Approximately one third of patients with cirrhosis who are admitted to the hospital present with altered mental status (AMS). Of those, about 50 percent will have hepatic encephalopathy (HE), a spectrum of reversible neuropsychiatric disorders in patients with chronic liver disease. Other potential causes of AMS include sepsis/infection, metabolic disturbances, drugs/toxins or structural brain lesions.

“Altered mental status represents a clinical challenge,” says Robert S. Rahimi, MD, MSCR, hepatologist on the medical staff at Baylor University Medical Center at Dallas, part of Baylor Scott & White Health, and clinical assistant professor. “Although most patients with AMS have uncomplicated HE, many cirrhotic patients have other causes of AMS. If a patient is hyponatremic with a serum sodium of 105, he or she is going to be altered. We have to rule out other causes before we come to an HE diagnosis.”

Diagnosis of HE is based primarily on clinical examination. Disorientation and asterixis – flapping hand tremors – are reliable markers in a patient with underlying cirrhosis. However, mild hypokinesia, psychomotor slowing and lack of attention are easily overlooked. The condition can range from Grade 0-1 or covert HE (characterized by decreased attention span, hypersomnia/insomnia) to Grades 2-4 or overt HE (lethargy, disorientation for time/space, coma.

“The exact cause of HE is unknown. It is a complex entity with multiple components that result in functional impairment of neuronal cells, none of which are well understood,” Dr.  Rahimi says. “But the main theory everyone focuses on is the neurotoxicity of the ammonia that builds up.”

Current treatment options for patients focus on intubation if patients can’t protect their airway during confusion, ruling out infection – the number-one precipitant of HE – head CT if there are focal deficits and catharsis (bowel movements) to eliminate ammonia from the body.

Lactulose, a non-absorbable disaccharide, is considered the gold standard. The drug is titrated to cause the patient to have two to four bowel movements per day. The drug increases fecal nitrogen excretion and decreases ammonia. Lactulose has been widely used since the 1960s. A study from India showed that patients taking lactulose for HE were readmitted 20 percent compared to 50 percent of the time when given placebo.¹ Another study favorably compared the use of lactulose and probiotics versus a placebo for the prevention of HE recurrence.²

“If a patient has sleep/wake disturbances which is the first sign of covert HE, probiotics may be considered to change the gut bacteria,” Dr. Rahimi says. “I think the future of HE treatment will be gut bacteria microbiota. HE is multifactorial, but gut bacteria is one of them.”

A 2010 study published in the New England Journal of Medicine showed that rifaximin (RIX), a non-absorbable antibiotic, is effective in preventing HE when given concomitantly with lactulose.³ Although only approved by the FDA after patients have failed lactulose, a 2014 study showed that long-term RIX therapy is safe with no adverse effects.⁴ RIX kills bad gut bacteria and increases the good gut bacteria that patients with cirrhosis lack. Baylor Dallas is currently involved in a large multicenter study looking at the simultaneous use of lactulose and RIX.

Ammonia Scavengers

Another group of ammonia-lowering agents include the compounds sodium benzoate/phenylacetate, glycerol phenylbutyrate and ornithine phenylacetate, known as ammonia scavengers. Although not quite ready for prime time, ammonia scavengers offer potential new mechanisms for treating HE.

In the recent Phase 2b STOP-HE Study, in which Baylor Dallas was the top enroller worldwide, ornithine phenylacetate (OCR-002) was confirmed to be a potent but safe ammonia scavenger. Through a series of complex metabolic processes, OCR-002 binds glutamate and ammonia, so now patients actively urinate ammonia.

Results of the study, which are pending publication, showed that OCR-002 use in cirrhotic patients hospitalized with HE reduced plasma ammonia levels to a greater extent than placebo, and reduced ammonia levels faster than placebo and standard of care. OCR-002 also led to faster clinical improvement when compared to placebo and standard of care in patients with confirmed elevated ammonia levels. The incidence of adverse events was comparable between treatment groups.

“OCR-002 is a potential game changer because people don’t want to have three bowel movements a day,” Dr. Rahimi says. “Patients come in with HE because they didn’t take their lactulose. OCR-002 leads to more urinary output of ammonia. We are currently designing the phase 3 protocol based on these results for continued OCR-002 development.”

Polyethylene glycol (PEG) vs Lactulose

In the HELP Randomized Clinical Trial – the first of its kind – Dr. Rahimi and his research team demonstrated that polyethylene glycol 3350-electrolyte solution (PEG), which is normally used for colonoscopy preps, is a safe, rapid, and effective immediate treatment strategy for patients presenting with acute overt HE.

“Because PEG causes rapid catharsis, clearing gut bacteria and reducing bacteria ammoniagenesis, we hypothesized that PEG should be more efficient than lactulose,” he says. “Objective measures of HE improved significantly faster in those receiving PEG compared to lactulose. Although our study showed no statistical difference in length of stay, initial treatment with PEG certainly has the potential to shorten hospitalizations.”

RIX + Lactulose vs Lactulose + Placebo

In an ongoing open label crossover study that will take two years to complete, Dr. Rahimi and his team are assessing the efficacy and safety of rifaximin SSD (soluble solid dispersion) tablets plus lactulose vs lactulose plus placebo in patients with overt HE. The primary endpoint in this study is time to resolution of OHE per the Hepatic Encephalopathy Grading Instrument (HEGI).

Brain Steroid Modulating Agent – GR3027

Prior research has focused on benzodiazepines that work on the GABA-A receptor, which is activated when alcoholics drink. More recent work has focused on a novel compound of interest, the brain steroid modulating agent GR3027, that targets this same pathway. GR3027 selectively antagonizes the enhanced activation of the GABA-A receptor complex by neurosteroids, including allopregnanolone and tetrahydrodeoxycorticosterone.

A Phase 1 trial of GR3027 looked at saccadic eye velocity (SEV), a rapid eye movement similar to asterixis, and self-rated somnolence in the antagonist arm. Tested in 90 healthy males, GR3027 was well tolerated and produced a statistically significant reduction in SEV and significant positive findings on both SEV and perceived sedation. A Phase 2a trial of GR3027 in HE is under way and began enrolling subjects as of February 2019 to investigate this compound further.

Fecal Microbiota Transplant

There are currently four active trials in phases 1 and 2 of fecal microbiota transplant (FMT) for the treatment of HE. In this procedure, stool is obtained from a rational donor. Researchers have determined that an effective donor has a specific amount of bacteria that patients with cirrhosis lack. In a phase 1 study, in which the endpoint was to determine the safety and efficacy of FMT first, they found that patients who received an FMT were admitted with fewer episodes of HE. “I think FMT will be the future because the microbiome is so complex,” Dr. Rahimi says. “There is definitely more to come on this. Overall, there are many studies of potential therapies under way. As we obtain more data, we hope to show the efficacy of these new approaches.”