Schizophrenia Complicated by Chronic Hepatitis C Virus and Hepatic Encephalopathy

Case Presentation

“Mr. H” is a 52-year-old homeless divorced Caucasian man with a history of paranoid schizophrenia, alcohol, opiate, and cocaine use disorders, and hepatitis C virus (HCV) infection complicated by cirrhosis and hepatic encephalopathy. After a 2-month inpatient psychiatric admission for worsening psychosis and suicidal ideation, Mr. H was referred to our partial hospital program for ongoing psychiatric treatment.

Mr. H’s psychiatric history first became notable for substance use and psychotic symptoms in his late teens, and his first psychiatric hospitalization occurred in his early 20s. In recent years, he exhibited a pattern of increasingly frequent psychiatric hospitalizations, of which he had 15 in the past 7 years. His hospitalizations were often precipitated by the emergence of command auditory hallucinations, paranoia, and thought broadcasting. His psychosis was sometimes accompanied by depressed mood, hopelessness, suicidal ideation, generalized anxiety, and active substance use involving alcohol, cocaine, or both. He had no history of suicide attempts or violence. He had been treated with a variety of antipsychotic and antidepressant medications, although he struggled to adhere to treatment. A remote clozapine trial was noted in his records, although no details were provided on the trial’s timing, dosage, duration, or efficacy, and Mr. H was unable to recall them. He had no documented treatment with long-acting antipsychotic injections.

Mr. H’s substance use consisted of significant and chronic alcohol use, and he had made multiple attempts to achieve sobriety with the assistance of detoxification and 12-step programs. He first used alcohol at age 13, and his use became regular and problematic in his late teens. He reported his drinking over the past 5 years as daily on average, with approximately 5–6 drinks per day, and more on some occasions. He often required detoxification with benzodiazepines on admission to psychiatric facilities. He was periodically treated with acamprosate, usually after inpatient admissions, but his adherence to the medication was inconsistent, and he did not report significant reductions in alcohol use. Mr. H also had a history of cocaine and opiate use (occasionally by intravenous injection, in his 20s and 30s). Coincident with his marriage in his mid-20s, he accrued 30 consecutive months of sobriety from drugs and alcohol, his longest substance-free period. His last use of alcohol and cocaine occurred just before his latest hospitalization. He had few social supports, and his substance use and repeated hospitalizations had contributed to his divorce after a few years of marriage and multiple episodes of homelessness lasting several months, including the loss of his apartment 3 months before his current partial hospital admission.

Mr. H’s medical history was notable for hypertension and untreated chronic HCV genotype 1 infection of unknown duration, diagnosed 5 years ago when elevated liver enzyme levels were noted during a psychiatric admission. Cirrhosis was identified 2 years after his HCV diagnosis, again during a psychiatric admission, in the setting of symptoms of hepatic encephalopathy. Mr. H had experienced persisting pancytopenia related to hypersplenism and liver disease over the past 5 years, with white blood cell counts ranging from 2.5 to 4.0×10⁹/L. Historically, his medical care was sporadic and suffered from fragmentation, limited coordination, and poor adherence to follow-up recommendations.

On admission to the partial hospital program, Mr. H reported no psychotic or mood symptoms. He identified urges to use alcohol but was motivated to remain sober. He was fully oriented, with grossly intact attention and memory. His medications included aripiprazole, 30 mg daily, and risperidone, 1 mg twice daily. To reduce the risk of recurrent hepatic encephalopathy, he was being treated with lactulose. He received diphenhydramine, 50 mg, and zolpidem, 5 mg, each night for insomnia. Because of a recent positive tuberculin skin test, he was being treated for latent tuberculosis with daily isoniazid and vitamin B₆.

Mr. H engaged in the partial hospital program’s cognitive-behavioral therapy-based group therapy program and met individually with members of a multidisciplinary treatment team. Over the next 8 weeks, his mental status was notable for fluctuations in mood, anxiety, and psychosis. He intermittently reported alcohol and cocaine use. Despite antipsychotic medication, Mr. H had ongoing persecutory delusions, auditory hallucinations that varied in frequency and perceived loudness, and occasional delusional misidentification (Capgras syndrome) and visual hallucinations. The Repeatable Battery for the Assessment of Neuropsychological Status, administered to Mr. H on two occasions when he did not have confusion or prominent mood or psychotic symptoms, demonstrated impairment in immediate memory, visuospatial construction, and attention.

To minimize potential hepatic stress from polypharmacy, antipsychotic monotherapy was pursued by discontinuing risperidone, which had not improved his psychotic symptoms appreciably after it was added to aripiprazole. Mr. H tolerated this change well, and aripiprazole was then slowly cross-tapered to quetiapine, 400 mg nightly, to address his ongoing psychosis, anxiety, and insomnia with a single agent, allowing discontinuation of diphenhydramine and zolpidem.

Two months into his treatment course, Mr. H was sent to the emergency department when clinical staff noted prominent disorientation and confusion, distinct from his impaired though stable psychiatric baseline. Results of routine laboratory tests were consistent with chronic liver disease but otherwise unremarkable, although the patient’s serum ammonia level was elevated at 70 µmol/L (reference range, 11–32 μmol/L). Head CT and chest radiography revealed no abnormalities, and a urine drug screen was negative. Mr. H was admitted to the internal medicine service for treatment of presumed hepatic encephalopathy.

After stabilization of his mental status in the hospital over 2 days and a decline in his serum ammonia level to 30 µmol/L, Mr. H returned to the partial hospital program with instructions to continue an increased dose of lactulose and a follow-up appointment with a gastroenterologist. With Mr. H’s permission, his psychiatric resident accompanied him to his appointment, assisting him in navigating a complex hospital registration process and serving as an additional informant and an advocate for the patient. Mr. H’s gastroenterologist switched him from lactulose—which was causing abdominal discomfort, fecal urgency, and diarrhea—to rifaximin, 500 mg twice daily. After this change, Mr. H remained largely adherent to his medication regimen, and his cognitive functioning gradually improved.

In the month following his medical hospitalization, Mr. H’s mental status remained stable, but his program attendance and participation lagged. He frequently acknowledged his understanding that the combination of his liver disease and any ongoing substance use could eventually prove fatal. At discharge, Mr. H was provided with both medical and psychiatric follow-up care and resources to help him maintain sobriety.

Discussion

Hepatitis C and Serious Mental Illness

HCV infection, alone or in combination with alcohol-related liver disease, accounts for nearly two-thirds of newly diagnosed chronic liver disease in the general population (1). Chronic HCV infection is present in 8.5%−30% of people with serious mental illness, a rate 5–16 times higher than in the general population (2). Substance use, particularly injection drug use, is an important vector for transmission of HCV (3). Nearly 50% of patients with schizophrenia meet criteria for a substance use disorder in their lifetime (4), and rates of lifetime injection drug use in samples of patients with serious mental illness range from 5% to 35%, compared with 1.4% in the general population (5).

HCV infection is the leading cause of cirrhosis and hepatocellular carcinoma (2). Cirrhosis occurs in 10%−20% of patients with chronic HCV, and hepatocellular carcinoma develops in patients with cirrhosis at a rate of 1%−4% annually (6). Decompensated cirrhosis (which includes ascites, upper gastrointestinal bleeding from varices or portal hypertension, and/or hepatic encephalopathy) develops in 30% of cases of cirrhosis by 10 years and has a 5-year survival rate of 50% (7). Alcohol abuse can hasten the development and progression of HCV-related complications, decrease HCV treatment response rates, and elevate mortality (8).

Notably, the current aging HCV-infected cohort will contribute to an increasing prevalence of HCV-related cirrhosis and its attendant complications, such as hepatic encephalopathy (9) and mortality from liver failure or hepatocellular carcinoma (10). Treatment is effective in preventing these long-term consequences (11), but 65%−75% of HCV-infected individuals in the United States are not aware that they are infected (12). For people with serious mental illness, screening and treatment remain difficult to access (13), despite arguments for universal screening in this patient population (14) and the recent publication of guidelines by the Centers for Disease Control and Prevention advocating screening for everyone born between 1945 and 1965, regardless of risk factors (15). Nevertheless, rates of screening, counseling, vaccination, and referral to treatment are low, although promising mental health system-level interventions exist and are effective in improving these rates (16). Mr. H very likely contracted HCV through intravenous drug use in his 20s and 30s, although his infection was not identified until he was 47 years old. After diagnosis, he was not evaluated for HCV treatment, and he had not received guideline-recommended hepatitis A or B vaccinations (16) before he presented to the partial hospital program, despite numerous interactions with the health care system through repeated psychiatric hospitalizations, many of which occurred in general hospitals and included specialty medical consultations to address abnormal results on liver function tests. Such consultations ended with recommendations for outpatient follow-up rather than further in-hospital assessment and treatment. It is quite possible that earlier identification and treatment of Mr. H’s HCV and cirrhosis would have prevented substantial morbidity.

Peginterferon alfa plus ribavirin is standard treatment for most chronic HCV infections (11). Substance use, even active alcohol or injection drug use, is not an absolute contraindication to treatment (11), and despite potential adverse psychiatric effects of interferon use (e.g., irritability, depression, and mood swings), people with serious mental illness are able to complete treatment safely and achieve outcomes comparable to those of patients without serious mental illness (17), particularly when treated in multidisciplinary integrated settings with close psychiatric follow-up (13). Additionally, recently approved and newly emerging direct-acting HCV antiviral agents, such as boceprevir and telaprevir, allow for highly effective, shorter-duration treatment regimens that may eventually obviate the need for interferon (18). The improved efficacy and lowered treatment burdens may rebalance the risk-benefit ratio overwhelmingly in favor of treatment under most, if not all, circumstances. While most HCV-infected patients without cirrhosis or with compensated cirrhosis are eligible for treatment, decompensated cirrhosis, as seen in Mr. H at the time of his presentation, is often a contraindication to treatment, as side effects are more burdensome and success rates lower, making liver transplantation the treatment of choice (11).

Hepatic Encephalopathy

Hepatic encephalopathy, a complication of advanced liver disease, is a neuropsychiatric syndrome characterized by broad impairments in cognitive, emotional, and behavioral domains. The pathogenesis of the disorder is not fully understood, but probable mechanisms involve impairment in the liver’s ability to detoxify portal venous blood, leading to accumulation of ammonia and other neurotoxins and inflammatory mediators, causing astrocyte swelling and cerebral edema (19). Clinical manifestations of hepatic encephalopathy exist on a continuum from no outwardly detectable changes in behavior or mental status to coma (20). Intermediate signs and symptoms include attentional impairments, confusion, disorientation, slurred speech, mood changes, disrupted sleep or alteration in sleep patterns, and lethargy or somnolence. Hepatic encephalopathy may also present with persecutory delusions, delusional misidentification (e.g., Capgras syndrome, as seen in Mr. H), and Schneiderian first-rank symptoms (21). Findings on physical examination may include flapping tremor (asterixis), clonus, nystagmus, and a positive Babinski sign.

Hepatic encephalopathy is classified as “overt” or “minimal,” depending on the presence or absence, respectively, of outward manifestations. Overt hepatic encephalopathy is seen in 30%−40% of people with cirrhosis (20), and one-third to one-half of hospitalizations for cirrhosis are related to overt hepatic encephalopathy (22). Minimal hepatic encephalopathy, which is the mildest form and is seen in up to 80% of people with cirrhosis, consists of deficits in immediate memory, attention, visuospatial abilities, and fine motor skills (23). Minimal hepatic encephalopathy increases the risk of progression to overt hepatic encephalopathy, impairs quality of life, including social interactions, and has been strongly associated with driving impairment (23). Minimal hepatic encephalopathy may be diagnosed with the aid of neuropsychiatric testing; the recommended batteries are the Psychometric Hepatic Encephalopathy Score and the Repeatable Battery for the Assessment of Neuropsychological Status (23). Mr. H’s results on the Repeatable Battery for the Assessment of Neuropsychological Status, with deficits in immediate memory, attention, and visuospatial construction, suggested the presence of minimal hepatic encephalopathy at baseline, although similar areas of cognitive impairment are found in schizophrenia (24), making it difficult to use these measures alone to identify minimal hepatic encephalopathy in patients with schizophrenia.

Differential Diagnosis of Hepatic Encephalopathy

Mr. H had multiple conditions that can present with mental status changes: a psychotic illness; cocaine, opiate, and alcohol use disorders; and chronic liver disease with a history of hepatic encephalopathy. To diagnose hepatic encephalopathy, it must be distinguished from these and other causes of mental status change, and the overlapping presenting symptoms and interplay between schizophrenia and advanced liver disease must be considered in diagnostic and treatment approaches (Figure 1). General indicators that may suggest delirium or encephalopathy rather than decompensation of a primary psychiatric disorder include a sudden and dramatic change in mental status, an underlying medical illness, visual hallucinations, fluctuating levels of consciousness, and the acute onset of new or different psychiatric symptoms with a known history of prior psychiatric illness (25). Such indicators may overlap with substance intoxication or withdrawal states, so toxicology screening is imperative. Atypicality of psychotic symptoms (e.g., predominant visual hallucinations) and temporal association with worsening laboratory indices may be useful in distinguishing exacerbations of a primary psychotic illness from secondary psychoses, such as psychosis caused by hepatic encephalopathy (26). For Mr. H, worsening hepatic encephalopathy was often associated with the emergence of visual hallucinations and delusional misidentification in the setting of increasing confusion, while exacerbations of schizophrenia were mostly characterized by increased frequency and intensity of auditory hallucinations.

If hepatic encephalopathy is suspected as the cause of mental status changes, it remains necessary to exclude other potential causes of delirium, including infections, metabolic disturbances, intracranial hemorrhage (as liver disease-related clotting deficiencies may increase bleeding risk), seizure, and stroke (22, 27). Physical findings associated with hepatic encephalopathy may be present, but they may only be markers of decompensated liver disease, not necessarily hepatic encephalopathy. Brain imaging (CT or MRI) can rule out intracranial pathology, such as stroke, tumor, and hemorrhage. EEG may show generalized slowing and triphasic waves in overt hepatic encephalopathy and a slowed mean dominant frequency in minimal hepatic encephalopathy (23), but these abnormalities are seen in other encephalopathies (27). Still, EEG may be useful in differentiating substance-induced mental status changes, seizure, and primary psychiatric illness (25).

Serum ammonia levels correlate with the severity of hepatic encephalopathy (28) and, in the setting of liver disease and absence of other sources of delirium, support the diagnosis of hepatic encephalopathy (22). However, improper blood drawing and sample handling techniques can lead to erroneous results (19), and elevations in ammonia levels are not specific for hepatic encephalopathy (20). Mild elevations may even occur in patients with cirrhosis without hepatic encephalopathy (22). While clinical improvement of Mr. H’s hepatic encephalopathy was associated with a decline in his ammonia level from mildly elevated to normal, serial monitoring of levels is not useful, as management of hepatic encephalopathy is based on clinical symptoms, not a target ammonia level (19).

Management of Hepatic Encephalopathy

Hepatic encephalopathy is usually reversible with prompt treatment, but symptoms tend to recur (22). Treatment addresses precipitants of hepatic encephalopathy and employs ammonia-reducing interventions (20). Common precipitants of hepatic encephalopathy include dehydration, gastrointestinal bleeding, constipation, infection, dietary protein excess, renal failure, electrolyte disturbances, and metabolic acidosis or alkalosis (19). Substances that contribute to further liver injury (e.g., alcohol) or CNS depression (medications such as sedatives, hypnotics, and opioids) can increase susceptibility to hepatic encephalopathy. No specific underlying precipitants were identified for Mr. H’s episode of hepatic encephalopathy, so only empiric treatment was provided.

Empiric treatment for hepatic encephalopathy has the goal of reducing ammonia production or absorption in the gut. Lactulose, a nonabsorbable disaccharide, administered at a dosage that produces two to three soft bowel movements a day, can reverse acute hepatic encephalopathy and prevent recurrence (19). Side effects include abdominal cramping, bloating, diarrhea, and flatulence, leading to low rates of adherence (19). Rifaximin is a nonabsorbable antibiotic that reduces the risk of recurrent hepatic encephalopathy and hospitalization from hepatic encephalopathy (29). While potentially better tolerated than lactulose, rifaximin is significantly more expensive (20), and Mr. H’s health insurance required that a prior authorization be completed before he was able to obtain this medication. Patients with hepatic encephalopathy need routine follow-up with a gastroenterologist to monitor progression of cirrhosis, adjust medications prescribed for hepatic encephalopathy, and screen for hepatocellular carcinoma (11).

The Psychiatrist’s Role

When treating patients with liver disease and related complications such as hepatic encephalopathy, psychiatrists must work to minimize potential CNS and hepatic insults from psychopharmacology. For hepatically metabolized medications, impaired hepatic functioning leads to delays in reaching steady-state concentrations and prolonged elimination half-lives, necessitating slower titrations and dose reductions of many commonly used psychiatric medications (27). In cirrhosis, glucuronidation pathways (phase II metabolism) may be relatively spared relative to oxidative pathways (phase I), making medications that rely primarily on phase II pathways (e.g., some benzodiazepines, such as oxazepam, lorazepam, temazepam) preferable (27).

Medications with extensive first-pass hepatic metabolism can produce excessive blood levels and side effects at standard dosages in the setting of liver disease and should be carefully titrated. Such medications include chlorpromazine, olanzapine, quetiapine, methylphenidate, buspirone, bupropion, fluvoxamine, sertraline, venlafaxine, and most tricyclic antidepressants (27). Long-acting injectable antipsychotics (with the possible exception of paliperidone palmitate, which undergoes minimal hepatic metabolism) should be used with great caution in the presence of liver disease, as altered metabolism can create difficulties in selecting appropriate dosing schedules and lead to drug accumulation, which would be difficult to address expeditiously in the event of emergent side effects (30).

The use of quetiapine, while allowing minimization of polypharmacy by targeting several of Mr. H’s symptoms with a single medication, has limitations given its extensive presystemic metabolism, as well as rare case reports associating it with acute liver failure (31). However, slow titration to a modest dosage and quetiapine’s relatively short half-life may help limit excessive drug levels and accumulation. Antipsychotics with minimal hepatic metabolism (e.g., paliperidone) may offer the most predictable pharmacokinetics in hepatic impairment (32), but Mr. H’s psychotic symptoms had responded suboptimally to risperidone, so paliperidone, a risperidone metabolite, was not considered.

Clozapine demonstrates superior efficacy in treatment-refractory schizophrenia compared with other antipsychotics, and its use should be considered when trials of adequate dosage and duration of other antipsychotics have produced inadequate results (33). Mr. H’s history of ongoing substance use and periodic nonadherence to antipsychotic medication made it difficult to determine whether he would obtain adequate benefit from non-clozapine antipsychotics, but limited response was suggested by his extensive list of prior antipsychotic trials, including trials that occurred during inpatient hospitalizations of up to 8 weeks. He had been treated with clozapine in the remote past, but no details of symptom response or reasons for clozapine’s discontinuation were available. Recently he had experienced several years of pancytopenia, and on presentation his white blood cell count was 2.85×10⁹/L, precluding the use of clozapine. Leukopenia notwithstanding, the use of clozapine in patients with HCV and advanced liver disease must be carefully considered. Clozapine-induced sedation and constipation can precipitate hepatic encephalopathy (30), and interferon treatment shares with clozapine a risk of agranulocytosis (34). Using clozapine earlier in Mr. H’s course of illness, however, might have had a positive impact on his prognosis given its effectiveness in treatment-refractory schizophrenia and its potential benefit in reducing alcohol and other substance use (35).

Since many medications affect hepatic function, it helps to consult the package insert or a medication reference book to guide prescribing for patients with liver impairment. Drugs with a risk of hepatotoxicity and potentially harmful over-the-counter agents, herbs, and supplements should be avoided. Benzodiazepines and other sedatives (including zolpidem), as well as medications with anticholinergic properties, can contribute to delirium or precipitate or exacerbate hepatic encephalopathy (20, 36). Illicit substances, including cocaine and opiates, may have an exaggerated physiological impact, so patients should be informed of the dangers, and abstinence should be a treatment goal.

Psychiatrists must also aggressively treat comorbid alcohol use disorders in patients with liver disease, again with abstinence as the goal. In addition to psychosocial approaches, effective pharmacotherapy exists for the treatment of alcohol dependence in patients with schizophrenia. Of three medications that have been approved by the Food and Drug Administration for alcohol dependence, disulfiram and naltrexone have modest evidence to support their use in schizophrenia (35). The third medication, acamprosate, has been shown in a case report (37) to be successful in treating alcohol dependence in schizophrenia, but a 12-week randomized placebo-controlled trial of acamprosate in 23 patients with schizophrenia and alcohol dependence showed no differences from placebo on any drinking measures (38). Mr. H had been treated periodically with acamprosate over several years, with seemingly little effect on his overall alcohol use, but his sporadic adherence made it difficult to assess what impact this medication might have on his drinking.

Disulfiram, naltrexone, and acamprosate have not been studied in advanced liver disease, and disulfiram and naltrexone can induce hepatotoxicity and liver failure, so these agents are not recommended for use in such populations (39). Acamprosate, which is not metabolized by the liver, may have a favorable safety profile in liver disease, although data supporting its safety in this setting are limited (39). Topiramate has shown promise for alcohol dependence, and a case report described its efficacy for this indication in schizophrenia (40). Like acamprosate, it has a favorable hepatic safety profile, but there is no specific evidence supporting its safety in liver disease (39). Baclofen is another emerging treatment for alcohol dependence. A case report supports its efficacy for alcohol dependence in schizophrenia (41), and a trial suggests efficacy and safety in patients with cirrhosis (42). Caution is advised in using these medications for alcohol dependence in patients with schizophrenia and liver disease at this point, as further rigorous studies are needed to evaluate the promise and safety of acamprosate, topiramate, and baclofen.

Proactive care coordination and advocacy are crucial aspects of the psychiatrist’s work with people with serious mental illness and serious medical morbidity. Patients with serious mental illness are at increased risk of experiencing poor health outcomes and receiving poor-quality health care owing to a number of patient, provider, and system factors (43). Unlike in the case of Mr. H, it is usually not feasible to have a psychiatrist accompany a patient to his or her specialty medical appointments. However, the psychiatrist must prioritize communication, coordination, and collaboration with medical providers and assess and troubleshoot barriers to access and adherence to treatment. Enlisting the assistance of community supports in such efforts is also advised whenever possible and appropriate. In Mr. H’s case, his inpatient psychiatry team, understanding the patient’s difficulty accessing and adhering to outpatient follow-up, may have been able to help the patient by advocating for initial assessment and treatment of HCV and cirrhosis, including recommended vaccinations, to occur before he was discharged. Similarly, his outpatient mental health providers may have been able to assist more directly in Mr. H’s pursuit of ongoing medical follow-up.

Conclusions

Liver disease and its most common underlying factors (alcohol and HCV infection) have an elevated prevalence in populations with serious mental illness. Mental health professionals caring for these patients must remain vigilant for hepatic impairment and its possible complications, such as hepatic encephalopathy. Psychiatrists need to be prepared to consider a complicated differential diagnosis for mental status changes in such patients and to prescribe medications in a manner that accounts for diminished hepatic capacity and minimizes further insult to the liver. Comorbid substance use must be actively addressed. Psychiatrists must also advocate for HCV screening and referral to treatment for patients with serious mental illness, as current screening rates are low and early identification and treatment of HCV infection can slow or prevent progression to decompensated liver disease. For these vulnerable patients with complex comorbidities, close coordination among general and specialist medical and mental health providers is imperative to ensure optimal outcomes.