Cirrhosis: Diagnosis and Management

 

Cirrhosis is the 12th leading cause of death in the United States. Newer research has established that liver fibrosis is a dynamic process and that early cirrhosis may be reversible. Only one in three people with cirrhosis knows they have it. Most patients with cirrhosis remain asymptomatic until the onset of decompensation. When clinical signs, symptoms, or abnormal liver function tests are discovered, further evaluation should be pursued promptly. The most common causes of cirrhosis are viral hepatitis, alcoholic liver disease, and nonalcoholic steatohepatitis. Initial workup includes viral hepatitis serologies, ferritin, transferrin saturation, and abdominal ultrasonography as well as complete blood count, liver function tests, and prothrombin time/international normalized ratio, if not already ordered. Additional testing is based on demographics and risk factors. Common serum and ultrasound-based screening tests to assess fibrosis include the aspartate transaminase to platelet ratio index score, Fibrosis 4 score, FibroTest/FibroSure, nonalcoholic fatty liver fibrosis score, standard ultrasonography, and transient elastography. Generally, noninvasive tests are most useful in identifying patients with no to minimal fibrosis or advanced fibrosis. Chronic liver disease management includes directed counseling, laboratory testing, and ultrasound monitoring. Treatment goals are preventing cirrhosis, decompensation, and death. Varices are monitored with endoscopy and often require prophylaxis with nonselective beta blockers. Ascites treatment includes diuresis, salt restriction, and antibiotic prophylaxis for spontaneous bacterial peritonitis, when indicated. Hepatic encephalopathy is managed with lifestyle and nutritional modifications and, as needed, with lactulose and rifaximin. Hepatocellular carcinoma screening includes ultrasound screening every six months for patients with cirrhosis.

Cirrhosis is a diffuse process of liver damage considered irreversible in its advanced stages. In 2016, more than 40,000 Americans died because of complications related to cirrhosis, making it the 12th leading cause of death in the United States.1 Recent projections suggest that this number is likely to grow.2 An estimated 630,000 Americans have cirrhosis, yet less than one in three knows it.3 Important racial and socioeconomic disparities exist, with prevalence highest among non-Hispanic blacks, Mexican Americans, and those living below the poverty level.3 Cirrhosis and advanced liver disease cost the United States between $12 billion and $23 billion dollars in health care expenses annually.4,5

WHAT'S NEW ON THIS TOPIC

Cirrhosis

Estimates suggest that nonalcoholic steatohepatitis will become the leading cause of cirrhosis in U.S. patients awaiting liver transplantation sometime between 2025 and 2035.

Liver biopsy remains the reference standard; however, transient elastography has become more widely available and is rapidly replacing biopsy as the preferred method for liver fibrosis staging.

Newer guidelines suggest targeted screening for esophageal varices in patients with clinically significant portal hypertension rather than screening all patients with cirrhosis.

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SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendationEvidence ratingComments

Further evaluation of patients with clinical signs or symptoms of liver disease or abnormal liver function tests should be pursued to determine the potential etiology, regardless of duration of the abnormality.19,20

C

Expert opinion and consensus guidelines in the absence of clinical trials

All patients with cirrhosis should be evaluated for hepatocellular carcinoma with ultrasonography every six months.43

C

Expert opinion and consensus guidelines with low-quality trials

Patients with cirrhosis who have a Model for End-Stage Liver Disease score of 15 or more, or complications of cirrhosis that include ascites, hepatic encephalopathy, or variceal hemorrhage, should be referred to a transplant center.37

B

Randomized controlled trials demonstrate acceptable survival benefits based on clinical criteria and Model for End-Stage Liver Disease results with some variability

Patients with clinically apparent (i.e., moderate to severe) ascites should be managed with salt restriction and spironolactone with or without loop diuretics.49

B

Data from multiple randomized controlled trials demonstrate more benefit than harm regarding patient comfort and reduced hospitalization times

Patients with cirrhosis who have medium, large, or high-risk varices (red wale markings) should be treated with nonselective beta blockers and/or endoscopic band ligation for primary prevention of variceal bleeds.7,9,46,53

B

Randomized controlled trials and meta-analyses comparing nonselective beta blockers, endoscopic band ligation, and placebo or no therapy, which generally show a reduction in variceal hemorrhage

Persistent hepatic encephalopathy that does not respond to conservative measures should be treated with lactulose and/or rifaximin (Xifaxan).54

B

Low-quality randomized controlled trials that demonstrate less recurrence of hepatic encephalopathy using lactulose and/or rifaximin

Oral antibiotic prophylaxis against spontaneous bacterial peritonitis should be initiated in patients with a history of spontaneous bacterial peritonitis or ascitic fluid protein < 1.5 g per dL (15 g per L) and advanced liver disease (Child-Pugh score ≥ 9 or bilirubin ≥ 3 mg per dL) or kidney disease (serum creatinine ≥ 1.2 mg per dL, serum sodium ≤ 130 per mmol per L).7,9,49,53

A

Multiple randomized controlled trials demonstrate a reduction in bacterial infections as well as mortality

Patients with decompensated cirrhosis or compensated cirrhosis and liver stiffness > 20 kilopascals (measured by transient elastography) or platelet count < 150,000 per mm3 should be screened for gastroesophageal varices with endoscopy. Repeat endoscopy should be performed every one to two years if small varices are found and every two to three years if no varices are found.46

C

Expert opinion, consensus guidelines, and unpublished studies in progress


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to https://www.aafp.org/afpsort.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendationEvidence ratingComments

Further evaluation of patients with clinical signs or symptoms of liver disease or abnormal liver function tests should be pursued to determine the potential etiology, regardless of duration of the abnormality.19,20

C

Expert opinion and consensus guidelines in the absence of clinical trials

All patients with cirrhosis should be evaluated for hepatocellular carcinoma with ultrasonography every six months.43

C

Expert opinion and consensus guidelines with low-quality trials

Patients with cirrhosis who have a Model for End-Stage Liver Disease score of 15 or more, or complications of cirrhosis that include ascites, hepatic encephalopathy, or variceal hemorrhage, should be referred to a transplant center.37

B

Randomized controlled trials demonstrate acceptable survival benefits based on clinical criteria and Model for End-Stage Liver Disease results with some variability

Patients with clinically apparent (i.e., moderate to severe) ascites should be managed with salt restriction and spironolactone with or without loop diuretics.49

B

Data from multiple randomized controlled trials demonstrate more benefit than harm regarding patient comfort and reduced hospitalization times

Patients with cirrhosis who have medium, large, or high-risk varices (red wale markings) should be treated with nonselective beta blockers and/or endoscopic band ligation for primary prevention of variceal bleeds.7,9,46,53

B

Randomized controlled trials and meta-analyses comparing nonselective beta blockers, endoscopic band ligation, and placebo or no therapy, which generally show a reduction in variceal hemorrhage

Persistent hepatic encephalopathy that does not respond to conservative measures should be treated with lactulose and/or rifaximin (Xifaxan).54

B

Low-quality randomized controlled trials that demonstrate less recurrence of hepatic encephalopathy using lactulose and/or rifaximin

Oral antibiotic prophylaxis against spontaneous bacterial peritonitis should be initiated in patients with a history of spontaneous bacterial peritonitis or ascitic fluid protein < 1.5 g per dL (15 g per L) and advanced liver disease (Child-Pugh score ≥ 9 or bilirubin ≥ 3 mg per dL) or kidney disease (serum creatinine ≥ 1.2 mg per dL, serum sodium ≤ 130 per mmol per L).7,9,49,53

A

Multiple randomized controlled trials demonstrate a reduction in bacterial infections as well as mortality

Patients with decompensated cirrhosis or compensated cirrhosis and liver stiffness > 20 kilopascals (measured by transient elastography) or platelet count < 150,000 per mm3 should be screened for gastroesophageal varices with endoscopy. Repeat endoscopy should be performed every one to two years if small varices are found and every two to three years if no varices are found.46

C

Expert opinion, consensus guidelines, and unpublished studies in progress


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to https://www.aafp.org/afpsort.

The most common causes of cirrhosis in the United States are viral hepatitis (primarily hepatitis C virus [HCV] and hepatitis B virus [HBV]), alcoholic liver disease, and non-alcoholic steatohepatitis. HCV remains the leading cause of cirrhosis in patients awaiting liver transplant. With an increasing prevalence of nonalcoholic fatty liver disease (NAFLD) in the United States, estimates suggest that non-alcoholic steatohepatitis, a severe progression of NAFLD characterized by inflammatory steatohepatitis, will become the leading cause of cirrhosis in patients awaiting liver transplant sometime between 2025 and 2035.6,7  Table 1 lists common etiologies of cirrhosis.8

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TABLE 1.

Common Etiologies of Cirrhosis

Viral hepatitis (hepatitis B, hepatitis C)

Alcoholic liver disease

Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

Storage diseases

 Hemochromatosis

 Wilson disease

 Alpha1-antitrypsin deficiency

Immune mediated

 Autoimmune hepatitis (types 1, 2, and 3)

 Primary biliary cholangitis

 Primary sclerosing cholangitis

 Immunoglobulin G4 cholangiopathy

Cardiovascular

 Veno-occlusive disease (Budd-Chiari syndrome)

 Congestive heart failure

 Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease)

Chronic biliary disease

 Recurrent bacterial cholangitis

 Bile duct stenosis

Other

 Medications (e.g., methotrexate, amiodarone)

 Erythropoietic protoporphyria

 Sarcoidosis

 Schistosomiasis


Note: Listed in order of generally decreasing prevalence.

Information from reference 8.

TABLE 1.

Common Etiologies of Cirrhosis

Viral hepatitis (hepatitis B, hepatitis C)

Alcoholic liver disease

Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

Storage diseases

 Hemochromatosis

 Wilson disease

 Alpha1-antitrypsin deficiency

Immune mediated

 Autoimmune hepatitis (types 1, 2, and 3)

 Primary biliary cholangitis

 Primary sclerosing cholangitis

 Immunoglobulin G4 cholangiopathy

Cardiovascular

 Veno-occlusive disease (Budd-Chiari syndrome)

 Congestive heart failure

 Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease)

Chronic biliary disease

 Recurrent bacterial cholangitis

 Bile duct stenosis

Other

 Medications (e.g., methotrexate, amiodarone)

 Erythropoietic protoporphyria

 Sarcoidosis

 Schistosomiasis


Note: Listed in order of generally decreasing prevalence.

Information from reference 8.

Pathophysiology and Natural History of Cirrhosis

Chronic liver injury causes inflammation and hepatic fibrosis. Regardless of the cause, this can lead to the formation of fibrous septae and nodules, collapse of liver structures, and distortion of hepatic parenchyma and vascular architecture. Progressive fibrosis and cirrhosis subsequently result in decreased metabolic and synthetic hepatic function, causing a rise in bilirubin and decreased production of clotting factors and thrombopoietin, as well as splenic platelet sequestration, increased portal pressure, and the development of ascites and esophageal varices.

Cirrhosis can result from chronic liver damage of any cause. In patients with the three most common causes of liver disease, 10% to 20% will develop cirrhosis within 10 to 20 years.9 Factors associated with an increased risk of progression to cirrhosis include increased age, medical comorbidities (particularly patients coinfected with HIV and HCV), and male sex (except in alcoholic liver disease, where females progress more rapidly).10 The point at which this process becomes irreversible, however, is not clear. Newer research has established that liver fibrosis is a dynamic process and that even early cirrhosis is reversible.11 Studies have demonstrated biopsy-proven fibrosis improvement rates as high as 88% after antiviral treatment in patients with HBV and HCV and as high as 85% after bariatric surgery in patients with nonalcoholic steatohepatitis.12,13

After cirrhosis is established, a patient may remain clinically stable, or compensated, for years. Patients with compensated cirrhosis caused by HBV, HCV, and alcoholic liver disease develop clinical signs of decompensation, which include ascites, hepatic encephalopathy, jaundice, or bleeding, at a rate of 4% to 10% per year.14 Variability of disease progression is influenced by the underlying cause and the presence or absence of treatment and ongoing liver injury. The median survival for those with compensated cirrhosis is 12 years, compared with two years once decompensation occurs.15

Clinical Presentation

HISTORY

Most patients with compensated cirrhosis remain asymptomatic. When symptoms occur, they include fatigue, weakness, loss of appetite, right upper quadrant discomfort, and unexplained weight loss. With the onset of decompensation, patients may report symptoms of impaired liver function such as jaundice, portal hypertension (including ascites and peripheral edema), and hepatic encephalopathy (such as confusion and disordered sleep).

PHYSICAL EXAMINATION

Physical examination findings that may be present in patients with advanced liver disease (cirrhosis) are summarized in Table 2.16,17 The Stanford Medicine 25 website is a good resource for photos and instructional videos that demonstrate findings associated with cirrhosis (http://stanfordmedicine25.stanford.edu/the25/liverdisease.html).16,17

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TABLE 2.

Physical Examination Findings That May Be Present in Patients with Cirrhosis

Body part/systemExamination finding

General

Muscle wasting

Central nervous system

Asterixis (tremor of the hand with wrist extension)

Drowsiness, confusion

Head

Fetor hepaticus: sweet odor of the breath attributable to increased concentrations of dimethyl sulfide

Jaundice: may see yellowing of mucous membranes beneath the tongue

Parotid enlargement

Scleral icterus

Spider nevi

Chest

Gynecomastia

Spider nevi

Thinning axillary hair

Abdomen

Ascites

Caput medusae (engorged superficial epigastric veins radiating from the umbilicus)

Contracted or enlarged liver

Hemorrhoids

Splenomegaly

Hands and nails

Clubbing

Dupuytren contracture (progressive fibrosis of palmar fascia, resulting in limited extension of the fingers)

Palmar erythema

Terry nails (whiteness of proximal half of nail plate)

Genitourinary (male)

Testicular atrophy

Lower extremities

Distal erythema

Edema

Petechiae


Information from references 16 and 17.

TABLE 2.

Physical Examination Findings That May Be Present in Patients with Cirrhosis

Body part/systemExamination finding

General

Muscle wasting

Central nervous system

Asterixis (tremor of the hand with wrist extension)

Drowsiness, confusion

Head

Fetor hepaticus: sweet odor of the breath attributable to increased concentrations of dimethyl sulfide

Jaundice: may see yellowing of mucous membranes beneath the tongue

Parotid enlargement

Scleral icterus

Spider nevi

Chest

Gynecomastia

Spider nevi

Thinning axillary hair

Abdomen

Ascites

Caput medusae (engorged superficial epigastric veins radiating from the umbilicus)

Contracted or enlarged liver

Hemorrhoids

Splenomegaly

Hands and nails

Clubbing

Dupuytren contracture (progressive fibrosis of palmar fascia, resulting in limited extension of the fingers)

Palmar erythema

Terry nails (whiteness of proximal half of nail plate)

Genitourinary (male)

Testicular atrophy

Lower extremities

Distal erythema

Edema

Petechiae


Information from references 16 and 17.

INITIAL LABORATORY FINDINGS

In early compensated disease, laboratory findings may be normal. Incidentally elevated liver enzymes or evidence of hepatic disease on imaging may prompt the initial suspicion of chronic liver injury. Findings suggestive of cirrhosis include low albumin (less than 3.5 g per dL [35 g per L]), thrombocytopenia (platelet count less than 160 × 103 per μL [160 × 109 per L]), aspartate transaminase (AST):alanine transaminase (ALT) ratio greater than 1, elevated bilirubin, and a prolonged prothrombin time (PT)/elevated international normalized ratio (INR).18

Evaluation of Chronic Liver Disease

When chronic liver disease is suspected, a history should be conducted, reviewing any potentially hepatotoxic medications, alcohol consumption, and family history of liver disease. Basic laboratory tests, including complete blood count, ALT, AST, albumin, alkaline phosphatase, gamma-glutamyl transferase, total bilirubin, and PT/INR, should be ordered.

For those with clinical signs or symptoms of liver disease or abnormal liver function test results, regardless of duration, further evaluation to determine the potential etiology should be pursued promptly.19,20  Viral hepatitis serologies, ferritin, transferrin saturation, and abdominal ultrasonography should be performed; complete blood count, liver function tests, and PT/INR should be completed, if not already ordered. If risk factors for NAFLD exist, testing of fasting lipid levels and A1C should be done. For patients with risk factors or demographics with concern for autoimmune hepatitis, antinuclear antibodies and smooth muscle antibodies should be tested. Table 3 lists additional suggested tests based on risk factors and clinical findings.19,21,22

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TABLE 3.

Clinical, Laboratory, and Imaging Findings to Identify Etiology of Chronic Liver Disease

EtiologyCharacteristics and risk factorsLaboratory and imaging findings

Alcoholic liver disease

Positive screening tests for alcohol use disorder

Aspartate transaminase ≥ 2 times alanine transaminase level in 70% of patients, especially if 3 times

History of excessive alcohol intake

Elevated glucose tolerance test and/or mean corpuscular volume [corrected]

Ultrasonography may show fatty change

Alpha1-antitrypsin deficiency

Autosomal recessive trait

Alpha1-antitrypsin phenotype

European ancestry

All other evaluations unrevealing

Autoimmune hepatitis

Young and middle-aged women (in type 1, the most common)

Antinuclear antibody and/or antismooth muscle antibody positive in titers ≥ 1:80

Total serum immunoglobulin G (polyclonal hypergammaglobulinemia > 1.5 times the upper limit of normal supports diagnosis)

Hemochromatosis

Autosomal recessive trait

Ferritin ≥ 250 to 300 ng per mL in men, ≥ 200 ng per mL in women

Northern European ancestry

Transferrin saturation (serum iron × 100/total iron-binding capacity) ≥ 45%

If ferritin or transferrin saturation is abnormal, order human hemochromatosis protein gene mutation analysis

Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

Obesity, diabetes mellitus

Lipids, A1C (not needed for diagnosis)

Improvement with weight loss

Ultrasonography may show fatty change

May need biopsy to diagnose nonalcoholic steatohepatitis

Primary biliary cholangitis (primary biliary cirrhosis)

Associated with other autoimmune disorders (80% with Sjögren syndrome; 5% to 10% with autoimmune hepatitis) Middle-aged women

Cholestasis (elevated alkaline phosphatase and glucose tolerance test) Antimitochondrial antibody positive

Primary sclerosing cholangitis

Middle-aged men

Cholestasis (elevated alkaline phosphatase and glucose tolerance test)

Associated with inflammatory bowel disease (70%)

Perinuclear antineutrophil cytoplasmic antibodies positive in 70% of patients Frequently positive antinuclear antibodies, antismooth muscle antibodies, other antibodies Magnetic resonance cholangiography

Viral hepatitis B (chronic)

Born in endemic country

Hepatitis B surface antigen

Hepatitis B core antibody

If either is positive, order hepatitis B virus DNA

Viral hepatitis C (chronic)

Born 1945 to 1965

Anti–hepatitis C virus antibody

Specific risk factors for hepatitis C virus*

If positive, order hepatitis C virus RNA

Wilson disease

Autosomal recessive trait

Low serum ceruloplasmin

Age younger than 40 years with chronic liver disease or fatty liver and negative workup for the above

If abnormal, serum copper, urinary copper excretion, liver biopsy, hepatic tissue copper measurement, and genetic marker testing can be considered

Kayser-Fleischer rings


*—Specific risk factors for hepatitis C virus include history of injection drug use (even once); men who have sex with men (especially if HIV infected); history of a blood transfusion before 1992; long-term hemodialysis; being born to a hepatitis C virus–infected mother; incarceration; intranasal drug use; having an unregulated tattoo (not performed in a regulated tattoo parlor); and other percutaneous exposures (see U.S. Preventive Services Task Force guidelines: https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/hepatitis-c-screening).

Information from references 19, 21, and 22.

TABLE 3.

Clinical, Laboratory, and Imaging Findings to Identify Etiology of Chronic Liver Disease

EtiologyCharacteristics and risk factorsLaboratory and imaging findings

Alcoholic liver disease

Positive screening tests for alcohol use disorder

Aspartate transaminase ≥ 2 times alanine transaminase level in 70% of patients, especially if 3 times

History of excessive alcohol intake

Elevated glucose tolerance test and/or mean corpuscular volume [corrected]

Ultrasonography may show fatty change

Alpha1-antitrypsin deficiency

Autosomal recessive trait

Alpha1-antitrypsin phenotype

European ancestry

All other evaluations unrevealing

Autoimmune hepatitis

Young and middle-aged women (in type 1, the most common)

Antinuclear antibody and/or antismooth muscle antibody positive in titers ≥ 1:80

Total serum immunoglobulin G (polyclonal hypergammaglobulinemia > 1.5 times the upper limit of normal supports diagnosis)

Hemochromatosis

Autosomal recessive trait

Ferritin ≥ 250 to 300 ng per mL in men, ≥ 200 ng per mL in women

Northern European ancestry

Transferrin saturation (serum iron × 100/total iron-binding capacity) ≥ 45%

If ferritin or transferrin saturation is abnormal, order human hemochromatosis protein gene mutation analysis

Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

Obesity, diabetes mellitus

Lipids, A1C (not needed for diagnosis)

Improvement with weight loss

Ultrasonography may show fatty change

May need biopsy to diagnose nonalcoholic steatohepatitis

Primary biliary cholangitis (primary biliary cirrhosis)

Associated with other autoimmune disorders (80% with Sjögren syndrome; 5% to 10% with autoimmune hepatitis) Middle-aged women

Cholestasis (elevated alkaline phosphatase and glucose tolerance test) Antimitochondrial antibody positive

Primary sclerosing cholangitis

Middle-aged men

Cholestasis (elevated alkaline phosphatase and glucose tolerance test)

Associated with inflammatory bowel disease (70%)

Perinuclear antineutrophil cytoplasmic antibodies positive in 70% of patients Frequently positive antinuclear antibodies, antismooth muscle antibodies, other antibodies Magnetic resonance cholangiography

Viral hepatitis B (chronic)

Born in endemic country

Hepatitis B surface antigen

Hepatitis B core antibody

If either is positive, order hepatitis B virus DNA

Viral hepatitis C (chronic)

Born 1945 to 1965

Anti–hepatitis C virus antibody

Specific risk factors for hepatitis C virus*

If positive, order hepatitis C virus RNA

Wilson disease

Autosomal recessive trait

Low serum ceruloplasmin

Age younger than 40 years with chronic liver disease or fatty liver and negative workup for the above

If abnormal, serum copper, urinary copper excretion, liver biopsy, hepatic tissue copper measurement, and genetic marker testing can be considered

Kayser-Fleischer rings


*—Specific risk factors for hepatitis C virus include history of injection drug use (even once); men who have sex with men (especially if HIV infected); history of a blood transfusion before 1992; long-term hemodialysis; being born to a hepatitis C virus–infected mother; incarceration; intranasal drug use; having an unregulated tattoo (not performed in a regulated tattoo parlor); and other percutaneous exposures (see U.S. Preventive Services Task Force guidelines: https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/hepatitis-c-screening).

Information from references 19, 21, and 22.

Staging Fibrosis and Diagnosing Cirrhosis

Liver fibrosis is scored on a scale from F0 to F4 (Table 4).23 Differentiating between significant (F2 or greater) and advanced (F3 or greater) fibrosis and cirrhosis (F4) is difficult even with complete clinical, laboratory, and imaging data because findings are often nonspecific or insensitive.24 Liver biopsy remains the reference standard for assessing liver fibrosis; however, use of noninvasive methods has become increasingly common in clinical practice.18

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TABLE 4.

Metavir Scoring System for the Assessment of Liver Fibrosis and Cirrhosis

Level of fibrosisScore

No fibrosis

F0

Minimal scarring

F1

Positive scarring with extension beyond area containing blood vessels

F2

Bridging fibrosis with connection to other areas of fibrosis

F3

Cirrhosis or advanced liver scarring

F4


Adapted with permission from Wilkins T, Akhtar M, Gititu E, et al. Diagnosis and management of hepatitis C. Am Fam Physician. 2015;91(12):838.

TABLE 4.

Metavir Scoring System for the Assessment of Liver Fibrosis and Cirrhosis

Level of fibrosisScore

No fibrosis

F0

Minimal scarring

F1

Positive scarring with extension beyond area containing blood vessels

F2

Bridging fibrosis with connection to other areas of fibrosis

F3

Cirrhosis or advanced liver scarring

F4


Adapted with permission from Wilkins T, Akhtar M, Gititu E, et al. Diagnosis and management of hepatitis C. Am Fam Physician. 2015;91(12):838.

Noninvasive testing includes serum-based and imaging modalities (Table 52537). Generally, noninvasive tests are most useful in identifying patients with no to minimal fibrosis (F0) or advanced fibrosis (F3 to F4) and are less accurate at distinguishing early or intermediate stages of liver disease (F1 to F2).24,38 They are most beneficial when combined with all available data, accounting for the pretest probability of fibrosis.24,38

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TABLE 5.

Select Noninvasive Tests to Aid in Fibrosis Staging

TestParametersCutoffs and interpretation*

AST to platelet ratio index score†

AST, platelets

< 0.5: good NPV (80% in HCV) for significant fibrosis25

> 2.0: high specificity for cirrhosis in HCV (46% sensitivity, 91% specificity)26; the World Health Organization recommended cutoff for HBV-related cirrhosis in low-resource settings (28% sensitivity, 87% specificity)26,27

Fibrosis 4 score‡

Age, platelets, AST, ALT

< 1.45: good NPV (95% in HCV) for advanced fibrosis28

> 3.25 (range: 2.67 to 3.60): good PPV for advanced fibrosis/cirrhosis in HCV, HBV, and NAFLD26,28,29

 In HCV with ≥ 3.25, PPV for advanced fibrosis = 82%28

 In NAFLD with ≥ 2.67, PPV for advanced fibrosis = 80%29

FibroTest/FibroSure

Alpha2 -macroglobulin, gamma-glutamyl transferase, haptoglobin, apolipoprotein A-I, bilirubin

< 0.30: good NPV (90%) for advanced fibrosis in NAFLD30

> 0.48: high specificity for significant fibrosis in HCV (specificity = 85%)31 and HBV (specificity = 80%)32

> 0.70: high specificity for advanced fibrosis or cirrhosis

 In NAFLD with > 0.70, PPV for advanced fibrosis = 73%30

 In HBV with > 0.74, specificity for cirrhosis = 91%32

NAFLD fibrosis score§

Age, body mass index, AST, ALT, glucose, platelets, albumin

< −1.455: good NPV (88%) for advanced fibrosis in NAFLD33

> 0.676: good PPV (82%) for advanced fibrosis in NAFLD33

Transient elastography

Liver stiffness measured in kPa

HCV (> 12.5 kPa): high sensitivity (87%) and specificity (91%) for cirrhosis; very accurate for F2 to F4 when combined with FibroTest34

HBV (> 9.0 to 12.0 kPa): good sensitivity (83%) and specificity (87%) but may be falsely elevated during flare-up26

NAFLD (> 10.3 kPa): good NPV (98.5%) but lower PPV (56%)35

Ultrasonography

Standard ultrasonography

Hepatic nodularity specific for severe fibrosis or cirrhosis in all forms of liver disease (sensitivity = 54%, specificity = 95%)36

Evidence of portal hypertension (splenomegaly, portosystemic collaterals)37


ALT = alanine transaminase; AST = aspartate transaminase; HBV = hepatitis B virus; HCV = hepatitis C virus; kPa = kilopascals; NAFLD = nonalcoholic fatty liver disease; NPV = negative predictive value; PPV = positive predictive value.

*—Vary based on etiology of liver disease and population studied.

†—AST to platelet ratio index score: https://www.mdcalc.com/ast-platelet-ratio-index-apri

§—NAFLD fibrosis score: http://nafldscore.com

Information from references 2537.

TABLE 5.

Select Noninvasive Tests to Aid in Fibrosis Staging

TestParametersCutoffs and interpretation*

AST to platelet ratio index score†

AST, platelets

< 0.5: good NPV (80% in HCV) for significant fibrosis25

> 2.0: high specificity for cirrhosis in HCV (46% sensitivity, 91% specificity)26; the World Health Organization recommended cutoff for HBV-related cirrhosis in low-resource settings (28% sensitivity, 87% specificity)26,27

Fibrosis 4 score‡

Age, platelets, AST, ALT

< 1.45: good NPV (95% in HCV) for advanced fibrosis28

> 3.25 (range: 2.67 to 3.60): good PPV for advanced fibrosis/cirrhosis in HCV, HBV, and NAFLD26,28,29

 In HCV with ≥ 3.25, PPV for advanced fibrosis = 82%28

 In NAFLD with ≥ 2.67, PPV for advanced fibrosis = 80%29

FibroTest/FibroSure

Alpha2 -macroglobulin, gamma-glutamyl transferase, haptoglobin, apolipoprotein A-I, bilirubin

< 0.30: good NPV (90%) for advanced fibrosis in NAFLD30

> 0.48: high specificity for significant fibrosis in HCV (specificity = 85%)31 and HBV (specificity = 80%)32

> 0.70: high specificity for advanced fibrosis or cirrhosis

 In NAFLD with > 0.70, PPV for advanced fibrosis = 73%30

 In HBV with > 0.74, specificity for cirrhosis = 91%32

NAFLD fibrosis score§

Age, body mass index, AST, ALT, glucose, platelets, albumin

< −1.455: good NPV (88%) for advanced fibrosis in NAFLD33

> 0.676: good PPV (82%) for advanced fibrosis in NAFLD33

Transient elastography

Liver stiffness measured in kPa

HCV (> 12.5 kPa): high sensitivity (87%) and specificity (91%) for cirrhosis; very accurate for F2 to F4 when combined with FibroTest34

HBV (> 9.0 to 12.0 kPa): good sensitivity (83%) and specificity (87%) but may be falsely elevated during flare-up26

NAFLD (> 10.3 kPa): good NPV (98.5%) but lower PPV (56%)35

Ultrasonography

Standard ultrasonography

Hepatic nodularity specific for severe fibrosis or cirrhosis in all forms of liver disease (sensitivity = 54%, specificity = 95%)36

Evidence of portal hypertension (splenomegaly, portosystemic collaterals)37


ALT = alanine transaminase; AST = aspartate transaminase; HBV = hepatitis B virus; HCV = hepatitis C virus; kPa = kilopascals; NAFLD = nonalcoholic fatty liver disease; NPV = negative predictive value; PPV = positive predictive value.

*—Vary based on etiology of liver disease and population studied.

†—AST to platelet ratio index score: https://www.mdcalc.com/ast-platelet-ratio-index-apri

§—NAFLD fibrosis score: http://nafldscore.com

Information from references 2537.

BIOMARKERS

Most serum tests show indirect markers of liver damage, except hyaluronic acid (found in the liver's extracellular matrix), which is included in biomarker panels such as FibroMeter or Hepascore.24 The AST to platelet ratio index (APRI; https://www.mdcalc.com/ast-platelet-ratio-index-apri), Fibrosis 4 score (http://gihep.com/calculators/hepatology/fibrosis-4-score/), and NAFLD fibrosis score (http://nafldscore.com/) are accessible, serum-based, nonproprietary calculations.18,39 FibroTest (FibroSure in the United States), FibroMeter, and Hepascore are patented calculations using several serum biomarkers, with FibroTest being the most validated.24

Biomarkers are most validated in chronic HCV,40 with the exception of the NAFLD fibrosis score for non-alcoholic steatohepatitis.33 For other etiologies of liver disease, including alcoholic liver disease, few studies of noninvasive methods exist.

STANDARD ULTRASONOGRAPHY

Given its relatively low cost, accessibility, and lack of radiation, ultrasonography is useful for diagnosing cirrhosis, cirrhosis complications (e.g., splenomegaly, portal hypertension, ascites, hepatocellular carcinoma), and comorbid liver diseases (e.g., extrahepatic cholestasis).24 Ultrasonography is good at detecting steatosis (94% sensitivity, 84% specificity), but it may frequently miss fibrosis or cirrhosis (for which it is 40% to 57% sensitive).41,42 Characteristics of cirrhosis include hepatic nodularity, coarseness, and echogenicity,24 with hepatic nodularity being the most specific.36 Additionally, features consistent with portal hypertension, such as splenomegaly and portosystemic collaterals, are suggestive of cirrhosis.37 Patients with cirrhosis and some with chronic HBV should undergo right upper quadrant ultrasonography every six months to screen for hepatocellular carcinoma.43

TRANSIENT ELASTOGRAPHY

Transient elastography, which has become more widely available, is rapidly replacing biopsy as the preferred method for fibrosis staging. Transient elastography, an ultrasound technique performed with a specialized machine (Fibro-Scan), determines liver stiffness in kilopascals (kPa) by measuring the velocity of low-frequency elastic shear waves propagating through the liver. It is a five-minute procedure performed in an outpatient setting and provides point-of-care results. In a meta-analysis of more than 10,000 patients spanning multiple etiologies of liver disease, transient elastography was sensitive (81%) and specific (88%) for detecting liver fibrosis and cirrhosis40  (see Table 52537 for cutoff values). Transient elastography performs better than the biomarker-based tools in detecting cirrhosis and is accurate at excluding cirrhosis (negative predictive value greater than 90%).38 Similar to serum tests, however, transient elastography is less accurate at distinguishing between intermediate stages of liver disease, and cutoff values vary depending on the etiology of liver disease and population studied.24,38

LIMITATIONS

Abnormal serum results may be seen from non–liver-related causes, including bone marrow disease, hemolysis, and medications. Transient elastography is less reliable in patients with obesity (though an extra-large probe has been developed), ascites, excessive alcohol intake, and extrahepatic cholestasis. If performed during an episode of acute hepatic inflammation, these tests can also lead to falsely elevated results.38

LIVER BIOPSY

Liver biopsy remains the reference standard in diagnosing cirrhosis; however, a 20% error rate still occurs in fibrosis staging.44 Pathologic changes may be heterogeneous; therefore, sampling error is common, and interpretation should be made by an experienced pathologist using validated scoring systems.38 Liver biopsy is recommended when concern for fibrosis remains after indeterminate or conflicting clinical, laboratory, and imaging results; in those for whom transient elastography is not suitable; or to clarify etiology of disease after inconclusive noninvasive evaluation.9 Liver biopsy may be indicated to diagnose necroinflammation (in HBV) and steatohepatitis (nonalcoholic steatohepatitis) because they are not easily distinguished by noninvasive methods.

Staging Cirrhosis

After the diagnosis of cirrhosis is established, Child-Pugh (https://www.mdcalc.com/child-pugh-score-cirrhosis-mortality) and Model for End-Stage Liver Disease (https://www.mdcalc.com/meld-score-model-end-stage-liver-disease-12-older) scores should be used to identify the stage of cirrhosis and mortality risk, respectively.9,45 A Child-Pugh grade B classification (seven to nine points) is consistent with early hepatic decompensation,46 whereas a Model for End-Stage Liver Disease score of 12 or more is predictive of increased risk for cirrhosis complications.9

Cirrhosis Management

The primary goals of liver disease management are to prevent cirrhosis complications, liver decompensation, and death. These goals are accomplished with rigorous prevention counseling, monitoring, and management by primary care physicians, in consultation with subspecialists as needed.

PREVENTION COUNSELING

For all patients with liver disease, counseling points should be discussed, including avoidance of alcohol; maintenance of a healthy weight; nutrition; medication and supplement review; prevention of infections (including receiving vaccinations); screening and treatment of causative factors; and avoidance of unnecessary surgical procedures. Table 6 provides more details on counseling for patients with chronic liver disease.7,9,18,21,45,4752

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TABLE 6.

Counseling for Patients with Chronic Liver Disease

Counseling pointRecommendations

Alcohol use

Brief physician counseling, behavioral counseling, and group support

Complete alcohol abstinence in cirrhosis

Medication-assisted treatment for alcohol use disorder

 Avoid naltrexone and acamprosate in patients with Child-Pugh grade C cirrhosis21,47

 Baclofen (Lioresal), 5 mg three times daily for three days, then 10 mg three times daily can be used, even with ascites48,49

Avoidance of unnecessary surgical procedures

Cirrhosis, especially if decompensated or with Model for End-Stage Liver Disease score ≥ 14, increases perioperative mortality risk7; an online calculator has been developed to help guide decision-making (https://www.mayoclinic.org/medical-professionals/transplant-medicine/calculators/post-operative-mortality-risk-in-patients-with-cirrhosis/itt-20434721/?vp=MPG-20426275)7

Coffee consumption

Three to four cups of coffee per day may reduce the risk of hepatocellular carcinoma and fibrosis progression in patients with nonalcoholic fatty liver disease and hepatitis C virus infection50

Infection prevention: bacterial exposures

Avoid exposure to brackish/salt water and consumption of raw seafood (Vibrio vulnificus can be fatal in patients with cirrhosis, iron overload, or immunocompromise)45

Avoid unpasteurized dairy (risk of serious Listeria infections in patients with cirrhosis)

Infection prevention: vaccinations

All patients with liver disease should receive yearly influenza vaccinations and hepatitis A and B vaccinations if not known to be immune

In patients with cirrhosis and chronic hepatitis B virus infection, 23-valent pneumococcal polysaccharide vaccine (Pneumovax 23) is recommended45

Medication and supplement review

For patients with cirrhosis

 Analgesics: acetaminophen preferred, limit to 2 g per day 7; nonsteroidal anti-inflammatory drugs contraindicated7,45; low-dose tramadol may be used for severe symptoms of pain7

 Antihypertensives: discontinue if patient has hypotension or ascites (linked to hepatorenal syndrome and mortality)7

 Aspirin: low-dose aspirin may be continued if cardiovascular disease severity exceeds the severity of cirrhosis7

 Metformin: should be continued for patients with diabetes mellitus51

 Proton pump inhibitors: avoid unnecessary use (linked to increased risk of spontaneous bacterial peritonitis)7

 Sedating medications: avoid benzodiazepines and opiates, especially in hepatic encephalopathy; hydroxyzine or trazodone may be considered for severe insomnia7

 Statins: may be safely used

 Supplements: avoid daily dosage of vitamin A > 5,000 IU (may increase fibrosis production); avoid multivitamins with iron45

Obesity and diabetes management

Maximize obesity and diabetes management because they increase the risk of cirrhosis9,18

Weight loss of 10% improves histopathologic features of nonalcoholic steatohepatitis, including fibrosis52

Screening for and treatment of underlying causative factors of liver disease

Treatment of alcohol use disorder, chronic hepatitis B or C virus infection, and nonalcoholic fatty liver disease can prevent progression and complications of liver disease and can improve fibrosis levels, even in patients with cirrhosis7


Information from references 7, 9, 18, 21, 45, and 4752.

TABLE 6.

Counseling for Patients with Chronic Liver Disease

Counseling pointRecommendations

Alcohol use

Brief physician counseling, behavioral counseling, and group support

Complete alcohol abstinence in cirrhosis

Medication-assisted treatment for alcohol use disorder

 Avoid naltrexone and acamprosate in patients with Child-Pugh grade C cirrhosis21,47

 Baclofen (Lioresal), 5 mg three times daily for three days, then 10 mg three times daily can be used, even with ascites48,49

Avoidance of unnecessary surgical procedures

Cirrhosis, especially if decompensated or with Model for End-Stage Liver Disease score ≥ 14, increases perioperative mortality risk7; an online calculator has been developed to help guide decision-making (https://www.mayoclinic.org/medical-professionals/transplant-medicine/calculators/post-operative-mortality-risk-in-patients-with-cirrhosis/itt-20434721/?vp=MPG-20426275)7

Coffee consumption

Three to four cups of coffee per day may reduce the risk of hepatocellular carcinoma and fibrosis progression in patients with nonalcoholic fatty liver disease and hepatitis C virus infection50

Infection prevention: bacterial exposures

Avoid exposure to brackish/salt water and consumption of raw seafood (Vibrio vulnificus can be fatal in patients with cirrhosis, iron overload, or immunocompromise)45

Avoid unpasteurized dairy (risk of serious Listeria infections in patients with cirrhosis)

Infection prevention: vaccinations

All patients with liver disease should receive yearly influenza vaccinations and hepatitis A and B vaccinations if not known to be immune

In patients with cirrhosis and chronic hepatitis B virus infection, 23-valent pneumococcal polysaccharide vaccine (Pneumovax 23) is recommended45

Medication and supplement review

For patients with cirrhosis

 Analgesics: acetaminophen preferred, limit to 2 g per day 7; nonsteroidal anti-inflammatory drugs contraindicated7,45; low-dose tramadol may be used for severe symptoms of pain7

 Antihypertensives: discontinue if patient has hypotension or ascites (linked to hepatorenal syndrome and mortality)7

 Aspirin: low-dose aspirin may be continued if cardiovascular disease severity exceeds the severity of cirrhosis7

 Metformin: should be continued for patients with diabetes mellitus51

 Proton pump inhibitors: avoid unnecessary use (linked to increased risk of spontaneous bacterial peritonitis)7

 Sedating medications: avoid benzodiazepines and opiates, especially in hepatic encephalopathy; hydroxyzine or trazodone may be considered for severe insomnia7

 Statins: may be safely used

 Supplements: avoid daily dosage of vitamin A > 5,000 IU (may increase fibrosis production); avoid multivitamins with iron45

Obesity and diabetes management

Maximize obesity and diabetes management because they increase the risk of cirrhosis9,18

Weight loss of 10% improves histopathologic features of nonalcoholic steatohepatitis, including fibrosis52

Screening for and treatment of underlying causative factors of liver disease

Treatment of alcohol use disorder, chronic hepatitis B or C virus infection, and nonalcoholic fatty liver disease can prevent progression and complications of liver disease and can improve fibrosis levels, even in patients with cirrhosis7


Information from references 7, 9, 18, 21, 45, and 4752.

MONITORING OF PATIENTS WITH CIRRHOSIS

For patients with cirrhosis, a basic metabolic panel, liver function tests, complete blood count, and PT/INR should be completed every six months to recalculate Child-Pugh and Model for End-Stage Liver Disease scores. Patients with a Model for End-Stage Liver Disease score of 15 or higher should be referred for liver transplantation evaluation37,45; patients with ascites, hepatic encephalopathy, or variceal hemorrhage should also be referred.37,53

Screening and Management for Specific Complications

Patients with cirrhosis are at risk of multiple complications, including hepatic decompensation, hepatocellular carcinoma, and other more common conditions (e.g., malnutrition, leg cramps, umbilical hernias). Table 7 includes specific recommendations for the screening and management of select complications of cirrhosis.7,9,43,45,46,49,5355

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TABLE 7.

Select Complications of Cirrhosis and Recommendations for Screening and Management

Cirrhosis complicationScreeningInterventionMedication dosing and other considerations

Abdominal hernia

Clinical

Defer surgery until medically optimized and ascites controlled

High perioperative risk and hernia recurrence in presence of ascites49

Increased risk with ascites

Consult with multidisciplinary team

Surgeon with experience in the care of patients with cirrhosis is best49

Ascites

Clinical Paracentesis if new-onset moderate to severe ascites or if concern for spontaneous bacterial peritonitis

Moderate (grade 2) and severe (grade 3) ascites:  Diuresis with mineralocorticoids for treatment and prophylaxis  Salt restriction < 2 g per day 7; no added salt; avoid preprepared meals49,53  Fluid restriction usually not helpful7 Large (grade 3) ascites:  Paracentesis: large-volume paracentesis with albumin infusion53

Spironolactone, 100 mg per day Titrate every three days to maximum of 400 mg daily Goal of no more than 1.1 to 2.2 lb (0.5 to 1 kg) daily of weight loss* Add furosemide (Lasix; or torsemide [Demadex]) if not responsive to spironolactone alone or if limiting adverse effects occur (e.g., hyperkalemia49,53) Decrease to lowest effective dosage

Esophageal varices

EGD at diagnosis of cirrhosis9 May defer EGD if compensated, transient elastography with liver stiffness < 20 kPa, and platelets > 150,000 per mm3 (< 5% probability of high-risk varices)46 Repeat EGD if decompensation develops; if no varices (every two to three years†); if small varices (every one to two years†); or if medium or large varices or high-risk timing of repeat EGD varies

Medium, large, or high-risk varices (red wale markings):  Endoscopic band ligation or nonselective beta blocker for prophylaxis7,9,46,53  Prophylaxis with nonselective beta blocker should be indefinite

Propranolol, 20 to 40 mg twice daily; maximum: 160 to 320 mg per day‡ Nadolol (Corgard), 20 to 40 mg daily; maximum: 80 to 160 mg per day‡ Carvedilol (Coreg), 6.25 mg daily; maximum: 12.5 mg per day Titrate every two to three days; goal 25% heart rate reduction, keep heart rate > 55 beats per minute45,46,53 Discontinue if hemodynamic instability: sepsis, spontaneous bacterial peritonitis, acute gastrointestinal bleeding, refractory ascites, systolic blood pressure < 90 mm Hg, sodium concentration < 120 to 130 mEq per L (120 to 130 mmol per L), or acute kidney injury 7,53

Hepatic encephalopathy

Clinical

Reverse precipitants

Lactulose syrup, 25 mL every one to two hours until two soft bowel movements per day Titrate to two to three soft bowel movements per day54 Rifaximin, 550 mg orally twice per day 7,54

Exclude other causes

Nutritional support

Ammonia levels should not be used for diagnosis or monitoring7,54

Medications  First episode: lactulose for treatment and prophylaxis  Second episode: add rifaximin (Xifaxan) for prophylaxis

Hepatocellular carcinoma

Right upper quadrant ultrasonography every six months for all patients with cirrhosis and in certain patients with chronic hepatitis B virus infection without cirrhosis43,55

Treat obesity, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, diabetes mellitus, and hepatitis B virus infection

Refer to hepatologist for suspicious findings

Leg cramps

Clinical

Manage electrolytes

Baclofen, 10 mg per day, titrate weekly up to 30 mg per day53

Especially if taking diuretics53

Baclofen (Lioresal) as needed and tolerated53

Malnutrition

Clinical

Multivitamin

Avoid protein restriction, even during hepatic encephalopathy Because of the increased risk of osteoporosis in chronic cholestasis and cirrhosis, performing a bone mineral density scan at the time of liver disease diagnosis or liver transplantation evaluation should be considered45

Especially if new hepatic encephalopathy

Small frequent meals and late-night snack

Protein intake of 1 to 1.5 g per kg per day, with supplementation as needed45,54

Consider bone mineral density scan

Spontaneous bacterial peritonitis53

Clinical Paracentesis if suspicion of disease (new or worsening ascites, gastrointestinal bleeding, hemodynamic instability, fever or signs of systemic inflammation, gastrointestinal symptoms, worsening liver or kidney function, new or worsening hepatic encephalopathy) Diagnosis Ascitic fluid neutrophil count > 250 per mm3

Treatment (empiric, IV antibiotics):  Community-acquired bacterial peritonitis: third-generation cephalosporin or piperacillin/tazobactam (Zosyn) Prophylaxis per criteria:  Ceftriaxone IV if acute gastrointestinal bleeding and Child-Pugh grade B/C  Trimethoprim/sulfamethoxazole or ciprofloxacin oral if acute gastrointestinal bleeding and Child-Pugh grade A [corrected] History of spontaneous bacterial peritonitis, ascitic protein < 1.5 g per dL and advanced liver disease (Child-Pugh score ≥ 9 or bilirubin ≥ 3 mg per dL) or kidney disease (creatinine ≥ 1.2 mg per dL, sodium ≤ 130 mmol per L)7,9,49,53

Treatment dosing:  Cefotaxime, 2 g IV every eight to 12 hours  Ceftriaxone, 2 g IV every 24 hours  Piperacillin/tazobactam, 3.375 g IV every six hours Prophylactic dosing:  Ceftriaxone, 1 g IV per day for seven days  Trimethoprim/sulfamethoxazole, one 800-mg/160-mg tablet per day  Ciprofloxacin, 500 mg per day  Norfloxacin, 400 mg per day (not available in United States) Routine use of antibiotic prophylaxis in ascites without spontaneous bacterial peritonitis or acute gastrointestinal bleeding is not recommended7


EGD = esophagogastroduodenoscopy; IV = intravenously; kPa = kilopascals.

*—Weight loss goal in the absence and presence of peripheral edema, respectively.

†—Frequency in presence and absence of ongoing liver injury, respectively.46

‡—Maximal daily dosage in presence and absence of ascites, respectively.

Information from references 7, 9, 43, 45, 46, 49, and 5355.

TABLE 7.

Select Complications of Cirrhosis and Recommendations for Screening and Management

Cirrhosis complicationScreeningInterventionMedication dosing and other considerations

Abdominal hernia

Clinical

Defer surgery until medically optimized and ascites controlled

High perioperative risk and hernia recurrence in presence of ascites49

Increased risk with ascites

Consult with multidisciplinary team

Surgeon with experience in the care of patients with cirrhosis is best49

Ascites

Clinical Paracentesis if new-onset moderate to severe ascites or if concern for spontaneous bacterial peritonitis

Moderate (grade 2) and severe (grade 3) ascites:  Diuresis with mineralocorticoids for treatment and prophylaxis  Salt restriction < 2 g per day 7; no added salt; avoid preprepared meals49,53  Fluid restriction usually not helpful7 Large (grade 3) ascites:  Paracentesis: large-volume paracentesis with albumin infusion53

Spironolactone, 100 mg per day Titrate every three days to maximum of 400 mg daily Goal of no more than 1.1 to 2.2 lb (0.5 to 1 kg) daily of weight loss* Add furosemide (Lasix; or torsemide [Demadex]) if not responsive to spironolactone alone or if limiting adverse effects occur (e.g., hyperkalemia49,53) Decrease to lowest effective dosage

Esophageal varices

EGD at diagnosis of cirrhosis9 May defer EGD if compensated, transient elastography with liver stiffness < 20 kPa, and platelets > 150,000 per mm3 (< 5% probability of high-risk varices)46 Repeat EGD if decompensation develops; if no varices (every two to three years†); if small varices (every one to two years†); or if medium or large varices or high-risk timing of repeat EGD varies

Medium, large, or high-risk varices (red wale markings):  Endoscopic band ligation or nonselective beta blocker for prophylaxis7,9,46,53  Prophylaxis with nonselective beta blocker should be indefinite

Propranolol, 20 to 40 mg twice daily; maximum: 160 to 320 mg per day‡ Nadolol (Corgard), 20 to 40 mg daily; maximum: 80 to 160 mg per day‡ Carvedilol (Coreg), 6.25 mg daily; maximum: 12.5 mg per day Titrate every two to three days; goal 25% heart rate reduction, keep heart rate > 55 beats per minute45,46,53 Discontinue if hemodynamic instability: sepsis, spontaneous bacterial peritonitis, acute gastrointestinal bleeding, refractory ascites, systolic blood pressure < 90 mm Hg, sodium concentration < 120 to 130 mEq per L (120 to 130 mmol per L), or acute kidney injury 7,53

Hepatic encephalopathy

Clinical

Reverse precipitants

Lactulose syrup, 25 mL every one to two hours until two soft bowel movements per day Titrate to two to three soft bowel movements per day54 Rifaximin, 550 mg orally twice per day 7,54

Exclude other causes

Nutritional support

Ammonia levels should not be used for diagnosis or monitoring7,54

Medications  First episode: lactulose for treatment and prophylaxis  Second episode: add rifaximin (Xifaxan) for prophylaxis

Hepatocellular carcinoma

Right upper quadrant ultrasonography every six months for all patients with cirrhosis and in certain patients with chronic hepatitis B virus infection without cirrhosis43,55

Treat obesity, nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, diabetes mellitus, and hepatitis B virus infection

Refer to hepatologist for suspicious findings

Leg cramps

Clinical

Manage electrolytes

Baclofen, 10 mg per day, titrate weekly up to 30 mg per day53

Especially if taking diuretics53

Baclofen (Lioresal) as needed and tolerated53

Malnutrition

Clinical

Multivitamin

Avoid protein restriction, even during hepatic encephalopathy Because of the increased risk of osteoporosis in chronic cholestasis and cirrhosis, performing a bone mineral density scan at the time of liver disease diagnosis or liver transplantation evaluation should be considered45

Especially if new hepatic encephalopathy

Small frequent meals and late-night snack

Protein intake of 1 to 1.5 g per kg per day, with supplementation as needed45,54

Consider bone mineral density scan

Spontaneous bacterial peritonitis53

Clinical Paracentesis if suspicion of disease (new or worsening ascites, gastrointestinal bleeding, hemodynamic instability, fever or signs of systemic inflammation, gastrointestinal symptoms, worsening liver or kidney function, new or worsening hepatic encephalopathy) Diagnosis Ascitic fluid neutrophil count > 250 per mm3

Treatment (empiric, IV antibiotics):  Community-acquired bacterial peritonitis: third-generation cephalosporin or piperacillin/tazobactam (Zosyn) Prophylaxis per criteria:  Ceftriaxone IV if acute gastrointestinal bleeding and Child-Pugh grade B/C  Trimethoprim/sulfamethoxazole or ciprofloxacin oral if acute gastrointestinal bleeding and Child-Pugh grade A [corrected] History of spontaneous bacterial peritonitis, ascitic protein < 1.5 g per dL and advanced liver disease (Child-Pugh score ≥ 9 or bilirubin ≥ 3 mg per dL) or kidney disease (creatinine ≥ 1.2 mg per dL, sodium ≤ 130 mmol per L)7,9,49,53

Treatment dosing:  Cefotaxime, 2 g IV every eight to 12 hours  Ceftriaxone, 2 g IV every 24 hours  Piperacillin/tazobactam, 3.375 g IV every six hours Prophylactic dosing:  Ceftriaxone, 1 g IV per day for seven days  Trimethoprim/sulfamethoxazole, one 800-mg/160-mg tablet per day  Ciprofloxacin, 500 mg per day  Norfloxacin, 400 mg per day (not available in United States) Routine use of antibiotic prophylaxis in ascites without spontaneous bacterial peritonitis or acute gastrointestinal bleeding is not recommended7


EGD = esophagogastroduodenoscopy; IV = intravenously; kPa = kilopascals.

*—Weight loss goal in the absence and presence of peripheral edema, respectively.

†—Frequency in presence and absence of ongoing liver injury, respectively.46

‡—Maximal daily dosage in presence and absence of ascites, respectively.

Information from references 7, 9, 43, 45, 46, 49, and 5355.

COMMON COMPLICATIONS IN DECOMPENSATED CIRRHOSIS

Ascites, which develops in 5% to 10% of patients with cirrhosis per year, leads to decreased quality of life, frequent hospitalizations, and directly increases risk of further complications such as spontaneous bacterial peritonitis, umbilical hernias, and respiratory compromise. It also portends a poor prognosis, with a 30% five-year survival.53 Hepatic encephalopathy, which occurs in 5% to 25% of patients within five years of a cirrhosis diagnosis, is likewise associated with increased medical cost and mortality, with a reported 15% inpatient mortality rate.54

SCREENING FOR VARICES

Portal hypertension predisposes patients with cirrhosis to develop esophageal varices. Patients with varices have a one in three chance of developing a variceal bleed in the two years after diagnosis, with a 20% to 40% mortality rate per episode.45 Endoscopy is the preferred screening method for esophageal varices. Many experts and guidelines recommend screening all patients with cirrhosis9; however, newer recommendations suggest targeted screening of patients with clinically significant portal hypertension.46 A liver stiffness greater than 20 kPa, alone or combined with a low platelet count (less than 150,000 per mm3) and increased spleen size, and/or the presence of portosystemic collaterals on imaging may be sufficient to diagnose clinically significant portal hypertension and warrant endoscopic screening for varices. Repeat endoscopy should be performed every one to two years if small varices are found and every two to three years if no varices are found.46

Consultation

Varices, hepatic encephalopathy, and ascites herald hepatic decompensation; these conditions warrant referral for subspecialist evaluation. The management of acute or refractory complications of cirrhosis (e.g., spontaneous bacterial peritonitis, acute gastrointestinal bleeding, hepatorenal syndrome, unresponsive portal hypertension, hepatic encephalopathy, ascites) is best addressed in the inpatient or referral setting.

This article updates previous articles on this topic by Starr and Raines,56 Heidelbaugh and Bruderly,57 and Riley and Bhatti.58

Data Sources: A literature search was completed in Medline via Ovid, EBSCOhost, DynaMed, and the Cochrane Database of Systematic Reviews using the keywords cirrhosis, end stage liver disease, management of liver disease, and liver fibrosis staging. Additionally, the EE+Evidence Summary literature search sent by the AFP medical editors was reviewed. Search dates: November 26, 2018; December 27, 2018; and August 7, 2019.

The Authors

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ANDREW SMITH, MD, is the director of obstetrics curriculum and a core faculty member of the Lawrence Family Medicine Residency Program at the Greater Lawrence (Mass.) Family Health Center and is an assistant professor at Tufts University Medical School, Boston, Mass....

KATRINA BAUMGARTNER, MD, is an HIV specialist and staff family physician and community faculty of the Lawrence Family Medicine Residency Program at the Greater Lawrence Family Health Center and is a clinical instructor at Tufts University Medical School.

CHRISTOPHER BOSITIS, MD, is the clinical program director of the HIV and Viral Hepatitis programs at Greater Lawrence Family Health Center, a core faculty member of the Lawrence Family Medicine Residency Program at the Greater Lawrence Family Health Center, and an assistant professor at Tufts University Medical School.

Address correspondence to Andrew Smith, MD, Greater Lawrence Family Health Center, 34 Haverhill St., Lawrence, MA 01841 (email: asmith@glfhc.org). Reprints are not available from the authors.

Author disclosure: No relevant financial affiliations.

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