Cirrhosis Diagnosis & Management: A Medical Review

Clinical Review & Education
JAMA | Review
Diagnosis and Management of Cirrhosis and Its Complications
A Review
Elliot B. Tapper, MD; Neehar D. Parikh, MD, MS
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IMPORTANCE Cirrhosis affects approximately 2.2 million adults in the US. From 2010 to 2021,
the annual age-adjusted mortality of cirrhosis increased from 14.9 per 100 000 to 21.9 per
100 000 people.
OBSERVATIONS The most common causes of cirrhosis in the US, which can overlap, include
alcohol use disorder (approximately 45% of all cases of cirrhosis), nonalcoholic fatty liver
disease (26%), and hepatitis C (41%). Patients with cirrhosis experience symptoms including
muscle cramps (approximately 64% prevalence), pruritus (39%), poor-quality sleep (63%),
and sexual dysfunction (53%). Cirrhosis can be diagnosed by liver biopsy but may also be
diagnosed noninvasively. Elastography, a noninvasive assessment of liver stiffness measured
in kilopascals, can typically confirm cirrhosis at levels of 15 kPa or greater. Approximately 40%
of people with cirrhosis are diagnosed when they present with complications such as hepatic
encephalopathy or ascites. The median survival time following onset of hepatic
encephalopathy and ascites is 0.92 and 1.1 years, respectively. Among people with ascites, the
annual incidence of spontaneous bacterial peritonitis is 11% and of hepatorenal syndrome is
8%; the latter is associated with a median survival of less than 2 weeks. Approximately 1% to
4% of patients with cirrhosis develop hepatocellular carcinoma each year, which is associated
with a 5-year survival of approximately 20%. In a 3-year randomized clinical trial of 201
patients with portal hypertension, nonselective β-blockers (carvedilol or propranolol)
reduced the risk of decompensation or death compared with placebo (16% vs 27%).
Compared with sequential initiation, combination aldosterone antagonist and loop diuretics
were more likely to resolve ascites (76% vs 56%) with lower rates of hyperkalemia (4% vs
18%). In meta-analyses of randomized trials, lactulose was associated with reduced mortality
relative to placebo (8.5% vs 14%) in randomized trials involving 705 patients and reduced risk
of recurrent overt hepatic encephalopathy (25.5% vs 46.8%) in randomized trials involving
1415 patients. In a randomized clinical trial of 300 patients, terlipressin improved the rate of
reversal of hepatorenal syndrome from 39% to 18%. Trials addressing symptoms of cirrhosis
have demonstrated efficacy for hydroxyzine in improving sleep dysfunction, pickle brine and
taurine for reducing muscle cramps, and tadalafil for improving sexual dysfunction in men.
CONCLUSIONS AND RELEVANCE Approximately 2.2 million US adults have cirrhosis. Many
symptoms, such as muscle cramps, poor-quality sleep, pruritus, and sexual dysfunction, are
common and treatable. First-line therapies include carvedilol or propranolol to prevent
variceal bleeding, lactulose for hepatic encephalopathy, combination aldosterone antagonists
and loop diuretics for ascites, and terlipressin for hepatorenal syndrome.
JAMA. 2023;329(18):1589-1602. doi:10.1001/jama.2023.5997
C
irrhosis affects approximately 2.2 million adults in the US1
and is associated with mortality rates of 21.9 per 100 000
people.2,3 Cirrhosis is defined as the fibrotic replacement
of liver tissue that can result from any chronic liver disease. Most
prevalent cases of cirrhosis are caused by alcohol use disorder (approximately 45% of all cirrhosis cases), hepatitis C (41%), and nonalcoholic fatty liver disease (26%), with many patients having
overlapping causes.4 However, hepatitis C is now curable with directacting antivirals and most newly diagnosed cirrhosis is due to nonalcoholic fatty liver disease (NAFLD) (accounting for 61.8% of incident cases) and alcohol use disorder (accounting for 20.0%).5
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Author Affiliations: Division of
Gastroenterology and Hepatology,
University of Michigan, Ann Arbor.
Corresponding Author: Elliot B.
Tapper, MD, Division of
Gastroenterology and Hepatology,
University of Michigan, 3912
Taubman, 1500 E Medical Center Dr,
Ann Arbor, MI 48109 (etapper@
umich.edu).
Section Editor: Mary McGrae
McDermott, MD, Deputy Editor.
Outcomes for patients with cirrhosis can be improved with
evidence-based therapies directed toward both the etiology of
cirrhosis6-12 and its complications.13-21 Recent innovations include
noninvasive risk stratification of cirrhosis22,23 as well as interventions that improve survival by preventing or reducing the complications of cirrhosis.24 Such complications include variceal hemorrhage, ascites, and hepatic encephalopathy. People with cirrhosis
have reduced quality of life.25 Poor quality of life is associated with
many common symptoms26 such as muscle cramps,27,28 poorquality sleep,29 pruritus,30,31 and sexual dysfunction,32,33 which can
be improved with therapy.
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Diagnosis and Management of Cirrhosis and Its Complications
Box. Common Questions on the Management and Complications
of Cirrhosis
Does my patient need a liver biopsy to diagnose cirrhosis?
No. Cirrhosis can be accurately diagnosed using sequential
noninvasive testing such as the fibrosis-4 index followed by a liver
stiffness measurement obtained by elastography (eg, vibrationcontrolled transient elastography or magnetic resonance
elastography). Because liver stiffness measurements are also
prognostic, they can be used, for example, to determine which
patients need endoscopy to screen for esophageal varices.
What is the most common cause of cirrhosis?
Most prevalent cases of cirrhosis in the US are caused by alcohol
use disorder, nonalcoholic fatty liver disease (NAFLD), and
hepatitis C infection. Most incident cases of cirrhosis are caused
by NAFLD; however, there is also an increase in alcohol-related
cirrhosis, particularly among young people.
What can be done to improve survival among patients with
compensated cirrhosis?
Survival for patients with cirrhosis is improved with control of
their underlying chronic liver disease (eg, alcohol use disorder,
viral hepatitis, NAFLD). Beyond that, screening for liver cancer
with biannual ultrasound and α-fetoprotein is associated with
higher rates of curative treatment when cancer is detected.
When patients develop portal hypertension, nonselective
β-blockers (particularly carvedilol or propranolol) are associated
with lower rates of decompensation or death.
This review summarizes the current evidence regarding the diagnosis and management of cirrhosis and its complications (Box).
Methods
We searched PubMed (January 1, 2000, to March 10, 2023) for systematic reviews, meta-analyses, randomized clinical trials (RCTs), and
relevant guidelines. We prioritized recent RCTs of higher quality
based on rigor of study design, sample size, and length of followup. Of 8887 articles retrieved, 115 were included, consisting of 9 practice guidelines, 3 consensus statements, 25 RCTs, 17 metaanalyses, 7 systematic reviews (without meta-analysis), and 54
observational cohort studies.
Discussion
Epidemiology
The causes of cirrhosis vary by context and many overlap. In a study
of 68 673 patients from a national sample of patients in the Veterans Administration (2020-2021), the causes of cirrhosis were hepatitis C (24.0%), alcohol related (27.9%), hepatitis C and alcohol related (17.4%), NAFLD related (25.9%), and due to other conditions
(3.7%).4 Patients diagnosed with cirrhosis typically have a mean
age of 59.5 to 62.4 years.34,35 Patients with NAFLD cirrhosis often
present at a mean age of 67 years.34 However, cirrhosis is now more
common among younger patients. The incidence of cirrhosis by age
35 years was 46.9 per 100 000 people among those born during
or after 1980 compared with 32.6 per 100 000 born between 1945
and 1960.36 A total of 54% to 60% of cirrhosis cases occur among
1590
men.35-37 Between 2010 and 2021, age-adjusted mortality from cirrhosis increased from 14.9 to 21.9 per 100 000 people.2,3 Cirrhosis
mortality increased from 1.1 to 3.3 per 100 000 people aged 25 to
34 years from 2010 to 20203 due to increases in alcohol-related liver
disease.2 The epidemiology of cirrhosis and its complications are described further in Table 1.24,34,36,38-56
Pathophysiology of Cirrhosis
Chronic inflammatory liver injury causes activation of hepatic myofibroblasts and macrophages, which increase collagen accumulation (fibrosis) in the extracellular matrix. This process disrupts the
connection between hepatocytes and sinusoids where blood flows,
leads to formation of nodules of fibrosis, and impedes portal inflow
resulting in portal venous hypertension. Chronic liver injury results
in increased vasoconstrictor signaling (such as endothelin-1) and
decreased production of vasodilators (such as nitric oxide), further
restricting sinusoidal flow. Inflammatory injury from alcohol or steatosis also increases vascular resistance. In both NAFLD and alcoholrelated liver disease, heritable factors in lipid metabolism have been
associated with progression of liver disease.57 In addition, chronic
liver injury causes hepatocyte loss and reduces the liver’s capacity
for metabolic activity including protein synthesis, detoxification, nutrient storage, and bilirubin clearance. Proteins synthesized by the
liver include albumin, hormones (eg, thrombopoietin [responsible
for platelet production]), and hemostatic factors (procoagulants and
anticoagulants).58 The multisystem impact of these processes is depicted in Figure 1.
Over time, patients may progress from compensated cirrhosis
without clinical manifestations to decompensated cirrhosis with
variceal hemorrhage, ascites, or hepatic encephalopathy. Portal hypertension, defined as a pressure gradient between the hepatic and
portal vein of 10 mm Hg or greater, promotes development of varices (collateral vessels that shunt portal blood to systemic veins and
often result in dilated esophagogastric channels prone to hemorrhage). Disrupted portal flow causes decreased cardiac return and
decreased central blood volume, leading to increased plasma renin
activity, increased renal-tubular affinity for sodium, peripheral volume expansion, and kidney vasoconstriction, predisposing patients to ascites, hyponatremia, and kidney injury, particularly in
the setting of volume depletion, infection, or hemorrhage. Increasing portal pressure induces ascites from hepatic sinusoids. Increased sinusoidal pressure causes increased lymph production,
which extravasates into the peritoneum when lymphatic drainage
capacity is exceeded. Gut-derived toxins, such as ammonia and
bacterial products that induce systemic inflammation, cause hepatic encephalopathy. Hepatic encephalopathy can develop at low
ammonia levels in the context of infection.59 While the mechanisms are incompletely characterized, the presence of hepatic fibrosis and hepatic injury from inflammation contribute to the genetic and epigenetic aberrations that lead to the development of
hepatocellular carcinoma.
Diagnosing Cirrhosis
Medical history and physical examination can identify patients with
or at risk for cirrhosis. Patients with cirrhosis frequently experience
muscle cramps (64% prevalence) and pruritus (39%),26 poorquality sleep (63%),60 and sexual dysfunction (53%).61 Risk factors, such as diabetes or alcohol use, and symptoms, such as muscle
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Diagnosis and Management of Cirrhosis and Its Complications
Review Clinical Review & Education
Table 1. Epidemiology of Cirrhosis and Its Complications in the US
Condition
Prevalence/incidence
Mortality
Hospitalization rates
Cirrhosis
Prevalence, 840-1058/100 00034,36
56 989 in 2020a
56.4-125.7 of every 100 000
hospitalizations involve cirrhosis38,39
Hepatic encephalopathy
(HE)
40% 5-y risk overall among patients with
cirrhosis
10% 1-y risk if Child Ab with portal
hypertension
25% 1-y risk if Child Bb with portal
hypertension41
Median survival, 0.95 y and 2.5 y for those
aged ≥65 y or <65 y, respectively44
HE presents in 10.1% of cirrhosis
hospitalizations45
25.8% 30-d readmission rate40
25%-80% Develop covert HEc depending
on Child class42,43a
Ascites
40% Lifetime risk among patients with
cirrhosis
5.1% at 1 y46
20% at 3 y24
Median survival, 1.08 y46
Ascites present in 47.7% of cirrhosis
hospitalizations45
Variceal bleeding
Varices form at a rate of 9%/y in patients
with cirrhosis47
17.7% 6-wk mortality after variceal
bleeding49
Variceal bleeding occurs in up to 70.6 of
every 100 000 hospitalizations in the US50
and 10.5% of cirrhosis hospitalizations45
Hepatocellular carcinoma Annual incidence in viral hepatitis B– and
hepatitis C–related cirrhosis was
approximately 3.2%-4.8%; and 1.4%-2.1%
in NAFLD51
<20% 5-y survival, dependent on stage of
detection; 11 000 annual deaths
nationally52
NA
Spontaneous bacterial
peritonitis
11% Annual risk in patients with ascites53
Median survival after diagnosis of
spontaneous bacterial peritonitis, 11 wk54
Spontaneous bacterial peritonitis occurs in
3.1% of cirrhosis hospitalizations55
Hepatorenal syndrome
8% Annual risk in patients with ascites56
Median survival is 2 wk after diagnosis of
hepatorenal syndrome56
Hepatorenal syndrome occurs in 1.2% of
cirrhosis hospitalizations45
Variceal bleeding occurs at a rate of
1.2%-4% within 3 y among patients with
cirrhosis48
ascites and normal albumin, bilirubin, and international normalized ratio; class B
refers to patients with ascites and/or mild abnormalities in laboratory indices.
Abbreviations: NA, not available; NAFLD, nonalcoholic fatty liver disease.
a
This estimate is derived from the primary cause of death listed on death
certificates compiled in the CDC WONDER database.
b
Child A and B refer to the Child classification: class A refers to patients without
Covert HE is an early stage of HE characterized by deficits in executive
function, poor sleep quality, and poor balance.
cramps, pruritus, sleep disorder, and sexual dysfunction, are neither
sensitive nor specific for the diagnosis of cirrhosis.62 Most physical
examination findings are not sensitive for cirrhosis but some offer
specificity greater than 90%: these include Terry nails (white discoloration, absent lunula, dark pink at tip), gynecomastia, caput medusa, facial telangiectasia, palmar erythema, decreased body hair,
testicular atrophy, and jaundice.62
Screening for cirrhosis in the general population is not currently recommended.63 However, patients with established chronic
liver disease with abnormal liver enzymes, hepatic steatosis on
imaging, or viral hepatitis should be evaluated for cirrhosis. Liver biopsy is considered the criterion standard to diagnose cirrhosis, although it is being increasingly replaced by noninvasive methods for
fibrosis assessment. Biopsy is reserved for patients with noninvasive testing that is inconclusive or technically inadequate or when
the underlying chronic liver disease is unclear.
Serologic measures and imaging-based indices are used to diagnose cirrhosis. Compared with biopsy, these measures are less expensive, safer, and simpler to follow longitudinally (Figure 2). The most
common serologic tests capture indirect signs of liver fibrosis and dysfunction (eg, thrombocytopenia, reflecting reduced platelet production and splenic sequestration and a higher ratio of aspartate aminotransferasetoalanineaminotransferase).62 Thefibrosis-4index(FIB-4;
age, alanine aminotransferase, aspartate aminotransferase, platelet
count) is a widely accepted risk-stratification tool that, for people with
either NAFLD or alcohol-related liver disease, classifies scores as low
(<1.30), intermediate (1.30-2.67), and high (>2.67). Age increases the
FIB-4; for patients older than 65 years, the lower risk threshold is 2.0
or less (while high-risk thresholds remain the same).64 Cutoffs such
as less than 1.45 and greater than 3.25 have been developed for hepatitis C. FIB-4 has high negative predictive value (96%) but low positive predictive value (63%) for cirrhosis.65 Risk stratification using
FIB-4, for which values less than 1.3 offer a negative likelihood ratio
of 0.4 for advanced fibrosis,66 is recommended by societal guidelines in patients with known NAFLD (or risk factors such as diabetes
or obesity).63
Additional testing is needed in the setting of an elevated FIB-4
score (eg, ⱖ1.3 for patients with NAFLD, ⱖ2.0 for patients >65 years
old).63 Sequential testing of patients with liver disease risk factors
using FIB-4 followed by elastography can provide posterior probabilities of cirrhosis of 89% or greater.66 Elastography provides a liver
stiffness measurement (LSM; measured in kilopascals [kPa]) that correlates with the abundance of fibrosis.66 LSM of 15 kPa or greater
by vibration-controlled transient elastography (VCTE), an ultrasoundbased method that uses a handheld probe for point-of-care assessments, identified cirrhosis with 95.5% specificity (62% positive predictive value) in a cohort of 5648 patients with both VCTE and liver
biopsy. Conversely, LSM of 10 kPa or greater had a sensitivity of
74.9% (88% negative predictive value).22,67 Magnetic resonance
elastography has fewer technical failures than VCTE in patients with
high (>40) body mass index (calculated as weight in kilograms divided by height in meters squared). However, cost and access limit
widespread use of magnetic resonance elastography. Liver inflammation (ie, alanine aminotransferase >120 IU/L68) and central venous congestion from heart failure can also increase liver stiffness,
generating false-positives from elastography.
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Diagnosis and Management of Cirrhosis and Its Complications
Figure 1. Impact of Portal Hypertension and Hepatic Insufficiency on Cirrhosis Pathophysiology
Cross section of cirrhotic liver lobule
Chronic inflammatory liver injury
(eg, alcohol use disorder, hepatitis C, or nonalcoholic fatty liver disease)
H E PATO C Y T ES
Hepatocyte death
Fibrosis accumulation
Reduced metabolic activity including
protein synthesis, detoxification,
nutrient storage, and bilirubin clearance
Formation of nodules
Portal flow blockage leading
to portal hypertension
Hepatocyte
death
Fibrosis
accumulation
CIRRHOTIC LIVER
Systemic effects of cirrhosis
CENTRAL
VEIN
H E PAT I C
ARTERY
SINUSO
ID
Vasoconst
Portal
hypertension
riction
Chronic inflammatory liver injury
Increased vasoconstrictor
signaling via endothelin-1
Decreased vasodilator production
P O RTA L
VEIN
Restriction of
sinusoidal flow
Increased
lymph
production
BILE
DUCT
Increased lymph production
Extravasation of lymph
into the peritoneum (ascites)
!
Hepatic fibrogenesis and
chronic inflammatory injury
can lead to the development
of hepatocellular carcinoma
Hepatic dysfunction
Increased nitric oxide levels
Increased vasodilatory
neurotransmitters
Increased ammonia levels
Hepatic encephalopathy (HE)
Cirrhosis leads to intrahepatic resistance, which causes portal hypertension and,
at later stages, hepatic insufficiency, which disrupts the liver’s normal metabolic
functions. Together these features cause gut-barrier disruption and
portosystemic shunting, resulting in the multisystem complications of cirrhosis,
eg, hepatic encephalopathy, sarcopenia, ascites, and kidney injury.
Diagnosis of Portal Hypertension
All patients with varices have CSPH. Because portal pressures are
not routinely measured, it is recommended to screen for varices in patients with cirrhosis every year if decompensated or every 2 to 3 years
if compensated (2 years if the patient is actively drinking alcohol or
chronic liver disease is uncontrolled, eg, untreated hepatitis B or C or
autoimmune hepatitis).23 However, guidelines also suggest that noninvasive tests can rule out CSPH22,23 and therefore obviate the need
for endoscopy. Among 7387 patients pooled from 26 studies, LSM less
than 20 kPa and platelet count greater than 150 × 109/L provided a
negative likelihood ratio of 0.09 for high-risk (large and/or thinwalled) varices.73 According to these data, only 2.2% of high-risk varices were missed if endoscopy was not performed.73
Portal pressures can be estimated using a transjugular catheter to
determine the hepatic venous pressure gradient, a measure of the
pressure gradient across the liver. Clinically significant portal hypertension (CSPH) is defined as a gradient of 10 mm Hg or greater (normal <5 mm Hg).22 In a study of 213 patients with pressure gradients
less than 10 mm Hg, approximately 90% remained decompensation free for at least 4 years.69 Pressure measurements, though safe,
are costly; can only be obtained in specialized units; and have high
(26%) within-individual variance.70 The optimal noninvasive alternative for identifying patients with CSPH involves a combination of
liver stiffness from VCTE and platelet counts.71 Thrombocytopenia
(ie, platelet count <110 × 109/L) in patients with liver disease is both
highly suggestive of cirrhosis62 and associated with a patient’s risk
of ascites and variceal bleeding.72 Among 518 persons with cirrhosis from Europe and Canada, a nomogram based on LSM and platelet counts was developed to predict CSPH.71 For example, patients
with an LSM of 25 kPa or greater and any platelet count have a prevalence of CSPH of at least 66%, increasing to 90% or more for patients with platelet counts of 110 × 109/L or less.71
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Disrupted portal flow
Development of varices
and variceal hemorrhage
Decreased cardiac return
and decreased central
blood volume
Increased plasma
renin activity
Peripheral volume expansion
Hyponatremia
Kidney vasoconstriction
and injury
Gut-barrier disruption
Enteric bacteria release
leading to inflammation
Ascites
Diagnosing Complications of Cirrhosis
The diagnosis of ascites can be made using abdominal ultrasonography or cross-sectional imaging. Flank dullness, shifting dullness,
and fluid wave elicited by physical examination offer 94%, 83%, and
50% sensitivity and 29%, 56%, and 82% specificity, respectively.74
Spontaneous bacterial peritonitis is diagnosed after paracentesis with
ascites concentrations of neutrophil count greater than 250/μL.75
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Figure 2. Noninvasive Diagnosis and Risk Stratification of Patients at Risk for Cirrhosis
Assess for risk factors and signs of cirrhosis
Risk factors
• Obesity
• Hepatitis C
• Hepatitis B
Signs of cirrhosis in the presence of chronic liver disease
• Type 2 diabetes
• Alcohol use disorder
• Other chronic liver disease
• Terry nailsa
• Gynecomastia
• Caput medusa
• Facial telangiectasia • Testicular atrophy • Jaundice
• Decreased body hair • Palmar erythema
Determine Fibrosis-4 Index (FIB-4) score
FIB-4 score calculation
Aspartate aminotransferase (AST) multiplied by age, divided by the platelet count
multiplied by the square root of the alanine aminotransferase (ALT)
Suggestive results: FIB-4 score ≥1.3 or ≥2.0 if patient is aged >65 years
Determine liver stiffness measurement (LSM)
Elastography testing selected based on patient BMI
BMI ≤40 Vibration-controlled
transient elastography (VCTE)
BMI >40 Magnetic resonance
elastography (MRE)
Suggestive results: High LSM (≥15 kPa on VCTE or ≥5 kPa on MRE)
Confirm diagnosis of cirrhosis with FIB-4 and LSM results
Highest degree of certainty:
FIB-4 score ≥2.67 and high LSM
Requires further confirmation:
FIB-4 score <2.67 and high LSM
Consider liver biopsyb
Cirrhosis is unlikely:
FIB-4 score >2.67 and low LSM
Noncirrhotic
Stage 4 fibrosis
Initiate evidence-based care
Screen for varices with endoscopy
or defer if VCTE result is <20 kPa
and platelet count is >150 x 109/L
Initiate nonselective β-blockers
(eg, carvedilol) if varices are found
Consider nonselective β-blockers
if VCTE result is >25 kPa
Screen for liver cancer
with biannual ultrasound
and α-fetoprotein
Refer to
hepatologist
Refer for transplant evaluation if patient
develops ascites, hepatic encephalopathy,
variceal bleeding, or liver cancer
Up to one-third of patients with spontaneous bacterial peritonitis
do not have fever or pain. Therefore, diagnostic paracentesis is recommended for all hospitalized patients with cirrhosis and ascites.53,76
Hepatorenal syndrome is defined as kidney injury in the presence
of large-volume ascites if there is a 50%, or 0.3 mg/dL, or greater
increase in serum creatinine within 7 days from the last measure that
does not respond to 2 days of intravenous fluids to establish normal intravascular volume.53
Hepatic encephalopathy is a clinical diagnosis. It presents as a
spectrum on the West Haven Criteria scale (0 to 4 scale, where 0
indicates no deficits and 4 indicates coma). Overt hepatic encephalopathy (grades ⱖ2) presents with asterixis, disorientation, lethargy, and coma. Covert hepatic encephalopathy (grades ⱕ1) may
present as deficits in executive function, sleep disorder, vegetative
behavior, and gait disturbance. The criterion-standard diagnostic
for covert hepatic encephalopathy is greater than or equal to 4 SDs
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Treat underlying liver disease
Address causal or comorbid
obesity and alcohol use disorder
The presence of cirrhosis is
associated with an increased risk of
complications such as liver cancer
and decompensation including
ascites, hepatic encephalopathy, and
variceal hemorrhage. It is important
to evaluate for the presence of
cirrhosis in people with risk factors or
any diagnosed chronic liver disease.
While physical examination findings
may be suggestive, it is
recommended to stratify risk for all
using the FIB-4 followed by
elastography for at-risk patients.
After identifying patients with
cirrhosis, optimal care may involve
referral to a hepatologist, liver cancer
screening, and consideration of
endoscopy for varices screening
and/or initiation of nonselective
β-blockers. BMI indicates
body mass index.
a
Terry nails identified by white
discoloration, absent lunula, and
dark pink tips.
b
Biopsy is of highest value when the
diagnosis of the underlying liver
disease is unclear or noninvasive
tests yield indeterminate or
discordant results. The role of
biopsy is also based on patient
preference and clinical context.
below healthy control performance on the 5-test paper-pencil battery called the Psychometric Hepatic Encephalopathy Score. This
battery can be replaced by some bedside measures42 including the
Animal Naming Test (in a prospective cohort of 327 patients, <15
and <10 animals per minute offered sensitivities for diagnosing
hepatic encephalopathy of 70% and 15%, respectively, and specificities of 63% and 92%, respectively) or the EncephalApp Stroop
Test (>198 seconds on a computerized version of the Stroop test
of attention offered 80% sensitivity and 61% specificity in a prospective cohort of 277 patients).42 Covert hepatic encephalopathy
can also present as recent falls (40% within the prior year for
those diagnosed with covert hepatic encephalopathy vs 12.9%
for those without)77 and poor-quality sleep (mean of 10.3 vs 7.6 on
the Pittsburgh Sleep Quality Index where >5 reflects poor sleep).78
An algorithm based on age, sex, and self-reported loss of balance,
irritability/impatience, anorexia, and disinterest in physical activity
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Figure 3. Natural History of Cirrhosis, Its Complications, and Modifiable Factors
Biomarkers and complications associated with increased risk of decompensation and death
Low risk
Indeterminate
High risk
Platelet count
≥150 x 109/L
110-149 x 109/L
<110 x 109/L
Liver stiffnessa
<10 kPa
10-19 kPa
≥20 kPa
5-9 mm Hg
≥10 mm Hg
Hepatic venous
<5 mm Hg
pressure gradient
Compensated
cirrhosis
Increasing risk of complications
Control of underlying liver disease
Alcohol abstinence
Weight loss (if obesity)
Hepatitis B viral suppression
Hepatitis C cure
Variceal bleeding
Variceal band ligation
Intravenous octreotide
Antibiotics plus
nonselective β-blockers
Decompensated
cirrhosis
Ascites
Aldosteroneantagonists
plus diuretics
TIPS
Nonselective
β-blockers
Transjugular intrahepatic
portosystemic shunt (TIPS)
Spontaneous
bacterial peritonitis
Hepatorenal
syndrome
Antibiotics
plus albumin
Terlipressin
Norepinephrine
Hepatic encephalopathy
Disease-modifying measures and interventions
Falls
Trauma
Death
or
Transplant
Coma
Lactulose Rifaximin High-protein diet
Risk of hepatocellular carcinoma
The consequences of cirrhosis are depicted on a timeline from the development
of compensated cirrhosis to death or transplant. Biomarkers associated with
lower risk of decompensation and death are shown in green, those of
indeterminate significance in yellow, and biomarkers and events associated
with a higher risk of decompensation and death in red; disease-modifying
measures and interventions are shown in blue. The liver stiffness measures are
can identify covert hepatic encephalopathy with a sensitivity of
80% and specificity of 79%.42
Screening for Hepatocellular Carcinoma
Although randomized trials of screening for hepatocellular carcinoma (HCC) are lacking, screening with biannual abdominal ultrasound and serum α-fetoprotein is recommended by the American
Association for the Study of Liver Diseases to improve early HCC detection in patients with cirrhosis, regardless of etiology.76,79 In a metaanalysis of 32 observational studies that included 13 367 patients,
screening for HCC was associated with early-stage detection (58.8%
vs 27.0%) and increased rates of curative therapies (58.2% vs 34.0%)
in comparison with no screening.80 Longer screening intervals
(ie, annual screening) have not been prospectively compared with
semiannual screening.
Patients with cirrhosis and a greater than 1.0-cm mass on screening ultrasound or with a rising or elevated α-fetoprotein level
(cutoff >20 ng/mL) should undergo further diagnostic workup to
evaluate for HCC. Though biopsy is diagnostic, multiphasic contrastenhanced cross-sectional imaging can be used to make the
diagnosis.79 A solid lesion exhibiting specific features (eg, arterialphase hyperenhancement and portal venous phase washout) in
a patient with cirrhosis can be diagnosed as HCC.79
Prognosis of Cirrhosis
Although survival varies with age at diagnosis and extrahepatic
comorbidities,81 patients with compensated cirrhosis have a median survival of 12 years according to a pooled analysis of 806 prospectively followed up patients.82 Survival is reduced after any decompensation (Figure 3). Patients with compensated cirrhosis and
small varices have a 6% 1-year risk of bleeding, while patients with
large varices and decompensated cirrhosis have a 42% to 76% 1-year
risk of bleeding.83 In-hospital mortality after variceal hemorrhage
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shown in kilopascals and are derived from vibration-controlled transient
elastography.
a
Ten to 19 kPa denotes intermediate risk, 15 kPa is the threshold for assuming
cirrhosis, 20 kPa is high risk, and 25 kPa is highest risk and assumes clinical
portal hypertension.
is approximately 14.5% overall and as low as 0% for patients with
previously compensated cirrhosis.84 Ascites in the setting of cirrhosis was associated with a median survival of 1.1 years in a cohort of
13 265 patients enrolled in Medicare.46 Median survival time following incident overt hepatic encephalopathy was 0.92 years in a study
of 49 164 patients with cirrhosis enrolled in Medicare.37,44 Compared with patients with cirrhosis without any hepatic encephalopathy, covert hepatic encephalopathy was also associated with
worse outcomes. Such outcomes included a higher 1-year risk of car
crashes (17% of 97 patients with covert hepatic encephalopathy vs
3% of 70 without)85 and, in a cohort of 170 patients with cirrhosis
(56% with covert hepatic encephalopathy), higher rates of hospitalization (47% vs 15%) and death (18% vs 3%).43
Prognostic Systems
Factors associated with reduced survival include lower serum levels
of albumin, higher international normalized ratios (INRs), and
elevated bilirubin levels. These are 3 components of the ChildTurcotte-Pugh (CTP) score, which also includes ascites and hepatic
encephalopathy. Bilirubin and INR are included in the Model for
End-stage Liver Disease–Sodium (MELD-Na) score along with creatinine and sodium levels. The CTP ranges from 5 (75% 5-year survival) to 15 (20% 5-year survival if >12)86; the MELD-Na ranges
from 6 (1.9% 90-day mortality) to 40 (71.3% 90-day mortality).87
MELD is best suited to short-term prognostication for patients with
decompensated cirrhosis and it is used to prioritize organ allocation
on the transplant waitlist; the CTP is used for long-term prognostics
and complements MELD by describing the patient’s compensation
status. When patients with cirrhosis require hospitalization,
patients with acute-on-chronic liver failure have an increased rate
of near-term mortality.88 Organ failures include severe hepatic
encephalopathy (disorientation and/or coma), shock, requirement
for mechanical ventilation, and kidney failure requiring dialysis.
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Diagnosis and Management of Cirrhosis and Its Complications
Thirty-day survival is 95% for patients with decompensated cirrhosis and no organ failure.88 Survival is reduced for patients with
organ failures and infections. For patients with 2 organ failures, survival with or without infection is 62% or 84%, respectively; for
those with 4 organ failures, survival is 0% or 24%.88
Treatment
Symptoms of Cirrhosis
Cirrhosis is associated with multiple common physical and psychological symptoms that can be improved with treatment
(Table 2).13-21,24,27-33,53,89-94 In an RCT of 80 patients, compared with
tap water, 1 sip of pickle brine at cramp onset significantly reduced
cramp severity at 28-day follow-up (2.3- vs 0.4-point reduction on
a 10-point visual analog scale).27 In a 2-week randomized, doubleblind, crossover trial of 30 patients, compared with placebo,
1000 mg of taurine twice daily significantly reduced leg cramping
(7 fewer cramps compared with placebo). 28 Cholestyramine
(4-16 g daily) is considered first-line therapy for pruritus given its
safety profile but randomized trials in cirrhosis are lacking.30 In a
4-week RCT of 16 patients with cirrhosis, naltrexone significantly improved pruritus compared with placebo with a mean (SD) 54% (10%)
reduction in pruritus severity compared with an 8% (10%) increase as measured by a 100-mm visual analog scale.31 In a 10-day
RCT of 35 patients with sleep disorder, compared with placebo, hydroxyzine, 25 mg, nightly was associated with a significant 40% improvement from baseline on a 10-point visual analog scale of sleep
quality (vs 0% for placebo).29 One patient in the hydroxyzine group
developed overt hepatic encephalopathy (disorientation). Alcohol
cessation may improve sexual function, with 25% of 60 men abstinent for 6 months or longer achieving self-reported normal sexual
function.32 In a 12-week, randomized trial of 140 men, compared with
placebo, tadalafil, 10 mg, improved erectile function based on patient report (63% vs 30%).33
Underlying Etiology of Cirrhosis
Patients with cirrhosis of any cause may benefit from evaluation for
liver transplant when they have developed a decompensation or
HCC.76 However, control of the underlying etiology improves the
prognosis of cirrhosis by slowing its progression and may reverse fibrosis. For example, after 12 months of follow-up, 43% of 37 patients with cirrhosis and hepatitis C cured with direct-acting antivirals experienced regression to a lower fibrosis stage.95 Among 96
patients with hepatitis B cirrhosis treated with tenofovir and followed up for 240 weeks, 28% no longer had cirrhosis on biopsy.96
Alcohol use can worsen the prognosis of any chronic liver disease;
alcohol use disorder should be identified and treated.97 In an observational longitudinal study of 33 682 patients with cirrhosis and
alcohol use disorder from the Veterans Administration, behavioral
or pharmacotherapy (eg, naltrexone) for alcohol use disorder was
associated with significantly reduced 180-day mortality (2.6% vs
3.9%) and cirrhosis decompensation (6.5% vs 11.6%).98 Etiologyspecific therapies and their effects on cirrhosis outcomes are provided in Table 3.6-12,99-104
Complications of Cirrhosis
Varices and Portal Hypertension
Nonselective β-blockers (eg, carvedilol or propranolol) reduce
portal pressure by reducing splanchnic blood flow. Because of its
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Review Clinical Review & Education
α-blocking effects, carvedilol also reduces intrahepatic resistance.22 β-Blockers are standard of care for people with large varices or prior bleeding.58,76 If large varices are encountered on
endoscopy, carvedilol (optimally dosed at 12.5 mg daily) is preferred to other β-blockers (grade B evidence, strong recommendation) according to the Baveno VII consensus statement.22 In an
RCT of 152 patients, compared with band ligation every 2 weeks
until variceal eradication, participants randomized to carvedilol
(without banding) had lower rates (10% vs 23%) of variceal
bleeding after 20 months of follow-up. 105 Esophageal ulcers
caused by the band ligation resulted in bleeding in about 8% of
patients in the band ligation group.105 Patients with portal hypertension alone also benefited from β-blockers. In a 3-year, placebocontrolled, RCT of 201 patients with CSPH, propranolol (or carvedilol for those who did not respond to propranolol) reduced the
risk of decompensation or death (16% vs 27%). 24,48 Variceal
bleeding should be treated with band ligation during timely
endoscopy (<24 hours after presentation),106 vasoactive medications (compared with placebo, octreotide was associated with
higher rates of hemostasis at 5 days [77% vs 58%] in a metaanalysis of randomized trials),17 and prophylactic antibiotics (associated with reduced short-term mortality to 18.5% vs 22.2%
with placebo in a meta-analysis of randomized trials18). In a randomized trial of 63 patients with acute variceal bleeding who
achieved initial hemostasis, transjugular intrahepatic portosystemic shunt (TIPS, a stent placed in a tract created to connect
branches of the hepatic and portal veins) performed within 72
hours (compared with no TIPS placement) improved 1-year survival (61% vs 86%).19
Ascites
In an RCT of 100 patients that compared sequential therapy
with aldosterone antagonists followed by the addition of loop
diuretics to a guideline-recommended combination of both
diuretics, ascites resolved at a higher rate with combination
therapy (76% vs 56%) and was associated with lower rates of
hyperkalemia (4% vs 18%).16,53 Sodium restriction (<2 g/d) is
recommended because greater intake may be associated with
worse ascites.53 However, sodium restriction must be carefully
monitored, ideally under the care of a nutritionist. Sodium restriction may not improve the effectiveness of diuretics (as seen in
a clinical trial of 115 hospitalized patients randomized to daily
sodium intake of 2760 mg or 920 mg resulting in rates of refractory ascites of 5.7% vs 4.8%, respectively). 107 Further, many
patients who successfully restrict sodium do not meet daily calorie
and protein goals.53
Paracentesis is associated with temporary relief for patients
with symptomatic ascites. Multiple paracenteses, despite
attempts to optimize diuretic dosage, should prompt referral for
TIPS. In a meta-analysis of 305 patients in randomized trials, compared with treatment without TIPS, TIPS was associated with
reduced risk of recurrent ascites (42% vs 89%) and reduced
2-year mortality (51% vs 65%), but more hepatic encephalopathy
episodes per year (mean [SD], 1.1 [1.9] vs 0.63 [1.2]).108 While the
risk of TIPS rises with MELD score and age, rather than using an
absolute MELD cutoff for TIPS candidacy, expert consensus recommends a multidisciplinary approach and shared decisionmaking (level of evidence, 2a).109
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Diagnosis and Management of Cirrhosis and Its Complications
Table 2. Treatment of Cirrhosis
Symptoms and diagnosis
First-line therapies
Effectiveness
Adverse effects
Acute therapy: sips of pickle juice
at cramp onset
Preventive therapy: taurine,
500-1000 mg, twice daily
Pickle juice: reduction of 2.3
points on VAS for cramp severity
compared with 0.4 for a
tap-water control among 80
patients in a randomized trial27
Pickle juice: none observed in
trial27
Symptoms of cirrhosis
Muscle cramps
Patient reported
Taurine: none observed in trial28
Taurine: 7 fewer cramps
compared with placebo over 2
wk28 in a randomized,
double-blind crossover trial of 30
patients
Pruritus
Patient reported
Moisturizers
Cholestyramine, 4-16 g daily
Naltrexone, 50 mg daily
Cholestyramine: efficacy data
from trials enrolling people with
cirrhosis are lacking but
considered first-line therapy
given safety30
Naltrexone: placebo-controlled
RCT of 16 patients followed up
for 4 wk; naltrexone significantly
improved pruritus as measured by
a 100-mm VAS of pruritus
severity with a mean (SD) 54%
(10%) reduction from baseline
compared with an 8% (10%) with
placebo31
Cholestyramine: none observed in
trials30
Naltrexone: 50% experienced 3 d
of malaise with nausea (vs 0% with
placebo); 62.5% experienced mild
abdominal cramps (vs 12.5% with
placebo)31
Sleep disorder
Patient reported
Sleep hygiene (improving
environment, relaxation, limiting
caffeine)
Hydroxyzine, 25 mg, nightly
Hydroxyzine: in a 10-d
randomized, double-blind,
placebo-controlled trial of 35
patients with covert HE, 40% with
improved self-reported sleep and
70% with improved sleep
efficiency by actigraphy
(noninvasive method of
monitoring rest/activity cycles)
compared with 0% and 16%
worsening among those receiving
placebo, respectively29
Hydroxyzine: risk of increased
confusion after 10 d (6% vs 0%
with placebo)29
Sexual
dysfunction
Patient reported
Cessation of smoking and
alcohol use, counseling, PDE-5i
(ie, tadalafil, 10 mg)
Cessation of alcohol use
associated with 25% rate of
achieving self-reported normal
sexual function among 60 men
abstinent from alcohol
for >6 mo32
None observed in trial
Tadalafil: in a 12-wk,
randomized, placebo-controlled
trial of 140 men, 63% had
improved erectile function
compared with 30% receiving
placebo33
Complications of cirrhosis
Hepatic
encephalopathy
(HE)
Covert HE: deficits in executive
function, sleep disorder,
vegetative behavior, and gait
disturbance
Overt HE: asterixis,
disorientation, lethargy,
and coma
Lactulose, 10-20 g, 2-3 times
daily with goal of 2-3 soft bowel
movements
Rifaximin, 550 mg, twice daily
Nutrition, 1.25 g of
protein/kilogram of actual body
weight/d and nighttime snack
(>250 kcal)
In meta-analyses of randomized
trials, lactulose was associated
with reduced mortality relative to
placebo (8.5% vs 14%) in
randomized trials involving 705
patients and reduced risk of
recurrent overt HE (25.5% vs
46.8%) in randomized trials
involving 1415 patients14
Lactulose: relative to placebo,
bloating (46% vs 15%), diarrhea
(29% vs 37% but higher if excess
intake), nausea (15% vs 2%)14
Rifaximin: high cost, no other
adverse events seen in trial13
High-protein diet: none15
In a 6-mo placebo-controlled,
double-blind RCT, rifaximin
reduced hospitalization for HE to
13.6% vs 22.6% with placebo
among 299 patients with prior HE
with lactulose13
In a 6-mo RCT of 120 patients
with covert HE, the 60 patients
receiving protein supplements to
achieve 1-1.5 g/kg daily protein
intake had lower rates of overt HE
relative to placebo (10% vs
21.7%)15
(continued)
87
Hyponatremia
Hyponatremia (<135 meq/L) is common among patients with decompensated cirrhosis, affecting up to 31% of a national sample of
1596
13 940 patients undergoing liver transplant evaluation. Though evidence supporting its management is limited, hyponatremia is treated
by addressing volume depletion (if present) and optimizing diuretic
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Review Clinical Review & Education
Table 2. Treatment of Cirrhosis (continued)
Ascites
Symptoms and diagnosis
First-line therapies
Effectiveness
Adverse effects
Physical examination (distended
abdomen, shifting dullness) and
free fluid on abdominal imaging
Aldosterone antagonists
(spironolactone, 50-400 mg)
Loop diuretics (furosemide,
40-160 mg)
Combined aldosterone
antagonists and loop diuretics
resolved ascites in 76% of
patients compared with 56% who
received aldosterone antagonists
alone in a randomized trial of 100
patients16
Combination aldosterone
antagonists and loop diuretics:
hyperkalemia (4%), kidney injury
(12%)
Aldosterone antagonists alone:
hyperkalemia (18%), kidney injury
(16%)
Not reported in trials of patients
with ascites but observed in other
trials of spironolactone:
gynecomastia (rate unknown)53
Paracentesis relieves abdominal
symptoms but ascites recurs
Varices and
variceal
bleeding
Endoscopic evaluation
Prevention of bleeding:
carvedilol, 12.5 mg, daily (can be
used for primary or secondary
prophylaxis); propranolol, 40 mg,
twice a day increased up to
160 mg twice a day with goal
heart rate of 55 beats/min
Active bleeding:
Intravenous octreotide/
terlipressin ceftriaxone
(1 g/d for 5 d)
Band ligation or sclerotherapy
of varices
Primary prophylaxis with
carvedilol or propranolol in a
double-blind, placebo-controlled
trial of 201 patients with CSPH,
carvedilol or propranolol reduced
risk of decompensation or death
(16% vs 27%) by 3 y24
Treatment of hemorrhage:
vasoactive medications (in
addition to endoscopic therapy)
Octreotide: associated with
hemostasis at 5 d in 77%
compared with 58% with placebo
in a meta-analysis of randomized
trials17
Carvedilol or propranolol:
weakness (23% vs 17%)24
Octreotide: hyperglycemia (23% vs
13% with placebo)17
Terlipressin: no difference
compared with placebo in
meta-analysis of trials, can be
associated with digital ischemia
and abdominal cramping90
TIPS: none observed in trial19
Terlipressin: associated with
hemostasis at 5 d in 65%
compared with 46% with placebo
in a meta-analysis of randomized
trials89
Prophylactic antibiotics (in
addition to endoscopic therapy):
associated with reduced mortality
to 18.5% vs 22.2% with placebo
in a meta-analysis of randomized
trials18
Secondary prophylaxis with
preemptive TIPS: in a randomized
trial of 63 patients with acute
variceal bleeding, preemptive
TIPS within 72 h improved 1-y
survival to 86% vs 61% for the
control group19
Spontaneous
bacterial
peritonitis
(SBP)
Ascites concentrations of
neutrophils >250/μL can present
without fever or pain in up to
one-third of cases
Hepatorenal
50% or ≥0.3 mg/dL increase in
syndrome (HRS) serum creatinine within 7 d from
the last measure and does not
respond to 2 d of volume
expansion
Third-generation cephalosporin
for 5 d
Albumin, 1.5g/kg, on day 1
and 1 g/kg on day 2
Meropenem and daptomycin for
nosocomial SBP
Terlipressin, 0.85 mg, IV every
6h
Norepinephrine, 0.5-3 mg/h, IV
Albumin: compared with
antibiotics alone, reduces 3-mo
mortality in RCT of 126 patients
from 41% to 22%; kidney injury
occurred in 33% vs 6%20
If nosocomial SBP: in a
randomized trial of 32 patients,
compared with ceftazidime,
meropenem and daptomycin
increased SBP resolution (87% vs
25%) but not 90-d survival91
In placebo-controlled (1:2 ratio),
randomized trial, terlipressin
improved kidney recovery (39%
vs 18%) in 300 patients with
HRS21
Not reported in trial. However,
albumin infusions can increase risk
of pulmonary edema (4% vs 1%
from placebo in a trial of albumin
for hospitalized patients with
cirrhosis)92
Terlipressin: death due to
respiratory failure (11% vs 2%
from placebo)21
Norepinephrine: none reported in
trial93; however, 25% experienced
tachyarrhythmia in a cohort study,
In a randomized trial of 46
patients comparing terlipressin vs 10% requiring treatment
discontinuation94
norepinephrine, the rate of
achieving creatinine <1.5 mg/dL
93
was 39.1% vs 43.4%
Abbreviations: CSPH, clinically significant portal hypertension; IV, intravenous;
PDE-5i, phosphodiesterase-5 inhibitor; RCT, randomized clinical trial;
TIPS, transjugular intrahepatic portosystemic shunt; VAS, visual analog scale.
SI conversion factor: to convert creatinine to μmol/L, multiply by 88.4.
doses; fluid restriction is reserved for patients with levels less than
125 mmol/L despite optimization.53
refractory to diuretics and hypoalbuminemia investigated the role
of weekly infusions of 40 g of 25% human albumin solution compared with no infusions110; 18-month survival was higher in the
albumin group (77%) compared with the no infusion group
(66%).110 However, albumin infusion is not yet recommended for
clinical care.53 In an open-label randomized trial enrolling 777
Hypoalbuminemia
Because hypoalbuminemia (<3.5 g/dL) is common among patients
with ascites, an open-label RCT enrolling 431 patients with ascites
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Diagnosis and Management of Cirrhosis and Its Complications
Table 3. Therapies for Cirrhosis and Its Complications, According to Etiologya
Risk factors
First-line therapies
Effectiveness
Alcohol-related
liver disease
Alcohol use disorder,
obesity
Abstinence from alcohol.
Counseling and
medications such as
naltrexone
In a meta-analysis of observational studies, NA
abstinence was associated with reduced
risk of mortality after 1.5 y (HR, 0.51
[95% CI, 0.33-0.81])12
Nonalcoholic fatty
liver disease
(NAFLD)
Insulin resistance,
obesity, metabolic
syndrome
Weight loss. Nutritionist
referral, medical weight
loss therapies, and
bariatric surgery in
highly selected patients
(ie, without portal
hypertension)
No randomized trials in patients with
cirrhosis
Among 1158 patients with NAFLD and
fibrosis, bariatric surgery was associated
with 2.3% 10-y risk of cirrhosis or
decompensation compared with 9.6% for
508 matched patients who did not
undergo surgery6
Rates of adverse events are unknown.
Inadvertent protein restriction while dieting
could worsen sarcopenia and increase the
risk of hepatic encephalopathy. Bariatric
surgery is associated with a 4.7% risk of
decompensation in patients with
compensated cirrhosis99
Hepatitis C
Blood transfusions prior
to 1990, shared needles
or drug implements,
rarely sexual
transmission
Direct-acting antivirals
(eg, sofosbuvir/
velpatisvir or
glecaprevir/pibrentasvir)
Observational data sources: SVR,
compared with not achieving SVR, is
associated with lower 10-y all-cause
mortality (8.9% vs 26.0%)7
Headache: 25%
Vertical transmission,
sexual transmission,
shared needles, or drug
implements
Virological control with
antiviral therapy
(eg, tenofovir
alafenamide, tenofovir
disoproxil fumarate,
entecavir)
Hepatitis B
1598
Adverse effects
SVR, compared with not achieving SVR,
is associated with a lower risk of HCC
(3.3 vs 13.2/1000 person-years)100
Randomized (2:1), placebo-controlled
trial of lamivudine in 651 patients with
advanced fibrosis or cirrhosis: compared
with placebo, treatment lowered risk of
HCC (3.9% vs 7.4%)8
Observational study of tenofovir
disoproxil fumarate: compared with no
treatment (291 patients), antiviral
therapy (797 patients) was associated
with a lower risk of HCC (9.8% vs 14.9%),
decompensation (1.1% vs 13.1%), and
death (1.1% and 13.1%) in people with
cirrhosis from Hong Kong, South Korea,
and California101
Lamivudine associated with cough relative
to placebo (14% vs 7%)8
Tenofovir disoproxil fumarate was
associated with decreased bone density
(1.72% in hip, 2.29% in spine) after 48 wk
of therapy102
Among patients with hepatitis B and HIV
coinfection, 0% receiving tenofovir
alafenamide discontinued therapy for
kidney complications within 144 wk
compared with 3.6% receiving tenofovir
disoproxil fumarate103
Hemochromatosis
Autosomal recessive
inheritance; 2 copies of
the C282Y variant of the
HFE gene
Iron depletion
(phlebotomy) with a
goal of 50-100 μg/L of
ferritin
In a nationwide, observational study of
Danish patients, 10-y overall survival was
70% among 66 patients receiving
phlebotomy and 20% of 62 untreated
patients9
Venipuncture site bleeding and infection,
anemia, and syncope (rates unknown)
Primary biliary
cholangitis (PBC)
More common among
women and first-degree
relatives of patients
with PBC
Ursodeoxycholic acid
(UDCA) at
13-15 mg/kg/d
In a pooled analysis of 548 patients in 3
randomized trials, UDCA improved
transplant-free 4-y survival compared
with placebo (17% vs 24%)10
Not observed in trials10
Rare adverse events may include weight
gain (<5 lbs),104 loose stool, and hair
thinning
Primary sclerosing
cholangitis (PSC)
Ulcerative colitis
No proven therapy
NA
NA
Autoimmune
hepatitis
Unknown
Combination prednisone
(20-40 mg/d) and
azathioprine
(50-150 mg/d)
In a meta-analysis of randomized trials of
3-4 y duration, the rates of remission and
overall mortality associated with
combination therapy (received by 44
patients) was 43% and 0% while placebo
(received by 33 patients) was associated
with 39% mortality and 0% remission11
Not reported in meta-analysis
Prednisone is associated with adverse
effects such as weight gain, rash, cataracts,
infection risk, and osteoporosis
Azathioprine is associated with leukopenia,
pancreatitis, nonmelanoma skin cancer,
lymphoma, and increased infection risk
Abbreviations: HCC, hepatocellular carcinoma; HR, hazard ratio; NA, not
applicable; SVR, sustained virologic response (cure of hepatitis C).
a
hospitalized patients with cirrhosis and albumin level less than
3.0 g/dL, albumin infusions (mean dose, 200 g) targeted to
increase the albumin level to more than 3.0 g/dL did not improve
the rate of a composite outcome (new infection, kidney dysfunction, or death) for up to 14 days (29.7% vs 30.2% for the standard
care group). The rate of pulmonary edema (4% vs 1%) was higher
for the albumin group.92
nitis, patients should receive secondary prophylaxis with suppressive oral antibiotics (eg, trimethoprim/sulfamethoxazole or
ciprofloxacin).53 Primary prophylaxis may not be effective given the
prevalence of resistant organisms in the community. Antibiotic use
is associated with adverse events (eg, trimethoprim-related hyperkalemia, antibiotic-related diarrhea, or Clostridioides difficile
infection).53
Spontaneous Bacterial Peritonitis
Hepatorenal Syndrome
Spontaneous bacterial peritonitis should be treated with guidelinerecommended third-generation cephalosporins such as ceftriaxone, 2 g, daily and intravenous albumin.53 In an RCT of 126 patients, compared with antibiotics alone, 25% albumin (1.5 g/kg on
day 1, 1 g/kg on day 2) reduced mortality from 41% to 22% at 3-month
follow-up.20 After a first episode of spontaneous bacterial perito-
Optimal therapy for hepatorenal syndrome includes carefully monitored volume expansion with intravenous albumin and vasoconstrictor therapy to increase mean arterial pressure and kidney perfusion. In an RCT of 300 patients, compared with placebo,
terlipressin improved kidney function (creatinine ⱕ1.5 mg/dL; 39%
vs 18%) but was associated with an increased risk of death due to
Liver transplant is the definitive therapy for decompensated cirrhosis of any
cause; the underlying chronic liver disease may recur and require treatment.
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respiratory failure (11% vs 2% with placebo).21 In a meta-analysis,
norepinephrine, 0.5 to 3 mg/h, was noninferior to terlipressin with
a 50% pooled rate of kidney injury reversal.111
Review Clinical Review & Education
Despite low platelet counts or prolonged INR, bleeding after lowrisk procedures (eg, paracentesis, endoscopy) is rare. For example,
the rate of major bleeding was 0.2% in a pooled analysis of 2113
patients with INR greater than 1.5 and/or platelet count less than
50 × 109/L undergoing paracentesis.112 In guidelines from the
American Association for the Study of Liver Diseases and the Society of Interventional Radiology, neither prophylactic plasma, platelet transfusions, nor vitamin K supplementation is recommended.58,112
in a meta-analysis of RCTs enrolling 1415 patients with hepatic
encephalopathy.14 In a meta-analysis of 3 clinical trials of 126 participants receiving lactulose, lactulose was associated with an
improvement of 6.92 (95% CI, 6.66-7.18) in the Sickness Impact
Profile (ranges from 0 [best] to 68 [worst]; clinically important differences are >4).113 In a 6-month placebo-controlled, double-blind
RCT, rifaximin reduced hospitalization for hepatic encephalopathy
from 22.6% to 13.6% among 299 patients with prior hepatic
encephalopathy taking lactulose.13 Guidelines recommend that all
patients should receive education about nutrition, including consumption of 1 g of protein per kilogram of actual body weight, 30 to
40 kCal/kg, and a nighttime snack, as overnight fasting exacerbates
catabolism (Table 2).114,115
Hepatic Encephalopathy
Limitations
Patients who present with clinically manifest hepatic encephalopathy (grade ⱖ2) should be evaluated for infection, gastrointestinal
bleeding, dehydration, and receipt of psychoactive medications.76
Patients should receive intravenous hydration and lactulose, starting at a dose of 60 cc, followed by 20 cc of lactulose every 1 to 2
hours until a bowel movement occurs, followed by maintenance
with sufficient lactulose to achieve 2 to 3 soft bowel movements
per day.43 After the acute episode resolves, secondary prophylaxis
also includes rifaximin, 550 mg, twice a day.13 In a meta-analysis of
705 patients with hepatic encephalopathy, compared with placebo, lactulose was associated with reduced mortality (8.5% vs
14%).14 Compared with placebo, lactulose was associated with
reduced recurrent overt hepatic encephalopathy (25.5% vs 46.8%)
This review has several limitations. First, this was not a systematic review. Second, some relevant research may have been missed. Third,
the quality of the included evidence was not formally assessed.
Coagulopathy
Approximately 2.2 million US adults have cirrhosis. Many symptoms
such as muscle cramps, poor sleep, pruritus, and sexual dysfunction
are common and treatable. First-line therapies include carvedilol or
propranolol to prevent variceal bleeding, lactulose for hepatic encephalopathy, combination aldosterone antagonists and loop diuretics for ascites, and terlipressin for hepatorenal syndrome.
2. Tapper EB, Parikh ND. Mortality due to cirrhosis
and liver cancer in the United States, 1999-2016. BMJ.
2018;362:k2817. doi:10.1136/bmj.k2817
8. Liaw YF, Sung JJ, Chow WC, et al; Cirrhosis Asian
Lamivudine Multicentre Study Group. Lamivudine
for patients with chronic hepatitis B and advanced
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https://wonder.cdc.gov/mcd-icd10-provisional.
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N, Fenger K. Clinically overt hereditary
hemochromatosis in Denmark 1948-1985. Ann
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s002770100371
4. Serper M, Tapper EB, Kaplan DE, Taddei TH,
Mahmud N. Patterns of care utilization and
hepatocellular carcinoma surveillance. Am J
Gastroenterol. 2023;118(2):294-303. doi:10.14309/
ajg.0000000000002011
10. Poupon RE, Lindor KD, Cauch-Dudek K,
Dickson ER, Poupon R, Heathcote EJ. Combined
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30349-8
ARTICLE INFORMATION
Accepted for Publication: March 27, 2023.
Conflict of Interest Disclosures: Dr Tapper
reported grants from Salix Pharmaceuticals and
consulting fees from Madrigal Pharmaceuticals and
Novo Nordisk, all paid to his institution, and
consulting fees from Bausch Health, Mallinckrodt
Pharmaceuticals, Axcella Health, Novo Nordisk,
Ambys Medicines, Lipocine, Kaleido, and Takeda
Pharmaceutical Company. Dr Parikh reported
receiving grants from Exact Sciences, Genentech,
Glycotest Inc, and Target PharmaSolutions and
personal fees from Eli Lilly, Freenome, Eisai, Gilead
Sciences, Bayer, Exelixis, and Fujifilm Medical.
Funding: This study was funded by a grant from the
National Institutes of Health (U01DK130113).
Role of the Funder/Sponsor: The funder had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Submissions: We encourage authors to submit
papers for consideration as a Review. Please
contact Mary McGrae McDermott, MD, at
[email protected].
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