Case Presentation: 74-year-old male with history of NASH cirrhosis with Grade I esophageal variceal bleeding history, SDH s/p burr hole drainage with course complicated by seizures on Keppra and Vimpat, type 2 diabetes mellitus, and coronary artery disease status post 1 drug eluting stent who presented with worsening confusion, fatigue and difficulty walking x 3-4 days. He was admitted for acute encephalopathy secondary to hepatic encephalopathy. His physical exam was notable for asterixis and bloodwork was notable for elevated ammonia level. Over the initial hospitalization, his home regimen of lactulose was increased to 45 mg Q4H titrated to 3-4 bowel movements daily. The rest of his home medications including rifaximin, spironolactone, propranolol, furosemide, levetiracetam and lacosamide were continued. His CT head did not reveal any acute intracranial process. His ultrasound abdomen did not show evidence of ascites. His EEG showed no epileptic activity, but showed non-specific multifocal cerebral dysfunction. Patient started having 3-4 bowel movements on the increased dose of lactulose. However, his mental status would not improve back to baseline despite uptitrating the lactulose to 45 mg Q4H and adding polyethylene glycol and lactulose enema. On day 7 of hospitalization, patient was perseverating, and remained AxO x 1 (name). MRI brain was ordered for further workup and it revealed small mamillary bodies. He was started on IV thiamine 500 mg TID for 3 days. The next morning, patient’s mental status and memory greatly improved and he was able to have normal conversations. He was subsequently discharged to subacute rehab on maintenance dose of thiamine.
Discussion: Hepatic encephalopathy (HE) is a common etiology of altered mental status. Since the 1930s, ammonia has been recognized as the precipitator of HE. In healthy individuals, 85% of ammonia is detoxified by the liver while the rest is metabolized by either the brain or muscle. Hyperammonemia state occurs as a result of hepatic dysfunction compounded by a state of decreased ammonia metabolism secondary to muscle atrophy. In the setting of hyperammonemia, brain astrocytes over-synthesize glutamine, resulting in cell swelling and accumulation of reactive oxygen species, leading to the eventual neuropsychiatric manifestation of HE. However, not everyone responds to ammonia lowering agents alone, such as the patient in our case. This incomplete resolution of neuropsychiatric symptoms following lactulose and rifaximin happened because chronic liver failure not only leads to hyperammonemia, it also creates a thiamine deficient state. Depletion of liver thiamine stores decreases the activity of alpha-ketoglutarate dehydrogenase, subsequently increasing glutamate concentration in peripheral tissues, which then passes into the central nervous system, manifesting as the symptomatology seen in HE.
Conclusions: Co-administering thiamine supplementation and ammonia reducing agents, regardless of the etiology of liver failure, has a synergistic effect in the treatment HE. Prompt thiamine supplementation should be considered in all patients with HE from end stage liver disease, especially when they do not adequately respond to standard ammonia lowering agents.