Diagnosis and Management of Hepatic Encephalopathy: Modeling Real-World Scenarios
Target Audience and Goal Statement
This activity is intended for hospitalists, liver specialists, gastroenterologists, emergency medicine physicians, and primary care physicians.
The goals of this activity are to improve competence in the ability to diagnose and treat early-stage hepatic encephalopathy.
Upon completion of this activity, participants will have greater competence related to
Evaluation and diagnosis of HE
Selection of evidence-based therapies and other management strategies for HE
Secondary prophylaxis of HE as part of a long-term management plan
Disclosures
As an organization accredited by the ACCME, Medscape, LLC, requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines "relevant financial relationships" as financial relationships in any amount, occurring within the past 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest.
Medscape, LLC, encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.
Case 1: Patient History
Carl is a 55-year-old black man who was diagnosed with nonalcoholic steatohepatitis (NASH) and compensated cirrhosis approximately 2 years ago. You have been following him since his diagnosis, and you are seeing him in clinic today for a routine follow-up appointment. He has been clinically stable and works full time as a high school teacher. His initial history from 2 years ago included cigarette smoking (15 pack years). He has received nutritional counseling for a heart-healthy, weight-loss diet. After greeting Carl, you elicit a recent history and perform a physical examination (Table 1). The results of laboratory tests performed today, prior to the appointment, are shown in Table 2.
Table 1. Current History and Physical Examination Findings
History Findings
Medical Metabolic syndrome: insulin resistance, hypertension, hyperlipidemia; chronic low back pain
Current medications Hydrocodone; OTC sleeping pills; lisinopril; simvastatin
Family No additional findings
Social/occupational Single, lives alone
Psychosocial Stopped smoking 8 months ago; drinks "an occasional beer"
Physical ExaminationFindings
Vital signs BP = 136/86 mm Hg; HR = 80 bpm; respiratory rate = 18 RR = 18 breaths/min; T =37.6○C
Body measurements BMI = 32 kg/m2; waist circumference = 41 in
Skin Normal
Head and neck Short and thick
Chest and lungs Normal
Abdomen No stigmata of chronic liver disease; slight RUQ discomfort
Upper and lower extremities Normal
Neurologic examNormal
General impressionObese, in no apparent distress, well groomed and neatly dressed, general behavior normal
BMI = body mass index; BP = blood pressure; HR = heart rate; OTC = over the counter; RR = respiratory rate; RUQ = right upper quadrant; T = oral temperature.
Table 2. Laboratory Tests
CBCResults
Hemoglobin, hematocrit12 g/dL, 45%
RBC count4.5 × 106 cells/µL
WBC count5200 cells/µL
Platelet count138,000 cells/µL
INR1.0
Metabolic PanelResults
BUN, creatinine22 mg/dL, 1.2 mg/dL
eCrCl80 mL/min
Fasting blood glucose HbA1c110 mg/dL 6.2%
AST, ALT GGT ALP75 U/L, 80 U/L 65 U/L 125 U/L
Fasting blood lipidsTG = 160 mg/dL; HDL = 39 mg/dL, HDL = 130 mg/dL
Viral HepatitisResults
HAV HBV< HCVIgG anti-HAV (−) HBsAg (−), anti-HBc (−), anti-HBs (+) anti-HCV (−)
ALT = alanine aminotransferase; ALP = alkaline phosphatase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CBC = complete blood count; eCrCl = estimated creatinine clearance; GGT = gamma glutamyl transferase; HAV = hepatitis A virus; HbA1c = glycated hemoglobin; HBc = hepatitis B core; HBs = hepatitis B surface; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HDL = high density lipoprotein; IgG = immunoglobulin G; INR = international normalized ratio; RBC = red blood cell; TG = triglycerides; WBC = white blood cell.
You ask Carl how he has been feeling in general, and he tells you he is having trouble sleeping at night and he doesn't have the energy he used to. You ask about his job and he says things are fine, other than feeling tired; sometimes he naps during breaks.
All of the questions are important to ask to assess Carl's current health status and health risks. Asking about Carl's sex life is important for at least 2 reasons. First, a sexual history should be taken during a patient's initial visit, during routine preventive exams, and when you see signs of sexually transmitted diseases (STDs).[1] The dialogue provides an opportunity for risk-reduction counseling regarding behaviors that may place your patient at risk of acquiring STDs, including HIV. People aged 55 and older accounted for 26% of all Americans living with diagnosed or undiagnosed HIV infection in 2013.[2]
Second, a study evaluating factors related to quality of life in persons with cirrhosis found that one of the main factors affecting quality of life in men was sex life, which is negatively impacted by cirrhosis[3] due to hypogonadism, erectile dysfunction, and low libido.[4] Both alcohol use and cigarette smoking will exacerbate Carl's liver disease.[5] Patients with minimal hepatic encephalopathy (HE) have impaired driving skills.[6] When asked about his driving, Carl said that he recently got a traffic ticket for a "minor fender bender."
Discussion
There are multiple clues as to potential explanations for the changes in Carl's history since you last saw him. He admits to drinking an occasional beer, which is a vague description of alcohol use and should be investigated. He is taking opiates that were prescribed, and he is now taking sleeping pills that were not prescribed. He now reports sleep disturbance, and he has the physical characteristics common in people with sleep apnea. He has a history of compensated cirrhosis, but his clinical picture is beginning to change. He may have HE.
Even though Carl denied alcohol use in earlier questioning, problem drinking should be ruled out using a reliable and valid method. The CAGE questionnaire (Table 3) is a useful and practical screening tool for identifying individuals who drink excessively.[7] It takes <1 minute to administer. It also requires no specialized training and can be done at the point of care by any healthcare provider.
Table 3. CAGE Questionnaire[8]
QuestionsCarl's Responses
Have you ever felt you needed to Cut down on your drinking?No
Have people Annoyed you by criticizing your drinking?No
Have you ever felt Guilty about drinking?No
Have you ever felt you needed a drink first thing in the morning (Eye-opener) to steady your nerves or to get rid of a hangover?No
Patients with cirrhosis report significantly more sleep disturbances than healthy individuals; common complaints are prolonged time to fall asleep, shortened sleep duration, daytime sleepiness, poor sleep quality, and frequent nocturnal awakenings.[9] Obstructive sleep apnea (OSA) is common in patients with liver cirrhosis.[10] The prevalence of cirrhosis in patients with OSA is more than 4 times greater than in the general population.[10] In a cross-sectional, prospective study, Bajaj et al studied the effects of OSA on cognition, sleep parameters, and driving in patients with cirrhosis.[11] They found that daytime sleepiness and sleep quality were worse in patients with OSA (with or without cirrhosis) than in patients with cirrhosis alone or controls. Psychomotor speed and attention issues are likely related to the cirrhosis in patients with cirrhosis and OSA, whereas executive function and simulator driving performance are affected by the OSA. People with OSA typically are overweight and have a short, thick neck; they complain of fatigue, sleepiness, and dozing off during sedentary activities, including while driving.[12] In Carl's case, his noticeably short, thick neck; body mass index and waist circumference; and complaint of sleep disturbance are indications for further evaluation. OSA should be considered in evaluating sleep impairment in patients with cirrhosis, and objective testing for sleep apnea can help confirm or exclude the diagnosis.
Carl is manifesting changes -- sleep disturbance, fatigue, and a traffic incident -- since his last visit 6 months ago that might not be apparent to a healthcare provider who does not know Carl over time. These changes could indicate worsening underlying disease or the presence of precipitating factors in someone with cirrhosis, and both potential factors should be investigated. Screening for cognitive impairment (but not mental status) can be done using the MMSE is a 30-point questionnaire.[13] It takes 5 to 10 minutes to administer and requires no specialized training, so it can be done at the point of care by any healthcare provider. It assesses registration (repeating named prompts), attention and calculation, recall, language, ability to follow simple commands, and orientation. A score ≥24 points indicates normal cognition. Carl's serum ammonia level is 47 μg/dL. The serum ammonia level can play a role in the pathogenesis of HE, but it does not necessarily correlate with the severity of encephalopathy, and does not add any specificity to the diagnosis of patients with HE.[14] Brain imaging tests in the absence of focal deficits, seizures, new changes in mental status or recent trauma, drug/alcohol use, or stroke are not useful.
The nurse practitioner in your clinic administers the MMSE and the CAGE questionnaire to Carl. His MMSE score is 29, indicating normal cognition, and his CAGE questionnaire responses are shown in Table 3, indicating that he does not have problem drinking and no further evaluation for alcohol use is necessary. You suspect Carl has some form of HE.
HE has historically been classified according to underlying cause (type A = associated with acute liver failure; type B = associated with portosystemic bypass without underlying intrinsic hepatocellular disease; type C = associated with cirrhosis and portal hypertension or portosystemic shunts), severity of manifestations, time course, and presence of precipitating factors.[15] Grading has traditionally been done using the West Haven Criteria (Table 4); grade I representing mild overt HE, and grades 2 through 4 representing more obvious symptomatic overt HE.[16]
Table 4. West Haven Criteria for Grading Hepatic Encephalopathy
Grade Features
0 No abnormalities
1 Minimal lack of awareness, shortened attention span, impairment of calculation ability, altered sleep pattern
2 Disorientation (usually to time), lethargy, inappropriate behavior, personality changes
3 Gross disorientation (time and place), marked confusion, somnolent but responsive to stimuli, incomprehensible speech
4 Coma, unresponsive to verbal or physical stimulation
Recently, the nomenclature of HE were updated to include 4 axes for describing episodes of HE (Figure).[17]
Figure. Four axes to define an episode of HE. Bajaj JS, et al., Introduction and setting the scene: New nomenclature of hepatic encephalopathy and American Association for the Study of Liver Diseases/European Association for the Study of the Liver Guidelines. Clinical Liver Disease. Clin Liver Dis. 2017; 9:48-51. John Wiley and Sons. © 2017 by the American Association for the Study of Liver Diseases.
Covert HE occurs in up to 84% of patients with cirrhosis.[18-21] Covert HE is defined as the presence of test-dependent or clinical signs of brain dysfunction in patients with chronic liver disease who are not disoriented or do not display asterixis.[22]Given the difficulty in diagnosing grade 1 HE consistently and without the input of caregivers, minimal and grade 1 have been combined to be called covert HE. In patients with covert HE, the clinical signs and symptoms seen in patients with overt HE are absent; however, patients with covert HE have neuropsychological findings that can be detected with psychometric or neuropsychological testing: impaired concentration, reduced attention span, delayed reaction time,[23] and decreased ability to perform simple mental tasks.
In addition, patients with covert HE may have personality changes, impaired fine motor skills,[18] a greater likelihood of falling,[24] and poor driving habits that result in traffic tickets or auto accidents.[25] The sleep disturbance day-night reversal may also occur.[26] Notably, asterixis and disorientation to time, place, and person are not present. Because of the absence of clinical signs, covert HE is often unrecognized or diagnosed. Covert HE is associated with decreased ability to performs daily functions, decreased quality of life, increased risk for overt HE, increased risk of hospitalization, and decreased survival.
Patients with cirrhosis and HE are generally optimistic about their driving abilities. A study by Kircheis et al. showed that 100% of patients with mild overt HE and 96% of those with covert HE were considered themselves to be good or very good drivers, compared with 92% of control subjects without HE.[27] However, there is no question that the driving ability of patients with HE, including covert HE, is impaired.[6,25,28,29] A diagnosis of covert HE does not automatically mean that the patient is a dangerous driver[28]; in addition, medical providers are not trained to formally evaluate fitness to drive and are not legal representatives.
So what should providers do when they have patients with HE who are driving? They should act in the best interests of both the patient and society, while following the applicable local laws,[28] but they should not evade the responsibility of counseling patients with diagnosed HE on the possible dangerous consequences of their driving.[30] In some cases, the safest advice may be for the patient to stop driving until a responsible driving authority has formally evaluated and cleared the patient for safe driving.[30] In difficult cases, providers should consult with the authorities who have the expertise to test driving ability and the authority to revoke the driving license.
Carl should be referred to a psychologist for neurophysiological and psychometric testing (Table 5).[22] Because HE affects several components of cognitive functioning, which may not be impaired to the same degree, the use of at least 2 tests, depending on the local population norms and availability, and preferably with 1 of the tests being more widely accepted so as to serve as a comparator, is recommended.[22] The tests used vary depending on the logistics, availability of tests, local norms, and cost. Testing should be done by a trained examiner adhering to scripts that accompany the testing tools. If the test result is normal (ie, negative for covert HE), testing should be repeated in 6 months. It is reasonable to discontinue Carl's pain and sleep medicines or start him on a trial of lactulose and evaluate him in 8 weeks for improvement in his cognitive function.
Table 5. Established Neurophysiological and Psychometric Testing Strategies[22]
Portosystemic encephalopathy syndrome test Critical Flicker Frequency test Continuous Reaction Time test Inhibitory Control test Stroop test SCAN test Electroencephalography
Conclusion
The EncephalApp Stroop test is used at the center where Carl is being managed to diagnose minimal HE. EncephalApp is a series of applications designed to evaluate patients with liver disease; the first of which is a Stroop task, demonstration of interference in the reaction time of a task.[31] The EncephalApp Stroop is a test of mental speed and flexibility (US-based norms), which have been found in selected patients at 2 study centers to be predictive of minimal HE.[32,33] The variable OffTime+OnTime has been shown to be the best discriminator between patients with and without minimal HE. Carl's OffTime+OnTime was >40 seconds over what would be expected for someone of his age, gender, and educational status. Given that he has no other reasons for this impairment, he was diagnosed with covert HE.
Covert HE can be reversed with short-term treatment, which improves functional performance and quality of life, and decreases road traffic accidents and episodes of overt HE.Carl was given a trial of lactulose 20 g twice daily for 8 weeks. After 8 weeks, he reported having some diarrhea and missing some doses, but he felt subjectively better and he had a significant improvement in his EncephalApp test results. However, he remains at higher risk for developing overt HE (grades 2-4) than patients without covert HE, so he was asked to identify a caregiver. He and the caregiver were counseled about the signs and symptoms of overt HE. Detailed written information on what to expect and who to call if he has any of the signs or symptoms was also given to them. There is no legal restriction against driving for patients with covert HE, but it was recommended that Carl not drive for long distances, avoid driving when fatigued and at night, and use a geographic positioning system when driving because patients with covert HE make navigation errors and become fatigued easily.[6]
Case 2: Patient History
Lena is a 48-year-old woman who was referred to you by her primary care physician 18 months ago. Lena was diagnosed with alcoholic cirrhosis after drinking a half pint of vodka daily for 8 years. You have been following her since his diagnosis. Lena is being seen in clinic today accompanied by her daughter, who says her mother "is not herself; she sits in her chair a lot and stares into space".
When Lena's Child-Pugh score (Table 6) increased from baseline at 12 months, she was placed on the waiting list for a liver transplant. An esophagogastroduodenoscopy (EGD) 6 months ago showed small esophageal varices and hepatic vein catheterization showed the hepatic venous pressure gradient (HVPG) was 4 mm Hg.
Seven weeks ago, Lena was also treated for a first episode of overt HE with lactulose syrup 25 mL titrated to produce 2 to 3 semi-loose bowel movements per day for 8 weeks. Lena's history and physical examination findings are in Table 7, and the results of laboratory tests performed earlier today are shown in Table 8.
Table 6. Child-Pugh Score[34]
Time HE, Ascites Total Bilirubin Serum PT Total Score CP Predicted
Grade (mg/dL) Albumin (s prolonged) (points) Class 1-y/2-y (g/dL) Survival (%)
Baseline No No 1.6 3.5 3.5 6 A 100/85
12 mo Grade I Mild 1.8 3.4 3.7 8 B 81/57
CP = Child-Pugh; HE = hepatic encephalopathy; PT = prothrombin time.
Table 7. History and Physical Examination Findings
HistoryFindings
Medical: Episode of grade 1 HE precipitated by a symptomatic, uncomplicated UTI 6 months ago; UTI was treated with fosfomycin, and HE was treated with lactulose
Current medications: Lactulose 20 g twice daily
Family: Divorced, lives alone
Social/occupational: Unemployed
Psychosocial: Stopped drinking, has been sober for approximately 12 months
Physical ExaminationCurrent Findings
Vital signs BP = 102/66 mm Hg; HR = 102/min; RR = 16/min; T = 37.7°C
BMI 25.0 kg/m2
Skin Terry nails (large white proximal nail bed), decreased skin turgor
Head and neck Normal
Chest and lungs Few spider angiomata
Abdomen Few spider angiomata, mild ascites, firm liver edge with nodular contour
GI system Abdominal cramping, 4 to 5 loose bowel movements per day
GU system Amenorrhea
Extremities Upper: palmar erythema, digital clubbing
Lower: muscle wasting
Neurologic exam Lethargy, confusion (disoriented to time), slurred speech, asterixis, positive Babinski sign
General impressionAnorexia
BMI = body mass index; BP = blood pressure; GI = gastrointestinal; GU = genitorurinary; HE = hepatic encephalopathy; HR = heart rate; RR = respiratory rate; T = oral temperature; UTI = urinary tract infection.
Table 8. Laboratory Tests
CBC Results
Hemoglobin, hematocrit10 g/dL, 38%
RBC count4.5 × 106 cells/µL
WBC count4,500 cells/µL
Platelet count125,000 cells/µL
PT INR3.7 s 1.3
Metabolic PanelResults
Creatinine 1.1 mg/dL Sodium 150 mEq/L
CrCl80 mL/min
Fasting blood glucose 110 mg/dL
AST, ALT ratio >2 GGT 65 U/L Total bilirubin 1.8 mg/dL Albumin 3.4 mg/dL UrinalysisResults
Color, clarity Dark, clear pH 6.5 Specific gravity 1.040 Glucose Negative Blood Negative Ketones Negative Protein Negative Urobilinogen Negative Bilirubin Negative Nitrite Negative WBCs 1/HPF RBCs None Bacteria None Yeast None Blood None
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CBC = complete blood count; eCrCl = estimated creatinine clearance; GGT = gamma glutamyl transferase; HPF = high-power field; INR = international normalized ratio; PT = prothrombin time; RBC = red blood cell; WBC = white blood cell.
You ask Lena how she is feeling today. After looking at her daughter and then you, she hesitates for about 10 seconds and says to you in a monotonous tone, "I need to water the flowers". You ask Lena if she knows where she is, and she says "the clinic, but I don't know why I'm here on Sunday" (it is Wednesday). You explain to Lena's daughter that her mother's altered mental status is due to HE.
According to the American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of the Liver (EASL) practice guideline, Lena's HE is considered overt, type C (resulting from cirrhosis), grade 2 (per the West Haven criteria), and recurrent (more than 1 episode of HE within 6 months or less).
Discussion
The clinical manifestations of types B and C overt HE are similar, but since Lena's varices are small and there are no red wale markings, it is unlikely that her HE is predominantly the result of portosystemic shunting. It is more likely that her HE is due to cirrhosis. There is not enough information to determine whether her HE is spontaneous or precipitated.
You explain to Lena's daughter that her mother's HE is called "type b, grade 2." Her daughter asks why it is happening now, and you tell her that you need to do some additional tests to determine if it is due to worsening liver function or whether it was precipitated by something physiologic.
Controlling precipitating factors in the management in patients with overt HE is very important because nearly 90% of patients can be treated with correction of the precipitating factor alone.[22]
Precipitating factors can be identified in nearly all bouts of episodic, overt, type C HE and should be actively investigated and treated. The most common precipitating factors, in order of decreasing frequency are[22]:
Electrolyte imbalance
Infection
Unidentified
Constipation
Diuretic overdose
GI bleeding
Although many patients are unable to tolerate lactulose, Lena's clinical picture indicates she has been adherent. Her laboratory test results show hypernatremia, one of the main side effects of lactulose (as a result of diarrhea), which can lead to deterioration in mental status. Signs of hypernatremia present in Lena include confusion, lethargy, dehydration, generalized weakness, dry skin turgor, and tachycardia. Lena has no obvious signs of GI bleeding, and her last HVPG was 5 mm Hg, but GI bleeding cannot be ruled out at this time.
Lena should be admitted to the hospital for further evaluation and treatment. Although oral BCSSs or intravenous L-ornithine L-aspartate can be used as an alternative or additional agent in patients who are nonresponsive to lactulose, and neomycin is an alternative choice for treatment, the definitive cause of Lena's recurrent HE, including unresponsiveness to lactulose, is unclear.
An episode of overt HE (whether spontaneous or precipitated) should be actively treated using a 4-pronged approach[22]:
Initiation of care for patients with altered mental status or altered consciousness
Identification and treatment of alternative causes of altered mental status
Identification and correction of of precipitating factors, and
Empiric treatment of HE
Although several signs point to diarrhea-induced hypernatremia as the cause of Lena's altered HE, and eliminating the probable cause (lactulose) would likely lead to improvement, Lena should be fully evaluated for all potential causes, and a plan of care that addresses her short-term problems as well as her long-term problems should be developed.
Lena is admitted to the hospital. She is hydrated with intravenous fluid (D5W) and receives hyperalimentation. Her serum sodium is corrected to 141 mEq/L, and her mental status improves. Her evaluation includes blood cultures, chest x-ray, paracentesis, and repeat EGD. There is no evidence of infection or GI bleeding, and her varices have not increased in size.
The standard of care is to indefinitely continue the treatment that successfully reversed a bout of overt HE, knowing that the risk of recurrence appears to worsen as liver function deteriorates. However, if a recurrent precipitating factor can be controlled, then recurrence of HE may no longer be a risk and therapy can be discontinued. Because this is Lena's second episode of overt HE, secondary prophylaxis with lactulose and rifaximin is recommended.[22]
Approximately 75% of patients with HE suffer from moderate-to-severe protein-calorie malnutrition with loss of muscle mass and energy depots.[22] Contrary to common belief, chronic protein restriction is detrimental to patients with HE because their protein requirements are actually greater than those of healthy patients, and they are at risk of accelerated fasting metabolism. Loss of muscle mass is a risk factor for development of HE and other complications of cirrhosis; thus, low-protein nutrition should be avoided in patients with HE.
The majority of HE patients require nutritional therapy. Substitution of milk-based or vegetable protein or supplementing with BCAAs is preferable to reduction of total protein intake. Oral BCAA-enriched nutritional supplements may be used to achieve and maintain the recommended nitrogen intake in patients who are intolerant of dietary protein.[35] Small frequent meals throughout the waking hours and a late-evening snack of 50 g of complex carbohydrate should be encouraged in all patients with HE.[35] Fiber-enriched diets, including diets made up of predominantly vegetable protein, may benefit patients with cirrhosis and HE. Ingestion of a diet containing 25 g to 45 g of fiber daily is recommended,[35] but care should be taken not to avoid diarrhea in patients who are already taking lactulose. A multivitamin may be recommended, although there are no firm data on the benefits of vitamin and mineral supplementation. Specific micronutrient replacement, such as zinc supplementation, may be considered.
Case2: Conclusion
HE is a complex complication of a complex disease, and treatment involves a multidisciplinary approach while the patient is hospitalized and while they are in the community. Appropriate planning for transition from inpatient care to outpatient care may depend on collaboration among healthcare providers from multiple disciplines (ie, medicine, pharmacy, nursing, social work, nutrition and dietetics, sleep medicine, psychology) and multiple specialties (ie, hepatology, gastroenterology, neurology, nephrology, endocrinology, infectious diseases, psychiatry, primary care), depending on the severity of disease and comorbidities (liver-related and non-liver-related).[36,37]
Central to the transition of care is patient adherence to the maintenance medication regimen for secondary prophylaxis of HE. Secondary prophylaxis for HE with lactulose and rifaximin is prescribed for Lena; discharge education for Lena and her caregiver includes:
The dosage of lactulose
What to do if she has fewer than 3 bowel movements in any day
What to do if she has difficulty sleeping at night, excessive drowsiness during the day, or confusion
What to do if she has more than 4 bowel movements in any 24-hour period and no symptoms
A diet to achieve a daily energy intake of 35 kcal/kg to 40 kcal/kg ideal body weight and a daily protein intake of 1.2 to 1.5 g/kg/d is prescribed for Lena. Follow-up appointments with you and the nutritionist are scheduled.
