Hepatic Encephalopathy with Normal Transaminases: Diagnostic and Management Approach
Immediate Assessment and Diagnosis
In a patient with confusion and suspected hepatic encephalopathy (HE) but normal ALT and AST, immediately assess for clinical signs of HE using the Conn score and asterixis grading, obtain a complete liver panel including bilirubin, albumin, PT/INR, and ammonia level, and evaluate for precipitating factors such as infection, GI bleeding, constipation, or medication non-compliance. 1, 2
Normal transaminases do not exclude significant liver disease or hepatic encephalopathy—up to 10% of patients with advanced fibrosis may have normal ALT using conventional thresholds 1. Standard liver function tests are only 38% sensitive for detecting hepatic fibrosis 1.
Understanding the Clinical Context
HE can occur with normal transaminases because the pathophysiology primarily involves disturbed urea cycle function, porto-systemic shunting, and astrocytic dysfunction rather than active hepatocellular necrosis (which elevates transaminases) 2
The key pathogenic mechanism is hyperammonemia causing astrocytic swelling and cerebral edema, compounded by neuroinflammation from systemic inflammatory cytokines (TNF-α, IL-6, IL-17) that cross the blood-brain barrier 2
Porto-systemic anastomoses with relatively intact liver function can cause HE by allowing gut-derived ammonia and toxins to bypass hepatic detoxification 2
Essential Diagnostic Workup
Immediate Laboratory Testing
Complete liver panel: AST, ALT, alkaline phosphatase, GGT, total and direct bilirubin, albumin, and PT/INR to assess synthetic function 1, 3
Serum ammonia level: Elevated ammonia supports the diagnosis of HE, though normal levels do not exclude it 2
Complete blood count with differential: To identify infection as a precipitating factor 2
Basic metabolic panel: To assess electrolyte disturbances and renal function 2
Blood cultures if febrile: Infection is a common precipitant of HE 2
Clinical Staging
Assess Conn score (0-4 scale): Grade 0-1 indicates covert HE with behavioral abnormalities but intact sensorium; Grade ≥2 indicates overt HE with marked neurological deterioration 4, 2
Evaluate for asterixis: Flapping tremor is a hallmark physical finding in HE 4
Screen for precipitating factors: Infection, GI bleeding, constipation, dehydration, electrolyte imbalances, medications (especially sedatives/opioids), dietary protein load 2
Immediate Management Algorithm
First-Line Therapy
Lactulose 15-30 mL orally 2-3 times daily, titrated to achieve 2-3 soft bowel movements per day—this reduces gut-generated ammonia and toxins by ensuring smooth bowel function and preventing stagnation 2
Rifaximin 550 mg orally twice daily in combination with lactulose—this reduces gut microbial load and ammonia production 4, 2
Addressing Precipitating Factors
Treat infections aggressively with appropriate antibiotics if identified 2
Discontinue or reduce hepatotoxic or sedating medications 2
Correct electrolyte abnormalities, particularly hypokalemia and hypomagnesemia 2
Address GI bleeding if present, as blood in the gut increases ammonia production 2
Advanced Therapy for Refractory Cases
L-ornithine L-aspartate (LOLA) can be used to lower ammonia levels by stimulating the urea cycle—L-ornithine stimulates urea synthesis while both amino acids serve as substrates for glutamate transaminase, leading to increased glutamate that combines with ammonia to form glutamine 2
Mannitol for cerebral edema management in severe cases 2
Consider liver transplant evaluation for resistant cases or patients with MELD scores suggesting end-stage liver disease 4, 2
Extracorporeal liver assist devices (MARS or SPAD) may be considered as bridge therapy 2
Critical Monitoring Parameters
Repeat Conn score and asterixis grading daily to assess treatment response 4
Monitor for breakthrough HE episodes: Defined as marked deterioration in neurological function with increase in Conn score to Grade ≥2, or in patients with baseline Conn score of 0, an increase in both Conn score and asterixis grade by 1 4
Assess for signs of hepatic decompensation: Ascites, variceal bleeding, coagulopathy 2
Serial ammonia levels if initially elevated, though clinical response is more important than biochemical normalization 2
Important Caveats and Pitfalls
Do not rely on transaminases to exclude liver disease or HE—synthetic function markers (albumin, bilirubin, PT/INR) and clinical assessment are far more relevant 1, 2
Rifaximin has not been studied in patients with MELD scores >25, and only 8.6% of patients in controlled trials had MELD scores over 19—there is increased systemic exposure in patients with more severe hepatic dysfunction 4
Caution in Child-Pugh Class C patients: Only 9% of patients in the pivotal trial were Child-Pugh Class C, and systemic rifaximin exposure increases with severe hepatic impairment 4
Neuroinflammation plays a significant role in advanced liver disease with systemic infection or inflammation—inflammatory cytokines synergize with hyperammonemia to induce neurotoxicity 2
Chronic HE can lead to permanent neurodegeneration with cognitive decline and motor disturbances (especially parkinsonian features and gait disturbances) from recurrent cerebral edema and astrocytic dysfunction 2
Hepatology Referral Criteria
Immediate referral if evidence of acute liver failure (INR >1.5, rapidly rising bilirubin, altered mental status) 3
Urgent referral for patients with recurrent HE episodes despite optimal medical therapy 4
Consider referral for liver transplant evaluation in patients with MELD scores suggesting end-stage disease or refractory HE 2