Propranolol-induced hallucinations mimicking encephalopathy in a patient with liver cirrhosis

Abstract

Hepatic encephalopathy (HE) is a frequent complication of liver cirrhosis, which is mostly characterized by psychomotor slowing. However, psychotic symptoms such as visual and olfactory hallucinations may sometimes also be present. In contrast, auditory hallucinations are uncommon in chronic liver disease. In this case report, we present a patient with liver cirrhosis due to excessive alcohol consumption who presented to the emergency department with disorientation and signs of infection. Initial assessment led to the diagnosis acute on chronic liver failure exacerbated by infection leading to encephalopathy. The patient was admitted and successfully treated with antibiotics, Lactulose and Rifaximin. Gastroscopy showed varices without bleeding stigmata and Propranolol 20 mg was initiated as primary prophylaxis. Upon follow-up, the patient was clinically stable but had developed visual and auditory hallucinations which raised the suspicion that HE was not the cause. CT scan of the brain was unremarkable and the hallucinations were considered to be caused by Propranolol and disappeared shortly after switching to Carvedilol.

Keywords:

• Hepatic encephalopathy
• hallucinations
• propranolol
• cirrhosis

Introduction

Hepatic encephalopathy (HE) is a frequent complication of liver cirrhosis affecting up to 40% of patients with liver cirrhosis [1]. It is usually observed in patients with hepatic insufficiency, both in the acute and chronic setting. In the acute setting where the patient presents with signs of acute fulminant liver failure, it is caused by a quick increase in intracranial pressure, which may lead to cerebral herniation. In chronic liver disease, the pathogenesis of HE is multifactorial. Among the different factors that cause HE are the liver’s inability to metabolize toxins from the intestine, such as ammonia. Another factor is the presence of porto-systemic shunts in patients with liver disease due to portal hypertension. Taken together, those changes result in swelling of the astrocytes in the brain and depending on their severity lead to either covert, or overt clinical symptoms of HE [2].

Clinically, HE is a neuropsychiatric syndrome characterized by changes in cognitive functions, behavior and personality. The initial symptoms are usually subtle and may be discovered only with psychomotor testing. As the disease progresses or upon a sudden precipitating factor, those changes progress to confusion, mental alterations, sleep pattern disturbances, and in severe cases to gross disorientation, bizarre behavior, somnolence and worst cases even coma [3].

HE is usually dominated by mental slowing, but psychotic symptoms dominated by hallucinations, aggression and manic behavior may sometimes also be present. In patients with chronic liver disease, such symptoms are often attributed to gradual worsening in liver function and may lead to frequent contact with the outpatient clinic as well as repetitive hospital admissions, which may result in patient evaluation for a possible liver transplantation to alleviate those symptoms. In this case report we discuss a patient with liver cirrhosis and a history of HE, who presented to the outpatient clinic repeatedly with hallucinations. Diagnostic workup led to the conclusion that her hallucinations were induced by treatment with low dose of the non-selective β-blocker Propranolol for primary prophylaxis of variceal bleeding. Switching the drug to Carvedilol resulted in immediate resolution of hallucinations and the patient was therefore removed from the liver transplantation evaluation list. This case highlights the importance of thorough clinical investigation of unusual neuropsychiatric symptoms in patients with chronic liver disease to avoid misdiagnosis and unnecessary medical costs of liver transplantation evaluation.

Case presentation

A 65-year-old woman with no relevant medical history other than solitary kidney and cholecystectomy earlier in life due to gallstone disease. She had a history of excessive alcohol consumption without a confirmed liver cirrhosis diagnosis at presentation. She was admitted to the emergency department with diffuse symptoms described as disorientation, confusion, dysarthria and general fatigue. She underwent a neurological exam that showed general mental slowing, followed by an acute CT scan of the brain to exclude a cerebrovascular event and a full blood panel. The CT was cleared from signs of an acute event. The blood panel showed thrombocytopenia <100,000 per microliter and INR 1.7, normal alanine aminotranspherase (ALT) and aspartate transaminase (AST), elevated alkaline phosphatase (ALP) 138 U/L, bilirubin 2.9 mg/dL and hemoglobin 95 g/L and normal kidney function. Upon physical examination she had signs of chronic liver disease with spider nevi and palmar erythema. She underwent an ultrasound of the abdomen that showed a cirrhotic liver with a slightly dilated portal vein, decreased portal vein flow velocity and splenomegaly indicating portal hypertension. Acute liver biopsy showed a cirrhotic liver tissue with islands of acute steatohepatitis, where the etiology could be attributed to alcohol. The diagnosis acute on chronic liver failure was made and the patient was admitted to the hepatology ward. During hospital admission, she was assessed by a hepatologist and showed classic signs of decompensated cirrhosis with hepatic encephalopathy exacerbated by an acute infection of unknown focus. She received high dose empiric antibiotic treatment, Lactulose and Rifaximin. She received benzodiazepines due to alcohol withdrawal symptoms. She underwent gastroscopy with only small esophageal varices that we chose to treat by primary prophylaxis with Propranolol 10 mg twice daily to be titrated later on. She was discharged 14 days later with no or minimal signs of HE and no signs of hallucinations or psychotic symptoms. At discharge, she had a Child-Pugh score11-C and MELD-Na of 20 points. She had an INR 1.8, slightly elevated AST, ALP 150 U/L μkat/L and bilirubin 3.7 mg/dL.

Upon follow up, she was doing well with an improved Child-Pugh score of 9-B and MELD-Na 17. She had since discharge stopped alcohol intake abruptly and followed a healthy nutritional plan designed by a dietician at our department. She continued her treatment with Lactulose and Rifaximin to prevent HE and Propranolol as primary variceal bleeding prophylaxis. She was subsequently followed up via the liver outpatient clinic where it became gradually apparent in the next few months that she has been suffering from visual and auditory hallucinations, noticed primarily by her family members. She described individuals being at her house on a daily basis and hearing a variety of voices from dead relatives. The rate of symptom awareness that the patient described raised suspicion about a different etiology behind her mental disturbances than HE. In the following days, she underwent clinical tests that showed minimal HE that could otherwise not be detected upon physical examination. Serum ammonium level was within reference range and a new CT scan of the brain showed minimal cortical atrophy. Neuropsychiatry consultation for incipient dementia was negative and it was ruled out as a differential diagnosis. The patient’s hallucinations persisted for several weeks.

Since Propranolol is known to induce hallucinations as a rare side effect and although the patients used it at low dosage, it was withdrawn and switched to Carvedilol as primary prophylaxis of variceal bleeding. Three days after the medication switch, the hallucinations ceased completely and the patient had no residual neurological symptoms. After 4 months of follow-up and to the date of manuscript preparation, no signs of recurrent hallucinations have been reported.

Discussion

HE results in a myriad of non-specific neurological and psychiatric manifestations that vary from minimal and undetectable symptoms upon physical examination to overt and severe symptoms, including hepatic coma and death [4]. HE is usually caused by an acute precipitating factor. In our case, it was an infection requiring hospitalization. Once the insulting factor was resolved, the patient was alert and showed no signs of cognitive dysfunction. In some cases where the liver function is severely impaired, HE can present intermittently without a clear precipitating factor, making diagnosis and treatment challenging and may lead to a lengthy and thorough assessment to investigate whether the patient is a suitable liver transplantation candidate [5,6]. Since the patient in this particular case had HE at presentation, we continued treatment with non-absorbable disaccharide Lactulose to achieve at least one bowel movement daily and the antibiotic Rifaximin 1100 mg/day to prevent further exacerbations of HE.

Recurrent HE is usually associated with worsening of liver biochemistry or an identifiable precipitating factor (or shunting). In the present case an improvement of liver function is described, and thus other ‘CNS cause’ should be sought. Despite psychomotor slowing being the usual presentation of HE, psychotic symptoms, such as hallucinations may sometimes also be present. However, in a cirrhotic patient other causes of hallucinations are quite often omitted due to the patient’s underlying diagnosis. Hallucinations may be caused by intrinsic factors (acute neurological disease, metabolic derangement, infection, chronic disease, sleep deprivation etc.), but may also be induced iatrogenically by a single or multiple pharmaceutical drugs or alcohol abuse [7]. Propranolol, a non-selective beta blocker (NSBB) is routinely used as primary or secondary prophylaxis against variceal bleeding in patients with liver cirrhosis [8]. Propranolol dosage is usually titrated to the maximum tolerated dose or to reach a target heart rate of 50 − 55 bpm and systolic blood pressure > 100 mmHg. In the case we have described the patient was unable to tolerate a dose > 20 mg daily due to low pulse and hypotensive episodes. Visual and auditory hallucinations are a less frequent side effect of Propranolol treatment that has been reported since the 1960s when the drug was first approved for the treatment of cardiovascular disease and they are usually encountered at much higher doses (average dose ∼200 mg daily) [9]. Propranolol is a lipophilic molecule that easily passes through the blood-brain barrier and may act as a central nervous system (CNS) depressant, cause sleep disturbances, dreaming, nightmares and even hallucinations. The CNS symptoms often do not appear immediately but some time after the start of the therapy, a fact which may account for both the patient’s and physician’s difficulties in correlating symptoms with therapy [10]. In addition, several factors may be considered that might affect serum concentration of Propranolol in this case [11]. Cirrhotic patients have much higher levels of circulating Propranolol compared to healthy controls upon administration of the same Propranolol dose due to the presence of small or large porto-systemic shunts. Moreover, patients with cirrhosis often have concomitant cholestasis and elevated concentrations of circulating bile acids, which may affect the serum levels of Propranolol [11]. In the case we described the patients had elevated ALP and bilirubin, however we did not measure serum bile acids. Therefore, it is not unexpected that NSBB induced hallucinations may occur at a much lower dose in a patient with alcoholic liver cirrhosis. Moreover, in the case we described the patient already had chronic alcohol brain damage presenting as cortical atrophy on CT scan. Chronic ethanol consumption damages the endothelial cells at the blood brain barrier and alters its permeability [12], a factor which may have also contributed to increased sensitivity to Propranolol side effects. In such cases, Propranolol withdrawal after careful review of the patient’s condition or switching to Carvedilol is advised and should result in prompt resolution of hallucinations. Of note, Carvedilol and Propranolol are metabolized by different hepatic cytochromes P450 (CYPs), thus we may also take into consideration a potential altered enzymatic activity in our case which might have predisposed the accumulation of Propranolol in circulation and thus inducing hallucinations as a side effect in such low doses [13]. Unfortunately, we did not measure the levels of Propranolol in the blood of our patient to support this hypothesis.

In conclusion, HE is a common complication of liver cirrhosis and it presents with a variety of symptoms requiring a swift diagnosis and treatment. Hallucinations may less frequently also occur, but in the setting of an otherwise stable patient with liver cirrhosis other causes of hallucinations should be reviewed. Since many cirrhotic patients are on NSBBs, those agents should be suspected as a causative factor of hallucinations and a withdrawal or switch should be attempted promptly. Misinterpretation of hallucinations induced by Propranolol or other conditions as true HE might lead to devastating, incorrect treatment of patients and avoidable lengthy unnecessary investigations. Therefore, vigilance is always warranted when interpreting uncommon cognitive symptoms in chronic liver disease.

Informed consent

Informed consent was obtained from this patient prior to submission and the identity of the individual is fully anonymized.

Acknowledgment

We are thankful to our patient for allowing us to publish this case report. We are also thankful to the nurses at our hepatology outpatient clinic for their vigilance in noticing unusual symptoms of HE.

Disclosure statement

No potential conflict of interest was reported by the author(s).