REVIEW ARTICLE

Complications of Cirrhosis in
Primary Care: Recognition and
Management of Hepatic
Encephalopathy
D1X XSteven L. Flamm, D2X XMD

Northwestern University Feinberg School of Medicine, Chicago, Illinois

ABSTRACT
Approximately 3.7% of patients in primary care settings have chronic liver disease, and 18% with chronic liver disease in the
specialty care setting have cirrhosis. For cirrhotic patients without complications, prognosis is generally favorable; increased
morbidity and mortality are observed when complications (i.e., hepatic encephalopathy [HE]) occur. HE occurs in up to 70%
of patients with cirrhosis. Neurologic signs in HE span a wide spectrum, from those not easily apparent (covert) to more clini-
cally obvious signs (overt). Providers should consider overt HE in patients with cirrhosis and signs of impaired cognition, con-
fusion, consciousness and/or personality changes, and/or impaired memory. Overt HE treatment includes identifying and
treating precipitating factors and reducing bacterial-derived toxin loads. For acute overt HE, lactulose is first-line treatment. To
prevent HE recurrence, lactulose plus rifaximin is recommended. Patients with cirrhosis and HE often present in primary care;
recognizing and properly managing HE are important in this setting.
Key Indexing Terms: Chronic liver disease; Complication; Hepatic encephalopathy, Rifaximin; Rifaximin; Lactulose. [Am J
Med Sci 2018;356(3):296 303.]

INTRODUCTION cognitive functioning, followed by a discussion of the

O
ver time, chronic hepatic injury, coupled with
environmental and/or genetic factors, can lead
to fibrosis.1 Without removal or treating the
source of liver damage, irreversible changes may occur
in hepatic architecture, causing impaired regeneration of
hepatocytes and loss of hepatic function (i.e., cirrhosis).
The natural history of cirrhosis includes a long phase
(i.e., compensated cirrhosis) without complications, and
a shorter phase (i.e., decompensated cirrhosis) with
complications (variceal bleeding, ascites, hepatic
encephalopathy [HE], jaundice, and bacterial infection);2-
5
complications may occur in no particular order.6 Prog-
nosis worsens when patients enter the decompensated
phase (median survival time, compensated vs. decom-
pensated phase, >12 years vs. »2 years, respec-
tively),4,7 the risk of which is increased in some patient
populations (e.g., patients with diabetes).8
Given that patients with cirrhosis may present in the
primary care setting, and that the diagnosis of cirrhosis
may be missed or delayed, potentially compromising
patient care, this article provides primary care physicians
with an overview of the burden, diagnosis of cirrhosis,
and clinical details of complications of cirrhosis (e.g., HE)
that may be overlooked in primary care settings. This
overview of cirrhosis is coupled with findings from a sys-
tematic literature review on HE and its impact on
diagnosis and management of HE, one complication of
cirrhosis that primary care providers are likely to encoun-
ter in their practices.
MATERIAL CONTENT
A PubMed search of English-language articles through
August 11, 2017 was conducted using the keywords “liver
cirrhosis,” “liver fibrosis,” “hepatic encephalopathy,”
“diagnosis,” “complications,” “burden of disease,” “epide-
miology,” “cognitive function,” and “management.” The
author identified additional publications for inclusion in
this review via article reference lists. Data from the Agency
for Healthcare Research and Quality’s Healthcare Cost
and Utilization Project were used to determine annual
hospitalizations for patients with HE, coded according to
the International Classification of Disease, Ninth Revision,
Clinical Modification code for HE (ICD-9-CM 572.2).9
CIRRHOSIS
Epidemiology and Burden of Cirrhosis
The current overall U.S. prevalence of chronic liver
disease (CLD) and cirrhosis is unclear; reported esti-
mates vary depending on the etiologic factors identified
(Table 1).10-22 CLD and cirrhosis are associated with sub-
stantial mortality; in 2015, these conditions were the 10th

296 THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

VOLUME 356 NUMBER 3 SEPTEMBER 2018

leading cause of mortality in males and 7th leading cause
of mortality in the Hispanic and Latino population in the
United States,23 although the number of deaths related
to CLD and cirrhosis may be underestimated.24 Between
2006 and 2011, an estimated 3.1 million U.S. emergency
department visits were attributed to underlying cirrho-
sis.25 In 2010, it was estimated that 101,000 U.S. hospi-
talizations (primary diagnosis) were attributed to CLD
and cirrhosis.26 A study of U.S. gastroenterology practi-
ces published in 2008 identified that 18% of patients
with newly diagnosed CLD had cirrhosis.27 Furthermore,
patients reported that the diagnosis of CLD was consid-
ered during a routine physical exam (35%), during con-
sultation for another medical problem (30%), or as a
result of symptoms (16%).27 Thus, primary care physi-
cians can play an important role in the recognition, diag-
nosis, and management of cirrhosis.
Beyond medical concerns, cirrhosis touches nearly
every aspect of affected individuals’ lives. These patients
experience worsening economic status and negative
effects on employment.28 Patient care may be negatively
impacted by the burden of cirrhosis-related medical
expenses (e.g., medical insurance coverage loss, missed
appointments),28 which often have a wide-ranging effect
on the well-being and daily life of the patient’s family (e.
g., incurrence of debt).28 Low health-related quality of life
(HRQOL) was reported by approximately 20% of patients
with cirrhosis, including those with compensated
cirrhosis.29
Subtle Signs of Cirrhosis
On physical examination, patients with cirrhosis may
present with spider nevi on the trunk, face, and arms,
prominent venous pattern on the abdomen, splenomeg-
aly, a large, firm liver with a prominent left lobe, palmar
erythema, increased abdominal girth, changes in menta-
tion, and asterixis (symmetrical hand flapping
tremor).10,30,31 Laboratory blood tests may show liver
TABLE 1. Causes and incidence of cirrhosis.10-22,77
Cause of cirrhosis Example(s)
Alcoholic liver disease Alcoholic hepatitis
Autoimmune hepatitis ‒ 10 patients per 50,000-100,000 individuals
Cholestatic liver disease Primary sclerosing cholangitis
Primary biliary cholangitis
Inherited metabolic disorders Wilson disease
a-1-Antitrypsin deficiency
Hemochromatosis
Nonalcoholic fatty liver disease ‒ 29-113 million
Nonalcoholic steatohepatitis ‒ 3.2-9.7 million
Vascular disease Budd Chiari syndrome
Viral infections HBV
HCV
Abbreviations: HBV, hepatitis B virus; HCV, hepatitis C virus; N/A, not available.
*Data for most common mutation in Caucasians in the United States (homozygous for HFE C282Y mutation).
Copyright © 2018 The Authors. Published by Elsevier Inc. on behalf of Southern Society for Clinical Investigation. This is an open access article
under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/)
www.amjmedsci.com  www.ssciweb.org
Cirrhosis in Primary Care
panel abnormalities (serum aminotransferases, alkaline
phosphatase, total bilirubin), and prothrombin time,30 but
many patients with cirrhosis have completely normal liver
panels, particularly patients with advanced liver disease
from nonalcoholic fatty liver disease, past alcohol use,
and hemochromatosis. Thrombocytopenia, mostly
resulting from splenic sequestration, is commonly
observed in patients with cirrhosis.32 Decreased platelet
production related to reductions in thrombopoietin pro-
duction or platelet production in bone marrow (e.g., alco-
hol use-related), and increased destruction of platelets
(e.g., patients with hepatitis C virus [HCV]) also cause
thrombocytopenia.32 A cirrhosis diagnosis should be
considered in patients with thrombocytopenia. Obtaining
a careful medical history regarding past alcohol use and
assessing risk factors for fatty liver (e.g., diabetes, obe-
sity) may further support a cirrhosis diagnosis. Abdomi-
nal imaging to evaluate for an enlarged liver or spleen
may support a diagnosis of cirrhosis in patients with
thrombocytopenia. Common signs of cirrhosis by imag-
ing include liver fibrosis, a nodular, irregular liver surface,
and evidence of varices and portal hypertension.31
Cirrhosis Complications
Potential cirrhosis-related complications are summa-
rized in Table 2.10,33-43 Some complications of cirrhosis
may be overlooked in primary care because many
patients with compensated cirrhosis are asymptom-
atic.33,34 Mild changes in mentation, without obvious
clinical signs, that represent early (covert) HE may also
be missed in primary care. Because HE is a complication
of cirrhosis that primary care providers are most likely to
manage in an outpatient clinical setting, this review
focuses on the diagnosis and management of patients
with HE. Further, an expert panel of European gastroen-
terologists and hepatologists recommended in 2016 that
primary care providers be able to recognize signs of HE
Estimated number affected
16.6 million U.S. adults with alcohol use disorder
Up to 40.2 per 100,000 individuals
Wilson disease: 3 per 100,000
a-1-Antitrypsin deficiency: 20 per 60,000-100,000 patients
Hemochromatosis*: 300 per 100,000
N/A
HBV: »2.2 million
HCV: >2.5 million (200,000 unaware of infection)
297
Flamm
TABLE 2. Complications of cirrhosis.10,33-43
Complication Clinical notes
Ascites Most common complication of
cirrhosis
Paracentesis required for diagnosis of
ascites
Bacterial infection excluded with
negative culture and PMN leuko-
cyte count <250 cells/mm3
Hepatic Spectrum of neurologic impairment,
encephalopathy ranging from minimal signs that are
not clinically apparent to coma in
the most severely affected patients
Hepatic Most patients are asymptomatic
hydrothorax Symptoms include dyspnea, cough,
hypoxemia, or respiratory failure
Hepatocellular Evaluation of patients with cirrhosis
carcinoma for HCC by ultrasonography every
6 months
Patients with abnormal findings
by ultrasonography should be
referred to a specialist for further
evaluation
Hepatopulmonary Most patients are asymptomatic
syndrome Symptoms include dyspnea, platyp-
nea-orthodeoxia syndrome, and
oxygen desaturation while sleeping
Hepatorenal May cause acute kidney injury
syndrome No specific diagnostic criteria; diag-
nosis of exclusion in patients with
cirrhosis
Signs include glomerular filtration rate
< 40 mL/min, serum creatinine >
1.5 mg/dL, sodium excretion < 10
mmol/L, hyponatremia (<130
mmol/L), decreased diuresis (<500
mL), and greater urine vs. plasma
osmolality
Spontaneous bacterial Common in patients with cirrhosis
peritonitis Symptoms include fever, abdominal
pain, and worsening ascites in
patients with existing ascites
Paracentesis is recommended for
diagnosis of SBP
Positive culture and PMN leukocyte
count  250 cells/mm3
Varices and/or variceal EGD is recommended to diagnose
bleeding varices
EGD should be performed when
patient receives diagnosis of
cirrhosis
Patients with compensated cirrho-
sis and no varices: repeat EGD in 2-
3 years
Patients with small varices: repeat
EGD in 1-2 years
Patients with decompensated cir-
rhosis: repeat EGD annually
Abbreviations: EGD, esophagogastroduodenoscopy; HCC, hepatocellular
carcinoma; PMN, polymorphonuclear; SBP, spontaneous bacterial
peritonitis.
298
in patients with cirrhosis, to minimize potential delays in
patient care.44
HEPATIC ENCEPHALOPATHY
HE is a common neurologic complication of cirrhosis
estimated to occur in 30-70% of patients with cirrho-
sis.45,46 The spectrum of HE includes covert (minimal)
HE, characterized by neurologic impairment that is not
clinically apparent, and symptomatic (overt) HE, which
may result in coma in the most severely affected
patients.40-42 Patients with cirrhosis may have episodic
HE, recurrent HE (i.e., HE episodes that occur within
6 months), and persistent HE (i.e., behavioral altera-
tions always present with recurrent overt HE epi-
sodes).41 Patients with stage 1 HE may have subtle
symptoms that a patient with cirrhosis may report,
such as increased fatigue, sleep-wake reversal (insom-
nia), poor short-term memory, and diminished concen-
tration. An expert consensus panel recommended that
HE be considered in patients with cirrhosis with cogni-
tive impairment.44
Burden of HE
The economic burden of HE on the U.S. healthcare
system is expected to increase,47 particularly since the
number of HE-related hospitalizations increased annually
in most years between 1993 and 2014, excepting 1994
and 2008; hospitalizations increased annually between
2008 and 2009 but remained below 2007 levels until
2010, when the number of hospitalizations exceeded the
number reported for 2007 (Figure 1).9 Patients with cir-
rhosis who present to the emergency department are at
a significantly increased risk of hospital admission if they
have HE (P < 0.01).25 Further, HE negatively affects
patient HRQOL and caregiver burden. The percentage of
patients with cirrhosis and HCV reporting symptoms of
depression increased with the severity of HE symptoms
in one study (no HE, 50%; covert HE, 67%; overt HE,
100%).48 Caregivers reported feeling “tied down” to
patients with HE, as they assumed responsibility for daily
household activities and patient care.49
Diagnosis and Classification of HE
Patients with covert (minimal) HE, who lack obvious
clinical signs (e.g., disorientation and asterixis) that help
define overt HE, may still have impairments in quality of
life, driving ability, and sleep habits.41,42,50-52 Patients
with covert HE may have mild neurologic or psychiatric
impairment as determined by psychometric and neuro-
physiological test results.41,42,44 However, only providers
trained to administer these tests should do so,41,44 and
then, only to individuals without neurologic or psychiatric
conditions, and nonusers of alcohol or psychoactive
agents.41 Further, at least 2 different tests should be
administered to patients, given the heterogeneity in cog-
nitive impairment in patients with covert HE and the
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
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 Cirrhosis in Primary Care

60,000
Hepatic Encephalopathy-related

covert HE, hepatologists should be responsible for diag-

nosis and management of these patients.44
Hospital Discharges (n)

50,000
Establishing a diagnosis of overt HE in patients with
40,000 cirrhosis includes identifying the precipitating factors for
HE 41,44 and excluding other conditions that can cause
30,000 neuropsychological abnormalities (Figure 2).41 It is not
uncommon for patients with overt HE to be misdiag-
20,000
nosed (e.g., stroke), thus exclusion of other causes for
10,000
neurologic impairment is critical.41 Patients with overt HE
are also known to present with asterixis59 and other
0 motor impairments (e.g., rigidity, tremors, ataxia, hyper-
tonia).45 However, these signs are not unique to patients
19 3
19 4
19 5
19 6
19 7
19 8
20 9
20 0
20 1
20 2
20 3
20 4
20 5
20 6
20 7
20 8
20 9
20 0
20 1
20 2
20 3
14
9
9
9
9
9
9
9
0
0
0
0
0
0
0
0
0
0
1
1
1
1
19

Year
FIGURE 1. Annual hospital discharges related to diagnosis of
hepatic encephalopathy in the United States. Primary and secondary
discharges related to a diagnosis of hepatic encephalopathy were
determined using the International Classification of Disease, Ninth
Revision, Clinical Modification discharge diagnosis code 572.2.
Source: Data from Agency for Healthcare Research and Quality.
Healthcare Cost and Utilization Project databases; https://www.hcup-
us.ahrq.gov/databases.jsp.9
differing sensitivities of independent tests used to detect
these neurologic abnormalities.41,42,53 Neuroimaging
studies have shown that patients with covert HE have
alterations in brain anatomy and functional brain net-
works (i.e., impaired communication between neural
regions) compared with healthy individuals or patients
without HE; low-grade cerebral edema has also been
observed in patients with covert HE.54-56 Patients with
covert HE should be monitored for progression to overt
HE,45 but it is worth noting that an individual patient’s
baseline health status (e.g., cognitive reserve, comorbid-
ities) may impact disease progression.57,58 Further, given
the level of expertise needed to establish a diagnosis of
with overt HE and there may be other issues (e.g. cere-
brovascular event, alcohol or prescription drug use) that
should be ruled out before establishing a diagnosis of
overt HE.41,45
The West Haven grading criteria, although subjective,
are commonly used to assess the cognitive status of
patients with cirrhosis (Table 3).41,42,60,61 In 2016, grad-
ing criteria were published that incorporated the West
Haven criteria with a caregiver-reported electronic diary
(i.e., HE Grading Instrument; Figure 3),60 an instrument
healthcare providers may find beneficial for screening
patients with overt HE and facilitating communication
with caregivers. Patients with overt HE may have obvious
changes in mental status, ranging in severity from dis-
orientation to coma.42,60 Features of overt HE include
impaired cognition, confusion, changes in conscious-
ness, personality changes, and impaired memory.60 For
some patients, cognitive impairment may limit daily func-
tion.42 Patients diagnosed with HE, a decompensation
event, should always be referred to a healthcare provider
who specializes in managing patients with CLD.44
Precipitating factors of overt HE can include dehy-
dration, upper gastrointestinal bleeding, infection,

Are there any precipitating factors

for the patient’s HE symptoms?

• Gastrointestinal bleeding Treat precipitating

• Infection Yes
factor(s)
• Constipation
• Electrolyte imbalance
• Diuretic overdose
Consider Refer patient
No
diagnosis of HE to a specialist

Does the patient have other medical

reasons for his/her altered mental status?
No
• Diabetes (e.g., hypoglycemia)
• Alcohol use (e.g., intoxication)
• Medication use (e.g., opioids)
• Electrolyte imbalance (e.g., hyponatremia)
• Infection
• Nonconvulsive epilepsy
• Psychiatric disorder
• Intracranial bleeding and stroke
• Dementia
• Brain lesions Treat condition
• Obstructive sleep apnea Yes
accordingly
• Severe medical stress (e.g., organ failure)

FIGURE 2. Diagnostic algorithm for overt hepatic encephalopathy (HE) in patients with cirrhosis. Source: Data from Vilstrup et al. Hepatology
2014; 60:715-735.41

Copyright © 2018 The Authors. Published by Elsevier Inc. on behalf of Southern Society for Clinical Investigation. This is an open access article 299
under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/)
www.amjmedsci.com  www.ssciweb.org
Flamm
TABLE 3. West Haven criteria.
Covert hepatic encephalopathy
Grade 0 Grade 1
No abnormalities Trivial lack of
present awareness
Euphoria or anxiety
Shortened attention
span
Impairment of addition
or subtraction
Source: Table created with data from Bajaj et al. Aliment Pharmacol Ther 2011; 33:739-747 ; and Conn et al. Gastroenterology 1977;72: 573-583.
constipation, electrolyte imbalances, and overdiure-
sis.41,45,62 Multiple factors may precipitate an episode of
overt HE 62. In patients with cirrhosis, the accumulation
of toxins (e.g. ammonia) in the brain is thought to lead to
the development of HE.63
Ammonia is produced by bacterial metabolism of
amino acids in the gastrointestinal tract and is further
metabolized in the liver,64 a process that is impaired in
patients with cirrhosis. However, evaluation of serum
ammonia concentrations is not considered clinically use-
ful, and is strongly discouraged, as concentrations are
not universally predictive of HE.63
Management of HE
Treatment of Patients With Overt HE
The initial goals of treatment for patients with overt
HE include treating the precipitating factor(s) and improv-
ing mental status.45 For patients experiencing an acute
episode of overt HE, the non-absorbable disaccharide
lactulose is commonly used as first-line therapy.41,45
Indeed, a meta-analysis of 22 clinical studies (N = 1,415)
showed that lactulose improved HE compared with pla-
cebo or no treatment (relative risk, 0.6; 95% confidence
interval, 0.5-0.7).65 Lactulose is often administered as an
oral syrup that patients self-titrate to achieve 2 to 4 soft
bowel movements daily. Patients receiving lactulose
may experience flatulence, abdominal pain, and diar-
rhea45—adverse effects that have been associated with
nonadherence to treatment.66 Treatment nonadherence
was associated with HE recurrence (P < 0.001)66 and
cited as a potentially preventable cause of rehospitaliza-
tion due to HE for patients with cirrhosis, possibly related
to inadequate titration of lactulose to the recommended
number of daily bowel movements.66,67 To induce the
remission of an acute HE episode or an improvement in
HE symptoms, efficacy of the oral nonsystemic antibiotic
rifaximin was demonstrated in various small controlled
and open-label clinical studies.45,68
For patients with HE who lack a response to lactu-
lose or rifaximin, oral branched-chain amino acids and
intravenous L-ornithine L-aspartate are recommended by
300
Overt hepatic encephalopathy
Grade 2 Grade 3 Grade 4
Lethargy Somnolence Coma
to semistupor
Disorientation Responsive Mental status
regarding time to stimuli cannot be evaluated
Obvious Confusion
personality change
Inappropriate Gross disorientation
behavior
Bizarre behavior
42 61
the American Association for the Study of Liver Diseases
(AASLD) and the European Association for the Study of
the Liver as alternatives or additional options, though evi-
dence for their use may be limited.41 Conventional antibi-
otics (i.e., neomycin, metronidazole) currently have a
limited role for patients with overt HE due to the potential
for ototoxicity, nephrotoxicity, and antibiotic resistance.
However, the AASLD recommends these agents as an
alternative treatment.41,45
Prevention of Recurrence of Overt HE
Patients with HE in remission should receive prophy-
laxis to both prevent the recurrence of overt HE and
potentially improve HRQOL.45 Guidelines from the
AASLD and the European Association for the Study of
the Liver recommend lactulose alone or in combination
with rifaximin to prevent the recurrence of overt HE.41
Failure to adhere to the guideline recommendations for
prevention of recurrence of HE may result in rehospitali-
zation, thus directly impacting patients and their families
and primary care physicians. Prophylaxis is relatively
effective but, unfortunately, has not been widely adopted
in clinical practice. Indeed, clinical studies with rifaximin
550 mg administered twice daily, with concomitant lactu-
lose permitted (»90% of patients), have demonstrated
rifaximin efficacy and safety in patients with histories of
recurrent overt HE.69,70
During a 6-month study, rifaximin significantly
reduced the risk of recurrence of overt HE by 58%
(P < 0.001), and the risk of HE-related hospitalizations
by 50% (P = 0.01), compared with placebo.69 Approxi-
mately 91% of patients in each group received concomi-
tant lactulose during the study. Common adverse events
(adverse events; i.e., experienced by 10% of patients)
reported more frequently with rifaximin versus placebo
included peripheral edema (15.0% vs. 8.2%, respec-
tively), nausea (14.3% vs. 13.2%), dizziness (12.9% vs.
8.2%), fatigue (12.1% vs. 11.3%), and ascites (11.4% vs.
9.4%), although differences were not statistically signifi-
cant. Notably, infection with Clostridium difficile was only
reported in 2 patients receiving rifaximin; both of these
patients had other risk factors for the development of
C difficile infection (i.e., older age, recent hospitalizations
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
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 Cirrhosis in Primary Care

Long-term treatment (i.e., 2 years) with open-label

Hepatic Encephalopathy Grading Instrument (HEGI)
The HEGI is used to standardize Investigator determination as to whether a patient with a
rifaximin (patients rolled over from the 6-month study
documented history of cirrhosis and HE is experiencing or has experienced an overt HE episode.
and newly enrolled patients with a history of overt HE)
Please complete the following, noting the source of the information.
The patient is considered to be having an overt HE episode if at least one of the following applies:
resulted in lower rates of HE-related and all-cause hospi-
• He/she is disoriented to time or place or person
• He/she is lethargic and has asterixis talizations compared with placebo in the 6-month study
• You are unable to assess the patient due to disorientation to time and place and person; and/or somnolence, and/or coma

Clinical findings must have been present for at least 1 hour to be considered an HE episode.
(HE-related: 0.21 events/person-years of exposure [PYE]
vs. 0.72 events/PYE, respectively; all-cause hospitaliza-
tion: 0.45 events/PYE vs. 1.3 events/PYE).70 In that
Information Sources
Clinical Findings HE Episode Severity (check all that apply for each)

Is the patient disoriented to time? Grade 2 HE episode: Clinician-observed study, 89.8% of patients received concomitant lactulose.
Patient does not know the year Observed by outside
YES NO
Not or medical professional The adverse event profile of patients receiving long-term
Caregiver input
If yes, check all that apply:

Knows the year

Yes No Assessed
at least 2 of the other items
are checked “No” Review of medical records
treatment with rifaximin was comparable with that
Knows the month
Knows day of the week
Other, specify:
_______________________
reported during the original 6-month study.
Knows date of the month
In addition, rifaximin treatment for patients with HE
Is the patient disoriented to place?
YES NO
Grade 2 HE episode:
At least 1 item is checked “No”
Clinician-observed
Observed by outside
was associated with a decrease in duration of hospitali-
If yes, check all that apply: Yes No
Not
Assessed
medical professional
Caregiver input
zation and a reduction in annual inpatient costs.71 On a
Knows the country
Knows the province/state
Review of medical records
Other, specify:
per-admission basis, the duration of hospitalization
Knows the city/town
Knows the type of place
_______________________ decreased from 13.5 days before rifaximin treatment to
(e.g., hospital, house)
8.6 days during rifaximin treatment; the overall decrease
Is the patient disoriented to person? Grade 2 HE episode: Clinician-observed
YES NO Either item is checked “No” Observed by outside with rifaximin was 31% (i.e., 24.4 days/year vs. 11.5
medical professional
If yes, check all that apply: Yes No
Not
Assessed Caregiver input days/year, respectively). Another study showed that
Remembers and states Review of medical records
his/her own name
Recalls name of designated
Other, specify: rifaximin reduced the total number of hospitalizations
family member/caregiver _______________________
compared with lactulose (rifaximin [n = 15], 3 hospitaliza-
Information Sources tions; lactulose [n = 24], 19 hospitalizations); further, the
Clinical Findings HE Episode Severity (check all that apply for each)
mean length of hospitalization was significantly
Does the patient have asterixis (demonstrates Grade 2 HE episode: Clinician-observed
at least 3 flaps in 30 seconds?) Asterixis and lethargy Observed by outside decreased with rifaximin versus lactulose (3.5 vs. 5.0
days, respectively; P < 0.0001).47 Rifaximin, although
are both checked “Yes” medical professional
YES NO
Caregiver input
Review of medical records
Is the patient lethargic (patient is inattentive
and sleepy, but awakens when spoken to?) Other, specify:
associated with greater monthly costs than lactulose,
YES NO
_______________________
decreased annual costs of hospitalization and emer-
Is the patient disoriented to time and place Grade 3 HE episode: gency department visits by $3,327 per patient, a savings
and person? Disorientation to time and

YES NO
place and person are all
checked “Yes”
estimated at $170,000 for the 39 patients included in the
Is the patient somnolent (patient is asleep but Grade 3 HE episode: Clinician-observed
analysis.47
temporarily arousable in response to verbal
or physical stimulation?)
Patient is somnolent
is checked “Yes”
Observed by outside
medical professional
The role of probiotics in the management of HE is
YES NO Review of medical records
Other, specify:
unclear, although data from a systematic review con-
_______________________ cluded significant benefit with probiotics for the reduc-
Is the patient comatose (patient does not open Grade 4 HE episode: Clinician-observed
tion in the risk of development of overt HE compared
eyes or speak recognizable words in response
to verbal or noxious stimulation?)
Patient is comatose
is checked “Yes”
Observed by outside
medical professional
with placebo or no treatment (P = 0.0002).72 In the same
YES NO Review of medical records
Other, specify:
systematic review, probiotics significantly improved
_______________________ covert HE compared with placebo (P = 0.005); however,
The HEGI is intended to standardize the assessment of overt HE episodes among investigators in an international clinical trial.
HE is a diagnosis of exclusion and patients may undergo medical evaluation for other causes of these abnormalities and/or
probiotics did not improve covert HE compared with lac-
HE precipitating factors as judged medically appropriate.
tulose (P = 0.5).72 Further, results for VSL#3 (Sigma-Tau
An HE episode (defined as HE Grade 2, 3, or 4) has occurred: YES NO

If YES, date of HE episode: ____________________________

Pharmaceuticals, Inc., Gaithersburg, MD) for the man-
If an HE episode has occurred, please grade its severity using the information provided above.
agement of HE were positive.45 When examined for the
If the patient exhibits symptoms of more than 1 grade, the most severe grade should be selected. prevention of recurrence of HE versus placebo, VSL#3
For example, if the patient is disoriented to time and place and also somnolent, the episode is Grade 3.
reduced the risk of hospitalization for breakthrough HE
Severity of the HE episode: Grade 2 Grade 3 Grade 4
(P = 0.02), reduced the mean time to hospitalization
Signature of Investigator: _____________________________________ Date: ____________________
(P = 0.01), improved liver function (i.e., Child-Turcotte-
Pugh score, P = 0.001; Model for End-Stage Liver Dis-
FIGURE 3. Hepatic encephalopathy grading instrument for clinicians.
ease score, P = 0.03), and improved HRQOL.73 However,
Intellectual property pertaining to the hepatic encephalopathy grading further studies are warranted to determine which probi-
instrument is owned by Horizon Pharma. HE, hepatic encephalopa- otic strain(s) should be administered and at what dose.
thy. Source: Metab Brain Dis, “Overt hepatic encephalopathy: devel-
opment of a novel clinician reported outcome tool and electronic
caregiver diary,” vol. 31, 2016, Bajaj et al. ÓSpringer Science+Busi-
ness Media New York 2016, with permission of Springer.60 CONCLUSIONS
The etiologies of cirrhosis are varied, and U.S. cirrho-
involving antibiotic administration, pantoprazole [proton sis prevalence is unclear, with the disease being associ-
pump inhibitor] use). These patients recovered from C ated with substantial healthcare utilization and
difficile infection after treatment for the infection was mortality,10,25,74,75 and burden on patients, families, and
administered concomitantly with rifaximin. caregivers.28 Cirrhosis is common in the primary care

Copyright © 2018 The Authors. Published by Elsevier Inc. on behalf of Southern Society for Clinical Investigation. This is an open access article 301
under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/)
www.amjmedsci.com  www.ssciweb.org
Flamm
population and patients may be asymptomatic for many
years, delaying the diagnosis and appropriate treatment
and follow-up. Patients with cirrhosis may have normal
liver panels. Thrombocytopenia is often an early clue to
the presence of cirrhosis.
HE is a common neurologic complication of cirrhosis,
and early HE may be subtle in presentation. Diagnosis of
HE includes identifying precipitating factors and ruling
out other conditions with similar signs.41 The burden of
HE is considerable, impacting not only the U.S. health-
care system, but also patient quality of life, and that of
patients’ family members and caregivers.28,47,76
Lactulose is commonly used as first-line treatment
for an acute episode of overt HE,41,45 and additional ther-
apies, such as rifaximin, may be considered for patients
without response to or intolerant of lactulose.45 Patients
with a history of overt HE should receive long-term pro-
phylaxis with lactulose, either alone or in combination
with rifaximin, to prevent overt HE recurrence.41,45
Indeed, the benefits of prophylactic treatment with lactu-
lose and rifaximin (e.g., reduction in the risk of recur-
rence)47,69-71 should encourage primary healthcare
providers to ensure patients with HE continue to receive
treatment for prevention of recurrence as prescribed by
hospitalists or specialists, especially given the marked
decrease in the risk of HE hospitalizations.69 Thus, the
recognition and management of cirrhosis and HE, a
decompensation event, in primary care may improve out-
comes for affected patients.
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Submitted February 5, 2018; accepted June 8, 2018.
Technical editorial assistance was provided, under the direction of the
author, by Mary Beth Moncrief, PhD, and Sophie Bolick, PhD, Synchrony
Medical Communications, LLC, West Chester, PA. Funding for this support
was provided by Salix Pharmaceuticals, Raleigh, NC.
Dr. Flamm has served as a consultant and on the speakers’ bureau for
Salix Pharmaceuticals.
Correspondence to: Steven L. Flamm, MD, Northwestern University
Feinberg School of Medicine, NMH/Galter Room 17-250, 675 N Saint Clair,
Chicago, IL 60611 (E-mail: s-flamm@northwestern.edu).
303