Hepatic Encephalopathy: More Than Just a Change in Mental Status

Early intervention key to improving patient outcomes.

Case

The emergency medical service box crackled again during a busy Monday evening shift: “84-year-old obese male, found obtunded in bed.” When the paramedics arrived, they started normal saline intravenously and intubated the patient. Vitals included blood pressure, 113/62 mmHg; heart rate, 70 beats/min (bpm); respiratory rate, 12 breaths/min; and pulse oxygen, 100% on room air. The result of a dextrose stick was 187 mg/dL, and the patient was administered vecuronium, midazolam and dopamine.

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At the hospital, vitals were recorded: blood pressure, 133/71 mmHg; heart rate, 60 bpm; respiratory rate, 19 breaths/min; and temperature, 94.5°F. Physical examination showed the patient had a Glasgow Coma Scale score of 3 (intubated), no signs of trauma and abdominal ascites (Figure). Medical records revealed a history of atrial fibrillation, cirrhosis, coronary artery disease, diabetes mellitus, and hypertension.

Surgical history included coronary artery bypass graft and pacemaker/defibrillator implantation. Current medications included amiodarone, carvedilol, furosemide, lactulose, levothyroxine, linagliptin, liraglutide, patiromer, sodium bicarbonate, spironolactone, tamsulosin and warfarin.

Evaluation: Differential & Treatment Concerns

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The differential diagnosis of altered mental status involves extensive examination, particularly in this patient with multiple comorbidities: stroke (ischemic, hemorrhagic), cardiac (acute coronary event, dysrhythmia), trauma, metabolic derangements (hypoglycemia, diabetic ketoacidosis, hepatic encephalopathy, hyponatremia), acute gastrointestinal bleed with hypovolemia, sepsis, toxidrome (alcohol intoxication or withdrawal, overdose – intentional, accidental), neoplasm, adrenal crisis and medication noncompliance.

Clinical course

Laboratory test results included: white blood cell count, 5 x 10³/µL; hemoglobin, 9 g/dL; hematocrit, 28%; platelet level, 176 x 10³/µL; sodium, 140 mmol/L; potassium, 2.8 mmol/L; blood urea nitrogen, 43 mg/dL; creatinine, 3 mg/dL; glucose, 193 mg/dL; international normalized ratio, 2; total bilirubin, 1.2 mg/dL; aspartate aminotransferase, 23 IU/L; alkaline phosphatase, 156 IU/L; ammonia, 155 µg/dL; and brain natriuretic peptide, 866 pg/mL.

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Creatine kinase, lactate and thyroid stimulating hormone levels were normal. Blood culture testing, toxicology screening and urinalysis results were negative. Electrocardiography (ECG) showed atrial fibrillation (75 bpm), occasional premature ventricular contractions, and non-specific T-wave abnormalities. Chest X-ray and computed tomography (CT) scans of the head and cervical spine revealed no acute abnormalities.

Serial troponins, ECGs, and extended focused assessment with sonography for trauma (eFAST) exam ruled out cardiac etiologies. Head and neck CT ruled out ischemic and hemorrhagic stroke or cervical spine injury, while head and neck CT angiography excluded a large vessel occlusion. Laboratory evaluation did not reveal metabolic derangements, signs of infection, or toxidrome; however, ammonia levels were three times the upper limit of normal. The patient remained hemodynamically stable with no signs of gastrointestinal bleed; therefore, dopamine was discontinued. The patient was diagnosed with hepatic encephalopathy (HE).

Discussion

In the United States, 85,099 patients with cirrhosis (primary diagnosis) visited the ED in 2014.(¹⁾ The prevalence of cirrhosis is increasing because of increased survival rates and increased diagnoses of alcoholic liver disease, hepatitis C, and, particularly, nonalcoholic fatty liver disease.(^2,3) The clinical course of cirrhosis includes an asymptomatic compensated phase followed by transition to a decompensated phase, during which cirrhosis-related complications (eg, ascites, HE) develop.(⁴⁾

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Given the complexity of the disease and typical comorbidities patients with cirrhosis have, the incidence of complications and ED visits is increasing.(¹⁾ According to the Healthcare Cost and Utilization Project Nationwide ED Sample, ED visits for HE increased annually between 2006 (42,687) and 2014 (57,578).(¹⁾

HE is a neurologic complication with a broad range of symptoms, ranging from mild cognitive impairment to disorientation and behavioral changes to confusion and, in the most severe cases, coma.(⁵⁾ HE should be considered in patients with cirrhosis with cognitive impairment, an altered sleep–wake cycle, and disorientation or confusion, as well as in those who are unconscious.(⁶⁾ Among 265 patients with cirrhosis with a prior HE episode (n=387 episodes), the most common features of HE were confusion (77.5%); changes in mental status (57.1%); disorientation to time, place or person (48.3%); lethargy (46.3%); and asterixis (45.2%).⁷ Of key importance, a high blood ammonia level alone in patients with HE does not provide value as a tool for diagnosis, severity staging or prognosis.(^5,8)

Early intervention and treatment of sepsis, ischemic and hemorrhagic stroke, hyponatremia and shock improve patient outcomes.(^9-13) Similarly, HE is a time-sensitive diagnosis and requires emergent treatment to optimize outcomes.(⁵⁾ For example, studies have demonstrated that treatment of HE with rifaximin decreased the number and duration of hospital stays.(^14-16)

Treatment of the current HE episode and precipitating factors, as well as prevention of future (ie, recurrent) episodes, are recommended.(⁵⁾ Notably, certain medications including analgesics (eg, opiates) and sedatives (eg, benzodiazepines) should be avoided in patients with cirrhosis because these medications may precipitate HE episodes.(^17,18)

Prevention of HE recurrence is important to minimize the risk of rehospitalization in patients with cirrhosis. In 2014, 25.3% of patients hospitalized for cirrhosis-related conditions were readmitted within 90 days (47.1% of these were related to HE).¹⁹ In one prospective study, 23.7% of patients with cirrhosis with a previous hospitalization experienced an HE-related rehospitalization within three months.²⁰ Data from a large urban healthcare system showed that the 30-day readmission rate for patients with HE was significantly greater than that for patients with cirrhosis without HE (33.3% vs 10.2%, respectively; P=0.02); further, patients with HE had a more than four times greater risk of 30-day hospital readmission versus patients without HE (odds ratio [OR], 4.4; P=0.02).²¹

Lactulose syrup, a nonabsorbable disaccharide titrated to maintain two to three bowel movements per day, is used as first-line therapy for patients with HE(.⁵⁾ However, nonadherence with lactulose monotherapy has been associated with three times greater odds of HE recurrence versus patients adherent to treatment (OR, 3.3); gastrointestinal-related adverse events, including diarrhea, abdominal pain and bloating, were associated with lactulose nonadherence.²² While the mean time to HE recurrence was shorter in 39 patients nonadherent to lactulose versus the overall study population of 137 patients (3 ± 2 vs 9 ± 1 months, respectively), the majority (75.2%) of the 137 patients experienced HE recurrence within 9 ± 1 months.(²²⁾ Of note, the excessively sweet taste of lactulose may also contribute to nonadherence.(²³⁾

Practice guidelines recommend rifaximin, which, at a dose of 550 mg twice daily, reduces the risk of HE recurrence in combination with lactulose.(^5,24) In a randomized, double-blind study of patients in remission from HE (≥two episodes during previous six months), rifaximin reduced the relative risk of HE recurrence by 58% versus placebo during a six-month period.(²⁵⁾ Further, rifaximin reduced the risk of HE-related hospitalization by 50% compared with placebo.(²⁵⁾ In that study, 91.2% of patients in each treatment group received concomitant lactulose. The incidence of diarrhea was comparable in the rifaximin and placebo groups (10.7% vs 13.2%, respectively).(²⁵⁾

Data from that trial also indicated that rifaximin treatment may reduce the risk of other cirrhosis-related complications, including spontaneous bacterial peritonitis, variceal bleeding and acute kidney injury/hepatorenal syndrome.(²⁶⁾

Recognition of HE as a neurologic complication of cirrhosis is critical, given that patients with cirrhosis and changes in mental status may present to the ED. Long-term prophylaxis with rifaximin with or without lactulose is recommended to reduce the risk of HE recurrence and reduce hospitalization and disease burden in patients with cirrhosis.

Clinical Course and Discharge

The patient with HE received treatment with rifaximin 550 mg twice daily and lactulose. As his mental status improved, he became less ventilator-dependent and was extubated. Upon discharge, the patient was instructed to increase lactulose dose until two to three bowel movements were maintained per day and take rifaximin 550 mg twice daily to reduce the risk of HE recurrence.

References

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