How to Cite This Chapter: Hejazifar N, Puglia M, Lee C, Wawrzynowicz-Syczewska M. Cirrhosis. McMaster Textbook of Internal Medicine. Kraków: Medycyna Praktyczna. Accessed August 10, 2022.
Last Updated: February 5, 2022
Last Reviewed: February 5, 2022
Chapter Information

Definition, Etiology, Natural HistoryTop

Cirrhosis refers to end-stage liver disease characterized by diffuse fibrosis, resulting in distortion of the normal liver architecture and development of structurally abnormal regenerative nodules. Cirrhosis may regress with treatment of the underlying cause but in most cases it is irreversible. Liver transplant should be considered following the development of complications secondary to liver cirrhosis.

The majority of complications associated with cirrhosis are secondary to the development of portal hypertension. The pressure gradient between the hepatic vein and the portal vein (hepatic venous pressure gradient [HVPG]) in a healthy liver is ≤5 mm Hg. Portal hypertension refers to an HVPG ≥6 mm Hg. Distortion of hepatic microcirculation via structural (eg, fibrosis) and dynamic changes (increased vasoconstrictors and decreased synthesis of endothelial vasodilators) leads to an increase in HVPG and development of portosystemic venous collaterals in the esophagus, rectum, and abdominal walls. Esophageal varices may develop with an HVPG ≥10 mm Hg. The risk of variceal bleeding and development of ascites increases with an HVPG ≥12 mm Hg.

Portal hypertension may also develop in a variety of situations unrelated to cirrhosis because of disruption of the blood flow due to prehepatic (eg, portal and splenic vein thrombosis), posthepatic (eg, Budd-Chiari syndrome, pericardial disease, heart failure), and many intrahepatic causes (eg, polycystic liver disease, malignancy, granulomatous liver lesions, sinusoidal obstructive syndrome, schistosomiasis). This discussion is beyond the scope of this chapter.

The etiology of cirrhosis is identified in up to 90% of patients. The most common causes of cirrhosis in high-income countries are nonalcoholic steatohepatitis (NASH), alcohol-related liver disease (ARLD), and viral hepatitis B and C. Other causes to consider include hereditary hemochromatosis, autoimmunity-related conditions (autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cholangitis), genetic conditions (Wilson disease, alpha1-antitrypsin deficiency, cystic fibrosis, glycogen storage diseases), medications (eg, methotrexate, amiodarone), chronic congestive hepatopathy (eg, heart failure). In clinical practice many instances of cirrhosis may be multifactorial (eg, a patient with metabolic syndrome and alcohol use disorder taking amiodarone for atrial fibrillation).

Natural history: Cirrhosis is a progressive disease that over time may lead to biochemical and clinical decompensation. Prognosis depends on etiology, disease severity, and presence of complications and other comorbidities. The most commonly used predictive models for prognostication of patients with cirrhosis are the Child-Pugh score (Table 7.3-3) and the Model for End-Stage Liver Disease and Serum Sodium Concentration (MELDNa) score (available at The median survival of patients with compensated cirrhosis is ≥12 years. Patients with decompensated cirrhosis have a 1-year mortality of ≥20% depending on severity of decompensation. In one systematic review of patients with decompensated cirrhosis, the median survival of patients with a Child-Pugh score ≥12 or a MELDNa score ≥21 was ≤6 months.

Clinical FeaturesTop

Clinical features depend on the duration of cirrhosis, amount of preserved functioning liver parenchyma, abnormalities of portal circulation, and treatment. Once the diagnosis is established, it is important to determine whether the patient has compensated or decompensated cirrhosis. Patients with compensated cirrhosis are often asymptomatic or present with nonspecific symptoms. They may have a variety of incidental findings including various laboratory abnormalities (eg, thrombocytopenia, macrocytic anemia, leukopenia), imaging findings (eg, splenomegaly, nodularity of the liver, portosystemic collaterals), or endoscopic features of portal hypertension (eg, portal gastropathy, esophageal and gastric varices). Patients with decompensated cirrhosis may present with one or more of ascites, hepatic encephalopathy, variceal bleeding, hepatic hydrothorax, spontaneous bacterial peritonitis, hepatopulmonary syndrome, and hepatorenal syndrome.

1. General manifestations: Patients with compensated cirrhosis may present with nonspecific symptoms, which include weakness, fatigability, weight loss, and decreased appetite. As the diseases progresses, other general manifestation such as muscle wasting, painful muscular cramps (particularly troublesome at night), pruritus, Dupuytren contracture, bleeding from mucous membranes (as a result of coagulopathy or thrombocytopenia) become more prevalent.

2. Cutaneous manifestations include jaundice, spider angiomas, easy bruising, telangiectasia, palmar and plantar erythema, skin hyperpigmentation, leukonychia, xanthomata, loss of chest and axillary hair in men, hirsutism, and dilated collateral veins on the abdominal walls (“caput medusae”). Petechiae as well as gingival, nasal, and mucosal bleeding may be present. This is because cirrhosis leads to a form of “rebalanced” hemostasis where all stages of the hemostatic process (primary hemostasis, coagulation, and fibrinolysis) may be abnormal and consequently lead to both procoagulant and anticoagulant effects.

3. Gastrointestinal (GI) manifestations include flatulence, nausea, vomiting, smoothing of the tongue, edema of the salivary glands, epigastric tenderness, splenomegaly (~60% of patients), hepatomegaly with palpable nodules on the liver surface, ascites, and hernias of the abdominal wall (most frequently umbilical hernia).

4. Cardiovascular manifestations include decreased mean arterial pressure and cardiac dysfunction called “cirrhotic cardiomyopathy,” where patients have increased cardiac output and contractility at rest combined with a blunted response to physiologic, pathologic, or pharmacologic stress.

5. Neurologic manifestations include asterixis (bilateral asynchronous flapping motion of outstretched dorsiflexed hands) and hepatic encephalopathy.

6. Abnormalities of the reproductive system: Men with cirrhosis may develop symptoms of hypogonadism (loss of libido, infertility, testicular atrophy, gynecomastia). Women with cirrhosis also have altered levels of testosterone, luteinizing hormone, prolactin, and estradiol, which clinically manifest as chronic anovulation or irregular menstrual bleeding.


Common laboratory findings in patients with cirrhosis include thrombocytopenia, macrocytic anemia, and leukopenia. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) may be normal in end-stage liver disease, as late-stage cirrhosis is representative of a “burnout” state due to the limited volume of remaining viable hepatic tissue. Elevated alkaline phosphatase (ALP) levels (2-3 × upper limit of normal [ULN]) are usually seen in patients with cholestatic liver disease. An isolated gamma-glutamyl transferase (GGT) elevation may be suggestive of alcoholic cirrhosis. Patients with decompensated cirrhosis may experience pruritis due to progressively worsening conjugated hyperbilirubinemia. Hyponatremia, hypokalemia or hyperkalemia, hypoalbuminemia, and elevated international normalized ratio (INR) may also occur with continued decompensation of liver disease. Although INR increases as synthesis of clotting factors becomes impaired, it poorly reflects the bleeding or clotting tendency in patients with cirrhosis.

In general, factors associated with increased likelihood of cirrhosis include the presence of ascites (odds of cirrhosis increase 7.2-fold if ascites is present; likelihood ratio [LR], 7.2), platelet counts <160×109/L (LR, 6.3), and spider angiomas (LR, 4.3).

Diagnostic Tests

1. Noninvasive tests helpful in establishing the presence of cirrhosis:

1) Blood tests: Serologic indices rely on a combination of tests, which include usually platelet counts, AST, ALT, and INR. The AST-to-platelet ratio index (APRI) and FIB-4 index can be found online (eg, at Other similar scores include the Lok index and Bonacini cirrhosis discriminant index.

2) Imaging studies:

a) Ultrasonography may be used to evaluate for hepatocellular carcinoma (HCC) and signs of portal hypertension. It may reveal hypertrophy of the left lobe and caudate lobe, right lobe atrophy, and irregular nodular outline of the liver edge. Features of portal hypertension include dilation of the portal vein >15 mm with monophasic or inverted flow, presence of collateral circulation (particularly in the left gastric, splenic, and umbilical veins), and splenomegaly. An enlarged thick-walled gallbladder and cholelithiasis are frequently observed. HCC usually presents as a hypoechoic focal lesion (for lesions >2 cm in diameter the probability of cancer is ~95%). In one study, high-resolution ultrasonography predicted cirrhosis with a sensitivity and specificity of 91% and 93%, respectively. Computed tomography (CT) is not superior to ultrasonography except for patients with suspected HCC (triphasic helical CT).

b) Vibration-controlled transient elastography (VCTE) cutoff scores for cirrhosis vary depending on etiology. A score >11 to 14 kPa has a sensitivity of 87% and a specificity of 91% for diagnosing cirrhosis.

c) Magnetic resonance elastography (sensitivity, 94%; specificity, 95%) is one of the most reliable noninvasive tests, but it is more expensive and therefore less readily available.

d) Ultrasonography-based elastography (shear wave elastography [SWE] and strain elastography) has similar sensitivity and specificity for diagnosis as VCTE but is less readily available.

2. Invasive tests: Liver biopsy is the gold standard in the diagnosis of cirrhosis. It has a sensitivity of 80% to 100% and can also aid in establishing etiology. Liver biopsy is not necessary if noninvasive tests are suggestive of cirrhosis and no change in management is expected.

3. Serologic tests helpful in identifying the etiology of cirrhosis:

1) Viral hepatitis: Hepatitis B surface antigen (HBsAg), hepatitis C antibodies (assess HCV RNA viral load and genotype if the HCV antibody test result is positive).

2) Autoimmune hepatitis: Antinuclear antibodies (ANAs), type 1 liver/kidney microsomal antigen (LKM1), smooth muscle antibodies (SMAs), IgG.

3) Primary biliary cholangitis: Antimitochondrial antibodies (AMAs), IgM.

4) Hemochromatosis: Iron, iron-binding capacity, serum ferritin, transferrin saturation. HFE genetic testing is performed if iron studies are indicative of hemochromatosis.

5) Wilson disease: Serum ceruloplasmin, serum copper, 24-hour urinary copper excretion.

6) Deficiency of alpha1 antitrypsin: Levels of alpha1 antitrypsin.

7) There are no specific serologic markers for the diagnosis of nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease. However, HbA1c levels and lipid panel may help identify prediabetes/diabetes and dyslipidemia as risk factors for NAFLD.

Complications and TreatmentTop

Liver transplant is the key treatment option in patients with decompensated cirrhosis. The severity of liver disease defined by the MELDNa score (ranging 6-40, available at is used to guide the priority on liver transplant listing. Specific guidelines have also been developed to allocate a minimum MELDNa score to certain complications of liver disease thought to be underestimated by the MELDNa score and thus lacking a true reflection of their mortality risk. These include hepatopulmonary syndrome, portopulmonary hypertension, HCC, familial amyloid polyneuropathy, hilar cholangiocarcinoma, primary sclerosing cholangitis, and certain metabolic disorders. Note that specific prerequisites must be met before MELDNa exception points are awarded. The scores range from 22 (HPS) to 28 (eg, HCC) at the time of transplant listing. Additional points are added every 3 months, equivalent to the patient's 10% increase in mortality risk, until a predefined maximum score is reached. For example, candidates with HCC are capped at 34 points. Any further increase in score is driven by the natural/calculated MELDNa score.

1. Malnutrition: Poor appetite and early satiety are frequently reported and in part due to ascites, delayed gastric emptying, and altered gut motility. Alcohol abstinence is important. Micronutrient and macronutrient deficiencies are common.


1) Cholestatic liver disease reduces digestion of fat and fat-soluble vitamins (A, D, E, K). Supplementation with vitamins is used when indicated.

2) Glycogenolysis and gluconeogenesis are impaired in fasting state and thus protein is used more readily as fuel. This leads to a catabolic state and muscle loss. Nocturnal hypoglycemia may also occur due to impaired hepatic gluconeogenesis. Patients should consume 25 to 35 kcal/kg of their actual body weight with protein intake optimized at 1.2 to 1.5 g/kg/d and lipids accounting for 20% to 40% of caloric requirements. Late-night snacks with complex carbohydrates are recommended to avoid night gluconeogenesis from protein.

2. Ascites: Ascites is the pathologic accumulation of fluid in the peritoneal space.

The pathogenesis of ascites is complex. The main mechanisms involve underlying portal hypertension, reduced effective arterial blood volume leading to activation of the renin-angiotensin-aldosterone system, and subsequent renal sodium and water retention. The presence of moderately to severely tense ascites is associated with a mortality rate of 50% within 2 years of the onset of ascites.

Treatment and prevention:

1) Where possible, ensure that the underlying cause of cirrhosis is being treated.

2) In patients with mild ascites initiate salt restriction (sodium <2 g/d) as first-line therapy.

3) If ascites persists or worsens, initiate diuretics with, for example, a combination of furosemide 40 mg and spironolactone 100 mg. If the desired effect is not observed after 3 to 5 days (weight reduction 0.3-0.5 kg/d in patients with ascites alone or 0.8-1 kg/d in those with concomitant peripheral edema), double the dose while maintaining the same ratio (maximum doses: spironolactone, 400 mg/d; furosemide, 160 mg/d). After ascites resolves continue the sodium intake restriction and diuretics at levels that prevent repeated fluid accumulation (measure body weight every 1-2 days).

4) The combination of a low-salt diet and diuretics controls ascites in 90% of cases. In patients with refectory ascites, large-volume paracentesis (LVP) may be used. LVP of >5 L can lead to hemodynamic changes and therefore IV albumin (a plasma volume expander) is given at a dose of 8 g/L of ascitic fluid removed.Evidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias and imprecision. Simonetti RG, Perricone G, Nikolova D, Bjelakovic G, Gluud C. Plasma expanders for people with cirrhosis and large ascites treated with abdominal paracentesis. Cochrane Database Syst Rev. 2019 Jun 28;6:CD004039. doi: 10.1002/14651858.CD004039.pub2. Review. PubMed PMID: 31251387; PubMed Central PMCID: PMC6598734. Other treatment modalities in patients with refractory or recurrent ascites include transjugular intrahepatic portosystemic shunt (TIPS), liver transplant, and peritoneovenous shunt (the last one is considered in patients who are not candidates for TIPS or transplant in whom paracentesis cannot be performed safely because of previous surgeries, scar tissue, or obesity).

The equivalent of ascites is the presence of ascites in the pleural cavities, especially on the right side (exclude heart failure and lung and pleural diseases). This carries a poor prognosis and consideration of liver transplant. In patients with dyspnea, perform pleural puncture and drain the fluid in a single session (chronic drainage is contraindicated due to the risk of complications, including infection). Pleurodesis may be considered only in patients not eligible for liver transplant or TIPS.

3. Spontaneous bacterial peritonitis (SBP) develops in 10% to 30% of patients with ascites and in 25% to 65% of patients with ascites and acute GI bleeding. The risk of SBP increases with progression of portal hypertension.

EtiologySBP is caused by infection of ascitic fluid without an evident intra-abdominal source of infection, most likely due to translocation of bacteria from the GI tract lumen and impaired antimicrobial activity of ascitic fluid.

Typical presentation: Asymptomatic (~10%) or nonspecific symptoms such as fever or hypothermia, abdominal pain, altered mental status/hepatic encephalopathy, and hypotension. It is associated with an 80% in-hospital mortality rate if left untreated.

Diagnosis: Ascitic fluid polymorphonuclear (PMN) cell count >0.25×109/L or a positive ascitic fluid culture (collect ≥10 mL of fluid in aerobic and anaerobic culture tubes). Cultures are negative in 20% to 40% of patients despite inflammatory features of ascitic fluid. Differential diagnosis should include secondary peritonitis developing in a patient with ascites.

Risk factors: Previous history of SBP, low total protein concentration in ascitic fluid (<15 g/L), acute upper GI bleeding, and presence of severe liver disease.

Common pathogens: Most common isolates (80% of patients) include gram-negative aerobic bacteria Escherichia coli and Klebsiella spp. Gram-positive cocci, predominantly Streptococcus spp, account for 20% of cases. Less common isolates include Enterococcus faecalis, Enterobacter spp, Serratia spp, Proteus spp, and Pseudomonas spp.

Treatment: Antibiotic regimens include a third-generation cephalosporin (eg, IV ceftriaxone 2 g every 24 h, IV cefotaxime 2 g every 8-12 h, or IV ceftazidime 1 g IV every 12-24 h). In patients with serum bilirubin levels >68 micromol/L (4 mg/dL) and serum creatinine levels >88.4 micromol/L (1 mg/dL), administer infusion of albumin solution (1.5 g/kg on day 1 followed by 1 g/kg on day 3). Consider repeat diagnostic paracentesis in 48 to 72 hours. If the PMN count has decreased by >25% or overall it is <0.25×109/L, continue therapy for a total of 5 to 7 days; if this does not occur, consider treatment with antibiotics for an extended course, changing antibiotics based on susceptibility, or an alternative diagnosis (secondary bacterial peritonitis).

Screening: Perform diagnostic paracentesis in all patients with cirrhosis presenting with new ascites. All patients with cirrhosis and ascites who present to the hospital for an acute illness should also undergo diagnostic paracentesis irrespective of their symptoms.

Primary prevention: Provide long-term antibiotic prophylaxis to patients with ascites, a low ascitic total protein level (<15 g/L), and evidence of either significant liver or renal dysfunction. Short-term antibiotic prophylaxis (a 7-day course) should be provided to all patients with cirrhosis who present with acute upper GI bleeding to help prevent SBP and bacteremia.

Secondary prevention: This should be provided to patients with a previous history of SBP until resolution of ascites or liver transplant. Options include oral norfloxacin 400 mg once daily (or another quinolone) or trimethoprim/sulfamethoxazole in double strength once daily or 5 days per week.

4. Portal hypertensive bleeding: The presence of esophageal and gastric varices may result in acute GI bleeding. Portal hypertensive gastropathy may cause occult GI blood losses. Among patients with cirrhosis, 50% have esophageal varices and 33% experience ≥1 episode of variceal hemorrhage. The risk of bleeding within 2 years of endoscopic diagnosis of esophageal varices is ~30%. Variceal bleeding is associated with 30-day mortality rates of 15% to 20%. Additionally, 1 in 3 patients has a recurrent hemorrhage within 6 weeks. Patients who survive the initial 2-week period after initial variceal bleeding have a 1-year survival rate of 52%.

Risk factors for esophageal variceal bleeding include size of varices, endoscopic features of varices (eg, red wale signs, cherry-red spots), severity of liver disease (Child-Pugh class C is at highest risk [Table 7.3-3]), and (rarely measured) HVPG (>12 mm Hg; >20 mm Hg is associated with refractory or recurrent bleeding). Risk factors for early rebleeding include age >60 years, renal failure, large varices, and severity of the initial bleeding (hemoglobin <80 g/L).

Primary prevention of esophageal variceal bleeding is imperative. Screening for varices with esophagogastroduodenoscopy (EGD) is done every 1 to 3 years, depending on the severity of liver disease. Nonselective beta-blockers (NSBBs), such as propranolol, carvedilol, or nadolol, are recommended as primary prophylaxis against the first variceal bleeding in those with medium to large varices, varices of any size with high-risk features (eg, red wale markings, cherry-red spots), and those with varices of any size and Child-Pugh class B or C cirrhosis. In patients with varices who do not fulfill these criteria, NSBBs may be withheld and repeat screening with EGD is recommended on an annual basis. In those without varices at the initial screening EGD, a repeat procedure is recommended every 2 to 3 years (EGD should be performed annually in those without varices who develop decompensated cirrhosis). There is little evidence to support the use of NSBBs solely as a means to prevent the development of varices. Variceal ligation may be used as primary prevention in those with large high-risk varices or those who do not tolerate NSBBs. There is little evidence to support the combination therapy of NSBBs and variceal ligation for primary prophylaxis.

When NSBBs are indicated, they should be initiated and then titrated to a resting heart rate of 55 to 60 beats/min (systolic blood pressure should remain >90 mm Hg). Repeat endoscopy is not indicated after initiation of NSBBs. NSBBs reduce the risk of first variceal hemorrhage by 50%. Alternatively, in patients not tolerating beta-blockers, variceal ligation should be performed every 2 to 8 weeks until all varices have been eradicated. Annual EGD is necessary thereafter for surveillance of esophageal varices.

Secondary prevention following variceal bleeding: An NSBB should be introduced shortly after resolution of variceal hemorrhage. A combination of NSBBs and variceal ligation is more effective than either modality alone for secondary prevention. EGD should be performed at an interval of 2 to 8 weeks until all esophageal varices have been eradicated. TIPS may be a reasonable additional procedure if the above measures are not effective in preventing subsequent bleeding.

Management of bleeding esophageal varices: see Gastrointestinal Bleeding.

5. Hepatic encephalopathy (HE): Potentially reversible neurocognitive impairment caused by liver dysfunction, a portosystemic shunt, or both. It is associated with a wide spectrum of clinical manifestations that range from subclinical to a comatose state. Hepatic encephalopathy can be broadly categorized as covert (CHE) or overt hepatic encephalopathy (OHE).

PathogenesisHE is most likely caused by the effects of endogenous neurotoxins (ammonia, mercaptans, short- and medium-chain fatty acids, phenols) in conjunction with excessive activation of the GABAergic system.

Natural course: CHE is subclinical and has a prevalence of 20% to 80% in patients with cirrhosis. OHE is diagnosed in 40% of patients with cirrhosis and is one of the most common indications for hospital admission. OHE is associated with a 1-year and 3-year survival probability of 42% and 23%, respectively.

Diagnosis: Because CHE is subclinical, the diagnosis can only be made using specialized neurocognitive testing. The clinical relevance of establishing a diagnosis of CHE is currently not clear and discussion of this subject is beyond the scope of this chapter. A diagnosis of OHE is based on clinical presentation. There are no specific or pathognomonic serologic or radiologic tests available. Although blood ammonia levels are commonly measured, this test is neither sensitive nor specific for the screening or diagnosis of OHE in patients with chronic liver disease. Patients with cirrhosis may have an elevated ammonia level at baseline without evidence of neurocognitive alterations. Conversely, OHE may be present in patients with normal serum ammonia levels (less frequent). Patients presenting with neurocognitive symptoms with known or suspected cirrhosis or other causes of portosystemic shunting should be investigated to exclude other causes of their neurocognitive symptoms and to identify potential precipitants of OHE (eg, infection, bleeding, electrolyte abnormalities, dehydration, HCC, portal vein thrombosis).

Clinical manifestations: Patients often present with varied degrees of impaired consciousness, cognition, behavior, and neuromotor deficits. Of note, severe OHE (in patients with cirrhosis) may result in focal neurologic/upper motor neuron symptoms without associated findings on brain imaging.

The severity of OHE can be quantified by the West Haven criteria (WHC). In clinical practice it is important to communicate the severity of OHE using the WHC grading scale, as it will impact disposition decisions (regarding admission to the hospital [a ward or intensive care unit]) and treatment intensity. WHC and summary of clinical manifestations: Table 7.3-4.

HE classification is based on 4 factors: presence of a precipitating factor (precipitant), severity, type, and time course. Most patients have an identifiable precipitant and resolution of HE episode coincides with correction of the suspected underlying precipitant. Common precipitating factors encountered in clinical practice: Table 7.3-5. If no precipitant is identified, the patient is said to have spontaneous HE.


1) First-line therapy is oral lactulose 20 g/30 mL to 30 g/45 mL tid to qid titrated to 2 to 3 bowel movements daily. Alternative routes (if oral administration is not possible) include a nasogastric (NG) tube or rectal enemas 300 mL in 700 mL of water or physiologic saline every 2 to 4 hours titrated to 2 to 3 bowel movements per day.

2) Second-line therapy is oral rifaximin 550 mg bid instituted in case of lactulose intolerance or no clinical improvement with lactulose monotherapy.

3) Other therapies have inconsistent evidence with respect to their efficacy in treating OHE. Consultation with a hepatologist is reasonable to assist in further management of a patient with suspected HE who has no adequate response to the initial and second-line management. A recent randomized clinical trial has suggested that administration of a single 4-L dose of polyethylene glycol (PEG) given by mouth or NG tube over 4 hours may be superior to lactulose for treating an episode of acute HE. NG administration of PEG was not associated with increased risk of aspiration in patients with OHE. Other pharmacologic therapies to be considered may include antibiotics such as metronidazole, branched-chain amino acids (BCAAs), and L-ornithine L-aspartate (LOLA).

Primary prevention: Routine prophylaxis is not indicated but should be considered in high-risk patients (eg, with active GI bleeding).

Secondary prevention:

1) Nonpharmacologic measures: Correct and reduce the risk of recurrence of precipitating factors (titrate doses of diuretic and laxative agents, reconcile all medications [periodically review all drugs to make sure the agents and dosage are correct]), ensure SBP prophylaxis is instituted when indicated, provide appropriate screening and treatment for esophageal varices and HCC.

2) Pharmacologic measures: All patients with a history of OHE should receive maintenance therapy of oral lactulose (20 g/30 mL to 30 g/45 mL given tid to qid and titrated to 2-3 bowel movements daily). If the patient is intolerant of lactulose, rifaximin may be started. If the patient has recurrent OHE while receiving lactulose therapy, oral rifaximin 550 mg bid should be added to lactulose or used as monotherapy in those with lactulose intolerance. The addition of rifaximin to lactulose may decrease mortality in patients with OHE.

6. Hepatorenal syndrome (HRS): Potentially reversible renal failure that occurs in patients with severe acute or chronic liver disease in the absence of shock or intrinsic renal disease. HRS develops in ~7% to 15% of patients admitted for tense ascites.

There are 2 type of HRS. Type 1 HRS (HRS-AKI) develops rapidly (<2 weeks) and is defined by a ≥2-fold increase in serum creatinine (50% reduction in creatinine clearance) to a level ≥221 micromol/L (2.5 mg/dL). It may be associated with oliguria with a urine output <500 mL/d. Type 1 HRS is more likely to occur in patients with acute liver failure, alcoholic hepatitis, or acute decompensation of cirrhosis, most commonly as a consequence of SBP or GI bleeding. Type 2 HRS (HRS–non AKI) develops slowly over weeks to months and is most commonly seen in patients with refractory ascites.

Pathogenesis: Portal hypertension leads to increased synthesis of nitric oxide in splanchnic circulation, which leads to vasodilation of systemic and splanchnic circulation. This in turn reduces the effective arterial volume and promotes renal vasoconstriction. Consequently, there is further decline in renal perfusion and glomerular filtration.

Diagnostic criteria:

1) Cirrhosis with ascites.

2) Acute or subacute kidney injury defined as a serum creatinine level >1.5 mg/dL (133 micromol/L) in the absence of shock or hypotension.

3) No improvement of renal function ≥2 days after discontinuation of diuretics and infusion of albumin solution (IV albumin 1 g/kg in divided doses for 48 hours, not exceeding 100 g of albumin per day).

4) No intrinsic renal disease (proteinuria <0.5 g/d, hematuria <50/high-power field, and no renal abnormalities observed on ultrasonography) and exclusion of alternative (competing) etiologies of renal impairment.

5) No recent or current use of nephrotoxic drugs.

6) Other findings: Urine sodium concentrations <10 mmol/L.


1) Nonpharmacologic therapy:

a) Discontinue diuretic agents, nephrotoxic drugs, and any agents that may reduce glomerular blood flow, including nonsteroidal anti-inflammatory drugs (NSAIDs), aminoglycosides, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs).

b) Monitor blood pressure, urine output, and fluid balance.

c) In patients with ascites perform diagnostic paracentesis to exclude SBP.

d) In patients with tense ascites consider therapeutic paracentesis while monitoring blood pressure and maintaining volume status using IV albumin infusions.

2) Pharmacologic and invasive therapies:

a) Liver transplant is the treatment of choice in type 1 and type 2 HRS. Pharmacologic and renal replacement therapy may be used to manage (bridge) patients awaiting liver transplant and can potentially improve transplant outcomes. Combined liver and kidney transplant may be necessary for patients who have required renal replacement therapy for an extended period of time. Liver transplant is associated with a 3-year survival rate of ~70%.

b) Terlipressin (a vasopressin analogue decreasing renal and hepatic arterial resistance) 0.5 to 1 mg as an IV bolus every 4 hours or 2 to 12 mg as an IV infusion per day in combination with albumin (1 g/kg IV on day 1, then 40 g/d on subsequent days). If a decrease >25% in serum creatinine levels is not achieved after 3 days of treatment, titrate the dose of terlipressin up to a maximum of 2 mg every 4 hours. Continue treatment until serum creatinine levels decrease to <1.5 mg/dL. Treatment should be discontinued if a complete response is not achieved after 2 weeks of therapy. It is effective in 30% of patients in HRS type 1, although a significant number relapse (15%-50%) with withdrawal of therapy. It is effective in up to 70% of patients with HRS type 2. Terlipressin is currently not available in Canada. In clinical practice vasoconstrictors (norepinephrine and vasopressin) are sometimes used as alternatives to terlipressin for the management of hepatorenal syndrome.

c) Start and titrate oral midodrine (an alpha1 adrenergic agonist/systemic vasoconstrictor) 2.5 to 7.5 mg every 8 hours (maximum dose, 15 mg orally every 8 hours) in combination with subcutaneous octreotide 100 microg (maximum dose, 200 microg subcutaneously every 8 hours, although IV octreotide 25-50 microg/h may be used as well) and IV albumin 50 to 100 g/d. In a retrospective study comparing albumin monotherapy with this treatment modality, combined therapy with midodrine + octreotide + albumin was associated with a higher rate of HRS resolution (40% vs 10%) and lower mortality (43% vs 71%).

7. Hepatopulmonary syndrome (HPS): Characterized by the presence of intrapulmonary arteriovenous right-to-left shunting among patients with cirrhosis or noncirrhotic portal hypertension in the absence of intrinsic lung disease. Patients with HPS have an arterial oxygen tension <80 mm Hg and an alveolar-arterial oxygen gradient >20. Transthoracic contrast echocardiography can be useful in establishing diagnosis.

The pathogenesis of HPS is not completely understood. Intrapulmonary vascular dilation occurs possibly secondary to excess synthesis or decreased breakdown of pulmonary vasodilators (eg, nitric oxide) and inhibition of circulating vasoconstrictive substances. The end result is hypoxemia via ventilation-perfusion mismatch, limitation in oxygen diffusion, and in rare instances shunt formation.

Clinical manifestations: Symptoms of HPS include exacerbation of dyspnea and hypoxemia in sitting or standing positions (improving in supine position). Clubbing may develop. HPS should be considered in every patient with the combination of hypoxemia (partial pressure of oxygen [PaO2] <65 mm Hg), underlying cirrhosis, and portal hypertension. It should be differentiated from pulmonary hypertension associated with portal hypertension and from other causes of hypoxemia that are unrelated to cirrhosis and portal hypertension.

Treatment: The only effective treatment of HPS is liver transplant. HPS is eligible for MELDNa exception points.

Screening: Screening is required in all patients undergoing liver transplant.

8. Hypersplenism usually requires no treatment. If it requires frequent transfusions of packed red blood cells or platelet concentrates or if the patient has painful splenomegaly, consider embolization of the splenic artery, TIPS, or splenectomy (rarely performed due to the high risk of complications in patients with cirrhosis).


1. Recommend regular follow-up for monitoring of abstinence from alcohol and early detection of complications of cirrhosis.

2. Perform ultrasonography with or without alpha-fetoprotein [AFP] every 6 months for HCC screening in patients with Child-Pugh classes A and B. Patients with Child-Pugh class C should undergo HCC screening if they are eligible for liver transplant.

3. Screen for esophageal varices with upper endoscopy every 1 to 3 years, depending on the severity of liver disease and history of previous varices.

4. Vaccinate against hepatitis A and B, influenza, and pneumococcal infections.

Special ConsiderationsTop


Mortality in pregnant women with cirrhosis is estimated at ~ 2% and increases with the degree of liver failure (when the MELDNa index is ≥10, the risk of liver decompensation in a pregnant woman exceeds 80%). Women with MELDNa ≥10 or a history of cirrhosis decompensation should be made aware of the significant risk of disease progression during pregnancy. Women with cirrhosis must be closely supervised and give birth in a unit ensuring intensive supervision of the newborn baby. A high concentration of unconjugated (free) bilirubin in a woman poses a risk of jaundice of the subcortical basal ganglia in the child and may be an indication for an exchange transfusion.

Bleeding from esophageal varices (risk is highest in the second trimester and during childbirth) poses a significant threat to pregnancy, as they increase in size during pregnancy. Upper GI endoscopy in women with cirrhosis should be performed in the year before pregnancy or, if not performed, at the beginning of the second trimester of pregnancy. If varicose veins are not detected during endoscopy before pregnancy or if primary prophylaxis of bleeding is applied, there is no need to repeat the test during pregnancy, unless there are signs of decompensation of cirrhosis or the liver damaging factor (eg, alcohol or HCV infection) has not been eliminated. In esophageal variceal hemorrhage management should be standard, except for the administration of terlipressin or vasopressin (it reduces blood supply to the uterus and may cause uterine contractions).



Table 7.3-3. Child-Pugh score









Grade 1-2

Grade 3-4





Bilirubin (mg/dL [micromol/L]) in PBC

<2 (35)

<4 (70)

2-3 (35-50)

4-10 (70-170)

>3 (50)

>10 (70)

Albumin (g/dL)








Total score




Child score




Compensated cirrhosis: Class A, no indication for liver transplant

Decompensated cirrhosis: Class B or C, indications for liver transplant

Adapted from Br J Surg. 1973;60(8):646-9.

INR, international normalized ratio; PBC, primary biliary cholangitis.

Table 7.3-4. West Haven criteria for grading the severity of hepatic encephalopathy


Neurocognitive manifestations


Increased incidence of motor-vehicle accidents, decreased quality of life, abnormal psychometric or neuropsychological examination 


Mild cognitive and behavioral impairment that is different from patient’s baseline. Manifested by disordered sleep, impaired attention span, mild confusion with intact orientation to time and space. Mild asterixis possible


Lethargy, moderate confusion, slurred speech, asterixis, dyspraxia, personality changes, disorientation to time


Stupor with intact arousability to stimuli, gross disorientation to time and space, incoherent speech. Clonus, nystagmus, Babinski sign, or rigidity may be seen on physical examination


Comatose state that does not respond to any stimuli, including pain

Adapted from Hejazifar N, Bajaj JS. Hepatic Encephalopathy. Reference Module in Biomedical Sciences. Elsevier; 2019.

MHE, minimal hepatic encephalopathy.

Table 7.3-5. Nomenclature for hepatic encephalopathy


1) Spontaneous (no obvious precipitating factor)

2) Precipitated:

– Factors causing increase in ammonia (infection, hypokalemia, metabolic alkalosis, GI bleed, excess protein intake)

– Hypovolemic state (diuretic overdose, large volume paracentesis, diarrhea, vomiting)

– Drugs (benzodiazepines, opioids, alcohol), malignancy (primary hepatocellular carcinoma)

– Vascular occlusion (portal and hepatic vein thrombosis), portosystemic shunts 


1) Type A: HE associated with acute liver failure

2) Type B: HE associated with portosystemic shunting/bypass in absence of intrinsic hepatocellular disease

3) Type C: HE associated with cirrhosis 


1) West Haven criteria: 0/MHE, 1, 2, 3, 4 (see Table 7.3-4)


– Cover hepatic encephalopathy: West Haven criteria grades 0/MHE and 1

– Overt hepatic encephalopathy: West Haven criteria grades 2, 3, 4

Time course

1) Episodic: 1 episode in 6 months

2) Recurrent: >1 episode in 6 months

3) Persistent: Persistent altered behavior interspersed with relapses of OHE

Adapted from Hejazifar N, Bajaj JS. Hepatic Encephalopathy. Reference Module in Biomedical Sciences. Elsevier; 2019.

GI, gastrointestinal; HCC, hepatocellular carcinoma; ISHEN, International Society for Hepatic Encephalopathy and Nitrogen Metabolism; MHE, minimal hepatic encephalopathy; OHE, overt hepatic encephalopathy.

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