Joshua Hanson, MD, MPH

The dogma

Patients with alcohol use disorders (AUD) are at risk for nutritional and vitamin deficiencies and may suffer from linked disease states, including Wernicke’s encephalopathy. These conditions may be underrecognized; for instance, an autopsy study suggests that Wernicke’s encephalopathy may have a prevalence rate of 12.5% among alcoholics.¹

When patients with AUD are hospitalized, they have often already received a standard IV solution (100 mg of thiamine, 1 mg of folate, 1-2 g of magnesium, and a multivitamin dissolved in saline or dextrose). The practice is common enough that the solution is informally referred to as a “banana bag,” due to the yellow hue imparted by thiamine and multivitamin. These fluids might then be readministered daily during the inpatient stay. But what is the evidence supporting this widespread practice?
 

The evidence

While the banana bag (or “rally pack”, as it’s also colloquially known) hanging at the patient’s side may look cool, it may not be helping her. Let’s break down the ingredients:

• Folate: Patients with alcohol use disorder are at higher risk for folate deficiency (attributable to poor intake and decreased absorption), but overall rates of folate deficiency are still quite low.² In addition, most oral and parenteral multivitamins already contain at least 400 mcg folate – the benefit of adding further intravenous folate is not clear.
• Magnesium. Patients with AUD are also at higher risk for magnesium deficiency attributable to increased excretion. While decreased magnesium levels could theoretically increase the risk of alcohol withdrawal symptoms, a Cochrane review found no evidence to support routine supplementation.³
• Multivitamin. Despite theoretical advantages in these (often) malnourished patients, there are no published studies on the benefit or harm of administering a “pan-vitamin” injection. The standard IV formulation is slightly different than an oral vitamin (the IV contains vitamin K, for instance, and lacks calcium), but the bioavailability should be roughly the same, except in rare patients with intestinal malabsorption.⁴
• IV fluids. Pharmacies typically mix these ingredients in a liter of normal saline or 5% dextrose. Once again, though, individual patients will have different needs. A dehydrated patient would benefit more from normal saline, a patient with alcoholic ketoacidosis would benefit more from dextrose, and a patient with alcohol-related cardiomyopathy likely shouldn’t be getting large volume IV fluids at all.
• Thiamine. Thiamine deficiency is likely the most common and most concerning vitamin deficiency in this patient population. The typical banana bag contains 100 mg of thiamine, which has been the traditional recommended daily amount for Wernicke’s treatment. This dosage, however, was apparently chosen arbitrarily in the 1950s (based on what the authors considered to be a high dose) and current recommendations suggest higher doses given more frequently because of the relatively short half-life of parenteral thiamine.⁵

Takeaway

The banana bag is a “one-size-fits-all” approach that offers too much of some of its ingredients and not enough of others. It’s better to individualize treatment based on a patient’s needs and consider high-dose thiamine (500 mg one to three times daily) for those at risk for, or showing signs of, Wernicke’s encephalopathy.

Dr. Sehgal and Dr. Hanson are clinical associate professors of medicine in the division of general and hospital medicine at the South Texas Veterans Health Care System and UT-Health San Antonio. Dr. Sehgal (@rtsehgal) is a member of the editorial advisory board for The Hospitalist.

References

1. Torvik A et al. Brain lesions in alcoholics: a neuropathological study with clinical correlation. J Neurol Sci. 1982 Nov;56(2-3):233-48.

2. Schwab RA et al. Prevalence in folate deficiency in emergency department patients with alcohol-related illness or injury. Am J Emerg Med. 1992 May;10(3):203-7.

3. Sarai M et al. Magnesium for alcohol withdrawal. Cochrane Database Syst Rev. 2013 Jun 5;(6):CD008358.

4. Krishel S et al. Intravenous vitamins for alcoholics in the emergency department: a review. J Emerg Med. 1998 May-Jun;16(3):419-24.

5. Donnino MW et al. Myths and misconceptions of Wernicke’s encephalopathy: what every emergency physician should know. Ann Emerg Med. 2007;50(6): 715-21.

The dogma

Patients with alcohol use disorders (AUD) are at risk for nutritional and vitamin deficiencies and may suffer from linked disease states, including Wernicke’s encephalopathy. These conditions may be underrecognized; for instance, an autopsy study suggests that Wernicke’s encephalopathy may have a prevalence rate of 12.5% among alcoholics.¹

When patients with AUD are hospitalized, they have often already received a standard IV solution (100 mg of thiamine, 1 mg of folate, 1-2 g of magnesium, and a multivitamin dissolved in saline or dextrose). The practice is common enough that the solution is informally referred to as a “banana bag,” due to the yellow hue imparted by thiamine and multivitamin. These fluids might then be readministered daily during the inpatient stay. But what is the evidence supporting this widespread practice?
 

The evidence

While the banana bag (or “rally pack”, as it’s also colloquially known) hanging at the patient’s side may look cool, it may not be helping her. Let’s break down the ingredients:

• Folate: Patients with alcohol use disorder are at higher risk for folate deficiency (attributable to poor intake and decreased absorption), but overall rates of folate deficiency are still quite low.² In addition, most oral and parenteral multivitamins already contain at least 400 mcg folate – the benefit of adding further intravenous folate is not clear.
• Magnesium. Patients with AUD are also at higher risk for magnesium deficiency attributable to increased excretion. While decreased magnesium levels could theoretically increase the risk of alcohol withdrawal symptoms, a Cochrane review found no evidence to support routine supplementation.³
• Multivitamin. Despite theoretical advantages in these (often) malnourished patients, there are no published studies on the benefit or harm of administering a “pan-vitamin” injection. The standard IV formulation is slightly different than an oral vitamin (the IV contains vitamin K, for instance, and lacks calcium), but the bioavailability should be roughly the same, except in rare patients with intestinal malabsorption.⁴
• IV fluids. Pharmacies typically mix these ingredients in a liter of normal saline or 5% dextrose. Once again, though, individual patients will have different needs. A dehydrated patient would benefit more from normal saline, a patient with alcoholic ketoacidosis would benefit more from dextrose, and a patient with alcohol-related cardiomyopathy likely shouldn’t be getting large volume IV fluids at all.
• Thiamine. Thiamine deficiency is likely the most common and most concerning vitamin deficiency in this patient population. The typical banana bag contains 100 mg of thiamine, which has been the traditional recommended daily amount for Wernicke’s treatment. This dosage, however, was apparently chosen arbitrarily in the 1950s (based on what the authors considered to be a high dose) and current recommendations suggest higher doses given more frequently because of the relatively short half-life of parenteral thiamine.⁵

Takeaway

The banana bag is a “one-size-fits-all” approach that offers too much of some of its ingredients and not enough of others. It’s better to individualize treatment based on a patient’s needs and consider high-dose thiamine (500 mg one to three times daily) for those at risk for, or showing signs of, Wernicke’s encephalopathy.

Dr. Sehgal and Dr. Hanson are clinical associate professors of medicine in the division of general and hospital medicine at the South Texas Veterans Health Care System and UT-Health San Antonio. Dr. Sehgal (@rtsehgal) is a member of the editorial advisory board for The Hospitalist.

References

1. Torvik A et al. Brain lesions in alcoholics: a neuropathological study with clinical correlation. J Neurol Sci. 1982 Nov;56(2-3):233-48.

2. Schwab RA et al. Prevalence in folate deficiency in emergency department patients with alcohol-related illness or injury. Am J Emerg Med. 1992 May;10(3):203-7.

3. Sarai M et al. Magnesium for alcohol withdrawal. Cochrane Database Syst Rev. 2013 Jun 5;(6):CD008358.

4. Krishel S et al. Intravenous vitamins for alcoholics in the emergency department: a review. J Emerg Med. 1998 May-Jun;16(3):419-24.

5. Donnino MW et al. Myths and misconceptions of Wernicke’s encephalopathy: what every emergency physician should know. Ann Emerg Med. 2007;50(6): 715-21.

The dogma

Patients with alcohol use disorders (AUD) are at risk for nutritional and vitamin deficiencies and may suffer from linked disease states, including Wernicke’s encephalopathy. These conditions may be underrecognized; for instance, an autopsy study suggests that Wernicke’s encephalopathy may have a prevalence rate of 12.5% among alcoholics.¹

When patients with AUD are hospitalized, they have often already received a standard IV solution (100 mg of thiamine, 1 mg of folate, 1-2 g of magnesium, and a multivitamin dissolved in saline or dextrose). The practice is common enough that the solution is informally referred to as a “banana bag,” due to the yellow hue imparted by thiamine and multivitamin. These fluids might then be readministered daily during the inpatient stay. But what is the evidence supporting this widespread practice?
 

The evidence

While the banana bag (or “rally pack”, as it’s also colloquially known) hanging at the patient’s side may look cool, it may not be helping her. Let’s break down the ingredients:

• Folate: Patients with alcohol use disorder are at higher risk for folate deficiency (attributable to poor intake and decreased absorption), but overall rates of folate deficiency are still quite low.² In addition, most oral and parenteral multivitamins already contain at least 400 mcg folate – the benefit of adding further intravenous folate is not clear.
• Magnesium. Patients with AUD are also at higher risk for magnesium deficiency attributable to increased excretion. While decreased magnesium levels could theoretically increase the risk of alcohol withdrawal symptoms, a Cochrane review found no evidence to support routine supplementation.³
• Multivitamin. Despite theoretical advantages in these (often) malnourished patients, there are no published studies on the benefit or harm of administering a “pan-vitamin” injection. The standard IV formulation is slightly different than an oral vitamin (the IV contains vitamin K, for instance, and lacks calcium), but the bioavailability should be roughly the same, except in rare patients with intestinal malabsorption.⁴
• IV fluids. Pharmacies typically mix these ingredients in a liter of normal saline or 5% dextrose. Once again, though, individual patients will have different needs. A dehydrated patient would benefit more from normal saline, a patient with alcoholic ketoacidosis would benefit more from dextrose, and a patient with alcohol-related cardiomyopathy likely shouldn’t be getting large volume IV fluids at all.
• Thiamine. Thiamine deficiency is likely the most common and most concerning vitamin deficiency in this patient population. The typical banana bag contains 100 mg of thiamine, which has been the traditional recommended daily amount for Wernicke’s treatment. This dosage, however, was apparently chosen arbitrarily in the 1950s (based on what the authors considered to be a high dose) and current recommendations suggest higher doses given more frequently because of the relatively short half-life of parenteral thiamine.⁵

Takeaway

The banana bag is a “one-size-fits-all” approach that offers too much of some of its ingredients and not enough of others. It’s better to individualize treatment based on a patient’s needs and consider high-dose thiamine (500 mg one to three times daily) for those at risk for, or showing signs of, Wernicke’s encephalopathy.

Dr. Sehgal and Dr. Hanson are clinical associate professors of medicine in the division of general and hospital medicine at the South Texas Veterans Health Care System and UT-Health San Antonio. Dr. Sehgal (@rtsehgal) is a member of the editorial advisory board for The Hospitalist.

References

1. Torvik A et al. Brain lesions in alcoholics: a neuropathological study with clinical correlation. J Neurol Sci. 1982 Nov;56(2-3):233-48.

2. Schwab RA et al. Prevalence in folate deficiency in emergency department patients with alcohol-related illness or injury. Am J Emerg Med. 1992 May;10(3):203-7.

3. Sarai M et al. Magnesium for alcohol withdrawal. Cochrane Database Syst Rev. 2013 Jun 5;(6):CD008358.

4. Krishel S et al. Intravenous vitamins for alcoholics in the emergency department: a review. J Emerg Med. 1998 May-Jun;16(3):419-24.

5. Donnino MW et al. Myths and misconceptions of Wernicke’s encephalopathy: what every emergency physician should know. Ann Emerg Med. 2007;50(6): 715-21.

The Case

A 50-year-old man with no known medical history presents with two months of increasing abdominal distension. Exam is notable for scleral icterus, telangiectasias on the upper chest, abdominal distention with a positive fluid wave, and bilateral pitting lower-extremity edema. An abdominal ultrasound shows large ascites and a nodular liver consistent with cirrhosis. How should this patient with newly diagnosed cirrhosis be evaluated and managed?

Background

Cirrhosis is a leading cause of death among people ages 25–64 and associated with a mortality rate of 11.5 per 100,000 people.1 In 2010, 101,000 people were discharged from the hospital with chronic liver disease and cirrhosis as the first-listed diagnosis.2 Given the myriad etiologies and the asymptomatic nature of many of these conditions, hospitalists frequently encounter patients presenting with advanced disease.

Evaluation

The gold standard for diagnosis is liver biopsy, although this is now usually reserved for atypical cases or where the etiology of cirrhosis is unclear. Alcohol and viral hepatitis (B and C) are the most common causes of chronic liver disease, with nonalcoholic steatohepatitis (NASH) increasing in prevalence. Other less common etiologies and characteristic test findings are listed in Figure 2.

Recently, the Centers for Disease Control and Prevention (CDC) recommended that adults born between 1945 and 1965 receive one-time testing for hepatitis C virus (HCV) infection, regardless of other risk factors, given the higher prevalence in this birth cohort and the introduction of newer oral treatments that achieve sustained virologic response.3

Management

The three classic complications of cirrhosis that will typically prompt inpatient admission are volume overload/ascites, gastrointestinal variceal bleeding, and hepatic encephalopathy.

Volume overload/ascites. Ascites is the most common major complication of cirrhosis, with roughly 50% of patients with asymptomatic cirrhosis developing ascites within 10 years.4 Ascites development portends a poor prognosis, with a mortality of 15% within one year and 44% within five years of diagnosis.4 Patients presenting with new-onset ascites should have a diagnostic paracentesis performed to determine the etiology and evaluate for infection.

Ascitic fluid should be sent for an albumin level and a cell count with differential. A serum-ascites albumin gradient (SAAG) of greater than or equal to 1.1 g/dL is consistent with portal hypertension and cirrhosis, while values less than 1.1 g/dL suggest a non-cirrhotic cause, such as infection or malignancy. Due to the high prevalence of spontaneous bacterial peritonitis (SBP) in hospitalized patients, fluid should also be immediately inoculated in aerobic and anaerobic culture bottles at the bedside, as this has been shown to improve the yield compared to inoculation of culture bottles in the laboratory. Other testing (such as cytology for the evaluation of malignancy) should only be performed if there is significant concern for a particular disease since the vast majority of cases are secondary to uncomplicated cirrhosis.4

In patients with a large amount of ascites and related symptoms (eg, abdominal pain, shortness of breath), therapeutic paracentesis should be performed. Although there is controversy over the need for routine albumin administration, guidelines currently recommend the infusion of 6–8 g of albumin per liter of ascites removed for paracentesis volumes of greater than 4–5 liters.4

No data support the routine administration of fresh frozen plasma (FFP) or platelets prior to paracentesis. Although significant complications of paracentesis (including bowel perforation and hemorrhage) may occur, these are exceedingly rare. Ultrasonography can be used to decrease risks and identify suitable pockets of fluid to tap, even when fluid is not obvious on physical exam alone.5

For patients with significant edema or ascites that is due to portal hypertension (SAAG >1.1 g/dL), the first-line therapy is sodium restriction to less than 2,000 mg/day. Consulting a nutritionist may be beneficial for patient education.

For patients with significant natriuresis (>78 mmol daily urine sodium excretion), dietary restriction alone can manage fluid retention. Most patients (85%–90%), however, require diuretics to increase sodium output. Single-agent spironolactone is more efficacious than single-agent furosemide, but diuresis is improved when both agents are used.4 A dosing regimen of once-daily 40 mg furosemide and 100 mg spironolactone is the recommended starting regimen to promote diuresis while maintaining normokalemia. Due to the long half-life of spironolactone, the dose can be increased every three to five days if needed for diuresis.4

Gastroesophageal variceal bleeding. Approximately 50% of patients with cirrhosis have gastroesophageal varices as a consequence of portal hypertension, with prevalence increasing in those with more severe disease.6 As many patients with cirrhosis have advanced disease at the time of diagnosis, it is recommended that patients be referred for endoscopic screening when diagnosed.6 Nonselective beta-blockers decrease the risk of bleeding in patients with known varices but should not be initiated empirically in all patients with cirrhosis given significant side effects, including worsening of ascites.

There is increasing evidence that there is a “window” period for beta-blocker use in cirrhosis with the window opening after the diagnosis of varices and the window closing at advanced stages of disease (marked by an episode of spontaneous bacterial peritonitis, refractory ascites, or hepatorenal syndrome, for example).7

Hepatic encephalopathy. Hepatic encephalopathy (HE) is another complication of portal hypertension and is seen in 10%–14% of patients at the time of cirrhosis diagnosis.8 Overt HE is estimated to occur in 30%–40% of patients with cirrhosis at some point during their disease course, and more subtle forms (minimal or covert HE) are seen in up to 80%.8 HE can cause numerous neurologic and psychiatric issues including personality changes, poor memory, sleep-wake disturbances, and alterations in consciousness.

In patients with an episode of encephalopathy, precipitating factors should be evaluated. Typical precipitants include infections, bleeding, electrolyte disorders, and constipation. Ammonia levels are frequently drawn as part of the evaluation of hepatic encephalopathy, but elevated levels do not significantly change diagnostic probabilities or add prognostic information.8 A low ammonia level, on the other hand, may be useful in lowering the probability of hepatic encephalopathy in a patient with altered mental status of unknown etiology.8

Routine primary prophylaxis of HE in all patients with cirrhosis is not currently recommended. Treatment is only recommended in patients with overt HE, with secondary prophylaxis administered following an episode due to the high risk for recurrence.

Other Issues

VTE prophylaxis. Although patients with cirrhosis are often presumed to be “auto-anticoagulated” due to an elevated international normalized ratio (INR), they experience thrombotic complications during hospitalization at the same rate or higher than patients with other chronic illnesses.9 Unfortunately, studies examining venous thromboembolism (VTE) prophylaxis in hospitalized patients have generally excluded cirrhotics. Therefore, risks/benefits of prophylaxis need to be considered on an individual basis, taking into account the presence of varices (if known), platelet count, and other VTE risk factors.

Drugs to avoid. As detailed above, nonselective beta-blockers should be avoided when outside the “window” period of benefit. Patients with cirrhosis should be counseled to avoid nonsteroidal anti-inflammatory drugs (NSAIDs) due to an increased risk of bleeding and renal dysfunction. ACE inhibitors (ACE-Is) and angiotensin-receptor blockers (ARBs) can also precipitate renal dysfunction and should generally be avoided unless strongly indicated for another diagnosis.

There is conflicting evidence with regard to whether the use of proton-pump inhibitors (PPIs) in cirrhotics increases the risk of SBP.10,11 Nevertheless, it is prudent to reevaluate the need for PPIs in patients with cirrhosis to determine where a true indication exists.

Post-hospitalization care. Patients with a new diagnosis of cirrhosis require screening for esophageal varices and hepatocellular carcinoma (HCC), with frequency of subsequent testing based on initial results. They should also be immunized against hepatitis A (HAV) and hepatitis B (HBV), if not already immune. Specific treatments are available for many causes of cirrhosis, including new antiviral agents against hepatitis C (HCV), and liver transplantation is an option for select patients. Given the complexity of subsequent diagnostic and treatment options, patients with new cirrhosis should be referred to a gastroenterologist or hepatologist, if possible.

Back to the Case

The patient is hospitalized, and a large-volume paracentesis is performed. Four liters are removed without the administration of albumin. Ascitic fluid analysis reveals a SAAG of greater than 1.1 g/dL and a polymorphonuclear cell count of 50 cell/mm3, suggesting ascites due to portal hypertension and ruling out infection. Nutrition is consulted and educates the patient on a restricted-sodium diet. Furosemide is started at 40 mg daily; spironolactone is started at 100 mg daily. Initial workup and serologies demonstrate active HCV infection (HCV RNA positive), with immunity to HBV due to vaccination. HAV vaccination is administered given lack of seropositivity. The patient is screened for alcohol and found not to drink alcohol. By the time of discharge, the patient is experiencing daily 0.5 kg weight loss due to diuretics and has stable renal function. The patient is referred to outpatient gastroenterology for gastroesophageal variceal screening and consideration of HCV treatment and/or liver transplantation.

Bottom Line

Workup and management of cirrhosis should focus on revealing the underlying etiology, managing complications, and discharging patients with a comprehensive follow-up plan. TH

Dr. Sehgal and Dr. Hanson are hospitalists in the division of hospital medicine at the University of Texas Health Science Center at San Antonio and the South Texas Veterans Health Care System.

References

1. Heron M. Deaths: leading causes for 2012. Natl Vital Stat Rep. 2015;64(10):1-93.
2. Chronic liver disease and cirrhosis. Centers for Disease Control and Prevention website. Accessed March 17, 2016.
3. Smith BD, Morgan RL, Beckett GA, Falck-Ytter Y, Holtzman D, Ward JW. Hepatitis C virus testing of persons born during 1945-1965: recommendations from the Centers for Disease Control and Prevention. Ann Intern Med. 2012;157(11):817-822. doi:10.7326/0003-4819-157-9-201211060-00529.
4. Runyon BA, AASLD. Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline management of adult patients with ascites due to cirrhosis 2012. Hepatology. 2013;57(4):1651-1653. doi:10.1002/hep.26359.
5. Udell JA, Wang CS, Tinmouth J, et al. Does this patient with liver disease have cirrhosis? JAMA. 2012;307(8):832-842. doi:10.1001/jama.2012.186.
6. Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W, Practice Guidelines Committee of the American Association for the Study of Liver Diseases, Practice Parameters Committee of the American College of Gastroenterology. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology. 2007;46(3):922-938. doi:10.1002/hep.21907.
7. Mandorfer M, Bota S, Schwabl P, et al. Nonselective β blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis. Gastroenterology. 2014;146(7):1680-90.e1. doi:10.1053/j.gastro.2014.03.005.
8. Vilstrup H, Amodio P, Bajaj J, et al. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014;60(2):715-735. doi:10.1002/hep.27210.
9. Khoury T, Ayman AR, Cohen J, Daher S, Shmuel C, Mizrahi M. The complex role of anticoagulation in cirrhosis: an updated review of where we are and where we are going. Digestion. 2016;93(2):149-159. doi:10.1159/000442877.
10. Terg R, Casciato P, Garbe C, et al. Proton pump inhibitor therapy does not increase the incidence of spontaneous bacterial peritonitis in cirrhosis: a multicenter prospective study. J Hepatol. 2015;62(5):1056-1060. doi:10.1016/j.jhep.2014.11.036.
11. Deshpande A, Pasupuleti V, Thota P, et al. Acid-suppressive therapy is associated with spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis. J Gastroenterol Hepatol. 2013;28(2):235-242. doi:10.1111/jgh.12065.

Key Points

• Cirrhosis has many etiologies, and new diagnoses require further investigation as to the underlying etiology.
• Initial management should focus on evaluation and treatment of complications, including ascites, esophageal varices, and hepatic encephalopathy.
• A diagnostic paracentesis, salt restriction, and a nutrition consult are the initial therapies for ascites although most patients will also require diuretics to increase sodium excretion.
• Once stabilized, the cirrhotic patient will require specialty care for possible liver biopsy (if etiology remains unclear), treatment (eg, HCV antivirals), and/or referral for liver transplantation.

The Case

A 50-year-old man with no known medical history presents with two months of increasing abdominal distension. Exam is notable for scleral icterus, telangiectasias on the upper chest, abdominal distention with a positive fluid wave, and bilateral pitting lower-extremity edema. An abdominal ultrasound shows large ascites and a nodular liver consistent with cirrhosis. How should this patient with newly diagnosed cirrhosis be evaluated and managed?

Background

Cirrhosis is a leading cause of death among people ages 25–64 and associated with a mortality rate of 11.5 per 100,000 people.1 In 2010, 101,000 people were discharged from the hospital with chronic liver disease and cirrhosis as the first-listed diagnosis.2 Given the myriad etiologies and the asymptomatic nature of many of these conditions, hospitalists frequently encounter patients presenting with advanced disease.

Evaluation

The gold standard for diagnosis is liver biopsy, although this is now usually reserved for atypical cases or where the etiology of cirrhosis is unclear. Alcohol and viral hepatitis (B and C) are the most common causes of chronic liver disease, with nonalcoholic steatohepatitis (NASH) increasing in prevalence. Other less common etiologies and characteristic test findings are listed in Figure 2.

Recently, the Centers for Disease Control and Prevention (CDC) recommended that adults born between 1945 and 1965 receive one-time testing for hepatitis C virus (HCV) infection, regardless of other risk factors, given the higher prevalence in this birth cohort and the introduction of newer oral treatments that achieve sustained virologic response.3

Management

The three classic complications of cirrhosis that will typically prompt inpatient admission are volume overload/ascites, gastrointestinal variceal bleeding, and hepatic encephalopathy.

Volume overload/ascites. Ascites is the most common major complication of cirrhosis, with roughly 50% of patients with asymptomatic cirrhosis developing ascites within 10 years.4 Ascites development portends a poor prognosis, with a mortality of 15% within one year and 44% within five years of diagnosis.4 Patients presenting with new-onset ascites should have a diagnostic paracentesis performed to determine the etiology and evaluate for infection.

Ascitic fluid should be sent for an albumin level and a cell count with differential. A serum-ascites albumin gradient (SAAG) of greater than or equal to 1.1 g/dL is consistent with portal hypertension and cirrhosis, while values less than 1.1 g/dL suggest a non-cirrhotic cause, such as infection or malignancy. Due to the high prevalence of spontaneous bacterial peritonitis (SBP) in hospitalized patients, fluid should also be immediately inoculated in aerobic and anaerobic culture bottles at the bedside, as this has been shown to improve the yield compared to inoculation of culture bottles in the laboratory. Other testing (such as cytology for the evaluation of malignancy) should only be performed if there is significant concern for a particular disease since the vast majority of cases are secondary to uncomplicated cirrhosis.4

In patients with a large amount of ascites and related symptoms (eg, abdominal pain, shortness of breath), therapeutic paracentesis should be performed. Although there is controversy over the need for routine albumin administration, guidelines currently recommend the infusion of 6–8 g of albumin per liter of ascites removed for paracentesis volumes of greater than 4–5 liters.4

No data support the routine administration of fresh frozen plasma (FFP) or platelets prior to paracentesis. Although significant complications of paracentesis (including bowel perforation and hemorrhage) may occur, these are exceedingly rare. Ultrasonography can be used to decrease risks and identify suitable pockets of fluid to tap, even when fluid is not obvious on physical exam alone.5

For patients with significant edema or ascites that is due to portal hypertension (SAAG >1.1 g/dL), the first-line therapy is sodium restriction to less than 2,000 mg/day. Consulting a nutritionist may be beneficial for patient education.

For patients with significant natriuresis (>78 mmol daily urine sodium excretion), dietary restriction alone can manage fluid retention. Most patients (85%–90%), however, require diuretics to increase sodium output. Single-agent spironolactone is more efficacious than single-agent furosemide, but diuresis is improved when both agents are used.4 A dosing regimen of once-daily 40 mg furosemide and 100 mg spironolactone is the recommended starting regimen to promote diuresis while maintaining normokalemia. Due to the long half-life of spironolactone, the dose can be increased every three to five days if needed for diuresis.4

Gastroesophageal variceal bleeding. Approximately 50% of patients with cirrhosis have gastroesophageal varices as a consequence of portal hypertension, with prevalence increasing in those with more severe disease.6 As many patients with cirrhosis have advanced disease at the time of diagnosis, it is recommended that patients be referred for endoscopic screening when diagnosed.6 Nonselective beta-blockers decrease the risk of bleeding in patients with known varices but should not be initiated empirically in all patients with cirrhosis given significant side effects, including worsening of ascites.

There is increasing evidence that there is a “window” period for beta-blocker use in cirrhosis with the window opening after the diagnosis of varices and the window closing at advanced stages of disease (marked by an episode of spontaneous bacterial peritonitis, refractory ascites, or hepatorenal syndrome, for example).7

Hepatic encephalopathy. Hepatic encephalopathy (HE) is another complication of portal hypertension and is seen in 10%–14% of patients at the time of cirrhosis diagnosis.8 Overt HE is estimated to occur in 30%–40% of patients with cirrhosis at some point during their disease course, and more subtle forms (minimal or covert HE) are seen in up to 80%.8 HE can cause numerous neurologic and psychiatric issues including personality changes, poor memory, sleep-wake disturbances, and alterations in consciousness.

In patients with an episode of encephalopathy, precipitating factors should be evaluated. Typical precipitants include infections, bleeding, electrolyte disorders, and constipation. Ammonia levels are frequently drawn as part of the evaluation of hepatic encephalopathy, but elevated levels do not significantly change diagnostic probabilities or add prognostic information.8 A low ammonia level, on the other hand, may be useful in lowering the probability of hepatic encephalopathy in a patient with altered mental status of unknown etiology.8

Routine primary prophylaxis of HE in all patients with cirrhosis is not currently recommended. Treatment is only recommended in patients with overt HE, with secondary prophylaxis administered following an episode due to the high risk for recurrence.

Other Issues

VTE prophylaxis. Although patients with cirrhosis are often presumed to be “auto-anticoagulated” due to an elevated international normalized ratio (INR), they experience thrombotic complications during hospitalization at the same rate or higher than patients with other chronic illnesses.9 Unfortunately, studies examining venous thromboembolism (VTE) prophylaxis in hospitalized patients have generally excluded cirrhotics. Therefore, risks/benefits of prophylaxis need to be considered on an individual basis, taking into account the presence of varices (if known), platelet count, and other VTE risk factors.

Drugs to avoid. As detailed above, nonselective beta-blockers should be avoided when outside the “window” period of benefit. Patients with cirrhosis should be counseled to avoid nonsteroidal anti-inflammatory drugs (NSAIDs) due to an increased risk of bleeding and renal dysfunction. ACE inhibitors (ACE-Is) and angiotensin-receptor blockers (ARBs) can also precipitate renal dysfunction and should generally be avoided unless strongly indicated for another diagnosis.

There is conflicting evidence with regard to whether the use of proton-pump inhibitors (PPIs) in cirrhotics increases the risk of SBP.10,11 Nevertheless, it is prudent to reevaluate the need for PPIs in patients with cirrhosis to determine where a true indication exists.

Post-hospitalization care. Patients with a new diagnosis of cirrhosis require screening for esophageal varices and hepatocellular carcinoma (HCC), with frequency of subsequent testing based on initial results. They should also be immunized against hepatitis A (HAV) and hepatitis B (HBV), if not already immune. Specific treatments are available for many causes of cirrhosis, including new antiviral agents against hepatitis C (HCV), and liver transplantation is an option for select patients. Given the complexity of subsequent diagnostic and treatment options, patients with new cirrhosis should be referred to a gastroenterologist or hepatologist, if possible.

Back to the Case

The patient is hospitalized, and a large-volume paracentesis is performed. Four liters are removed without the administration of albumin. Ascitic fluid analysis reveals a SAAG of greater than 1.1 g/dL and a polymorphonuclear cell count of 50 cell/mm3, suggesting ascites due to portal hypertension and ruling out infection. Nutrition is consulted and educates the patient on a restricted-sodium diet. Furosemide is started at 40 mg daily; spironolactone is started at 100 mg daily. Initial workup and serologies demonstrate active HCV infection (HCV RNA positive), with immunity to HBV due to vaccination. HAV vaccination is administered given lack of seropositivity. The patient is screened for alcohol and found not to drink alcohol. By the time of discharge, the patient is experiencing daily 0.5 kg weight loss due to diuretics and has stable renal function. The patient is referred to outpatient gastroenterology for gastroesophageal variceal screening and consideration of HCV treatment and/or liver transplantation.

Bottom Line

Workup and management of cirrhosis should focus on revealing the underlying etiology, managing complications, and discharging patients with a comprehensive follow-up plan. TH

Dr. Sehgal and Dr. Hanson are hospitalists in the division of hospital medicine at the University of Texas Health Science Center at San Antonio and the South Texas Veterans Health Care System.

References

1. Heron M. Deaths: leading causes for 2012. Natl Vital Stat Rep. 2015;64(10):1-93.
2. Chronic liver disease and cirrhosis. Centers for Disease Control and Prevention website. Accessed March 17, 2016.
3. Smith BD, Morgan RL, Beckett GA, Falck-Ytter Y, Holtzman D, Ward JW. Hepatitis C virus testing of persons born during 1945-1965: recommendations from the Centers for Disease Control and Prevention. Ann Intern Med. 2012;157(11):817-822. doi:10.7326/0003-4819-157-9-201211060-00529.
4. Runyon BA, AASLD. Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline management of adult patients with ascites due to cirrhosis 2012. Hepatology. 2013;57(4):1651-1653. doi:10.1002/hep.26359.
5. Udell JA, Wang CS, Tinmouth J, et al. Does this patient with liver disease have cirrhosis? JAMA. 2012;307(8):832-842. doi:10.1001/jama.2012.186.
6. Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W, Practice Guidelines Committee of the American Association for the Study of Liver Diseases, Practice Parameters Committee of the American College of Gastroenterology. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology. 2007;46(3):922-938. doi:10.1002/hep.21907.
7. Mandorfer M, Bota S, Schwabl P, et al. Nonselective β blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis. Gastroenterology. 2014;146(7):1680-90.e1. doi:10.1053/j.gastro.2014.03.005.
8. Vilstrup H, Amodio P, Bajaj J, et al. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014;60(2):715-735. doi:10.1002/hep.27210.
9. Khoury T, Ayman AR, Cohen J, Daher S, Shmuel C, Mizrahi M. The complex role of anticoagulation in cirrhosis: an updated review of where we are and where we are going. Digestion. 2016;93(2):149-159. doi:10.1159/000442877.
10. Terg R, Casciato P, Garbe C, et al. Proton pump inhibitor therapy does not increase the incidence of spontaneous bacterial peritonitis in cirrhosis: a multicenter prospective study. J Hepatol. 2015;62(5):1056-1060. doi:10.1016/j.jhep.2014.11.036.
11. Deshpande A, Pasupuleti V, Thota P, et al. Acid-suppressive therapy is associated with spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis. J Gastroenterol Hepatol. 2013;28(2):235-242. doi:10.1111/jgh.12065.

Key Points

• Cirrhosis has many etiologies, and new diagnoses require further investigation as to the underlying etiology.
• Initial management should focus on evaluation and treatment of complications, including ascites, esophageal varices, and hepatic encephalopathy.
• A diagnostic paracentesis, salt restriction, and a nutrition consult are the initial therapies for ascites although most patients will also require diuretics to increase sodium excretion.
• Once stabilized, the cirrhotic patient will require specialty care for possible liver biopsy (if etiology remains unclear), treatment (eg, HCV antivirals), and/or referral for liver transplantation.

The Case

A 50-year-old man with no known medical history presents with two months of increasing abdominal distension. Exam is notable for scleral icterus, telangiectasias on the upper chest, abdominal distention with a positive fluid wave, and bilateral pitting lower-extremity edema. An abdominal ultrasound shows large ascites and a nodular liver consistent with cirrhosis. How should this patient with newly diagnosed cirrhosis be evaluated and managed?

Background

Cirrhosis is a leading cause of death among people ages 25–64 and associated with a mortality rate of 11.5 per 100,000 people.1 In 2010, 101,000 people were discharged from the hospital with chronic liver disease and cirrhosis as the first-listed diagnosis.2 Given the myriad etiologies and the asymptomatic nature of many of these conditions, hospitalists frequently encounter patients presenting with advanced disease.

Evaluation

The gold standard for diagnosis is liver biopsy, although this is now usually reserved for atypical cases or where the etiology of cirrhosis is unclear. Alcohol and viral hepatitis (B and C) are the most common causes of chronic liver disease, with nonalcoholic steatohepatitis (NASH) increasing in prevalence. Other less common etiologies and characteristic test findings are listed in Figure 2.

Recently, the Centers for Disease Control and Prevention (CDC) recommended that adults born between 1945 and 1965 receive one-time testing for hepatitis C virus (HCV) infection, regardless of other risk factors, given the higher prevalence in this birth cohort and the introduction of newer oral treatments that achieve sustained virologic response.3

Management

The three classic complications of cirrhosis that will typically prompt inpatient admission are volume overload/ascites, gastrointestinal variceal bleeding, and hepatic encephalopathy.

Volume overload/ascites. Ascites is the most common major complication of cirrhosis, with roughly 50% of patients with asymptomatic cirrhosis developing ascites within 10 years.4 Ascites development portends a poor prognosis, with a mortality of 15% within one year and 44% within five years of diagnosis.4 Patients presenting with new-onset ascites should have a diagnostic paracentesis performed to determine the etiology and evaluate for infection.

Ascitic fluid should be sent for an albumin level and a cell count with differential. A serum-ascites albumin gradient (SAAG) of greater than or equal to 1.1 g/dL is consistent with portal hypertension and cirrhosis, while values less than 1.1 g/dL suggest a non-cirrhotic cause, such as infection or malignancy. Due to the high prevalence of spontaneous bacterial peritonitis (SBP) in hospitalized patients, fluid should also be immediately inoculated in aerobic and anaerobic culture bottles at the bedside, as this has been shown to improve the yield compared to inoculation of culture bottles in the laboratory. Other testing (such as cytology for the evaluation of malignancy) should only be performed if there is significant concern for a particular disease since the vast majority of cases are secondary to uncomplicated cirrhosis.4

In patients with a large amount of ascites and related symptoms (eg, abdominal pain, shortness of breath), therapeutic paracentesis should be performed. Although there is controversy over the need for routine albumin administration, guidelines currently recommend the infusion of 6–8 g of albumin per liter of ascites removed for paracentesis volumes of greater than 4–5 liters.4

No data support the routine administration of fresh frozen plasma (FFP) or platelets prior to paracentesis. Although significant complications of paracentesis (including bowel perforation and hemorrhage) may occur, these are exceedingly rare. Ultrasonography can be used to decrease risks and identify suitable pockets of fluid to tap, even when fluid is not obvious on physical exam alone.5

For patients with significant edema or ascites that is due to portal hypertension (SAAG >1.1 g/dL), the first-line therapy is sodium restriction to less than 2,000 mg/day. Consulting a nutritionist may be beneficial for patient education.

For patients with significant natriuresis (>78 mmol daily urine sodium excretion), dietary restriction alone can manage fluid retention. Most patients (85%–90%), however, require diuretics to increase sodium output. Single-agent spironolactone is more efficacious than single-agent furosemide, but diuresis is improved when both agents are used.4 A dosing regimen of once-daily 40 mg furosemide and 100 mg spironolactone is the recommended starting regimen to promote diuresis while maintaining normokalemia. Due to the long half-life of spironolactone, the dose can be increased every three to five days if needed for diuresis.4

Gastroesophageal variceal bleeding. Approximately 50% of patients with cirrhosis have gastroesophageal varices as a consequence of portal hypertension, with prevalence increasing in those with more severe disease.6 As many patients with cirrhosis have advanced disease at the time of diagnosis, it is recommended that patients be referred for endoscopic screening when diagnosed.6 Nonselective beta-blockers decrease the risk of bleeding in patients with known varices but should not be initiated empirically in all patients with cirrhosis given significant side effects, including worsening of ascites.

There is increasing evidence that there is a “window” period for beta-blocker use in cirrhosis with the window opening after the diagnosis of varices and the window closing at advanced stages of disease (marked by an episode of spontaneous bacterial peritonitis, refractory ascites, or hepatorenal syndrome, for example).7

Hepatic encephalopathy. Hepatic encephalopathy (HE) is another complication of portal hypertension and is seen in 10%–14% of patients at the time of cirrhosis diagnosis.8 Overt HE is estimated to occur in 30%–40% of patients with cirrhosis at some point during their disease course, and more subtle forms (minimal or covert HE) are seen in up to 80%.8 HE can cause numerous neurologic and psychiatric issues including personality changes, poor memory, sleep-wake disturbances, and alterations in consciousness.

In patients with an episode of encephalopathy, precipitating factors should be evaluated. Typical precipitants include infections, bleeding, electrolyte disorders, and constipation. Ammonia levels are frequently drawn as part of the evaluation of hepatic encephalopathy, but elevated levels do not significantly change diagnostic probabilities or add prognostic information.8 A low ammonia level, on the other hand, may be useful in lowering the probability of hepatic encephalopathy in a patient with altered mental status of unknown etiology.8

Routine primary prophylaxis of HE in all patients with cirrhosis is not currently recommended. Treatment is only recommended in patients with overt HE, with secondary prophylaxis administered following an episode due to the high risk for recurrence.

Other Issues

VTE prophylaxis. Although patients with cirrhosis are often presumed to be “auto-anticoagulated” due to an elevated international normalized ratio (INR), they experience thrombotic complications during hospitalization at the same rate or higher than patients with other chronic illnesses.9 Unfortunately, studies examining venous thromboembolism (VTE) prophylaxis in hospitalized patients have generally excluded cirrhotics. Therefore, risks/benefits of prophylaxis need to be considered on an individual basis, taking into account the presence of varices (if known), platelet count, and other VTE risk factors.

Drugs to avoid. As detailed above, nonselective beta-blockers should be avoided when outside the “window” period of benefit. Patients with cirrhosis should be counseled to avoid nonsteroidal anti-inflammatory drugs (NSAIDs) due to an increased risk of bleeding and renal dysfunction. ACE inhibitors (ACE-Is) and angiotensin-receptor blockers (ARBs) can also precipitate renal dysfunction and should generally be avoided unless strongly indicated for another diagnosis.

There is conflicting evidence with regard to whether the use of proton-pump inhibitors (PPIs) in cirrhotics increases the risk of SBP.10,11 Nevertheless, it is prudent to reevaluate the need for PPIs in patients with cirrhosis to determine where a true indication exists.

Post-hospitalization care. Patients with a new diagnosis of cirrhosis require screening for esophageal varices and hepatocellular carcinoma (HCC), with frequency of subsequent testing based on initial results. They should also be immunized against hepatitis A (HAV) and hepatitis B (HBV), if not already immune. Specific treatments are available for many causes of cirrhosis, including new antiviral agents against hepatitis C (HCV), and liver transplantation is an option for select patients. Given the complexity of subsequent diagnostic and treatment options, patients with new cirrhosis should be referred to a gastroenterologist or hepatologist, if possible.

Back to the Case

The patient is hospitalized, and a large-volume paracentesis is performed. Four liters are removed without the administration of albumin. Ascitic fluid analysis reveals a SAAG of greater than 1.1 g/dL and a polymorphonuclear cell count of 50 cell/mm3, suggesting ascites due to portal hypertension and ruling out infection. Nutrition is consulted and educates the patient on a restricted-sodium diet. Furosemide is started at 40 mg daily; spironolactone is started at 100 mg daily. Initial workup and serologies demonstrate active HCV infection (HCV RNA positive), with immunity to HBV due to vaccination. HAV vaccination is administered given lack of seropositivity. The patient is screened for alcohol and found not to drink alcohol. By the time of discharge, the patient is experiencing daily 0.5 kg weight loss due to diuretics and has stable renal function. The patient is referred to outpatient gastroenterology for gastroesophageal variceal screening and consideration of HCV treatment and/or liver transplantation.

Bottom Line

Workup and management of cirrhosis should focus on revealing the underlying etiology, managing complications, and discharging patients with a comprehensive follow-up plan. TH

Dr. Sehgal and Dr. Hanson are hospitalists in the division of hospital medicine at the University of Texas Health Science Center at San Antonio and the South Texas Veterans Health Care System.

References

1. Heron M. Deaths: leading causes for 2012. Natl Vital Stat Rep. 2015;64(10):1-93.
2. Chronic liver disease and cirrhosis. Centers for Disease Control and Prevention website. Accessed March 17, 2016.
3. Smith BD, Morgan RL, Beckett GA, Falck-Ytter Y, Holtzman D, Ward JW. Hepatitis C virus testing of persons born during 1945-1965: recommendations from the Centers for Disease Control and Prevention. Ann Intern Med. 2012;157(11):817-822. doi:10.7326/0003-4819-157-9-201211060-00529.
4. Runyon BA, AASLD. Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline management of adult patients with ascites due to cirrhosis 2012. Hepatology. 2013;57(4):1651-1653. doi:10.1002/hep.26359.
5. Udell JA, Wang CS, Tinmouth J, et al. Does this patient with liver disease have cirrhosis? JAMA. 2012;307(8):832-842. doi:10.1001/jama.2012.186.
6. Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W, Practice Guidelines Committee of the American Association for the Study of Liver Diseases, Practice Parameters Committee of the American College of Gastroenterology. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology. 2007;46(3):922-938. doi:10.1002/hep.21907.
7. Mandorfer M, Bota S, Schwabl P, et al. Nonselective β blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis. Gastroenterology. 2014;146(7):1680-90.e1. doi:10.1053/j.gastro.2014.03.005.
8. Vilstrup H, Amodio P, Bajaj J, et al. Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014;60(2):715-735. doi:10.1002/hep.27210.
9. Khoury T, Ayman AR, Cohen J, Daher S, Shmuel C, Mizrahi M. The complex role of anticoagulation in cirrhosis: an updated review of where we are and where we are going. Digestion. 2016;93(2):149-159. doi:10.1159/000442877.
10. Terg R, Casciato P, Garbe C, et al. Proton pump inhibitor therapy does not increase the incidence of spontaneous bacterial peritonitis in cirrhosis: a multicenter prospective study. J Hepatol. 2015;62(5):1056-1060. doi:10.1016/j.jhep.2014.11.036.
11. Deshpande A, Pasupuleti V, Thota P, et al. Acid-suppressive therapy is associated with spontaneous bacterial peritonitis in cirrhotic patients: a meta-analysis. J Gastroenterol Hepatol. 2013;28(2):235-242. doi:10.1111/jgh.12065.

Key Points

• Cirrhosis has many etiologies, and new diagnoses require further investigation as to the underlying etiology.
• Initial management should focus on evaluation and treatment of complications, including ascites, esophageal varices, and hepatic encephalopathy.
• A diagnostic paracentesis, salt restriction, and a nutrition consult are the initial therapies for ascites although most patients will also require diuretics to increase sodium excretion.
• Once stabilized, the cirrhotic patient will require specialty care for possible liver biopsy (if etiology remains unclear), treatment (eg, HCV antivirals), and/or referral for liver transplantation.