Liver Cirrhosis and Its Associated Complications Hospital Physician Board Review Manual www.turner-white.com Introduction 1 Ascites 1 Variceal Hemorrhage 10 Hepatic Encephalopathy 17 Conclusion 20 Board Review Questions 20 References 20 Table of Contents GASTROENTEROLOGY BOARD REVIEW MANUAL Liver Cirrhosis and Its Associated Complications Contributor: Eric S Orman, MD, MSCR Assistant Professor of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN STATEMENT OF EDITORIAL PURPOSE The Hospital Physician Gastroenterology Board Review Manual is a study guide for fellows and practicing physicians preparing for board examinations in gastroenterology. Each manual reviews a topic essential to current practice in the subspecialty of gastroenterology. PUBLISHING STAFF PRESIDENT, GROUP PUBLISHER Bruce M. White SENIOR EDITOR Robert Litchkofski EXECUTIVE VICE PRESIDENT Barbara T. White EXECUTIVE DIRECTOR OF OPERATIONS Jean M. Gaul NOTE FROM THE PUBLISHER: This publication has been developed with- out involvement of or review by the Amer- ican Board of Internal Medicine.
Transcript
L i v e r C i r r h o s i s a n d I t s A s s o c i a t e d C o m p l i c a t i o n s
liver Cirrhosis and Its associated ComplicationsContributor:eric s . orman, Md, MsCrAssistant Professor of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN
Statement of editorial PurPoSe
The Hospital Physician Gastroenterology Board Review Manual is a study guide for fellows and practicing physicians preparing for board examinations in gastroenterology. Each manual reviews a topic essential to current practice in the subspecialty of gastroenterology.
PuBliSHinG Staff
PRESIDENT, GRouP PuBLISHERBruce M. White
SENIoR EDIToRRobert Litchkofski
ExEcuTIvE vIcE PRESIDENTBarbara T. White
ExEcuTIvE DIREcToR of oPERaTIoNS
Jean M. Gaul
NoTE fRoM THE PuBLISHER:This publication has been developed without involvement of or review by the American Board of Internal Medicine.
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GastroenteroloGy Board reVIew Manual
liver Cirrhosis and Its associated ComplicationsEric S. Orman, MD, MSCR
introduCtion
Liver cirrhosis is a histologic entity characterized by fibrous septae surrounding regenerative nodules of hepatocytes. It is the end-stage of progressive hepatic fibrosis and can be caused by a variety of insults, most commonly viral hepatitis, alcohol, and nonalcoholic steatohepatitis. The resulting archi-tectural distortion that is seen in end-stage disease leads to increased resistance to portal blood flow and increased portal collateral circulation, both of which contribute to portal hypertension. Portal hypertension in turn leads to the clinical manifesta-tions of end-stage liver disease: ascites, varices, and hepatic encephalopathy. These features carry significant associated morbidity and mortality, and their appearance heralds a poor prognosis. Man-agement of these conditions is a common clinical challenge and an important component of the care of patients with chronic liver disease.
aSCiteS
Case
initial Presentation and HistoryA 56-year-old man with chronic hepatitis C
virus infection presents with a 2-month history of
malaise, progressive abdominal distention, early satiety, and weight gain of 10 kg. In the past week, he has noted orthopnea as well as poorly local-ized abdominal discomfort that is worse in a sit-ting position. He endorses low-grade nausea but no vomiting, and there have been no changes in his bowel movements. He denies chest pain, ex-ertional dyspnea, and lower extremity edema. He has tried acetaminophen and ibuprofen with little relief.
In addition to his hepatitis C, which has not been previously treated, he has hypertension and well-controlled diabetes. There is a prior history of heavy alcohol abuse, between 6 and 12 bottles of beer daily for 20 to 25 years. He has been abstinent from alcohol for the past 8 years, and there is no history of illicit drug use. Current medications include low-dose aspirin, metoprolol, and metformin.
Physical examinationOn exam, he is chronically ill appearing but in
no acute distress. He is afebrile, with a pulse of 80 beats/min and blood pressure of 112/70 mm Hg. Room air oxygen saturation is 99%. There is no-ticeable temporal wasting but no jaundice. Lungs are clear to auscultation throughout. The abdomen is grossly distended, with shifting dullness, and
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there is no lower extremity edema. Multiple spider angiomata are present.
• Howisthediagnosisofascitesmade?
Diagnosis
Ascites is the most common complication of cirrhosis, occurring in 50% of patients within 10 years.1 Diagnosis based on history and physical exam may be obvious when there is massive fluid accumulation and the abdomen is tense; however, in many cases, diagnosis can be difficult, particu-larly in obese patients. The most useful finding is the presence of shifting dullness, which has a sensitivity of 77% and specificity of 72%.2 Other signs, such as puddle sign, are less accurate for diagnosis. When ascites is suspected, diagnostic paracentesis is mandatory to determine the etiol-ogy. Ascites analysis provides invaluable informa-tion, and paracentesis has a low complication rate, even in the presence of thrombocytopenia and coagulopathy.3 In developed countries, most cases
of ascites are due to cirrhosis, but other etiologies must be considered because the differential diag-nosis is broad (Table 1).
• Whatanalysesshouldbeperformedonasci-tesfluid?
The initial ascites fluid evaluation should include assessment of albumin and total protein concentra-tions, cell count with differential, and culture. An algorithmic approach can be used to reliably clas-sify the underlying etiology (Figure1). The serum-ascites albumin gradient (SAAG), calculated as al-buminserum – albuminascites, is a good initial diagnostic test.4 A SAAG of 1.1 g/dL or greater is consistent with ascites due to portal hypertension or heart failure. Ascites due to cirrhosis will also have a total protein less than 2.5 g/dL, and cardiac ascites has a total protein of 2.5 g/dL or greater. A SAAG below 1.1 g/dL may indicate malignant ascites or infection and should be investigated with additional tests such as ascites cytology, acid-fast staining and cul-ture, amylase, triglycerides, bilirubin, and abdominal imaging to identify potential cancer.
Spontaneous bacterial peritonitis (SBP) occurs in 25% of patients with cirrhosis and ascites, and SBP can be asymptomatic.5,6 Therefore, a cell count and culture should be performed every time a paracentesis is done for low-protein ascites. An as-cites polymorphonuclear cell count of 250 cells/µL or greater with a positive culture is diagnostic of SBP. An elevated cell count with a negative culture is termed culture-negative neutrocytic ascites. Ap-proximately 35% of these patients will have a posi-tive culture on repeated paracentesis;7 therefore, they should be considered an SBP equivalent.
• What additional diagnostic tests should beperformedfornew-onsetascites?
Table 1. Differential Diagnosis of Ascites
Cirrhosis
Alcoholic hepatitis
Heart failure
Cancer
Pancreatitis
Nephrotic syndrome
Tuberculous peritonitis
Acute liver failure
Budd-Chiari syndrome
Sinusoidal obstruction syndrome
Postoperative lymphatic leak
Myxedema
Reproduced with permission from Runyon BA. Management of adult pa-tients with ascites due to cirrhosis: update 2012. Alexandria (VA): American Association for the Study of Liver Diseases; 2013.
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Additional evaluation for new-onset ascites can be guided by the history. At a minimum, a complete blood count, comprehensive metabolic panel, and prothrombin time should be obtained. Thrombocy-topenia, hypoalbuminemia, hyperbilirubinemia, and prolongation of the prothrombin time may indicate portal hypertension and hepatic dysfunction. Hypo-natremia develops in 28% of patients with cirrhosis and ascites and indicates a worse prognosis.5,8 B-type natriuretic peptide elevated above 1000 pg/mL can distinguish cardiac ascites from ascites due to portal hypertension.9 Transabdominal ultrasonog-
raphy may show liver nodularity and splenomegaly and can also confirm the presence of ascites when physical exam findings are equivocal. A transthoracic echocardiogram should be obtained when there is suspicion of heart failure. When cirrhosis is pres-ent, echocardiography should also be performed to screen for portopulmonary hypertension, which can contribute to fluid retention.
New or worsening decompensation of previously compensated cirrhosis may indicate the presence of hepatocellular carcinoma (HCC) or portal vein thrombosis. Abdominal imaging is required to iden-
tify these complications. The usual initial test in this circumstance is a Doppler ultrasound, which has a sensitivity of 60% for HCC.10 Dynamic computed tomography (CT) or magnetic resonance imaging (MRI) should also be considered. These tests have the advantage of improved sensitivity for HCC. They can also delineate the extent of portal vein thrombosis and can be diagnostic for HCC when typical enhancement characteristics are present (arterial enhancement with venous washout). The disadvantage of CT and MRI is their high cost compared to ultrasound.
Case ConTinueD
The platelet count is 60 × 103/µL. The serum sodium is 130 mEq/L, and creatinine is 0.8 mg/dL. Serum albumin is 2.9 g/dL, aspartate amino-
transferase (AST) is 66 U/L, alanine amino-transferae (ALT) is 42 U/L, and total bilirubin is 2.3 mg/dL. The INR is 1.6. Transabdominal Dop-pler ultrasound and triple-phase CT show a nodular liver and splenomegaly. There are no enhancing liver masses, and the portal and hepatic venous sys-tems are patent. A diagnostic paracentesis is per-formed. The ascites albumin is less than 1.0 g/dL, and total protein is 1.3 g/dL. There are 120 nucle-ated cells, of which 15% are neutrophils.
• Whatistreatmentforascites?
TreaTmenT
The primary treatment for cirrhotic ascites is sodium restriction and diuretics (Table 2). Di-etary sodium should be limited to 2000 mg daily. More restrictive limits on sodium are discouraged because they may contribute to severe caloric re-strictions that could worsen malnutrition. It can be difficult for patients to adhere to this level of sodium restriction; the average daily sodium intake for U.S. adults is nearly 3500 mg.11 Moreover, patients may misunderstand sodium restriction as a “no added salt” diet, without realizing the high amount of sodium often present in pre-prepared and restau-rant meals.12 Patients also often assume that they need to restrict their fluid intake to reduce ascites accumulation. However, fluid restriction is not ad-vised in the absence of significant hyponatremia. Referral to a dietician can be helpful to reinforce the appropriate diet. In addition, there are many reputable sources for patient education on the Web (eg, the University of California San Francisco’s low-sodium diet guidelines http://www.ucsfhealth.org/education/guidelines_for_a_low_sodium_diet/).
Aldosterone antagonists and loop diuretics are effective medications for the treatment of asci-tes. The most studied and most commonly used
Table 2. Treatment Options for Patients with Cirrhosis and Ascites
First-LineCessation of alcohol use, when present
Sodium-restricted diet and diet education
Dual diuretics, usually spironolactone and furosemide, orally with single daily dosing
Reproduced with permission from Runyon BA. Management of adult patients with ascites due to cirrhosis: update 2012. Alexandria (VA): American Association for the Study of Liver Diseases; 2013.
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agents in these classes are spironolactone and furosemide, respectively. Spironolactone is more effective than furosemide13 and can be started as monotherapy. However, spironolactone can be limited by hyponatremia and hyperkalemia. The decision to use spironolactone monotherapy ini-tially versus combination therapy with furosemide is controversial, with differing recommendations in clinical practice guidelines.7,14 Typical initial dosing of combination therapy is 100 mg of spironolactone and 40 mg of furosemide, with dosage increases every 3 to 5 days as necessary, keeping the 100:40 ratio. This ratio in general maintains normo-kalemia but may need to be altered depending on the individual patient’s response. Typical maximum doses are 400 mg of spironolactone and 160 mg of furosemide. For patients with tender gynecomas-tia, amiloride can be substituted for spironolactone, although it is less effective.15 Eplerenone is another aldosterone antagonist that is more selective for the mineralocorticoid receptor and therefore has fewer side effects; however, it is costlier and has not been studied in this population. Regardless of the chosen regimen, concurrent sodium re-striction is vital to the success of this approach. Patients should be advised that nonadherence to dietary instructions will result in ineffective diuresis.
Patients with tense ascites should be treated with large-volume paracentesis (LVP), which removes fluid more rapidly and effectively than diuretics.16 Following LVP, patients can develop paracentesis-induced circulatory dysfunction, characterized by reduced effective arterial blood volume and acti-vation of the renin-angiotensin system.17 To avoid this complication, when more than 4 to 5 L of fluid is removed, albumin infusion (6–8 g/L of fluid re-moved) is recommended.7 Concentrated albumin (20%–25%) should be used to avoid the exces-
sive volume and sodium load present in dilute 5% preparations. Albumin is superior to other colloid agents (eg, dextran-70) for this purpose.18 Follow-ing LVP, diuretic therapy should be initiated to avoid the need for repeated LVPs.
The development of ascites is associated with a poor prognosis, with nearly 50% mortality after 5 years.5 Therefore, patients with cirrhosis and ascites should be considered for liver transplanta-tion.19
• Howshouldtreatedpatientsbemonitored?
Patients receiving diuretics need to have inter-mittent blood monitoring of electrolytes and renal function, as abnormalities in these parameters are common. The frequency of such monitoring is not standardized and depends on various clini-cal factors. Closer monitoring is definitely recom-mended after dose adjustments. Urine electrolyte determination can also be helpful, particularly for patients who are not responding clinically to diuret-ics. An elevated 24-hour urine sodium (>78 mEq) is indicative of excessive sodium intake. Because 24-hour urine collection is burdensome, a spot urine sodium/potassium ratio is a useful surrogate for urinary sodium excretion. A ratio greater than 1 also suggests excessive sodium in the diet.7
• Whatmedicationsshouldpatientsavoid?
Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit renal prostaglandin synthesis and thereby induce renal vasoconstriction and reduce glo-merular filtration in patients with cirrhosis.20 These effects serve to blunt the response to diuretics and can trigger the hepatorenal syndrome. NSAIDs should therefore be avoided in these patients. When analgesia is needed, acetaminophen is
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preferred.21 Angiotensin-converting enzyme inhibi-tors and angiotensin receptor blockers can induce arterial hypotension and renal failure and should also be avoided.22 Nonselective beta-blockers are a standard therapy for portal hypertension and varices; however, they may negatively impact out-comes in patients with refractory ascites.23 Blood pressure and renal function should be closely monitored in patients with refractory ascites; those with deterioration may benefit from stopping these medications.
Case ConTinueD
Despite sodium restriction and diuretic titration up to maximum recommended doses, recurrent ascites is noted, requiring LVP of 8 to 10 L every 2 weeks. Dietary and medication compliance is confirmed, and the urinary sodium excretion is low. The patient presents to clinic to discuss alternative therapies for refractory ascites.
• Whatare the treatmentoptions forpatientswithrefractoryascites?
Refractory ascites refers to ascites that cannot be controlled by medical therapy either due to lack of response or to diuretic-induced complications.24 This complication occurs in 10% of patients with ascites.5 Treatment involves either serial LVPs or placement of a transjugular intrahepatic portosystemic shunt (TIPS). As noted above, albumin infusions should be provided at the time of LVP to prevent paracentesis-induced circulatory dysfunction. The use of albumin in this setting is also associated with reduced mortality.18
TIPS is a side-to-side portacaval shunt that re-duces portal pressure and improves the control of ascites (Figure2). It is placed by an interventional radiologist using an endovascular approach. In pa-tients with refractory ascites, TIPS induces natriure-sis and reduction in the renin-angiotensin axis with consequent improvement in ascites.25 Multiple con-trolled trials and meta-analyses have demonstrated the efficacy of TIPS in controlling ascites. One of the more recent of these meta-analyses demonstrated improved survival with TIPS as well.26 Patients should be advised that adequate natriuresis and mobiliza-tion of ascites might take several weeks following TIPS placement.25 Patients should also be advised of the risks and complications associated with TIPS. Up to 30% of patients can develop hepatic encepha-lopathy following TIPS, with some developing refrac-tory hepatic encephalopathy.27 Shunt stenosis and thrombosis can also occur, although the risk of these complications may be reduced with newer polytetra-fluoroethylene-covered stents.28
Patient selection is vital to achieving good out-comes. The Model for End-Stage Liver Disease (MELD) was developed to predict 3-month mortality following TIPS.29 Patients with a MELD score greater than 15 to 18 have a high risk of complication and death; TIPS should not be placed in these patients in most circumstances.30 Several contraindications and complications of TIPS are shown in Table 3.
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As mentioned above, beta-blockers have been associated with reduced survival in patients with refractory ascites.23 The necessity of these medica-tions should be evaluated in individual patients and consideration should be given to stopping them in some cases.7 Oral midodrine has also been shown to improve ascites in a pilot study and has been recommended as a treatment option in clinical practice guidelines.7,31 Peritoneovenous shunting as a treatment modality was favored historically, but has largely been supplanted by TIPS and is no longer in widespread use. Importantly, patients with refractory ascites have a poor prognosis, and liver transplantation should be considered.
CONDITIONSASSOCIATEDWITHCIRRHOSISanD asCiTes
HepaticHydrothoraxHepatic hydrothorax is a pleural effusion that
results from the movement of ascites fluid across
congenital diaphragmatic defects. The negative intrathoracic pressure generated from respiration causes fluid to preferentially collect in the pleural space. Most cases of hydrothorax occur on the right side, but they can be bilateral or left-sided only. Patients with hepatic hydrothorax are often symptomatic with dyspnea and hypoxemia. Treat-ment is similar to the general treatment of ascites, with dietary sodium restriction and diuretics as the first-line therapy and serial thoracentesis or TIPS for refractory cases. Thoracentesis is often needed in the acute setting to relieve symptoms as well. Chest tubes should not be placed to treat hydrotho-rax, as they are associated with unacceptably high morbidity and mortality.32,33 As in ascites, hepatic hydrothorax can become spontaneously infected, a condition known as spontaneous bacterial empy-ema. This infection is often seen without coexisting SBP.34 It can be treated similarly to SBP and does not typically require placement of a chest tube.
Table 3. Transjugular Intrahepatic Portosystemic Shunt (TIPS) Contraindications and Complications
Contraindications Complications
Absolute TIPS dysfunction
Primary prevention of variceal bleeding Thrombosis
Congestive heart failure Occlusion/stenosis
Multiple hepatic cysts Transcapsular puncture
Uncontrolled systemic infection or sepsis Intraperitoneal bleed
Unrelieved biliary obstruction Hepatic infarction
Severe pulmonary hypertension Fistulae
Relative Hemobilia
Hepatoma, especially if central Sepsis
Obstruction of all hepatic veins Infection of TIPS
Portal vein thrombosis Hemolysis
Severe coagulopathy (INR > 5) Encephalopathy
Thrombocytopenia of < 20,000/µL Stent migration or misplacement
Moderate pulmonary hypertension
Adapted from Boyer TD, Haskal ZJ; American Association for the Study of Liver Diseases. The role of transjugular intrahepatic portosystemic shunt (TIPS) in the management of portal hypertension: update 2009. Hepatology 2010;51:306.
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SpontaneousBacterialPeritonitisSBP is defined by an ascites polymorphonuclear
cell count of 250 cells/µL or greater, as previously discussed. Early diagnosis and treatment of this condition is critical, as unrecognized infection can lead to sepsis, multisystem organ failure, and death. Physician clinical impression is insensitive for the presence of SBP, which can occur in the absence of abdominal pain or fever;6 thus, routine determination of ascites cell count should be per-formed universally at the time of paracentesis. For those with localized abdominal symptoms or an unusual exam, or with a very high neutrophil count or multiple organisms identified on culture, second-ary peritonitis should be considered and additional imaging studies should be performed to exclude a perforated viscus.14
Empiric therapy should be instituted once an elevated ascites cell count is confirmed; treat-ment should not be delayed while awaiting cul-ture results. Intravenous cefotaxime 2 g every 8 hours is recommended for those with community-acquired infection without recent β-lactam antibi-otic exposure.7 A 5-day course of therapy is ad-equate.35 For those with nosocomial infections and those receiving SBP prophylaxis, the incidence of fluoroquinolone-resistant gram-negative infection and gram-positive infection is increased, and broader coverage may be required.36 The use of albumin 1.5 g/kg body weight at diagnosis and 1.0 g/kg on day 3 reduces renal insufficiency and mortality, and should also be given with antibiot-ics.37 For patients with typical presentations of SBP and clear improvement, repeat paracentesis is not needed, but paracentesis should be re-peated after 48 hours of therapy if any atypical findings are present to document culture clear-ance and improvement in the ascites neutrophil count.7
Antibiotic prophylaxis to prevent SBP is an impor-tant component of the management of patients with cirrhosis and ascites. Primary prophylaxis reduces the risk of SBP and mortality for those without a his-tory of SBP but with low-protein ascites (<1.5 g/dL) and advanced liver failure (Child-Pugh ≥9 with serum bilirubin ≥3 mg/dL, serum creatinine ≥1.2 mg/dL, blood urea nitrogen level ≥25 mg/dL, or serum so-dium ≤130 mmol/L).38 Antibiotic prophylaxis also reduces infection and mortality in those with gastro-intestinal bleeding39 and for those with a previous epi-sode of SBP.40 Norfloxacin has been the most widely studied antibiotic for this indication, but it can be expensive. Alternative agents include trimethoprim/sulfamethoxazole and weekly ciprofloxacin.41,42
HyponatremiaHyponatremia is a common problem for patients
with cirrhosis and ascites. It results from the system-ic vasodilatation seen in portal hypertension, which causes an increase in the release of antidiuretic hor-mone. This elevation in antidiuretic hormone in turn impairs renal water excretion, resulting in increased total body water and hyponatremia.43 Hyponatremia is an indicator of poor prognosis in these patients. It is associated with more severe ascites, worse renal function, and more hepatic encephalopathy, SBP, and hepatorenal syndrome (HRS).44 Patients on the liver transplant waiting list with hyponatremia have increased mortality independent of MELD,8 and the incorporation of serum sodium into the MELD has been proposed as an alternative measure for organ allocation (MELD-Na).45
Treatment of hyponatremia in cirrhosis is con-troversial. Patients rarely exhibit symptoms as the progression of hyponatremia is slow and very few patients develop profound hyponatremia below 120 mEq/L.44 For more mild levels of hyponatre-mia, the benefit of treatment is therefore question-
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able, especially in patients who are not candidates for liver transplantation. For transplant candidates, treatment prior to surgery is reasonable to avoid rapid sodium correction during the transplant surgery itself, which can induce central pontine myelinolysis.46 Fluid restriction is a common first-line therapy for hyponatremia but is not evidence-based. When fluid restriction is used, it is unclear how much fluid should be allowed. Limits are often set at 1 or 1.5 L/day, which are difficult to achieve. Another option for the treatment of hyponatremia is the vasopressin receptor antagonist class of medications. These agents selectively block the V2 receptor, which is responsible for the effects of antidiuretic hormone. They therefore cause an in-crease in water excretion without affecting sodium or potassium excretion. Several studies have dem-onstrated their short-term efficacy in increasing the serum sodium in patients with hypervolemic hyponatremia,47,48 and tolvaptan (an oral agent) and conivaptan (intravenous) are approved for this indication in the United States. However, the long-term efficacy and safety profile of these medica-tions remain a concern.49 Long-term safety data are needed before this class of medication can be routinely used in patients with cirrhosis.
HepatorenalSyndromeHRS is the onset of renal failure in a patient
with cirrhosis and ascites after exclusion of other causes of renal failure.50 The diagnostic criteria for HRS are shown in Table 4. The pathophysiology of HRS is related to the circulatory dysfunction as-sociated with end-stage liver disease (splanchnic vasodilatation and insufficient cardiac output) that triggers intense renal vasoconstriction. HRS can be further classified into type 1 and type 2. Type 1 HRS is a rapidly progressive process in which the serum creatinine doubles to a level greater than
2.5 mg/dL in less than 2 weeks. Type 1 HRS can occur spontaneously, but is more often triggered by a precipitating event such as SBP. Type 2 is a more slowly progressive disease characterized by more moderate elevations in the serum cre-atinine typically associated with refractory ascites. HRS has a markedly worse prognosis compared to renal failure of other etiologies in patients with cirrhosis;51 those with type 1 HRS have a median survival of only 1 month.52
There are limited treatment options for patients with HRS. The vasopressin analogue terlipressin is the most extensively studied medication. This class of medication exerts its effect through splanch-nic arterial vasoconstriction and increases in the systemic arterial blood pressure. Multiple random-ized clinical trials in the United States and Europe have demonstrated the efficacy of terlipressin with albumin in improving renal function and reversing HRS.53,54 A meta-analysis suggested that terlipres-sin may reduce mortality in type 1 HRS as well.55 However, terlipressin is not approved for use in the United States. The combination of midodrine and octreotide has also been studied for this indication
Table 4. Hepatorenal Syndrome Diagnostic Criteria
Cirrhosis with ascites
Serum creatinine >1.5 mg/dL
No improvement of serum creatinine (decrease to a level ≤1.5 mg/dL) after at least 2 days with diuretic withdrawal and volume expansion with albumin. The recommended dose of albumin is 1 g/kg of body weight per day up to a maximum of 100 g/day.
Absence of shock
No current or recent treatment with nephrotoxic drugs
Absence of parenchymal kidney disease as indicated by protein-uria >500 mg/day, microhematuria (>50 red blood cells per high power field) and/or abnormal renal ultrasonography
Reproduced with permission from Salerno F, Gerbes A, Ginès P, et al. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis.Gut 2007;56:1310–8.
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and is commonly used in the United States. Several nonrandomized studies have shown improvement in renal function with these medications in combina-tion with albumin.56,57 Midodrine is given orally and octreotide subcutaneously 3 times daily, with doses titrated up to a maximum of 12.5 mg and 200 µg, respectively, to achieve an increase of 15 mm Hg in the mean arterial pressure. The vasopressor norepinephrine has also been studied, and can be an option for patients in the intensive care unit.58 Patients with progressive renal failure may require renal replacement therapy to maintain electrolyte balance, acid-base status, and volume status while awaiting liver transplantation. Liver transplantation is an effective therapy for HRS, and an expedited evaluation for transplant should be undertaken for this group. Those who require prolonged renal replacement therapy (at least 8 weeks) may not recover renal function and should be considered for simultaneous kidney transplant as well.59
VariCeal HemorrHaGe
Case
initial Presentation and HistoryA 43-year-old woman with alcoholic cirrhosis pres-
ents with hematemesis. She was in her usual state of health until the day of admission, when she vomited several cups of bright red blood and was brought to the emergency department by her family. She feels lightheaded and weak and is unable to stand. She has also been having black, tarry bowel movements, which started the morning of presentation. She de-nies fevers, chills, dyspnea, or abdominal distention.
Her cirrhosis has been complicated by ascites, which is well-controlled with diuretics and dietary sodium restriction. There is no history of encepha-lopathy or varices, though she has never had an upper gastrointestinal (GI) endoscopy. She has no
additional past medical history. She has a long-standing history of alcohol abuse since age 16, and has undergone several unsuccessful attempts at alcohol rehabilitation. She continues to drink several pints of vodka every week. Current medi-cations include furosemide, spironolactone, and thiamine.
Physical examinationThe patient is ill-appearing but in no distress. She
is afebrile, with a pulse of 110 beats/min and blood pressure of 98/62 mm Hg. She is sluggish in her responses but oriented to time and place. Lungs are clear to auscultation, and the cardiovascular exam reveals sinus tachycardia. The abdomen is soft, flat, and nontender. Multiple spider angiomata are present, and asterixis is apparent. There are no other focal deficits on the neurologic exam.
DiagnosticEvaluationThe hemoglobin is 6.5 g/dL, hematocrit is 20.1%,
and the platelet count is 88 × 103/µL. The INR is 2.3. Serum sodium is 133 mEq/L, potassium is 3.3 mEq/L, blood urea nitrogen is 35 mg/dL, and creatinine is 1.2 mg/dL. The serum albumin is 2.4 g/dL, and the total bilirubin is 4.4 mg/dL. A chest radiograph dem-onstrates no acute abnormalities. Doppler ultrasound of the liver shows nodularity, splenomegaly, and small volume ascites, without any focal masses. The portal and hepatic veins are patent.
ePiDemioLogy anD CLassiFiCaTion
Gastroesophageal varices form as a result of portal hypertension, most often due to cirrhosis, and are found in approximately 50% of these patients.60 They occur in nearly 10% of patients per year, and are found more frequently in patients with more severe liver disease and portal hypertension.61–63 Those with small varices have progression to me-
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dium or large varices at a rate of approximately 10% per year, with higher rates for those with more se-vere liver disease, alcoholic cirrhosis, and red wale marks on varices at initial endoscopy.61 Examples of different-sized varices with and without red wale marks are shown in Figure3. Bleeding occurs in 5% to 15% per year, and is also more likely in those with more advanced liver disease, larger varices, and red wale marks on the varices.64 Despite ad-vances in therapy and the fact that bleeding stops spontaneously in up to 40% of patients, short-term mortality remains high at 20%, and many re-bleed in the subsequent years.60,65,66
Gastric varices are less common than esopha-geal. In one large series, they were present in ap-proximately 20% of patients with cirrhosis and portal hypertension, with bleeding in 25% during 2 years of follow-up.67 Gastric varices can be classified based on their location and relationship with esoph-ageal varices (Figure4). Type 1 gastroesophageal varices (GOV1) represent extension of esophageal varices along the lesser curvature of the stomach. Type 2 (GOV2) varices are associated with esopha-geal varices but extend along the fundus. Simi-
larly to GOV2, type 1 isolated gastric varices (IGV1) without esophageal varices are also located in the fundus, and type 2 (IGV2) are found elsewhere in the stomach, such as the body, antrum, or pylorus. Although gastric varices have a lower incidence of bleeding compared to esophageal, the bleeding episodes tend to be more severe.67 In addition, the risk of bleeding from gastric varices is related to the type. GOV1 are the most prevalent, but they have a lower risk of bleeding compared to GOV2 and IGV1, which have the highest risk of bleeding (55%–78%). IGV1 can result from sinistral portal hypertension;
Figure4.Classification of gastric varices on the basis of lo-cation and relationship with esophageal varices. (Reproduced with permission from Sarin SK, Lahoti D, Saxena SP, et al. Preva-lence, classification and natural history of gastric varices: a long-term follow-up study in 568 portal hypertension patients.Hepatology 1992;16:1343–9.)
GOV1 GOV2
IGV1 IGV2
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an evaluation for splenic vein thrombosis (often associated with pancreatitis) should therefore be undertaken in such cases.
• Howisthediagnosisofvaricesmade?
Diagnosis, sCreening, anD surveiLLanCe
Esophagogastroduodenoscopy (EGD) is the di-agnostic test of choice for varices. In addition to its diagnostic utility, direct therapy of varices with liga-tion or sclerotherapy can be performed at the time of EGD as well. Clinical practice guidelines recommend that esophageal varices be graded as small or large (diameter >5 mm), as surveillance and bleeding prophylaxis recommendations differ depending on the size.60 When 3 grades are used (small, medium, and large), medium-sized varices should be treated as large for management purposes.
Because of the high prevalence of varices in patients with cirrhosis, the significant morbidity and mortality associated with hemorrhage, and the effi-cacy of prophylactic measures to prevent bleeding, screening for varices is recommended.60 EGD is the recommended screening modality. Alternative noninvasive tests such as transient elastography in combination with standard laboratory values and capsule endoscopy have been studied, but are not sufficiently accurate to replace EGD.68,69
The risk of bleeding is related to the severity of liver disease and the size and features of the vari-
ces; therefore, recommended intervals for surveil-lance EGD differ depending on patient character-istics. For patients with compensated cirrhosis but without varices, EGD should be performed every 2 to 3 years (Table 5).60 For those with a history of decompensation (ascites or hepatic encephalopa-thy), EGD should be performed yearly. EGD should also be repeated at the time of hepatic decom-pensation for those with previously compensated disease. Patients with small varices who are not given prophylaxis should receive an EGD every 2 years, except following decompensation as noted above.
The prevention of variceal bleeding can be achieved through medical, endoscopic, and endo-vascular approaches that either target the underly-ing portal hypertension or the varices themselves. Portal pressure-lowering therapies work by reducing either portal blood flow or resistance. Nonselective beta-blockers (nadolol and propranolol) cause mes-enteric arteriolar vasoconstriction and thus decrease portal blood flow, which reduces portal pressure. Their doses can be titrated based on the resting heart rate or the hepatic venous pressure gradient. The heart rate is typically used, as measurement
Table 5. Variceal Bleeding Primary Prophylaxis
SizeofVaricesnone small Large
HemorrhageRisk* Low EGD every 2–3 years EGD every 2 years or beta-blocker Beta-blocker preferred; consider band ligation
High EGD annually Beta-blocker Beta-blocker or band ligation
*Low-risk patients are Child-Pugh A without red wale marks on varices; high-risk patients are Child-Pugh B/C and/or with red wale marks on varices.EGD = esophagogastroduodenoscopy.
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of the hepatic venous pressure gradient is invasive, costly, and requires significant expertise. The goal of dose titration is to achieve a resting heart rate of 55 to 60 or a reduction in the pressure gradient of 20% or to ≤12 mm Hg, since variceal bleeding does not occur when the pressure gradient is less than 12 mm Hg.70 Carvedilol, another nonselective beta-blocker with anti-alpha-adrenergic activity, may also have a role for prophylaxis.71 Nitrates cause systemic hypotension, which in turn reduces portal flow as well.72 Nitrates have been studied in several randomized clinical trials, with inconsistent results and high rates of adverse events, and are therefore not recommended for prophylaxis in those with or without a prior history of bleeding.60,73–75
Additional measures to prevent bleeding include endoscopic variceal band ligation, which directly disrupts variceal blood flow and results in throm-bosis (Figure5), and TIPS, which reduces resis-tance to portal blood flow (Figure 2). When band ligation is utilized, it should be repeated every 1 to 2 weeks until eradication.60 Additional surveillance
EGD is then required to monitor for potential recur-rence, initially after 1 to 3 months, and then every 6 to 12 months.
PrimaryProphylaxisNonselective beta-blockers do not prevent the
development of varices in patients with cirrhosis who do not have varices at baseline.63 These patients should undergo screening and surveil-lance EGD as noted above. Therapies for primary prophylaxis (for those without a history of bleed-ing) are summarized in Table 5. Those with small varices may benefit from prophylaxis.76 Clinical practice guidelines recommend beta-blockers in this group when additional risk factors are present (Child-Pugh B/C or presence of red wale marks).60 When these risk factors are not present, beta-blockers can be used, although their long-term benefit is not yet proven.
Beta-blockers do benefit patients with large vari-ces; for every 10 patients treated with a beta-blocker, 1 episode of bleeding is prevented.77 Endoscopic
band ligation is also beneficial.78 In a meta-analysis, band ligation was superior to beta-blockers in reduc-ing variceal bleeding, but did not reduce mortality.79 Importantly, the benefit was not seen when lower-quality studies were excluded from the analysis. Furthermore, band ligation can cause esophageal ulcer bleeding, which is often severe and can be fatal.80 Considering all of the available data, prac-tice guidelines recommend that beta-blockers are preferred to band ligation for Child-Pugh A patients with large varices that do not have red wale marks.60 For Child-Pugh B/C patients or those with red wale marks, either beta-blockers or band ligation can be used. Additional patient characteristics, preferences and provider resources and expertise should also be considered when choosing the modality. The combination of beta-blockers and band ligation is not more effective than either alone, and should not be used for primary prophylaxis in those without a history of bleeding.81,82
Several therapies that have roles in the treat-ment of active variceal bleeding or in secondary prophylaxis (for those with a history of bleeding) are not recommended for primary prophylaxis. In a randomized trial, endoscopic sclerotherapy in-creased mortality compared to sham treatment.83 Similarly, controlled studies of portacaval shunt surgery demonstrated an increased mortality as-sociated with the intervention.84 Although TIPS has
not been studied in this population, it is not recom-mended based on extrapolation from the surgical shunt data (Table 3).60
GeneralMeasuresVarices are the cause of upper GI bleeding in
a substantial proportion of patients with cirrhosis. Therefore, patients with cirrhosis and signs of upper GI bleeding should be treated for presumed variceal bleeding until proven otherwise (Table 6). In general, patients with suspected bleeding should be admitted to an intensive care unit. Volume re-suscitation should be a priority, particularly in those with signs of hemodynamic instability. Care should be given to avoid over-transfusion, as excessive volume and blood products can increase portal pressure and potentiate rebleeding.85,86 In a ran-domized trial, a conservative transfusion strategy using a target hemoglobin of 7 g/dL resulted in better clinical outcomes than a liberal strategy with a target of 9 g/dL.87 Patients with cirrhosis often have defects in hemostasis as a result of thrombo-cytopenia from portal hypertension and decreased production of coagulation factors. However, stan-dard measures of coagulation do not correlate well with bleeding risk, and the optimal management of these hemostatic defects is poorly defined.88,89 Platelets should generally be given to achieve a target of 50 to 60 × 103/µL.89 Fresh frozen plasma is often given in the setting of a prolonged pro-thrombin time. However, in actuality, the volume of plasma needed to adequately correct the coagu-lation abnormalities is excessive and can further contribute to worsening portal hypertension, ad-
Table 6. Treatment of Active Variceal Hemorrhage
Hemodynamic stabilization
Blood transfusion to a goal hemoglobin of 7 g/dL
Antibiotic prophylaxis with a fluoroquinolone or intravenous ceftriaxone
Vasoactive medication (terlipressin or octreotide)
Urgent endoscopy with band ligation or sclerotherapy
TIPS for those who fail endoscopic therapy
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ditional bleeding, and cardiopulmonary complica-tions. Recombinant factor VIIa is an expensive therapy that cannot be recommended based on currently available data.90
Patients with cirrhosis and gastrointestinal bleed-ing have a high risk of bacterial infection, which is related to a higher Child-Pugh score and portends a greater incidence of rebleeding and death.91 An-tibiotic prophylaxis reduces infections, rebleeding, hospital length of stay, and mortality, and is recom-mended in clinical practice guidelines.60,92 The most widely studied antibiotic regimen is oral norfloxacin 400 mg twice daily for 7 days. However, changing bacterial resistance patterns may favor broader an-timicrobial coverage.93 Clinical practice guidelines recommend oral norfloxacin or intravenous cipro-floxacin; ceftriaxone may be preferable in patients with advanced cirrhosis, especially in settings with a high prevalence of quinolone resistance.60
SpecificMedicalTherapyVasoactive medications play an important role
in the control of acute variceal bleeding by causing splanchnic vasoconstriction and reducing portal blood flow. The most widely used medication in the United States is octreotide, a long-acting somat- ostatin analogue, which is given as an intravenous bolus of 50 µg followed by a continuous infusion of 50 µg per hour. In combination with endoscopic treatment, it improves control of bleeding compared to endoscopic treatment alone.94 Terlipressin is a vasopressin analogue that is not available in the United States, but is effective in this setting and is associated with improved all-cause mortality.95 Va-sopressin has also been studied for this purpose, but is limited by adverse events related to ischemia and is less efficacious than somatostatin.96 Regard-less of the vasoactive medication used, therapy should be continued for 3 to 5 days.60
EndoscopicTherapyIn addition to pharmacological therapy, endo-
scopic therapy is the mainstay of treatment of ac-tive variceal hemorrhage. Thus, EGD should be performed as soon as possible after admission, as it serves both important diagnostic and therapeutic roles. Options for endoscopic therapy include band ligation (Figure 5) and sclerotherapy. Band ligation is generally preferred, as it is more effective and has fewer adverse events, particularly esophageal stricture formation.97 However, there are situations in which sclerotherapy may be preferred for tech-nical reasons, such as when excessive bleeding limits visibility.
SalvageTherapyBleeding cannot be controlled with standard
pharmacologic and endoscopic therapy in 10% to 20% of patients.60 In such circumstances, with on-going bleeding, definitive therapy with either TIPS or surgery should be considered. While awaiting these types of definitive therapies, temporization with balloon tamponade is often needed. Although there are different types of balloons available, they all work by the same principle: a gastric balloon is inflated in the stomach and traction is applied to maintain pressure on the gastroesophageal junc-tion. Some tubes have an esophageal balloon as well that can provide additional tamponade in the esophagus when the gastric balloon fails to control bleeding. Although balloon tamponade is effective in achieving hemostasis, bleeding often recurs shortly after balloon deflation. Further major com-plications are common, and can include esopha-geal rupture, which is often fatal.98 Therefore, bal-loon tamponade should only be used for a limited time (<24 hours) while awaiting definitive therapy.60
TIPS is effective in reducing portal hyperten-sion and achieving hemostasis for those who fail
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endoscopic therapy (Figure 2).99 It is therefore rec-ommended as the preferred therapy in this popula-tion.100 Shunt surgery can also be performed in this setting, though this is less commonly practiced and should be done by a surgeon with sufficient exper-tise.101
gasTriC variCes
GOV1 can be treated similarly to esophageal varices, as they are simply extensions of esopha-geal varices along the lesser curvature of the stom-ach (Figure 4). Treatment for other types of gastric varices is often more technically challenging than for esophageal varices. Cyanoacrylate can be injected endoscopically into a gastric varix, which causes polymerization within the varix and throm-bosis. It is effective in controlling active bleeding and preventing rebleeding, with a low incidence of complications.102,103 This therapy is not approved by the US Food and Drug Administration, but is used in several centers under research protocols. Alternatively, TIPS is effective in controlling gastric variceal hemorrhage and can be considered.104
Case ConCLusion
The patient is transfused packed red blood cells to a target hemoglobin of 7 g/dL, with a reduction in the heart rate and stabilization of the blood pres-sure. Ceftriaxone 1 g intravenously (IV) is given, and the patient is started on the appropriate dose of intravenous octreotide. Urgent endoscopy is per-formed, demonstrating large esophageal varices in the distal esophagus with active bleeding. No gas-tric varices are present. Six bands are placed, with hemostasis achieved. The patient is continued on ceftriaxone and an octreotide infusion for 72 hours without signs of rebleeding. She is discharged with norfloxacin to complete a 7-day course of antibiot-ics and nadolol, with repeat EGD scheduled in 2
weeks. She is counseled against ongoing alcohol use and is referred to a substance abuse provider.
Up to 60% of patients will rebleed in the 1 to 2 years following an episode of bleeding, with substantial associated mortality.60 Secondary pro-phylaxis to prevent recurrent bleeding is therefore essential in improving clinical outcomes for these patients. Combination therapy with nonselective beta-blockers and band ligation is more effective than either therapy alone and is recommended in clinical practice guidelines.60,105 Because of the data favoring band ligation over sclerotherapy in the treatment of bleeding varices, band ligation is also recommended as the endoscopic treatment of choice for secondary prophylaxis, in combination with beta-blockers.97 Following the initial endoscopic treatment, repeat ligation should be performed every 1 to 2 weeks until obliteration, with the next surveillance EGD performed 1 to 3 months after obliteration and then every 6 to 12 months thereaf-ter. The dose of the beta-blocker should be titrated as is done for primary prophylaxis.
Multiple studies have compared TIPS with endo-scopic therapy in the prevention of rebleeding. A meta-analysis demonstrated a reduced incidence of rebleeding with TIPS at a cost of increased in-cidence of hepatic encephalopathy, with no differ-ence in overall mortality.106 A subsequent random-ized trial of early TIPS (within 72 hours) in high-risk patients with Child-Pugh B and C cirrhosis demon-strated improved rebleeding and survival with no increase in adverse events.107 Although early TIPS is not standard practice, some groups recommend consideration of this approach in select patients.100 Importantly, patients have a high risk of death after
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an episode of variceal hemorrhage. Those who are otherwise candidates for liver transplantation should therefore be referred for evaluation.
HePatiC enCePHaloPatHY
Case
initial Presentation and HistoryA 67-year-old man with cirrhosis due to nonalcoholic
steatohepatitis is admitted to the hospital with acute confusion. He was noted by relatives to be sluggish upon awakening in the morning, and became progres-sively more confused and incoherent over the course of the day. Because of his changing mental status, he has been unable to take lactulose. By the time he is brought to the emergency department, he is somno-lent but arousable. His family denies fevers, signs of abdominal pain, melena, or other focal symptoms.
He has a prior history of hepatic encephalopathy, which has been treated with lactulose therapy. He takes 3 tablespoons daily, and has 3 bowel move-ments per day. He has been hospitalized twice in the past year for similar symptoms; each episode resolved with intravenous fluids and lactulose. His cirrhosis has also been complicated by ascites, for which he takes 40 mg of furosemide and 100 mg of spironolactone. He requires LVP every 1 to 2 months. He is unable to take higher doses of diuretics due to renal insufficiency and hyponatre-mia. In addition to cirrhosis, he has coronary artery disease, hypertension, diabetes, and osteoarthritis.
Physical examinationOn exam, the patient is somnolent but arous-
able. He is afebrile, with normal vital signs. He is able to protect his airway. There is no jaundice. The lungs are clear to auscultation, and he is in normal sinus rhythm. The abdomen is distended with ascites, though nontender, and there is pit-
ting edema bilaterally. Asterixis is present. There are no additional focal deficits on the neurologic exam.
• Whatdiagnosticworkupisindicated?
nomenCLaTure
Hepatic encephalopathy refers to a broad spec-trum of neurocognitive impairment in cirrhosis, ranging from subtle neuropsychological distur-bances and perceptual motor dysfunction in those with normal mental status all the way to profound alterations in mental status and coma.108 Stan-dardized definitions and categorization of hepatic encephalopathy were formalized at the 1998 Word Congress of Gastroenterology.109 Although hepatic encephalopathy can result from other liver diseas-es (eg, acute liver failure), this article focuses on hepatic encephalopathy associated with cirrhosis and portal hypertension. In this schema, hepatic encephalopathy is classified as episodic, persis-tent, or minimal. Episodic hepatic encephalopathy, a form of delirium, is further classified as precipi-tated or spontaneous, and recurrent (≥2 episodes in a year). Minimal hepatic encephalopathy refers to neuropsychiatric abnormalities that are not clinically apparent and can only be diagnosed with specialized testing, in contrast to overt hepatic encephalopathy, which can be diagnosed clinically and graded according to the West Haven criteria (Table 7).
PaTHogenesis
The pathophysiology of hepatic encephalopathy is poorly understood and multifactorial. Hyperam-monemia is clearly important, and is the most rec-ognized contributor to the disorder. In healthy hu-mans, ammonia is produced in the gut and cleared by the liver. In cirrhosis, impaired liver function and
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portosystemic blood shunting result in increased blood concentrations of ammonia. Hyperammone-mia causes brain dysfunction through several path-ways, including induction of neuroinflammation and alteration of neurotransmission.110 The clear link between ammonia and hepatic encephalopathy is the basis for ammonia-lowering agents in thera-peutic regimens. Additional potential mechanisms of brain dysfunction include changes in several dif-ferent neurotransmitter systems and alterations in the blood-brain barrier.
Diagnosis
Patients with overt hepatic encephalopathy can be diagnosed clinically, based on typical signs and symptoms (Table 7). Many patients will have a pre-cipitating factor which should be identified promptly so that specific therapy can be initiated, in addition to general treatment of hepatic encephalopathy. Such
factors can include infection, GI bleeding, drugs, electrolyte abnormalities, renal failure, and volume depletion, among others.111 In particular, for those with acute changes, a thorough investigation for in-fection should be undertaken, and patients with asci-tes should undergo a diagnostic paracentesis to rule out SBP. Oftentimes, empiric antibiotics are given while the infectious workup is ongoing, as infection and sepsis are common precipitating factors. Con-sideration should also be given to alternative primary neurologic conditions in the appropriate setting, and brain imaging with CT or MRI may be required.
Because of the clear relationship between hyper-ammonemia and hepatic encephalopathy, serum ammonia measurements are often used in diag-nosis. However, this testing has many limitations. Venous and arterial ammonia levels do correlate with the degree of hepatic encephalopathy. However, there is significant overlap; a substantial proportion of patients with low-grade hepatic encephalopathy have elevated ammonia levels, and similarly, many pa-tients with grade 3 or higher hepatic encephalopathy have normal levels.112 Furthermore, differences in the handling of samples can influence the results, and there are several nonhepatic causes of hyperammo-nemia (eg, medications and GI bleeding). The utility of ammonia measurement in the diagnosis of hepatic encephalopathy is therefore ill-defined.
By definition, minimal hepatic encephalopathy cannot be diagnosed on the basis of clinical infor-mation and requires specialized testing. Multiple tests have been studied for this purpose, includ-ing psychometric and neurophysiologic testing.113 These tests are mainly used in research settings and are not widely available for clinical use.
Case ConTinueD
The patient is admitted to the hospital. The white blood cell count is normal, the hemoglobin is
Table 7. West Haven Criteria for Semiquantitative Grading of Mental State
grade 1 Trivial lack of awareness
Euphoria or anxiety
Shortened attention span
Impaired performance of addition
grade 2 Lethargy or apathy
Minimal disorientation for time or place
Subtle personality change
Inappropriate behavior
Impaired performance of subtraction
grade 3 Somnolence to semistupor, but responsive to verbal stimuli
Confusion
Gross disorientation
grade 4 Coma (unresponsive to verbal or noxious stimuli)
Reproduced with permission from Ferenci P, Lockwood A, Mullen K, et al. Hepatic encephalopathy--definition, nomenclature, diagno-sis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 2002;35:716–21.
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12.9 g/dL, and the platelet count is 120 × 103/µL. The sodium is 123 mEq/L, potassium is 5.2 mEq/L, and creatinine is 2.4 mg/dL, which is increased from 1.3 mg/dL at the most recent outpatient visit. The bilirubin is 1.1 mg/dL, and the INR is 1.4. A chest x-ray shows no focal infiltrates, and a urinaly-sis is unremarkable. Blood cultures are obtained. A diagnostic paracentesis shows 460 nucleated cells (88% polymorphonuclear leukocytes), and ascites culture is obtained. The patient is placed on appro-priate antibiotics and albumin for SBP treatment, and lactulose is administered.
GeneralMeasuresPatients with low-grade hepatic encephalopathy
can often be managed as outpatients, with ammonia- lowering therapy. For those with gross disorien-tation (grades 2–4), admission to the hospital is often needed to provide appropriate therapy and to investigate potential precipitating causes. This is particularly the case for those with grades 3 and 4 hepatic encephalopathy, who may need admis-sion to intensive care, and in some cases intuba-tion for airway protection. Identification and treat-ment of precipitating causes is a vital component of management, as untreated infections or other conditions can progress to sepsis or death. One other precipitating factor deserves special mention. Hypokalemia is accompanied by a metabolic alka-losis which favors the conversion of charged am-monium (NH4
+) to neutral ammonia (NH3), which more readily crosses the blood-brain barrier and contributes to hepatic encephalopathy. Therefore, providers should carefully assess for hypokalemia and correct it.
SpecificTherapyBecause of its central role in the pathogenesis of
hepatic encephalopathy, ammonia is the primary target of most therapies specific for hepatic en-cephalopathy. The synthetic disaccharides lactulose and lactitol are the most commonly used ammonia- lowering therapies. Lactitol is not available in the United States. These agents are catabolized by co-lonic bacterial flora into short chain fatty acids, which acidifies the colonic lumen, converting ammonia to ammonium, which is trapped in the lumen and excreted in the stool. They are effective in improv-ing hepatic encephalopathy, although many of the studies are of poor quality.114 Lactulose is typically given in doses of 20 to 30 g, and should be titrated to achieve 2 to 3 soft bowel movements per day. For inpatients who are unable to take oral medications, lactulose can be administered via nasogastric tube or as an enema.115
Oral antibiotics are also frequently used for the treatment of hepatic encephalopathy, most often as an adjunctive therapy with lactulose. They pur-portedly work by altering the gut microbiota, there-by reducing ammonia production and absorption. Rifaximin, a poorly absorbed antibiotic, is the best studied agent. In a randomized trial, rifaximin twice daily reduced the risk of recurrent overt hepatic encephalopathy and reduced the risk of hepatic encephalopathy–related hospitalizations compared to placebo.116 Rifaximin also improves health-related quality of life in these patients.117 Other an-tibiotics have also been used, including neomycin, metronidazole, and oral vancomycin. None has been as rigorously tested as rifaximin, and poten-tial safety concerns have limited enthusiasm for their use (eg, ototoxicity and nephrotoxicity with neomycin, and neurotoxicity with metronidazole). Probiotics have also been used, although their clinical efficacy is not well established.118
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Other therapies have limited data to support their use. One theory of hepatic encephalopathy is that an increased ratio of aromatic to branched-chain amino acids may serve to increase the level of false neu-rotransmitters, which may inhibit neurotransmission. Branched-chain amino acid supplements have been studied, with a potential benefit detected, though further research is needed to establish this therapy as effective.119 Another theory is that zinc deficiency contributes to hepatic encephalopathy, as zinc may modulate neurotransmission and zinc deficiency is common in patients with cirrhosis.120 There is limited evidence for the effectiveness of zinc supplementa-tion for hepatic encephalopathy.121 Because of the importance of GABA neurotransmission in hepatic encephalopathy, the benzodiazepine receptor an-tagonist flumazenil has also been studied for hepatic encephalopathy.122 Although it does improve hepatic encephalopathy, the effects are short-lived, and the medication can precipitate seizures. It is therefore not recommended for routine use in this setting.
The traditional teaching that protein restriction would reduce nitrogenous substrate for ammonia production has not played out in clinical studies. Pro-tein restriction does not reduce hepatic encephalop-athy, but does result in more protein breakdown.123 Malnutrition is common in advanced liver disease, and can be worsened with protein restriction. For those who have hepatic encephalopathy sensitive to protein intake, substitution of animal proteins with vegetable proteins may be beneficial.124
ConCluSion
The chief complications of cirrhosis and portal hypertension are ascites, varices, and hepatic en-cephalopathy. These complications are highly mor-bid and require careful monitoring and treatment to improve the quality and duration of patients’ lives.
Adherence to evidence-based therapies offers the best chance of obtaining favorable outcomes. Most importantly, the development of these complications heralds a poor prognosis, and liver transplantation should be considered for those who are eligible.
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BOARDREVIEWQUESTIONStest your knowledge of this topic .
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