathy. J Gastroenterol Hepatol 1998; 13:752–760[Medline]
182. McCrea M, Cordoba J, Vessey G, et al: Neuropsychological characterization and detection of subclinical hepatic encephalopathy. Arch Neurol 1996; 53:758–763[Abstract/Free Full Text]
183. Weissenborn K, Heidenreich S, Ennen J, et al: Attention deficits in minimal hepatic encephalopathy. Metab Brain Dis 2001; 16:13–19[CrossRef][Medline]
184. Wein C, Koch H, Popp B, et al: Minimal hepatic encephalopathy impairs fitness to drive. Hepatology 2004; 39:739–745[CrossRef][Medline]
185. Schomerus H, Hamster W: Quality of life in cirrhotics with minimal hepatic encephalopathy. Metab Brain Dis 2001; 16:37–41[CrossRef][Medline]
186. Groeneweg M, Moerland W, Quero JC, et al: Screening for subclinical hepatic encephalopathy. J Hepatol 2000; 32:748–753[CrossRef][Medline]
187. Groeneweg M, Quero JC, De Bruijn I, et al: Subclinical hepatic encephalopathy impairs daily functioning. Hepatology 1998; 19:787–805[CrossRef]
188. Das A, Dhiman RK, Sarawat VA, et al: Prevalence and natural history of subclinical hepatic encephalopathy in cirrhosis. J Gastroenterol Hepatol 2001; 16:531–535[CrossRef][Medline]
189. Hartmann IJC, Groeneweg M, Quero JC, et al: The prognostic significance of subclinical hepatic encephalopathy. Am J Gastroenterol 2000; 95:2029–2034[CrossRef][Medline]
190. Romero-Gomez M, Boza F, Garcia-Valdecasas MS, et al: Subclinical hepatic encephalopathy predicts the development of overt hepatic encephalopathy. Am J Gastroenterol 2001; 96:2718–2723[Medline]
191. Kullmann F, Hollerbach S, Hosltege A, et al: Subclinical hepatic encephalopathy: the diagnostic value of evoked potentials. J Hepatol 1995; 22:101–110[CrossRef][Medline]
192. Duseja A, Dhiman RK, Saraswat VA, et al: Minimal hepatic encephalopathy: natural history, impact on daily functioning, and role of treatment. Indian Journal of Gastroenterology 2003; 22(suppl2):S42-S44
193. Victor M, Adams RA, Cole M: The acquired (non-Wilsonian) type of chronic hepatocerebral degeneration. Medicine 1965; 44:345–396[Medline]
194. Finlayson MH, Superville B: Distribution of cerebral lesions in acquired hepatocerebral degeneration. Brain 1981; 104:79–95[Free Full Text]
195. Jog MS, Lang AE: Chronic acquired hepatocerebral degeneration: case reports and new insights. Mov Disord 1995; 10:714–722[CrossRef][Medline]
196. Layrargues GP: Movement dysfunction and hepatic encephalopathy. Metab Brain Dis 2001; 16:27–35[CrossRef][Medline]
197. Bleasel AF, Waugh RC, McCaughan GW: Development of chronic hepatocerebral degeneration eight years after a distal splenorenal (Warren) shunt. Gut 1989; 30:1419–1423[Abstract/Free Full Text]
198. Thobois S, Giraud P, Debat P, et al: Orofacial dyskinesias in a patient with primary biliary cirrhosis: a clinicopathological case report and review. Mov Disord 2002; 17:415–419[CrossRef][Medline]
199. Burkhard PR, Delavelle J, Du Pasquier R, et al: Chronic parkinsonism associated with cirrhosis: a distinct subset of acquired hepatocerebral degeneration. Arch Neurol 2003; 60:521–528[Abstract/Free Full Text]
200. Kulisevsky J, Ruscalleda J, Grau JM: MR imaging of acquired hepatocerebral degeneration. AJNR 1991; 12:527–528[Medline]
201. Brunberg JA, Kanal E, Hirsch W, et al: Chronic acquired hepatic failure: MR imaging of the brain at 1.5 T. AJNR 1991; 12:909–914[Abstract]
202. Hanner JS, Li KCP, Davis GL: Acquired hepatocerebral degeneration: MR similarity with Wilson’s disease. Journal of Computer-Assisted Tomography 1988; 12:1076–1077[Medline]
203. Lee J, Lacomis D, Comu S, et al: Acquired hepatocerebral degeneration: MR and pathologic findings. AJNR 1998; 19:485–487[Abstract]
204. Ueki Y, Isozaki E, Miyazaki Y, et al: Clinical and neuroradiological improvement in chronic acquired hepatocerebral degeneration after branched-chain amino acid therapy. Acta Neurol Scand 2002; 106:113–116[CrossRef][Medline]
205. Powell EE, Pender MP, Chalk JB, et al: Improvement in chronic hepatocerebral degeneration following liver transplantation. Gastroenterology 1990; 98:1079–1082[Medline]
206. Stracciari A, Guarino M, Pazzaglia P, et al: Acquired hepatocerebral degeneration: full recovery after liver transplantation. J Neurol Neurosurg Psychiatry 2001; 70:136–137[Free Full Text]
207. Wijdicks EFM, Wiesner RH: Acquired (non-Wilsonian) hepatocerebral degeneration: complex management decisions. Liver Transpl 2003; 9:993–994[CrossRef][Medline]

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