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 Author Affiliations: Division of
taurine for reducing muscle cramps, and tadalafil for improving sexual dysfunction in men. Gastroenterology and Hepatology,
University of Michigan, Ann Arbor.
CONCLUSIONS AND RELEVANCE Approximately 2.2 million US adults have cirrhosis. Many
Corresponding Author: Elliot B.
symptoms, such as muscle cramps, poor-quality sleep, pruritus, and sexual dysfunction, are Tapper, MD, Division of
common and treatable. First-line therapies include carvedilol or propranolol to prevent Gastroenterology and Hepatology,
variceal bleeding, lactulose for hepatic encephalopathy, combination aldosterone antagonists University of Michigan, 3912
Taubman, 1500 E Medical Center Dr,
and loop diuretics for ascites, and terlipressin for hepatorenal syndrome.
Ann Arbor, MI 48109 (etapper@
umich.edu).
JAMA. 2023;329(18):1589-1602. doi:10.1001/jama.2023.5997 Section Editor: Mary McGrae
McDermott, MD, Deputy Editor.

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 (ap-
proximately 45% of all cirrhosis cases), hepatitis C (41%), and non-
alcoholic fatty liver disease (26%), with many patients having
overlapping causes.4 However, hepatitis C is now curable with direct-
acting antivirals and most newly diagnosed cirrhosis is due to non-
alcoholic fatty liver disease (NAFLD) (accounting for 61.8% of inci-
dent cases) and alcohol use disorder (accounting for 20.0%).5
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 interven-
tions that improve survival by preventing or reducing the compli-
cations of cirrhosis.24 Such complications include variceal hemor-
rhage, 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 poor-
quality sleep,29 pruritus,30,31 and sexual dysfunction,32,33 which can
be improved with therapy.

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 Clinical Review & Education Review
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, vibration-
controlled 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 di-
agnosis and management of cirrhosis and its complications (Box).
Methods
We searched PubMed (January 1, 2000, to March 10, 2023) for sys-
tematic 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 follow-
up. Of 8887 articles retrieved, 115 were included, consisting of 9 prac-
tice guidelines, 3 consensus statements, 25 RCTs, 17 meta-
analyses, 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 Veter-
ans Administration (2020-2021), the causes of cirrhosis were hepa-
titis C (24.0%), alcohol related (27.9%), hepatitis C and alcohol re-
lated (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
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Diagnosis and Management of Cirrhosis and Its Complications
men.35-37 Between 2010 and 2021, age-adjusted mortality from cir-
rhosis 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 de-
scribed further in Table 1.24,34,36,38-56
Pathophysiology of Cirrhosis
Chronic inflammatory liver injury causes activation of hepatic myo-
fibroblasts and macrophages, which increase collagen accumula-
tion (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 ste-
atosis also increases vascular resistance. In both NAFLD and alcohol-
related 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, nu-
trient 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 de-
picted 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 hy-
pertension, defined as a pressure gradient between the hepatic and
portal vein of 10 mm Hg or greater, promotes development of vari-
ces (collateral vessels that shunt portal blood to systemic veins and
often result in dilated esophagogastric channels prone to hemor-
rhage). 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 vol-
ume expansion, and kidney vasoconstriction, predisposing pa-
tients to ascites, hyponatremia, and kidney injury, particularly in
the setting of volume depletion, infection, or hemorrhage. Increas-
ing portal pressure induces ascites from hepatic sinusoids. In-
creased 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 he-
patic encephalopathy. Hepatic encephalopathy can develop at low
ammonia levels in the context of infection.59 While the mecha-
nisms are incompletely characterized, the presence of hepatic fi-
brosis and hepatic injury from inflammation contribute to the ge-
netic 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 poor-
quality sleep (63%),60 and sexual dysfunction (53%).61 Risk fac-
tors, such as diabetes or alcohol use, and symptoms, such as muscle
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Diagnosis and Management of Cirrhosis and Its Complications
Table 1. Epidemiology of Cirrhosis and Its Complications in the US
Condition Prevalence/incidence
Cirrhosis Prevalence, 840-1058/100 00034,36
Hepatic encephalopathy 40% 5-y risk overall among patients with
(HE) cirrhosis
10% 1-y risk if Child Ab with portal
hypertension
25% 1-y risk if Child Bb with portal
hypertension41
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
Variceal bleeding Varices form at a rate of 9%/y in patients
with cirrhosis47
Variceal bleeding occurs at a rate of
1.2%-4% within 3 y among patients with
cirrhosis48
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
Spontaneous bacterial 11% Annual risk in patients with ascites53
peritonitis
Hepatorenal syndrome 8% Annual risk in patients with ascites56
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
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 dis-
coloration, absent lunula, dark pink at tip), gynecomastia, caput me-
dusa, facial telangiectasia, palmar erythema, decreased body hair,
testicular atrophy, and jaundice.62
Screening for cirrhosis in the general population is not cur-
rently 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 bi-
opsy is considered the criterion standard to diagnose cirrhosis, al-
though it is being increasingly replaced by noninvasive methods for
fibrosis assessment. Biopsy is reserved for patients with noninva-
sive 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 diag-
nose cirrhosis. Compared with biopsy, these measures are less ex-
pensive, safer, and simpler to follow longitudinally (Figure 2). The most
common serologic tests capture indirect signs of liver fibrosis and dys-
function (eg, thrombocytopenia, reflecting reduced platelet produc-
tion and splenic sequestration and a higher ratio of aspartate amino-
transferasetoalanineaminotransferase).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
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Review Clinical Review & Education
Mortality Hospitalization rates
56 989 in 2020a 56.4-125.7 of every 100 000
hospitalizations involve cirrhosis38,39
25.8% 30-d readmission rate40
Median survival, 0.95 y and 2.5 y for those HE presents in 10.1% of cirrhosis
aged ≥65 y or <65 y, respectively44 hospitalizations45
Median survival, 1.08 y46 Ascites present in 47.7% of cirrhosis
hospitalizations45
17.7% 6-wk mortality after variceal Variceal bleeding occurs in up to 70.6 of
bleeding49 every 100 000 hospitalizations in the US50
and 10.5% of cirrhosis hospitalizations45
<20% 5-y survival, dependent on stage of NA
detection; 11 000 annual deaths
nationally52
Median survival after diagnosis of Spontaneous bacterial peritonitis occurs in
spontaneous bacterial peritonitis, 11 wk54 3.1% of cirrhosis hospitalizations55
Median survival is 2 wk after diagnosis of Hepatorenal syndrome occurs in 1.2% of
hepatorenal syndrome56 cirrhosis hospitalizations45
ascites and normal albumin, bilirubin, and international normalized ratio; class B
refers to patients with ascites and/or mild abnormalities in laboratory indices.
c
Covert HE is an early stage of HE characterized by deficits in executive
function, poor sleep quality, and poor balance.
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 hepa-
titis C. FIB-4 has high negative predictive value (96%) but low posi-
tive 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 guide-
lines 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 prob-
abilities of cirrhosis of 89% or greater.66 Elastography provides a liver
stiffness measurement (LSM; measured in kilopascals [kPa]) that cor-
relates with the abundance of fibrosis.66 LSM of 15 kPa or greater
by vibration-controlled transient elastography (VCTE), an ultrasound-
based method that uses a handheld probe for point-of-care assess-
ments, identified cirrhosis with 95.5% specificity (62% positive pre-
dictive 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 di-
vided by height in meters squared). However, cost and access limit
widespread use of magnetic resonance elastography. Liver inflam-
mation (ie, alanine aminotransferase >120 IU/L68) and central ve-
nous congestion from heart failure can also increase liver stiffness,
generating false-positives from elastography.
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 Clinical Review & Education Review 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
CIRRHOTIC LIVER
Reduced metabolic activity including Formation of nodules
protein synthesis, detoxification, Portal flow blockage leading
nutrient storage, and bilirubin clearance to portal hypertension

Systemic effects of cirrhosis

Hepatocyte Fibrosis
death accumulation Disrupted portal flow
Development of varices
CENTRAL and variceal hemorrhage
VEIN
Decreased cardiac return
H E PAT I C and decreased central
ARTERY blood volume
Increased plasma
SINUSO renin activity
ID
Vasoconst Portal
riction Peripheral volume expansion
hypertension
Chronic inflammatory liver injury Hyponatremia
Increased vasoconstrictor P O RTA L Kidney vasoconstriction
signaling via endothelin-1 VEIN and injury
Decreased vasodilator production Restriction of
sinusoidal flow Gut-barrier disruption
Enteric bacteria release
leading to inflammation
BILE
Increased DUCT Ascites
lymph
production Hepatic dysfunction
Increased lymph production
Extravasation of lymph Increased nitric oxide levels
into the peritoneum (ascites) Increased vasodilatory
neurotransmitters
Hepatic fibrogenesis and Increased ammonia levels
chronic inflammatory injury
! can lead to the development
Hepatic encephalopathy (HE)
of hepatocellular carcinoma

Cirrhosis leads to intrahepatic resistance, which causes portal hypertension and, portosystemic shunting, resulting in the multisystem complications of cirrhosis,
at later stages, hepatic insufficiency, which disrupts the liver’s normal metabolic eg, hepatic encephalopathy, sarcopenia, ascites, and kidney injury.
functions. Together these features cause gut-barrier disruption and

Diagnosis of Portal Hypertension
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 hyper-
tension (CSPH) is defined as a gradient of 10 mm Hg or greater (nor-
mal <5 mm Hg).22 In a study of 213 patients with pressure gradients
less than 10 mm Hg, approximately 90% remained decompensa-
tion 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 alter-
native 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 cirrho-
sis from Europe and Canada, a nomogram based on LSM and plate-
let counts was developed to predict CSPH.71 For example, patients
with an LSM of 25 kPa or greater and any platelet count have a preva-
lence of CSPH of at least 66%, increasing to 90% or more for pa-
tients with platelet counts of 110 × 109/L or less.71
All patients with varices have CSPH. Because portal pressures are
not routinely measured, it is recommended to screen for varices in pa-
tients 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 non-
invasive 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 thin-
walled) varices.73 According to these data, only 2.2% of high-risk vari-
ces were missed if endoscopy was not performed.73
Diagnosing Complications of Cirrhosis
The diagnosis of ascites can be made using abdominal ultrasonog-
raphy 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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Diagnosis and Management of Cirrhosis and Its Complications Review Clinical Review & Education

Figure 2. Noninvasive Diagnosis and Risk Stratification of Patients at Risk for Cirrhosis

Assess for risk factors and signs of cirrhosis

Risk factors Signs of cirrhosis in the presence of chronic liver disease

• Obesity • Type 2 diabetes • Terry nailsa • Gynecomastia • Caput medusa
• Hepatitis C • Alcohol use disorder • Facial telangiectasia • Testicular atrophy • Jaundice
• Hepatitis B • Other chronic liver disease • 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

The presence of cirrhosis is

Determine liver stiffness measurement (LSM) associated with an increased risk of
Elastography testing selected based on patient BMI complications such as liver cancer
and decompensation including
BMI ≤40 Vibration-controlled BMI >40 Magnetic resonance ascites, hepatic encephalopathy, and
transient elastography (VCTE) elastography (MRE) variceal hemorrhage. It is important
to evaluate for the presence of
Suggestive results: High LSM (≥15 kPa on VCTE or ≥5 kPa on MRE)
cirrhosis in people with risk factors or
any diagnosed chronic liver disease.
While physical examination findings
Confirm diagnosis of cirrhosis with FIB-4 and LSM results may be suggestive, it is
recommended to stratify risk for all
Highest degree of certainty: Requires further confirmation: Cirrhosis is unlikely: using the FIB-4 followed by
FIB-4 score ≥2.67 and high LSM FIB-4 score <2.67 and high LSM FIB-4 score >2.67 and low LSM elastography for at-risk patients.
After identifying patients with
cirrhosis, optimal care may involve
referral to a hepatologist, liver cancer
Consider liver biopsyb Noncirrhotic screening, and consideration of
endoscopy for varices screening
Stage 4 fibrosis and/or initiation of nonselective
β-blockers. BMI indicates
Initiate evidence-based care body mass index.
a
Terry nails identified by white
Screen for varices with endoscopy Screen for liver cancer Refer to Treat underlying liver disease discoloration, absent lunula, and
or defer if VCTE result is <20 kPa with biannual ultrasound hepatologist Address causal or comorbid
and platelet count is >150 x 109/L and α-fetoprotein dark pink tips.
obesity and alcohol use disorder
b
Biopsy is of highest value when the
diagnosis of the underlying liver
Initiate nonselective β-blockers Refer for transplant evaluation if patient disease is unclear or noninvasive
(eg, carvedilol) if varices are found develops ascites, hepatic encephalopathy,
tests yield indeterminate or
Consider nonselective β-blockers variceal bleeding, or liver cancer
discordant results. The role of
if VCTE result is >25 kPa
biopsy is also based on patient
preference and clinical context.

Up to one-third of patients with spontaneous bacterial peritonitis
do not have fever or pain. Therefore, diagnostic paracentesis is rec-
ommended 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 nor-
mal 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 encepha-
lopathy (grades ⱖ2) presents with asterixis, disorientation, leth-
argy, 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
below healthy control performance on the 5-test paper-pencil bat-
tery 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 speci-
ficities 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 pro-
spective 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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 Clinical Review & Education Review
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
Hepatic venous <5 mm Hg 5-9 mm Hg ≥10 mm Hg
pressure gradient
Compensated Increasing risk of complications Decompensated
cirrhosis
Control of underlying liver disease Nonselective
Alcohol abstinence β-blockers
Weight loss (if obesity)
Hepatitis B viral suppression
Hepatitis C cure
Disease-modifying measures and interventions
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 carci-
noma (HCC) are lacking, screening with biannual abdominal ultra-
sound and serum α-fetoprotein is recommended by the American
Association for the Study of Liver Diseases to improve early HCC de-
tection in patients with cirrhosis, regardless of etiology.76,79 In a meta-
analysis 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 screen-
ing 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 contrast-
enhanced cross-sectional imaging can be used to make the
diagnosis.79 A solid lesion exhibiting specific features (eg, arterial-
phase 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 me-
dian survival of 12 years according to a pooled analysis of 806 pro-
spectively followed up patients.82 Survival is reduced after any de-
compensation (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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Diagnosis and Management of Cirrhosis and Its Complications
Variceal bleeding
Variceal band ligation Transjugular intrahepatic
Intravenous octreotide portosystemic shunt (TIPS)
Antibiotics plus
nonselective β-blockers
Spontaneous Hepatorenal Death
cirrhosis Ascites bacterial peritonitis syndrome or
Transplant
Aldosterone- Antibiotics Terlipressin
antagonists plus albumin Norepinephrine
plus diuretics
TIPS
Falls
Hepatic encephalopathy Trauma Coma
Lactulose Rifaximin High-protein diet
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 cirrho-
sis was associated with a median survival of 1.1 years in a cohort of
13 265 patients enrolled in Medicare.46 Median survival time follow-
ing incident overt hepatic encephalopathy was 0.92 years in a study
of 49 164 patients with cirrhosis enrolled in Medicare.37,44 Com-
pared with patients with cirrhosis without any hepatic encepha-
lopathy, 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 hospi-
talization (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 Child-
Turcotte-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 cre-
atinine and sodium levels. The CTP ranges from 5 (75% 5-year sur-
vival) 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 cirrho-
sis and no organ failure.88 Survival is reduced for patients with
organ failures and infections. For patients with 2 organ failures, sur-
vival 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 psy-
chological 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, double-
blind, 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 im-
proved pruritus compared with placebo with a mean (SD) 54% (10%)
reduction in pruritus severity compared with an 8% (10%) in-
crease as measured by a 100-mm visual analog scale.31 In a 10-day
RCT of 35 patients with sleep disorder, compared with placebo, hy-
droxyzine, 25 mg, nightly was associated with a significant 40% im-
provement 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 absti-
nent 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 pa-
tient 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 fi-
brosis. For example, after 12 months of follow-up, 43% of 37 pa-
tients with cirrhosis and hepatitis C cured with direct-acting antivi-
rals experienced regression to a lower fibrosis stage.95 Among 96
patients with hepatitis B cirrhosis treated with tenofovir and fol-
lowed 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 ob-
servational 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 Etiology-
specific therapies and their effects on cirrhosis outcomes are pro-
vided 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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© 2023 American Medical Association. All rights reserved.
Review Clinical Review & Education
α-blocking effects, carvedilol also reduces intrahepatic resis-
tance.22 β-Blockers are standard of care for people with large vari-
ces or prior bleeding.58,76 If large varices are encountered on
endoscopy, carvedilol (optimally dosed at 12.5 mg daily) is pre-
ferred to other β-blockers (grade B evidence, strong recommen-
dation) 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 hyper-
tension alone also benefited from β-blockers. In a 3-year, placebo-
controlled, RCT of 201 patients with CSPH, propranolol (or carve-
dilol 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 medica-
tions (compared with placebo, octreotide was associated with
higher rates of hemostasis at 5 days [77% vs 58%] in a meta-
analysis of randomized trials),17 and prophylactic antibiotics (as-
sociated with reduced short-term mortality to 18.5% vs 22.2%
with placebo in a meta-analysis of randomized trials18). In a ran-
domized trial of 63 patients with acute variceal bleeding who
achieved initial hemostasis, transjugular intrahepatic portosys-
temic 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 sur-
vival (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 restric-
tion 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 refrac-
tory 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, com-
pared 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 rec-
ommends a multidisciplinary approach and shared decision-
making (level of evidence, 2a).109
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 Clinical Review & Education Review Diagnosis and Management of Cirrhosis and Its Complications

Table 2. Treatment of Cirrhosis

Symptoms and diagnosis First-line therapies Effectiveness Adverse effects

Symptoms of cirrhosis
Muscle cramps Patient reported Acute therapy: sips of pickle juice
at cramp onset
Preventive therapy: taurine,
500-1000 mg, twice daily
Pruritus Patient reported Moisturizers
Cholestyramine, 4-16 g daily
Naltrexone, 50 mg daily
Sleep disorder Patient reported Sleep hygiene (improving
environment, relaxation, limiting
caffeine)
Hydroxyzine, 25 mg, nightly
Sexual Patient reported Cessation of smoking and
dysfunction alcohol use, counseling, PDE-5i
(ie, tadalafil, 10 mg)
Complications of cirrhosis
Hepatic Covert HE: deficits in executive Lactulose, 10-20 g, 2-3 times
encephalopathy function, sleep disorder, daily with goal of 2-3 soft bowel
(HE) vegetative behavior, and gait movements
disturbance Rifaximin, 550 mg, twice daily
Overt HE: asterixis,
Nutrition, 1.25 g of
disorientation, lethargy, protein/kilogram of actual body
and coma
weight/d and nighttime snack
(>250 kcal)
Pickle juice: reduction of 2.3 Pickle juice: none observed in
points on VAS for cramp severity trial27
compared with 0.4 for a Taurine: none observed in trial28
tap-water control among 80
patients in a randomized trial27
Taurine: 7 fewer cramps
compared with placebo over 2
wk28 in a randomized,
double-blind crossover trial of 30
patients
Cholestyramine: efficacy data Cholestyramine: none observed in
from trials enrolling people with trials30
cirrhosis are lacking but Naltrexone: 50% experienced 3 d
considered first-line therapy of malaise with nausea (vs 0% with
given safety30 placebo); 62.5% experienced mild
Naltrexone: placebo-controlled abdominal cramps (vs 12.5% with
RCT of 16 patients followed up placebo)31
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
Hydroxyzine: in a 10-d Hydroxyzine: risk of increased
randomized, double-blind, confusion after 10 d (6% vs 0%
placebo-controlled trial of 35 with placebo)29
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
Cessation of alcohol use None observed in trial
associated with 25% rate of
achieving self-reported normal
sexual function among 60 men
abstinent from alcohol
for >6 mo32
Tadalafil: in a 12-wk,
randomized, placebo-controlled
trial of 140 men, 63% had
improved erectile function
compared with 30% receiving
placebo33
In meta-analyses of randomized Lactulose: relative to placebo,
trials, lactulose was associated bloating (46% vs 15%), diarrhea
with reduced mortality relative to (29% vs 37% but higher if excess
placebo (8.5% vs 14%) in intake), nausea (15% vs 2%)14
randomized trials involving 705 Rifaximin: high cost, no other
patients and reduced risk of
adverse events seen in trial13
recurrent overt HE (25.5% vs
46.8%) in randomized trials High-protein diet: none15
involving 1415 patients14
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 13 940 patients undergoing liver transplant evaluation. Though evi-
Hyponatremia (<135 meq/L) is common among patients with de- dence supporting its management is limited, hyponatremia is treated
compensated cirrhosis, affecting up to 31% of a national sample of by addressing volume depletion (if present) and optimizing diuretic

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Diagnosis and Management of Cirrhosis and Its Complications Review Clinical Review & Education

Table 2. Treatment of Cirrhosis (continued)

Symptoms and diagnosis First-line therapies Effectiveness Adverse effects

Ascites Physical examination (distended Aldosterone antagonists
abdomen, shifting dullness) and (spironolactone, 50-400 mg)
free fluid on abdominal imaging Loop diuretics (furosemide,
40-160 mg)
Varices and Endoscopic evaluation Prevention of bleeding:
variceal carvedilol, 12.5 mg, daily (can be
bleeding 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
Spontaneous Ascites concentrations of Third-generation cephalosporin
bacterial neutrophils >250/μL can present for 5 d
peritonitis without fever or pain in up to Albumin, 1.5g/kg, on day 1
(SBP) one-third of cases and 1 g/kg on day 2
Meropenem and daptomycin for
nosocomial SBP
Hepatorenal 50% or ≥0.3 mg/dL increase in Terlipressin, 0.85 mg, IV every
syndrome (HRS) serum creatinine within 7 d from 6h
the last measure and does not Norepinephrine, 0.5-3 mg/h, IV
respond to 2 d of volume
expansion
Abbreviations: CSPH, clinically significant portal hypertension; IV, intravenous; SI conversion factor: to convert creatinine to μmol/L, multiply by 88.4.
PDE-5i, phosphodiesterase-5 inhibitor; RCT, randomized clinical trial;
TIPS, transjugular intrahepatic portosystemic shunt; VAS, visual analog scale.
Combined aldosterone Combination aldosterone
antagonists and loop diuretics antagonists and loop diuretics:
resolved ascites in 76% of hyperkalemia (4%), kidney injury
patients compared with 56% who (12%)
received aldosterone antagonists Aldosterone antagonists alone:
alone in a randomized trial of 100 hyperkalemia (18%), kidney injury
patients16 (16%)
Paracentesis relieves abdominal Not reported in trials of patients
symptoms but ascites recurs with ascites but observed in other
trials of spironolactone:
gynecomastia (rate unknown)53
Primary prophylaxis with Carvedilol or propranolol:
carvedilol or propranolol in a weakness (23% vs 17%)24
double-blind, placebo-controlled Octreotide: hyperglycemia (23% vs
trial of 201 patients with CSPH, 13% with placebo)17
carvedilol or propranolol reduced
risk of decompensation or death Terlipressin: no difference
(16% vs 27%) by 3 y24 compared with placebo in
meta-analysis of trials, can be
Treatment of hemorrhage: associated with digital ischemia
vasoactive medications (in and abdominal cramping90
addition to endoscopic therapy)
TIPS: none observed in trial19
Octreotide: associated with
hemostasis at 5 d in 77%
compared with 58% with placebo
in a meta-analysis of randomized
trials17
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
Albumin: compared with Not reported in trial. However,
antibiotics alone, reduces 3-mo albumin infusions can increase risk
mortality in RCT of 126 patients of pulmonary edema (4% vs 1%
from 41% to 22%; kidney injury from placebo in a trial of albumin
occurred in 33% vs 6%20 for hospitalized patients with
cirrhosis)92
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), Terlipressin: death due to
randomized trial, terlipressin respiratory failure (11% vs 2%
improved kidney recovery (39% from placebo)21
vs 18%) in 300 patients with Norepinephrine: none reported in
HRS21 trial93; however, 25% experienced
In a randomized trial of 46 tachyarrhythmia in a cohort study,
patients comparing terlipressin vs 10% requiring treatment
norepinephrine, the rate of discontinuation94
achieving creatinine <1.5 mg/dL
93
was 39.1% vs 43.4%

doses; fluid restriction is reserved for patients with levels less than
125 mmol/L despite optimization.53
Hypoalbuminemia
Because hypoalbuminemia (<3.5 g/dL) is common among patients
with ascites, an open-label RCT enrolling 431 patients with ascites
refractory to diuretics and hypoalbuminemia investigated the role
of weekly infusions of 40 g of 25% human albumin solution com-
pared 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

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 Clinical Review & Education Review 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 Adverse effects

Alcohol-related Alcohol use disorder, Abstinence from alcohol. In a meta-analysis of observational studies, NA
liver disease obesity Counseling and abstinence was associated with reduced
medications such as risk of mortality after 1.5 y (HR, 0.51
naltrexone [95% CI, 0.33-0.81])12
Nonalcoholic fatty Insulin resistance, Weight loss. Nutritionist No randomized trials in patients with Rates of adverse events are unknown.
liver disease obesity, metabolic referral, medical weight cirrhosis Inadvertent protein restriction while dieting
(NAFLD) syndrome loss therapies, and Among 1158 patients with NAFLD and could worsen sarcopenia and increase the
bariatric surgery in fibrosis, bariatric surgery was associated risk of hepatic encephalopathy. Bariatric
highly selected patients with 2.3% 10-y risk of cirrhosis or surgery is associated with a 4.7% risk of
(ie, without portal decompensation compared with 9.6% for decompensation in patients with
hypertension) 508 matched patients who did not compensated cirrhosis99
undergo surgery6
Hepatitis C Blood transfusions prior Direct-acting antivirals Observational data sources: SVR, Headache: 25%
to 1990, shared needles (eg, sofosbuvir/ compared with not achieving SVR, is
or drug implements, velpatisvir or associated with lower 10-y all-cause
rarely sexual glecaprevir/pibrentasvir) mortality (8.9% vs 26.0%)7
transmission SVR, compared with not achieving SVR,
is associated with a lower risk of HCC
(3.3 vs 13.2/1000 person-years)100
Hepatitis B Vertical transmission, Virological control with Randomized (2:1), placebo-controlled Lamivudine associated with cough relative
sexual transmission, antiviral therapy trial of lamivudine in 651 patients with to placebo (14% vs 7%)8
shared needles, or drug (eg, tenofovir advanced fibrosis or cirrhosis: compared Tenofovir disoproxil fumarate was
implements alafenamide, tenofovir with placebo, treatment lowered risk of associated with decreased bone density
disoproxil fumarate, HCC (3.9% vs 7.4%)8 (1.72% in hip, 2.29% in spine) after 48 wk
entecavir) Observational study of tenofovir of therapy102
disoproxil fumarate: compared with no Among patients with hepatitis B and HIV
treatment (291 patients), antiviral coinfection, 0% receiving tenofovir
therapy (797 patients) was associated alafenamide discontinued therapy for
with a lower risk of HCC (9.8% vs 14.9%), kidney complications within 144 wk
decompensation (1.1% vs 13.1%), and compared with 3.6% receiving tenofovir
death (1.1% and 13.1%) in people with disoproxil fumarate103
cirrhosis from Hong Kong, South Korea,
and California101
Hemochromatosis Autosomal recessive Iron depletion In a nationwide, observational study of Venipuncture site bleeding and infection,
inheritance; 2 copies of (phlebotomy) with a Danish patients, 10-y overall survival was anemia, and syncope (rates unknown)
the C282Y variant of the goal of 50-100 μg/L of 70% among 66 patients receiving
HFE gene ferritin phlebotomy and 20% of 62 untreated
patients9
Primary biliary More common among Ursodeoxycholic acid In a pooled analysis of 548 patients in 3 Not observed in trials10
cholangitis (PBC) women and first-degree (UDCA) at randomized trials, UDCA improved Rare adverse events may include weight
relatives of patients 13-15 mg/kg/d transplant-free 4-y survival compared gain (<5 lbs),104 loose stool, and hair
with PBC with placebo (17% vs 24%)10 thinning
Primary sclerosing Ulcerative colitis No proven therapy NA NA
cholangitis (PSC)
Autoimmune Unknown Combination prednisone In a meta-analysis of randomized trials of Not reported in meta-analysis
hepatitis (20-40 mg/d) and 3-4 y duration, the rates of remission and Prednisone is associated with adverse
azathioprine overall mortality associated with effects such as weight gain, rash, cataracts,
(50-150 mg/d) combination therapy (received by 44 infection risk, and osteoporosis
patients) was 43% and 0% while placebo
(received by 33 patients) was associated Azathioprine is associated with leukopenia,
with 39% mortality and 0% remission11 pancreatitis, nonmelanoma skin cancer,
lymphoma, and increased infection risk
a
Abbreviations: HCC, hepatocellular carcinoma; HR, hazard ratio; NA, not Liver transplant is the definitive therapy for decompensated cirrhosis of any
applicable; SVR, sustained virologic response (cure of hepatitis C). cause; the underlying chronic liver disease may recur and require treatment.

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 dysfunc-
tion, 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 suppres-
sive 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 hyper-
kalemia, antibiotic-related diarrhea, or Clostridioides difficile
infection).53

Spontaneous Bacterial Peritonitis Hepatorenal Syndrome

Spontaneous bacterial peritonitis should be treated with guideline-
recommended third-generation cephalosporins such as ceftriax-
one, 2 g, daily and intravenous albumin.53 In an RCT of 126 pa-
tients, 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 moni-
tored volume expansion with intravenous albumin and vasocon-
strictor therapy to increase mean arterial pressure and kidney per-
fusion. 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

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Diagnosis and Management of Cirrhosis and Its Complications Review Clinical Review & Education

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
Coagulopathy
Despite low platelet counts or prolonged INR, bleeding after low-
risk 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 Soci-
ety of Interventional Radiology, neither prophylactic plasma, plate-
let 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 par-
ticipants 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 dif-
ferences 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 con-
sumption 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 encephalopa-
thy (grade ⱖ2) should be evaluated for infection, gastrointestinal
bleeding, dehydration, and receipt of psychoactive medications.76
Patients should receive intravenous hydration and lactulose, start-
ing 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 pla-
cebo, 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 re-
view. Second, some relevant research may have been missed. Third,
the quality of the included evidence was not formally assessed.
Conclusions
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 en-
cephalopathy, combination aldosterone antagonists and loop diuret-
ics for ascites, and terlipressin for hepatorenal syndrome.

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
mdm608@northwestern.edu.
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